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('LID', '10.1016/j.ccell.2025.02.024') | PAI-1-driven SFRP2(high) cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy. | Zhang, Yan-Pei, Guo, Ze-Qin, Cai, Xiao-Ting, Rong, Zi-Xuan, Fang, Yuan, Chen, Jia-Qi, Zhuang, Kui-Mao, Ruan, Min-Jie, Ma, Si-Cong, Lin, Le-Yi, Han, Duan-Duan, Li, Yang-Si, Wang, Yuan-Yuan, Wang, Jian, Cao, Chuan-Hui, Tang, Xin-Ran, Xie, Qian-Kun, Chen, Yue, Lin, Yan, Tan, Jia-Le, Yu, Zi-Hang, Wu, Ze-Nan, Wei, Wei, Zheng, Da-Yong, Zeng, Yu-Jie, Ruan, Ying-Chen, Xu, Zi-Peng, Gu, Jun-Zi, Xiao, Lu-Shan, Liu, Li, Guan, Jian, Bai, Xue, Wu, De-Hua, Dong, Zhong-Yi | The abscopal effect of radioimmunotherapy, wherein tumor shrinkage occurs beyond the irradiated field, is therapeutically promising but clinically rare. The mechanisms underlying this effect remain elusive. Here, in vivo genome-wide CRISPR screening identifies SFRP2 as a potential stromal regulator of the abscopal effect. SFRP2 exhibits cancer-associated fibroblast (CAF)-specific expression and radioimmunotherapy-mediated upregulation in unirradiated tumors. Conditional Sfrp2 knockout in CAFs boosts the abscopal effect by rewiring the vascular-immune microenvironment to promote CD8(+) T cell recruitment to unirradiated tumors. In vivo lineage tracing reveals that elevated SFRP2 correlates with radioimmunotherapy-driven pericyte lineage commitment. Serum proteomics reveals that irradiated-tumor-secreted PAI-1 triggers distant tumor pericyte cell-fate transition into SFRP2(high) CAFs via the LRP1/p65 axis. Pharmacologically blocking SFRP2 or PAI-1 enhances the abscopal effect in humanized patient-derived xenograft models. Our findings collectively illustrate that PAI-1-induced SFRP2(high) CAFs serve as critical stromal regulator to hijack the abscopal effect, providing promising targets for enhancing radioimmunotherapy effectiveness. | Cancer cell | 12/03/2025 |
('LID', '10.1038/s41590-025-02104-y') | Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation. | Feng, Xiaogang, Andersson, Tilde, Flüchter, Pascal, Gschwend, Julia, Berest, Ivan, Muff, Julian L, Lechner, Antonie, Gondrand, Aurelia, Westermann, Patrick, Brander, Nina, Carchidi, Daniele, De Tenorio, Jeshua C, Pan, Tianlang, Boehm, Ulrich, Klose, Christoph S N, Artis, David, Messner, Christoph B, Leinders-Zufall, Trese, Zufall, Frank, Schneider, Christoph | The tuft cell-group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca(2+) flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states. | Nature immunology | 12/03/2025 |
('LID', '10.1126/science.adm9805') | Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling. | Koundouros, Nikos, Nagiec, Michal J, Bullen, Nayah, Noch, Evan K, Burgos-Barragan, Guillermo, Li, Zhongchi, He, Long, Cho, Sungyun, Parang, Bobak, Leone, Dominique, Andreopoulou, Eleni, Blenis, John | Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid-binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype. | Science (New York, N.Y.) | 14/03/2025 |
('LID', '10.5546/aap.2020.eng.433') | Scientific paper management. How do articles get published in medical journals? | Serra, María E | The life-cycle of a manuscript from writing to publication is not usually taught during health care professionals' training. This article reviews the process that goes from from the authors' decision to communicate to its eventual publication, detailing practical aspects to be considered in each step. The responsibilities of the different roles involved are specified: author, editor, and reviewer. International guidelines supporting the writing of medical-scientific papers are also described. | Archivos argentinos de pediatria | 00/12/2020 |
('LID', '10.1053/j.gastro.2025.01.252') | Mucosal macrophages govern intestinal regeneration in response to injury. | Moraitis, Ilias, Taelman, Jasin, Arozamena, Borja, Mularoni, Loris, Wienskowska, Olga, Sanjuan Garriga, Xavier, Arregui, Laura, Stefanovic, Milica, Modolell Farré, Ignasi, Guedea, Ferran, Diaz, Mònica, Guiu, Jordi | BACKGROUND & AIMS: Cancer patients treated with radiotherapy in the abdominal and pelvic cavity develop radiation-induced enteritis, a condition that impairs their quality of life. Radiation injury depletes proliferative intestinal stem cells (ISCs); in response to this, the epithelium activates a regenerative program that facilitates the healing of the intestine. However, the mechanisms that induce the activation of the intestinal regenerative program are poorly characterized. METHODS: In this study, we induced radiation-induced enteritis in mice through abdominal irradiation, mimicking clinical scenarios. Through imaging and flow cytometric analysis, we investigated the recruitment of macrophages to the small intestine during injury and healing. Additionally, we developed a co-culture system for mouse and human intestinal organoids and macrophages to explore the crosstalk between these cells. Then combining in vivo ablation of macrophages, fluorescent lineage tracing, imaging, bulk RNA-sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), human intestinal organoids and cell trajectory analysis, we study at cellular and molecular level the macrophage induction of intestinal regeneration. RESULTS: Our findings revealed that macrophages are recruited around the intestinal stem cell compartment upon radiation injury, promoting a fetal-like reprogramming and proliferation of epithelial cells that drives the regeneration process. In contrast macrophage ablation led to compromised regeneration. Moreover, our scRNA-seq analysis identified key secreted molecules, nrg1 and spp1, as pivotal players in regulating this process. Additionally, characterization of human macrophage/organoid co-cultures and cell trajectory inference confirmed the conservation of macrophages' role in triggering the regenerative program in primary human cells. CONCLUSIONS: This study identifies macrophages as essential contributors to intestinal regeneration beyond their innate immune response. Targeting macrophages therapeutically may hold promise in enhancing regeneration and improving the quality of life for cancer survivors. | Gastroenterology | 03/03/2025 |
('LID', '10.1186/s40359-023-01477-9') | The development of the fear of earthquake scale: validity and reliability study in Türkiye after the 2023 earthquake. | Sarı, Tuğba, Taşdelen-Karçkay, Arzu, Tarcan, Şule | BACKGROUND: In 2023, Türkiye experienced a significant earthquake disaster that profoundly impacted 11 provinces. The enduring consequences of these earthquakes on daily life triggered widespread fears and anxieties in society, leading to scholarly investigations in this field. OBJECTIVE: The primary objective of this study was to create and evaluate the psychometric properties of the Fear of Earthquake Scale (FES), a modified adaptation of the Fear of COVID-19 Scale (FCV-19 S), tailored to measure earthquake-related experiences in Türkiye. METHODS: A total of 315 Turkish adult participants (106 men, 209 women), with a mean age of 37.71 years, completed the FES, along with the Brief Psychological Resilience Scale (BPRS). Psychometric analyses included confirmatory factor analysis as well as the evaluation of alternative factor structures, internal consistency, convergent validity, and criterion validity with respect to resilience. RESULTS: The findings indicate that the Turkish version of the Fear of Earthquake Scale has strong psychometric properties in terms of validity and reliability. After assessing various factor structures, it was observed that the two-factor model which represents the emotional and somatic response to fear, exhibited the best-fit values The Cronbach's alpha coefficients were calculated as 0.89 for the overall FES, 0.84 for the emotional subscale and 0.86 for the somatic subscale, indicating high internal consistency. Additionally, the negative correlation between resilience and the FES supports the criterion validity of the scale, and multi-group confirmatory factor analyses proved that measurement invariance held across genders and whether they experienced an earthquake or not for all groups. Furthermore, the results of the study revealed that women and individuals with prior earthquake experience reported higher levels of fear of earthquakes. CONCLUSIONS: The FES emerged as a reliable and valid tool for assessing earthquake-related fears among the Turkish population. | BMC psychology | 07/12/2023 |
('LID', '10.1126/science.ado4188') | Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis. | Lin, Hui, Ma, Chuanshun, Cai, Kui, Guo, Lulu, Wang, Xuemei, Lv, Lin, Zhang, Chao, Lin, Jun, Zhang, Daolai, Ye, Chuan, Wang, Tengwei, Huang, Shenming, Han, Jifei, Zhang, Zihao, Gao, Junyan, Zhang, Mingxiang, Pu, Zhao, Li, Fengyang, Guo, Yongyuan, Zhou, Xiaojun, Qin, Chengxue, Yi, Fan, Yu, Xiao, Kong, Wei, Jiang, Changtao, Sun, Jin-Peng | Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify FPR2 as a membrane receptor that specifically binds long-chain ceramides (C14-C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via G(i)-cyclic AMP signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with G(i) trimers bound to C16:0, C18:0 and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2. | Science (New York, N.Y.) | 13/03/2025 |
('LID', '10.1038/s41586-025-08668-x') | Spatial immune scoring system predicts hepatocellular carcinoma recurrence. | Jia, Gengjie, He, Peiqi, Dai, Tianli, Goh, Denise, Wang, Jiabei, Sun, Mengyuan, Wee, Felicia, Li, Fuling, Lim, Jeffrey Chun Tatt, Hao, Shuxia, Liu, Yao, Lim, Tony Kiat Hon, Ngo, Nye-Thane, Tao, Qingping, Wang, Wei, Umar, Ahitsham, Nashan, Björn, Zhang, Yongchang, Ding, Chen, Yeong, Joe, Liu, Lianxin, Sun, Cheng | Given the high recurrence rates of hepatocellular carcinoma (HCC) post-resection(1-3), improved early identification of patients at high risk for post-resection recurrence would help to improve patient outcomes and prioritize healthcare resources(4-6). Here we observed a spatial and HCC recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumour centre from 61 patients. Using extreme gradient boosting and inverse-variance weighting, we developed the tumour immune microenvironment spatial (TIMES) score based on the spatial expression patterns of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM and HLA-DRB1) to predict HCC recurrence risk. The TIMES score (hazard ratio = 88.2, P < 0.001) outperformed current standard tools for patient risk stratification including the TNM and BCLC systems. We validated the model in 231 patients from five multicentred cohorts, achieving a real-world accuracy of 82.2% and specificity of 85.7%. The predictive power of these biomarkers emerged through the integration of their spatial distributions, rather than individual marker expression levels alone. In vivo models, including NK cell-specific Spon2-knockout mice, revealed that SPON2 enhances IFNγ secretion and NK cell infiltration at the invasive front. Our study introduces TIMES, a publicly accessible tool for predicting HCC recurrence risk, offering insights into its potential to inform treatment decisions for early-stage HCC. | Nature | 12/03/2025 |
('LID', '10.1021/ja503015f') | Thieno-pyrrole-fused 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-fullerene dyads: utilization of near-infrared sensitizers for ultrafast charge separation in donor-acceptor systems. | Bandi, Venugopal, Das, Sushanta K, Awuah, Samuel G, You, Youngjae, D'Souza, Francis | Donor-acceptor dyads featuring near-IR sensitizers derived from thieno-pyrrole-fused BODIPY (abbreviated as SBDPiR) and fullerene, C60 have been newly synthesized and characterized. Occurrence of ultrafast photoinduced electron transfer (PET) leading to the formation of charge-separated state in these dyads, capable of harvesting light energy from the near-IR region, is established from femtosecond transient absorption studies. | Journal of the American Chemical Society | 28/05/2014 |
('LID', '10.1186/s12883-025-04122-7') | Cognition, mental health, and quality of life in patients with chronic and episodic migraine during the interictal period. | López-Medina, Diana Carolina, Arboleda-Ramírez, Alejandra, Ríos-Díaz, Sara, Zambrano-Cruz, Renato, Arboleda-Jaramillo, Andrés, Betancur-Henao, Cristian, Henao-Pérez, Marcela | INTRODUCTION: Migraine is a highly prevalent and disabling condition, not only due to its painful symptoms but also because of its significant impact on mental health and cognitive functioning, leading to a considerable deterioration in quality of life. This study aimed to evaluate the cognitive profile, mental health, and quality of life in patients with chronic and episodic migraine during the interictal period, and to explore their relationship with sociodemographic and clinical variables. METHOD: This observational, descriptive, cross-sectional analytical study included 60 patients diagnosed with chronic or episodic migraine, who were enrolled in a health program for headache patients between 2010 and 2016. Cognitive function, anxiety and/or depression symptoms, and quality of life during the interictal period were assessed. Descriptive analyses were conducted, and associations were evaluated by configuring primary (type of migraine) and alternative events (cognitive impairment, depression and/or anxiety, and poor quality of life). RESULTS: The mean age of the participants was 45 years (SD ± 8), with 83.3% being women and 93.3% belonging to middle and low socioeconomic strata. Of the 60 patients, 83.3% (50) were diagnosed with chronic migraine, while the remaining had episodic migraine. The use of one or more cognition-altering medications was observed in 90% of patients with chronic migraine and 60% of those with episodic migraine (p = 0.02). Anxiety was more prevalent in patients with episodic migraine, whereas depression was more common among those with chronic migraine. Female gender, middle socioeconomic status, and longer disease duration were significantly associated with chronic migraine. Among the 57 patients who completed the Mini-Mental State Examination, 38.6% had cognitive impairment, which decreased with longer migraine duration and better social interaction. Memory and selective attention were the most affected cognitive domains in both groups. No significant associations were found for the other variables after adjusting for confounders. CONCLUSIONS: Chronic migraine significantly impacts mental health, cognition, and quality of life, with depression and cognitive impairments being prevalent. Social interaction and longer disease duration may protect against cognitive decline, highlighting the need for multidisciplinary, personalized interventions addressing neurological and psychosocial challenges. | BMC neurology | 14/03/2025 |
('LID', '10.1038/s41392-025-02170-6') | Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer. | Ma, Sheng, Wang, Zixian, Xiong, Zezhong, Ge, Yue, Xu, Meng-Yao, Zhang, Junbiao, Peng, Yuzheng, Zhang, Qin, Sun, Jiaxue, Xi, Zirui, Peng, Hao, Xu, Wenjie, Wang, Yanan, Li, Le, Zhang, Chunyu, Chao, Zheng, Wang, Baojun, Gao, Xu, Zhang, Xu, Wei, Gong-Hong, Wang, Zhihua | Enhancer RNAs (eRNAs), a subclass of non-coding RNAs transcribed from enhancer regions, have emerged as critical regulators of gene expression; however, their functional roles in prostate cancer remain largely unexplored. In this study, we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues. By incorporating chromatin immunoprecipitation sequencing data, we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways. Among these, lactotransferrin-eRNA (LTFe) was markedly downregulated in prostate cancer tissues, with functional analyses revealing its tumor-suppressive role. Mechanistically, LTFe promotes the transcription of its target gene, lactotransferrin (LTF), by interacting with heterogeneous nuclear ribonucleoprotein F (HNRNPF) and facilitating enhancer-promoter chromatin interactions. Furthermore, we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport. Notably, androgen receptor (AR) signaling disrupts LTFe-associated chromatin looping, leading to ferroptosis resistance. Therapeutically, co- administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth, offering a promising strategy for castration-resistant prostate cancer. Collectively, this study provides novel insights into the mechanistic role of eRNAs in prostate cancer, highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes. | Signal transduction and targeted therapy | 14/03/2025 |
('LID', '10.1016/S0140-6736(25)00263-6') | A multifaceted intervention to improve diagnosis and early management of hospitalised patients with suspected acute brain infections in Brazil, India, and Malawi: an international multicentre intervention study. | Singh, Bhagteshwar, Lipunga, Gareth D, Thangavelu, Premkumar, Dhar, Shalley, Ferreira Cronemberger, Lorena, Abhilash, Kundavaram Paul Prabhakar, Abraham, Asha Mary, de Brito, Carlos Alexandre Antunes, Brito Ferreira, Maria Lúcia, Chandrashekar, Nagarathna, Duarte, Rui, Fajardo Modol, Anna, Ghale, Ben Chirag, Kang, Gagandeep, Gowda, Vykuntaraju K, Kuriakose, Kevin, Lant, Suzannah, Mallewa, Macpherson, Mbale, Emmie, Moore, Shona C, Mwangalika, Gloria, Kamath, Prasanna B T, Navvuga, Patricia, Nyondo-Mipando, Alinane Linda, Phiri, Tamara J, Pimentel Lopes de Melo, Camila, Pradeep, B S, Rawlinson, Rebecca, Sheha, Irene, Thomas, Priya Treesa, Newton, Charles R, de Sequeira, Patricia Carvalho, Sejvar, James J, Dua, Tarun, Turtle, Lance, Verghese, Valsan Philip, Arraes, Luciano Wagner de Melo Santiago, Desmond, Nicola, Easton, Ava, Jones, Jessica Anne, Lilford, Richard J, Netravathi, M, McGill, Fiona, Michael, Benedict D, Mwapasa, Victor, Griffiths, Michael J, Parry, Christopher M, Ravi, Vasanthapuram, Burnside, Girvan, Cornick, Jennifer, França, Rafael Freitas de Oliveira, Desai, Anita S, Rupali, Priscilla, Solomon, Tom | BACKGROUND: Brain infections pose substantial challenges in diagnosis and management and carry high mortality and morbidity, especially in low-income and middle-income countries. We aimed to improve the diagnosis and early management of patients admitted to hospital (adults aged 16 years and older and children aged >28 days) with suspected acute brain infections at 13 hospitals in Brazil, India, and Malawi. METHODS: With hospital stakeholders, policy makers, and patient and public representatives, we co-designed a multifaceted clinical and laboratory intervention, informed by an evaluation of routine practice. The intervention, tailored for each setting, included a diagnostic and management algorithm, a lumbar puncture pack, a testing panel, and staff training. We used multivariable logistic regression and interrupted time series analysis to compare the coprimary outcomes-the percentage of patients achieving a syndromic diagnosis and the percentage achieving a microbiological diagnosis before and after the intervention. The study was registered at ClinicalTrials.gov (NCT04190303) and is complete. FINDINGS: Between Jan 5, 2021, and Nov 30, 2022, we screened 10 462 patients and enrolled a total of 2233 patients at 13 hospital sites connected to the four study centres in Brazil, India, and Malawi. 1376 (62%) were recruited before the intervention and 857 (38%) were recruited after the intervention. 2154 patients (96%) had assessment of the primary outcome (1330 [62%] patients recruited pre-intervention and 824 [38%] recruited post-intervention). The median age across centres was 23 years (IQR 6-44), with 1276 (59%) being adults aged 16 years or older and 888 (41%) children aged between 29 days and 15 years; 1264 (59%) patients were male and 890 (41%) were female. Data on race and ethnicity were not recorded. 1020 (77%) of 1320 patients received a syndromic diagnosis before the intervention, rising to 701 (86%) of 813 after the intervention (adjusted odds ratio [aOR] 1·81 [95% CI 1·40-2·34]; p<0·0001). A microbiological diagnosis was made in 294 (22%) of 1330 patients pre-intervention, increasing to 250 (30%) of 824 patients post-intervention (aOR 1·46 [95% CI 1·18-1·79]; p=0·00040). Interrupted time series analysis confirmed that these increases exceeded a modest underlying trend of improvement over time. The percentage receiving a lumbar puncture, time to appropriate therapy, and functional outcome also improved. INTERPRETATION: Diagnosis and management of patients with suspected acute brain infections improved following introduction of a simple intervention package across a diverse range of hospitals on three continents. The intervention is now being implemented in other settings as part of the WHO Meningitis Roadmap and encephalitis control initiatives. FUNDING: UK National Institute for Health and Care Research. | Lancet (London, England) | 10/03/2025 |
('LID', '10.1016/j.neuron.2025.02.014') | Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum. | Ali, Muhammad, Timsina, Jigyasha, Western, Daniel, Liu, Menghan, Beric, Aleksandra, Budde, John, Do, Anh, Heo, Gyujin, Wang, Lihua, Gentsch, Jen, Schindler, Suzanne E, Morris, John C, Holtzman, David M, Ruiz, Agustin, Alvarez, Ignacio, Aguilar, Miquel, Pastor, Pau, Rutledge, Jarod, Oh, Hamilton, Wilson, Edward N, Guen, Yann Le, Khalid, Rana R, Robins, Chloe, Pulford, David J, Tarawneh, Rawan, Ibanez, Laura, Wyss-Coray, Tony, Sung, Yun Ju, Cruchaga, Carlos | Changes in β-amyloid (Aβ) and hyperphosphorylated tau (T) in brain and cerebrospinal fluid (CSF) precede Alzheimer's disease (AD) symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 analytes (2,029 unique proteins) dysregulated in AD. Of these, 865 (43%) were previously reported, and 1,164 (57%) are novel. The identified proteins cluster in four different pseudo-trajectories groups spanning the AD continuum and were enriched in pathways including neuronal death, apoptosis, and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfunction (mid stages), brain plasticity and longevity (mid stages), and microglia-neuron crosstalk (late stages). Using machine learning, we created and validated highly accurate and replicable (area under the curve [AUC] > 0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD. | Neuron | 12/03/2025 |
('LID', '10.1016/j.cell.2025.02.012') | Simultaneous CRISPR screening and spatial transcriptomics reveal intracellular, intercellular, and functional transcriptional circuits. | Binan, Loϊc, Jiang, Aiping, Danquah, Serwah A, Valakh, Vera, Simonton, Brooke, Bezney, Jon, Manguso, Robert T, Yates, Kathleen B, Nehme, Ralda, Cleary, Brian, Farhi, Samouil L | Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but they have not yet leveraged the power of highly plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present a combination of imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs (Perturb-FISH). Perturb-FISH recovers intracellular effects that are consistent with single-cell RNA-sequencing-based readouts of perturbation effects (Perturb-seq) in a screen of lipopolysaccharide response in cultured monocytes, and it uncovers intercellular and density-dependent regulation of the innate immune response. Similarly, in three-dimensional xenograft models, Perturb-FISH identifies tumor-immune interactions altered by genetic knockout. When paired with a functional readout in a separate screen of autism spectrum disorder risk genes in human-induced pluripotent stem cell (hIPSC) astrocytes, Perturb-FISH shows common calcium activity phenotypes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a general method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution. | Cell | 10/03/2025 |
('LID', '10.1016/j.intimp.2025.114388') | Indole-3-propionic acid alleviates DSS-induced colitis in mice through macrophage glycolipid metabolism. | Li, Jiahong, Zou, Peicen, Xiao, Ruiqi, Wang, Yajuan | Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease for which current therapeutic approaches still face many dilemmas, and targeting macrophage polarization and metabolism for the treatment of this disease is a potentially effective strategy. The gut microbial metabolite indole-3-propionic acid (IPA) has favorable anti-inflammatory and antioxidant effects and plays a role in a variety of disease models. IPA is effective in the treatment of UC, but the underlying mechanisms have not been well explored. In the present study, we investigated the mechanisms by which IPA ameliorates colitis in mice from the perspective of macrophage polarization and metabolism. In this study, mice colitis was induced by sodium dextran sulfate and treated with oral IPA. RAW264.7 cells were induced by LPS to polarize into M1 macrophages and treated with IPA. The results showed that IPA could improve colitis by inhibiting M1 polarization of colonic macrophages and promoting M2 polarization. The inhibition of IPA on M1 macrophages was verified in vitro through JNK/MAPK pathway, which inhibited the glycolysis of macrophages. IPA promotes macrophage M2 polarization and enhances fatty acid oxidation through upregulating of CPT1A and ACSL1, which may be related to the activation of PPAR-γ. In summary, IPA can improve colitis by regulating macrophage glucose and lipid metabolism, and targeting intestinal macrophage metabolism may be an effective target for the treatment of UC. | International immunopharmacology | 13/03/2025 |
('LID', '10.1016/j.foodchem.2018.04.067') | Transglutaminase mediated microencapsulation of sea buckthorn supercritical CO(2) extract in whey protein isolate and valorization in highly value added food products. | Mihalcea, Liliana, Turturică, Mihaela, Barbu, Vasilica, Ioniţă, Elena, Pătraşcu, Livia, Cotârleţ, Mihaela, Dumitraşcu, Loredana, Aprodu, Iuliana, Râpeanu, Gabriela, Stănciuc, Nicoleta | Sea buckthorn carotenoids extracted using CO(2) supercritical fluids method were encapsulated within whey proteins isolate by transglutaminase (TG) mediated crosslinking reaction, coacervation and freeze drying. The encapsulation efficiency was 36.23 ± 1.58%, with β-carotene the major carotenoid present in the powder. The confocal analysis revealed that TG-ase mediated cross-linking reaction enhanced the complexes stability to such a manner that a double microencapsulation was performed. The powder showed an antioxidant activity of 2.16 ± 0.14 mMol Trolox/g DW and an antifungal activity against Penicillium expansum MIUG M11. Four variants of domestic ice creams were obtained, with a total carotenoids content variation of 1.63 ± 0.03 mg/g D.W. in sample with 2% powder and 6.38 ± 0.04 mg/g D.W. in samples with 4% extract, having satisfactory antioxidant activity. The storage stability test showed a decrease in both total carotenoids content and antioxidant activity in all samples during 21 days at -18 °C. A protective effect of microencapsulation was evidenced. | Food chemistry | 01/10/2018 |
('LID', '10.1016/S0140-6736(24)02722-3') | Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. | Xiong, Anwen, Wang, Lei, Chen, Jianhua, Wu, Lin, Liu, Baogang, Yao, Jun, Zhong, Hua, Li, Jie, Cheng, Ying, Sun, Yulan, Ge, Hui, Yao, Jifang, Shi, Qin, Zhou, Ming, Chen, Bolin, Han, Zhengxiang, Wang, Jinliang, Bu, Qing, Zhao, Yanqiu, Chen, Junqiang, Nie, Ligong, Li, Gaofeng, Li, Xingya, Yu, Xinmin, Ji, Yinghua, Sun, Daqiang, Ai, Xiaohong, Chu, Qian, Lin, Yu, Hao, Jiqing, Huang, Dingzhi, Zhou, Chengzhi, Shan, Jinlu, Yang, Hongzhong, Liu, Xuewen, Wang, Jing, Shang, Yanhong, Mei, Xiaodong, Yang, Jie, Lu, Dongmei, Hu, Mingxiu, Wang, Zhongmin Maxwell, Li, Baiyong, Xia, Michelle, Zhou, Caicun | BACKGROUND: Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer. METHODS: HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later. FINDINGS: Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38-0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1-49% (HR 0·54 [95% CI 0·37-0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29-0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups. INTERPRETATION: Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer. FUNDING: Akeso Biopharma. | Lancet (London, England) | 08/03/2025 |
('LID', '10.1002/anie.201601989') | Positioning a Carbon-Fluorine Bond over the π Cloud of an Aromatic Ring: A Different Type of Arene Activation. | Holl, Maxwell Gargiulo, Struble, Mark D, Singal, Prakhar, Siegler, Maxime A, Lectka, Thomas | It is known that the fluoro group has only a small effect on the rates of electrophilic aromatic substitutions. Imagine instead a carbon-fluorine (C-F) bond positioned tightly over the π cloud of an aryl ring-such an orthogonal, noncovalent arrangement could instead stabilize a positively charged arene intermediate or transition state, giving rise to novel electrophilic aromatic substitution chemistry. Herein, we report the synthesis and study of molecule 1, containing a rigid C-F⋅⋅⋅Ar interaction that plays a prominent role in both its reaction chemistry and spectroscopy. For example, we established that the C-F⋅⋅⋅Ar interaction can bring about a >1500 fold increase in the relative rate of an aromatic nitration reaction, affording functionalization on the activated ring exclusively. Overall, these results establish fluoro as a through-space directing/activating group that complements the traditional role of fluorine as a slightly deactivating aryl substituent in nitrations. | Angewandte Chemie (International ed. in English) | 11/07/2016 |
('LID', '10.1038/s41591-025-03600-2') | A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial. | Ma, Yuxiang, Yang, Yunpeng, Huang, Yan, Fang, Wenfeng, Xue, Jinhui, Meng, Xiangjiao, Fan, Yun, Fu, Siqing, Wu, Lin, Zheng, Yulong, Liu, Jian, Liu, Zhihua, Zhuang, Wu, Rosen, Seth, Qu, Song, Li, Bihui, Li, Mingjun, Zhao, Yanqiu, Yang, Shujun, Ji, Yinghua, Sommerhalder, David, Luo, Suxia, Yang, Kunyu, Li, Jingao, Lv, Dongqing, Zhang, Peng, Zhao, Yuanyuan, Hong, Shaodong, Zhang, Yang, Zhao, Shen, Chin, Steve, Zhang, Xian, Lian, Wei, Cai, Jiaqiang, Xue, Tongtong, Zhang, Li, Zhao, Hongyun | Antibody-drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg(-1), and the recommended expansion dose was selected as 2.0 mg kg(-1) and 2.4 mg kg(-1) every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 . | Nature medicine | 13/03/2025 |
('LID', '10.1126/science.adv3451') | Cryo-EM reveals mechanisms of natural RNA multivalency. | Wang, Liu, Xie, Jiahao, Gong, Tao, Wu, Hao, Tu, Yifan, Peng, Xin, Shang, Sitong, Jia, Xinyu, Ma, Haiyun, Zou, Jian, Xu, Sheng, Zheng, Xin, Zhang, Dong, Liu, Yang, Zhang, Chong, Luo, Yongbo, Huang, Zirui, Shao, Bin, Ying, Binwu, Cheng, Yu, Guo, Yingqiang, Lai, Ying, Huang, Dingming, Liu, Jianquan, Wei, Yuquan, Sun, Siqi, Zhou, Xuedong, Su, Zhaoming | Homo-oligomerization of biological macromolecules leads to functional assemblies that are critical to understanding various cellular processes. However, RNA quaternary structures have been rarely reported. Comparative genomics analysis has identified RNA families containing hundreds of sequences that adopt conserved secondary structures and likely fold into complex three-dimensional (3D) structures. We use cryo-electron microscopy (cryo-EM) to determine structures from four RNA families, including ARRPOF and OLE forming dimers, and ROOL and GOLLD forming hexameric, octameric and dodecameric nanostructures, at 2.6 to 4.6 Å resolutions. These homo-oligomeric assemblies reveal a plethora of structural motifs that contribute to RNA multivalency, including kissing loop, palindromic base-pairing, A-stacking, metal ion coordination, pseudoknot and minor-groove interactions. These results provide the molecular basis of intermolecular interactions driving RNA multivalency with potential functional relevance. | Science (New York, N.Y.) | 13/03/2025 |
('LID', '10.1016/j.ccell.2025.02.009') | Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis. | Chang, Jiang, Lu, Junting, Liu, Qingyi, Xiang, Tao, Zhang, Shaosen, Yi, Yonglin, Li, Dongxu, Liu, Tianyuan, Liu, Zeyuan, Chen, Xinjie, Dong, Zhenghao, Li, Cainan, Yi, HanZhang, Yu, Siqi, Huang, Luwei, Qu, Fangfei, Wang, Mengdi, Wang, Dehe, Dong, Hao, Cheng, Guoyu, Zhu, Liang, Li, Jiachen, Li, Chenying, Wu, Pujie, Xie, Xiaoting, Teschendorff, Andrew E, Lin, Dongxin, Wang, Xiaoqun, Wu, Chen | Cancer development involves the co-evolution of cancer cells and their surrounding microenvironment, yet the dynamics of this interaction within the physical architecture remains poorly understood. Here, we present a spatial transcriptomic map at single-cell resolution, encompassing 127 multi-stage fields of view from 43 patients, to chart the evolutionary trajectories of human esophageal squamous cell carcinoma (ESCC). By analyzing 6.4 million cells, we reveal that ESCC progression is driven by a proliferative epithelial cell subpopulation that acquires dedifferentiated and invasive characteristics. At the late precancerous stage, these cells disrupt the epithelial-stromal interface and recruit normal fibroblasts via JAG1-NOTCH1 signaling, transforming them into cancer-associated fibroblasts (CAFs). This interaction leads to the formation of a "CAF-Epi" (CAF and epithelial cell) niche at the tumor edge that shields the tumor from immune surveillance. The CAF-Epi niche formation is a key indicator of progression in ESCC and other squamous cell carcinomas and patient outcomes. | Cancer cell | 10/03/2025 |
('LID', '10.1158/0008-5472.CAN-24-1879') | Genomic Characterization of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features in Black Individuals. | Lawson-Michod, Katherine A, Marks, Jeffrey R, Collin, Lindsay J, Nix, David A, Davidson, Natalie R, Huff, Chad D, Yu, Yao, Atkinson, Aaron, Johnson, Courtney E, Salas, Lucas A, Peres, Lauren C, Greene, Casey S, Schildkraut, Joellen M, Doherty, Jennifer A | Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared to historical data from The Cancer Genome Atlas (TCGA). Despite technical differences (e.g., formalin-fixed vs. fresh-frozen tissue), the distribution of mutations and their variant classifications for major HGSC genes were nearly identical across study populations. However, de novo significantly mutated gene analysis identified genes not previously reported in the TCGA analysis, including the oncogene KRAS and the potential tumor suppressor OBSCN. The prevalence of the homologous recombination deficiency signature was higher among Black individuals with the immunoreactive gene expression subtype compared with the mesenchymal and proliferative subtypes. These findings were confirmed by comparing the data from Black patients to 123 White patients with identical tissue collection and processing. Overall, this study suggests that, while most features of HGSC tumor phenotypes are similar in Black and White populations, there may be clinically-relevant differences. If validated, these phenotypes may be important for clinical decision-making and would have been missed by characterizing tumors from White individuals only. | Cancer research | 10/03/2025 |
('LID', '10.1016/S2468-1253(24)00390-X') | The intestinal barrier: a pivotal role in health, inflammation, and cancer. | Neurath, Markus F, Artis, David, Becker, Christoph | The intestinal barrier serves as a boundary between the mucosal immune system in the lamina propria and the external environment of the intestinal lumen, which contains a diverse array of microorganisms and ingested environmental factors, including pathogens, food antigens, toxins, and other foreign substances. This barrier has a central role in regulating the controlled interaction between luminal factors and the intestinal immune system. Disruptions of intestinal epithelial cells, which serve as a physical barrier, or the antimicrobial peptides and mucins they produce, which act as a chemical barrier, can lead to a leaky gut. In this state, the intestinal wall is unable to efficiently separate the intestinal flora and luminal contents from the intestinal immune system. The subsequent activation of the immune system has an important role in the pathogenesis of inflammatory bowel disease, as well as in metabolic dysfunction-associated steatohepatitis, primary sclerosing cholangitis, and colorectal cancer. Dysregulated intestinal barrier integrity has also been described in patients with chronic inflammatory diseases outside the gastrointestinal tract, including rheumatoid arthritis and neurodegenerative disorders. Mechanistic studies of barrier dysfunction have revealed that the subsequent local activation and systemic circulation of activated immune cells and the cytokines they secrete, as well as extracellular vesicles, promote proinflammatory processes within and outside the gastrointestinal tract. In this Review, we summarise these findings and highlight several new therapeutic concepts currently being developed that attempt to control inflammatory processes via direct or indirect modulation of intestinal barrier function. | The lancet. Gastroenterology & hepatology | 11/03/2025 |
('LID', '10.1016/j.ccell.2025.02.026') | Distinct CD8(+) T cell dynamics associate with response to neoadjuvant cancer immunotherapies. | Li, Housaiyin, Zandberg, Dan P, Kulkarni, Aditi, Chiosea, Simion I, Santos, Patricia M, Isett, Brian R, Joy, Marion, Sica, Gabriel L, Contrera, Kevin J, Tatsuoka, Curtis M, Brand, Matthias, Duvvuri, Umamaheswar, Kim, Seungwon, Kubik, Mark, Sridharan, Shaum, Tu, Fei, Chen, Jie, Bruno, Tullia C, Vignali, Dario A A, Cillo, Anthony R, Bao, Riyue, Wang, Jing Hong, Vujanovic, Lazar, Ferris, Robert L | We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8(+) tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8(+) TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (T(EM)/T(RM)). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing T(EM)/T(RM) CD8(+) TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8(+) T cells. | Cancer cell | 12/03/2025 |
('LID', '10.1038/s41593-025-01914-5') | Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration. | Omar, Omar M F, Kimble, Amy L, Cheemala, Ashok, Tyburski, Jordan D, Pandey, Swati, Wu, Qian, Reese, Bo, Jellison, Evan R, Hao, Bing, Li, Yunfeng, Yan, Riqiang, Murphy, Patrick A | Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases. | Nature neuroscience | 14/03/2025 |
('LID', '10.1016/j.freeradbiomed.2025.03.014') | Astragalin alleviates lipopolysaccharide-induced depressive-like behavior in mice by preserving blood-brain barrier integrity and suppressing neuroinflammation. | Cao, Min-Min, Guo, Zhe, Wang, Jun, Ma, Hui-Yong, Qin, Xiao-Yan, Hu, Yang, Lan, Rongfeng | Astragalin (AST) is a flavonoid glycoside commonly found in edible plants and medicinal herbs with a variety of therapeutic effects. This study aimed to investigate whether AST protects the integrity of the blood-brain barrier (BBB) and inhibits neuroinflammation, thereby alleviating depressive-like behaviors. LPS-stimulated cultured cells and LPS-induced BBB disruption and depressive-like behavior mice models were employed. We founded that AST inhibited LPS-induced inflammatory responses in microglial BV2 cells and protected SH-SY5Y cells from inflammatory injury. In mice, AST effectively ameliorated LPS-induced depressive-like behaviors, which was attributed to its ability to maintain BBB integrity and inhibit inflammatory damage caused by LPS invasion. Furthermore, AST suppressed LPS-induced activation of glial cells, protecting neuronal dendritic spines, synapses, and mitochondria from inflammatory damage. It also reduced the elevation of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, and normalized the aberrant activation of inflammatory signaling pathways, including RIPK1/RIPK3/MLKL and mTOR/NF-κB. In conclusion, AST protects BBB integrity and brain tissue from inflammatory damage, offering new insights for drug development and clinical interventions in systemic inflammatory responses, such as sepsis-induced encephalitis. | Free radical biology & medicine | 13/03/2025 |
('LID', '10.1001/jamanetworkopen.2025.0648') | Mizoribine or Cyclophosphamide for Lupus Nephritis: A Randomized Clinical Trial. | Dong, Zheyi, Luo, Ping, Sun, Shiren, Ni, Zhaohui, He, Yani, Huang, Xiangyang, Liu, Zhangsuo, Wu, Zhenbiao, Zhang, Xinzhou, Liao, Yunhua, Zhao, Jianhong, Lin, Hongli, Zhang, Xiao, Fu, Rongguo, Ding, Guohua, Xu, Yan, Wang, Lihua, Xiao, Yuefei, Shi, Shumei, Zuo, Xiaoxia, Li, Zhanguo, Qiao, Li, Wang, Rong, Li, Wenge, Wan, Jianxin, Li, Ying, Guan, Tianjun, Deng, Xiaoli, Wu, Xiaoyan, Zheng, Hongguang, Chen, Jianghua, He, Lan, Yamaguchi, Seika, Wang, Hua, Cai, Guang-Yan, Zhang, Li, Chen, Xiangmei | IMPORTANCE: Lupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking. OBJECTIVE: To assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020. INTERVENTIONS: Oral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid. MAIN OUTCOMES AND MEASURES: Total remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified). RESULTS: A total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively). CONCLUSIONS AND RELEVANCE: This randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02256150. | JAMA network open | 03/03/2025 |
('LID', '10.1038/s42255-025-01235-8') | SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1. | Zhao, Qian, Jing, Ying, Jiang, Xiaoyu, Zhang, Xin, Liu, Feifei, Huang, Haoyan, Zhang, Zhihua, Wang, Haijun, Sun, Shuhui, Ma, Shuai, Zhang, Weiqi, Yu, Yang, Fu, Xiaobing, Zhao, Guoguang, Qu, Jing, Wang, Si, Liu, Guang-Hui | Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5-TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration. | Nature metabolism | 14/03/2025 |
('AID', '10.3347/kjp.1983.21.1.41') | [Aspartate And Alanine Aminotransferase In Fasciola Hepatica]. | Park, Sun Hyo, Kwon, Nyon Soo, Lee, Hi Sung, Song, Chul Yong | The activity and distribution of aspartate aminotransferase (EC 2.6.1.1) and alanine aminotransferase (EC 2.6.1.2) in adult Fasciola hepatica have been studied. Fasciola hepatica was fractionated by differential centrifugation into nuclear, mitochondrial and cytosolic fractions. The activity of GOT and GPT was measured by the method of Reitman and Frankel. Isozyme patterns of those enzyme were also examined by DEAE-cellulose column chromatography. The results obtained were as follows: 1. The activity of aspartate and alanine aminotransferase was about 0.55 unit and 0.92 unit per 1 g of Fasciola hepatica, respectively. 2. The activity of those enzymes was relatively low compared with those in mammalian tissues. 3. The distribution of aspartate aminotransferase in the subcellular organelles showed that 71 % of the activity was in cytosolic, 24 % in mitochondrial and 5 % was in nuclear fraction. 4. About 22 % of the total alanine aminotransferase activity was found in the mitochondrial fraction, about 66 percent in the cytosolic fraction. 5. Aspartate aminotransferase from cytosolic fraction was separated into two types of isozymes, whereas alanine aminotransferase from cytosolic fraction gave only one active peak on DEAE-cellulose column chromatography. | Kisaengch'unghak chapchi. The Korean journal of parasitology | 00/06/1983 |
('LID', '10.1038/s41586-025-08721-9') | MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC. | Fiorini, Elena, Malinova, Antonia, Schreyer, Daniel, Pasini, Davide, Bevere, Michele, Alessio, Giorgia, Rosa, Diego, D'Agosto, Sabrina, Azzolin, Luca, Milite, Salvatore, Andreani, Silvia, Lupo, Francesca, Veghini, Lisa, Grimaldi, Sonia, Pedron, Serena, Castellucci, Monica, Nourse, Craig, Salvia, Roberto, Malleo, Giuseppe, Ruzzenente, Andrea, Guglielmi, Alfredo, Milella, Michele, Lawlor, Rita T, Luchini, Claudio, Agostini, Antonio, Carbone, Carmine, Pilarsky, Christian, Sottoriva, Andrea, Scarpa, Aldo, Tuveson, David A, Bailey, Peter, Corbo, Vincenzo | Intratumour heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance(1,2). Oncogene dosage variation contributes to cell-state transitions and phenotypic heterogeneity(3), thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In the absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides a detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC. | Nature | 12/03/2025 |
('LID', '10.1016/j.jaci.2025.02.034') | Cigarette smoke-induced epithelial cell ferroptosis promotes neutrophilic inflammation in patients with nasal polyps. | Pan, Li, Yu, Ze, Xiang, Wen-Xuan, Sun, Shi-Ran, Li, Jing-Xian, Deng, Yi-Ke, Wang, Meng-Chen, Zhong, Ji-Xin, Huang, Kun, Gao, Pei-Song, Zhu, Li-Ping, Yao, Yin, Liu, Zheng | BACKGROUND: Regulation of epithelial cell death has emerged as a key mechanism maintaining immune homeostasis in the airway. However, the mechanisms governing epithelial cell survival in nasal polyps (NPs) remains poorly understood. OBJECTIVE: To investigate the ferroptosis of nasal epithelial cell and its implications in the pathogenesis of NPs. METHODS: The cell death, lipid peroxidation, and ferrous iron levels in nasal epithelial cells were determined by flow cytometry. Biomarkers and signaling pathways associated with ferroptosis were evaluated by quantitative RT-PCR, single-cell and bulk RNA-sequencing, immunofluorescence staining, and western blotting. Human nasal epithelial cells (HNECs) and 16HBE cells were stimulated with different agents. Mitochondrial ultrastructure in HNECs were visualized by transmission electron microscopy. Cytokine levels were quantified using ELISA. A cigarette smoke extract (CSE)-induced mouse model was established and treated with deferoxamine. RESULTS: Nasal epithelial cells from both eosinophilic and noneosinophilic NPs showed intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis. Ferroptosis triggered C-X-C motif ligand (CXCL)8 production in 16HBE cells and HNECs through the activation of mitogen-activated protein kinase pathway. CSE exposure elevated ferrous iron levels by upregulating transferrin receptor 1, led to ferroptosis and subsequent CXCL8 production in HNECs. Deferoxamine treatment inhibited nasal epithelial cell ferroptosis, CXCL8 levels, and neutrophilic numbers in a CSE-induced mice model. Smoking burden was correlated with CXCL8 levels and neutrophil infiltration in patients with NPs. An analysis of 494,176 UK Biobank participants revealed smoking as a risk factor for NPs (Odds Ratio: 1.346, 95% Confidence Interval: 1.245-1.456, P < 0.001). CONCLUSION: Smoking-induced ferroptosis promotes CXCL8 production in nasal epithelial cells and thus potentially exacerbates neutrophilic inflammation in NPs. | The Journal of allergy and clinical immunology | 12/03/2025 |
('LID', '10.1016/j.biortech.2011.11.059') | A novel and efficient method for the immobilization of thermolysin using sodium chloride salting-in and consecutive microwave irradiation. | Chen, Feifei, Zhang, Fangkai, Du, Fangchuan, Wang, Anming, Gao, Weifang, Wang, Qiuyan, Yin, Xiaopu, Xie, Tian | Sodium chloride salting-in and microwave irradiation were combined to drive thermolysin molecules into mesoporous support to obtain efficiently immobilized enzyme. When the concentration of sodium chloride was 3 M and microwave power was 40 W, 93.2% of the enzyme was coupled to the support by 3 min, and the maximum specific activity of the immobilized enzyme was 17,925.1 U mg(-1). This was a 4.5-fold increase in activity versus enzyme immobilized using conventional techniques, and a 1.6-fold increase versus free enzyme. Additionally, the thermal stability of the immobilized thermolysin was significantly improved. When incubated at 70°C, there was no reduction in activity by 3.5h, whereas free thermolysin lost most of its activity by 3h. Immobilization also protected the thermolysin against organic solvent denaturation. The microwave-assisted immobilization technique, combined with sodium chloride salting-in, could be applied to other sparsely soluble enzymes immobilization because of its simplicity and high efficiency. | Bioresource technology | 00/07/2012 |
('LID', '10.1016/j.ccell.2025.02.014') | Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy. | Song, Huan, Chen, Lin, Pan, Xuanxuan, Shen, Yuru, Ye, Maolin, Wang, Guohong, Cui, Can, Zhou, Qi, Tseng, Yujen, Gong, Zheng, Zhong, Bin, Cui, Haoshu, Mo, Shaocong, Zheng, Jiayue, Jin, Bryan, Zheng, Wanwei, Luo, Feifei, Liu, Jie | STING is an important DNA sensing machinery in initiating immune response, yet therapies targeting STING have shown poor outcomes in clinical trials. Here, we reveal that STING signaling induces PD-L1(hi) tumor monocytes (Tu.Mons) that dominate the resistance against STING agonist therapy. Cell-intrinsic PD-L1, induced by the STING-IRF3-IFN-I axis, is identified as the driving factor for protumoral PD-L1(hi) Tu.Mons. Notably, TLR2-activated Tu.Mons resist STING-induced upregulation of cell-intrinsic PD-L1 and the associated protumoral functions. Mechanistically, TLR2 stimulation remodels STING signaling by facilitating STING and TRAF6 interaction, which suppresses the IRF3-IFN-I response and enhances NF-κB activation. Moreover, we demonstrate that combining STING agonists with TLR2 agonist pretreatment significantly improves antitumor efficacy in murine syngeneic and humanized models. Our findings uncover a protumoral aspect of STING activation mediated by cell-intrinsic PD-L1 and propose a promising strategy to boost antitumor immunity by fine-tuning STING signaling outputs. | Cancer cell | 10/03/2025 |
('LID', '10.1038/s42255-025-01246-5') | Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control. | Jiang, Zengliang, He, Liuqing, Li, Diyin, Zhuo, Laibao, Chen, Lingjun, Shi, Rui-Qi, Luo, Jianhua, Feng, Yuhui, Liang, Yuhui, Li, Danyang, Congmei, Xiao, Fu, Yuanqing, Chen, Yu-Ming, Zheng, Ju-Sheng, Tao, Liang | Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites. | Nature metabolism | 14/03/2025 |
('LID', '10.1002/cac2.70016') | Blocking ITGA5 potentiates the efficacy of anti-PD-1 therapy on glioblastoma by remodeling tumor-associated macrophages. | Zhao, Rongrong, Pan, Ziwen, Qiu, Jiawei, Li, Boyan, Qi, Yanhua, Gao, Zijie, Qiu, Wei, Tang, Weijie, Guo, Xiaofan, Deng, Lin, Li, Gang, Xue, Hao | BACKGROUND: Glioblastoma (GBM) is largely refractory to antibodies against programmed cell death 1 (anti-PD-1) therapy. Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM. This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM. METHODS: We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations. The biological functions of a novel circular RNA (circRNA) were validated both in vitro and in vivo. Mechanically, co-immunoprecipitation, RNA immunoprecipitation and pull-down assays were conducted. RESULTS: Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)(+) myeloid-derived macrophages (SPP1(+) MDMs), a unique subpopulation of MDMs with complex functions, preferentially accumulated in non-responders to anti-PD-1 therapy, indicating that MES-GBM cells and SPP1(+) MDMs were the main anti-PD-1-resistant cell subpopulations. Functionally, we determined that circular RNA succinate dehydrogenase complex assembly factor 2 (circSDHAF2), which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations, facilitated the formation of a regional MES-GBM and SPP1(+) MDM cell interaction loop, resulting in a spatially specific adaptive immunosuppressive microenvironment. Mechanically, we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5 (ITGA5) protein through N-glycosylation. Meanwhile, the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1(+) MDMs, which in turn maintained the MES-GBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway, ultimately promoting GBM immune escape. Importantly, our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity. CONCLUSIONS: This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells, MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of targeting ITGA5 to reduce anti-PD-1 resistance in GBM. | Cancer communications (London, England) | 14/03/2025 |
('LID', '10.1182/blood.2024026622') | Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma. | Ma, Sha, Xia, Jieyun, Zhang, Miao, Li, Wenyu, Xiao, Meng, Sha, Yuqian, Wang, Wenya, Zhou, Jianteng, Wang, Ying, Qi, Kunming, Fu, Chunling, Sun, Zengtian, Zhou, Dian, Sun, Qian, Qiu, Tingting, Yan, Zhiling, Zhu, Feng, Chen, Wei, Cheng, Hai, Sang, Wei, Cao, Jiang, Li, Depeng, Li, Zhenyu Zhen, Fulciniti, Mariateresa, Yao, Yao, Xu, Kailin, Niu, Mingshan | G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a novel target for chimeric antigen receptor (CAR) T-cell therapy, demonstrating promising efficacy in multiple myeloma (MM). However, disease relapse is still common, and the mechanism of resistance remains poorly understood. In this study, we conducted whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) on MM samples from 10 patients who relapsed after GPRC5D CAR T-cell therapy. Among these patients, 8 had GPRC5D loss, while 2 presented mixed expression (GPRC5D+/-). Genetic alterations were identified in three cases: one had a homozygous deletion in the GPRC5D gene, another had a biallelic loss in the regulatory regions of GPRC5D, and the third had homozygous deletions in both TNFRSF17 and GPRC5D after sequential anti-BCMA and anti-GPRC5D CAR T-cell therapies. No genetic changes were detected at GPRC5D locus in the remaining 7 cases. However, multiple hypermethylation sites were present in the transcriptional regulatory elements of the GPRC5D gene in 5 post-treatment MM samples. In MM cell lines, GPRC5D expression was inversely correlated with methylation levels in its regulatory regions. Furthermore, azacitidine treatment induced GPRC5D mRNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance. | Blood | 16/03/2025 |
('LID', '10.1097/HEP.0000000000001302') | Pre-B-Cell leukemia transcription factor 1 contributes to liver fibrosis by enabling IL-7 signaling in hepatic stellate cells. | Zhao, Qianwen, Liu, Hong, Yang, Zhen, Han, Xingxing, Kang, Aoqi, Li, Hao, Ren, Wenjing, Chen, Qianqian, Huan, Yue, Xu, Yong, Li, Jie, Kong, Ming, Li, Zilong | BACKGROUND AND AIMS: Liver fibrosis, when dysregulated, contributes to irreversible loss of hepatic structure and function heralding end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSCs) represent the common progenitor to myofibroblasts that produce extracellular matrix (ECM) proteins to mediate liver fibrosis. In the present study, we investigated the role of Pre-B-Cell leukemia transcription factor 1 (PBX1) in this process. METHODS: Liver fibrosis was induced by CCl4 injection or bile duct ligation (BDL). Cellular transcriptome was examined by RNA-seq and CUT&Tag-seq. RESULTS: PBX1 was screened out of mining through liver fibrosis-related single-cell RNA-seq datasets as the most prominently up-regulated transcription factor during HSC activation. Ingenuity pathway analysis (IPA) coupled with reporter assay and ChIP assay demonstrated that Notch3 mediated elevation of PBX1 expression at the transcriptional level in HSCs. PBX1 knockdown attenuated HSC-myofibroblast transition in vitro and liver fibrosis in mice. Integrated transcriptomic analysis suggested that PBX1 contributed to HSC activation by activating a host of pro-fibrogenic molecules including interleukin 7 receptor (IL7R/CD127). Consistently, exposure to recombinant IL-7 promoted HSC activation whereas IL7R knockdown hampered HSC activation. Mechanistically, IL7R interacted with TGF-β receptors (TβRI/II) to trigger a pro-fibrogenic signaling cascade. Importantly, blockade of the IL-7-IL7R signaling with neutralizing antibodies markedly ameliorated liver fibrosis in mice. Finally, a positive correlation between PBX1, IL7R and HSC activation was identified in cirrhotic patients. CONCLUSIONS: Our data uncover a previously unappreciated role for PBX1 in HSC activation and provide proof-of-concept for targeting IL-7 signaling in the intervention of liver fibrosis. | Hepatology (Baltimore, Md.) | 13/03/2025 |
('LID', '10.1146/annurev-immunol-101721-032910') | Regulation of the cGAS-STING Pathway. | Zhang, Bing, Xu, Pengbiao, Ablasser, Andrea | The cGAS-cGAMP-STING pathway is essential for immune defense against pathogens. Upon binding DNA, cGAS synthesizes cGAMP, which activates STING, leading to potent innate immune effector responses. However, lacking specific features to distinguish between self and nonself DNA, cGAS-STING immunity requires precise regulation to prevent aberrant activation. Several safeguard mechanisms acting on different levels have evolved to maintain tolerance to self DNA and ensure immune homeostasis under normal conditions. Disruption of these safeguards can lead to erroneous activation by self DNA, resulting in inflammatory conditions but also favorable antitumor immunity. Insights into structural and cellular checkpoints that control and terminate cGAS-STING signaling are essential for comprehending and manipulating DNA-triggered innate immunity in health and disease. | Annual review of immunology | 14/03/2025 |
('LID', '10.1038/s41467-025-57823-5') | Identification of a non-inhibitory aptameric ligand to CRL2(ZYG11B) E3 ligase for targeted protein degradation. | Yang, Zhihao, Chen, Miao, Ge, Ruixin, Zhou, Ping, Pan, Wei, Song, Jiayi, Ma, Shuwen, Chen, Song, Xu, Chenyu, Zhou, Mengyu, Mi, Wenyi, Ni, Hua, Chen, He, Yao, Xue, Dong, Xifeng, Chen, Yan, Zhou, Jun, Xuan, Chenghao, Dong, Cheng, Yan, Hua, Xie, Songbo | As a crucial element of proteolysis targeting chimeras (PROTACs), the choice of E3 ubiquitin ligase significantly influences degradation efficacy and selectivity. However, the available arsenal of E3 ligases for PROTAC development remains underexplored, severely limiting the scope of targeted protein degradation. In this study, we identify a non-inhibitory aptamer targeting ZYG11B, a substrate receptor of the Cullin 2-RING ligase complex, as an E3 warhead for targeted protein degradation. This aptamer-based PROTAC platform, termed ZATAC, is facilely produced through bioorthogonal chemistry or self-assembly and shows promise in eliminating several undruggable target proteins, including nucleolin (NCL), SRY-box transcription factor 2 (SOX2), and mutant p53-R175H, underscoring its universality and versatility. To specifically deliver ZATACs into cancer cells, we further develop DNA three-way junction-based ZATACs (3WJ-ZATACs) by integrating an additional aptamer that selectively recognizes the protein overexpressed on the surface of cancer cells. The 3WJ-ZATACs demonstrate in vivo tumor-specific distribution and achieve dual-target degradation, thereby suppressing tumor growth without causing noticeable toxicity. In summary, ZATACs represent a general, modular, and straightforward platform for targeted protein degradation, offering insights into the potential of other untapped E3 ligases. | Nature communications | 13/03/2025 |
('LID', '10.1038/s43587-025-00816-2') | Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis. | Schneeberger, Shirin, Kim, Seung Joon, Geesdorf, Maria N, Friebel, Ekaterina, Eede, Pascale, Jendrach, Marina, Boltengagen, Anastasiya, Braeuning, Caroline, Ruhwedel, Torben, Hülsmeier, Andreas J, Gimber, Niclas, Foerster, Marlene, Obst, Juliane, Andreadou, Myrto, Mundt, Sarah, Schmoranzer, Jan, Prokop, Stefan, Kessler, Wiebke, Kuhlmann, Tanja, Möbius, Wiebke, Nave, Klaus-Armin, Hornemann, Thorsten, Becher, Burkhard, Edgar, Julia M, Karaiskos, Nikos, Kocks, Christine, Rajewsky, Nikolaus, Heppner, Frank L | Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer's disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD. | Nature aging | 13/03/2025 |
('LID', '10.1016/j.dsx.2025.103212') | Comparative efficacy and safety of semaglutide 2.4 mg and tirzepatide 5-15 mg in obesity with or without type 2 diabetes: A systematic review of Phase 3 clinical trials. | Singh, Akriti, Singh, Awadhesh Kumar, Singh, Ritu, Misra, Anoop | BACKGROUND AND AIMS: Both semaglutide 2.4 mg and tirzepatide have been recently approved for chronic use in obesity. There is a lack of literature comparing the efficacy and safety of both these agents in people with obesity/overweight with or without type 2 diabetes (T2D). We systematically reviewed Phase 3 randomized controlled trials (RCTs) conducted with two agents to synthesize the comparative efficacy and safety outcomes. METHODS: We systematically searched PubMed electronic databases until December 15, 2024, using selected keywords and Boolean "AND." Subsequently, we compared the most closely matched trials conducted with semaglutide 2.4 mg and tirzepatide through an adjusted (if baseline imbalance in treatment outcome modifiers present) or unadjusted (in the absence of baseline imbalance) indirect treatment comparison method. RESULTS: We identified one trial each of semaglutide 2.4 mg (STEP-1) and tirzepatide 5, 10, and 15 mg (SURMOUNT-1) in obese or overweight people without T2D and one trial each of semaglutide 2.4 mg (STEP-2) and tirzepatide 10 and 15 mg (SURMOUNT-2) in overweight people with T2D that were almost entirely comparable concerning baseline outcome modifier characteristics. Our unadjusted analysis without individual patients' data found relatively higher (4 and 5.4 % additional) weight loss, HbA1c (-0.4 % additional) reduction, and fewer gastrointestinal side effects (GI S/E) with tirzepatide 10 and 15 mg, respectively, than with semaglutide 2.4 mg, in the intention-to-treat analysis. CONCLUSION: Tirzepatide 10 and 15 mg are more effective and have fewer GI S/E than semaglutide 2.4 mg. A well-powered head-to-head RCT is currently needed to confirm these findings. | Diabetes & metabolic syndrome | 08/03/2025 |
('LID', '10.1136/jitc-2024-010639') | Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer. | Duan, Jinlin, Chen, Tao, Li, Qiwei, Zhang, Yu, Lu, Ting, Xue, Junyan, Sun, Yang, Gao, Ling, Zhang, Yonglong | BACKGROUND: The emergence of immunotherapy has revolutionized the paradigm of cancer treatment with immune checkpoint blockades (ICB) in solid cancers, including colorectal cancer (CRC). However, only a small subset of CRC patients harboring deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) benefits from ICB therapy. A very limited response to ICB therapy has been achieved in MMR-proficient CRC, representing a significant challenge limiting the clinical application of immunotherapy. MMR is the critical DNA repair pathway that maintains genomic integrity by correcting DNA mismatches, which is mediated by the MutSα or MutSβ complex consisting of MSH2 with MSH6 and MSH3, respectively. Given that MMR status directs effective immune response, we sought to determine whether targeting MMR capacity boosts ICB efficacy. METHODS: Azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC and xenograft model were used to evaluate the function of PRMT6 and response to PRMT6 inhibitor EPZ020411 and combination therapy of PD1 and EPZ020411. Biochemical assays were performed to elucidate the underlying mechanism of PRMT6-mediated MSH2 methylation and immune evasion. RESULTS: We have identified PRMT6 as a crucial regulator of MMR capacity via MSH2 dimethylation at R171 and R219. Such a modification abrogates its MMR capacity and prevents the recruitment of MSH3 and MSH6. PRMT6 loss or inhibition triggers cytosolic DNA accumulation and cGAS-STING signaling activation, leading to enhanced immune response in PRMT6-deficient colon tumors or xenografts. Pharmacological inhibition of PRMT6 using EPZ020411 promotes mutagenesis and destabilizes MutSα or MutSβ assembly, and prolonged EPZ020411 exposure maintains an MSI-like phenotype in microsatellite stability (MSS) cells. EPZ020411 treatment sensitizes ICB efficacy of MSS cells, but not MSI cells in vivo. Similar effects have been observed in MSS colon tumors induced by AOM/DSS. CONCLUSIONS: Our study provides a preclinical proof of concept to overcome resistance to immunotherapy by targeting PRMT6 in CRC with MSS. | Journal for immunotherapy of cancer | 13/03/2025 |
('LID', '10.1161/CIRCRESAHA.124.325049') | March2 Alleviates Aortic Aneurysm/Dissection by Regulating PKM2 Polymerization. | Li, Yiran E, Liu, Shuolin, Wang, Litao, Du, Yuxin, Wu, Lin, Chen, Haoran, Zhu, Tingfang, Lin, Jie, Xiong, Shengjun, Wang, Yayu, Zheng, Qijun, Zou, Rongjun, Lin, Ling, Li, Zheyun, Wang, Lixin, Ge, Junbo, Ren, Jun, Zhang, Yingmei | BACKGROUND: Aortic aneurysm/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the E3 ubiquitin ligase March2 (membrane-associated RING finger protein 2) to the cause of AAD remains elusive. METHODS: Integrated single-cell RNA sequencing analysis was conducted in human AAD tissues. Based on the screening results, we generated a mouse line of smooth muscle cell-specific March2 knockout. β-Aminopropionitrile monofumarate was used to establish AAD. Cleavage under targets and tagmentation and cleavage under targets and tagmentation-quantitative polymerase chain reaction were performed to identify possible target genes for histone H3K18 lactylation. RESULTS: March2 expression was downregulated in aorta from patients with AAD or β-aminopropionitrile monofumarate-induced AAD mice. β-Aminopropionitrile monofumarate-induced AAD was significantly accentuated in March2 global (March2(-/-)) and vascular smooth muscle cell-specific deletion (March2(fl/fl); Tagln(Cre)) mice, whereas the AAD pathology was rescued by rAAV9-SM22α-March2 (recombinant adeno-associated virus serotype 9 expressing Flag-tagged March2 under SM22α promoter). March2 interacted with PKM2 (pyruvate kinase M2) to promote K33-linked polyubiquitination. Deficiency of March2 lessened PKM2 dimer-to-tetramer conversion in AAD and overtly exacerbated AAD-induced histone H3K18 lactylation in vascular smooth muscle cells by fostering glucose metabolism reprogramming, thereby promoting p53-driven apoptotic transcriptional response-a hallmark of AAD pathogenesis. TEPP-46, a PKM2-specific activator, pronouncedly alleviated March2 deficiency-deteriorated AAD pathology. CONCLUSIONS: Our findings demonstrated that March2 is a novel endogenous defender that prevents AAD by inhibiting vascular smooth muscle cell apoptosis, suggesting that March2 represents a potential therapeutic target for AAD. | Circulation research | 13/03/2025 |
('LID', '10.1016/j.neuron.2025.02.003') | Population coding of predator imminence in the hypothalamus. | Cheung, Kathy Y M, Nair, Aditya, Li, Ling-Yun, Shapiro, Mikhail G, Anderson, David J | Hypothalamic VMHdm(SF1) neurons are activated by predator cues and are necessary and sufficient for instinctive defensive responses. However, such data do not distinguish which features of a predator encounter are encoded by VMHdm(SF1) neural activity. To address this issue, we imaged VMHdm(SF1) neurons at single-cell resolution in freely behaving mice exposed to a natural predator in varying contexts. Our results reveal that VMHdm(SF1) neurons do not encode different defensive behaviors but rather represent predator identity and multiple predator-evoked internal states, including threat-evoked fear/anxiety, arousal or neophobia, predator imminence, and safety. Notably, threat and safety are encoded bi-directionally by anti-correlated subpopulations. Strikingly, individual differences in predator defensiveness are correlated with individual differences in VMHdm(SF1) response dynamics. Thus, different threat-related internal state variables are encoded by distinct neuronal subpopulations within a genetically defined, anatomically restricted hypothalamic cell class. | Neuron | 13/03/2025 |
('LID', '10.1016/j.ccell.2025.02.018') | Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. | Mayr, Lisa, Neyazi, Sina, Schwark, Kallen, Trissal, Maria, Beck, Alexander, Labelle, Jenna, Eder, Sebastian K, Weiler-Wichtl, Liesa, Marques, Joana G, de Biagi-Junior, Carlos A O, Lo Cascio, Costanza, Chapman, Owen, Sridhar, Sunita, Kenkre, Rishaan, Dutta, Aditi, Wang, Shanqing, Wang, Jessica, Hack, Olivia, Nascimento, Andrezza, Nguyen, Cuong M, Castellani, Sophia, Rozowsky, Jacob S, Groves, Andrew, Panditharatna, Eshini, Cruzeiro, Gustavo Alencastro Veiga, Haase, Rebecca D, Tabatabai, Kuscha, Madlener, Sibylle, Wadden, Jack, Adam, Tiffany, Kong, Seongbae, Miclea, Madeline, Patel, Tirth, Bruckner, Katharina, Senfter, Daniel, Lämmerer, Anna, Supko, Jeffrey, Guntner, Armin S, Palova, Hana, Neradil, Jakub, Stepien, Natalia, Lötsch-Gojo, Daniela, Berger, Walter, Leiss, Ulrike, Rosenmayr, Verena, Dorfer, Christian, Dieckmann, Karin, Peyrl, Andreas, Azizi, Amedeo A, Baumgartner, Alicia, Slaby, Ondrej, Pokorna, Petra, Clark, Louise M, Cameron, Amy, Nguyen, Quang-De, Wakimoto, Hiroaki, Dubois, Frank, Greenwald, Noah F, Bandopadhayay, Pratiti, Beroukhim, Rameen, Ligon, Keith, Kramm, Christof, Bronsema, Annika, Bailey, Simon, Stucklin, Ana Guerreiro, Mueller, Sabine, Skrypek, Mary, Martinez, Nina, Bowers, Daniel C, Jones, David T W, Jones, Chris, Jäger, Natalie, Sterba, Jaroslav, Müllauer, Leonhard, Haberler, Christine, Kumar-Sinha, Chandan, Chinnaiyan, Arul, Mody, Rajen, Chavez, Lukas, Furtner, Julia, Koschmann, Carl, Gojo, Johannes, Filbin, Mariella G | PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG. | Cancer cell | 13/03/2025 |
('LID', '10.1016/j.cels.2025.101205') | Proliferation history and transcription factor levels drive direct conversion to motor neurons. | Wang, Nathan B, Lende-Dorn, Brittany A, Beitz, Adam M, Han, Patrick, Adewumi, Honour O, O'Shea, Timothy M, Galloway, Kate E | The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates. | Cell systems | 11/03/2025 |
('LID', '10.1177/15333175251325091') | Automatic Detection of Cognitive Impairment in Patients With White Matter Hyperintensity Using Deep Learning and Radiomics. | Feng, Junbang, Le, Xingyan, Li, Li, Tang, Lin, Xia, Yuwei, Shi, Feng, Guo, Yi, Zhou, Yueqin, Li, Chuanming | White matter hyperintensity (WMH) is associated with cognitive impairment. In this study, 79 patients with WMH from hospital 1 were randomly divided into a training set (62 patients) and an internal validation set (17 patients). In addition, 29 WMH patients from hospital 2 were used as an external validation set. Cognitive status was determined based on neuropsychological assessment results. A deep learning convolutional neural network of VB-Nets was used to automatically identify and segment whole-brain subregions and WMH. The PyRadiomics package in Python was used to automatically extract radiomic features from the WMH and bilateral hippocampi. Delong tests revealed that the random forest model based on combined features had the best performance for the detection of cognitive impairment in WMH patients, with an AUC of 0.900 in the external validation set. Our results provide clinical doctors with a reliable tool for the early diagnosis of cognitive impairment in WMH patients. | American journal of Alzheimer's disease and other dementias | 00/01/2025 |
('LID', '10.1016/j.ccell.2025.02.018') | Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. | Mayr, Lisa, Neyazi, Sina, Schwark, Kallen, Trissal, Maria, Beck, Alexander, Labelle, Jenna, Eder, Sebastian K, Weiler-Wichtl, Liesa, Marques, Joana G, de Biagi-Junior, Carlos A O, Lo Cascio, Costanza, Chapman, Owen, Sridhar, Sunita, Kenkre, Rishaan, Dutta, Aditi, Wang, Shanqing, Wang, Jessica, Hack, Olivia, Nascimento, Andrezza, Nguyen, Cuong M, Castellani, Sophia, Rozowsky, Jacob S, Groves, Andrew, Panditharatna, Eshini, Cruzeiro, Gustavo Alencastro Veiga, Haase, Rebecca D, Tabatabai, Kuscha, Madlener, Sibylle, Wadden, Jack, Adam, Tiffany, Kong, Seongbae, Miclea, Madeline, Patel, Tirth, Bruckner, Katharina, Senfter, Daniel, Lämmerer, Anna, Supko, Jeffrey, Guntner, Armin S, Palova, Hana, Neradil, Jakub, Stepien, Natalia, Lötsch-Gojo, Daniela, Berger, Walter, Leiss, Ulrike, Rosenmayr, Verena, Dorfer, Christian, Dieckmann, Karin, Peyrl, Andreas, Azizi, Amedeo A, Baumgartner, Alicia, Slaby, Ondrej, Pokorna, Petra, Clark, Louise M, Cameron, Amy, Nguyen, Quang-De, Wakimoto, Hiroaki, Dubois, Frank, Greenwald, Noah F, Bandopadhayay, Pratiti, Beroukhim, Rameen, Ligon, Keith, Kramm, Christof, Bronsema, Annika, Bailey, Simon, Stucklin, Ana Guerreiro, Mueller, Sabine, Skrypek, Mary, Martinez, Nina, Bowers, Daniel C, Jones, David T W, Jones, Chris, Jäger, Natalie, Sterba, Jaroslav, Müllauer, Leonhard, Haberler, Christine, Kumar-Sinha, Chandan, Chinnaiyan, Arul, Mody, Rajen, Chavez, Lukas, Furtner, Julia, Koschmann, Carl, Gojo, Johannes, Filbin, Mariella G | PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG. | Cancer cell | 13/03/2025 |
('LID', '10.1016/j.cels.2025.101205') | Proliferation history and transcription factor levels drive direct conversion to motor neurons. | Wang, Nathan B, Lende-Dorn, Brittany A, Beitz, Adam M, Han, Patrick, Adewumi, Honour O, O'Shea, Timothy M, Galloway, Kate E | The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates. | Cell systems | 11/03/2025 |
('LID', '10.1177/15333175251325091') | Automatic Detection of Cognitive Impairment in Patients With White Matter Hyperintensity Using Deep Learning and Radiomics. | Feng, Junbang, Le, Xingyan, Li, Li, Tang, Lin, Xia, Yuwei, Shi, Feng, Guo, Yi, Zhou, Yueqin, Li, Chuanming | White matter hyperintensity (WMH) is associated with cognitive impairment. In this study, 79 patients with WMH from hospital 1 were randomly divided into a training set (62 patients) and an internal validation set (17 patients). In addition, 29 WMH patients from hospital 2 were used as an external validation set. Cognitive status was determined based on neuropsychological assessment results. A deep learning convolutional neural network of VB-Nets was used to automatically identify and segment whole-brain subregions and WMH. The PyRadiomics package in Python was used to automatically extract radiomic features from the WMH and bilateral hippocampi. Delong tests revealed that the random forest model based on combined features had the best performance for the detection of cognitive impairment in WMH patients, with an AUC of 0.900 in the external validation set. Our results provide clinical doctors with a reliable tool for the early diagnosis of cognitive impairment in WMH patients. | American journal of Alzheimer's disease and other dementias | 00/01/2025 |
('LID', '10.1126/sciadv.adr3757') | Genetically supported targets and drug repurposing for brain aging: A systematic study in the UK Biobank. | Yi, Fan, Yuan, Jing, Somekh, Judith, Peleg, Mor, Zhu, Yi-Cheng, Jia, Zhilong, Wu, Fei, Huang, Zhengxing | Brain age gap (BAG), the deviation between estimated brain age and chronological age, is a promising marker of brain health. However, the genetic architecture and reliable targets for brain aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)-based brain age using deep learning models trained on the UK Biobank and validated with three external datasets. A genome-wide association study for BAG identified two unreported loci and seven previously reported loci. By integrating Mendelian Randomization (MR) and colocalization analysis on eQTL and pQTL data, we prioritized seven genetically supported druggable genes, including MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB, and C1RL, as promising targets for brain aging. We rediscovered 13 potential drugs with evidence from clinical trials of aging and prioritized several drugs with strong genetic support. Our study provides insights into the genetic basis of brain aging, potentially facilitating drug development for brain aging to extend the health span. | Science advances | 14/03/2025 |
('LID', '10.1038/s41572-025-00600-x') | Primary sclerosing cholangitis. | Manns, Michael P, Bergquist, Annika, Karlsen, Tom H, Levy, Cynthia, Muir, Andrew J, Ponsioen, Cyriel, Trauner, Michael, Wong, Grace, Younossi, Zobair M | Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival. | Nature reviews. Disease primers | 13/03/2025 |
('LID', '10.1001/jamanetworkopen.2025.0669') | Probiotics and Fever Duration in Children With Upper Respiratory Tract Infections: A Randomized Clinical Trial. | Bettocchi, Silvia, Comotti, Anna, Elli, Marina, De Cosmi, Valentina, Berti, Cristiana, Alberti, Ilaria, Mazzocchi, Alessandra, Rosazza, Chiara, Agostoni, Carlo, Milani, Gregorio Paolo | IMPORTANCE: Upper respiratory tract infections (URTIs) are prevalent in children, prompting frequent health care consultations, especially among those with fever. Probiotics show potential as an adjuvant treatment for URTIs, but evidence in children is limited. OBJECTIVE: To evaluate the efficacy of a probiotic mixture containing Bifidobacterium breve M-16V, Bifidobacterium lactis HN019, and Lactobacillus rhamnosus HN001 in shortening fever duration among children with URTIs. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted between November 19, 2021, and June 20, 2023, at the pediatric emergency department of the Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy. Patients between 28 days and 4 years of age with a fever (≥38.5 °C) and URTI were eligible. Exclusion criteria included recent probiotic use, chronic autoimmune diseases, immunosuppressive treatment, and requirement for hospitalization. Randomization was computer generated and assigned participants to either the intervention (probiotics) or control (placebo) group. Participants, parents or caregivers, and investigators were masked to the group assignments. The primary analysis followed the intention-to-treat approach. INTERVENTIONS: The probiotic group received daily single dose of 0.5 mL probiotic mixture containing Bifidobacterium breve M-16V, Bifidobacterium lactis HN019, and Lactobacillus rhamnosus HN001 for 14 days. The placebo group received daily single dose of 0.5 mL placebo for 14 days. MAIN OUTCOMES AND MEASURES: The primary outcome was fever duration, defined as the number of days between the first and the last days with fever. RESULTS: Of the 128 patients enrolled (69 males [54%]; mean [SD] age 2.5 [1.3] years), 65 (51%) were randomly assigned to receive placebo and 63 (49%) to receive probiotics. The median (IQR) fever duration was shorter in the probiotic group than the placebo group (median [IQR], 3 [2-4] days vs 5 [4-6] days; adjusted risk ratio, 0.64; 95% CI, 0.51-0.80). Few mild adverse events were reported and did not significantly differ between the probiotic and placebo groups, including constipation (6 [16%] and 6 [12%]; P = .80) and abdominal pain (3 [8%] and 2 [4%]; P = .65). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, administering a probiotic mixture reduced fever duration by 2 days compared with placebo, with no meaningful safety concerns. The probiotic mixture under investigation could be an effective adjuvant for shortening fever duration in children with URTIs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06052540. | JAMA network open | 03/03/2025 |
('LID', '10.1016/j.ygyno.2015.01.552') | Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons. | Bakkum-Gamez, Jamie N, Wentzensen, Nicolas, Maurer, Matthew J, Hawthorne, Kieran M, Voss, Jesse S, Kroneman, Trynda N, Famuyide, Abimbola O, Clayton, Amy C, Halling, Kevin C, Kerr, Sarah E, Cliby, William A, Dowdy, Sean C, Kipp, Benjamin R, Mariani, Andrea, Oberg, Ann L, Podratz, Karl C, Shridhar, Viji, Sherman, Mark E | OBJECTIVE: We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. METHODS: Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). RESULTS: Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. CONCLUSION: DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC. | Gynecologic oncology | 00/04/2015 |
('LID', '10.1093/jimmun/vkaf005') | Sustained activation induced cytidine deaminase (AID) expression in B cells following Plasmodium falciparum malaria infection in Kenyan children. | Ariera, Bonface, Guyah, Bernard, Rahkola, Jeremy, Arao, Ian, Waomba, Kevin, Koech, Emmily, Samayoa-Reyes, Gabriela, Sabourin, Katherine R, Ogolla, Sidney, Rochford, Rosemary | Burkitt lymphoma (BL) is characterized by elevated levels of the enzyme activation-induced cytidine deaminase (AID), an enzyme critical for MYC translocation that is the hallmark of BL. Both EBV and Plasmodium falciparum malaria are cofactors in the etiology of BL. However, how these 2 pathogens drive BL pathogenesis is not yet understood. In this study, we tested the hypothesis that P. falciparum and EBV synergize to induce dysregulated expression of AID. Using flow cytometry, intracellular AID expression was measured in PBMCs from a cohort of children from Western Kenya with uncomplicated malaria and community controls. Children with uncomplicated malaria had elevated levels of CD19+ AID+ B cells compared to controls. This high level of AID was sustained up to 8 weeks after parasite clearance. Using ImageStream flow cytometry, we found that 52% of AID was localized in the nucleus of CD19+ B cells in children with malaria. To test whether EBV and P. falciparum synergized to drive the expression of AID, we stimulated CD19+ B cells with EBV, CpG (to mimic P. falciparum DNA), or BAFF (induced during P. falciparum infection), or as a combination. Individually, EBV, BAFF and CpG induced AID expression. However, when combined, there was a significant increase of ∼30% in the frequency of CD19+AID+ cells above cells treated with EBV, BAFF, or CpG individually. Collectively, these data suggest that P. falciparum malaria and EBV coinfection result in sustained AID expression, potentially influencing the MYC translocation that is characteristic of BL. | Journal of immunology (Baltimore, Md. : 1950) | 14/03/2025 |
('LID', '10.1016/j.annonc.2025.03.005') | Redefining Clinical Trial Strategic Design to Support Drug Approval in Medical Oncology. | Antonarelli, G, Pérez-García, J M, Gion, M, Rugo, H, Schmid, P, Bardia, A, Hurvitz, S, Harbeck, N, Tolaney, S M, Curigliano, G, Llombart-Cussac, A, Cortés, J | Randomized clinical trials represent the gold standard for the introduction of innovative therapies in medical oncology, and they provide the highest level of evidence to ascertain the clinical activity of new drugs or novel combinations. However, the current infrastructure of clinical trials supporting innovative drug approvals is challenged by an increased body of knowledge concerning tumor biology and therapy resistance, a fast-growing armamentarium of novel anti-cancer compounds, an impressively upscaled data analysis capacity, as well as increasing costs related to clinical trials' management. In this scenario, modern clinical trial designs need to evolve to expedite new drug approvals by tailoring patients' treatment strategies according to their medical needs. Balanced, patient-oriented, clinical trial designs are eagerly warranted to increase their efficiency, to include the fast-pace of technological innovations and scientific discoveries, and ultimately to face the challenges of the modern medical oncology field. | Annals of oncology : official journal of the European Society for Medical | 12/03/2025 |
('LID', '10.7554/eLife.96519') | A microglia clonal inflammatory disorder in Alzheimer's disease. | Vicario, Rocio, Fragkogianni, Stamatina, Weber, Leslie, Lazarov, Tomi, Hu, Yang, Hayashi, Samantha Y, Craddock, Barbara, Socci, Nicholas D, Alberdi, Araitz, Baako, Ann, Ay, Oyku, Ogishi, Masato, Lopez-Rodrigo, Estibaliz, Kappagantula, Rajya, Viale, Agnes, Iacobuzio-Donahue, Christine A, Zhou, Ting, Ransohoff, Richard M, Chesworth, Richard, Abdel-Wahab, Omar, Boisson, Bertrand, Elemento, Olivier, Casanova, Jean-Laurent, Miller, W Todd, Geissmann, Frédéric | Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer's disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. | eLife | 14/03/2025 |
('LID', '10.1016/j.amjmed.2025.03.010') | Vaccines for International Travelers: Current Status and Recent Developments. | Murray, Henry W | Immunizations, malaria chemoprophylaxis, insect repellent use, and prevention and management of travelers' diarrhea are the cornerstones of the pretravel consultation. This report updates one of these topics, vaccine immunizations, for adult international travelers. | The American journal of medicine | 12/03/2025 |
('LID', '10.1021/acsami.4c19748') | Stem Cells from Human Exfoliated Deciduous Teeth-Derived Exosomes for the Treatment of Acute Liver Injury and Liver Fibrosis. | Wang, Ziyuan, Zhong, Danyang, Yan, Tingting, Zheng, Qiang, Zhou, Enjie, Ye, Zhichao, He, Xiaoyan, Liu, Yu, Yan, Jianing, Yuan, Yuyang, Wang, Yifan, Cai, Xiujun | Mesenchymal stem cells (MSCs) play a crucial role in regenerative medicine due to their regenerative potential. However, traditional MSC-based therapies are hindered by issues such as microvascular obstruction and low cell survival after transplantation. Exosomes derived from MSCs (MSC-Exo) provide a cell-free, nanoscale alternative, mitigating these risks and offering therapeutic potential for liver diseases. Nonetheless, the functional variability of MSCs from different sources complicates their clinical application. Stem cells derived from human exfoliated deciduous teeth (SHED) offer advantages such as ease of procurement and robust proliferative capacity, but their secretome, particularly SHED-Exo, remains underexplored in the context of liver disease therapy. This study analyzed MSC-Exo from various sources via small RNA sequencing to identify differences in microRNA profiles, aiding in the selection of optimal MSC sources for clinical use. SHED-Exo was subsequently tested in an acute liver injury model, showing notable regenerative effects, including enhanced hepatocyte proliferation, macrophage polarization, and reduced inflammation. Despite strong liver-targeting properties, the rapid hepatic clearance of SHED-Exo limits its effectiveness in chronic liver diseases. To address this challenge, a GelMA-based hydrogel was developed for in situ delivery, ensuring sustained release and enhanced antifibrotic efficacy, providing a promising strategy for chronic liver disease management. | ACS applied materials & interfaces | 14/03/2025 |
('LID', '10.1002/advs.202413125') | Integration of Circulating Tumor DNA and Metabolic Parameters on (18)F-Fludeoxyglucose Positron Emission Tomography for Outcome Prediction in Unresectable Locally Advanced Non-Small Cell Lung Cancer. | Wu, Leilei, Zhang, Zhenshan, Jiang, Chenxue, Li, Li, Sun, Xiaojiang, Bai, Menglin, Liu, Ming, Xiong, Kangli, Shang, Jinbiao, Yu, Jinming, Yuan, Shuanghu, Yang, Yang, Xu, Yaping | This prospective study explores the prognostic value of circulating tumor DNA (ctDNA) and positron emission tomography/computed tomograpy (PET/CT) in unresectable locally advanced non-small cell lung cancer (LA-NSCLC) treated with definitive chemoradiotherapy (CRT). The discovery set includes 62 patients, with 62 baseline and 53 post-CRT plasma samples. PET/CT is performed at baseline, and 33 patients undergo mid-treatment scans after 40 Gy. Baseline ctDNA is detected in 71.0% of patients. Pre-treatment ctDNA concentration correlates with total metabolic tumor volume (TMTV) (p < 0.001) and total lesion glycolysis (TLG) (p = 0.001) but not treatment response or survival. However, patients with undetectable ctDNA and low TMTV show significantly longer progression-free survival (PFS) (34.2 vs 10.1 months, p = 0.027). Post-CRT, ctDNA is detected in 47.2% of patients, while ctDNA concentration (p = 0.005) and variant allele frequency (VAF) (p = 0.005) significantly decline. Undetectable post-CRT ctDNA associates with longer PFS (p < 0.001) and overall survival (OS) (p = 0.001). Higher ∆TMTV correlates with improved PFS and OS. Similar findings were obtained in a test of 19 patients. These results highlight post-CRT ctDNA and ∆TMTV as robust prognostic markers, potentially identifying patients who may forgo ICI consolidation. | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 16/03/2025 |
('LID', '10.1182/blood.2024025440') | A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR-T cell therapy in B-cell acute lymphoblastic leukemia. | Falgàs, Aïda, Lázaro-Gorines, Rodrigo, Zanetti, Samanta Romina, Rubio-Pérez, Laura, Martinez-Moreno, Alba, Vinyoles, Meritxell, Guerrero-Murillo, Mercedes, Fernandez-Fuentes, Narcís, Roca-Ho, Heleia, Tirado, Néstor, Panisello, Carla, Velasco-Hernandez, Talía, Mayado, Andrea, Pérez-Pons, Alba, Genesca, Eulalia, Ribera, Josep-Maria, Ribera, Jordi, Camos, Mireia, Ramírez-Orellana, Manuel, Anguita, Eduardo, Ballerini, Paola, Fuster, José Luis, Juan, Manel, González-Navarro, Europa Azucena Azucena, Locatelli, Franco, Stam, Ronald W W, Querol, Sergio, Velasco, Pablo, Ortiz-Maldonado, Valentín, Martínez-Cibrian, Nuria, Delgado, Julio, Orfao, Alberto, Alvarez-Vallina, Luis, Bueno, Clara, Menendez, Pablo | Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with a dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19)-T cell therapy, >50% of patients relapse within a year. Both leukemia cell-intrinsic factors favoring immune escape and poor CAR-T cell persistence contribute significantly to clinical failure. Moreover, the expression of immune checkpoint receptors (ICRs) and their ligands within the complex bone marrow (BM) microenvironment may contribute to leukemia progression and therapy resistance. Here, we comprehensively characterized the expression of ICRs and their ligands in leukemic blasts, T cells, and mesenchymal stromal cells (MSCs) from B-ALL BM samples at diagnosis (n=47) and relapse (n=38), comparing them with age-matched healthy BM controls. Our findings reveal a significant upregulated expression of TIM-3 in T cells, and its ligand galectin-9 in both blasts and MSCs throughout disease progression. The expression levels of galectin-9 in B-ALL blasts and TIM-3 in CAR19-T cells negatively correlate with clinical outcome. Furthermore, we demonstrate that galectin-9 impairs CAR19-T cell homeostasis and cytotoxicity. Notably, an engineered TIM-3-Fc decoy receptor, delivered either by primary T cells co-administered with CAR19-T cells or via a bicistronic all-in-one CAR19-TIM-3-Fc construct, improved the anti-leukemia efficacy and persistence of CAR19-T cells in B-ALL patient-derived xenograft models. Mechanistically, CAR19-TIM-3-Fc-T cell treatment promotes the in vivo expansion of both transduced and bystander effector and memory T cells, as determined by spectral flow cytometry. Collectively, these potent and persistent TIM-3-Fc decoy-armored CAR19-T cells offer a promising therapeutic strategy for R/R B-ALL patients. | Blood | 16/03/2025 |
('LID', '10.1016/S2352-3026(24)00377-6') | Talicabtagene autoleucel for relapsed or refractory B-cell malignancies: results from an open-label, multicentre, phase 1/2 study. | Jain, Hasmukh, Karulkar, Atharva, Kalra, Devanshi, Ravikumar, Smrithi, Shah, Shreshtha, Firfiray, Afrin, Pendhari, Juber, Jaiswal, Ankesh Kumar, Khan, Aalia, Sundharam, Manivasagam, Vaibhaw, Anand, Saroha, Ashish, Rajyopadhye, Shreewardhan, Basu, Moumita, Asija, Sweety, Chowdhury, Ambalika, Beher, Rohit, Banik, Ankit, Dwivedi, Alka, Purwar, Shalini, Narula, Gaurav, Banavali, Shripad, Jain, Nitin, Highfill, Steven L, Stroncek, David, Fry, Terry, Melinkeri, Sameer, Wilson, Lovin, Agarwal, Narendra, Aribandi, Anil, Boyella, Pavan Kumar, Shah, Nirali N, Neelapu, Sattva S, Sengar, Manju, Purwar, Rahul | BACKGROUND: In low-income and middle-income counties (LMICs), the outcome of relapsed or refractory B-cell malignancies is poor due to the absence of effective therapies. We report the results of a phase 1/2 study of a novel humanised anti-CD19 4-1BB chimeric antigen receptor (CAR) T-cell therapy, talicabtagene autoleucel, for patients with relapsed or refractory B-cell malignancies. METHODS: This open-label, multicentre, phase 1/2 study was done at six tertiary cancer centres in India. Phase 1 was a single-centre study done in Tata Memorial Hospital, India, in patients aged 18 years or older with relapsed or refractory B-cell lymphomas. Phase 2 was a single-arm, multicentre, basket trial done in five tertiary cancer centres in patients aged 15 years and older with relapsed or refractory B-cell acute lymphoblastic leukaemia or B-cell lymphoma. Eligible patients had a life expectancy of 12 weeks or more, an ECOG performance status of 0-1 (phase 1) or 0-2 (phase 2), and an adequate organ function. Patients underwent apheresis to obtain at least 1 × 10(9) lymphocytes to manufacture CAR T cells. Lymphodepletion therapy was done with cyclophosphamide 500 mg/m(2) and fludarabine 30 mg/m(2) for 3 days or bendamustine 90 mg/m(2) for 2 days. Patients were then infused intravenously with talicabtagene autoleucel 1 × 10(7)-5 × 10(9) CAR T cells in a fractionated schedule (10%, 30%, and 60%, on days 0, 1, and 2, respectively) during phase 1 or at least 5 × 10(6) CAR T cells per kg (up to 2 × 10(9) CAR T cells) on day 0 during phase 2. The primary endpoints were safety (phase 1) and overall response rate (phase 2). The efficacy analysis was done in the efficacy evaluable cohort (all patients who received the target dose and 3 days of lymphodepletion therapy). The safety analysis was done in the safety population (all patients who received talicabtagene autoleucel). The trials are registered with Clinical Trial Registry-India (CTRI/2021/04/032727 and CTRI/2022/12/048211), and enrolment is closed. FINDINGS: Of 64 patients, 14 were enrolled in phase 1 (from May 11, 2021, to May 13, 2022) and 50 were enrolled in phase 2 (Dec 27, 2022, to Aug 31, 2023). The median age of the overall cohort was 44 years (IQR 27-57), and 49 (77%) of 64 patients were male and 15 (23%) were female. In phase 1, no dose-limiting toxicities occurred at doses of 2 × 10(6)-17 × 10(6) CAR T cells per kg. A dose of at least 5 × 10(6) CAR T cells per kg was chosen for phase 2 based on a complete response in three of seven patients at this dose. The most common grade 3 or worse toxicities were haematological events: anaemia (35 [61%] of 57 patients), thrombocytopenia (37 [65%] patients), neutropenia (55 [96%] patients, and febrile neutropenia (27 [47%]) patients). There were two treatment-related deaths, one due to febrile neutropenia, immune-effector cell associated haemophagocytic lymphohistiocytosis, and septic shock, and the second due to pulmonary bleed, multiorgan dysfunction syndrome, and cytokine release syndrome. In 51 efficacy-evaluable patients (36 with B-cell lymphoma and 15 with B-cell acute lymphoblastic leukaemia), the overall response rate was 73% (37 of 51; 95% CI 59-83). INTERPRETATION: Talicabtagene autoleucel had a manageable safety profile and induced durable responses in patients with relapsed or refractory B-cell malignancies. This therapy addresses an important unmet need for patients with relapsed or refractory B-cell malignancies in India. FUNDING: Immunoadoptive Cell Therapy (ImmunoACT) and Indian Council of Medical Research (ICMR). | The Lancet. Haematology | 13/03/2025 |
('LID', '10.1126/sciadv.ads8694') | A multimodal defect-rich nanoreactor triggers sono-piezoelectric tandem catalysis and iron metabolism disruption for implant infections. | Zheng, Fuyuan, Wan, Xufeng, Zhang, Yangming, Yue, Yan, Li, Qiaochu, Zhang, Zhuang, Li, Shuoyuan, Xu, Hong, Su, Qiang, Chen, Xiaoting, Tong, Le, Zhao, Long, Cao, Jian, Tang, Xin, Yang, Xiao, Wu, Jiagang, Li, Jian, Lv, Xiang, Zhou, Zongke, Wang, Duan | Tracking and eradicating drug-resistant bacteria are critical for combating implant-associated infections, yet effective antibacterial therapies remain elusive. Herein, we propose an oxygen vacancy-rich (BiFe)(0.9)(BaTi)(0.1)O(3-)(x) nanoreactor as a piezoelectric sonosensitizer by spatiotemporal ultrasound-driven sono- and chemodynamic tandem catalysis to amplify antibacterial efficacy. The piezoelectric charge carriers under a built-in electric field synchronize the reaction of O(2) and H(2)O, efficiently generating H(2)O(2). The electron-rich oxygen vacancies modulate the local electronic structure of an Fe site. It facilitates reactive oxygen species generation by piezoelectric electrons and accelerates valence state cycles of Fe(III)/Fe(II) to achieve the sustained maintenance of hydroxyl radicals via H(2)O(2)/Fe(II)-catalyzed chemodynamic reactions, which lead to bacterial membrane damage. Transcriptomics analysis revealed that intracellular Fe overload induced by excessive Fe(II)-mediated dysregulation of the two-component system disrupts bacterial metabolism, triggering bacterial ferroptosis-like death. Thus, the porous titanium scaffold, engineered with a piezoelectric nanoreactor, demonstrates superior antibacterial efficacy under ultrasound and facilitates osteogenesis via piezoelectric immunomodulation-activated therapy. | Science advances | 14/03/2025 |
('LID', '10.1038/s41586-025-08697-6') | TGFβ links EBV to multisystem inflammatory syndrome in children. | Goetzke, Carl Christoph, Massoud, Mona, Frischbutter, Stefan, Guerra, Gabriela Maria, Ferreira-Gomes, Marta, Heinrich, Frederik, von Stuckrad, Anne Sae Lim, Wisniewski, Sebastian, Licha, Jan Robin, Bondareva, Marina, Ehlers, Lisa, Khaldi-Plassart, Samira, Javouhey, Etienne, Pons, Sylvie, Trouillet-Assant, Sophie, Ozsurekci, Yasemin, Zhang, Yu, Poli, Maria Cecilia, Discepolo, Valentina, Lo Vecchio, Andrea, Sahin, Bengü, Verboom, Murielle, Hallensleben, Michael, Heuhsen, Anja Isabelle, Astudillo, Camila, Espinosa, Yazmin, Vial Cox, Maria Cecilia, Dobbs, Kerry, Delmonte, Ottavia M, Montealegre Sanchez, Gina A, Magliocco, Mary, Barron, Karyl, Danielson, Jeffrey, Petrov, Lev, Unterwalder, Nadine, Sawitzki, Birgit, Matz, Mareen, Lehmann, Katrin, Gratopp, Alexander, von Bernuth, Horst, Burkhardt, Lisa-Marie, Wiese, Niklas, Peter, Lena, Schmueck-Henneresse, Michael, Amini, Leila, Maurer, Marcus, Roehmel, Jobst Fridolin, Gewurz, Benjamin E, Yonker, Lael M, Witkowski, Mario, Kruglov, Andrey, Mall, Marcus Alexander, Su, Helen C, Ozen, Seza, Radbruch, Andreas, Belot, Alexandre, Durek, Pawel, Kallinich, Tilmann, Mashreghi, Mir-Farzin | In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock(1) termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion(2) and systemic hyperinflammation(3). The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. (4,5)). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation. | Nature | 12/03/2025 |
('LID', '10.1016/j.cell.2025.02.009') | Engineering mtDNA deletions by reconstituting end joining in human mitochondria. | Fu, Yi, Land, Max, Kavlashvili, Tamar, Cui, Ruobing, Kim, Minsoo, DeBitetto, Emily, Lieber, Toby, Ryu, Keun Woo, Choi, Elim, Masilionis, Ignas, Saha, Rahul, Takizawa, Meril, Baker, Daphne, Tigano, Marco, Lareau, Caleb A, Reznik, Ed, Sharma, Roshan, Chaligne, Ronan, Thompson, Craig B, Pe'er, Dana, Sfeir, Agnel | Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies. | Cell | 05/03/2025 |
('LID', '10.1186/s40337-023-00900-1') | A case series to test the acceptability, feasibility and preliminary efficacy of AVATAR therapy in anorexia nervosa. | Thompson, Alistair, Calissano, Chiara, Treasure, Janet, Ball, Hannah, Montague, Alice, Ward, Thomas, Cardi, Valentina | BACKGROUND: Patients with anorexia nervosa tend to experience an inner "eating disorder" voice. They struggle to recognise and assert their own identity over the illness's identity and relate to it from a powerless and subordinate position. AVATAR therapy was developed to help patients with psychosis to gain greater power and control over distressing voices. The goal of this study was to test the feasibility, acceptability, safety and preliminary efficacy of an adaptation of AVATAR therapy for anorexia nervosa. METHODS: Twelve adult patients with anorexia nervosa were recruited. Ten completed an assessment session and between five to seven therapy sessions. The assessment session consisted in the creation of an avatar to represent the "eating disorder". This was accomplished by manipulating auditory and visual characteristics through a specialist computer software. During the therapy sessions, patients interacted with the avatar to assert their own desires and will. Patients completed baseline, end of intervention and follow-up (4-week) online questionnaires. A non-concurrent multiple baselines single case experimental design (SCED) was used (A(1)BA(2)). Feasibility, acceptability, safety and preliminary efficacy of the intervention were assessed. RESULTS: The therapy met pre-specified criteria relating to (1) Feasibility: sample recruited within three months; retention rate at the end of the treatment phase = 81.9%; therapy completion rate = 90.1%. (2) Safety: no serious adverse events associated with the intervention. (3) Acceptability: mean ratings = 7.5 (SD = 2.61) out of ten, on a 0-10 scale of acceptability (10 = complete satisfaction). With regards to efficacy, participants reported significantly lower levels of distress associated with the eating disorder voice and higher levels of self-compassion at the end of treatment. No other significant changes were observed in frequency of the eating disorder voice, voice's characteristics, such as omnipotence and malevolence, eating disorder symptoms and symptoms of anxiety, depression and stress. Patients' feedback indicated that the therapy had helped with their ability to stand up to the illness, make positive changes around eating, and increase their motivation to recover and self-compassion. CONCLUSION: AVATAR therapy for anorexia nervosa is feasible, acceptable and safe for patients. Larger studies are needed to test clinical efficacy. TRIAL REGISTRATION: The study was pre-registered on the clinicaltrials.gov registry (https://clinicaltrials.gov/ct2/show/NCT04778423). | Journal of eating disorders | 13/10/2023 |
('LID', '10.1038/s41467-025-57924-1') | Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice. | Chi, Dongmei, Zhang, Kun, Zhang, Jianxing, He, Zhaoli, Zhou, Hongxia, Huang, Wan, Liu, Yang, Huang, Jingxiu, Zeng, Weian, Bai, Xiaohui, Ou, Chaopeng, Ouyang, Handong | Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) is an important brain region involved in major depressive disorder (MDD). However, the underlying mechanism by which astrocytes within PFC contribute to MDD remains unclear. Using single-nucleus RNA sequencing analyses, we show a significant reduction in astrocytes and attenuated pleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1) signaling in astrocyte-to-excitatory neuron communication in the PFC of male MDD patients. We find reduced astrocytes and PTN in the dorsomedial PFC of male mice with depression induced by chronic restraint and social defeat stress. Knockdown of astrocytic PTN induces depression-related responses, which is reversed by exogenous PTN supplementation or overexpression of astrocytic PTN. The antidepressant effects exerted by astrocytic PTN require interaction with PTPRZ1 in excitatory neurons, and PTN-PTPRZ1 activates the AKT signaling pathway to regulate depression-related responses. Our findings indicate the PTN-PTPRZ1-AKT pathway may be a potential therapeutic target for MDD. | Nature communications | 14/03/2025 |
('LID', '10.1093/cvr/cvaf023') | Opportunities and challenges for the use of human samples in translational cardiovascular research: a scientific statement of the ESC Working Group on Cellular Biology of the Heart, the ESC Working Group on Cardiovascular Surgery, the ESC Council on Basic Cardiovascular Science, the ESC Scientists of Tomorrow, the European Association of Percutaneous Cardiovascular Interventions of the ESC, and the Heart Failure Association of the ESC. | Davidson, Sean M, Andreadou, Ioanna, Antoniades, Charalambos, Bartunek, Jozef, Basso, Cristina, Brundel, Bianca J J M, Byrne, Robert A, Chiva-Blanch, Gemma, da Costa Martins, Paula, Evans, Paul C, Girão, Henrique, Giricz, Zoltan, Gollmann-Tepeköylü, Can, Guzik, Tomasz, Gyöngyösi, Mariann, Hübner, Norbert, Joner, Michael, Kleinbongard, Petra, Krieg, Thomas, Liehn, Elisa, Madonna, Rosalinda, Maguy, Ange, Paillard, Melanie, Pesce, Maurizio, Petersen, Steffen E, Schiattarella, Gabriele G, Sluijter, Joost P G, Steffens, Sabine, Streckfuss-Bömeke, Katrin, Thielmann, Matthias, Tucker, Art, Van Linthout, Sophie, Wijns, William, Wojta, Johann, Wu, Joseph C, Perrino, Cinzia | Animal models offer invaluable insights into disease mechanisms but cannot entirely mimic the variability and heterogeneity of human populations, nor the increasing prevalence of multi-morbidity. Consequently, employing human samples-such as whole blood or fractions, valvular and vascular tissues, myocardium, pericardium, or human-derived cells-is essential for enhancing the translational relevance of cardiovascular research. For instance, myocardial tissue slices, which preserve crucial structural and functional characteristics of the human heart, can be used in vitro to examine drug responses. Human blood serves as a rich source of biomarkers, including extracellular vesicles, various types of RNA (miRNA, lncRNA, and circRNAs), circulating inflammatory cells, and endothelial colony-forming cells, facilitating detailed studies of cardiovascular diseases. Primary cardiomyocytes and vascular cells isolated from human tissues are invaluable for mechanistic investigations in vitro. In cases where these are unavailable, human induced pluripotent stem cells serve as effective substitutes, albeit with specific limitations. However, the use of human samples presents challenges such as ethical approvals, tissue procurement and storage, variability in patient genetics and treatment regimens, and the selection of appropriate control samples. Biobanks are central to the efficient use of these scarce and valuable resources. This scientific statement discusses opportunities to implement the use of human samples for cardiovascular research within specific clinical contexts, offers a practical framework for acquiring and utilizing different human materials, and presents examples of human sample applications for specific cardiovascular diseases, providing a valuable resource for clinicians, translational and basic scientists engaged in cardiovascular research. | Cardiovascular research | 14/03/2025 |
('LID', '10.1097/HEP.0000000000001307') | HLA-DQB1*03:01 and risk of Hepatitis B virus-related hepatocellular carcinoma. | Zhang, Ting, Huang, Chih-Jen, Chen, Hai-Tao, Huang, Yu-Han, Pan, Mei-Hung, Lee, Mei-Hsuan, Viard, Mathias, Hildesheim, Allan, Pfeiffer, Ruth M, Carrington, Mary, Chen, Chien-Jen, Zhu, Bin, Lenz, Tobias L, Jiang, Deke, Yang, Hwai-I, Liu, Zhiwei | BACKGROUND AIMS: The human leukocyte antigen (HLA) locus is implicated in hepatocellular carcinoma (HCC) among chronic hepatitis B virus (HBV) carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence (HED) with HBV-related HCC in Han Chinese and explored biological mechanisms. APPROACH RESULTS: We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and HED with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6,197 chronic HBV carriers in Taiwan). Significant signals were validated in independent set (636 cases, 560 controls in Qidong, PR China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni-correction for multiple testing (p<1.6×10-4). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (ORmeta-analysis=1.33, Pmeta-analysis=2.6×10-8). Three amino acids within DQβ1 peptide-binding region, HLA-DQβ1Ala13, HLA-DQβ1Tyr26, and HLA-DQβ1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) (P<0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 (Pmeta-analysis=3.3×10-3). CONCLUSIONS: HLA-DQB1*03:01 and its three key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels. | Hepatology (Baltimore, Md.) | 14/03/2025 |
('LID', '10.1016/j.ccell.2025.02.015') | Hypoxia inducible factor-1α drives cancer resistance to cuproptosis. | Yang, Zhou, Su, Wei, Wei, Xiyi, Pan, Yitong, Xing, Mengying, Niu, Lili, Feng, Baijie, Kong, Weiyu, Ren, Xiaohan, Huang, Feng, Zhou, Jingwan, Zhao, Wei, Qiu, Yingyi, Liao, Tian, Chen, Qi, Qu, Shuang, Wang, Yunjun, Guan, Qing, Li, Duanshu, Zen, Ke, Chen, Yun, Qin, Chao, Wang, Yu, Zhou, Xiang, Xiang, Jun, Yao, Bing | Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis. | Cancer cell | 04/03/2025 |
('LID', '10.1038/s41467-025-57610-2') | A skin organoid-based infection platform identifies an inhibitor specific for HFMD. | Li, Jun, Ma, Jie, Cao, Ruiyuan, Zhang, Qiyu, Li, Mansheng, Wang, Wenwen, Wang, Yujie, Li, Wei, Zhu, Yunping, Leng, Ling | The EV-A71 poses a serious threat to the health and lives of children. The EV-A71 can be transmitted by direct and indirect skin contact. Therefore, there is an urgent need to create novel skin models using human-derived cells to study the biology and pathogenesis of the virus and facilitate drug screening. Here, we use human induced pluripotent stem cells-derived skin organoids (hiPSC-SOs) as a model for EV-A71 infection and find that multiple cell types within the skin organoids, including epidermal cells, hair follicle cells, fibroblasts, and nerve cells, express EV-A71 receptors and are susceptible to EV-A71 infection. We elucidate the specific response of different cell types to EV-A71 and reveal that EV-A71 infection can degrade extracellular collagen and affect fibroblasts. We find that EV-A71 can mediate epidermal cell damage through autophagy and Integrin/Hippo-YAP/TAZ signaling pathways, thereby promoting hyperproliferation of progenitor cells. Based on this finding, we identify an autophagy-associated protein as a drug target of EV-A71 and discover an EV-A71 replication inhibitor. Altogether, these data suggest that hiPSC-SOs can be used as an infectious disease model to study skin infectious diseases, providing a valuable resource for drug screening to identify candidate virus therapeutics. | Nature communications | 13/03/2025 |
('LID', '10.1186/s12933-025-02670-3') | Proteomic signatures of type 2 diabetes predict the incidence of coronary heart disease. | Li, Yujian, Li, Dun, Lin, Jing, Zhou, Lihui, Yang, Weiling, Yin, Xin, Xu, Chenjie, Cao, Zhi, Wang, Yaogang | Emerging evidence reveals a complex association between type 2 diabetes (T2D) and coronary heart disease (CHD), which share common risk factors and biological pathways. This study aims to identify the shared proteomic signatures of T2D and CHD, as well as whether the shared proteins predict incident CHD in T2D patients, and to develop predictive models. Utilizing data from 53,014 UK Biobank participants and 2923 plasma proteins, we identified 488 proteins associated with T2D, of which 125 proteins were also associated with CHD. Among the shared proteins, we determine nine proteins showing causal associations with CHD, including PCSK9, NRP1, and CD27. Mediation analyses suggest that the nine proteins mediate the association between T2D and CHD. By integrating these proteins into our predictive model, we achieved a desirable prediction (AUC = 0.819) for future CHD onset in T2D patients. Additionally, druggability evaluation show 32 potential therapeutic agents, including established antihypertensives and nine novel compounds, suggesting avenues for dual-targeted treatment strategies. Collectively, our findings unveil the proteomic signatures associated with both T2D and CHD, providing implications for screening and predicting future CHD onset in T2D patients. | Cardiovascular diabetology | 14/03/2025 |
('LID', '10.1148/rycan.240213') | Deep Learning Radiopathomics Models Based on Contrast-enhanced MRI and Pathologic Imaging for Predicting Vessels Encapsulating Tumor Clusters and Prognosis in Hepatocellular Carcinoma. | Yu, Yixing, Cao, Lixiu, Shen, Binqing, Du, Mingzhan, Gu, Wenhao, Gu, Chunyan, Fan, Yanfen, Shi, Cen, Wu, Qian, Zhang, Tao, Zhu, Mo, Wang, Ximing, Hu, Chunhong | Purpose To develop deep learning (DL) radiopathomics models based on contrast-enhanced MRI and pathologic imaging to predict vessels encapsulating tumor clusters (VETC) and survival in hepatocellular carcinoma (HCC). Materials and Methods In this retrospective, multicenter study, 578 patients with HCC (mean age [±SD], 59 years ± 10; 442 male, 136 female) were divided into the training (n = 317), internal (n = 137), and external (n = 124) test sets. DL radiomics and pathomics models were developed to predict VETC using gadoxetic acid-enhanced MR and pathologic images. Deep radiomics score (DRS) and handcrafted and deep pathomics scores were compared between the group with VETC pattern in HCC (VETC+) and group without VETC pattern in HCC (VETC-). Multivariable Cox regression analyses were performed to identify independent prognostic factors, and the radiopathomics nomogram models were developed for early recurrence and progression-free survival (PFS). The prognostic power was evaluated using the concordance index (C index) and time-dependent receiver operating characteristic (ROC) curves. Results In the external test set, the Swin Transformer showed good performance for predicting VETC in both DL radiomics (area under the ROC curve [AUC], 0.77-0.79) and pathomics (AUC, 0.79) models. Patients with VETC+ HCC had significantly higher DRS and handcrafted and deep pathomics scores compared with patients with VETC- HCC in all datasets (all P < .001). The radiopathomics nomogram model incorporating DRS in the arterial phase and the handcrafted and deep pathomics scores achieved C indexes of 0.69, 0.60, and 0.67 for early recurrence and time-dependent AUCs of 0.83 (95% CI: 0.76, 0.91), 0.81 (95% CI: 0.68, 0.94), and 0.78 (95% CI: 0.67, 0.88) for 3-year PFS in the training, internal, and external test sets, respectively. Early recurrence and PFS rates statistically significantly differed between the high- and low-risk patients stratified by the radiopathomics nomogram model (all P < .05). Conclusion DL radiopathomics models effectively helped to predict VETC in HCC and assess the risk for early recurrence and PFS. Keywords: Hepatocellular Carcinoma, Deep Learning, MRI, Radiopathomics, Survival Supplemental material is available for this article. © RSNA, 2025. | Radiology. Imaging cancer | 00/03/2025 |
('LID', '10.1007/s13304-025-02166-5') | Diagnosis and management of caustic ingestion: an interdisciplinary nationwide cross-sectional survey from the Italian society of endoscopic surgery and new technologies (SICE), the Italian society of digestive endoscopy (SIED), the world society of emergency surgery-Italy chapter (WSESit), and the Italian society of surgical endoscopy and digestive diseases (ISSE). | Giordano, Alessio, Mastronardi, Manuela, Podda, Mauro, Bonavina, Luigi, Cuccurullo, Diego, Anania, Gabriele, Bergamini, Carlo, Galloro, Giuseppe, Hassan, Cesare, Parodi, Maria Caterina, Agresta, Ferdinando, Montori, Giulia, Sartelli, Massimo, Catena, Fausto, Fugazzola, Paola, Ansaloni, Luca, Marciano, Emanuele, Geraci, Girolamo, Maurano, Attilio, Avellino, Manuela, Massella, Arianna, Orlandini, Beatrice | Caustic ingestion (CI) in adults represents a potentially life-threatening condition. Diagnosis and management of CI in real life remain challenging. The aim of the survey is to evaluate on a national scale the multidisciplinary management of these patients. 24-item online Survey was sent to the mailing lists and social media of Italian Society of Endoscopic Surgery and New Technologies, Italian Society of Digestive Endoscopy, World Society of Emergency Surgery-Italy Chapter, and Italian Society of Surgical Endoscopy and Digestive Diseases. Overall, 240 subjects answered to the survey, corresponding to 22.1% of the total members of the scientific societies involved. 131 (54.5%) respondents evaluated fewer than ten CI patients per year. The recommendations provided by the WSES and SIED guidelines were followed by 133 (55.2%) and 83 (34.4%) participants, respectively. Emergency surgery was advocated by 180 (77.6%) of the respondents for patients with transmural necrosis or signs of perforation, using minimally invasive surgery in 47% of the cases and considering initial esophagojejunal anastomosis as safe in 33 (14.2%) of the responses. Our study is the first to provide real-life data on how the management of CI varies across Italian physicians, according to regional, institutional, and specialty-related factors. This survey highlights the need for standardized and uniform guidelines. | Updates in surgery | 13/03/2025 |
('LID', '10.1016/j.cell.2025.02.010') | Genome-scale resources in the infant gut symbiont Bifidobacterium breve reveal genetic determinants of colonization and host-microbe interactions. | Shiver, Anthony L, Sun, Jiawei, Culver, Rebecca, Violette, Arvie, Wynter, Char, Nieckarz, Marta, Mattiello, Samara Paula, Sekhon, Prabhjot Kaur, Bottacini, Francesca, Friess, Lisa, Carlson, Hans K, Wong, Daniel P G H, Higginbottom, Steven, Weglarz, Meredith, Wang, Weigao, Knapp, Benjamin D, Guiberson, Emma, Sanchez, Juan, Huang, Po-Hsun, Garcia, Paulo A, Buie, Cullen R, Good, Benjamin H, DeFelice, Brian, Cava, Felipe, Scaria, Joy, Sonnenburg, Justin L, Van Sinderen, Douwe, Deutschbauer, Adam M, Huang, Kerwyn Casey | Bifidobacteria represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest in bifidobacteria as a live biotic therapy, our understanding of colonization, host-microbe interactions, and the health-promoting effects of bifidobacteria is limited. To address these major knowledge gaps, we used a large-scale genetic approach to create a mutant fitness compendium in Bifidobacterium breve. First, we generated a high-density randomly barcoded transposon insertion pool and used it to determine fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. Second, to enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1,462 genes. We leveraged these tools to reveal community- and diet-specific requirements for colonization and to connect the production of immunomodulatory molecules to growth benefits. These resources will catalyze future investigations of this important beneficial microbe. | Cell | 07/03/2025 |
('LID', '10.1016/j.immuni.2025.02.008') | Lactate: A key regulator of the immune response. | Llibre, Alba, Kucuk, Salih, Gope, Atrayee, Certo, Michelangelo, Mauro, Claudio | Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases. | Immunity | 11/03/2025 |
('LID', '10.1016/j.apnr.2025.151911') | Effects of a 12-week lower limb resistance training with breathing regulation in patients with diabetes-related foot ulcers: A randomized controlled trial. | Wu, Jia-Ling, Yeh, Mei-Ling, Liao, Jocelyn | Patients with diabetes-related foot ulcers may require hospitalization and face an increased risk of amputation, which can significantly impact their quality of life. One potential solution is exercise, which can regulate blood glucose levels, improve wound healing, and enhance overall well-being. This randomized controlled trial aimed to evaluate the impact of a lower limb resistance training program combined with breathing-regulation techniques on glycemic control, wound healing, and quality of life in patients with diabetes-related foot ulcers. Patients hospitalized for type 2 diabetes-related foot ulcers were recruited from a single medical center and randomly divided into two groups. The control group (n = 31) received standard treatment, while the exercise group (n = 28) received standard treatment along with lower limb resistance training and breathing-regulation techniques. Assessments of fasting blood glucose levels, hemoglobin A1c (HbA1c) levels, wound healing, and quality of life were carried out at the start of the study and week 4, week 8, and week 12 of the intervention. The exercise group demonstrated significant improvements in fasting blood glucose and HbA1c levels, as well as in physical health, psychological well-being, social relationships, and environmental aspects of quality of life over the 12 weeks compared to both the control group and the baseline (p < .05). However, no significant change was observed in wound healing (p > .05). The resistance training program for the lower limbs, combined with breathing-regulation techniques, is recommended for improving blood glucose levels and quality of life over 12 weeks. | Applied nursing research : ANR | 00/04/2025 |
('LID', '10.1182/blood.2024027999') | Clonal Hematopoiesis Landscape in Frequent Blood Donors. | Karpova, Darja, Huerga Encabo, Hector Dr, Donato, Elisa, Calderazzo, Silvia, Scherer, Michael, Llorian-Sopena, Miriam, Leppä, Aino-Maija, Würth, Roberto, Stelmach, Patrick, Papazoglou, Despoina, Ferrelli, Alessandra, Ngo, Steven, Kotova, Iuliia, Harenkamp, Sabine, Zimmer, Kai, Wolf, Dominik, Panten, Jasper, Reed, John, Przybylla, Adriana, Tonn, Torsten, Kopp-Schneider, Annette, Velten, Lars, DiPersio, John F, Wong, Terrence N, Bonnet, Dominique Prof, Bonig, Halvard, Trumpp, Andreas | Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time donations, 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex matched control donor (CD) cohorts. Functional analysis of FD enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while no significant lineage bias was observed in HSCs harboring EPO responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations. | Blood | 11/03/2025 |
('LID', '10.1111/jocd.70102') | Finasteride Use: Evaluation of Depression and Suicide Risk. | Gupta, Aditya K, Bamimore, Mary A, Williams, Greg, Talukder, Mesbah | BACKGROUND: Oral finasteride 1 mg/day is indicated for androgenetic alopecia (AGA), while 5 mg/day is for benign prostatic hyperplasia (BPH). Oral finasteride has been linked with depression and suicide; however, a causal association is uncertain. The so-called post-finasteride syndrome (PFS) refers to a "cluster" of side effects experienced by some men (i.e., cis men) after taking oral finasteride. AIMS: The objective of the current study was to evaluate the association of depression and suicide with oral finasteride in males, using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). As a secondary objective, we conducted disproportionality analyses of FAERS data to assess whether oral dutasteride use was linked to psychological symptoms related to depression and suicidality. METHODS: We conducted disproportionality analyses for 5 AEs using MedDRA terms. Associations were metricized with the reporting odds ratio (ROR) across 3 time periods, namely, 2006-2011, 2013-2018, and 2019-2023. RESULTS: No significant AEs/signals were detected with oral finasteride from 2006 to 2011 for any of the 5 AEs (completed suicide, depression suicidal, suicidal behavior, suicidal ideation, attempted suicide). Signals were detected for some AEs during 2013-2018 and 2019-2023. For example, there was a greater likelihood of reporting suicidal ideations in individuals taking oral finasteride during 2013-2018 (ROR = 2.8, p < 0.05) and 2019-2023 (ROR = 5.0, p < 0.05). In contrast, no signals were detected with oral dutasteride during 2006-2011, 2013-2018, and 2019-2023. CONCLUSION: The study found no significant correlation between oral finasteride and depression/suicide reports from 2006 to 2011 but noted a significant number of such reports in 2013-2018 and 2019-2023. This increase may be linked to heightened awareness of AEs following the recognition of so-called PFS in 2012. | Journal of cosmetic dermatology | 00/03/2025 |
('LID', '10.1016/j.cell.2025.02.013') | Crop root bacterial and viral genomes reveal unexplored species and microbiome patterns. | Dai, Rui, Zhang, Jingying, Liu, Fang, Xu, Haoran, Qian, Jing-Mei, Cheskis, Shani, Liu, Weidong, Wang, Binglei, Zhu, Honghui, Pronk, Lotte J U, Medema, Marnix H, de Jonge, Ronnie, Pieterse, Corné M J, Levy, Asaf, Schlaeppi, Klaus, Bai, Yang | Reference genomes of root microbes are essential for metagenomic analyses and mechanistic studies of crop root microbiomes. By combining high-throughput bacterial cultivation with metagenomic sequencing, we constructed comprehensive bacterial and viral genome collections from the roots of wheat, rice, maize, and Medicago. The crop root bacterial genome collection (CRBC) significantly expands the quantity and phylogenetic diversity of publicly available crop root bacterial genomes, with 6,699 bacterial genomes (68.9% from isolates) and 1,817 undefined species, expanding crop root bacterial diversity by 290.6%. The crop root viral genome collection (CRVC) contains 9,736 non-redundant viral genomes, with 1,572 previously unreported genus-level clusters in crop root microbiomes. From these, we identified conserved bacterial functions enriched in root microbiomes across soils and host species and uncovered previously unexplored bacteria-virus connections in crop root ecosystems. Together, the CRBC and CRVC serve as valuable resources for investigating microbial mechanisms and applications, supporting sustainable agriculture. | Cell | 10/03/2025 |
('LID', '10.1038/s41467-025-57452-y') | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes. | Sevilla-González, Magdalena, Smith, Kirk, Wang, Ningyuan, Jensen, Aubrey E, Litkowski, Elizabeth M, Kim, Hyunkyung, DiCorpo, Daniel A, Hsu, Sarah, Cui, Jinrui, Liu, Ching-Ti, Yu, Chenglong, McNeil, John J, Lacaze, Paul, Westerman, Kenneth E, Chang, Kyong-Mi, Tsao, Philip S, Phillips, Lawrence S, Goodarzi, Mark O, Sladek, Rob, Rotter, Jerome I, Dupuis, Josée, Florez, Jose C, Merino, Jordi, Meigs, James B, Zhou, Jin J, Raghavan, Sridharan, Udler, Miriam S, Manning, Alisa K | Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease. | Nature communications | 15/03/2025 |
('LID', '10.1186/s12943-025-02288-9') | ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma. | Bandi, Dhana Sekhar Reddy, Nagaraju, Ganji Purnachandra, Sarvesh, Sujith, Carstens, Julienne L, Foote, Jeremy B, Graff, Emily C, Fang, Yu-Hua D, Keeton, Adam B, Chen, Xi, Valiyaveettil, Jacob, Berry, Kristy L, Bae, Sejong, Akce, Mehmet, Gorman, Greg, Yoon, Karina J, Manne, Upender, Boyd, Michael R, Buchsbaum, Donald J, Azmi, Asfar S, Maxuitenko, Yulia Y, Piazza, Gary A, El-Rayes, Bassel F | BACKGROUND: Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models. METHODOLOGY: Murine PDAC cells with KRAS(G12D) mutation (KPC-luc or 2838c3-luc) were orthotopically implanted into the pancreas of C57BL/6J mice, and four PDX PDAC tumors with KRAS mutations were implanted subcutaneously in NSG mice. To assess potential to overcome RAS inhibitor resistance, parental and resistant MIA PaCa-2 PDAC cells (KRAS(G12C) mutation) were implanted subcutaneously. Subcutaneously implanted RAS(WT) BxPC-3 cells were used to assess the selectivity of ADT-1004. RESULTS: ADT-1004 potently blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated RAS and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRAS(G12D), KRAS(G12V), KRAS(G12C), or KRAS(G13Q) mutations and increased CD4(+) and CD8(+) T cells in the TME consistent with exhaustion and increased MHCII(+) M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models resistant to these KRAS(G12C) inhibitors and MRTX1133 resistant KRAS(G12D) mutant cells. As evidence of selectivity for tumors with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS(WT) PDAC cells. CONCLUSION/SIGNIFICANCE: ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC. | Molecular cancer | 13/03/2025 |
('LID', '10.1111/acel.70022') | Phosphorylation of an RNA-Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging. | Yeom, Eunbyul, Mun, Hyejin, Lim, Jinhwan, Chun, Yoo Lim, Min, Kyung-Won, Lambert, Johana, Cowart, L Ashley, Pierce, Jason S, Ogretmen, Besim, Cho, Jung-Hyun, Chang, Jeong Ho, Buchan, J Ross, Pitt, Jason, Kaeberlein, Matt, Kang, Sung-Ung, Kwon, Eun-Soo, Ko, Seungbeom, Choi, Kyoung-Min, Lee, Yong Sun, Ha, Yoon-Su, Kim, Seung-Jin, Lee, Kwang-Pyo, Kim, Hyo-Sung, Yang, Seo Young, Shin, Chang Hoon, Yoon, Je-Hyun, Lee, Kyu-Sun | The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism. | Aging cell | 11/03/2025 |
('LID', '10.1080/0886022X.2025.2471016') | The association between nutritional-inflammatory status and chronic kidney disease prognosis: a population-based study. | Zhang, Xinyu, Hu, Xuanhan, Qian, Lin, Chen, Zeqi, Hua, Xintao, Zhang, Dahong, Wei, Haibin | BACKGROUND: Chronic kidney disease (CKD) prognosis is closely tied to the interplay between nutrition and inflammation. However, comprehensive nutritional-inflammatory indices for prognostic evaluation are rare in CKD. This study explored the association of the advanced lung cancer inflammation index (ALI) with estimated glomerular filtration rate (eGFR) and all-cause mortality in CKD patients. METHODS: A total of 1,982 CKD patients from the National Health and Nutrition Examination Survey (NHANES) database (2011-2018) were included in the analysis. Analytical methods included linear regression, cox regression, and restricted cubic spline (RCS) analysis. Subgroup and sensitivity analyses were performed, and further evaluation was conducted using the receiver operating characteristic (ROC) curve and C-index for all-cause mortality across different CKD stages. RESULTS: Among CKD patients, 1,103 patients (55.7%) were classified as stage I-II, and 879 patients (44.3%) as stage III-V. After adjusting covariates, ALI was found to be positively correlated with eGFR (Beta = 0.11; 95% CI: 0.07-0.15), and negatively related with all-cause mortality (HR = 0.72; 95% CI: 0.63-0.83). Subgroup analysis showed that the positive correlation between ALI and eGFR was stronger in CKD stage III-V compared to stage I-II. However, ALI's protective effect on mortality was weaker in stage III-V. The C-index for ALI was 0.648 in stage I-II and 0.660 in stage III-V. CONCLUSION: ALI was significantly associated with eGFR and all-cause mortality in CKD patients. Nutritional and anti-inflammatory interventions in early-stage CKD may improve prognosis, and ALI may have great potential as a multifaceted biomarker to influence the prognosis of CKD, particularly in stages III-V. | Renal failure | 00/12/2025 |
('LID', '10.1182/blood.2024027336') | Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study. | Kuter, David J, Ghanima, Waleed, Cooper, Nichola, Liebman, Howard Allen, Zhang, Lei, Hu, Yu, Miyakawa, Yoshitaka, Homenda, Wojciech, Morales Galindo, Luisa Elena Elena MD, Basquiera, Ana Lisa, Tan, Chuen Wen, Saydam, Guray Prof Dr, Hütter-Krönke, Marie Luise, Chai-Adisaksopha, Chatree, Gomez-Almaguer, David, Tran, Huy, Shin, Ho-Jin, Dantas da Cunha Junior, Ademar, Lazar, Zsolt, Pascual-Izquierdo, Cristina, Kirgner, Ilya, Lucchini, Elisa, Kuzmina, Ganna, Fillitz, Michael, Audia, Sylvain, Taparia, Minakshi, Cordoba, Matias, Diab, Remco, Yao, Mengjie, Gouia, Imene Dr, Lee, Michelle, Daak, Ahmed Abd Almalik | Rilzabrutinib is a covalent, reversible BTK inhibitor with multiple mechanisms targeting key immune thrombocytopenia (ITP) disease pathophysiology. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg bid (n=133) vs placebo (n=69) for 24 weeks. At baseline overall, median age was 47 years (range, 18-80), 63% female, 7.7 year (range, 0.3-52.2) median duration of ITP, and 28% were splenectomized. Overall (N=202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50×109/L or 30×109/L-<50×109/L and doubled from baseline) during the first 12 weeks and were eligible to complete the double-blind period. The primary endpoint durable platelet response (platelet count ≥50×109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy) was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P<0.0001). All secondary efficacy endpoints were significantly superior for rilzabrutinib (P<0.05). Median time to first platelet response was 15 d in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P=0.0007) and improved week 25 bleeding scores (P=0.0006). Improved physical fatigue was sustained from week 13 (P=0.01) through 25 (P=0.0003). Treatment-related adverse events were mainly grade 1-2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg) and another died from unrelated pneumonia. Rilzabrutinib-- in ITP patients who failed multiple previous therapies (splenectomy, TPO-RA, rituximab and/or fostamatinib) resulted in rapid and durable platelet response, reduced rescue medication use and bleeding, significantly improved physical fatigue, and showed favorable safety. NCT04562766; EudraCT 2020-002063-60. | Blood | 16/03/2025 |
('LID', '10.1016/j.cgh.2025.01.016') | Proton Pump Inhibitors for Inducing and Maintaining Remission in Eosinophilic Esophagitis: An Updated Systematic Review and Meta-Analysis. | Lucendo, Alfredo J, Gutiérrez-Ramírez, Lucía, Tejera-Muñoz, Antonio, Molina-Infante, Javier, Arias, Ángel | BACKGROUND & AIMS: Proton pump inhibitor (PPI) therapy results in clinical and histological remission in approximately 50% of eosinophilic esophagitis (EoE) patients. We aimed to systematically update this topic due to cumulative data from pediatric/adult populations in wider geographical settings. METHODS: A search in MEDLINE, EMBASE, and SCOPUS databases was performed. Primary outcomes were clinical response and histological remission (< 15 eos/HPF). Subgroup analyses included age group, PPI drug and dosage, study design, data origin, and risk of bias. Data were pooled using random-effects models. RESULTS: Seventy-three studies comprising 7304 patients were included. PPI therapy led to clinical response in 65% (95%CI, 57.2-72.4; I(2) 0), and histological remission in 45.4% (95%CI, 41.6- 49.3) of patients, without differences between children and adults (41.2% vs. 48%, p 0.17). Overall, 34.1% (95%CI, 27.9-40.5) achieved <5 eos/HPF. Pooled effectiveness was significantly superior (p<0.001) in Western Pacific areas, principally Japan (67.9%), compared to American and European (40.6% and 44.4%, respectively). Histological remission was significantly higher with double PPI doses compared to standard (51.7% vs. 28.3%, p 0.005). Response was significantly higher in studies with lower risk of bias. Maintenance half doses led to sustained histological remission in 68.2% (95%CI, 63.7%-72.6%; I(2)=0) of patients. CONCLUSIONS: PPI therapy induces clinic-histological remission in almost half of pediatric and adult EoE patients. Response to PPIs is significantly higher in Japan. Sustained remission is common on tapering PPI doses. | Clinical gastroenterology and hepatology : the official clinical practice journal | 13/03/2025 |
('LID', '10.1038/s43856-025-00785-y') | Identifying and ranking non-traditional risk factors for cardiovascular disease prediction in people with type 2 diabetes. | Dziopa, Katarzyna, Chaturvedi, Nishi, Asselbergs, Folkert W, Schmidt, Amand F | BACKGROUND: Cardiovascular disease (CVD) prediction models perform poorly in people with type 2 diabetes (T2DM). We aimed to identify potentially non-traditional CVD predictors for six facets of CVD (including coronary heart disease, ischemic stroke, heart failure, and atrial fibrillation) in people with T2DM. METHODS: We analysed data on 600+ features from the UK Biobank, stratified by history of CVD and T2DM: 459,142 participants without diabetes or CVD, 14,610 with diabetes but without CVD, and 4432 with diabetes and CVD. A penalised generalized linear model with a binomial distribution was used to identify CVD-related features. Subsequently, a 20% hold-out set was used to replicate identified features and provide an importance based ranking. RESULTS: Here we show that non-traditional risk factors are of particular importance in people with diabetes. Classical CVD risk factors (e.g. family history, high blood pressure) rank highly in people without diabetes. For individuals with T2DM but no CVD, top predictors include cystatin C, self-reported health satisfaction, biochemical measures of ill health. In people with diabetes and CVD, key predictors are self-reported ill health and blood cell counts. Unique diabetes-related risk factors include dietary patterns, mental health and biochemistry measures (e.g. oestradiol, rheumatoid factor). Adding these features improves risk stratification; per 1000 people with diabetes, 133 CVD and 165 HF cases receive a higher risk. CONCLUSIONS: This study identifies numerous replicated non-traditional CVD risk factors for people with T2DM, providing insight to improve guideline recommended risk prediction models which currently overlook these features. | Communications medicine | 14/03/2025 |
('LID', '10.1016/j.ygyno.2019.11.028') | Combining copy number, methylation markers, and mutations as a panel for endometrial cancer detection via intravaginal tampon collection. | Sangtani, Ajleeta, Wang, Chen, Weaver, Amy, Hoppman, Nicole L, Kerr, Sarah E, Abyzov, Alexej, Shridhar, Viji, Staub, Julie, Kocher, Jean-Pierre A, Voss, Jesse S, Podratz, Karl C, Wentzensen, Nicolas, Kisiel, John B, Sherman, Mark E, Bakkum-Gamez, Jamie N | OBJECTIVE: We aimed to assess whether endometrial cancer (EC) can be detected in shed DNA collected with vaginal tampon by analyzing copy number, methylation markers, and mutations. METHODS: Tampons were collected prior to hysterectomy from 38 EC patients and 28 women with benign indications. Extracted tampon DNA underwent the following: 1) low-coverage whole genome sequencing (LC-WGS) to assess copy number, 2) pyrosequencing to measure percent promotor methylation of HOXA9, RASSF1, and CDH13 and 3) next generation sequencing (NGS) to identify mutations in 19 genes associated with EC identified through The Cancer Genome Atlas. Sensitivity and specificity for each test and test combinations were calculated. RESULTS: Methylation analysis yielded the highest specificities but lowest sensitivities (37-40% sensitivity; 100% specificity for HOXA9, RASSF1 and HTR1B) while mutation analysis had improved sensitivity (50% sensitivity; 83% specificity). Only one "false positive" result for copy number variants was identified among women with benign surgical indications, which was based on detection of copy number changes, and associated with a leiomyosarcoma that was only recognized at hysterectomy. Considering any of the 3 biomarker classes as a positive, resulted in a sensitivity of 92% and specificity of 86%. Mutation analysis did not add sensitivity to the combination of analysis of copy number and methylation. CONCLUSIONS: This study demonstrates a proof-of-principle for non-invasive yet precise detection of endometrial cancer. We propose that with improved biomarker testing, it may be possible to develop a clinically useful test for detecting EC. | Gynecologic oncology | 00/02/2020 |
('LID', '10.1016/j.esmoop.2025.104301') | The role of physical activity, sedentary behaviour, diet, adiposity and body composition on health-related quality of life and cancer-related fatigue after diagnosis of colorectal cancer: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis. | Markozannes, G, Cividini, S, Aune, D, Becerra-Tomás, N, Kiss, S, Balducci, K, Vieira, R, Cariolou, M, Jayedi, A, Greenwood, D C, Brockton, N T, Croker, H, Mitrou, P, Copson, E, Renehan, A G, Bours, M, Demark-Wahnefried, W, Hudson, M M, May, A M, Odedina, F T, Skinner, R, Steindorf, K, Tjønneland, A, Velikova, G, Baskin, M L, Chowdhury, R, Hill, L, Lewis, S J, Seidell, J, Weijenberg, M P, Krebs, J, Cross, A J, Tsilidis, K K, Chan, D S M | BACKGROUND: The impact of physical activity, sedentary behaviour, diet, adiposity, and body composition on health-related quality of life (HRQoL) and cancer-related fatigue among colorectal cancer survivors remains uncertain. METHODS: PubMed, Embase, and CENTRAL were systematically searched until April 2023 for relevant randomised controlled trials (RCTs) and cohort studies. Random-effects meta-analyses or descriptive syntheses were conducted depending on the number of studies. The evidence was interpreted and graded by an independent World Cancer Research Fund Expert Committee and Expert Panel. RESULTS: We included 31 RCTs (18 exercise, 14 diet) and 30 cohort studies (8 physical activity, 3 sedentary behaviour, 13 diet, 9 adiposity and body composition). Meta-analyses were possible for exercise RCTs that showed non-significant effects but indicative of improved HRQoL (overall four trials for global HRQoL, physical and emotional well-being) and fatigue (five trials). These studies were rated at a high risk of bias (RoB), and evidence was graded as 'very low certainty of an effect'. Descriptive synthesis of interventions to improve diet quality suggested small improvements in global HRQoL and physical well-being, but with a high RoB rating leading to a 'low certainty' grading. Evidence from RCTs on probiotics and supplements and evidence from observational studies on sedentary behaviour, and various dietary and body composition factors was generally inconsistent and too scarce to draw conclusions. CONCLUSIONS: Exercise and diet quality interventions might improve HRQoL and fatigue outcomes in colorectal cancer survivors. The evidence overall was limited and should be strengthened by larger, well-designed RCTs across the cancer continuum. | ESMO open | 13/03/2025 |
('LID', '10.7189/jogh.15.04025') | The impact of physical activity on inhibitory control of adult ADHD: a systematic review and meta-analysis. | Yang, Yi, Wu, Chang-Hong, Sun, Liang, Zhang, Ting-Ran, Luo, Jiong | OBJECTIVE: We aimed to Investigate physical activity's effects on inhibitory control in adult attention deficit hyperactivity disorder (ADHD).The benefits of physical activity on the inhibitory control of adult ADHD were explored in the hope of providing some suggestions for approaches to treating adult ADHD. METHODS: We searched the databases PubMed, Web of Science, CNKI and Wanfang for randomised controlled trials (RCTs) of the effect of physical activity on inhibitory control in adults with ADHD, using PRISMA guidelines. We used used the Cochrane Bias Risk Assessment Criteria to assess the methodological quality of the included studies. Finally, we performed a heterogeneity analysis and a potential publication bias analysis using Revman 5.4. RESULTS: A total of eight articles, 14 studies, and 373 experimental subjects were included in the systematic review and meta-analysis. The meta-analysis results showed that both acute exercise (standard mean deviation (SMD) = -0.65, 95% confidence interval (CI) = -1.10,-0.2, P = 0.005) and chronic exercise (SMD = -1.77, 95% CI = -2.84, -0.69, P = 0.0001) have a positive effect on the inhibitory control of adult ADHD. Pilates (SMD = -2.22, 95% CI = -2.97, -1.47, P < 0.0001), Tai Chi (SMD = -2.20, 95% CI = -6.25, -1.8, P = 0.25), cycling (SMD = -0.67, 95% CI = -1.27, -0.08, P = 0.03), vibration training (SMD = -0.67, 95% CI = -1.39, -0.05, P = 0.07), yoga (SMD = 0.01, 95% CI = -0.50, -0.48, P = 0.97), and other different exercise styles have significant differences in their effects on adult ADHD inhibitory control. CONCLUSIONS: Physical activity has a beneficial effect on inhibitory control in adults with ADHD. However, more research is needed to examine the beneficial effects of different types of physical activity, intervention modalities, and dose-response effects of intensity. REGISTRATION: This review was registered with INPLASY (registration number: 202490109). | Journal of global health | 14/03/2025 |
('LID', '10.1002/ctm2.70270') | Targeting YBX1-m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma. | Li, Ouwen, An, Ke, Wang, Han, Li, Xianbin, Wang, Yueqin, Huang, Lan, Du, Yue, Qin, Nuo, Dong, Jiasheng, Wei, Jingyao, Sun, Ranran, Shi, Yong, Guo, Yanjia, Sun, Xiangyi, Yang, Ying, Yang, Yun-Gui, Kan, Quancheng, Tian, Xin | BACKGROUND: RNA 5-methylcytosine (m5C) plays an important role in the progression of hepatocellular carcinoma (HCC). Dysregulation of ferroptosis is closely associated with HCC. However, the effect of the epigenetic mRNA m5C modification on ferroptosis in HCC remains unclear. METHODS: In this study, ferroptosis was evaluated by detecting lipid reactive oxygen species (lipid ROS), ferrous ion and 4-hydroxynonenal (4-HNE) in xenograft mouse model, diethylnitrosamine (DEN)-initiated HCC model and so forth. The regulatory mechanisms of YBX1 in mRNA translation were elucidated using RNA sequencing, ribosome sequencing, RNA immunoprecipitation (RIP)-sequencing, bisulphite sequencing and immunoprecipitation (IP)-mass spectrometry assays. Dual-luciferase reporter, RIP-qPCR, Co-IP, RNA pulldown and methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) assays were performed to validate the mechanism of YBX1 in regulating mRNA translation by m5C modification. RESULTS: Here, we found that YBX1 promoted the translation of Ring Finger Protein 115 (RNF115) mRNA through m5C modification, thereby inhibiting ferroptosis and promoting HCC development. Moreover, RNF115 was identified as an E3 ubiquitin ligase for dihydroorotate dehydrogenase (DHODH), promoting Lys27 (K27) ubiquitination and inhibiting its autophagic degradation to counteract ferroptosis. In addition, YBX1 bound to the m5C modification sites of RNF115 3'-untranslated region (UTR) and interacted with Eukaryotic Translation Initiation Factor 4A1 (EIF4A1) to bridge the 5'-UTR regions, promoting mRNA circularisation and translation, while NOP2/Sun RNA methyltransferase 2 (NSUN2) was identified as responsible for m5C modification of RNF115 mRNA in HCC. CONCLUSIONS: The current work revealed that YBX1 promoted RNF115 mRNA translation in an m5C-dependent manner, thereby regulating DHODH ubiquitination and expression to suppress ferroptosis. This research sheds light on the mechanism of YBX1 in m5C-modified mRNAs translation and ferroptosis, highlighting its promise as a biomarker for prognosis and a target for therapy in HCC. KEY POINTS: YBX1 inhibits ferroptosis in HCC by regulating the RNF115-DHODH axis. RNF115, an E3 ligase, mediates K27 ubiquitination and autophagic degradation of DHODH. YBX1 binds to the m5C sites of RNF115 mRNA 3'-UTR and interacts with EIF4A1 to bridge the 5'-UTR, promoting mRNA circularisation and translation. High expression of YBX1/RNF115 predicts the poor overall survival in HCC. | Clinical and translational medicine | 00/03/2025 |
('LID', '10.1038/s41589-025-01864-w') | Post-translational modifications orchestrate the intrinsic signaling bias of GPR52. | Zhang, Bingjie, Ge, Wei, Ma, Mengna, Li, Shanshan, Yu, Jie, Yang, Guang, Wang, Huilan, Li, Jingwen, Li, Qingrun, Zeng, Rong, Lu, Boxun, Shui, Wenqing | Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifications (PTMs) remains largely unexplored. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G-protein activity that is emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. After profiling the N-glycosylation and phosphorylation patterns, we found that these two types of PTMs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive G(s) signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein in brain striatal cells. Our study provides new insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR through distinct PTMs in different motifs. | Nature chemical biology | 14/03/2025 |
('LID', '10.1016/j.ccell.2025.02.010') | Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients. | Chen, Jianzhou, Levy, Antonin, Tian, Ai-Ling, Huang, Xuehan, Cai, Guoxin, Fidelle, Marine, Rauber, Conrad, Ly, Pierre, Pizzato, Eugénie, Sitterle, Lisa, Piccinno, Gianmarco, Liu, Peng, Durand, Sylvère, Mao, Misha, Zhao, Liwei, Iebba, Valerio, Felchle, Hannah, Mallard de La Varende, Anne-Laure, Fischer, Julius Clemens, Thomas, Simon, Greten, Tim F, Jones, Jennifer C, Monge, Cecilia, Demaria, Sandra, Formenti, Silvia, Belluomini, Lorenzo, Dionisi, Valeria, Massard, Christophe, Blanchard, Pierre, Robert, Charlotte, Quevrin, Clément, Lopes, Eloise, Clémenson, Céline, Mondini, Michele, Meziani, Lydia, Zhan, Yizhou, Zeng, Chengbing, Cai, Qingxin, Morel, Daphne, Sun, Roger, Laurent, Pierre-Antoine, Mangoni, Monica, Di Cataldo, Vanessa, Arilli, Chiara, Trommer, Maike, Wegen, Simone, Neppl, Sebastian, Riechelmann, Rachel P, Camandaroba, Marcos P, Neto, Elson Santos, Fournier, Pierre-Edouard, Segata, Nicola, Holicek, Peter, Galluzzi, Lorenzo, Buqué, Aitziber, Alves Costa Silva, Carolina, Derosa, Lisa, Kroemer, Guido, Chen, Chuangzhen, Zitvogel, Laurence, Deutsch, Eric | The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8(+) T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential. | Cancer cell | 10/03/2025 |
('LID', '10.1007/s12031-025-02317-8') | The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases. | Aydın, Şeyma, Özdemir, Selçuk, Adıgüzel, Ahmet | Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders. | Journal of molecular neuroscience : MN | 13/03/2025 |
('LID', '10.1186/s13046-025-03358-y') | Viral expression of NE/PPE enhances anti-colorectal cancer efficacy of oncolytic adenovirus by promoting TAM M1 polarization to reverse insufficient effector memory/effector CD8(+) T cell infiltration. | Wang, Shuo, Kong, Lingkai, Wang, Linpei, Zhuang, Yan, Guo, Ciliang, Zhang, Yuxin, Cui, Huawei, Gu, Xiaosong, Wu, Junhua, Jiang, Chunping | BACKGROUND: Oncolytic adenoviruses are among the most widely utilized oncolytic viruses due to their notable anti-tumor and gene expression capabilities, and modification of ADVs to create armed adenoviruses remains a popular research direction. Nonetheless, immune suppression triggered by ADV and targeted enhancements based on this limitation have been relatively unexplored. METHODS: Flow cytometry was employed to assess immune infiltration in the tumor microenvironment following ADV therapy. Targeted novel recombinant oncolytic viruses, ADV(NE) and ADV(PPE), were designed, and their antitumor efficacy, safety, and ability to reshape immune infiltration were evaluated in both subcutaneous tumor models in mice and in vitro experiments. Immune cell depletion assays confirmed the critical role of macrophages. The impact of HMGB1 on macrophage polarization was investigated using shRNA, qRT-PCR, ELISA, and flow cytometry. Furthermore, the importance of TLR4 and its downstream pathways was validated through immunoprecipitation, Western blotting, homozygous knockout mice, and TLR4 inhibitors. RESULTS: We demonstrated that ADV limits the infiltration of effector memory/effector CD8 + T cells (T(EM)/T(E)) within the tumor microenvironment. To address this, we leveraged the strong capacity of NE or PPE to recruit T(EM)/T(E) by constructing novel recombinant oncolytic adenoviruses, ADV(NE) or ADV(PPE), armed with NE or PPE. These recombinant viruses induce pyroptosis in colorectal cancer cells accompanied by the release of HMGB1. HMGB1 binds to TLR4 on the surface of macrophages, activating the MyD88-NFκB-NLRP3 (ASC) pathway and promoting M1 polarization of TAMs, thereby increasing T(EM)/T(E) cell infiltration and enhancing antitumor efficacy. CONCLUSIONS: In summary, this study presents the development of the novel oncolytic adenoviruses ADV(NE) and ADV(PPE) with enhanced anti-tumor efficacy and provides an in-depth exploration of their specific anti-tumor mechanisms. These findings indicate promising clinical therapeutic prospects and offer new insights for advancing oncolytic adenovirus therapies. | Journal of experimental & clinical cancer research : CR | 14/03/2025 |
('LID', '10.1038/s41593-025-01910-9') | Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals. | Andersen, Katrine B, Krishnamurthy, Anushree, Just, Mie Kristine, Van Den Berge, Nathalie, Skjærbæk, Casper, Horsager, Jacob, Knudsen, Karoline, Vogel, Jacob W, Toledo, Jon B, Attems, Johannes, Polvikoski, Tuomo, Saito, Yuko, Murayama, Shigeo, Borghammer, Per | Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson's disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression. | Nature neuroscience | 13/03/2025 |
('LID', '10.1038/s41392-025-02193-z') | PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial. | Wang, Yakun, Lu, Jialin, Chong, Xiaoyi, Wang, Chang, Chen, Xiaofeng, Peng, Zhi, Gu, Yanhong, Wang, Yizhuo, Wang, Xicheng, Li, Jian, Gong, Jifang, Qi, Changsong, Yuan, Jiajia, Lu, Zhihao, Lu, Ming, Zhou, Jun, Cao, Yanshuo, Chen, Yang, Zhang, Cheng, Hou, Zhiguo, Kou, Hongyi, Shen, Lin, Zhang, Xiaotian | Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0-81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1(+)) CD8(+) T cell densities and effective scores. First-line treatment with camrelizumab plus apatinib and SOX, followed by maintenance treatment with camrelizumab plus apatinib, is effective and safe in AFP-G/GEJ adenocarcinoma. Further studies are necessary to validate these findings. | Signal transduction and targeted therapy | 14/03/2025 |
('LID', '10.1001/jama.2025.1604') | High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. | Thouvenot, Eric, Laplaud, David, Lebrun-Frenay, Christine, Derache, Nathalie, Le Page, Emmanuelle, Maillart, Elisabeth, Froment-Tilikete, Caroline, Castelnovo, Giovanni, Casez, Olivier, Coustans, Marc, Guennoc, Anne-Marie, Heinzlef, Olivier, Magy, Laurent, Nifle, Chantal, Ayrignac, Xavier, Fromont, Agnès, Gaillard, Nicolas, Caucheteux, Nathalie, Patry, Ivania, De Sèze, Jérôme, Deschamps, Romain, Clavelou, Pierre, Biotti, Damien, Edan, Gilles, Camu, William, Agherbi, Hanane, Renard, Dimitri, Demattei, Christophe, Fabbro-Peray, Pascale, Mura, Thibault, Rival, Manon | IMPORTANCE: Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting. OBJECTIVE: To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS. DESIGN, SETTING, AND PARTICIPANTS: The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited. INTERVENTION: Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months. MAIN OUTCOMES AND MEASURES: The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes. RESULTS: Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol. CONCLUSIONS AND RELEVANCE: Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01817166. | JAMA | 10/03/2025 |
('LID', '10.1136/jitc-2024-011149') | Voxel-level radiomics and deep learning for predicting pathologic complete response in esophageal squamous cell carcinoma after neoadjuvant immunotherapy and chemotherapy. | Zhang, Zhen, Luo, Tianchen, Yan, Meng, Shen, Haixia, Tao, Kaiyi, Zeng, Jian, Yuan, Jingping, Fang, Min, Zheng, Jian, Bermejo, Inigo, Dekker, Andre, Ruysscher, Dirk De, Wee, Leonard, Zhang, Wencheng, Jiang, Youhua, Ji, Yongling | BACKGROUND: Accurate prediction of pathologic complete response (pCR) following neoadjuvant immunotherapy combined with chemotherapy (nICT) is crucial for tailoring patient care in esophageal squamous cell carcinoma (ESCC). This study aimed to develop and validate a deep learning model using a novel voxel-level radiomics approach to predict pCR based on preoperative CT images. METHODS: In this multicenter, retrospective study, 741 patients with ESCC who underwent nICT followed by radical esophagectomy were enrolled from three institutions. Patients from one center were divided into a training set (469 patients) and an internal validation set (118 patients) while the data from the other two centers was used as external validation sets (120 and 34 patients, respectively). The deep learning model, Vision-Mamba, integrated voxel-level radiomics feature maps and CT images for pCR prediction. Additionally, other commonly used deep learning models, including 3D-ResNet and Vision Transformer, as well as traditional radiomics methods, were developed for comparison. Model performance was evaluated using accuracy, area under the curve (AUC), sensitivity, specificity, and prognostic stratification capabilities. The SHapley Additive exPlanations analysis was employed to interpret the model's predictions. RESULTS: The Vision-Mamba model demonstrated robust predictive performance in the training set (accuracy: 0.89, AUC: 0.91, sensitivity: 0.82, specificity: 0.92) and validation sets (accuracy: 0.83-0.91, AUC: 0.83-0.92, sensitivity: 0.73-0.94, specificity: 0.84-1.0). The model outperformed other deep learning models and traditional radiomics methods. The model's ability to stratify patients into high and low-risk groups was validated, showing superior prognostic stratification compared with traditional methods. SHAP provided quantitative and visual model interpretation. CONCLUSIONS: We present a voxel-level radiomics-based deep learning model to predict pCR to neoadjuvant immunotherapy combined with chemotherapy based on pretreatment diagnostic CT images with high accuracy and robustness. This model could provide a promising tool for individualized management of patients with ESCC. | Journal for immunotherapy of cancer | 15/03/2025 |
('LID', '10.1016/j.immuni.2025.02.017') | Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME. | Benmebarek, Mohamed-Reda, Oguz, Cihan, Seifert, Matthias, Ruf, Benjamin, Myojin, Yuta, Bauer, Kylynda C, Huang, Patrick, Ma, Chi, Villamor-Payà, Marina, Rodriguez-Matos, Francisco, Soliman, Marlaine, Trehan, Rajiv, Monge, Cecilia, Xie, Changqing, Kleiner, David E, Wood, Bradford J, Levy, Elliot B, Budhu, Anuradha, Kedei, Noemi, Mayer, Christian T, Wang, Xin Wei, Lack, Justin, Telford, William, Korangy, Firouzeh, Greten, Tim F | Anti-vascular endothelial growth factor (VEGF) treatment has shown clinical activity together with immune checkpoint blockade (ICB), but the exact mechanism is not known. We show that VEGF blockade in combination with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) + anti-programmed death-ligand 1 (PD-L1) in cholangiocarcinoma (CCA) potentiated a multimodal mechanism dependent on B cell activating factor (BAFF), leading to a proinflammatory B cell response. It led to a BAFF- and interleukin (IL)-12-dependent expansion and rewiring of T regulatory cells (Tregs) toward an anti-tumor T helper-1 (Th-1)-like fragile state. We translated this approach to the clinic and observed immunological changes characterized by Treg cell expansion and rewiring toward fragile and unstable states. We explored the effect of VEGF receptor 2 (VEGFR2) signaling on Treg cell transcriptional programming and established a mouse model ablating VEGFR2 expression on Treg cells. This study reveals the immunological interplay resulting from targeting VEGF together with CTLA-4 and PD-L1 blockade. | Immunity | 08/03/2025 |
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