DOI
stringlengths 28
49
| Title
stringlengths 19
460
| Authors
stringlengths 12
2.65k
| Abstract
stringlengths 279
7.2k
| Journal
stringlengths 3
82
| Date
stringclasses 49
values |
|---|---|---|---|---|---|
('LID', '10.1038/s41571-025-01011-3') | Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials. | Ernst, Sophie M, Aldea, Mihaela, von der Thüsen, Jan H, de Langen, Adrianus J, Smit, Egbert F, Paats, Marthe S, Aerts, Joachim G J V, Mezquita, Laura, Popat, Sanjay, Besse, Benjamin, Remon, Jordi, Rolfo, Christian, Dubbink, Hendrikus J, Dingemans, Anne-Marie C | Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset. Circulating tumour DNA, owing to the need for only minimally invasive sampling and a potential role as both a prognostic and predictive biomarker, is increasingly being used in both research and clinical practice. Several studies have explored the landscape of acquired resistance to targeted therapies using this approach. However, the methodologies of the published studies vary widely, and several major challenges remain in addressing the practical difficulties associated with these methods. These challenges currently limit the depth of research insight provided by the available data. In this Perspective, we review clinical reports describing the use of circulating tumour DNA to detect mechanisms of acquired resistance to targeted therapies, predominantly in patients with advanced-stage non-small-cell lung cancer, and highlight key unresolved questions with the aim of moving towards more-informative research studies. | Nature reviews. Clinical oncology | 14/03/2025 |
('LID', '10.1002/14651858.CD014792.pub2') | Postoperative nutritional support after pancreaticoduodenectomy in adults. | Robertson, Rachel H, Russell, Kylie, Jordan, Vanessa, Pandanaboyana, Sanjay, Wu, Dong, Windsor, John | BACKGROUND: Resection of the head of the pancreas is most commonly done by a pancreaticoduodenectomy, known as a Whipple procedure. The most common indication for pancreaticoduodenectomy is malignancy, but can include benign tumours and chronic pancreatitis. Complete surgical resection, with negative margins, provides the best prospect of long-term survival. Pancreaticoduodenectomy involves specific and unique alterations to the digestive system and maintaining nutritional status (optimising outcomes and achieving resumption of a normal diet) in patients with cancer after major surgery is a challenge. Malnutrition is a risk factor following pancreaticoduodenectomy, due to the magnitude of the operation and the frequency of complications. Postoperatively, patients are fed either orally, enterally or parenterally. Oral intake may start with fluids and then progress to solid food, or may be ad libitum. Enteral feeding may be via a nasojejunal tube or feeding tube jejunostomy. Parenteral nutrition can be delivered via a central or peripheral intravenous line, and may provide full nutrition (TPN) or partial nutrition (supplemental PN). OBJECTIVES: To assess the effects of postoperative nutritional support strategies on complications and recovery in adults after pancreaticoduodenectomy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS and CINAHL (from inception to October 2022), ongoing trials registers and other internet databases. We searched previous systematic reviews, relevant publications on the same topic and the references of included studies. SELECTION CRITERIA: Randomised controlled trials of postoperative nutritional interventions in an inpatient setting for patients undergoing pancreaticoduodenectomy. We specifically looked for studies comparing route or timing rather than nutritional content. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, judged the risk of bias and extracted data. Studies requiring translation were assessed for inclusion, risk of bias and data extraction by an external translator and another author. We used GRADE to evaluate the certainty of the evidence. MAIN RESULTS: We included 17 studies (1897 participants). Of these, eight studies could be included in a meta-analysis. The route, timing and target of nutritional support varied widely between studies. Enteral feeding (jejunostomy, nasojejunal or gastrojejunostomy) was used in at least 13 studies (one study did not specify the method of enteral route), parenteral nutrition (PN) was used in at least 10 studies (two studies had a control of 'surgeon's preference' and no further details were given) and oral intake was used in seven studies. Overall, the evidence presented in this review is of low to very low certainty. Four studies compared jejunostomy feeding with total parenteral nutrition. When we pooled these four studies, the evidence demonstrated that jejunostomy likely results in a reduced length of hospital stay (mean difference (MD) -1.61 days, 95% confidence interval (CI) -2.31 to -0.92; 3 studies, 316 participants; moderate-certainty evidence). The evidence suggested that there may be no difference in postoperative pancreatic fistula (risk ratio (RR) 0.77, 95% CI 0.41 to 1.47; 4 studies, 346 participants; low-certainty evidence) and that there may be no difference in delayed gastric emptying (RR 0.38, 95% CI 0.04 to 3.50; 2 studies, 270 participants; very low-certainty evidence) or post pancreatectomy haemorrhage (RR 0.36, 95% CI 0.06 to 2.29; 2 studies, 270 participants; very low-certainty evidence), but the evidence is uncertain. There were no data for major and minor complications defined by the Clavien-Dindo classification. Two studies compared nasojejunal feeding with total parenteral nutrition. When the two studies were pooled, the evidence suggested that there may be little to no difference between nasojejunal feeding and TPN in the length of hospital stay (MD 1.07 days, 95% CI -2.64 to 4.79; 2 studies, 242 participants; low-certainty evidence), delayed gastric emptying (RR 1.26, 95% CI 0.83 to 1.91; 2 studies, 242 participants; low-certainty evidence) or post pancreatectomy haemorrhage (RR 1.00, 95% CI 0.62 to 1.62; 2 studies, 242 participants; low-certainty evidence). TPN may slightly improve rates of clinically relevant postoperative pancreatic fistula (RR 2.13, 95% CI 1.21 to 3.74; 2 studies, 242 participants; low-certainty evidence). One study reported on major complications (RR 1.27, 95% CI 0.83 to 1.94; very low-certainty evidence) and minor complications (RR 1.01, 95% CI 0.68 to 1.50; 204 participants; very low-certainty evidence) defined by the Clavien-Dindo classification and there may be little to no difference in effect, but the evidence is uncertain. Two studies compared jejunostomy feeding with oral intake. Of note, one of the studies used a modified surgical technique as part of the intervention. We pooled these studies and found that there may be little to no difference in the length of hospital stay (MD -1.99 days, 95% CI -4.90 to 0.91; 2 studies, 301 participants; very low-certainty evidence) or delayed gastric emptying (RR 0.98, 95% CI 0.33 to 2.88; 2 studies, 307 participants; very low-certainty evidence). One study reported on major complications (RR 1.01, 95% CI 0.44 to 2.34; 247 participants; very low-certainty evidence) and minor complications (RR 0.83, 95% CI 0.59 to 1.15; 247 participants; very low-certainty evidence) defined by the Clavien-Dindo classification, postoperative pancreatic fistula (RR 0.86, 95% CI 0.30 to 2.50; 247 participants; very low-certainty evidence) and post pancreatectomy haemorrhage (RR 2.02, 95% CI 0.52 to 7.88; 247 participants; very low-certainty evidence) and there may be little to no difference in effect on these outcomes, but the evidence is uncertain. No difference in mortality was detected in any of the analyses (Clavien-Dindo Grade V) (very low-certainty evidence). AUTHORS' CONCLUSIONS: When compared with parenteral nutrition, enteral nutrition by jejunostomy likely results in a decreased length of hospital stay and may lead to no difference in the incidence of postoperative complications. When compared with parenteral nutrition, enteral feeding by nasojejunal tube may result in no difference in the incidence of postoperative complications or length of hospital stay. When compared with oral nutrition, enteral nutrition by jejunostomy feeding may result in no difference in the incidence of postoperative complications or length of hospital stay, but the evidence is very uncertain. Further high-quality research is required and there are several ongoing studies. Given the number of different nutritional interventions available in the postoperative setting, a network meta-analysis would be more appropriate in future. | The Cochrane database of systematic reviews | 14/03/2025 |
('LID', '10.1186/s12916-025-03975-6') | Prevalence, trends, and geographic distribution of human papillomavirus infection in Chinese women: a summative analysis of 2,728,321 cases. | Han, Sirui, Lin, Mengyue, Liu, Mengyu, Wu, Shiwan, Guo, Pi, Guo, Jiubiao, Xie, Longxu, Qiu, Song, Xu, Aijuan, Cai, Yingmu, Chen, Yequn | BACKGROUND: Cervical cancer (CC), primarily caused by human papillomavirus (HPV) infection, remains a significant global health concern. We aimed to comprehensively investigate the epidemiological status of HPV in China. METHODS: Data from 2,728,321 women undergoing routine cervical examinations at 2127 medical institutions nationwide from January 2017 to June 2023 were analyzed. HPV genotype testing was conducted using HPV DNA typing kits. RESULTS: The overall HPV prevalence was 17.70%, with 13.12% classified as high-risk HPV (HR-HPV) and 4.58% as low-risk HPV (LR-HPV). Notably, HPV52 emerged as the most common carcinogenic type, followed by HPV58 and HPV16. Age-specific prevalence revealed a bimodal distribution, with peaks observed in women under 21 and over 61 years of age. Geographically, the south (19.48%) exhibited the highest infection rate, while the northwest (12.36%) had the lowest. Furthermore, HPV infection rates were higher during winter and spring. Although HPV infection rates have remained stable overall over the past 7 years, the infection rate in 2023 (14.76%) has declined relative to 2017 (16.17%) (P < 0.05). CONCLUSIONS: This study provides comprehensive insight into HPV epidemiology in China and guidance for future vaccine development and cervical cancer prevention strategies. | BMC medicine | 13/03/2025 |
('LID', '10.1038/s41419-025-07505-3') | TIMM23 overexpression drives NSCLC cell growth and survival by enhancing mitochondrial function. | Zha, Jianhua, Li, Jiaxin, Yin, Hui, Shen, Mingjing, Xia, Yingchen | Mitochondrial hyperfunction is implicated in promoting non-small cell lung cancer (NSCLC) cell growth. TIMM23 (translocase of inner mitochondrial membrane 23) is a core component of the mitochondrial import machinery, facilitating the translocation of proteins across the inner mitochondrial membrane into the matrix. Its expression and potential functions in NSCLC were tested. Comprehensive bioinformatic analysis revealed a strong correlation between TIMM23 overexpression and adverse clinical outcomes in NSCLC patients. Single-cell RNA sequencing data further corroborated these findings, demonstrating elevated TIMM23 expression within the cancer cells of NSCLC mass. Subsequent experimental validation confirmed significantly increased TIMM23 mRNA and protein levels in locally-treated NSCLC tissues compared to matched normal lung tissues. Moreover, TIMM23 expression was consistently elevated across multiple primary/established NSCLC cells. Silencing or ablation of TIMM23 via shRNA or CRISPR/Cas9 in NSCLC cells resulted in impaired mitochondrial function, characterized by reduced complex I activity, ATP depletion, mitochondrial membrane potential dissipation, oxidative stress, and lipid peroxidation. These mitochondrial perturbations coincided with attenuated cell viability, proliferation, and migratory capacity, and concomitant induction of apoptosis. Conversely, ectopic overexpression of TIMM23 significantly enhanced mitochondrial complex I activity and ATP production, promoting NSCLC cell proliferation and motility. In vivo, intratumoral delivery of a TIMM23 shRNA-expressing adeno-associated virus significantly suppressed the growth of subcutaneous NSCLC xenografts in nude mice. Subsequent analysis of tumor tissues revealed depleted TIMM23 expression, ATP reduction, oxidative damage, proliferative arrest, and apoptotic induction. Collectively, these findings establish TIMM23 as a critical pro-tumorigenic factor in NSCLC, highlighting its potential as a prognostic biomarker and therapeutic target. | Cell death & disease | 13/03/2025 |
('LID', '10.1016/j.neuron.2025.02.007') | Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration. | Vicario, Rocio, Fragkogianni, Stamatina, Pokrovskii, Maria, Meyer, Carina, Lopez-Rodrigo, Estibaliz, Hu, Yang, Ogishi, Masato, Alberdi, Araitz, Baako, Ann, Ay, Oyku, Plu, Isabelle, Sazdovitch, Véronique, Heritier, Sebastien, Cohen-Aubart, Fleur, Shor, Natalia, Miyara, Makoto, Nguyen-Khac, Florence, Viale, Agnes, Idbaih, Ahmed, Amoura, Zahir, Rosenblum, Marc K, Zhang, Haochen, Karnoub, Elias-Ramzey, Sashittal, Palash, Jakatdar, Akhil, Iacobuzio-Donahue, Christine A, Abdel-Wahab, Omar, Tabar, Viviane, Socci, Nicholas D, Elemento, Olivier, Diamond, Eli L, Boisson, Bertrand, Casanova, Jean-Laurent, Seilhean, Danielle, Haroche, Julien, Donadieu, Jean, Geissmann, Frederic | Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1(+) clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion. | Neuron | 05/03/2025 |
('LID', '10.1038/s41467-025-57829-z') | GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis. | Yuan, Shuai, Chen, Jie, Geng, Jiawei, Zhao, Sizheng Steven, Yarmolinsky, James, Arkema, Elizabeth V, Abramowitz, Sarah, Levin, Michael G, Tsilidis, Kostas K, Burgess, Stephen, Damrauer, Scott M, Larsson, Susanna C | Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins. | Nature communications | 12/03/2025 |
('LID', '10.1001/jamainternmed.2014.8071') | Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. | Miller, Matthew, Barber, Catherine W, Leatherman, Sarah, Fonda, Jennifer, Hermos, John A, Cho, Kelly, Gagnon, David R | IMPORTANCE: The unprecedented increase in unintentional overdose events that has occurred in tandem with escalating sales of prescription opioids over the past 2 decades has raised concerns about whether the therapeutic use of opioids has contributed to increases in overdose injury. Few controlled studies have examined the extent to which ecologic measures of increases in opioid prescribing and overdose injuries reflect risk among patients prescribed opioids, let alone whether some opioid regimens are safer than others. OBJECTIVE: To examine whether the risk of unintentional overdose injury is associated with the duration of opioid action (ie, long-acting vs short-acting formulations). DESIGN, SETTING, AND PARTICIPANTS: A propensity score-adjusted cohort study was conducted using population-based health care utilization data from the Veterans Administration Healthcare System. The patients were veterans with chronic painful conditions who began therapy with opioid analgesics between January 1, 2000, and December 31, 2009. MAIN OUTCOMES AND MEASURES: Unintentional overdoses that are explicitly coded using International Classification of Disease, Ninth Revision codes as drug or medication poisonings of accidental intent (E850.x-860.x) or undetermined intent (E980.x or drug poisoning [960.x-980.x] without an accompanying external cause of injury code). RESULTS: A total of 319 unintentional overdose events were observed. Patients initiating therapy with long-acting opioids were more than twice as likely to overdose compared with persons initiating therapy with short-acting opioids. After adjustment for age, sex, opioid dose, and other clinical characteristics, patients receiving long-acting opioids had a significantly higher rate of overdose injury than did those receiving short-acting opioids (hazard ratio [HR], 2.33; 95% CI, 1.26-4.32). The risk associated with long-acting agents was particularly marked during the first 2 weeks after initiation of treatment (HR, 5.25; 1.88-14.72). CONCLUSIONS AND RELEVANCE: To our knowledge, the findings of the present study provide the first evidence that the risk of unintentional overdose injury is related to the prescribed opioid's duration of action. If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regimens should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first 2 weeks of therapy. | JAMA internal medicine | 00/04/2015 |
('LID', '10.1080/17425255.2025.2478167') | Drug-drug interactions in metastatic hormone-sensitive prostate cancer (mHSPC): practical considerations for treating men with androgen receptor pathway inhibitors and common medications in this stage. | Ibáñez, Cristina, Touris-Lores, Manuel, Montesa, Álvaro, López-Campos, Fernando, Ríos, Emilio, Usán, Paola, Moretones, Cristina, Conde-Estévez, David | INTRODUCTION: New androgen receptor pathway inhibitors (ARPIs) are an essential part of the treatment strategy for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Despite the good tolerability of ARPIs, after treatment is started, drug-drug interactions (DDIs) between these and other medications frequently taken by these patients may appear. DDIs may reduce the therapeutic effect of both and lead to increased adverse events. DDIs should be carefully assessed before an ARPI is started. AREAS COVERED: We first review the current therapeutic landscape for mHSPC, common age-related comorbidities and other comorbidities or adverse events arising from previous or current treatments for prostate cancer, and patients' symptomatology. We then analyze the potential toxicities arising from medications for these conditions and those of mHSPC: ARPIs (abiraterone acetate plus prednisone/prednisolone, enzalutamide, apalutamide, and darolutamide) and docetaxel. EXPERT OPINION: Before mHSPC patients are treated with an ARPI, careful assessment of patient eligibility for each treatment alternative and potential DDIs between these and treatments for current comorbidities is a fundamental component in clinical decision-making. ARPIs with low potential DDIs allow keeping current concomitant medications without significant relevant dose adjustments and help reduce the risk of toxicities and comorbidity-related decompensation. | Expert opinion on drug metabolism & toxicology | 14/03/2025 |
('LID', '10.1186/s12974-025-03406-6') | Targeted activation of ErbB4 receptor ameliorates neuronal deficits and neuroinflammation in a food-borne polystyrene microplastic exposed mouse model. | Liu, Chong, Zhao, Yan, Zhang, Wei, Dao, Ji-Ji, Li, Qian, Huang, Jia, Li, Zhen-Feng, Ma, Yu-Ke, Qiao, Chen-Meng, Cui, Chun, Chen, Shuang-Xi, Yu, Li, Shen, Yan-Qin, Zhao, Wei-Jiang | The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented in the literature. Numerous studies have demonstrated that the activation of the epidermal growth factor receptor 4 (ErbB4) is crucial in neuronal injury and regeneration processes. This study investigated the role of targeted activation of ErbB4 receptor through a small molecule agonist, 4-bromo-1-hydroxy-2-naphthoic acid (C11H7BrO3, E4A), in mitigating PS-MPs-induced neuronal injury. The findings revealed that targeted activation of ErbB4 receptor significantly ameliorated cognitive behavioral deficits in mice exposed to PS-MPs. Furthermore, E4A treatment upregulated the expression of dedicator of cytokinesis 3 (DOCK3) and Sirtuin 3 (SIRT3) and mitigated mitochondrial and synaptic dysfunction within the hippocampus of PS-MPs-exposed mice. E4A also diminished the activation of the TLR4-NF-κB-NLRP3 signaling pathway, consequently reducing neuroinflammation. In vitro experiments demonstrated that E4A partially alleviated PS-MPs-induced hippocampal neuronal injury and its effects on microglial inflammation. In conclusion, the findings of this study indicate that targeted activation of ErbB4 receptor may mitigate neuronal damage and subsequent neuroinflammation, thereby alleviating hippocampal neuronal injury induced by PS-MPs exposure and ameliorating cognitive dysfunction. These results offer valuable insights for the development of potential therapeutic strategies. | Journal of neuroinflammation | 15/03/2025 |
('LID', '10.1186/s12974-025-03406-6') | Targeted activation of ErbB4 receptor ameliorates neuronal deficits and neuroinflammation in a food-borne polystyrene microplastic exposed mouse model. | Liu, Chong, Zhao, Yan, Zhang, Wei, Dao, Ji-Ji, Li, Qian, Huang, Jia, Li, Zhen-Feng, Ma, Yu-Ke, Qiao, Chen-Meng, Cui, Chun, Chen, Shuang-Xi, Yu, Li, Shen, Yan-Qin, Zhao, Wei-Jiang | The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented in the literature. Numerous studies have demonstrated that the activation of the epidermal growth factor receptor 4 (ErbB4) is crucial in neuronal injury and regeneration processes. This study investigated the role of targeted activation of ErbB4 receptor through a small molecule agonist, 4-bromo-1-hydroxy-2-naphthoic acid (C11H7BrO3, E4A), in mitigating PS-MPs-induced neuronal injury. The findings revealed that targeted activation of ErbB4 receptor significantly ameliorated cognitive behavioral deficits in mice exposed to PS-MPs. Furthermore, E4A treatment upregulated the expression of dedicator of cytokinesis 3 (DOCK3) and Sirtuin 3 (SIRT3) and mitigated mitochondrial and synaptic dysfunction within the hippocampus of PS-MPs-exposed mice. E4A also diminished the activation of the TLR4-NF-κB-NLRP3 signaling pathway, consequently reducing neuroinflammation. In vitro experiments demonstrated that E4A partially alleviated PS-MPs-induced hippocampal neuronal injury and its effects on microglial inflammation. In conclusion, the findings of this study indicate that targeted activation of ErbB4 receptor may mitigate neuronal damage and subsequent neuroinflammation, thereby alleviating hippocampal neuronal injury induced by PS-MPs exposure and ameliorating cognitive dysfunction. These results offer valuable insights for the development of potential therapeutic strategies. | Journal of neuroinflammation | 15/03/2025 |
('LID', '10.1161/CIRCULATIONAHA.124.070248') | Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction. | Filipp, Mallory, Ge, Zhi-Dong, DeBerge, Matthew, Lantz, Connor, Glinton, Kristofor, Gao, Peng, Smolgovsky, Sasha, Dai, Jingbo, Zhao, You-Yang, Yvan-Charvet, Laurent, Alcaide, Pilar, Weinberg, Samuel E, Schiattarella, Gabriele G, Hill, Joseph A, Feinstein, Matthew J, Shah, Sanjiv J, Thorp, Edward B | BACKGROUND: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. METHODS: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms. RESULTS: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. CONCLUSIONS: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction. | Circulation | 12/03/2025 |
('LID', '10.1182/bloodadvances.2024014707') | Subgroup analysis of elderly patients (≥60 years) with diffuse large B-cell lymphoma in the phase 3 POLARIX study. | Hu, Bei, Reagan, Patrick M, Sehn, Laurie H, Sharman, Jeff P, Hertzberg, Mark, Zhang, Huilai, Kim, Austin I, Herbaux, Charles, Molina, Lysiane, Maruyama, Dai, Stenner, Frank, Chohan, Saibah, Kothari, Rucha, Batlevi, Connie Lee, Hirata, Jamie, Sahin, Deniz, Lee, Calvin MD, Sugidono, Matthew, Tilly, Hervé | In the phase 3 POLARIX study, polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) improved progression-free survival (PFS) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This post hoc subgroup analysis of POLARIX evaluated the efficacy and safety of Pola-R-CHP versus R-CHOP in elderly patients ≥60, ≥65, ≥70, and ≥75 years. As of June 15, 2022 (median follow-up 40 months), 629 patients ≥60 years were included (Pola-R-CHP, n = 311; R-CHOP, n = 318). Clinically meaningful improvements in PFS with Pola-R-CHP versus R-CHOP were observed across all age groups, particularly in patients ≥70 years whereby the risk of disease progression, relapse or death was reduced by 37% (unstratified hazard ratio [HR] 0.63; 95% confidence interval [CI]: 0.41-0.96). In patients ≥ 60 years, overall survival was similar with Pola-R-CHP versus R-CHOP (unstratified HR 0. 99; 95% CI: 0.67 -1.47 ). Safety profiles were similar for Pola-R-CHP versus R-CHOP among patients ≥60 years, including rates of grade 3-4 adverse events (AEs; 62.7% vs 61.5%), grade 3-5 infections (15.0% vs 12.9%), and grade 5 AEs (3.6% vs 3.2%); no novel toxicities were reported. Incidence of grade 3-4 febrile neutropenia was higher with Pola-R-CHP than R-CHOP (16.3% vs 7.6%), highlighting the importance of G-CSF prophylaxis in elderly patients receiving Pola-R-CHP. The benefit-risk profile favored Pola-R-CHP versus R-CHOP in elderly patients with previously untreated DLBCL. This trial was registered at ClinicalTrials.gov as #NCT03274492. | Blood advances | 14/03/2025 |
('LID', '10.1111/irv.70073') | Mortality Risk Among Patients With Influenza Illness Admitted to the ICU: A Systematic Review and Meta-Analysis. | Suárez-Sánchez, Pablo, Majuelos-Melguizo, Jara, Hinojosa-Campos, Marina, Podmore, Bélène, Gillespie, Iain A, Han, Jennifer, Sloot, Rosa, Christensen, Dina | BACKGROUND: Despite vaccination programs and available treatments, seasonal influenza carries a large mortality burden, especially in intensive care unit (ICU) settings. Understanding the influenza mortality burden in ICU settings can inform treatment planning and resource allocation. Nonetheless, surveillance data on mortality in ICU-admitted patients are scarce and estimates vary greatly. This systematic literature review (SLR) and meta-analysis investigated all-cause mortality risk among ICU-admitted patients with influenza in Europe. METHODS: We included observational studies conducted in Europe that reported mortality among patients ≥ 6 months of age with influenza admitted to the ICU. Studies published between January-2009 and December-2019 were included. Quality was assessed using a modified Newcastle-Ottawa scale. Pooled all-cause mortality risk was calculated as a proportion using a random-effects model with an inverse variance method. A sensitivity analysis was also conducted, including only studies identified as having low risk of bias. RESULTS: Thirty-seven studies, reporting on 13,616 patients, were included. All-cause mortality ranged from 0% to 67%. The overall pooled mortality risk estimate was 0.24 (95% CI: 0.20, 0.27). Study heterogeneity was high (Cochran's Q test p < 0.01, I(2) = 93%). The sensitivity analysis using only studies identified as having low risk of bias produced a pooled mortality risk of 0.25 (95%CI: 0.21, 0.29). CONCLUSIONS: These results indicate that approximately a quarter of patients with influenza admitted to the ICU die, reinforcing the need for effective vaccination programs and treatment optimization. | Influenza and other respiratory viruses | 00/03/2025 |
('LID', '10.1007/s00011-025-02019-2') | CUR-PDT induces ferroptosis of RA-FLS via the Nrf2/xCT/GPX4 pathway to inhibit proliferation in rheumatoid arthritis. | Sun, Lihua, Niu, Yajuan, Liao, Bo, Liu, Linlin, Peng, Yi, Li, Kaiting, Chen, Xinhua, Chen, Qing, Bai, Dingqun | OBJECTIVE: Ferroptosis is a non-apoptotic cell death mechanism driven by reactive oxygen species (ROS) and iron. Its significance in inflammatory arthritis is well-established, but its role in rheumatoid arthritis (RA) remains uncertain. This study aimed to clarify the mechanisms through which curcumin-mediated photodynamic therapy (CUR-PDT) triggers ferroptosis in RA fibroblast-like synoviocytes (FLSs). METHODS: In vivo studies using a collagen-induced arthritis (CIA) rat model evaluated CUR-PDT effects on joint edema, synovial inflammation, and fibrosis through paw volume measurements and H&E and Masson's trichrome staining. The expression of Nrf2, xCT, and GPX4 in FLSs was assessed via ELISA and immunohistochemistry. In vitro, MH7A cells treated with TNF-α were analyzed for viability, proliferation, invasion, and migration through various assays. Mitochondrial potential and morphology were examined using JC-1 staining and transmission electron microscopy (TEM). Ferroptosis biomarkers, including ROS, malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and Fe(2+) levels, were measured. Nrf2, xCT, and GPX4 levels were quantified with RT-qPCR, Western blot, and immunofluorescence. Small interfering RNA (siRNA) was employed to knock down Nrf2 to validate the effect of CUR-PDT on ferroptosis in RA-FLS. RESULTS: The CUR-PDT therapy markedly reduced joint inflammation and collagen deposition in the synovial tissue of CIA rats. It effectively alleviated both inflammation and hyperplasia. Moreover, this therapy facilitated ferroptosis within the synovial tissue. In vitro analyses indicated that CUR-PDT diminished the proliferation and viability of FLSs, resulting in increased ROS levels in the cells. This cascade initiated ferroptosis, as evidenced by decreased glutathione, heightened iron concentrations, mitochondrial shrinkage, and reduced mitochondrial membrane potential. Crucially, the expression of xCT and GPX4 was significantly lowered. Interestingly, knocking down the Nrf2 gene amplified this effect, leading to an even greater reduction in xCT and GPX4 expression. In this context, RA-FLSs exhibited more pronounced ferroptotic traits, including diminished proliferation, invasion, and migration. CONCLUSIONS: This study elucidated a mechanism by which CUR-PDT triggers ferroptosis in FLSs through the downregulation of the Nrf2-xCT-GPX4 signaling cascade, thereby effectively hindering the progression of RA and emphasizing the importance of targeting Nrf2 in disease advancement. | Inflammation research : official journal of the European Histamine Research | 14/03/2025 |
('LID', '10.1136/bmjophth-2024-002103') | Identifying potential key metabolic pathways and biomarkers in glaucoma: a systematic review and meta-analysis. | Golpour, Navid, Brautaset, Rune L, Hui, Flora, Nilsson, Maria, Svensson, Jonas E, Williams, Pete A, Tribble, James R | BACKGROUND: Glaucoma, a leading cause of irreversible blindness worldwide, is characterised by retinal ganglion cell degeneration. Increasing evidence points to metabolic dysfunction, particularly mitochondrial dysfunction, as a contributing factor to glaucomatous neurodegeneration. This systematic review and meta-analysis aimed to identify key metabolic pathways and biomarkers associated with primary open-angle glaucoma (POAG). METHODS: A systematic literature search was conducted to identify studies measuring metabolites in plasma and aqueous humour from patients with POAG using metabolomics techniques. Enrichment analyses for significantly increased metabolites were conducted using MetaboAnalyst. Meta-analyses were performed using random-effects models to calculate effect sizes for metabolites reported in at least three studies. RESULTS: 17 studies involving patients with POAG were included. Pathway analysis revealed significant enrichment of the arginine and proline metabolism pathway in both aqueous humour and plasma. Additionally, the phenylalanine metabolism pathway was enriched in plasma. These pathways are associated with oxidative stress and neurodegeneration, both of which are key factors in POAG pathology. Meta-analysis identified several significantly elevated metabolites, including lysine, glutamine, alanine, histidine, carnitine and creatinine in aqueous humour, as well as methionine in plasma. CONCLUSIONS: This study underscores the central role of metabolic dysfunction in POAG, highlighting specific metabolites and pathways that could serve as biomarkers for early diagnosis and therapeutic intervention. Future research should prioritise longitudinal studies and untargeted metabolomic profiling to further deepen our understanding of metabolic changes and their contributions to glaucoma progression. PROSPERO REGISTRATION NUMBER: CRD42024512098. | BMJ open ophthalmology | 13/03/2025 |
('LID', '10.1038/s41467-025-57760-3') | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders. | Cilleros-Portet, Ariadna, Lesseur, Corina, Marí, Sergi, Cosin-Tomas, Marta, Lozano, Manuel, Irizar, Amaia, Burt, Amber, García-Santisteban, Iraia, Garrido-Martín, Diego, Escaramís, Geòrgia, Hernangomez-Laderas, Alba, Soler-Blasco, Raquel, Breeze, Charles E, Gonzalez-Garcia, Bárbara P, Santa-Marina, Loreto, Chen, Jia, Llop, Sabrina, Fernández, Mariana F, Vrijheid, Martine, Ibarluzea, Jesús, Guxens, Mònica, Marsit, Carmen, Bustamante, Mariona, Bilbao, Jose Ramon, Fernandez-Jimenez, Nora | Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation. We construct a public placental cis-mQTL database including 214,830 CpG sites calculated in 368 fetal placenta DNA samples from the INMA project, and run cell type-, gestational age- and sex-imQTL models. We combine these data with summary statistics of GWAS on ten neuropsychiatric disorders using summary-based Mendelian randomization and colocalization. We also evaluate the influence of identified DNA methylation sites on placental gene expression in the RICHS cohort. We find that placental cis-mQTLs are enriched in placenta-specific active chromatin regions, and establish that part of the genetic burden for schizophrenia, bipolar disorder, and major depressive disorder confers risk through placental DNA methylation. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, the involvement of cell type-imQTLs, and the correlation of identified DNA methylation sites with the expression levels of relevant genes in the placenta. | Nature communications | 14/03/2025 |
('LID', '10.1136/bcr-2024-263274') | Dengue haemorrhagic fever (DHF) in pregnancy. | Chigateri, Seema, Kamat, Vidya S, Jain, Apoorva, Oli, Ajay Kumar | Dengue haemorrhagic fever (DHF) is a common tropical disease. An increasing frequency of dengue fever and DHF in pregnancy is being observed, with a rising incidence among adults. This case report describes the management of a woman in her early 30s, gravida 3, para 2, at 34 weeks of gestation, presenting with DHF and dengue shock syndrome, with a history of two previous caesarean sections. The patient developed severe complications, including preterm labour, atonic postpartum haemorrhage and significant haematoma formation, requiring complex multidisciplinary care. Despite these challenges, both maternal and fetal outcomes were successfully managed through vigilant monitoring and timely interventions. | BMJ case reports | 14/03/2025 |
('LID', '10.1016/j.numecd.2025.103901') | Social, cultural and ethnic determinants of obesity: From pathogenesis to treatment. | Capoccia, Danila, Milani, Ilaria, Colangeli, Luca, Parrotta, Maria Eugenia, Leonetti, Frida, Guglielmi, Valeria | AIMS: Obesity is a multifactorial disease influenced by several factors including poor diet, physical inactivity, and genetic predisposition. In recent years, the social and environmental context, along with race/ethnicity and gender, have been recognized as factors influencing obesity risk beyond traditional risk factors. This review aims to increase knowledge of these causal determinants and their implications for the treatment and management of obesity, addressing not only the individual but also the societal sphere. DATA SYNTHESIS: A growing body of evidence emphasizes the interaction between the physical and social environments in shaping personal behaviors related to obesity. Social disparities, such as socioeconomic status (income, education, employment), racial/ethnic differences, and gender, contribute significantly to weight gain from childhood to adulthood. These factors increase the risk of obesity and related cardiovascular risk factors, independent of clinical and demographic variables, and may lead to stigma and discrimination against those affected. CONCLUSIONS: Obesity prevention solutions, from community programs to national policies, may be more effective if they address social, gender, and ethnic barriers. Understanding obesity requires a comprehensive approach that includes social, environmental, and psychological factors, as well as biological causes, to help obesity experts develop more effective interventions tailored to obesity and related diseases. | Nutrition, metabolism, and cardiovascular diseases : NMCD | 01/02/2025 |
('LID', '10.1158/1078-0432.CCR-24-2911') | Protein profiles predict treatment responses to the PI3K inhibitor umbralisib in patients with chronic lymphocytic leukemia. | Yin, Yanping, Xu, Haifeng, He, Liye, Brown, Jennifer R, Mato, Anthony R, Aittokallio, Tero, Skånland, Sigrid S | PURPOSE: The management of chronic lymphocytic leukemia (CLL) has significantly improved with targeted therapies. However, many patients experience a suboptimal response. To optimally select the best therapy, predictive biomarkers are necessary. Here, we used the PI3K inhibitor umbralisib as a model to (i) understand how targeted treatment affects cell signaling and immunophenotypes in responders and non-responders; (ii) identify molecular features that predict individual treatment responses; and (iii) suggest alternative treatment options for the non-responders. EXPERIMENTAL DESIGN: We performed functional phenotyping of CLL cells from patients enrolled in two clinical trials with umbralisib, administered either as a monotherapy (NCT02742090, n=55) or in combination with the BTK inhibitor acalabrutinib (NCT04624633, n=12). RESULTS: We found that umbralisib monotherapy led to significant changes in (phospho)protein levels, including AKT (pS473), in responders but not in non-responders. Furthermore, the proportion of cytotoxic natural killer cells increased at the end of study, but only in responders, suggesting a role in the anti-tumor response. To identify molecular predictors of response, we used the baseline levels of 30 (phospho)proteins in the monotherapy cohort as input features for a machine learning model, which achieved a significant prediction accuracy in cross-validation and maintained its predictive power in the combination cohort. Drug sensitivity profiling of the CLL cells at baseline suggested that PI3K + Bcl-2 inhibitors are effective in umbralisib non-responders. CONCLUSIONS: Functional phenotyping reveals differential cellular responses to umbralisib treatment in responders and non-responders; predicts treatment response of individual CLL patients; and suggests alternative treatment options for the non-responders. | Clinical cancer research : an official journal of the American Association for | 14/03/2025 |
('LID', '10.1001/jama.2025.0228') | Prostate Cancer: A Review. | Raychaudhuri, Ruben, Lin, Daniel W, Montgomery, R Bruce | IMPORTANCE: Prostate cancer is the most common nonskin cancer in men in the US, with an estimated 299 010 new cases and 35 250 deaths in 2024. Prostate cancer is the second most common cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022. OBSERVATIONS: The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years. More than 50% of prostate cancer risk is attributable to genetic factors; older age and Black race (annual incidence rate, 173.0 cases per 100 000 Black men vs 97.1 cases per 100 000 White men) are also strong risk factors. Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening. At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Based on risk stratification that incorporates life expectancy, tumor grade (Gleason score), tumor size, and PSA level, one-third of patients with localized prostate cancer are appropriate for active surveillance with serial PSA measurements, prostate biopsies, or magnetic resonance imaging, and initiation of treatment if the Gleason score or tumor stage increases. For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options; treatment decision-making should include consideration of adverse events and comorbidities. Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors. At presentation, approximately 14% of patients have metastases to regional lymph nodes. An additional 10% of men have distant metastases that are associated with a 5-year survival rate of 37%. Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists. For patients with newly diagnosed metastatic prostate cancer, the addition of androgen receptor pathway inhibitors (eg, darolutamide, abiraterone) improves survival. Use of abiraterone improved the median overall survival from 36.5 months to 53.3 months (hazard ratio, 0.66 [95% CI, 0.56-0.78]) compared with medical castration alone. Chemotherapy (docetaxel) may be considered, especially for patients with more extensive disease. CONCLUSIONS AND RELEVANCE: Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of patients present with cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Management includes active surveillance, prostatectomy, or radiation therapy, depending on risk of progression. Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%. First-line therapies for metastatic prostate cancer include androgen deprivation and novel androgen receptor pathway inhibitors, and chemotherapy for appropriate patients. | JAMA | 10/03/2025 |
('LID', '10.1007/s12035-025-04829-1') | DNA Methylation-Regulated ZDHHC13 Promotes the Progression of Parkinson's Disease. | Liao, Jing, Bei, Liyuan, Nie, Pengbing, Liu, Pinjing, Zhang, Yongquan | Recent studies suggest that palmitoylation may influence proteins involved in neurotransmission and neurodegenerative changes, such as pathological α-synuclein. However, the role of palmitoylation in Parkinson's disease (PD) has not been systematically investigated. Additionally, findings on DNA methylation changes and PD-associated gene expression remain inconsistent. This study aims to explore the causal relationship and mechanisms between palmitoylation genes, DNA methylation, and PD using Mendelian Randomization (MR). This study employed two-sample MR analysis, summary-data-based Mendelian Randomization (SMR) analysis, and mediation analysis, utilizing PD GWAS data from the Finngen database, palmitoylation genes data from the eQTLGen database, and DNA methylation data from the GoDMC database. First, a two-sample MR analysis was used to evaluate the causal relationship between the palmitoylation genes and PD. Then, the SMR method was applied to validate the association between gene expression and PD. Finally, mediation analysis was conducted to explore the mediating effect of DNA methylation on the relationship between expression of palmitoylation genes and PD. Our study found a significant positive correlation between high expression of the ZDHHC13 gene and increased PD risk. Each 1 standard deviation increase in ZDHHC13 expression was associated with a 24.20% increase in PD risk. Further DNA methylation analysis identified two key methylation sites (cg00161556 and cg27379915), which indirectly influenced the occurrence of PD by regulating the expression of the ZDHHC13 gene. Mediation effect analysis revealed that the methylation sites cg00161556 and cg27379915 indirectly promoted the development of PD by regulating the expression of the ZDHHC13 gene, with the mediation effect of ZDHHC13 gene expression accounting for 63.72% and 57.61% of the total effect, respectively. Sensitivity analysis and SMR analysis supported our findings, indicating high statistical robustness. This study highlights the role of DNA methylation in regulating ZDHHC13 during PD progression, suggesting potential clinical applications such as ZDHHC13 as a biomarker or therapeutic target for early PD diagnosis and treatment. | Molecular neurobiology | 15/03/2025 |
('LID', '10.1016/j.canlet.2025.217639') | CircRUNX1 enhances the Warburg effect and immune evasion in non-small cell lung cancer through the miR-145/HK2 pathway. | Li, Jinyou, Xu, Shiwei, Zhan, Yangyang, Lv, Xinyi, Sun, Zhenyu, Man, Li, Yang, Donghua, Sun, Yahong, Ding, Shengguang | Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear.. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC. | Cancer letters | 14/03/2025 |
('LID', '10.1016/j.jad.2025.03.040') | Gender-specific network analysis of parenting styles, depressive symptoms, and anxiety symptoms among 5157 Chinese adolescents. | Suo, Xingbo, Zhang, Yang, Qin, Yan, Niu, Xingmeng, Niu, Sifang, Guo, Yangziye, Mu, Fuqin, Hu, Maorong, Liu, Yan, Zhang, Ying | BACKGROUND: In this study, we aimed to use network analyses to explore the gender-specific interactions between individual items of depressive symptoms, anxiety symptoms, and parenting styles in Chinese adolescents. METHODS: We conducted a cross-sectional study with a total of 5157 adolescents in 5 primary schools, 8 junior high schools, and 2 senior high schools in Shandong province, China. Male and female adolescents' networks were assessed in all grades using the Egna Minnen Betraffande Uppfostran (EMBU), the 9-item Patient Health Questionnaire (PHQ-9), and the 7-item Generalized Anxiety Disorder Assessment (GAD-7). Network differences by gender and educational stages were further assessed stratified. Network analysis was used to identify central items and edges with important associations between depressive symptoms, anxiety symptoms, and parenting styles. All analyses in this study were performed using the R program (version 4.3.2). RESULTS: Parenting styles can influence the overall depressive network by acting on PHQ9 (Suicidal thoughts) through EMBU1 (Punishment denial) and EMBU2 (Emotional warmth) in adolescents. Parenting styles had displayed gender-specific emotional impacts on adolescents. EMBU1 (Punishment denial) affected the anxiety network in senior high school male adolescents by increasing GAD6 (Easily annoyed/Irritable) and impacting their depression network by reducing the PHQ6 (Failure). However, none of these effects were found in senior high school female adolescents. CONCLUSIONS: The mood disorder and anxiety in male students were susceptible to the influence of the manner of upbringing. Depressive and anxiety symptom-specific issues related to parenting styles may be important in the development and maintenance of mood disorders in adolescents. Punishment rejection and emotional warmth might be the strong influencing factors. | Journal of affective disorders | 11/03/2025 |
('LID', '10.1016/j.ccell.2025.02.011') | Multimodal integration of liquid biopsy and radiology for the noninvasive diagnosis of gallbladder cancer and benign disorders. | Yang, Mao, Zhao, Yuhao, Li, Chen, Weng, Xiaoling, Li, Zhizhen, Guo, Wu, Jia, Wenning, Feng, Feiling, Hu, Jiaming, Sun, Haonan, Wang, Bo, Li, Huaifeng, Li, Ming, Wang, Ting, Zhang, Wei, Jiang, Xiaoqing, Zhang, Zongli, Liu, Fubao, Hu, Hai, Wu, Xiangsong, Gu, Jianfeng, Yang, Guocai, Li, Guosong, Zhang, Hui, Zhang, Tong, Zang, Hong, Zhou, Yan, He, Min, Yang, Linhua, Wang, Hui, Chen, Tao, Zhang, Junfeng, Chen, Wei, Wu, Wenguang, Li, Maolan, Gong, Wei, Lin, Xinhua, Liu, Fatao, Liu, Yun, Liu, Yingbin | Gallbladder cancer (GBC) frequently mimics gallbladder benign lesions (GBBLs) in radiological images, leading to preoperative misdiagnoses. To address this challenge, we initiated a prospective, multicenter clinical trial (ChicCTR2100049249) and proposed a multimodal, non-invasive diagnostic model to distinguish GBC from GBBLs. A total of 301 patients diagnosed with gallbladder-occupying lesions (GBOLs) from 11 medical centers across 7 provinces in China were enrolled and divided into a discovery cohort and an independent external validation cohort. An artificial intelligence (AI)-based integrated model, GBCseeker, is created using cell-free DNA (cfDNA) genetic signatures, radiomic features, and clinical information. It achieves high accuracy in distinguishing GBC from GBBL patients (93.33% in the discovery cohort and 87.76% in the external validation cohort), reduces surgeons' diagnostic errors by 56.24%, and reclassifies GBOL patients into three categories to guide surgical options. Overall, our study establishes a tool for the preoperative diagnosis of GBC, facilitating surgical decision-making. | Cancer cell | 10/03/2025 |
('LID', '10.1186/s13059-025-03499-5') | A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients. | Pita-Juarez, Yered, Karagkouni, Dimitra, Kalavros, Nikolaos, Melms, Johannes C, Niezen, Sebastian, Delorey, Toni M, Essene, Adam L, Brook, Olga R, Pant, Deepti, Skelton-Badlani, Disha, Naderi, Pourya, Huang, Pinzhu, Pan, Liuliu, Hether, Tyler, Andrews, Tallulah S, Ziegler, Carly G K, Reeves, Jason, Myloserdnyy, Andriy, Chen, Rachel, Nam, Andy, Phelan, Stefan, Liang, Yan, Gregory, Mark, He, Shanshan, Patrick, Michael, Rane, Tushar, Wardhani, Aster, Amin, Amit Dipak, Biermann, Jana, Hibshoosh, Hanina, Veregge, Molly, Kramer, Zachary, Jacobs, Christopher, Yalcin, Yusuf, Phillips, Devan, Slyper, Michal, Subramanian, Ayshwarya, Ashenberg, Orr, Bloom-Ackermann, Zohar, Tran, Victoria M, Gomez, James, Sturm, Alexander, Zhang, Shuting, Fleming, Stephen J, Warren, Sarah, Beechem, Joseph, Hung, Deborah, Babadi, Mehrtash, Padera, Robert F Jr, MacParland, Sonya A, Bader, Gary D, Imad, Nasser, Solomon, Isaac H, Miller, Eric, Riedel, Stefan, Porter, Caroline B M, Villani, Alexandra-Chloé, Tsai, Linus T-Y, Hide, Winston, Szabo, Gyongyi, Hecht, Jonathan, Rozenblatt-Rosen, Orit, Shalek, Alex K, Izar, Benjamin, Regev, Aviv, Popov, Yury V, Jiang, Z Gordon, Vlachos, Ioannis S | BACKGROUND: The molecular underpinnings of organ dysfunction in severe COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we perform single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. RESULTS: We identify hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells, and a central role in a pro-fibrotic TGFβ signaling cell-cell communications network. Integrated analysis and comparisons with healthy controls reveal extensive changes in the cellular composition and expression states in COVID-19 liver, providing the underpinning of hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis characteristic of COVID-19 cholangiopathy. We also observe Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition is dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. CONCLUSIONS: Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding. | Genome biology | 14/03/2025 |
('LID', '10.1007/s12264-025-01384-6') | Comprehensive Brain-wide Mapping of Afferent and Efferent Nuclei Associated with the Heart in the Mouse. | Liu, Haiying, Huang, Xin, Xia, Ruixin, Zhao, Xin, Li, Zimeng, Liu, Qian, Li, Congye, Mao, Honghui, Wang, Wenting, Wu, Shengxi | Normal heart function depends on complex regulation by the brain, and abnormalities in the brain‒heart axis affect various diseases, such as myocardial infarction and anxiety disorders. However, systematic tracking of the brain regions associated with the input and output of the heart is lacking. In this study, we injected retrograde transsynaptic pseudorabies virus (PRV) and anterograde transsynaptic herpes simplex virus (HSV) into the left ventricular wall of mice to identify the whole-brain regions associated with the input to and output from the heart. We successfully detected PRV and HSV expression in at least 170 brain subregions in both male and female mice. Sex differences were discovered mainly in the hypothalamus and medulla, with male mice exhibiting greater correlation and hierarchical clustering than female mice, indicating reduced similarity and increased modularity of virus expression patterns in male mice. Further graph theory and multiple linear regression analysis of different injection timelines revealed that hub regions of PRV had highly similar clusters, with different brain levels, suggesting a top-down, hierarchically transmitted neural control pattern of the heart. Hub regions of HSV had scattered clusters, with brain regions gathered in the cortex and brainstem, suggesting a bottom-up, leapfrog, multipoint neural sensing pattern of the heart. Both patterns contain many hub brain regions that have been previously overlooked in brain‒heart axis studies. These results provide brain targets for future research and will lead to deeper insight into the brain mechanisms involved in specific heart conditions. | Neuroscience bulletin | 15/03/2025 |
('LID', '10.1038/s41467-025-57364-x') | Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules. | Su, Hang, Chen, Li, Wu, Jun, Cheng, Zhongyi, Li, Jing, Ren, Yijiu, Xu, Junfang, Dang, Yifang, Zheng, Mengge, Cao, Yajuan, Gao, Jiani, Dai, Chenyang, Hu, Xuefei, Xie, Huikang, Chen, Jianxia, Luo, Tao, Zhu, Jun, Wu, Chunyan, Sha, Wei, Chen, Chang, Liu, Haipeng | Lung adenocarcinoma (LUAD) radiologically displayed as subsolid nodules (SSNs) is prevalent. Nevertheless, the precise clinical management of SSNs necessitates a profound understanding of their tumorigenesis and progression. Here, we analyze 66 LUAD displayed as SSNs covering 3 histological stages including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) by incorporating genomics, proteomics, phosphoproteomics and glycoproteomics. Intriguingly, cholesterol metabolism is aberrantly regulated in the preneoplastic AIS stage. Importantly, target ablation of proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the initiation of LUAD. Furthermore, sustained endoplasmic reticulum stress is demonstrated to be a hallmark and a reliable biomarker of AIS progression to IAC. Consistently, target promotion of ER stress profoundly retards LUAD progression. Our study provides comprehensive proteogenomic landscape of SSNs, sheds lights on the tumorigenesis and progression of SSNs and suggests preventive and therapeutic strategies for LUAD. | Nature communications | 11/03/2025 |
('LID', '10.1126/science.adr5507') | Evolutionary adaptations of doublet microtubules in trypanosomatid parasites. | Doran, Matthew H, Niu, Qingwei, Zeng, Jianwei, Beneke, Tom, Smith, James, Ren, Peter, Fochler, Sophia, Coscia, Adrian, Höög, Johanna L, Meleppattu, Shimi, Lishko, Polina V, Wheeler, Richard J, Gluenz, Eva, Zhang, Rui, Brown, Alan | The movement and pathogenicity of trypanosomatid species, the causative agents of trypanosomiasis and leishmaniasis, are dependent on a flagellum that contains an axoneme of dynein-bound doublet microtubules (DMTs). In this work, we present cryo-electron microscopy structures of DMTs from two trypanosomatid species, Leishmania tarentolae and Crithidia fasciculata, at resolutions up to 2.7 angstrom. The structures revealed 27 trypanosomatid-specific microtubule inner proteins, a specialized dynein-docking complex, and the presence of paralogous proteins that enable higher-order periodicities or proximal-distal patterning. Leveraging the genetic tractability of trypanosomatid species, we quantified the location and contribution of each structure-identified protein to swimming behavior. Our study shows that proper B-tubule closure is critical for flagellar motility, exemplifying how integrating structural identification with systematic gene deletion can dissect individual protein contributions to flagellar motility. | Science (New York, N.Y.) | 14/03/2025 |
('LID', '10.1177/14230380251316788') | External validation of a serum tumor marker algorithm for early prediction of no durable benefit to immunotherapy in metastastic non-small cell lung carcinoma. | Schuurbiers, Milou M F, van Delft, Freek A, Koffijberg, Hendrik, IJzerman, Maarten J, Monkhorst, Kim, Ligtenberg, Marjolijn J L, van den Broek, Daan, van Rossum, Huub H, van den Heuvel, Michel M | BackgroundImmune checkpoint inhibitors (ICIs) provide a significant survival benefit in non-small cell lung cancer (NSCLC) patients; however, accurately predicting which patients will benefit remains a challenge. As previously shown, the STOP model, a machine learning model based on serum tumor markers, is capable of identifying non-responders after 6 weeks of ICIs.ObjectiveThis study aims to externally validate this model and to assess the predictive value in combination with radiological response assessment using RECIST criteria.MethodsIn a cohort of 242 metastatic NSCLC patients, CYFRA, CEA, and NSE were measured before start and after 6 weeks of ICI treatment. The ability of the STOP model to predict no durable benefit (NDB; progressive disease, death within 6 months or disease control of less than 6 months) was assessed using specificity and positive predictive value (PPV). Moreover, a combination of the STOP model with RECIST after 6-8 weeks of ICIs was investigated.ResultsThe STOP model achieved a specificity of 96% (95% CI 95%-97%) and a PPV of predicting NDB of 88.1% (95% CI 85.9%-90.3%). Combining the STOP model with RECIST improved specificity and PPV to 100% and predicted NDB on average 11.6 weeks (IQR 1.8-18.0 weeks) prior to developing radiologically defined progression.ConclusionsAfter 6 weeks of ICIs, the blood-based STOP model was capable of accurately predicting NDB in metastatic NSCLC patients, earlier than conventional radiological assessment. The combined serological and radiological response assessment creates an early opportunity to safely stop ICI treatment in patients who will not benefit, although the clinical utility of the assay is limited since the high specificity comes at the cost of a lower sensitivity. | Tumour biology : the journal of the International Society for Oncodevelopmental | 00/01/2025 |
('LID', '10.1007/s00420-025-02127-w') | Association of long-term exposure to air pollutants with benign prostatic hyperplasia among middle-aged and older men in China. | Shi, Wenming, Zhao, Jie V | PURPOSE: Air pollution has been an important risk factor for human health. However, little is known about the impacts of air pollutants on benign prostatic hyperplasia (BPH) in men. We aimed to explore the association of long-term exposure to air pollutants with BPH among men. METHODS: We leveraged the nationally representative data from the China Health and Retirement Longitudinal Study, a total of 8,826 participants aged 45 years and above from 125 Chinese cities were enrolled in 2015. Annual fine particulate matter (PM(2.5)), coarse particles (PM(2.5-10)), nitrogen dioxide (NO(2)), sulfur dioxide, carbon monoxide, and ozone were estimated using satellite-based models. Multivariate logistic regression models were used to assess the risk of BPH associated with air pollutants. The restricted cubic spline model was performed to explore the exposure-response relationships with BPH. RESULTS: Of the 8,826 participants (mean age: 60.3 years), the prevalence of BPH was 14.5%. Each 10 µg/m(3) rise in PM(2.5) (odds ratio 1.04, 95% confidence intervals: 1.01-1.07) and PM(2.5-10) (1.06, 1.02-1.10) were associated with prevalent BPH. Compared with the lowest quartile levels, higher PM(2.5) and PM(2.5-10) exposure were related to an increased risk of BPH. There were non-linear relationship between PM(2.5-10) and NO(2) exposure with prevalent BPH. The association with BPH was more pronounced in participants who were overweight/obesity. CONCLUSION: This study suggests that long-term air pollutants exposure, especially for PM(2.5) and PM(2.5-10), is associated with BPH among middle-aged and older men. Our findings provide epidemiological evidence for policymakers and researchers to improve prostate health by reducing air pollution. | International archives of occupational and environmental health | 14/03/2025 |
('LID', '10.1016/S0140-6736(25)00107-2') | Human African trypanosomiasis. | Lejon, Veerle, Lindner, Andreas K, Franco, Jose R | Human African trypanosomiasis or sleeping sickness is caused by infection with Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense parasites, which are transmitted by tsetse flies in sub-Saharan Africa. Control of human African trypanosomiasis is based on case detection, treatment, and vector control. In the past decade, simple rapid diagnostic tests were introduced for gambiense human African trypanosomiasis, facilitating screening in primary health-care facilities. A new oral drug, fexinidazole, became the first-line treatment for gambiense human African trypanosomiasis without severe meningo-encephalitic disease, as well as for rhodesiense human African trypanosomiasis. Medical interventions, in some areas combined with tiny target-based vector control, have substantially reduced human African trypanosomiasis incidence, despite temporary disruptions to health-care systems. The elimination of human African trypanosomiasis as a public health problem has been achieved, and elimination of gambiense human African trypanosomiasis transmission is now targeted for 2030. Improved diagnostics and drugs, continued involvement of populations at risk of disease, health staff, national authorities, and partners and donors all contribute to achieve this goal. | Lancet (London, England) | 15/03/2025 |
('LID', '10.1136/gutjnl-2024-334010') | GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism. | Kou, Fushun, Li, Xiao-Yu, Feng, Zhongsheng, Hua, Jinghan, Wu, Xiaohan, Gao, Han, Lin, Jian, Kang, Dengfeng, Li, Ai, Li, Junxiang, Ding, Yao, Ban, Ting, Zhang, Qing, Liu, Zhanju | BACKGROUND: GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear. OBJECTIVE: We aimed to investigate the role of GPR171 in modulating CD4(+) T cell effector functions in IBD and evaluate its therapeutic potential. DESIGN: We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4(+) T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RB(high)CD4(+) T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis. RESULTS: GPR171 was markedly increased in inflamed mucosa and CD4(+) T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RB(high)CD4(+) T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 (-/-) mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice. CONCLUSIONS: GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment. | Gut | 12/03/2025 |
('LID', '10.1016/j.redox.2025.103588') | Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: Insights from traditional and machine learning approaches. | Chen, Yang, Wu, Shuang, Liu, Hongyu, Zhong, Ziyi, Bucci, Tommaso, Wang, Yimeng, Zhao, Manlin, Liu, Yang, Yang, Zhengkun, Gue, Ying, McDowell, Garry, Huang, Bi, Lip, Gregory Y H | OBJECTIVES: To evaluate the roles of oxidative balance score (OBS) in staging and mortality risk of cardiovascular-kidney-metabolic syndrome (CKM). METHODS: Data of this study were from the National Health and Nutrition Examination Survey 1999-2018. We performed cross-sectional analyses using multinomial logistic regression to investigate the relationship between OBS and CKM staging. Cox proportional hazards models were used to assess the impact of OBS on mortality outcomes in CKM patients. Additionally, mediation analyses were performed to explore whether OBS mediated the relationships between specific predictors (Life's Simple 7 score [LS7], systemic immune-inflammation index [SII], frailty score) and mortality outcomes. Then, machine learning models were developed to classify CKM stages 3/4 and predict all-cause mortality, with SHapley Additive exPlanations values used to interpret the contribution of OBS components. RESULTS: 21,609 participants were included (20,319 CKM, median [IQR] age: 52.0 [38.0-65.0] years, 54.3% male, median [IQR] follow-up: 9.4 [5.3-14.1] years). Lower OBS quartiles were associated with advanced CKM staging. Moreover, lower OBS quartiles were related to increased mortality risk, compared to Q4 of OBS (all-cause mortality: Q1: HR 1.31, 95% CI 1.18-1.46, Q2: HR 1.27, 95% CI 1.14-1.42, Q3: HR 1.18, 95% CI 1.06-1.32; cardiovascular mortality: Q1: HR 1.44, 95% CI 1.16-1.79, Q2: HR 1.39, 95% CI 1.11-1.74, Q3: HR 1.26, 95% CI 1.01-1.57; non-cardiovascular mortality, Q1: HR 1.27, 95% CI 1.12-1.44, Q2: HR 1.23, 95% CI 1.08-1.40, Q3: HR 1.16, 95% CI 1.02-1.31), with optimal risk stratification threshold for OBS was 22. Additionally, OBS mediated (ranging 4.25%-32.85 %) effects of SII, LS7, frailty scores on mortality outcomes. Moreover, light gradient boosting machine achieved the highest performance for predicting advanced CKM staging (area under curve: 0.905) and all-cause mortality (area under curve: 0.875). Cotinine increased risk, while magnesium, vitamin B6, physical activity were protective. CONCLUSIONS: This study highlights OBS as a risk stratification tool for CKM, emphasizing oxidative stress's role in CKM staging and mortality risk management. | Redox biology | 07/03/2025 |
('LID', '10.1128/spectrum.02112-24') | Elevating fungal care: bridging Brazil's healthcare practices to global standards. | Salmanton-García, Jon, Falci, Diego R, Cornely, Oliver A, Pasqualotto, Alessandro C | Brazil faces unique challenges in managing invasive fungal infections (IFIs) due to diverse ecosystems, a rural workforce, and prevalent health conditions. In Europe, IFIs are primarily associated with transplantation, intensive care, and chronic diseases. Inspired by initiatives in the Caribbean and Latin America in 2019, efforts to map global diagnostic and treatment resources expanded to Africa, Europe, and Asia/Pacific. This study conducts a comparative analysis, mainly drawing data from Brazil and Europe, to investigate IFI epidemiology and management. Data were collected through online surveys distributed to Brazilian and European institutions, with collaborations from scientific organizations. Surveys covered institutional profiles, IFI diagnoses, accessibility to diagnostic techniques, and antifungal drugs. A comparative survey involving 96 Brazilian and 388 European institutions revealed variations in the perception and practices related to fungal pathogens. Differences in ranking and prevalence were observed, along with variations in diagnostic procedures, fluorescence dye usage, culture practices, antifungal medication availability, and technological approaches. Europe exhibited higher utilization rates for molecular diagnostic approaches, including PCR tests, and therapeutic drug monitoring (TDM) was more widespread in Europe compared with Brazil, indicating substantial differences in understanding and managing fungal infections. Customized IFI management is crucial, considering regional differences and addressing technological gaps like underutilized PCR. The study advocates for increased international collaboration, targeted training, and enhanced resources to foster a unified global approach in preventing, diagnosing, and treating IFI. IMPORTANCE: This work is significant as it highlights the unique challenges Brazil faces in managing invasive fungal infections (IFIs) due to its diverse ecosystems and public health landscape. By comparing Brazil's situation with Europe-where IFIs are mainly linked to transplantation and intensive care-this study identifies key disparities in diagnostic and treatment practices. The findings reveal substantial differences in the availability and use of molecular diagnostics, antifungal drugs, and therapeutic drug monitoring, with Europe demonstrating more advanced practices. By mapping these variations, the study underscores the importance of tailored approaches to IFI management that consider regional differences and technological gaps. Ultimately, it calls for enhanced international collaboration, targeted training, and resource allocation to improve IFI outcomes globally, particularly in regions with limited access to advanced diagnostic tools and treatments. | Microbiology spectrum | 10/03/2025 |
('LID', '10.1016/j.ymthe.2025.03.018') | CD47 Peptide-Cloaked Lipid Nanoparticles Promote Cell-Specific mRNA Delivery. | Papp, Tyler Ellis, Zeng, Jianhao, Shahnawaz, Hamna, Akyianu, Awurama, Breda, Laura, Yadegari, Amir, Steward, Joseph, Shi, Ruiqi, Li, Qin, Mui, Barbara L, Tam, Ying K, Weissman, Drew, Rivella, Stefano, Shuvaev, Vladimir, Muzykantov, Vladimir R, Parhiz, Hamideh | mRNA-based therapeutics delivered via lipid nanoparticles (LNP-mRNA) hold great promise for treating diverse diseases. However, further improvements are needed to refine outcomes in non-vaccine, extrahepatic applications, such as minimizing the mononuclear phagocyte system's (MPS)' rapid clearance and off-target toxicity in undesired tissues. We propose modifying LNP surfaces with the phagocytic cell "don't eat me" signal, CD47, in combination with our previously established antibody-based targeted LNP (tLNP) to create a CD47/tLNP platform with reduced phagocytic clearance and off-target effects, and improved efficiency for cell-specific delivery. We showed that CD47 modification decreased macrophage and hepatic uptake both in vitro and in vivo. Combining CD47 modification with antibodies targeting endothelial cells, T cells, or hematopoietic stem cells (HSCs) increased targeting efficiency up to 3-fold compared to tLNP alone. Enhanced targeting of CD47/tLNP to HSCs with reduced off-targeting enabled the delivery of pro-apoptotic mRNA for HSC depletion as a preconditioning strategy prior to bone marrow transplant. Additionally, CD47-modified LNPs showed diminished inflammatory effects on hepatic tissue and an altered protein corona. Our CD47/tLNP-mRNA platform, with its reduced phagocytic clearance, mitigated inflammatory effects, and enhanced targeted delivery, should further facilitate the development of in vivo mRNA therapeutics. | Molecular therapy : the journal of the American Society of Gene Therapy | 13/03/2025 |
('LID', '10.1186/s12889-025-21910-5') | Long-term exposure to air pollution and gastrointestinal disease: findings from a nationwide cohort study in China. | Kou, Yanqi, Ye, Shicai, Du, Weimin, Lu, Zhuoyan, Yang, Ke, Zhan, Liping, Huang, Yujie, Qin, Ling, Yang, Yuping | BACKGROUND AND AIMS: Air pollution poses significant risks to human health, but its impact on gastrointestinal (GI) health remains underexplored. This study assesses the long-term effects of air pollution on GI diseases using data from the China Health and Retirement Longitudinal Study (CHARLS). METHODS: This nationwide cohort study utilized CHARLS data from participants recruited in 2011, followed by surveys in 2013, 2015, 2018, and 2020. Long-term exposure to PM(2.5), PM(10), SO(2), NO(2), CO, and O(3) was assessed using geocoded residential addresses linked to air quality data. Cox proportional hazards models and subgroup interaction analyses were used to evaluate associations between pollutants and GI disease incidence, adjusting for demographic and behavioral confounders. RESULTS: The incidence of GI disease was 21.4% among participants. Long-term exposure to PM(2.5) (HR = 1.38, 95% CI: 1.33-1.44), PM(10) (HR = 1.31, 95% CI: 1.26-1.36), SO(2) (HR = 1.74, 95% CI: 1.68-1.81), NO(2) (HR = 1.21, 95% CI: 1.17-1.25), CO (HR = 1.48, 95% CI: 1.42-1.54), and O(3) (HR = 0.56, 95% CI: 0.54-0.59) was significantly associated with GI disease. Interaction analyses showed that the effects of pollutants varied by region, residence, smoking, and alcohol use. Urban residents and those living in specific regions experienced stronger associations, likely due to higher pollution levels and different environmental factors. Smokers and alcohol users were also more susceptible to the adverse effects of pollutants. CONCLUSIONS: Long-term exposure to multiple air pollutants increases the risk of GI diseases, while ozone may potentially offer some protective effects. Public health measures to reduce air pollution, especially in urban areas, and to protect high-risk groups are urgently needed. | BMC public health | 14/03/2025 |
('LID', '10.1038/s41591-025-03515-y') | Hospital admissions attributable to reduced air pollution due to clean-air policies in China. | Liu, Huimeng, Lei, Jian, Liu, Yuewei, Zhu, Tong, Chan, Kahung, Chen, Xi, Wei, Jing, Deng, Furong, Li, Ge, Jiang, Yunxing, Bai, Lijun, Wang, Kai, Chen, Juan, Lan, Yang, Xia, Xi, Wang, Jinxi, Wei, Chen, Li, Yinxiang, Chen, Renjie, Gong, Jicheng, Duan, Xiaoli, Zhang, Kai, Kan, Haidong, Shi, Xiaoming, Guo, Xinbiao, Wu, Shaowei | The Air Pollution Prevention and Control Action Plan (APPCAP) is considered to be the most stringent air pollution control policy in China implemented since 2013. This policy is a milestone in China to mitigate serious air pollution. However, health benefits attributable to reduced fine-particulate air pollution after the implementation of the APPCAP have not been quantitatively estimated on a PM(2.5) constituent-specific and morbidity cause-specific basis. Here we conducted a nationwide case-crossover study based on hospital admission records in 292 Chinese cities during 2013-2017. Compared with 2013, the annual average concentrations of PM(2.5) and black carbon (BC) in 2017 decreased by 28.61% and 20.35%, respectively. As a result, the average relative reductions in annual attributable fractions of nine major cause-specific hospital admissions associated with PM(2.5) and BC were 30.00% and 21.14%, respectively, among which annual attributable fraction for depression showed the largest reduction. Nationally, cities with higher reductions in PM(2.5) and BC were found to have higher absolute reductions in annual hospital admission attributable fractions associated with PM(2.5) and BC, and geographic inequality in health benefits still existed. Our study highlights the substantial wide-ranging health benefits of reduced PM(2.5) and BC levels following the nationwide implementation of the APPCAP in China. | Nature medicine | 14/03/2025 |
('LID', '10.1126/sciadv.adu7614') | An enzymatic cleavage-triggered minimally invasive nanosensor for urine-based detection of early atherosclerosis. | Wu, Zhina, Liu, Rui, Chen, Jianai, Cai, Xueying, Yi, Jingzheng, Wang, Jiasi, Wang, Di, Hu, Min | Timely detection of early atherosclerosis (AS) is crucial for improving cardiovascular outcomes, creating a growing demand for diagnostic tools that are simple, sensitive, and cost-effective. Here, we introduce a synthetic nanosensor for early AS detection that leverages the fluorescence and renal clearance properties of carbon quantum dots (CQDs). This nanosensor, designed to respond to the proteolytic activity of AS-associated dysregulated enzymes, entails CQDs as signal reporters to convert AS-associated proteolytic activity to fluorometric readings enabling a sensitive and cost-effective urine-based assay for early AS detection. Our findings demonstrated that the nanosensor provided distinct signals in atherosclerotic versus healthy mice at early AS stages, indicating its diagnostic potential. Moreover, toxicity tests showed no notable adverse effects, supporting its safety for diagnostic applications. This minimally invasive diagnostic approach could facilitate personalized therapy design and continuous efficacy assessment. It is expected that such a modular nanosensor platform can be integrated with simple urine tests to offer cost-effective detection of various diseases. | Science advances | 14/03/2025 |
('LID', '10.1177/03635465251323001') | Mitochondria Isolated From Bone Mesenchymal Stem Cells Restrain Muscle Disuse Atrophy and Fatty Infiltration After Rotator Cuff Tears. | Shi, Yulong, Qin, Jun, Yin, Enzhi, Xu, Jian, Chen, Yuanyuan, Tie, Kai, Chen, Liaobin | BACKGROUND: Rotator cuff tears (RCTs) commonly lead to muscle atrophy, fibrosis, and fatty infiltration, complicating treatment. PURPOSE: To investigate the use of mitochondria isolated from bone mesenchymal stem cells (BMSC-Mito) for mitigating complications after RCT, focusing on muscle protection. STUDY DESIGN: Controlled laboratory study. METHODS: RCTs were induced by transecting the tendons of the supraspinatus and infraspinatus in Sprague-Dawley rats. In vivo, 90 rats were randomized into 3 groups: sham (no intervention), RCTs treated with BMSC-Mito, and RCTs treated with phosphate-buffered saline. After 6 weeks of intramuscular injections of BMSC-Mito or phosphate-buffered saline, supraspinatus muscles were harvested for analysis. Evaluations included wet muscle weight, muscle fiber cross-sectional area, fibrosis, fatty infiltration, slow-fast myofiber types and muscle biomechanics, capillary density, mitochondria respiratory chain complex activity, adenosine triphosphate (ATP) concentration, oxidative stress, and mitochondrial ultrastructure. In vitro experiments utilized primary rat skeletal muscle cells pretreated with rhodamine 6G to induce mitochondrial dysfunction, assessing the effects of BMSC-Mito on cell viability, mitochondrial membrane potential, and oxidative stress levels. RESULTS: BMSC-Mito can be effectively transplanted into muscles and integrated into the local mitochondrial network. After RCT, the supraspinatus showed significant mass loss, reduced fiber cross-sectional area, fatty infiltration, and a shift from slow to fast myofiber types, which negatively affected muscle biomechanics. These changes were reversed by BMSC-Mito. BMSC-Mito also preserved vascularity (CD31 and α-SMA) impaired by RCT. Additionally, BMSC-Mito notably improved disuse-induced mitochondrial changes, leading to increased mitochondrial number and COX IV expression; furthermore, BMSC-Mito protected mitochondria morphology and enhanced cytosolic superoxide dismutase activity. This treatment also improved mitochondria respiratory chain complex activity and ATP concentration, reducing oxidative stress. In vitro, BMSC-Mito treatment effectively maintained the mitochondrial membrane potential of skeletal muscle cells, improved cell viability, and restored its mitochondrial function and ATP levels. CONCLUSION: These findings suggest that BMSC-Mito might play a role in preventing muscle atrophy and fatty infiltration after RCT through the protection of mitochondrial function and the promotion of angiogenesis. CLINICAL RELEVANCE: BMSC-Mito present a promising therapeutic approach for addressing rotator cuff muscle degeneration. | The American journal of sports medicine | 15/03/2025 |
('LID', '10.3892/ijo.2025.5739') | SLC4A7 suppresses lung adenocarcinoma oncogenesis by reducing lactate transport and protein lactylation. | Yan, Haojie, He, Qian, Gao, Yubiao, He, Xiaomei, Luo, Haitao, Shao, Lijuan, Dong, Jun, Li, Furong | Lactate and protein lactylation serve a key role in tumor pathogenesis. Solute carrier 4A7 (SLC4A7), a key transporter, participates in cellular acid homeostasis. However, its impact on lactate transport and protein lactylation in solid tumors, particularly lung adenocarcinoma (LUAD), remains largely unexplored. In the present study, lactylome analysis, Transwell and wound healing assay, animal experiments were conducted to validate functional regulation mediated by SLC4A7 in LUAD. SLC4A7 inhibited tumor progression, including metastasis, invasion and proliferation. Mechanistically, SLC4A7 decreased both intracellular and extracellular lactate accumulation and inhibited overall protein lactylation, as confirmed by lactylome analysis. Analyzing the lactylome revealed that SLC4A7 suppressed lysine lactylation of numerous genes like HSP90AA1 and pathways such as focal adhesion associated with carcinogenesis. Additionally, low expression levels of SLC4A7 in LUAD cancer stem cells were validated using tumor tissue samples from patients with LUAD. Moreover, the inhibitory role of SLC4A7 in regulating tumor stemness was verified. Collectively, the present results uncovered the inhibitory effect exerted by SLC4A7 on tumor progression via its regulation of lactate transport, protein lactylation and stemness properties. Targeting SLC4A7 may hold promise as a novel therapeutic strategy for LUAD. | International journal of oncology | 00/05/2025 |
('LID', '10.1177/15357597241258514') | Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication. | Pack, Alison M, Oskoui, Maryam, Roberson, Shawniqua Williams, Donley, Diane K, French, Jacqueline, Gerard, Elizabeth E, Gloss, David, Miller, Wendy R, Clary, Heidi M Munger, Osmundson, Sarah S, McFadden, Brandy, Parratt, Kaitlyn, Pennell, Page B, Saade, George, Smith, Don B, Sullivan, Kelly, Thomas, Sanjeev V, Tomson, Torbjörn, O'Brien, Mary Dolan, Botchway-Doe, Kylie, Silsbee, Heather M, Keezer, Mark R | This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neuro-developmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring. | Epilepsy currents | 11/03/2025 |
('LID', '10.1186/s12891-025-08500-7') | Effects of early exercise and immobilization after arthroscopic rotator cuff repair surgery: a systematic review and meta-analysis of randomized controlled trials. | Hao, Boran, Li, Hongqiu, Liang, A | OBJECTIVE: Early exercise is a physical adjuvant therapy that begins on day 1 postoperatively. It prevents postoperative stiffness, fatty infiltration, muscle atrophy and loss of range of motion. Usually, use of a brace fixation that immobilizes the shoulder in 30° of abduction during the postoperative rehabilitation period reduces tension on the repaired tendon, which improves tendon-bone healing. To investigate the effect of early exercise and brace fixation on postoperative recovery after arthroscopic rotator cuff repair by systematic review, thereby providing evidence-based evidence for clinical practice. METHODS: Chinese and English databases (PubMed, Web of Science, Cochrane Library, CNKI, Wanfang database, and VIP database) were searched by keywords until November 15, 2024. Randomized controlled studies comparing early exercise versus brace fixation after arthroscopic rotator cuff repair surgery were included, along with an evaluation of such studies using the Cochrane Collaboration risk assessment tool. Afterward, the effect of the intervention on the visual analogue scale (VAS) for pain, function, shoulder range of motion (forward flexion, abduction, internal rotation, external rotation), and postoperative complications (stiffness, re-tear) was evaluated based on a fixed or random effects model. RESULTS: Eleven high-quality randomized controlled studies were included. Compared with brace fixation, early exercise improved the range of motion of the subjects' shoulders. Compared with brace fixation, shoulder flexion (WMD of 6 weeks = 10.57, 95% CI: 1.30, 19.84, WMD of 3 months = 12.39, 95% CI: 7.51, 17.27, WMD of 6 months = 2.88, 95% CI: 1.02, 4.73, WMD of 1 year = 2.59, 95% CI: 0.40, 4.77) and shoulder abduction (WMD of 6 weeks = 13.17, 95% CI: 9.80, 16.55, respectively). The improvement degree of WMD = 2.28 in 6 months and internal rotation (WMD = 5.08, 95% CI: 3.16, 7.01, in 6 weeks and WMD = 8.23, 95% CI: 4.23, 12.23, in 3 months) was statistically different. Early exercise also reduced the risk of postoperative stiffness (RR = 0.34; 95%CI:0.19, 0.60). However, compared with brace fixation, there was no statistical difference in pain score (WMD = 0.05, 95% CI:0.09, 0.18) and shoulder joint recovery score (SMD = 0.05, 95% CI: 0.12, 0.03). CONCLUSION: Early exercise can improve the range of motion of early shoulder joint and reduce the risk of postoperative stiffness, but the effect of pain and function improvement is not obvious, which can play a positive role in postoperative rehabilitation of patients, but it needs more comprehensive research and improvement to guide clinical practice. | BMC musculoskeletal disorders | 13/03/2025 |
('LID', '10.1016/j.jare.2025.03.018') | SAMD4A inhibits abdominal aortic aneurysm development and VSMC phenotypic transformation through targeting KDM2B. | Chen, Qing, Liu, Shenrong, Zhou, Haobin, Wang, Junfen, Xiao, Xiaoyong, Chen, Guojun, Du, Juan, Zhong, Lintao, Song, Haoyu, Huang, Xianying | INTRODUCTION: Abdominal aortic aneurysm (AAA) is a fatal vascular disease without effective drug treatments. Pathological vascular smooth muscle cell (VSMC) phenotypic transformation is the underlying cause of AAA. However, the underlying mechanism has not been fully elucidated. OBJECTIVE: We aimed to determine whether the RNA binding protein SAMD4A suppresses VSMC phenotype transformation and inhibits AAA formation. METHODS: Single-cell RNA sequencing (scRNA-seq) was conducted to reveal smooth muscle cell phenotypic heterogeneity and RNA-binding protein dysregulation during AAA formation. A pancreatic elastase (PPE)-induced mouse AAA model was generated to confirm the function of SAMD4A in vivo. RNA-seq combined with RNA immunoprecipitation (RIP) sequencing and chromatin immunoprecipitation (ChIP)-qPCR was used for mechanistic exploration. RESULTS: We identified 3 smooth muscle cell subtypes, and demonstrated their transformation from contractile to inflammatory-like VSMCs during AAA formation. SAMD4A expression was increased in contractile VSMCs and significantly reduced in AAAs. The results of functional experiments revealed that VSMC-specific knockout of SAMD4A exacerbated PPE-induced AAA formation, whereas VSMC knock-in attenuated AAA formation. SAMD4A regulated VSMC contraction by binding to KDM2B. Further in vivo studies revealed that overexpression of KDM2B abolished the protective effect of SAMD4A in AAA. ChIP-qPCR demonstrated that KDM2B suppressed the transcription of VSMC contractile markers by binding to their promoters and reducing H3K4me3 and H3K36me2 levels. CONCLUSIONS: SAMD4A inhibits AAA development and VSMC phenotypic transformation by targeting KDM2B. This work highlights the potential of SAMD4A as a new therapeutic option to prevent AAA formation. | Journal of advanced research | 11/03/2025 |
('LID', '10.1093/brain/awac416') | Reduced grid-like theta modulation in schizophrenia. | Convertino, Laura, Bush, Daniel, Zheng, Fanfan, Adams, Rick A, Burgess, Neil | The hippocampal formation has been implicated in the pathophysiology of schizophrenia, with patients showing impairments in spatial and relational cognition, structural changes in entorhinal cortex and reduced theta coherence with medial prefrontal cortex. Both the entorhinal cortex and medial prefrontal cortex exhibit a 6-fold (or 'hexadirectional') modulation of neural activity during virtual navigation that is indicative of grid cell populations and associated with accurate spatial navigation. Here, we examined whether these grid-like patterns are disrupted in schizophrenia. We asked 17 participants with diagnoses of schizophrenia and 23 controls (matched for age, sex and IQ) to perform a virtual reality spatial navigation task during magnetoencephalography. The control group showed stronger 4-10 Hz theta power during movement onset, as well as hexadirectional modulation of theta band oscillatory activity in the right entorhinal cortex whose directional stability across trials correlated with navigational accuracy. This hexadirectional modulation was absent in schizophrenia patients, with a significant difference between groups. These results suggest that impairments in spatial and relational cognition associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex. | Brain : a journal of neurology | 02/05/2023 |
('LID', '10.1007/s40257-025-00931-1') | Long-Term Disease Control and Minimal Disease Activity of Head and Neck Atopic Dermatitis in Patients Treated with Tralokinumab up to 4 Years. | Chovatiya, Raj, Ribero, Simone, Wollenberg, Andreas, Park, Chang Ook, Silvestre, Juan Francisco, Hong, H Chih-Ho, Seneschal, Julien, Saeki, Hidehisa, Thyssen, Jacob P, Øland, Christian Bjerregård, Gjerum, Le, Maslin, Douglas, Blauvelt, Andrew | BACKGROUND AND OBJECTIVE: There is a need for long-term atopic dermatitis (AD) treatments that can effectively improve AD involvement of the head and neck (H&N) region (referred to as H&N AD). Tralokinumab, a high-affinity monoclonal antibody that neutralizes interleukin-13, is approved for the treatment of moderate-to-severe AD. Recent real-world studies have observed the effectiveness of tralokinumab for H&N AD. Here, data from phase III parent trials, ECZTRA 1 and ECZTRA 2, and the long-term extension trial, ECZTEND, were used to assess impacts of long-term tralokinumab treatment on H&N AD and the association between improvements in H&N AD and patient quality of life, and to evaluate whether a proportion of patients developed paradoxical H&N erythema. METHODS: These post hoc analyses included data from all patients initiated on tralokinumab in ECZTRA 1 or ECZTRA 2. Patients were treated up to 4 years (i.e., up to 52 weeks in ECZTRA 1 or ECZTRA 2 plus up to 152 weeks in ECZTEND). Outcomes included body region subscores of the Eczema Area and Severity Index (EASI; H&N, upper limbs, trunk, lower limbs) and the Dermatology Life Quality Index (DLQI). Correlations between H&N EASI and DLQI were assessed with Spearman's correlation coefficient (ρ). The incidence of paradoxical H&N erythema (defined as H&N EASI erythema increasing from baseline to a score of 3, while all other regional EASI subscores are 0 or 1, during two or more consecutive visits) was also assessed. RESULTS: Overall, 1192 patients who were initiated on tralokinumab in ECZTRA 1 and ECZTRA 2, of whom 523 patients opted to continue in ECZTEND, were analyzed. Percentages of patients who had H&N EASI ≤ 1 increased from 12.2% at parent trial baseline to 87.2% by week 152 of ECZTEND. Improvements in EASI subscore outcomes from parent trial baseline were comparable across body regions throughout all timepoints of the study. At parent trial week 16, H&N EASI was moderately correlated with total DLQI (ρ = 0.47), with the strongest numerical correlations observed for DLQI questions regarding skin discomfort (ρ = 0.43) and embarrassment due to skin (ρ = 0.40). During up to 4 years of treatment, seven tralokinumab-treated patients exhibited paradoxical H&N erythema, five of whom improved to absent or mild H&N EASI erythema with continued tralokinumab treatment. CONCLUSIONS: Tralokinumab provided progressive and sustained improvements in H&N AD, with H&N EASI 0/1 observed in nearly 90% of patients treated up to 4 years. Improvements in H&N EASI were similar to improvements observed for other body regions and were associated with improvements in patient quality of life, particularly for skin discomfort and self-consciousness/embarrassment due to skin. CLINICAL TRIAL REGISTRATION: NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. NCT03587805 (ECZTEND); study start date: 18 March, 2018; data cut-off date: 30 April, 2022; primary completion date: 3 July, 2024; study completion date: 3 July, 2024. | American journal of clinical dermatology | 14/03/2025 |
('LID', '10.1186/s12943-025-02256-3') | Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers. | Hyeon, Do Young, Nam, Dowoon, Shin, Hye-Jin, Jeong, Juhee, Jung, Eunsoo, Cho, Soo Young, Shin, Dong Hoon, Ku, Ja-Lok, Baek, Hye Jung, Yoo, Chong Woo, Hong, Eun-Kyung, Lim, Myong Cheol, Lee, Sang-Jin, Bae, Young-Ki, Kim, Jong Kwang, Bae, Jingi, Choi, Wonyoung, Kim, Su-Jin, Back, Seunghoon, Kang, Chaewon, Madar, Inamul Hasan, Kim, Hokeun, Kim, Suhwan, Kim, Duk Ki, Kang, Jihyung, Park, Geon Woo, Park, Ki Seok, Shin, Yourae, Kim, Sang Soo, Jung, Keehoon, Hwang, Daehee, Lee, Sang-Won, Kim, Joo-Young | We report proteogenomic analysis of locally advanced cervical cancer (LACC). Exome-seq data revealed predominant alterations of keratinization-TP53 regulation and O-glycosylation-TP53 regulation axes in squamous and adeno-LACC, respectively, compared to in early-stage cervical cancer. Integrated clustering of mRNA, protein, and phosphorylation data identified six subtypes (Sub1-6) of LACC among which Sub3, 5, and 6 showed the treatment-resistant nature with poor local recurrence-free survival. Elevated immune and extracellular matrix (ECM) activation mediated by activated stroma (PDGFD and CXCL1(high) fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AC(high) epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10(high) ECs. We further demonstrated that CIC mutations could trigger EMT activation by upregulating ETV4, and the elevation of the immune checkpoint PVR and neutrophil-like myeloid-derived suppressive cells (FCN1 and FCGR3B(high) macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AC(high) ECs. These results provide a battery of somatic mutations, cellular pathways, and cellular players that can be used to predict treatment-resistant LACC subtypes and can serve as potential therapeutic targets for these LACC subtypes. | Molecular cancer | 14/03/2025 |
('LID', '10.1016/j.ecoenv.2025.118030') | Efficient evaluation of osteotoxicity and mechanisms of endocrine disrupting chemicals using network toxicology and molecular docking approaches: triclosan as a model compound. | Wang, Zhongyuan, Wang, Jian, Fu, Qiang, Zhao, Hui, Wang, Zaijun, Gao, Yuzhong | This study aimed to demonstrate the utility of a network toxicology strategy in elucidating osteotoxicity and the molecular mechanisms of endocrine-disrupting chemicals (EDCs) using triclosan exposure in postmenopausal osteoporosis (PMOP) as a case study. The potential targets of triclosan were identified using the Comparative Toxicogenomics Database, SwissTargetPrediction, and TargetNet. PMOP-related targets were obtained from GeneCards, DisGeNET, and DrugBank. A total of 478 overlapping genes between disease targets and triclosan effectors were identified. Subsequent analysis using STRING and Cytoscape, applying the Matthews correlation coefficient algorithm, identified five core genes: STAT3, TP53, EGFR, MYC, and JUN. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses performed using R revealed that triclosan-induced PMOP is primarily associated with disrupted endocrine signaling and activation of the Phosphoinositide 3-kinase (PI3K)-Protein kinase B (Akt) signaling pathway. Molecular docking using CB-Dock2 confirmed strong binding affinities between triclosan and the core targets. Collectively, these results indicate that triclosan adversely affects bone health by disrupting endocrine regulation and energy metabolism through the PI3K-Akt pathway. This study establishes a theoretical framework for understanding how long-term triclosan exposure induces or exacerbates PMOP by investigating the underlying molecular mechanisms. These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants. | Ecotoxicology and environmental safety | 11/03/2025 |
('LID', '10.1016/j.pnpbp.2025.111317') | Integrated genetic analysis and single cell-RNA sequencing for brain image-derived phenotypes and Parkinson's disease. | Pan, Lin, Yang, Laiyu, Ding, Weijie, Hu, Yongfei, Yang, Wenzhuo, Wang, Jingning, Zhang, Zhiyun, Fan, Kangli, Sun, Zhihui, Liang, Yue, Lin, Xiaoyue, Chen, Jun, Zhang, Ying | BACKGROUND: Previous studies have reported Parkinson's disease (PD) patients usually have changes in brain image-derived phenotypes (IDPs). However, the role of genetic factors in their association and biological mechanism remains unclear. We aimed to unveil genetic and biological links between brain IDPs and PD. METHODS: Using genome-wide association study (GWAS) summary statistics and single-cell RNA sequencing (scRNA-seq) data, we performed a comprehensive analysis between 624 brain IDPs and PD. The genetic correlations and causality were examined by linkage disequilibrium score regression (LDSC), two-sample bidirectional Mendelian randomization (MR) and meta-analysis. Potential shared genes were identified using MAGMA and PLACO. Finally, pathway enrichment using FUMA and Metascape, and scRNA-seq analysis were performed to determine biological mechanisms and gene expression atlas across various cell types in brain tissue. RESULTS: LDSC revealed that 50 brain IDPs were genetically correlated with PD (P < 0.05), in which 5 IDPs, exhibited putative causality on PD through MR (P < 0.05). For instance, we identified that the increased volume of the right thalamus (IVW: OR = 2.08, 95 % CI: 1.33 to 3.25, PFDR = 0.03) was positively correlated with the risk of PD, which was also supported by replicated MR (IVW: OR = 1.63, 95 % CI: 1.17-2.26, PFDR = 0.02) in FinnGen and meta-analysis (OR = 1.78, 95 % CI: 1.36-2.31, PFDR = 5.00 × 10(-4)). Additionally, we identified 56 unique pleiotropic genes, such as FAM13A, with notable enrichment in neuronal cells. Biological mechanism analysis revealed these genes were enriched in brain tissues and a variety of pathways such as negative regulation of neuron apoptotic processes. CONCLUSION: We indicated the shared genetic architecture and biological mechanisms between brain IDPs and PD. These findings might provide insights on the therapeutic intervention and early prediction of PD at the brain imaging level. | Progress in neuro-psychopharmacology & biological psychiatry | 11/03/2025 |
('LID', '10.1186/s40337-023-00897-7') | The validity of the Czech version of Body Appreciation Scale-2 for adolescents. | Kvardova, Nikol, Lacko, David, Machackova, Hana | BACKGROUND: Understanding the formation of body image is critical for the prevention and treatment of eating disorders, especially in adolescence, when body image develops significantly. One of the important facets of body image is body appreciation, which consists of positive feelings and attitudes towards the body regardless of its perceived "flaws". To measure body appreciation, Body Appreciation Scale-2 (Tylka and Wood-Barcalow in Body Image 12:53-67, 2015a), a unidimensional 10-item measure, has been developed and routinely used in body image research. The current study examined the validity (i.e., factor structure, gender and age invariance, associations with other constructs) of the Czech version of Body Appreciation Scale-2 for adolescents. METHODS: The study used two large samples of Czech adolescents, aged 13-18 (N(1) = 613, M = 15.5, 52% girls; N(2) = 1,530, M = 15.4, 50% girls). The data were collected in August 2021 (N(1)) and November 2020 (N(2)) through an online survey. For the data analysis, we used confirmatory factor analysis (CFA), multi-group confirmatory factor analysis (MG-CFA), and Structural Equation Modeling (SEM). RESULTS: Our findings supported the proposed unidimensional factor structure and the gender (i.e., girls, boys) and age (i.e., 13-15, 16-18) scalar invariance of the Czech version of Body Appreciation Scale-2. The data also showed the expected positive correlations with body satisfaction and self-esteem, and negative correlations with media-ideal internalization, appearance schematicity, and depression. Furthermore, we discovered that body appreciation was more strongly connected to media-ideal internalization and depression for girls than boys. CONCLUSIONS: The present study provided robust evidence that supports the validity of the Czech version of Body Appreciation Scale-2 and its usability for the assessment of body appreciation in Czech adolescents. We also proposed future directions for the research on body appreciation based on the explored gender differences. | Journal of eating disorders | 05/10/2023 |
('LID', '10.1002/jcb.70010') | Effects of Melatonin on the Expression of Invasion-Related Markers (MMP2 and MMP9) in Breast Cancer Cells. | Ghadimi, Parvin, Ghorbian, Saeid | Breast cancer is one of the most common types of cancer in women, and metastasis is a leading cause of mortality in patients with this disease. This study investigated the effects of melatonin, a natural hormone, on the migration of cancer cells in two cell lines, MCF-7 and MDA-MB-231. MCF-7 and MDA-MB-231 cells were cultured in their respective media. The effective dose of melatonin in each cell line was determined using the MTT assay. The effects of IC50 melatonin on cell migration were assessed using the wound-healing assay. The expression of the invasion-related genes (MMP2 and MMP9), as well as the melatonin receptors MT1 and MT2, was analyzed using Real-Time RT-PCR. The wound-healing assay results indicated that 48 h of melatonin treatment at doses of 2.5 and 3.5 M significantly reduced migration in MCF-7 and MDA-MB-231 cells. In addition, melatonin treatment decreased the invasion-related markers of both cell lines. Melatonin also increased the expression of MT1 and MT2 receptors in both cell lines, and the expression of MMP2 and MMP9 was significantly reduced by melatonin (p < 0.05). Our results indicate that melatonin, a naturally occurring compound, possesses the potential to inhibit the movement and spread of breast cancer cells by elevating the levels of MT1 and MT2 receptors, resulting in a reduction of matrix metalloproteinases 2 and 9 expression. | Journal of cellular biochemistry | 00/03/2025 |
('LID', '10.1126/scitranslmed.adp2124') | Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models. | Hu, Xingyuan, Kang, Xiaoyan, Zhao, Faming, Cui, Yaoyuan, Fu, Yu, Yang, Xiaohang, Yin, Jingjing, Li, Wenting, Fan, Junpeng, Yang, Bin, Fang, Zixuan, Qin, Tianyu, Zhuang, Xucui, Liu, Yiting, Feng, Chenzhao, Yang, Yunyi, Lu, Funian, Zhang, Li, Chen, Weihao, Wu, Miaofang, Du, Ning, Sheng, Xia, Zhou, Xin, Li, Jing, Chen, Gang, Sun, Chaoyang | The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition-activated tumor cells and matrix metallopeptidase 11 (MMP-11)(+) cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer. | Science translational medicine | 12/03/2025 |
('LID', '10.1053/j.gastro.2025.02.032') | Evolution of Esophageal Adenocarcinoma from Precursor Lesion Stem Cells. | Xian, Wa, Wang, Shan, Xie, Jingzhong, Yamamoto, Yusuke, Khorrami, Melina, Zhang, Yanting, Montes, Raul Caballero, Desales, Caycel, Khorrami, Melika, Mory, Zaal, Hoffman, Ashley, Su, Amber, Nguyen, Crystal, Davies, Peter J A, Stephan, Clifford, Pan, Shuang, Wu, Wengen, Liu, Yuxin, Siegelman, Jeremy, Waters, Rebecca E, Ross, William A, Song, Shumei, Metersky, Mark, Beer, David G, Crum, Christopher P, Stewart, Alexander J, Vincent, Matthew, Russell, Richard, Izard, Robert A, Ho, Khek Yu, Lai, Jack Hung-Sen, Bachovchin, William W, Ajani, Jaffer A, McKeon, Frank D | BACKGROUND AND AIMS: Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), co-exist in an accessible, two-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC. METHODS: Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1,000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics. RESULTS: Each of the lesions in the evolution of EAC possess a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveal intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LDG, HGD, and EAC. CONCLUSIONS: All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets. | Gastroenterology | 14/03/2025 |
('LID', '10.1016/j.cell.2025.02.002') | Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization. | Chang, Zhiguang, Guo, Xuan, Li, Xuefei, Wang, Yan, Zang, Zhongsheng, Pei, Siyu, Lu, Weiqi, Li, Yang, Huang, Jian-Dong, Xiao, Yichuan, Liu, Chenli | Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10R(hi) state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8(+) T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10R(hi) state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy's dual challenge in solid tumors and provides a framework for intratumoral immunomodulation. | Cell | 20/02/2025 |
('LID', '10.1016/j.autrev.2025.103801') | Association between breastfeeding and the risk of autoimmune diseases: A systematic review and meta-analysis. | Li, Wen-Jie, Gao, Yue-Can, Hu, Xiao, Tan, Yu-Tong, Deng, Jia-Jun, Pan, Hai-Feng, Tao, Sha-Sha | OBJECTIVES: Previous studies on the association between breastfeeding and autoimmune diseases risk have yielded inconsistent findings. This study employed a systematic review and meta-analysis to explore the effect of breastfeeding and its duration against autoimmune diseases. METHODS: Six databases (PubMed, Web of Science, Embase, CINAHL, Cochrane Library, PsycINFO) were systematically searched from inception to September 24, 2024. Studies on the association between breastfeeding and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), multiple sclerosis (MS) and type 1 diabetes mellitus (T1D) published within this period were included. Dichotomous outcome data from multiple studies were subjected to a random-effects meta-analysis using the Mantel-Haenszel method to estimate the pooled effect size. The Newcastle-Ottawa Scale was employed to evaluate quality. RESULTS: Of the 40 included studies (35 case-control studies and 5 cohort studies), 12 were stratified by the duration of breastfeeding. The combined effect showed a protective association between breastfeeding and a reduced risk of autoimmune diseases (OR = 0.80; 95 %CI: 0.72 to 0.89; P < 0.001). This protective effect was significant for RA (OR = 0.66; 95 %CI: 0.46 to 0.93; P = 0.018), MS (OR = 0.78; 95 % CI: 0.63 to 0.98; P = 0.030) and T1D (OR = 0.80; 95 %CI: 0.66 to 0.98; P = 0.028), and was more pronounced with breastfeeding duration of at least four months (OR = 0.81; 95 %CI: 0.72 to 0.90; P < 0.001). CONCLUSION: Breastfeeding provides an overall protective effect against autoimmune diseases and a significant protective effect on RA, MS and T1D. This protective effect appears stronger with breastfeeding duration of at least 4 months. These results highlight the necessity of promoting breastfeeding and supporting related policies to improve infant health. | Autoimmunity reviews | 11/03/2025 |
('LID', '10.1001/jama.2025.1483') | Atezolizumab in High-Risk Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial. | Haddad, Robert, Fayette, Jérôme, Teixeira, Maria, Prabhash, Kumar, Mesia, Ricard, Kawecki, Andrzej, Dechaphunkul, Arunee, Dinis, José, Guo, Ye, Masuda, Muneyuki, Hsieh, Ching-Yun, Ghi, Maria Grazia, Vaz de Melo Sette, Claudia, Harrington, Kevin, Tahara, Makoto, Saba, Nabil F, Lau, Agnes, Jiang, Tao, Yan, Yibing, Ballinger, Marcus, Kaul, Monika, Matheny, Christina, Cuchelkar, Vaikunth, Wong, Deborah J | IMPORTANCE: Treating locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) involves any combination of surgery, radiation, and chemotherapy, followed by routine monitoring for local recurrence or distant metastases. Given the poor patient outcomes, a significant unmet clinical need for improved treatment options remains. OBJECTIVE: To evaluate efficacy and safety of maintenance atezolizumab in patients with LA SCCHN at high risk of disease progression after multimodal definitive treatment. DESIGN, SETTING, AND PARTICIPANTS: IMvoke010 was a phase 3, global, double-blind, randomized clinical trial. Patients were recruited at 128 sites in 23 countries between April 3, 2018, and February 14, 2020 (clinical cutoff date: September 27, 2023). Eligible patients had LA SCCHN (stage IVa/IVb involving the oral cavity, larynx, hypopharynx, or human papillomavirus-negative oropharynx, or stage III human papillomavirus-positive oropharynx [AJCC Cancer Staging Manual, eighth edition]) without disease progression after multimodal definitive treatment. INTERVENTION: Patients were randomized (1:1) to receive atezolizumab 1200 mg or placebo every 3 weeks for 1 year or until disease recurrence, disease progression, unacceptable toxicity, or consent withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed event-free survival. Other end points included overall survival and safety. RESULTS: Overall, 406 patients were randomized to receive atezolizumab (n = 203) or placebo (n = 203); baseline demographics were balanced between both treatment groups (<65 years, 142 [70.0%] vs 155 [76.4%]; male, 168 [82.8%] vs 174 [85.7%]; Asian, 68 [35.6%] vs 61 [31.0%]; Black, 1 [0.5%] vs 1 [0.5%]; and White, 121 [63.4%] vs 135 [68.5%], respectively). At clinical cutoff (median follow-up, 46.5 months), median investigator-assessed event-free survival was 59.5 months (95% CI, 46.8 to not estimable) with atezolizumab vs 52.7 months (95% CI, 41.4 to not estimable) with placebo (hazard ratio, 0.94; 95% CI, 0.70-1.26; P = .68). There was no difference in overall survival between atezolizumab and placebo (24-month overall survival, 82.0% vs 79.2%, respectively). No new or unexpected safety signals were identified. CONCLUSIONS AND RELEVANCE: In this study, atezolizumab did not improve clinical outcomes in patients with LA SCCHN at high risk of disease progression after multimodal definitive treatment. These data contribute to evidence on the limited activity of checkpoint inhibitors in the global population of this disease setting. Overall, the role of immunotherapy for patients with LA SCCHN remains to be determined. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03452137. | JAMA | 13/03/2025 |
('LID', '10.1016/j.molcel.2025.02.011') | The role of protein lactylation: A kaleidoscopic post-translational modification in cancer. | Iozzo, Marta, Pardella, Elisa, Giannoni, Elisa, Chiarugi, Paola | The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment. | Molecular cell | 05/03/2025 |
('LID', '10.1182/blood.2024027109') | Efficacy of Combined CD38 and PD1 Inhibition with Isatuximab and Cemiplimab for Relapsed/Refractory NK/T-Cell Lymphoma. | Kim, Seok Jin, Lim, Jing Quan, Yoon, Sang Eun, Yang, Deok-Hwan, Lee, Ji Hyun, Oh, Sung Yong, Choi, Yoon Seok, Jeong, Seong Hyun, Kim, Min Kyoung, Lim, Sung-Nam, Cho, Junhun, Park, Bon, Ryu, Kyung Ju, Choi, Seunghyun, Park, Yoon, Lim, Kerry May Huifen, Binte Muhammad Taib, Nur Ayuni, Ong, Choon Kiat, Lim, Soon Thye, Kim, Won Seog | This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-PD1 antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL). The hypothesis was that CD38 blockade could enhance the antitumor activity of PD1 inhibitors. Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) intravenously every four weeks for six cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every three weeks for up to 24 months. The primary endpoint was the complete response (CR) rate based on the best response. Out of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary endpoint of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% CI: 25.6-34.8 months), the median progression-free survival was 9.5 months (95% CI: 1.4-17.6 months), while the median overall survival had not yet been reached. Patients achieving CR received a median of 28 cycles (range: 4-33), and the median duration of response for responders (n = 24) was 29.4 months (95% CI: 15.4-43.4 months). Structural variations disrupting the 3'-UTR of PD-L1 and high PD-L1 expression were observed in responders. Most adverse events were mild (grade 1-2), with grade ≥3 events (32%) and no treatment-related deaths. The combination of isatuximab and cemiplimab demonstrated sustained antitumor activity and a manageable safety profile in R/R ENKTL. This phase II trial is registered at www.clinicaltrials.gov as #NCT04763616. | Blood | 12/03/2025 |
('LID', '10.1016/j.ymthe.2025.03.016') | Current and future treatments for sickle cell disease - from hematopoietic stem cell transplantation to in vivo gene therapy. | Ball, Julia, Bradley, Avery, Le, Anh, Tisdale, John F, Uchida, Naoya | Sickle cell disease (SCD) is a single-gene disorder caused by a point mutation of the β-globin gene, resulting in hemolytic anemia, acute pain, multiorgan damage, and early mortality. Hydroxyurea is a first-line drug therapy that switches sickle-globin to non-pathogenic γ-globin; however, it requires lifelong oral administration. Allogeneic hematopoietic stem cell (HSC) transplantation allows for a one-time cure for SCD, albeit with histocompatibility limitations. Therefore, autologous HSC gene therapy was developed to cure SCD in a single treatment, without HSC donors. Current HSC gene therapy is based on the ex vivo culture of patients' HSCs with lentiviral gene addition and gene editing, followed by autologous transplantation back to the patient. However, the complexity of the treatment process and high costs hinder the universal application of ex vivo gene therapy. Therefore, the development of in vivo HSC gene therapy, where gene therapy tools are directly administered to patients, is desirable to provide a more accessible, cost-effective solution that can cure SCD worldwide. In this review, we discuss current treatments including drug therapies, HSC transplantation, and ex vivo gene therapy, the development of gene therapy tools, and progress toward curative in vivo gene therapy in SCD. | Molecular therapy : the journal of the American Society of Gene Therapy | 12/03/2025 |
('LID', '10.1186/s12890-025-03557-5') | Nonlinear association between blood urea nitrogen to creatinine ratio and obstructive sleep apnea: a cross-sectional study from NHANES. | Yang, Lei, Li, Lanying, Zeng, TingTing, Li, Yang, Li, Yating, Jiang, DePeng, Yue, Hongmei | BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder that is closely associated with metabolic conditions. The Blood Urea Nitrogen to Creatinine Ratio(BUCR) is commonly utilized as a tool for evaluating renal function, particularly in cases where there are concerns about pre-renal or renal causes of azotemia. However, the connection between OSA and BUCR is not yet fully understood. METHODS: This study examined the link between BUCR and OSA in adults over 20 using National Health and Nutrition Examination Surveys(NHANES) data from 2005-2008. Logistic regression models adjusted for multiple variables were used to analyze the relationship. The non-direct correspondence relationship were explored with a smooth curve and a two-part linear regression model, which revealed a threshold effect. Subgroup analyses were conducted to assess variations among different populations. RESULTS: The survey, encompassing a total of 8826 participants, revealed that the median age of all respondents was 48 years, with a notable OSA prevalence of 51.3%. Upon adjusting for pertinent covariates using Model III(age, sex, marital status, education level, BMI, smoking status, drinking, hypertension, and diabetes), our findings indicated a significant association between OSA and BUCR, as evidenced by an odds ratio (OR) of 1.01 (95% CI: 1.00-1.02, P = 0.005). Furthermore, the risk association was found to be non-linear, featuring an inflection point for BUNR at 10.86. This non-linear relationship adds complexity to our understanding of the interplay between OSA and BUCR. In addition, a subgroup analysis underscored the influence of diabetes on the association between BUCR and OSA. CONCLUSION: This study reveals a significant correlation between elevated BUCR levels and the incidence of OSA, particularly in the presence of diabetes. This discovery underscores the necessity for additional research to investigate the underlying mechanisms and ramifications of this connection within the diabetic context. | BMC pulmonary medicine | 13/03/2025 |
('LID', '10.1038/s41420-025-02381-4') | Lactylation: a promising therapeutic target in ischemia-reperfusion injury management. | Wang, Fei-Xiang, Mu, Guo, Yu, Zi-Hang, Shi, Zu-An, Li, Xue-Xin, Fan, Xin, Chen, Ye, Zhou, Jun | Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer's disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI. | Cell death discovery | 13/03/2025 |
('LID', '10.1002/advs.202415563') | Homocysteine Promotes the Pathogenesis of Atherosclerosis through the Circ-PIAS1-5/miR-219a-2-3p/TEAD1 Axis. | Ma, Shengchao, Ma, Fei, Ding, Ning, Xie, Lin, Yang, Anning, Shen, Jiangyong, Jiao, Yun, Wu, Kai, Chai, YueE, Bai, Zhigang, Xiong, Jiantuan, Li, Nan, Zhang, Huiping, Jiang, Yideng | Previous studies have established a possible link between hyperhomocysteinemia (HHcy) and dyslipidemia. Circular RNAs (circRNAs) play important regulatory roles in the development of atherosclerosis. However, the biological functions and potential molecular mechanisms of circRNAs in HHcy-induced lipid accumulation leading to atherosclerosis are still unclear. In this study, it is determined that homocysteine (Hcy) downregulates the expression of circ-PIAS1-5 by global circRNA expression profiling and that circ-PIAS1-5 inhibits Hcy-mediated lipid accumulation in foam cells and the pathogenesis of atherosclerosis by acting as a sponge for miR-219a-2-3p. Circ-PIAS1-5 is identified as a potential diagnostic biomarker of HHcy-associated atherosclerosis in male "apolipoprotein E knockout (ApoE(-/-))" mice. Mechanistically, circ-PIAS1-5 activates the adenosine 5'-monophosphate (AMP)-activated protein kinase pathway by regulating TEAD1 through miR-219a-2-3p, and Hcy mediates the m(6)A modification and nuclear export of circ-PIAS1-5 via YTHDC1 to increase lipid accumulation in foam cells and accelerate the pathogenesis of atherosclerosis. Taken together, these results highlight the role of circ-PIAS1-5 in the Hcy-mediated pathogenesis of atherosclerosis and suggest its potential application as a prognostic biomarker of atherosclerosis induced by HHcy. | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 16/03/2025 |
('LID', '10.1016/S2213-2600(20)30407-0') | Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19. | Dhawan, Ranju T, Gopalan, Deepa, Howard, Luke, Vicente, Angelito, Park, Mirae, Manalan, Kavina, Wallner, Ingrid, Marsden, Peter, Dave, Surendra, Branley, Howard, Russell, Georgina, Dharmarajah, Nishanth, Kon, Onn M | A compelling body of evidence points to pulmonary thrombosis and thromboembolism as a key feature of COVID-19. As the pandemic spread across the globe over the past few months, a timely call to arms was issued by a team of clinicians to consider the prospect of long-lasting pulmonary fibrotic damage and plan for structured follow-up. However, the component of post-thrombotic sequelae has been less widely considered. Although the long-term outcomes of COVID-19 are not known, should pulmonary vascular sequelae prove to be clinically significant, these have the potential to become a public health problem. In this Personal View, we propose a proactive follow-up strategy to evaluate residual clot burden, small vessel injury, and potential haemodynamic sequelae. A nuanced and physiological approach to follow-up imaging that looks beyond the clot, at the state of perfusion of lung tissue, is proposed as a key triage tool, with the potential to inform therapeutic strategies. | The Lancet. Respiratory medicine | 00/01/2021 |
('LID', '10.1016/j.jacc.2024.11.042') | Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy. | Judge, Daniel P, Alexander, Kevin M, Cappelli, Francesco, Fontana, Marianna, Garcia-Pavia, Pablo, Gibbs, Simon D J, Grogan, Martha, Hanna, Mazen, Masri, Ahmad, Maurer, Mathew S, Obici, Laura, Soman, Prem, Cao, Xiaofan, Lystig, Ted, Tamby, Jean-François, Siddhanti, Suresh, Castaño, Adam, Katz, Leonid, Fox, Jonathan C, Mahaffey, Kenneth W, Gillmore, Julian D | BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. In a phase 3, randomized, double-blind study (ATTRibute-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]), acoramidis was well tolerated and showed clinical efficacy in improving the primary endpoint, a hierarchical combination of all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal pro-B-type natriuretic peptide level, and 6-minute walk distance. OBJECTIVES: The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH. METHODS: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to receive acoramidis hydrochloride (800 mg twice daily) or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population (participants with a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m(2)). CVH and the composite of ACM or first CVH were plotted by using Kaplan-Meier curves and summarized with a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed by using a negative binomial regression model. Subgroup analyses were conducted for the composite of ACM or first CVH. RESULTS: Of the 632 participants randomized to treatment, 611 (97%) were included in efficacy analyses (acoramidis, n = 409; placebo, n = 202). Compared with placebo, acoramidis reduced the occurrence of the composite of ACM or first CVH (acoramidis, 35.9%; placebo, 50.5%; HR: 0.64; 95% CI: 0.50-0.83; P = 0.0008) and of first CVH (acoramidis, 26.7%; placebo, 42.6%; HR: 0.60; 95% CI: 0.45-0.80; P = 0.0005), with Kaplan-Meier curves separating at month 3 and continuing to diverge through month 30. Annualized frequency of CVH was reduced with acoramidis compared with placebo (acoramidis, 0.22; placebo, 0.45; relative risk ratio: 50%; 95% CI: 0.36-0.70; P < 0.0001). The efficacy of acoramidis on the composite of ACM or first CVH was consistent across subgroups. Acoramidis was well tolerated, with no safety signals of potential clinical concern identified. CONCLUSIONS: In participants with ATTR-CM, acoramidis reduced the composite of ACM or first CVH vs placebo, with an early effect driven by a reduction in CVH. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935). | Journal of the American College of Cardiology | 18/03/2025 |
('LID', '10.1016/j.lfs.2025.123559') | Type I interferon protects against bone loss in periodontitis by mitigating an interleukin (IL)-17-neutrophil axis. | Zhang, Jinmei, Ding, Qiong, Wang, Angela X, Lin, Maoxuan, Yu, Ning, Moss, Kevin, Williamson, Megumi A, Miao, Di, Marchesan, Julie T, Zeng, Erliang, Shi, Wei, Sun, Hongli, Lei, Yu Leo, Zhang, Shaoping | Type I interferons (IFNs-I), a group of pleiotropic cytokines, critically modulate host response in various inflammatory diseases. However, the role of the IFN-I pathway in periodontitis remains largely unknown. In this report, we describe that the IFN-β levels in the gingival crevicular fluid of human subjects were negatively associated with periodontitis and clinical gingival inflammation. Disruption of IFN-I signaling worsened alveolar bone resorption in a ligature-induced periodontitis murine model. Deficiency of the IFN-I pathway resulted in a more exaggerated inflammatory response in myeloid cells and drastically increased the interleukin-17 (IL-17)-mediated neutrophil recruitment in the gingiva. We further identified that the myeloid lineage-specific IFN-I response was essential in safeguarding against periodontal inflammation by suppressing the IL-17-producing γδ T cells in the gingiva. IFN-I signaling also directly repressed osteoclastogenesis in monocytes, which are precursor cells for osteoclasts. Therefore, our findings demonstrate that an integral myeloid-specific IFN-I pathway plays a protective role against bone loss by keeping the IL-17-neutrophil axis in check and directly inhibiting osteoclast formation in periodontitis. | Life sciences | 12/03/2025 |
('LID', '10.1038/s41467-025-56320-z') | HC-Pro inhibits HEN1 methyltransferase activity, leading to autophagic degradation of AGO1. | Pan, Zhao-Jun, Wei, Wei-Lun, Tran, Phuong-Anh, Fang, Ru-Ying, Pham, Thanh Ha, Bowman, John L, Chung, Chao-Tzu, Shen, Bing-Nan, Yang, Ju-Ting, Chang, Han-Han, Jane, Wann-Neng, Cheng, Chiung-Hsiang, Wang, Chia-Chi, Wu, Hsin-Yi, Hong, Syuan-Fei, Shang, Qian-Wen, Hu, Sin-Fen, Lin, Pin-Chun, Wu, Fu-Hui, Lin, Choun-Sea, Hung, Yu-Ling, Shen, Tang-Long, Lin, Shih-Shun | Helper-component proteinase (HC-Pro), encoded by potyviruses, function as viral suppressors of RNA silencing (VSRs). Despite their conserved role, HC-Pros share approximately 40% similarity, implying potential differences in VSR efficiency, particularly in their ability to inhibit HEN1 methyltransferase activity. This study investigated the inhibitory potential of HC-Pros from different potyviruses in transgenic plants. P1/HC-Pro from turnip mosaic virus (P1/HC-Pro(Tu)) exhibited the most potent inhibition of HEN1, followed by P1/HC-Pro from zucchini yellow mosaic virus (P1/HC-Pro(Zy)), while P1/HC-Pro from tobacco etch virus (P1/HC-Pro(Te)) showed the weakest inhibitory effect. These differential effectual effects corresponded to variations in unmethylated microRNAs (unMet-miRNAs) accumulation across the transgenic lines. Fluorescence resonance energy transfer (FRET) analysis indicated that HC-Pro(Tu) recruits HEN1 and ATG8a to HC-Pro bodies (H-bodies) and indirectly associates with AGO1, potentially influencing the assembly of the RNA-induced silencing complex (RISC) and leading to the accumulation of free-form miRNA duplexes. The ability of HC-Pro(Tu) to sequester HEN1 and AGO1 in H-bodies may, therefore, modulate miRNA loading. This observation aligns with the finding that P1/HC-Pro(Tu) plants harbored approximately 50% unMet-miRNAs and exhibited the lowest AGO1 levels, suggesting a positive correlation between HEN1 inhibition and autophagic degradation of AGO1. Interestingly, unMet-miRNAs are absent in the AGO1 of P1/HC-Pro(Tu) plants but reappeared in P1/HC-Pro(Tu)/hen1-8/heso1-1 plants, accompanied by signs of AGO1 recovery. These findings highlight the functional diversity of HC-Pro VSRs and provide new insights into their differential effects on miRNA methylation, RISC assembly, and the regulation of RNA silencing pathways. | Nature communications | 13/03/2025 |
('LID', '10.1111/cpr.70021') | Targeting FABP4 to Inhibit AGEs-RAGE/NF-κB Signalling Effectively Ameliorates Nucleus Pulposus Dysfunction and Angiogenesis in Obesity-Related Intervertebral Disc Degeneration. | Han, Lin, Li, Fudong, Wu, Huiqiao, Wang, Weiheng, Chen, Peiwen, Xia, Weicheng, Liu, Yang, Sun, Kaiqiang, Lin, Wenbo | Intervertebral disc degeneration (IVDD) is a primary contributor to low back pain, posing significant social and economic burdens. Increasing evidence shows that obesity contributes to IVDD, yet the underlying mechanisms remain elusive. Here, we firstly revealed a causal correlation between obesity and IVDD via a two-sample mendelian randomization analysis and identified fatty acid-binding protein 4 (FABP4) as the potential regulator to associate IVDD and obesity. Elevated FABP4 expression promoted extracellular matrix (ECM) disequilibrium and angiogenesis to exacerbate IVDD progression. Genetically knocking out or pharmacologically inhibiting FABP4 in high-fat diet-induced mice alleviated IVDD. Mechanistically, obesity activated the mammalian target of rapamycin complex 1 (mTORC1), which upregulated FABP4 expression, leading to the accumulation of advanced glycation end-products (AGEs) in intervertebral disc tissue. AGEs further activated the NF-κB signalling pathway, exacerbating ECM degradation and neovascularization. Conversely, rapamycin-mediated inhibition of mTORC1 suppressed FABP4 expression in nucleus pulposus cells (NPCs), alleviating IVDD in vivo. Collectively, our findings reveal a critical role of the obesity-induced mTORC1-FABP4 axis in ECM degradation and angiogenesis during IVDD progression. Targeting FABP4 may represent a promising therapeutic strategy for IVDD in obese individuals. | Cell proliferation | 16/03/2025 |
('LID', '10.1016/j.jmb.2025.169083') | Geraldine Seydoux. | Seydoux, Geraldine | I am the Huntington Sheldon Professor of Medical Discovery in the Department of Molecular Biology and Genetics in the School of Medicine at the Johns Hopkins University, where I have been running a lab for 30 years. Our research focusses on the molecular control of embryonic polarity and germline development, with an emphasis on asymmetric cell division and biomolecular condensates. We have uncovered mechanisms that localize proteins and RNAs in the cytoplasm by controlling protein diffusion and RNA condensation. My lab has also characterized a repressive program that launches the germline by inhibiting somatic gene expression in germline progenitors. | Journal of molecular biology | 12/03/2025 |
('LID', '10.1016/j.drup.2025.101226') | Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer. | Saleem, Muhammad Zubair, Huang, Ruyi, Huang, Yingying, Guo, Xin, Liu, Yang, Gao, Miao, Fan, Yinjuan, Chen, Zhe-Sheng, Ke, Zun-Fu, Ye, Shengnan, Xu, Jianhua | AIMS: TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1. METHODS: Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model. RESULTS: In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition. CONCLUSIONS: C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics. | Drug resistance updates : reviews and commentaries in antimicrobial and | 03/03/2025 |
('LID', '10.1016/j.ebiom.2025.105645') | The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice. | Hu, Bo, Yin, Mei-Yu, Zhang, Chu-Yi, Shi, Zhe, Wang, Lu, Lei, Xiaoming, Li, Ming, Li, Shi-Wu, Tuo, Qin-Hui | BACKGROUND: Chromosome 16p11.2 is one of the most significant loci in the genome-wide association studies (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies having been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. METHODS: We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed a murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of adeno-associated virus (AAV), followed by behavioural assessments, dendritic spine analyses and RNA sequencing. FINDINGS: We identified significant associations between elevated INO80E mRNA expression in the frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviours, including increased anxiety behaviour, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labelling assay showed that the density of stubby spines in the pyramidal neurons of mPFC was significantly increased in Ino80e-OE mice compared with control mice. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e. INTERPRETATION: Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviours in mice, further supporting the hypothesis that INO80E is an authentic risk gene. FUNDING: This project received support from the National Key Research and Development Program of China, National Natural Science Foundation of China, Key Research and Development Projects of Hunan Provincial Science and Technology Department, Science and Technology Innovation team of Hunan Province, etc. | EBioMedicine | 14/03/2025 |
('LID', '10.1007/s13668-025-00636-1') | Antioxidant Supplementation for Management of Gestational Diabetes Mellitus in Pregnancy: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. | van der Pligt, Paige, Wadley, Glenn D, Lee, I-Lynn, Ebrahimi, Sara, Spiteri, Sheree, Dennis, Kim, Mason, Shaun | PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy globally. Hyperglycaemia and associated production of reactive oxygen species can lead to oxidative stress in pregnancy. However, the potential effectiveness of increased antioxidant intake in the management of GDM has not been widely examined. Its usefulness alongside medical nutrition therapy (MNT) for assisting glycaemic control in women with GDM is poorly understood. This review aimed to establish the effect of antioxidant supplementation on the risk and management of gestational diabetes mellitus (GDM). RECENT FINDINGS: A systematic review of intervention studies was conducted based on PRISMA guidelines. Databases searched were MEDLINE, CINAHL, Global Health, Scopus, Embase and Cochrane until September 2024. Random effects meta-analyses using Cochrane Review Manager software to establish the effect of antioxidant supplementation on glucose outcomes in women with GDM were conducted. A total of 13 studies (1380 participants) were included in the review with four different antioxidants used (selenium (n = 3); alpha-lipoic (n = 4); zinc (n = 5); e-3-gallate (n = 1)). Significant pre-post differences between antioxidant supplementation and control groups were found for fasting insulin (SMD, 95%CI) (-0.97 [-1.69 -0.24]; p = 0.009, HOMA-IR (-0.90 [-1.25, -0.54]; p < 0.0000, HOMA-B (-0.86 [-1.05, -0.67]; p < 0.00001 and QUICKI (1.09 [0.32,1.87]; p = 0.005 Heterogeneity was substantial (I(2) > 50%, p < 0.05) for all models except for HOMA-B (I(2) = 0%, p > 0.05). Antioxidant supplementation has possible benefit as an adjunct therapy to current dietary management for women with GDM. Further clinical trials are needed to establish the preferred type and dosage of antioxidants likely to be effective. | Current nutrition reports | 14/03/2025 |
('LID', '10.1111/dom.16330') | Real-world use of tirzepatide among individuals without evidence of type 2 diabetes: Results from the Veradigm® database. | Hunter Gibble, Theresa, Chinthammit, Chanadda, Ward, Jennifer M, Cappell, Katherine, Sedgley, Robert, Bonafede, Machaon, Liao, Birong, Hankosky, Emily R | AIMS: To understand real-world tirzepatide use among individuals without type 2 diabetes (T2D) diagnoses in a US electronic health record (EHR) database. MATERIALS AND METHODS: This retrospective, descriptive, cohort study used Veradigm's® Network EHR database linked with administrative claims. Adults (≥18 years) included had ≥1 tirzepatide prescription (index period: 13 May 2022-31 August 2023); continuous medical and pharmacy enrolment for ≥12 months pre-index; and no T2D diagnosis or baseline T2D medications except metformin (overall cohort). 'Anti-obesity medication (AOM)-eligible cohort' included individuals with body mass index (BMI) ≥30 or ≥27 kg/m(2) and ≥1 obesity-related complication (ORC) and ≥6 months of continuous post-index enrollment. RESULTS: The overall cohort included 10,193 individuals (mean age: 45.0 years; female: 77.1%). Among 6623 individuals with BMI data, 5931 were AOM-eligible. Of these, 3470 had 6-month follow-up data (AOM-eligible cohort; ≥1 ORC: 76.5%; ≥2 ORCs: 51.8%). Treatment patterns at 6 months were assessed among 755 individuals with complete claims data in the AOM-eligible cohort. Most individuals (95.6%) were initiated on a tirzepatide dose of ≤5 mg. At the fifth prescription refill (n = 448), 91.1% were receiving tirzepatide doses of ≤10 mg. At 6 months, tirzepatide adherence was 55.5% and persistence was 54.2%. Among discontinued individuals (n = 346), 10.1% switched to an alternate AOM. CONCLUSIONS: Majority of individuals in the AOM-eligible cohort had ≥1 ORC, and half had ≥2 ORCs, indicating that in this study cohort tirzepatide was being used in people with multimorbidity. Tirzepatide dose escalation in this real-world cohort was slower than in clinical trials, which may have implications for its real-world effectiveness. | Diabetes, obesity & metabolism | 14/03/2025 |
('LID', '10.1016/j.inpsyc.2024.100012') | Correlation between changes in apathy and cognition in Alzheimer's disease associated apathy: Analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2). | Sankhe, Krushnaa, Tumati, Shankar, Perin, Jamie, Rivet, Luc, Vieira, Danielle, Rosenberg, Paul B, Herrmann, Nathan, Shade, David, Lerner, Alan J, Padala, Prasad R, Brawman-Mintzer, Olga, van Dyck, Christopher H, Porsteinsson, Anton P, Craft, Suzanne, Levey, Allan I, Mintzer, Jacobo, Lanctôt, Krista L | BACKGROUND: Previous trials have shown improvements in both apathy and cognition with methylphenidate (MPH). OBJECTIVES: To assess whether changes in apathy correlated with changes in cognition in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2). PARTICIPANTS: Mild to moderate AD patients with clinically significant apathy randomized to MPH (20 mg/day) or placebo for 6 months. MEASUREMENTS: Apathy was measured with the Neuropsychiatric Inventory-apathy (NPI-A) domain. Cognition was measured using the Mini-Mental State Exam (MMSE), Hopkins Verbal Learning (immediate [HVLT-I], delayed [HVLT-D] recall), Digit Span (Forward [DF], Backward [DB]), Trail Making (TMT-A, TMT-B), Action Verbal Fluency (AV), Category Fluency (CF), and the Short Boston Naming Test (BNT). DESIGN: Linear mixed models included cognitive change scores as dependent variables and time, treatment, change in NPI-A and the interaction between treatment and change in NPI-A as independent variables, which were additionally adjusted for baseline NPI-A and cognitive scores, age, sex, level of education and presence of diabetes. RESULTS: 199 participants (66 % male) were included (98-MPH, 101-placebo). Among all participants, worsening CF was associated with worsening apathy (-0.15 (0.05), p = .003). In addition, change in HVLT-I was associated with the interaction between changes in apathy and treatment (-0.31 (0.07), p = 0.0000158). CONCLUSION: Changes in apathy are mostly independent of cognitive changes and apathy response to MPH may be independent from cognition. These results are consistent with the view that apathy as a syndrome is related to but distinct from cognition. | International psychogeriatrics | 00/03/2025 |
('LID', '10.1016/j.jmb.2025.169088') | A (scientific) lifetime affair with nucleic acids. | Feigon, Juli | I am Distinguished Professor in the Chemistry and Biochemistry Department at University of California, Los Angeles, where I was hired in 1985 as the first female assistant professor in the department. I received my PhD from University of California, San Diego, under the guidance of Professor David Kearns, where I used NMR spectroscopy to study drug binding to random sequence DNA and published the first two-dimensional NMR spectra of short synthetic DNA duplexes. From 1982-1985 I was a Damon Runyon-Walter Winchell Postdoctoral fellow in the Professor Alexander Rich laboratory, where I investigated structures of Z-DNA by NMR. At UCLA, my lab pioneered the application of macromolecular NMR spectroscopy to the study of DNA and RNA structure, folding, and interactions with cations, drugs, and proteins. We published the first NMR structures of DNA triplexes, quadruplexes, and aptamers, and our work has provided fundamental insights into DNA A-tract bending, cation interactions with DNA, Hoogsteen base pairs, and drug binding to DNA. My lab has made major contributions to understanding RNA folding, dynamics, and function, including pseudoknots, aptamers, ribozymes, and riboswitches, and recognition of RNA by proteins. Over the past 2 decades, the Feigon laboratory pioneered structure-function studies of telomerase, from solution NMR and X-ray crystal structures and dynamics studies of RNA and RNA-protein domains of human and Tetrahymena telomerase, to the first structure of a telomerase holoenzyme, by negative stain EM in 2013, and subsequent cryo-EM structures of telomerase and associated proteins. Recent work also includes structural biology of 7SK RNP. | Journal of molecular biology | 12/03/2025 |
('LID', '10.1177/13872877251317720') | Salivary biomarkers for the molecular diagnosis of dementia with Lewy bodies. | D'Antonio, Fabrizia, Vivacqua, Giorgio, Serrentino, Marco, Nalepa, Martyna, Skweres, Aleksandra, Peconi, Martina, De Bartolo, Maria Ilenia, Panigutti, Massimiliano, Sepe Monti, Micaela, Talarico, Giuseppina, Fabbrini, Giovanni, Bruno, Giuseppe | BackgroundDespite dementia with Lewy bodies (DLB) being the second most common form of neurodegenerative dementia, more than 80% of DLB cases are initially misdiagnosed. Alpha-synuclein (a-syn) and tau species have been detected in peripheral tissues and biological fluids of DLB patients and among different biological fluids, saliva represent an easely accessible and non-invasive source for biomarker detection.ObjectiveThis study aimed to investigate salivary a-syn and tau species as molecular disease biomarkers, assessing their potential in the diagnosis of DLB and in the differential diagnosis on respect to Alzheimer's disease (AD) and Parkinson's disease (PD).MethodsWe measured total and oligomeric a-syn, total-tau, and S199-phosphorylated-tau (pS199-tau) in the saliva of 21 DLB, 20 AD, 20 PD patients, and 20 healthy subjects (HS) using quantitative enzyme-linked immunosorbent assay (ELISA) analyses.ResultsSalivary total a-syn was not significantly changed between the different groups, whereas all pathological groups had a higher oligomeric a-syn concentration than HS. Salivary total-tau concentration was higher in all the pathological groups than HS, whereas the concentrations did not differ among patients' groups. Conversely, salivary levels of pS199-tau was higher in DLB and AD patients than in HS and PD patients. Both correlation matrix and principal component analysis showed that core clinical DLB features were related to a-syn pathology, while cognitive decline was associated with salivary levels of pS199-tau in both DLB and AD patients. Receiver operating characteristic analysis reported high diagnostic accuracy for both a-syn oligomers and pS199-tau, between DLB and HS, and an adequate accuracy between DLB and PD. Conversely, the diagnostic accuracy was not optimal between DLB patients and AD patients.ConclusionsThese findings provide preliminary evidence that salivary a-syn and tau species might be promising in identifying DLB patients on respect to PD patients and HS, while the diagnostic potential is limited on respect to AD. | Journal of Alzheimer's disease : JAD | 14/03/2025 |
('LID', '10.1177/17534666251323190') | Optimal intensity and type of lower limb aerobic training for patients with chronic obstructive pulmonary disease: a systematic review and network meta-analysis of RCTs. | Qiao, Zhengtong, Kou, Ziwei, Zhang, Jiazhen, Lv, Daozheng, Cui, Xuefen, Li, Dongpan, Jiang, Tao, Yu, Xinjuan, Liu, Kai | BACKGROUND: Lower limb aerobic exercise is the core component of pulmonary rehabilitation for chronic obstructive pulmonary disease (COPD) patients. The optimal intensity and type (e.g., interval or continuous) of exercise training remains to be determined. OBJECTIVES: We aimed to evaluate the optimal intensities and types of lower limb aerobic exercise in patients with COPD. DESIGN: Systematic review and network meta-analysis of randomized controlled trials. DATA SOURCES AND METHODS: The PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant data. The interventions were classified according to their intensity and type as high-intensity interval training (HIIT), high-intensity continuous training (HICT), moderate-intensity continuous training (MICT), and low-intensity continuous training (LICT). We assessed exercise capacity using peak work rate (Wpeak) and the 6-min walking test (6-MWT). Lung function was evaluated by measuring peak minute ventilation (VE) and the percentage of predicted FEV(1) (FEV(1)pred%). Dyspnea was assessed using the Modified Medical Research Council (mMRC) scale. Quality of life was measured with the Chronic Respiratory Questionnaire (CRQ). RESULTS: Fifteen studies were identified (979 subjects). HIIT showed the greatest improvement in Wpeak, 6-MWT, VE, and mMRC compared to usual care (MD 18.48 (95% CI 12.35, 24.60), 67.73 (34.89, 100.57), 6.26 (2.81, 9.72), and -0.53 (-0.89, -0.17), respectively) and showed the improvement in CRQ (MD 10.80 (95% CI 1.65, 19.95)). MICT showed improvement in Wpeak and 6-MWT (MD 18.28 (95% CI 11.20, 25.22), 61.92 (28.34, 95.51)) similar to HICT (MD 16.08 (95% CI 8.19, 23.84), 64.64 (28.70, 100.57)) and showed the highest improvement in CRQ compared to usual care (MD 10.83 (95% CI 1.68, 19.98)). LICT significantly improved Wpeak compared to usual care (MD 13.47 (95% CI 4.77, 22.13)). The quality of evidence for outcomes varied from very low to moderate. CONCLUSION: HIIT and MICT might be optimal training approaches for patients with COPD. LICT exhibited limited clinical efficacy. While HICT was as effective as MICT, it caused more dyspnea. TRIAL REGISTRATION: This systematic review and network meta-analysis was prospectively registered with PROSPERO (No. CRD 42024520134). | Therapeutic advances in respiratory disease | 00/01/2025 |
('LID', '10.1038/s41598-025-86213-6') | Relationship between plasma atherogenic index and incidence of cardiovascular diseases in Chinese middle-aged and elderly people. | Zhao, Mengjie, Xiao, Mengli, Zhang, Huie, Tan, Qin, Ji, Jinjin, Cheng, Yurong, Lu, Fang | The atherogenic index of plasma (AIP), a novel composite lipid index, is closely linked to cardiovascular disease (CVD). However, lipid levels fluctuate dynamically, and it is unclear whether there are differences in the association of single-timescale, multiple-timescale, or AIP change trajectories with new-onset cardiovascular disease. Hence, the aim of this study was to investigate the correlation between different AIP parameters and the occurrence of CVD. Data were derived from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2011, 2015, 2018, and 2020, focusing on middle-aged and elderly populations aged over 45 years. Changes in AIP were classified into three groups using K-means cluster analysis: the low-level growth group (Class 1), the medium-level growth group (Class 2), and the high-level decline group (Class 3). Furthermore, participants were grouped based on tertiles (T) of cumulative AIP (Cum-AIP). Our multivariate logistic regression model integrated adjustments for potential confounders in order to investigate the association between Cum-AIP and the occurrence of CVD. Additionally, we employed restricted cubic spline (RCS) modeling to illustrate the dose-response relationship of baseline AIP, mean AIP, and Cum-AIP with CVD risk. During the 5-year follow-up period, 927 participants experienced the onset of CVD. After controlling for various potential confounding factors, it was observed that individuals in Class 2 demonstrated a notably heightened risk of CVD (OR = 1.23, 95% CI: 1.03, 1.46) and stroke (OR = 1.35, 95% CI: 1.02, 1.80) in comparison to those in Class 1. However, there was no significant difference in the risk of heart disease (OR = 1.21, 95% CI: 0.99, 1.48). In contrast, a noteworthy correlation was solely observed in the Class 3 group concerning the risk of stroke occurrence (OR = 1.60, 95% CI: 1.06, 2.42). The adjusted OR (95% CI) for CVD in the T2 and T3 groups were 1.21 (1.00, 1.46) and 1.30 (1.05, 1.62), respectively, compared to the T1 Cum-AIP group (P for trend = 0.017). Through the RCS model, we identified a positive and linear relationship between baseline AIP, mean AIP, and Cum-AIP with the incidence of CVD. However, the association between baseline AIP and CVD was weak. Sustained elevation of AIP is linked to a heightened risk of CVD in the general population. The elevated mean, and Cum-AIP levels are associated with a heightened risk of CVD. These findings indicate that AIP can serve as a valuable indicator of dyslipidemia, and continuous monitoring and early intervention targeting AIP may contribute to a further reduction in the incidence of CVD. | Scientific reports | 13/03/2025 |
('LID', '10.1136/jitc-2024-010897') | Optimization of Adcitmer, a Monomethyl-Auristatin E bearing antibody-drug conjugate for the treatment of CD56-expressing cancers. | Drouin, Aurelie, Durand, Laurine, Esnault, Clara, Gaboriaud, Pauline, Leblond, Valérie, Karim, Shawk, Fouché, Morgane, Dhommée, Christine, Baltus, Christine B, Boursin, Fanny, Aubrey, Nicolas, Houben, Roland, Schrama, David, Guyétant, Serge, Desgranges, Audrey, Viaud-Massuard, Marie Claude, Gouilleux-Gruart, Valérie, Samimi, Mahtab, Kervarrec, Thibault, Touzé, Antoine | The cell adhesion protein CD56 has been identified as a potential therapeutic target in several solid tumors and hematological malignancies. Recently, we developed a CD56-directed antibody-drug conjugate (ADC), called Adcitmer and demonstrated its antitumor properties in preclinical models of the rare and aggressive skin cancer Merkel cell carcinoma (MCC).The present study aims to further optimize Adcitmer to overcome the therapeutic limitations observed with previously evaluated CD56-targeting ADCs, which were partially related to toxic effects on leukocytes. To this end, we aimed to avoid interaction of Adcitmer with immune cells via Fc gamma receptor (FcγR) binding. Since glycosylation is essential for FcγR binding, an aglycosylated form of Adcitmer was generated and evaluated on human leukocytes and MCC cell lines using cell death (annexin V/7-aminoactinomycine D) and proliferation (2,3-Bis-(2-methoxy-4Nitro-5-sulfophenyl)-2H-tetrazolium-5carboxanilide) assays. Finally, the therapeutic performance of Adcitmer and its aglycosylated form was assessed in an MCC xenograft mouse model.Investigating the Adcitmer interaction with immune cells demonstrated that it is mostly mediated by Fc recognition. Accordingly, Adcitmer aglycosylation led to reduced immune cell toxicity and strikingly also to improved therapeutic performance even in an MCC xenograft model using immunodeficient mice.Our study suggests that aglycosylated Adcitmer should be considered as a therapeutic option in patients with advanced MCC or other CD56-positive tumors. | Journal for immunotherapy of cancer | 13/03/2025 |
('LID', '10.1093/cid/ciaf109') | Development and Evaluation of a Novel Algorithm to Identify Doxy-PEP Users at a Large Healthcare System in the Bronx, New York. | Mullis, Caroline E, Bishop, Derek, Fazzari, Melissa, Tappen, Nataliya, Felsen, Uriel, Meyerowitz, Eric A | Doxy-PEP is used to prevent chlamydia, syphilis and gonorrhea infections in sexual and gender minority men and transgender women. We describe a systematic process for developing algorithms that allow for the identification of doxy-PEP prescriptions. Using an identified algorithm will allow for improved monitoring of implementation and effectiveness. | Clinical infectious diseases : an official publication of the Infectious Diseases | 11/03/2025 |
('LID', '10.1186/s13058-025-01989-9') | Pathologic response rates in HER2-low versus HER2-zero early breast cancer patients receiving neoadjuvant therapy: a systematic review and meta-analysis. | de Moraes, Francisco Cezar Aquino, de Castro Ribeiro, Caio Henrique Duarte, Pessôa, Felipe Dircêu Dantas Leite, Chaves, Juliana Ramos, de Souza, Ana Paula Borges, Di Felipe Ávila Alcantara, Diego, Imbiriba, Margareth Maria Braun Guimarães, Magalhães, Maria Cristina Figueroa, Burbano, Rommel Mario Rodríguez | BACKGROUND: Currently, the primary methods for detecting HER2 expression levels are immunohistochemistry (IHC) and in situ hybridization (ISH), with the traditional standard being a HER2-positive score of 3 + accompanied by ERBB2 gene amplification detected through ISH. However, a new entity has recently emerged: HER2-low, defined as HER2 IHC 1 + or 2 + with negative ISH. HER2-low breast cancer, representing 45-60% of all HER2-negative tumors, has distinct biological characteristics and uncertain responses to conventional HER2-targeted therapies. Recent studies suggest varied clinical outcomes, highlighting the need for further investigation into the impact of HER2-low status on treatment efficacy and prognosis. OBJECTIVE: This meta-analysis evaluates the difference in complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) between HER2-low and HER2-zero phenotypes. METHODS: We systematically searched the main databases PubMed, Scopus, and Web of Science for articles evaluating women in neoadjuvant therapy expressing HER2-low and HER2-zero. We computed odds ratios (ORs) or hazard ratios (HRs) using DerSimonian and Laird random-effect models for all endpoints, with 95% confidence intervals (CIs). We assessed the heterogeneity using I(2) statistics. R, version 4.2.3, was used for statistical analyses. RESULTS: 38 studies totaling 70,104 patients were included. The HER2-low group accounted for 61.3% of patients while HR + status represented 52.4% in the whole research. In 67,839 women, the pCR was analyzed, which in the overall cohort analysis favored the HER2-zero group (OR 0.84; 95% CI 0.78-0.90; p = 0.000005; I(2) = 15%). Subgroup analyses for triple-negative breast cancer (TNBC) and HR + patients also favored HER2-zero expression, with an OR of 0.91 (95% CI 0.83-1.0; p < 0.041; I(2) = 12%) and 0.75 (95% CI 0.70-0.81; p < 0.000001; I(2) = 0%), respectively. In the multivariate analysis across all patients, both DFS and OS outcomes were significantly favorable for the HER2-low expression group, with HR 0.8317 (95% CI 0.7036-0.9832; p = 0.031) for DFS and HR 0.806 (95% CI 0.663-0.979; p = 0.03) for OS. CONCLUSION: Based on our findings, HER2-zero status is associated with a significantly higher pathological complete response (pCR) rate compared to HER2-low in early-stage breast cancer, and other survival outcomes. These results suggest that HER2-zero should be considered a prognostic factor in early-stage breast cancer and taken into account in neoadjuvant treatment planning and future clinical research. | Breast cancer research : BCR | 15/03/2025 |
('LID', '10.1038/s41598-025-93357-y') | The comparative efficacy of L-glutamine, celecoxib, and glucosamine sulfate in osteoarthritis management. | Hu, Zhongyao, Wang, Changming, Wang, Chen, He, Junyan, Yan, Yiqun, Xu, Zelin, Yu, Yangmang, Yu, Ya, Cheng, Huan, Liu, Lei, Tang, Miao, Zhang, Chun, Yu, Haoran, Jing, Juehua, Cheng, Wendan | To explore the therapeutic efficacy of L-glutamine (L-Gln) on pathological progression and clinical symptoms of osteoarthritis (OA), and compare with glucosamine sulfate (GS), and celecoxib (CXB). Rats were administered sodium chloride, L-Gln, GS, or CXB via gavage for eight weeks starting from the fifth week after sham operation or Anterior Cruciate Ligament Transection (ACLT) + Medial Meniscectomy (MMx). Then the severity of knee OA in rats was evaluated by serological analysis, histological examination and imaging examination. In addition, patients with mild primary OA were administered L-Gln, GS, or CXB orally for 12 weeks in accordance with the randomization principle. The efficacy end points were the change from baseline to week 24 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and Lequesne score. Treatment with L-Gln alleviated the increased concentration of serum cartilage degradation markers caused by OA in rats. Histological tests showed improvement in knee joint cartilage destruction after treatment. Three-dimensional CT scans and reconstructions revealed a reduction in osteophyte formation and subchondral bone loss. L-glutamine performed as well as or better than glucosamine sulfate and celecoxib in all comparative measures among the three treatment groups. In clinical trials, the WOMAC pain and physical function subscale scores, as well as the Lequesne score, decreased from baseline in all three patient groups during follow-up, with no significant differences observed between the groups. Our research indicates that L-Gln is comparable to GS and CXB in improving the pathological progression and clinical efficacy of OA, which makes it a promising drug for the treatment of osteoarthritis. | Scientific reports | 15/03/2025 |
('LID', '10.1016/j.semnephrol.2025.151567') | The Genetics of IgA Nephropathy: Implications for Future Therapies. | Zhou, Xu-Jie, Zhang, Hong | IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. The etiology of IgAN, however, remains incompletely understood, and effective treatment is lacking. Although the multihit model effectively identifies key steps in IgAN development and, to date, provides the best description of IgAN pathogenesis, it remains under development to fully capture the complexity of immune system dysregulation. Large-scale genome-wide association studies have revealed clues regarding the association between IgAN and genes in both innate and adaptive immune pathways. Hence, genetic investigations may shed light on the aberrant molecular mechanisms, thereby presenting new opportunities for therapeutic advancements. This review discusses the genetic associations that have been robustly connected with IgAN, placing them within the framework of disease mechanism. Altogether, these findings highlight numerous new possibilities for the development of treatments and the road to personalized medicine. | Seminars in nephrology | 13/03/2025 |
('LID', '10.1002/ana.27226') | Regional Brain Metabolism across the Alzheimer's Disease Continuum in Down Syndrome. | Arriola-Infante, José Enrique, Morcillo-Nieto, Alejandra O, Zsadanyi, Sara E, Franquesa-Mullerat, María, Vaqué-Alcázar, Lídia, Rozalem-Aranha, Mateus, Arranz, Javier, Rodríguez-Baz, Íñigo, Maure-Blesa, Lucia, Videla, Laura, Barroeta, Isabel, Del Hoyo Soriano, Laura, Benejam, Bessy, Fernández, Susana, Sanjuan-Hernández, Aida, Giménez, Sandra, Alcolea, Daniel, Belbin, Olivia, Flotats, Albert, Camacho, Valle, Lleó, Alberto, Carmona-Iragui, María, Fortea, Juan, Bejanin, Alexandre | OBJECTIVE: The goal was to examine the effect of sociodemographic variables, Alzheimer's disease (AD) clinical stages and pathology on brain metabolism in Down syndrome (DS). METHODS: We included 71 euploid healthy controls (HC) and 105 adults with DS (67 asymptomatic, 12 prodromal, and 26 with dementia) from the Down-Alzheimer Barcelona Neuroimaging Initiative. Participants underwent [18F]fluorodeoxyglucose positron emission tomography, 3 Tmagnetic resonance imaging, and lumbar puncture to measure cerebrospinal fluid (CSF) biomarkers (ratio beween amyloid β peptide 42 and 40, phosphorylated tau 181, and neurofilament light chain [NfL]). Voxel-wise analyses in SPM12 examined the effects of age, sex, intellectual disability, Alzheimer's clinical stage, and CSF biomarkers on brain metabolism. RESULTS: In HC, brain metabolism decreased with age primarily in the frontal lobe. By contrast, a more distributed pattern of metabolic loss was observed in DS with age, predominating in temporoparietal regions. Compared to asymptomatic DS participants, those at the prodromal stage exhibited medial parietal hypometabolism, which later extended to other temporoparietal and frontal regions at the dementia stage. In asymptomatic individuals, we observed a widespread hypometabolism compared to HC, mainly in medial frontal and parietal regions. All CSF biomarkers were closely associated with hypometabolism in regions affected by the disease, with the strongest association observed for NfL in medial parietal structures. INTERPRETATION: The brain metabolic decline in DS with age reflects Alzheimer's pathological processes and involves temporoparietal regions in a similar pattern to that found in other forms of AD. Hypometabolism is more tightly related to CSF NfL levels than to core AD biomarkers. ANN NEUROL 2025. | Annals of neurology | 14/03/2025 |
('LID', '10.1016/j.modpat.2025.100753') | Spatial expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and metastases: Implications for pathological and clinical management. | Dernbach, Gabriel, Eich, Marie-Lisa, Dragomir, Mihnea P, Anders, Philipp, Jurczok, Nadia, Stief, Christian, Jurmeister, Philipp, Schlomm, Thorsten, Klauschen, Frederick, Horst, David, Schulz, Gerald Bastian, Schallenberg, Simon | Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges. Antibody-drug conjugates (ADCs) targeting HER2, TROP-2, and NECTIN4 offer promising therapeutic options. This study examined the spatial expression of HER2, TROP-2, and NECTIN4 in MIBC and metastases, their association with molecular subtypes, and clinical outcomes. Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 251 MIBC patients were analyzed using immunohistochemistry and tissue microarrays (TMA). Expression patterns between the tumor front (TF) and center (TC) were compared, and statistical analyses assessed associations with molecular subtypes and clinical parameters. Additionally, 67 matched lymph node metastases and a secondary cohort comprising 16 distant metastases, including seven matched primary tumors, were examined to explore the expression patterns in advanced tumor stages. In primary tumors, HER2 was predominantly negative (83%) but showed higher positivity in the TC. TROP-2 exhibited high overall expression (58% score 3+), while NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Spatial overexpression of TROP-2 and NECTIN4 at the tumor front relative to the tumor center was associated with a better disease free survival. Accurate assessment required four biopsies for HER2 and NECTIN4 and three for TROP-2. HER2 expression was associated with urothelial-like and genomically unstable molecular subtypes, whereas TROP-2 was widely expressed except in the mesenchymal-like subtype. NECTIN4 showed absence of staining in basal, mes-like and Sc/Nec-like subtypes. Paired lymph node metastases showed higher expression scores for all three markers, while distant metastases showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed a considerable heterogeneity for HER2 compared to their matched primary tumors. The spatial heterogeneity of HER2, TROP-2, and NECTIN4 expression necessitates multiple biopsies, particularly from the TC, for accurate evaluation. These findings underscore the need for personalized treatment strategies in MIBC, considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the TC. Implementing a multi-biopsy approach is critical to enhance diagnostic accuracy. | Modern pathology : an official journal of the United States and Canadian Academy | 12/03/2025 |
('LID', '10.1038/s41598-024-62048-5') | Sustainable coatings for green solar photovoltaic cells: performance and environmental impact of recyclable biomass digestate polymers. | Alhodaib, Aiyeshah, Yahya, Zeinebou, Khan, Osama, Equbal, Azhar, Equbal, Md Shaquib, Parvez, Mohd, Kumar Yadav, Ashok, Idrisi, M Javed | The underutilization of digestate-derived polymers presents a pressing environmental concern as these valuable materials, derived from anaerobic digestion processes, remain largely unused, contributing to pollution and environmental degradation when left unutilized. This study explores the recovery and utilization of biodegradable polymers from biomass anaerobic digestate to enhance the performance of solar photovoltaic (PV) cells while promoting environmental sustainability. The anaerobic digestion process generates organic residues rich in biodegradable materials, often considered waste. However, this research investigates the potential of repurposing these materials by recovering and transforming them into high-quality coatings or encapsulants for PV cells. The recovered biodegradable polymers not only improve the efficiency and lifespan of PV cells but also align with sustainability objectives by reducing the carbon footprint associated with PV cell production and mitigating environmental harm. The study involves a comprehensive experimental design, varying coating thickness, direct normal irradiance (DNI) (A), dry bulb temperature (DBT) (B), and relative humidity (C) levels to analyze how different types of recovered biodegradable polymers interact with diverse environmental conditions. Optimization showed that better result was achieved at A = 8 W/m(2), B = 40 °C and C = 70% for both the coated material studied. Comparative study showed that for enhanced cell efficiency and cost effectiveness, EcoPolyBlend coated material is more suited however for improving durability and reducing environmental impact NanoBioCelluSynth coated material is preferable choice. Results show that these materials offer promising improvements in PV cell performance and significantly lower environmental impact, providing a sustainable solution for renewable energy production. This research contributes to advancing both the utilization of biomass waste and the development of eco-friendly PV cell technologies, with implications for a more sustainable and greener energy future. This study underscores the pivotal role of exploring anaerobic digestate-derived polymers in advancing the sustainability and performance of solar photovoltaic cells, addressing critical environmental and energy challenges of our time.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 7 Given name: [Ashok] Last name [Kumar Yadav]. Also, kindly confirm the details in the metadata are correct.correct. | Scientific reports | 16/05/2024 |
('LID', '10.1186/s13018-025-05658-7') | The effectiveness of kinesiotaping in treating chronic lateral epicondylitis: a randomized, sham-controlled, single-blind study. | Akkurt, Halil Ekrem, Yilmaz, Ramazan, Suna, Fatma Sümeyye, Karpuz, Savaş, Yilmaz, Halim | OBJECTIVES: Kinesiotaping (KT), with its non-restrictive nature, is a preferred treatment option, yet there remains insufficient evidence regarding its effectiveness in managing lateral epicondylitis (LE). This study aims to investigate the efficacy of KT on pain intensity, functional status, and quality of life in patients with chronic LE. METHODS: Between February and August 2024, 42 patients (17 females, 25 males; mean age: 44.5 ± 9.1 years; range: 27-61) with chronic LE were included in this single-blind, parallel-group randomized controlled trial (RCT). Patients were randomized into either the KT or sham-controlled group. Kinesiotaping and sham-taping were applied six times over three weeks. Both groups received recommendations for activity modification and a home-based stretching and strengthening exercise program. Outcome measures were the visual analog scale (VAS) pain score; the Patient-Rated Forearm Evaluation Questionnaire (PRFEQ); grip strength; Disabilities of Arm, Shoulder, and Hand (DASH); quality of life in Short Form-36 (SF-36), and the Roles and Maudsley patient satisfaction score. The participants were assessed before treatment, at the end of treatment (week three), and four weeks after the end of treatment (week seven). RESULTS: Both groups showed improvements from the baseline in all outcome parameters. At the third and seventh week follow-up, KT was superior to sham-taping in all outcome measures, except for two SF-36 subscales, with effect sizes further supporting the clinical relevance of these findings by indicating meaningful differences in favor of KT. CONCLUSIONS: The results of the present study suggest that KT using the epidermis, dermis, fascia (EDF), and muscle inhibition technique effectively reduces pain, improves disability and quality of life, and achieves high patient satisfaction levels without any adverse effects in LE. CLINICALTRIALS: gov identifer: NCT06611709. | Journal of orthopaedic surgery and research | 14/03/2025 |
('LID', '10.1016/j.freeradbiomed.2025.03.012') | The Nuclear-Mitochondrial Crosstalk in Aging: From Mechanisms to Therapeutics. | Feng, Yifei, Lu, Yan | Aging is a complex physiological process characterized by an irreversible decline in tissue and cellular functions, accompanied by an increased risk of age-related diseases, including neurodegenerative, cardiovascular, and metabolic disorders. Central to this process are epigenetic modifications, particularly DNA methylation, which regulate gene expression and contribute to aging-related epigenetic drift. This drift is characterized by global hypomethylation and localized hypermethylation, impacting genomic stability and cellular homeostasis. Simultaneously, mitochondrial dysfunction, a hallmark of aging, manifests as impaired oxidative phosphorylation, excessive reactive oxygen species production, and mitochondrial DNA mutations, driving oxidative stress and cellular senescence. Emerging evidence highlights a bidirectional interplay between epigenetics and mitochondrial function. DNA methylation modulates the expression of nuclear genes governing mitochondrial biogenesis and quality control, while mitochondrial metabolites, such as acetyl-CoA and S-adenosylmethionine, reciprocally influence epigenetic landscapes. This review delves into the intricate nuclear-mitochondrial crosstalk, emphasizing its role in aging-related diseases and exploring therapeutic avenues targeting these interconnected pathways to counteract aging and promote health span extension. | Free radical biology & medicine | 12/03/2025 |
('LID', '10.1038/s41467-025-57764-z') | FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations. | Verschuren, Jip, van Schendel, Robin, van Bostelen, Ivo, Verkennis, Alex E E, Knipscheer, Puck, Tijsterman, Marcel | To counteract the damaging effects of DNA interstrand crosslinks (ICLs), cells have evolved various specialized ICL repair pathways. However, how ICL repair impacts genetic integrity remains incompletely understood. Here, we determined the mutagenic consequences of psoralen ICL repair in the animal model C. elegans and identify two mutagenic repair mechanisms: (i) translesion synthesis through POLH and REV1/3-mediated bypass, leading to single nucleotide polymorphisms (SNVs), and (ii) end joining via POLQ or HELQ action resulting in deletions. While we found no role for the Fanconi anemia genes FANCD2 and FANCI, disruption of TRAIP, which triggers unloading of the CMG helicase at sites of blocked replication, led to a strikingly altered repair profile, suggesting a role for DNA replication in the etiology of ICL-induced deletions. TRAIP deficiency did not affect SNV formation; instead, we found these SNVs to depend on the functionality of the Fanconi anemia-associated nuclease FAN1. | Nature communications | 13/03/2025 |
('LID', '10.1186/s40729-025-00611-z') | Comparison of cone-beam computed tomography with photon-counting detector computed tomography for dental implant surgery. | Al-Haj Husain, Adib, Mergen, Victor, Valdec, Silvio, Al-Haj Husain, Nadin, Stadlinger, Bernd, Essig, Harald, Frauenfelder, Thomas, Kessler, Peter, Lie, Suen An Nynke, Alkadhi, Hatem, Winklhofer, Sebastian | PURPOSE: To compare cone-beam computed tomography (CBCT) with photon-counting detector computed tomography (PCD-CT) at equivalent radiation doses, focusing on qualitative and quantitative parameters relevant to dental implant surgery. METHODS: This ex vivo comparative study of porcine specimens assessed five imaging protocols with both CBCT and PCD-CT at three effective radiation dose levels (high: 360µSv, standard: 145µSv, low: 20µSv) to evaluate image quality, artifact burden, metal artifact susceptibility, and quantitative bone measurements in the mandibular region. Three blinded readers analyzed the data using a 5-point Likert scale (5 = highest to 1 = lowest rating) and performed linear bone measurements at implant planning sites. Statistical analysis included descriptive statistics and inter-reader reliability assessment using intraclass correlation coefficients (ICC). RESULTS: Each reader evaluated 30 data sets (12 CBCT, 18 PCD-CT), with 24 implant planning sites per imaging protocol. High-dose PCD-CT demonstrated the best image quality and diagnostic interpretability (4.89 ± 0.27), followed by standard-dose PCD-CT and CBCT (4.50 ± 0.73; 4.33 ± 0.61), with low-dose protocols showing intermediate quality with higher artifact burden. In comparison to CBCT, PCD-CT demonstrated superior performance in reducing implant-induced artifacts across all protocols. Quantitative bone measurements showed minimal variability, meeting clinical precision requirements for computer-assisted implant surgery. Both qualitative (ICCs:0.70-0.89; p < 0.001) and quantitative (ICCs:0.79-1; p < 0.001) analyses demonstrated high reliability, regardless of the reader's experience. CONCLUSIONS: PCD-CT demonstrated superior image quality and reduced artifacts compared with CBCT at all radiation dose levels. These findings highlight PCD-CT's potential to enhance implant planning and improve clinical outcomes with reduced radiation exposure while maintaining diagnostic accuracy. | International journal of implant dentistry | 13/03/2025 |
('LID', '10.1007/s00784-025-06267-8') | Anti-inflammatory and antimicrobial efficacy of coconut oil for periodontal pathogens: a triple-blind randomized clinical trial. | Pardiñas López, Simón, García-Caro, Mónica E, Vallejo, Juan A, Aja-Macaya, Pablo, Conde-Pérez, Kelly, Nión-Cabeza, Paula, Khouly, Ismael, Bou, Germán, Cendal, Ana Isabel Rodríguez, Díaz-Prado, Silvia, Poza, Margarita | OBJECTIVES: To evaluate the effect of coconut oil on the oral bacteriome and inflammatory response in patients with periodontitis by integrating next-generation sequencing analyses of pathogenic bacterial shifts and quantification of inflammatory markers, thereby assessing its potential as a natural adjunct to standard nonsurgical periodontal therapy. MATERIALS AND METHODS: A triple-blind clinical trial was conducted with 30 participants diagnosed with periodontitis, randomized into 3 groups: (1) coconut oil, (2) chlorhexidine and (3) placebo. Saliva and gingival crevicular fluid (GCF) samples were collected before treatment, one month after treatment, and one month post-non-surgical periodontal therapy. Bacterial DNA was extracted, and the V3-V4 region of the 16 S rRNA gene was PCR-amplified and sequenced using Illumina MiSeq technologies. Inflammatory biomarkers, including Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were quantified from GCF samples. RESULTS: Coconut oil treatment significantly reduced pathogenic bacterial families such as Spirochaetaceae and Tannerellaceae while promoting beneficial bacteria such as Streptococcaceae. At the genus and species levels, coconut oil reduced pathogens such as Tannerella forsythia and Treponema denticola along with increase in beneficial bacteria such as Streptococcus. The subgingival microbial dysbiosis index improved significantly in both coconut oil and chlorhexidine groups. Furthermore, the coconut oil demonstrated a reduction in IL-6 and TNF-α levels, indicating decreased local inflammation. CONCLUSIONS: Coconut oil treatment significantly modulated the oral microbiome and reduced inflammatory markers in patients with periodontitis, suggesting its potential as a natural and effective adjunct in periodontal therapy. CLINICAL RELEVANCE: This study highlights coconut oil's potential as a natural adjunct in periodontal therapy, effectively reducing pathogenic bacteria and inflammatory markers (IL-6, TNF-α). It offers a safe alternative to chlorhexidine, promoting microbiome balance and improved periodontal health. | Clinical oral investigations | 14/03/2025 |
('LID', '10.1016/S2213-8587(24)00378-4') | Adrenocortical carcinoma: a practical guide for clinicians. | Fassnacht, Martin, Puglisi, Soraya, Kimpel, Otilia, Terzolo, Massimo | Adrenocortical carcinoma is a rare endocrine malignancy. The management of patients with adrenocortical carcinoma is challenging for several reasons, including its heterogeneous but frequently aggressive biological behaviour; tumour-related hormonal excess (eg, Cushing's syndrome or virilisation); the overall paucity of evidence regarding diagnostic investigation and treatment; the approval of only one drug (mitotane); and the scarcity of centres with sufficient experience. In this Review, we present 25 questions on the most important aspects of the clinical management of adult patients with adrenocortical carcinoma that we have frequently asked ourselves over the past 25 years. We offer our personal answers and perspectives, drawing upon published evidence as well as more than 60 years of collective clinical experience and insights from our management of more than 1700 patients across two centres in Germany and Italy. | The lancet. Diabetes & endocrinology | 11/03/2025 |
('LID', '10.1212/NXI.0000000000200386') | Diagnostic Utility of Kappa Free Light Chain Index in Adults With Inaugural Optic Neuritis. | Demortiere, Sarah, Stolowy, Natacha, Perriguey, Marine, Boutiere, Clemence, Rico, Audrey, Hilezian, Frederic, Ndjomo-Ndjomo, Blaise-Roger, Durozard, Pierre, Stellmann, Jan-Patrick, Marignier, Romain, Boucraut, José, Pelletier, Jean, Maarouf, Adil, Audoin, Bertrand | BACKGROUND AND OBJECTIVES: A simple, quick, and reproducible procedure for distinguishing multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) at inaugural optic neuritis (ION) could be highly valuable in guiding early management. METHODS: We included all adults admitted to the MS center of Marseille for ION between March 2016 and April 2024, with CSF analysis including the kappa free light chain (K-FLC) index. Receiver operating characteristic curves were used to measure the diagnostic ability of the K-FLC index. RESULTS: Two hundred twenty-seven adults were admitted for ION; 210 (93%) had a K-FLC index measurement. MS was diagnosed in 84 (40%); clinically isolated syndrome suggestive of MS in 77 (36.5%), including 20 with future conversion to MS (CISwc); MOGAD in 26 (12.5%); NMOSD in 13 (6%); and other inflammatory disorders in 10 (5%). A K-FLC index ≥6.7 differentiated MS/CISwc from other diagnoses with specificity 86% and sensitivity 95% (area under the curve [AUC] 0.94). A K-FLC index <4.9 differentiated MOGAD from other diagnoses with specificity 63% and sensitivity 92% (AUC 0.78) and MOGAD from MS/CISwc with specificity 96% and sensitivity 92% (AUC 0.97). Among all patients, 93 (44%) had a K-FLC index <4.9: 24 of these (26%) had MOGAD and 5 (5.5%) MS/CISwc. Among the remaining patients with a K-FLC index ≥4.9 (n = 117), 2 (1.7%) had MOGAD (K-FLC index of 7.9 and 16.2) and 99 (85%) MS/CISwc. Among patients with normal MRI (n = 96), 73 (76%) had a K-FLC index <4.9: 22 of these (30%) had MOGAD, and none showed conversion to MS. Among the remaining patients with a K-FLC index ≥4.9 (n = 23), 2 (8.5%) had MOGAD and 7 (30.5%) showed conversion to MS. The K-FLC index did not differentiate NMOSD from other diagnoses and only moderately differentiated NMO from MS/CISwc (AUC 0.80). DISCUSSION: The K-FLC index is an accessible biomarker to guide early diagnosis in patients with ION. The probability of MOGAD in patients with ION and a K-FLC index ≥4.9 is low even in case of normal brain/spinal cord MRI. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with ION, the K-FLC index can distinguish between MS/CISwc and MOGAD. | Neurology(R) neuroimmunology & neuroinflammation | 00/05/2025 |
('LID', '10.1136/jnnp-2024-335547') | Sex hormone-related factors and the risk of PIRA in women with multiple sclerosis. | Giordano, Antonino, Giliberti, Arianna, Clarelli, Ferdinando, Misra, Kaalindi, Mascia, Elisabetta, Sorosina, Melissa, Visentin, Giulia, Margoni, Monica, Moiola, Lucia, Rocca, Maria A, Filippi, Massimo, Esposito, Federica | BACKGROUND: Sex-related differences affect multiple sclerosis (MS), but the impact of sex hormones on disease progression remains unclear. We investigated whether sex hormone-related factors influence progression independent of relapse activity (PIRA) in women with MS over a long-term follow-up. METHODS: The study analysed 1210 female MS patients from the San Raffaele MS Center using data from an environmental survey (2019-2023). PIRA was defined as 12-week confirmed disability progression independent of recent relapses (<30 days). Cox proportional-hazard models (adjusted for confounding factors) were used to assess the effect of hormone-related factors on PIRA risk. RESULTS: Patients who used oral contraceptives before MS diagnosis had a 26% lower risk of PIRA and a delayed median time to the first PIRA event (9.94 vs 7.5 years; HR=0.74; 95% CI 0.61 to 0.89; p=0.0018). Conversely, menopause at diagnosis (HR=1.82; 95% CI 1.24 to 2.67; p=0.0022) and pregnancy before diagnosis (HR=1.22; 95% CI 1.006 to 1.47; p=0.043) were associated with a shorter time to PIRA. No significant differences were found with abortion, menstrual irregularity or fertility therapy. CONCLUSIONS: This study suggests that early oral contraceptives may delay future disability progression, supporting the importance of sex hormones in MS and prompting further prospective investigations on oral contraceptives to slow disease progression. | Journal of neurology, neurosurgery, and psychiatry | 13/03/2025 |
('LID', '10.1007/s12016-025-09037-2') | The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis. | Wu, Xinxin, Liu, Changya, Zhang, Caiyun, Kuai, Le, Hu, Sheng, Jia, Ning, Song, Jiankun, Jiang, Wencheng, Chen, Qilong, Li, Bin | Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms. | Clinical reviews in allergy & immunology | 13/03/2025 |
('LID', '10.1182/blood.2024026139') | Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China. | Zhou, De, Huang, Xianbo, Zhu, Lixia, Hu, Xuelian, Yang, Xiudi, Xie, Mixue, Huang, Xin, Yu, Fang, Wei, Juying, Ma, Liya, Zhu, Jingjing, Zhao, Shuqi, Xie, Wanzhuo, Tong, Hongyan, Jin, Jie, Ye, Xiujin | Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome, and the overall survival of adult patients is poor. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has shown promise in treating HLH and exerts synergistic effects when combined with dexamethasone. Our pilot study preliminarily demonstrated that the combination of ruxolitinib and dexamethasone (the Ru-D regimen) had a high response rate and led to favorable short-term survival outcomes in adult HLH patients. In this prospective phase 2 clinical trial, we propose the Ru-D regimen as a first-line treatment for adults newly diagnosed with HLH with unknown triggers (chictr.org.cn identifier: ChiCTR2100049996). A total of 28 Chinese patients were enrolled, and the median follow-up time was 25.1 months (range, 0.87-34.0). The 2-month OS rate (the primary endpoint) was 85.7%, which exceeded our expected 2-month OS rate of 75%. The 6-month and 2-year OS rates were 67.9% (19/28) and 53.6% (15/28), respectively. The median OS of lymphoma-associated HLH (LAHS) patients was 5.8 months, and most of these patients had NK/T-cell lymphoma. In contrast, the 2-year OS rate of non-LAHS patients was 75%. The overall response rate (ORR) was 85.7% (24/28); 17.9% (5/28) of patients achieved a complete response (CR) during the Ru-D regimen. Overall, the Ru-D regimen was well tolerated in HLH patients. This study demonstrates the efficacy and safety of the Ru-D regimen in adults newly diagnosed with HLH with unknown triggers and warrants a phase 3 randomized controlled study. | Blood | 16/03/2025 |
('LID', '10.1186/s12888-025-06676-9') | The association between triglyceride-glucose index and its combination with post-stroke depression: NHANES 2005-2018. | Liang, Fengjiao, Shan, Xiaoqian, Chen, Xiang, Yang, Banghua | BACKGROUND: Growing evidence indicates a link between insulin resistance and post-stroke depression (PSD). This study employed the triglyceride glucose (TyG) index as a measure of insulin resistance to investigate its relationship with PSD. METHODS: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2005-2018). PSD was assessed using data from patient health questionnaires, while the TyG index was calculated based on fasting venous blood glucose and fasting triglyceride levels. The formula used for the TyG index is ln[triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Participants were categorized into four groups according to the TyG index quartiles. A weighted multivariable logistic regression model was applied to examine the relationship between the TyG index and PSD. RESULTS: A total of 1217 patients were included in the study, of which 232 were diagnosed with PSD. The TyG index was divided into quartiles (Q1-Q4) for analysis. After adjusting for potential confounders, we found a significant positive association between the highest quartile of the TyG index (Q4: ≥9.33) and PSD (OR = 2.51, 95% CI: 1.04-6.07, p = 0.041). This suggests that in the U.S. adult stroke population, individuals with higher TyG indices are more likely to experience depressive symptoms. Subgroup analysis further confirmed a stable and independent positive association between the TyG index and PSD (all trend p > 0.05). CONCLUSION: In this large cross-sectional study, our results suggest that among US adults who have experienced a stroke, those with higher TyG index levels are more likely to exhibit depressive symptoms. This provides a novel approach for the clinical prevention of PSD. Patients with higher TyG indices in the stroke population may require closer psychological health monitoring and timely intervention. Additionally, since the TyG index is calculated using only fasting blood glucose and triglyceride levels, it can help identify high-risk PSD patients, particularly in regions with limited healthcare resources. | BMC psychiatry | 14/03/2025 |
('LID', '10.1038/s41593-025-01906-5') | An axonal brake on striatal dopamine output by cholinergic interneurons. | Zhang, Yan-Feng, Luan, Pengwei, Qiao, Qinbo, He, Yiran, Zatka-Haas, Peter, Zhang, Guofeng, Lin, Michael Z, Lak, Armin, Jing, Miao, Mann, Edward O, Cragg, Stephanie J | Depolarization of axons is necessary for somatic action potentials to trigger axonal neurotransmitter release. Here we show that striatal cholinergic interneurons (ChIs) and nicotinic receptors (nAChRs) on mouse dopamine axons interrupt this relationship. After nAChR-mediated depolarization, dopamine release by subsequent depolarization events was suppressed for ~100 ms. This suppression was not due to depletion of dopamine or acetylcholine, but to a limited reactivation of dopamine axons after nAChR-mediated depolarization, and is more prominent in dorsal than in ventral striatum. In vivo, nAChRs predominantly depressed dopamine release, as nAChR antagonism in dorsal striatum elevated dopamine detected with optic-fiber photometry of dopamine sensor GRAB(DA2m) and promoted conditioned place preference. Our findings reveal that ChIs acting via nAChRs transiently limit the reactivation of dopamine axons for subsequent action potentials in dopamine neurons and therefore generate a dynamic inverse scaling of dopamine release according to ChI activity. | Nature neuroscience | 13/03/2025 |
('LID', '10.1007/s10753-025-02282-9') | TXM-CB13 Improves the Intestinal Mucosal Barrier and Alleviates Colitis by Inhibiting the ROS/TXNIP/TRX/NLRP3 and TLR4/MyD88/NF-κB/NLRP3 Pathways. | Cao, Ruijie, Zhou, Jinhui, Liu, Jiale, Wang, Yaxuan, Dai, Yandong, Jiang, Yun, Yamauchi, Akira, Atlas, Daphne, Jin, Tiancheng, Zhou, Jiedong, Wang, Cuixue, Tan, Qihuan, Chen, Yifei, Yodoi, Junji, Tian, Hai | The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways. | Inflammation | 14/03/2025 |
('LID', '10.1016/j.cbpc.2025.110192') | Acute hypoxia induces sleep disorders via sima/HIF-1α regulation of circadian rhythms in adult Drosophila. | Wang, Shuwei, Zhou, Shihong, Jiang, Xiaolin, Yang, Dan, He, Jianzheng, Xiu, Minghui | The atmospheric oxygen concentration is significantly reduced in highland regions compared to lowland areas. The first entering the plateau can induce sleep disorders in individuals, primarily attributed to insufficient oxygen supply. This study used Drosophila melanogaster as a model organism to better understand the molecular mechanism of acute hypoxia-induced sleep disorders. The Drosophila activity monitoring system (DAMS) was employed to observe the sleep-wake in adult (w(1118), sima(KG07607), and clock(jrk)) female flies. Quantifying the relative mRNA expression levels of sima and circadian clock genes in the head of flies was accomplished by utilizing qRT-PCR. Acute hypoxia caused sleep disorders in w(1118) flies, such as shortened sleep duration and length, and prolonged sleep latency. PCR results showed that sima and clock genes were up-regulated in ZT6 and ZT12 and down-regulated in ZT0 and ZT18 in acute hypoxic w(1118) flies compared to normoxic w(1118) flies. Under normoxic conditions, sleep indexes in sima(KG07607) flies were not substantially different from w(1118) flies. However, clock(jrk) flies demonstrated a reduced sleep duration, decreased sleep bout length, and increased sleep latency and activities. Sleep and gene expression in sima(KG07607) flies under acute hypoxic conditions were not significantly different from those under normoxic conditions. Surprisingly, sleep and gene expression in clock(jrk) flies showed opposite trends to w(1118) flies. The present study indicates that acute hypoxia disrupt circadian rhythms through the activation of sima/HIF-1α, leading to the onset of sleep disorders, with Clock signaling potentially serving as a contributing factor. | Comparative biochemistry and physiology. Toxicology & pharmacology : CBP | 12/03/2025 |
('LID', '10.1073/pnas.2417674122') | Characterization of diverse Cas9 orthologs for genome and epigenome editing. | Butterfield, Gabriel L, Rohm, Dahlia, Roberts, Avery, Nethery, Matthew A, Rizzo, Anthony J, Morone, Daniel J, Garnier, Lisa, Iglesias, Nahid, Barrangou, Rodolphe, Gersbach, Charles A | CRISPR-Cas9 systems have revolutionized biotechnology, creating diverse new opportunities for biomedical research and therapeutic genome and epigenome editing. Despite the abundance of bacterial CRISPR-Cas9 systems, relatively few are effective in human cells, limiting the overall potential of CRISPR technology. To expand the CRISPR-Cas toolbox, we characterized a set of type II CRISPR-Cas9 systems from select bacterial genera and species encoding diverse Cas9s. Four systems demonstrated robust and specific gene repression in human cells when used as nuclease-null dCas9s fused with a KRAB domain and were also highly active nucleases in human cells. These systems have distinct protospacer adjacent motifs (PAMs), including AT-rich motifs and sgRNA features orthogonal to the commonly used Staphylococcus aureus and Streptococcus pyogenes Cas9s. Additionally, we assessed gene activation when fused with the p300 catalytic domain. Notably, S. uberis Cas9 performed competitively against benchmarks with promising repression, activation, nuclease, and base editing activity. This study expands the CRISPR-Cas9 repertoire, enabling effective genome and epigenome editing for diverse applications. | Proceedings of the National Academy of Sciences of the United States of America | 18/03/2025 |
('LID', '10.1186/s12872-025-04574-2') | Effects of diltiazem and metoprolol on levels of high-sensitivity troponin I in patients with permanent atrial fibrillation: a randomized trial. | Enge, Katrine, Ulimoen, Sara Reinvik, Enger, Steve, Onarheim, Sophia, Olufsen, Mona, Pripp, Are Hugo, Steinsvik, Trude, Hall, Christian, Hetland, Mathias, Tveit, Arnljot | BACKGROUND: High-sensitive (hs-) cardiac troponin assays provide prognostic information in atrial fibrillation (AF) patients. Few studies have explored the impact of long-term rate control therapy on levels of troponin in AF patients without coronary heart disease and heart failure. This substudy of the RATe control in Atrial Fibrillation (RATAF) II study aimed to compare the effects of six months' treatment with diltiazem and metoprolol on hs-troponin I (TnI) levels both at rest and during exercise testing in patients with permanent AF. METHODS: This was a parallel-group, randomized, investigator-blinded clinical trial. The cohort consisted of 93 patients (28 women, mean age 71 ± 7 years) with symptomatic, permanent AF with preserved left ventricular systolic function and no coronary heart disease. Participants were randomized in a 1:1 ratio to receive either diltiazem 360 mg (n = 49) or metoprolol 100 mg (n = 44) once daily for six months. Blood tests were drawn at rest and during peak exercise testing at baseline, one month and six months' treatment. This research has been supported by grants from the South-Eastern Norway Regional Health Authority and Vestre Viken Hospital Trust. RESULTS: Six months' treatment with diltiazem and metoprolol significantly lowered the heart rate at rest and peak exercise. Both treatment groups exhibited a decrease in hs-TnI levels at rest (diltiazem p = 0.008, metoprolol p = 0.03) and peak exercise (diltiazem p < 0.001, metoprolol p = 0.004) at six months compared to baseline levels, with no significant differences observed between the groups. CONCLUSIONS: In patients with permanent AF, six months of rate control therapy with diltiazem or metoprolol lowered levels of hs-TnI. Further research is warranted to determine whether this reduction translates into an improved prognosis. TRIAL REGISTRATION: NCT02695992. Registration date: 2015-04-28. | BMC cardiovascular disorders | 14/03/2025 |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.