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Gastric Stem Cells: Physiological and Pathological Perspectives. Gastric epithelium operates in a hazardous environment that curtails the lifespan of the constituent cells, imposing a requirement for continuous epithelial renewal. Stem cells that reside in the stomach are thus essential for regulating physiological tissue renewal and injury repair because of their self-renewal, high proliferation capacity and multiple differentiation potentials. Recent investigations using lineage tracing models have identified diverse populations of gastric stem cells and even fully differentiated cells that can regain stem cell capacity, so enriching our understanding on the identity and plasticity of gastric stem cells. These cell populations include the Villin promotor, Lgr5+, CCKR2+, Axin2+ and AQP5+ stem cells in the antrum, TFF2 mRNA, Mist1+ cells and Troy+ mature chief cells in the corpus, as well as Sox2, eR1, Lrig1, Bmi1-marked cell in both the antrum and the corpus. Establishment of gastric organoids derived from primary gastric tissues and pluripotent stem cells or embryonic stem cells characterizes niche factors required by the gastric stem cell populations, and further provides new insights into stomach development, host-Helicobacter pylori interactions and malignant transformation. Furthermore, focus on the gastric stem cells and their niches uncovers the initiation of stomach precancerous lesions and origin of gastric cancer, providing options for cancer prevention and intervention. In summary, with the development of stem cell research, gastric stem cells give us more opportunities to prevent and treat stomach diseases. | gastric cancer |
Prevalence, Severity, and Self-Reported Characteristics of Taste Alterations in Patients Receiving Chemotherapy. To describe the prevalence, severity, and self-reported characteristics of taste alterations (TAs) induced by chemotherapy and to investigate TAs across chemotherapy regimens. 243 adult patients from five outpatient practices in Northern Italy. Correlation, univariate, and multivariate linear regression analyses. Variables include TAs, symptoms reported by patients, and the effect of TAs on quality of life. A majority of the study sample reported TAs. Difficulty in tasting saltiness was most common, followed by difficulty in tasting umami and sweetness. The severity and characteristics of TAs changed across chemotherapy regimens. TAs correlated with quality of life and were significantly associated with patient's age and a 21-day chemotherapy schedule. TAs are a frequent side effect of chemotherapy, with varying characteristics that have a negative effect on quality of life. Healthcare professionals should routinely assess for TAs and provide patients with specific management strategies depending on the nature of TAs. | no data |
Understanding of chemoprophylaxis and concordance in inflammatory bowel disease. To assess patients' understanding for the reasons for taking 5-aminosalicylic acid or ursodeoxycholic acid as chemoprophylaxis against colorectal carcinoma associated with inflammatory bowel disease (IBD). A questionnaire-based study using a 5-point opinion scale was performed. One hundred and ninety-two patients with colitis only and 74 patients with primary sclerosing cholangitis and IBD were invited to take part. Overall response rate was 58%. Sixty-four percent of patients claimed full concordance with chemoprophylaxis for maintenance of remission. Eighty-four percent of patients considered daily concordance during remission to be very important. Seventy-five percent stated they understood the reasons for taking the drugs. However, only 50% of the patients were aware of any link of their condition to bowel cancer. Seventy-nine percent of patients felt their concordance and understanding would be improved if they were informed of the chemoprophylactic potential of the medication. Despite good self-reported concordance, half of the patients were unaware of an association between colitis and bowel cancer. Explaining the potential chemoprophylactic benefits may enhance patients' overall concordance to 5-aminosalicylic acid and ursodeoxycholic acid and help maintain remission. | colorectal cancer |
Induction of high incidence of mammary tumour in female Noble rats with a combination of 17beta-oestradiol and testosterone. Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Despite extensive research, the precise mechanisms of breast carcinogenesis remain unclear. One of the reasons for this is due, at least in part, to a lack of a suitable animal model which can closely mimic the breast carcinogenesis in normal situations without using chemical carcinogens. We have developed an animal model of mammary gland carcinogenesis using a combination of oestradiol and testosterone, and succeeded in inducing a high percentage of female Noble rats to develop mammary cancer in a relatively short time (approximately 6 months). The results showed that androgens might work as a promoter to shorten the latency time of mammary gland carcinogenesis. Histopathological examination revealed that hyperplasia and dysplasia were first observed 2 months after treatment, in situ carcinoma after 3 months, and fully developed carcinoma of various forms including cribriform, papillary and camedo types were observed from 5 to 6 months after hormone implantation. Animals implanted with oestrogen or testosterone alone also developed mammary cancers, though with a lower overall incidence than the two hormones combined. They ranged from well differentiated to poorly differentiated forms with predominantly infiltrating ductal carcinoma. We have also observed a case of secondary cancer in the uterus. In addition to the high incidence of carcinoma, there was also a peculiar unexplained ipsilateral correlation between the site of hormonal implantation and the location of tumours, and the highest incidence of carcinogenesis was found to be in thoracic mammary gland. The study showed that both oestrogens and androgens are important in mammary cancer development. The animal model would prove to be a useful model for analysis of the mechanism(s) of hormonal carcinogenesis. | breast cancer |
Is there significant regional variation in hospital antibiotic consumption in Germany? Outpatient antibiotic use in Germany differs substantially between eastern and southern parts of the country (low use) and the western part (high use). Whether similar regional variation exists in hospital antibiotic consumption is not known. We investigated this issue using a convenience sample of 145 hospitals providing data for the year 2003. Data on hospital consumption of systemic antibiotics in Anatomical Therapeutic Chemical (ATC) class J01 were obtained from acute care hospitals that participated in an IMS survey and had complete data (dispensed drugs and patient-days per year) for at least one non-pediatric, non-psychiatric department or ward. A total of 275 non-ICU surgical departments/wards, 229 non-ICU non-surgical (general medicine, haematology-oncology, neurology/stroke) departments/wards, and 184 ICUs were analysed. Data were expressed in DDD (WHO/ATC definition version 2003) or daily doses adapted for recommendations in hospitalized patients (RDD) per 100 patient days (DDD/100 and RDD/100). The weighted mean over all departments/wards was 49.6 DDD/100 or 31.3 RDD/100, respectively. As expected, ICU antibiotic use density was much higher than use in non-ICU areas, and use in haematology-oncology was higher than in other non-surgical departments/wards. In univariate analyses, region, hospital bed-size category, university affiliation and haematology-oncology as specialty were associated with use density, but these associations were only partly confirmed in multivariate logistic regression analyses of factors associated with excess (> or = 75%) use density which showed university affiliation and haematology-oncology but not hospital location to be independently associated with comparatively high use. Antibiotic use density in German acute care hospitals does not appear to differ significantly between regions. Overall hospital consumption of antibiotics in this country appears to be similar to what has been described from other parts of Europe. In comparative analyses of hospital antibiotic consumption, data need to be adjusted at least for university affiliation and haematology-oncology. | no data |
Immunomodulatory effects of astragalus polysaccharide on human peripheral blood mononuclear cells co-cultured with cervical cancer cell line. To investigate immunomodulatory effects of Astragalus polysaccharides (APS) on the co-culture of peripheral blood mononuclear cells (PBMCs) with HeLa cervical cancer cell line. To assess the proliferation of PBMCs, carboxyfluorescein succinimidyl ester (CFSE)-labeled PBMCs were co-cultured with HeLa cells and treated with different concentrations of APS. Supernatants of cell culture were collected for cytokines assay via enzyme-linked immunosorbent assay (ELISA). The impact of APS on the proliferation of PBMCs, induction of regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) was carried out by flow cytometry. It was observed that APS could increase the proliferation of PBMCs co-cultured with HeLa cells (P < 0.05). However, APS had no significant effects on the induction of Tregs and MDSCs in the co-culture assay (P > 0.05). Furthermore, ELISA results demonstrated that APS could decrease IL-10 and TGF-β concentration (P < 0.05). The above-mentioned characteristics showed that APS might be able to modulate immune responses and improve anti-tumor effects through increasing the proliferation of PBMCs and decreasing inhibitory cytokines secretion as critical mediators of immune suppression in the tumor microenvironment. | cervical cancer |
B2 Prognostic Index in Determining Prognosis in Metastatic Breast Cancer. To determine the relationship between the B2 prognostic index (B2PI) scoring method and prognosis in metastatic breast cancer, and to create a formula based on parameters that can be easily accessed in daily practice. Descriptive study. Place and Duration of the Study: Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkiye, between May 2010 and June 2021. The clinicopathological characteristics of the patients were compared between the groups. All female breast cancer patients over the age of 18 years with de novo metastatic and non-metastatic breast cancers who developed metastasis during follow-up, were included in the study. Those with a second solid cancer or haematological malignancy and with a life expectancy of less than 3 months were excluded from the study. Chi-square and Fisher's exact tests were used to compare categorical data between the groups. Overall survival evaluations were made using the Kaplan-Meier analysis method and Log-Rank test. Risk factors for mortality were evaluated in Cox regression analysis. In all statistical tests, p <0.05 was considered statistically significant. There were 176 patients in this study, out of which 111 (63.1%) were de novo metastatic. When the effect of B2PI risk groups on overall survival in intrinsic subtypes was analysed, significant differences were found in the overall survival of B2PI risk groups in all subtypes except HER2+ ER- (HER2 overexpression subtype). According to the B2PI scoring system, the median overall survival was higher for both low-risk and moderate-risk patients compared to those in the high-risk category. For metastatic breast cancer patients, the B2PI can be used to determine prognosis and develop treatment strategies, as it is a clinical decision-making tool based on parameters that are easily accessible in daily practice. Metastatic breast cancer, B2 prognostic index, Prognosis, Survival. | breast cancer |
HuH-7-Lunet BLR Cells Propagate Rat Hepatitis E Virus (HEV) in a Cell Culture System Optimized for HEV. The family Hepeviridae comprises the species Orthohepevirus A-D (HEV-A to -D). HEV-C genotype 1 (HEV-C1, rat HEV) is able to infect humans. This study investigated whether an optimized HEV-A cell culture system is able to propagate the cell culture-derived rat HEV, and if de novo isolation of the virus from rat liver is possible. We tested the liver carcinoma cell lines PLC/PRF/5, HuH-7, and HuH-7-Lunet BLR for their susceptibility to HEV-C1 strains. Cells were infected with the cell culture-derived HEV-C1 strain R63 and rat liver-derived strain R68. Cells were maintained in MEMM medium, which was refreshed every 3-4 days. The viral load of HEV-C1 was determined by RT-qPCR in the supernatant and expressed as genome copies per mL (c/mL). Rat HEV replication was most efficient in the newly introduced HuH-7-Lunet BLR cell line. Even if the rat HEV isolate had been pre-adapted to PLC/PRF/5 by multiple passages, replication in HuH-7-Lunet BLR was still at least equally effective. Only HuH-7-Lunet BLR cells were susceptible to the isolation of HEV-C1 from the liver homogenate. These results suggest HuH-7-Lunet BLR as the most permissive cell line for rat HEV. Our HEV-C1 cell culture system may be useful for basic research, the animal-free generation of large amounts of the virus as well as for the testing of antiviral compounds and drugs. | liver cancer |
Focus on treatment of lung carcinoid tumor. Bronchial typical carcinoid tumors are neuroendocrine bronchopulmonary tumors with a low-grade malignancy, and an atypical carcinoid is an intermediate form of these tumors. There is a lack of knowledge on the optimal treatment for these tumors. The surgical treatment of choice consists of a lobectomy supplemented by dissection. The benefit of chemotherapy and radiotherapy is unclear. Targeted therapy could be used in this condition, but there is a lack of research recommending it. | lung cancer |
Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics. RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival. Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001). Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice. | pancreatic cancer |
Outcomes and prognostic factors for women with breast cancer in Malawi. Breast cancer incidence in sub-Saharan Africa (SSA) is increasing, and SSA has the highest age-standardized breast cancer mortality rate worldwide. However, high-quality breast cancer data are limited in SSA. We examined breast cancer patient and tumor characteristics among women in Lilongwe, Malawi and evaluated risk factor associations with patient outcomes. We consecutively enrolled 100 women ≥ 18 years with newly diagnosed, pathologically confirmed breast cancer into a prospective longitudinal cohort with systematically assessed demographic data, HIV status, and clinical characteristics. Tumor subtypes were further determined by immunohistochemistry, overall survival (OS) was estimated using Kaplan-Meier methods, and hazards ratios (HR) were calculated by Cox proportional hazard analyses. Of the 100 participants, median age was 49 years, 19 were HIV-positive, and 75 presented with late stage (III/IV) disease. HER2-enriched and triple-negative/basal-like subtypes represented 17% and 25% tumors, respectively. One-year OS for the cohort was 74% (95% CI 62-83%). Multivariable analyses revealed mortality was associated with HIV (HR, 5.15; 95% CI 1.58-16.76; p = 0.006), stage IV disease (HR, 8.86; 95% CI 1.07-73.25; p = 0.043), and HER2-enriched (HR, 7.46; 95% CI 1.21-46.07; p = 0.031), and triple-negative subtypes (HR, 7.80; 95% CI 1.39-43.69; p = 0.020). Late stage presentation, HER2-enriched and triple-negative subtypes, and HIV coinfection were overrepresented in our cohort relative to resource-rich settings and were associated with mortality. These findings highlight robust opportunities for population- and patient-level interventions across the entire cascade of care to improve breast cancer outcomes in low-income countries in SSA. | breast cancer |
Lymphangiogenesis and tumor metastasis. The lymphatic system transports interstitial fluid and macromolecules from tissues back to the blood circulation, and plays an important role in the immune response by directing the traffic of lymphocytes and antigen-presenting cells. The lymphatic system also constitutes one of the most important pathways of tumor dissemination. In many human cancers, increased expression of vascular endothelial growth factor-C (VEGF-C) is correlated with regional lymph node metastases. Experimental studies using transgenic mice overexpressing VEGF-C or xenotransplantation of VEGF-C-expressing tumor cells into immunodeficient mice have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node metastases. However, there is at present little evidence for lymphangiogenesis in human tumors and the relative importance of preexisting vs. newly formed lymphatics for metastasis in humans remains to be determined. Nonetheless, the striking correlation between the levels of VEGF-C in primary human tumors and lymph node metastases predicts its importance in cancer spread. Aside from promoting lymphangiogenesis, VEGF-C may also activate lymphatics to promote tumor cell chemotaxis, lymphatic intravasation and hence tumor cell dissemination. | multi cancer |
ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno- (AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity. The difference in the Wnt microenvironment in AC and SCC leads to variations in ABC transporter expression. Cisplatin via induction of canonical Wnt signaling up-regulates ABCB1 and ABCG2 drug transporters that are not transporters for cisplatin itself but are transporters for drugs that are frequently used in combination therapy with cisplatin modulating drug response. | lung cancer |
Radiotherapy for Diffuse Intrinsic Pontine Glioma: Insufficient but Indispensable. Diffuse intrinsic pontine gliomas (DIPGs) account for 10%-20% of all central nervous system tumors in children and are the leading cause of death in children with brain tumors. Although many clinical trials have been conducted over the past decades, the survival outcome has remained unchanged. Over 90% of children die within 2 years of the diagnosis, and radiotherapy remains the standard treatment to date. To improve the prognosis, hyperfractionated and hypofractionated radiotherapy and/or addition of radiosensitizers have been investigated. However, none of the radiotherapy approaches have shown a survival benefit, and the overall survival of patients with DIPG is approximately 11 months. Here, we comprehensively review the management of DIPG with focus on radiotherapy. | brain cancer |
Survival benefits from postoperative radiation therapy on lymph node positive patients with pancreatic adenocarcinoma. The benefit of combining postoperative radiation therapy (PORT) with chemotherapy for resected patients with pancreatic adenocarcinoma is controversial. We sought to determine the effects of PORT on survival in patients with pancreatic adenocarcinoma who underwent primary site surgery. Patients with pancreatic adenocarcinoma receiving primary tumor surgery between 1988 and 2012 were identified from the Surveillance, Epidemiology and End Results (SEER) database. We estimated the association between PORT and other clinicopathologic factors and survival. In total, 5304 patients were identified who underwent pancreatic resection including 2093 patients who had PORT and 3211 patients who had no PORT. Median overall, cancer-specific, and other-cause survival were 19.0, 20.0, and 196.0 months, respectively, with PORT versus 14.0, 15.0, and 163.0 months, respectively, without PORT (all P < 0.001). Subset analysis revealed that the benefit of PORT was limited to patients with N1 disease. Median overall, cancer-specific, and other-cause survival for patients with N1 disease were 18.0, 18.0, and NA months, respectively, with PORT versus 12.0, 13.0, and 154.0 months, respectively, without PORT (all P < 0.001). Regardless the number of positive lymph node count (PLN) and lymph node ratio (LNR), PORT was always associated with increased survival on multivariate analysis in patients with N1 disease (all P < 0.001). In summary, survival benefits might be obtained from PORT on lymph node positive patients with pancreatic adenocarcinoma. | pancreatic cancer |
Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction. MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes' ΔGbinding extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔGbinding to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent. | multi cancer |
A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers. | brain cancer |
Early-stage adenocarcinoma of the esophagus with mid to deep submucosal invasion (pT1b sm2-3): the frequency of lymph-node metastasis depends on macroscopic and histological risk patterns. The rate of lymph-node (LN) metastasis in early adenocarcinoma (EAC) of the esophagus with mid to deep submucosal invasion (pT1b sm2/3) has not yet been precisely defined. The aim of the this study was to evaluate the rate of LN metastasis in pT1b sm2/3 EAC depending on macroscopic and histological risk patterns to find out whether there may also be options for endoscopic therapy as in cancers limited to the mucosa and the upper third of the submucosa. A total of 1.718 pt with suspicion of EAC were referred for endoscopic treatment (ET) to the Dept. of Internal Medicine II at HSK Wiesbaden 1996-2010. In 230/1.718 pt, the suspicion (endoscopic ultrasound, EUS) or definitive diagnosis of pT1b EAC (ER/surgery) was made. Of these, 38 pt had sm2 lesions, and 69 sm3. Rate of LN metastasis was analyzed depending on risk patterns: histologically low-risk (hisLR): G1-2, L0, V0; histologically high-risk (hisHR): ≥1 criterion not fulfilled; macroscopically low-risk (macLR): gross tumor type I-II, tumor size ≤2 cm; macroscopically high-risk (macHR): ≥1 criterion not fulfilled; combined low-risk (combLR): hisLR+macLR; combined high-risk (combHR): at least 1 risk factor. LN rate was only evaluated in pt who had proven maximum invasion depth of sm2/sm3, and who in case of ET had a follow-up (FU) by EUS of at least 24 months. 23/38 pt with pT1b sm2 lesions and 39/69 pt with sm3 lesions fulfilled our inclusion criteria. In the pT1b sm2 group, rate of LN metastasis in the hisLR, hisHR, combLR, and combHR groups were 8.3% (1/12), 36.3% (4/11), 0% (0/5), and 27.8% (5/18). In the pT1b sm3 group, rate of LN metastasis in the hisLR, hisHR, combLR and combHR groups were 28.6% (2/7), 37.5% (12/32), 25% (1/4), and 37.1% (13/35). 30-day mortality of surgery was 1.7% (1/58 pt). In EAC with pT1b sm2/3 invasion, the frequency of LN metastasis depends on macroscopic and histological risk patterns. Surgery remains the standard treatment, because the rate of LN metastasis appears to be higher than the mortality risk of surgery. Whether a highly selected group of pT1b sm2 patients with a favourable risk pattern may be candidates for endoscopic therapy cannot be decided until the results of larger case volumes are available. | no data |
In situ immune response in human chromoblastomycosis--a possible role for regulatory and Th17 T cells. Chromoblastomycosis is a chronic fungal infection that affects skin and subcutaneous tissue. Lesions can be classified in tumorous, verrucous, cicatricial and plaque type. The cellular immune response in the severe form of the disease seems to correlate with a Th2 pattern of cytokines. The humoral immune response also seems to play a role. We intended to explore the populations of regulatory T cells and the Th17 pattern. Twenty-three biopsies of verrucous form were obtained from patients with clinical, culture and histopathological diagnostic of chromoblastomycosis, without treatment. It was performed an immunohistochemistry method to detect Foxp3, CD25, TGF-β, IL-6, IL-17 and IL-23. IL-17 was the only cytokine with high expression in CBM when compared to normal skin. The expression of Treg cells, TGF- β, IL-6 and IL-23 were similar to normal skin. The constitution of a local immune response with high expression of IL-17 and low expression of other cytokines could be at least in part, an attempt to help the immune system against fungal infection. On the other hand, high levels of local immune response mediated by Th17 profile could overcome the role of Treg cells. The inefficient immunomodulation as a consequence of the unbalance by Treg/Th17 cells seems to corroborate with the less effective immune response against fungi. | no data |
Unraveling the role of Major Vault Protein as a novel immune-related biomarker that promotes the proliferation and migration in pancreatic adenocarcinoma. Pancreatic adenocarcinoma (PAAD) is a formidable challenge in oncology research, with a complex pathogenesis that requires to be explored. Major Vault Protein (MVP) is the principal structural component of the vault complex, and its expression level is remarkably upregulated in various cancers. Extensive investigations have been conducted to explore the role of MVP in specific cancer contexts, yet the potential molecular mechanisms and biological functions of MVP in PAAD still remain considerably elusive. This study aims to explore the role of MVP as a novel immune-related biomarker in the pathogenesis and clinical treatment of PAAD. Gene expression data and clinical information were collected from TCGA, GTEx and GEO databases. Survival, prognostic and functional enrichment analysis were employed with R software. Immunological correlation analysis was performed using TIMER2.0, TIDE scores, TISIDB and TISCH. Epigenetic analysis was implemented by MethSurv, CPTAC, UALCAN, and cBioPortal. Drug analysis was conducted using Enrichr and CellMiner. Moreover, cellular experiments, like RNA interference, qRT-PCR, Western blot, cell cycle analysis, cell apoptosis analysis, colony formation assay, transwell assay, and wound healing assay, were performed for verifying the functional properties of MVP in the PAAD progression. We demonstrated an abnormally upregulated expression of MVP in PAAD tissues, which notably correlated with an adverse prognosis in PAAD patients. Functional analysis suggested the conceivable involvement of MVP in immune modulation, and immunotherapy. Additionally, we identified genetic alterations, reduced promoter methylation, and heightened phosphorylation in MVP. We also clarified Suloctidil and Tetradioxin as the most notable potential drugs targeting MVP in PAAD. Moreover, our experimental observations consistently highlighted the significant impact of MVP deficiency on impeding PAAD cell proliferation, inhibiting cell migration, and accelerating cell apoptosis. Interestingly, a potential link between MVP and ERK or AKT pathways was displayed, which opens new avenues for further exploration of the molecular mechanisms of MVP-targeted therapies in PAAD. This study systematically describes MVP as an immune-related biomarker with remarkable potential for predicting the prognosis, tumor progression and immunotherapeutic efficacy in PAAD. | pancreatic cancer |
Cytotoxicity and apoptosis induction of the marine Conus flavidus venom in HepG2 cancer cell line. Cancer is still an area of continuous research for finding more effective and selective agents, so our study aimed to explore new anticancer medicines from Cone snails' venoms as marine natural products with promising biological activities. Venoms from seven cone snails collected from two locations on the Red Sea coast (Marsa Alam (Ma) and Hurghada (Hu)) were extracted and subjected to SDS for protein concentrations. The venoms of C. vexillum (Ma), C. vexillum (Hu), and C. flavidus were found to have the highest protein concentrations (2.66, 2.618, and 2.611 mg/mL, respectively). The venom of C. vexillum (Ma) was found to be cytotoxic against the lung cancer cell line A549 (IC50 = 4.511 ± 0.03 µg/mL). On the other hand, the venom of C. flavidus showed a strong cytotoxic effect on both liver and lung cancer cell lines (IC50 = 1.593 ± 0.05 and 7.836 ± 0.4 µg/mL, respectively) when compared to their normal cell lines. Investigating the apoptotic cell death of C. flavidus venom on HepG2 cell lines, it showed total apoptotic cell death by 22.42-fold compared to untreated control and arresting the cell cycle at G2/M phase. Furthermore, its apoptotic cell death in HepG2 cells was confirmed through the upregulation of pro-apoptotic markers and down-regulation of Bcl-2 in both gene and protein expression levels. These findings confirmed the cytotoxic activity of C. flavidus venom through apoptotic cell death in HepG2 cells. So, a detailed study highlighting its structure and molecular target for developing new anticancer agents from natural sources is required.Communicated by Ramaswamy H. Sarma. | liver cancer |
A549 cells as a model to study endogenous LPA1 receptor signaling and regulation. Lysophosphatidic acid (LPA) modulates the function of many organs, including the lung. A549 is a lung carcinoma-derived cell line, frequently used as a model for type II pneumocytes. Here we show that these cells expressed messenger RNA coding for LPA1-3 receptors with the following order of abundance: LPA1 > LPA2 > LPA3 and that LPA was able to increase intracellular calcium, extracellular signal-regulated kinases 1/2 phosphorylation, and cell contraction. These effects were blocked by Ki16425, an antagonist selective for LPA1 and LPA3 receptors, and by the LPA1-selective antagonist, AM095. Activation of protein kinase C inhibited LPA-induced intracellular calcium increase. This action was blocked by protein kinase C inhibitors and enzyme down-regulation. Phorbol myristate acetate and AM095, but not Ki16425, decreased the baseline intracellular calcium concentration. Ki16425 blocked the effect of AM095 but not that of phorbol myristate acetate. The data indicate that LPA1 receptors exhibit constitutive activity and that AM095 behaves as an inverse agonist, whereas Ki16425 appears to be a classic antagonist. Furthermore, the LPA agonist, 1-oleoyl-2-O-methyl-rac-glycerophosphothionate, OMPT, induced a weak increase in intracellular calcium, but was able to induce full ERK 1/2 phosphorylation and cell contraction. These effects were blocked by AM095. These data suggest that OMPT is a biased LPA1 agonist. A549 cells express functional LPA1 receptors and seem to be a suitable model to study their signaling and regulation. | lung cancer |
Incidence, risk factors and survival of patients with brain metastases at initial metastatic breast cancer diagnosis in China. To characterize the incidence, risk factors and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China. The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 and 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively. Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40-4.04; p < 0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p = 0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p = 0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p = 0.09). Factors that independently decreased BM death risk were ECOG<2, brain metastases only and multidisciplinary treatment. HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive disease at MBC diagnosis, and further prospective randomized study is warranted. | breast cancer |
Gadolinium-hybridized mesoporous organosilica nanoparticles with high magnetic resonance imaging performance for targeted drug delivery. Magnetic resonance (MR) imaging techniques, which can provide images with excellent anatomical detail, are widely used in clinical diagnosis. However, the current clinical small molecule gadolinium (Gd) contrast agents have the defects of relatively low sensitivity and poor tumor-target specificity, preventing their adoption in biology and medicine. Herein, a facile synthetic strategy to fabricate gadolinium-hybridized mesoporous organosilica nanoparticles (MOSG) through a nanoprecipitation reaction, with the surface of nanoparticles grafted with the fluorescent dye isothiocyanate (FITC) and arginine-glycine-aspartic acid (RGD) for delivery of the antitumour drug doxorubicin hydrochloride (DOX), resulting in a high-performance nanotheranostic (RGD-MOSG-FITC/DOX) for targeted magnetic resonance imaging and chemotherapy of tumors. The prepared MOSG had a particle size of 60-80 nm and gadolinium elements were distributed in clusters that exhibited boosted longitudinal relaxivity. Routine blood tests and histopathology indicated good biocompatibility of MOSG. Furthermore, after being decorated with Arg-Gly-Asp peptide (RGD), RGD-MOSG-FITC demonstrated more preferable cellular uptake by HeLa cells (high expression of αⅤβ3) than MOSG without RGD grafting. Additionally, the tumor growth inhibition effect of RGD-MOSG-FITC/DOX was substantially more effective than that of the other groups. Therefore, this new delivery platform has good application potential in the field of tumor diagnosis and treatment. | no data |
The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion. Gliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-beta (TGF-beta) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-beta(1-3) as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-gamma activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-gamma-independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-beta(1-3) and their receptors I and II and associated with reduced TGF-beta release. Due to its capacity to counteract TGF-beta release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities. | brain cancer |
A 15-long non-coding RNA signature to improve prognosis prediction of cervical squamous cell carcinoma. Long non-coding RNAs (lncRNAs), which have little or no protein-coding capacity, caught a particular interest since their potential roles in the cancer paradigm. As the most common cancer in women, cervical squamous cell carcinoma remains one of the leading causes of deaths from cancer. However, limited evidence is available to determine the role of lncRNAs in the prognosis of cervical squamous cell carcinoma. In this study, we collected lncRNA expression profiling to identify prognosis related lncRNAs for cervical squamous cell carcinoma from TCGA database. In addition, we developed a 15-lncRNA signature based risk score to comprehensively assess the prognostic function of lncRNA. Furthermore, we performed a ROC analysis to identify the optimal cut-off point for classification risk level of the patients. Univariate Cox regression models were used to assess the association between lncRNAs and prognosis of patients with cervical squamous cell carcinoma. A 15-lncRNA based risk score was developed based on the Cox co-efficient of the individual lncRNAs. The prognostic value of this risk score was validated in the complete set and internal testing set. In summary, a 15-lncRNA expression signature (BAIAP2-AS1, RP11-203J24.8, LINC01133, RP1-7G5.6, RP11-147L13.15, SERHL, CTC-537E7.3, RP11-440L14.1, RP11-131N11.4, ILF3-AS1, RP11-80H18.4, RP11-1096G20.5, CTD-2192J16.26, RP11-621L6.3, and RP11-571M6.18) were identified and validated which can predict cervical cancer patient survival. The potential functions of this 15-lncRNA expression signature and individual lncRNAs as prognostic targets of cervical cancer were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the cervical squamous cell carcinoma patients. | cervical cancer |
Cancer risk of Lichen planus: A cohort study of 13,100 women in Finland. The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population-based Finnish register data. All women with the diagnosis of LP (n = 13,100) were identified from the Finnish Hospital Discharge Registry from 1969-2012. These patients were linked with subsequent cancer diagnoses from the Finnish Cancer Registry until 2014. Standardized incidence ratios (SIRs) were counted for different cancers by dividing the observed numbers of cancers by expected numbers, which were based on national cancer incidence rates. In total, 1,520 women with LP were diagnosed with cancer (SIR 1.15, 95% confidence interval [CI] 1.09-1.20). LP was associated with an increased risk of cancer of lip (SIR 5.17, 95% CI 3.06-8.16), cancer of tongue (SIR 12.4, 95% CI 9.45-16.0), cancer of oral cavity (SIR 7.97, 95% CI 6.79-9.24), cancer of esophagus (SIR 1.95, 95% CI 1.17-3.04), cancer of larynx (SIR of 3.47, 95% CI 1.13-8.10) and cancer of vulva (SIR 1.99, 95% CI 1.18-3.13). The risk of cancer was not increased in other locations where LP manifests (pharynx and skin). Patients with diagnosed LP have an increased risk of developing cancer of lip, tongue, oral cavity, esophagus, larynx and vulva. These data are important when considering treatment and follow-up of patients with LP diagnosis. | head and neck cancer |
Cancer Malignancy Is Correlated with Upregulation of PCYT2-Mediated Glycerol Phosphate Modification of α-Dystroglycan. The dystrophin-glycoprotein complex connects the cytoskeleton with base membrane components such as laminin through unique O-glycans displayed on α-dystroglycan (α-DG). Genetic impairment of elongation of these glycans causes congenital muscular dystrophies. We previously identified that glycerol phosphate (GroP) can cap the core part of the α-DG O-glycans and terminate their further elongation. This study examined the possible roles of the GroP modification in cancer malignancy, focusing on colorectal cancer. We found that the GroP modification critically depends on PCYT2, which serves as cytidine 5'-diphosphate-glycerol (CDP-Gro) synthase. Furthermore, we identified a significant positive correlation between cancer progression and GroP modification, which also correlated positively with PCYT2 expression. Moreover, we demonstrate that GroP modification promotes the migration of cancer cells. Based on these findings, we propose that the GroP modification by PCYT2 disrupts the glycan-mediated cell adhesion to the extracellular matrix and thereby enhances cancer metastasis. Thus, the present study suggests the possibility of novel approaches for cancer treatment by targeting the PCYT2-mediated GroP modification. | colorectal cancer |
Chemotherapy for recurrent and metastatic cervical cancer. Our purpose is to review the chemotherapy for recurrent and metastatic cervical cancer. We reviewed the phase II and III clinical trials of chemotherapy regimens and recent advances of targeted therapy for treatment of recurrent and metastatic cervical cancer. We also reviewed chemotherapy for rare histological subtypes of cervical cancer. Recent data has shown that the combination of cisplatinum and topotecan is the only regimen to demonstrate a progression-free survival and overall survival advantage over single agent cisplatin in the setting of recurrent cervical cancer. Preliminary study results indicate that targeted therapies may have an important role in the management of recurrent or metastatic cervical cancer. There remains a need for novel agents and further research focusing on the management of recurrent and metastatic cervical cancer. Future goals of therapy are to increase efficacy of treatment options while decreasing toxicity. | cervical cancer |
Helicobacter pylori eradication for low-grade gastric mucosa-associated lymphoid tissue lymphoma is more successful in inducing remission in distal compared to proximal disease. A series of studies has shown that Helicobacter pylori eradication induces remission in most patients with low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, there have been few reports about the effect of bacterial treatment on the gastric MALT lymphoma in Korea, a well-known H. pylori endemic area. A total of 111 H. pylori-infected patients were prospectively enrolled in Seoul National University Hospital and 99 among them were completely followed up according to our protocol. After H. pylori eradication, tumoural response was evaluated by endoscopy and histopathology every 2-3 months till complete remission (CR) and every 6 months after achieving CR. Median follow-up period was 41 months (range, 11-125 months). Helicobacter pylori was successfully eradicated in all 99 patients and CR was obtained in 84 (84.8%) of 99 patients. The median time to reach CR was 3 months and 94% of CR is in continuous complete remission. Five patients with CR relapsed after 10-22 months without the evidence of H. pylori reinfection. Cumulative recurrence rate was 2.3, 7.7 and 9.3% at 1, 2 and 3 years, respectively. Tumours were mainly located in distal stomach (67.7%) and tumours in distal stomach were associated with more favourable response than those in proximal stomach (P=0.001). Majority of patients with low-grade gastric MALT lymphoma treated by exclusive H. pylori eradication have a favourable long-term outcome, offering a real chance of cure. Tumour location could be a predictive factor for remission following H. pylori eradication. | gastric cancer |
In vivo and in vitro expression of somatostatin receptors in two human thymomas with similar clinical presentation and different histological features. [(111)In-DTPA0]octreotide scintigraphy allows the in vivo visualization of several types of SS receptor (SSR)-expressing tumors. Among these, thymomas have been recently detected. Here we report on 2 patients admitted for myasthenia gravis and radiological evidence of thymic mass. Although these patients had similar clinical presentation, in vivo SSR scintigraphy displayed a difference in the degree of the [(111)In-DTPA0]octreotide uptake. Considering that both thymic masses had comparable volume, [(111)In-DTPA0]octreotide level was significantly higher in one of the 2 tumors (tumor/background ratio of 5.7 vs 2.6). The SSR subtype expression pattern was studied in vitro on the surgically resected specimens by ligand binding techniques, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. According to the recent World Health Organization classification, the 2 tumors were classified A and B2 thymomas respectively. In membrane homogenates, we found a higher number of high affinity [125I-Tyr11]-SS-14 binding sites in the B2 thymomas (23.5+/-2.5 vs 12.0+/-0.4 fmol/mg membrane protein; p<0.05). RT-PCR analysis showed sst1, sst2A and sst3 mRNA in the 2 thymoma tissues, whereas SS mRNA was detectable only in the A thymoma. Quantitative evaluation of RT-PCR data showed a comparable expression of the relative amount of sst2A mRNA in both tumors, whereas a significant higher expression of sst3 mRNA in the B2 thymoma. Sst2A immunoreactivity was localized mainly on the endothelium of intratumoral vessels, whereas sst3 was present on either tumoral epithelial cells or normal reactive thymocytes. The expression of sst2A receptors in these tumors is in line with the in vivo visualization by [(111)In-DTPA0]octreotide, which is considered a sst2-preferring ligand. However, since radioligand uptake was significantly higher in the B2 thymoma, which expressed the largest sst3 mRNA levels, it might be possible that this subtype is involved in determining the tumor visualization during SSR scintigraphy. Apart from the affinity of the radioligand for the receptor, also the efficacy of the internalization of the radioligand-receptor complex might play a role in radioactivity accumulation during in vivo SSR scintigraphy. In fact, although octreotide binds with lower affinity to sst3 receptors, this subtype displayed the highest amount of agonist-dependent receptor internalization compared to the other SSR subtypes. Moreover, sst3 was localized on both tumor cells and reactive thymocytes, and these latter cells are characterized by a very active turnover of membrane molecules. Finally, although more cases need to be evaluated, the lack of detection of SS mRNA in the tumor presenting a more aggressive phenotype (B2 thymoma) might have physiopathological or prognostic significance. | rare cancer |
New molecular targets in canine hemangiosarcoma-Comparative review and future of the precision medicine. Human angiosarcoma and canine hemangiosarcoma reveal similarities not only in their aggressive clinical behaviour, but especially in molecular landscape and genetic alterations involved in tumorigenesis and metastasis formation. Currently, no satisfying treatment that allows for achieving long overall survival or even prolonged time to progression does not exist. Due to the progress that has been made in targeted therapies and precision medicine the basis for a new treatment design is to uncover mutations and their functions as possible targets to provide tailored drugs for individual cases. Whole exome or genome sequencing studies and immunohistochemistry brought in the last few years important discoveries and identified the most common mutations with probably crucial role in this tumour development. Also, despite a lack of mutation in some of the culprit genes, the cancerogenesis cause may be buried in main cellular pathways connected with proteins encoded by those genes and involving, for example, pathological angiogenesis. The aim of this review is to highlight the most promising molecular targets for precision oncology treatment from the veterinary perspective aided by the principles of comparative science. Some of the drugs are only undergoing laboratory in vitro studies and others entered the clinic in the management of other cancer types in humans, but those used in dogs with promising responses have been mentioned as priorities. | rare cancer |
A noncanonical role for the CKI-RB-E2F cell-cycle signaling pathway in plant effector-triggered immunity. Effector-triggered immunity (ETI), the major host defense mechanism in plants, is often associated with programmed cell death (PCD). Plants lack close homologs of caspases, the key mediators of PCD in animals. So although the NB-LRR receptors involved in ETI are well studied, how they activate PCD and confer disease resistance remains elusive. We show that the Arabidopsis nuclear envelope protein, CPR5, negatively regulates ETI and the associated PCD through a physical interaction with cyclin-dependent kinase inhibitors (CKIs). Upon ETI induction, CKIs are released from CPR5 to cause overactivation of another core cell-cycle regulator, E2F. In cki and e2f mutants, ETI responses induced by both TIR-NB-LRR and CC-NB-LRR classes of immune receptors are compromised. We further show that E2F is deregulated during ETI, probably through CKI-mediated hyperphosphorylation of retinoblastoma-related 1 (RBR1). This study demonstrates that canonical cell-cycle regulators also play important noncanonical roles in plant immunity. | no data |
Imaging tumor microscopic viscosity in vivo using molecular rotors. The microscopic viscosity plays an essential role in cellular biophysics by controlling the rates of diffusion and bimolecular reactions within the cell interior. While several approaches have emerged that have allowed the measurement of viscosity and diffusion on a single cell level in vitro, the in vivo viscosity monitoring has not yet been realized. Here we report the use of fluorescent molecular rotors in combination with Fluorescence Lifetime Imaging Microscopy (FLIM) to image microscopic viscosity in vivo, both on a single cell level and in connecting tissues of subcutaneous tumors in mice. We find that viscosities recorded from single tumor cells in vivo correlate well with the in vitro values from the same cancer cell line. Importantly, our new method allows both imaging and dynamic monitoring of viscosity changes in real time in live animals and thus it is particularly suitable for diagnostics and monitoring of the progress of treatments that might be accompanied by changes in microscopic viscosity. | no data |
Epigenetics and Precision Oncology. Epigenetic alterations such as DNA methylation defects and aberrant covalent histone modifications occur within all cancers and are selected for throughout the natural history of tumor formation, with changes being detectable in early onset, progression, and ultimately recurrence and metastasis. The ascertainment and use of these marks to identify at-risk patient populations, refine diagnostic criteria, and provide prognostic and predictive factors to guide treatment decisions are of growing clinical relevance. Furthermore, the targetable nature of epigenetic modifications provides a unique opportunity to alter treatment paradigms and provide new therapeutic options for patients whose malignancies possess these aberrant epigenetic modifications, paving the way for new and personalized medicine. DNA methylation has proven to be of significant clinical utility for its stability and relative ease of testing. The intent of this review is to elaborate upon well-supported examples of epigenetic precision medicine and how the field is moving forward, primarily in the context of aberrant DNA methylation. | multi cancer |
Metal speciation, phytochemicals and Helicobacter pylori infection. Helicobacter pylori (HP) acquired in childhood is an important risk factor for gastric carcinoma. Once colonization is established, infection may be carried for life. The relationship between food intake and HP infection, the presence of metals and phytochemicals closely associated with oxidative stress within everyday diet are important topics to be considered. The possible anti-HP effects of phytochemicals, prooxidant effects exerted in the presence of metal species, intimate relations between some metals and HP, bivalent effects of some metal species in cancer, interactions between metal species and phytochemicals in HP infection are the topics, which require further research. Formulas or diets enriched with phytochemicals and metals against HP and, which are devoid of metals known to favour the growth of HP, may be suggested as the supplements to the classical treatment regimens. The importance of collective consideration of HP, metal species and phytochemicals should be emphasized. | gastric cancer |
Differential Prognostic Value of Vascular Invasion in Resected Lung Adenocarcinomas According to Epidermal Growth Factor Receptor Mutational Status. It is unclear whether all patients with stage IB to IIIA epidermal growth factor receptor (EGFR)-mutant adenocarcinoma should receive adjuvant osimertinib. We investigated the prognostic value of vascular invasion for risk stratification according to EGFR mutational status. This retrospective study evaluated patients with stage IB to IIIA lung adenocarcinoma resected between 2011 and 2016 at a tertiary care center. The study outcome was overall survival (OS). The prognostic value of vascular invasion was analyzed using the adjusted log-rank test and multivariable Cox regression with clinico-pathological factors as covariates. A sensitivity analysis, which included the presence of ground-glass opacity on CT scans as an additional covariate, and subgroup analyses according to the pathological stage were performed. In total, 272 patients were included (146 women; median age, 66 years [interquartile range: 58, 72 years]; 128 EGFR-mutant adenocarcinomas). The 5-year OS rate was 90.8% (95% CI: 84.0%, 98.1%) in EGFR-mutant, vascular invasion-absent lung adenocarcinomas, which was higher than in other subgroups (P < .05). Vascular invasion was an independent, negative prognostic factor in EGFR-mutant lung adenocarcinomas (adjusted log-rank test, P = .02; adjusted hazard ratio, 3.01; 95% CI: 1.30, 7.02; P = .01). However, the prognosis of EGFR wild-type adenocarcinomas was not associated with the presence of vascular invasion (adjusted log-rank test, P = .95; adjusted hazard ratio, 1.32; 95% CI: 0.74, 2.34; P = .35). Similar results were observed in the sensitivity analysis and subgroup analyses. Vascular invasion-absent, EGFR-mutant, resected lung adenocarcinomas showed a very good prognosis, and vascular invasion had a differential prognostic value according to EGFR mutational status. | lung cancer |
Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer. We conducted the current review of the paraneoplastic neurologic syndromes (PNSs) associated with gynecologic and breast carcinomas to describe their clinical and immunologic characteristics and their relative frequency. We retrospectively reviewed 92 patients whose serum was sent to our laboratories to detect onconeural antibodies and who were diagnosed as having PNSs associated with breast or gynecologic tumors. PNSs were defined as "definitive" and "possible" (atypical PNS, no onconeural antibodies, and no improvement after tumor treatment). Forty-nine patients had breast and 43 had gynecologic cancer. Sixty-three patients had onconeural antibodies (50 Yo-ab, 5 Hu-ab, 5 Ri-ab, and 3 amphiphysin-ab). Cerebellar ataxia represented 57 (62%) of all PNSs and was associated with anti-Yo in 88%. All Yo-abnegative patients had breast cancer; 4 of them had a mild cerebellar syndrome that improved after tumor treatment. Sensorypredominant neuropathies were present in 17 (18%) patients. Seven of them had Hu-ab (5) or amphiphysin-ab (2). Other PNSs were opsoclonus-myoclonus syndrome (4 cases, Ri-ab in 2), sensorimotor neuropathy (4 cases), paraneoplastic encephalomyelitis (4 cases, Ri-ab in 3), paraneoplastic retinopathy (2 cases), amyotrophic lateral sclerosis (2 cases), stiff-person syndrome (1 with amphiphysin-ab), and limbic encephalitis (1 case). All patients with gynecologic cancer presented definitive PNS, and onconeural antibodies were diagnosed in 93% of them. In contrast, 20% of PNSs associated with breast cancer were defined as possible and the incidence of onconeural antibodies was 51%, excluding the 2 patients with paraneoplastic retinopathy in whom antiretinal antibodies were not analyzed. In patients with possible PNS, a coincidental association between the tumor and the neurologic disorder cannot be excluded. | breast cancer |
Gold-Nanoparticles-Enhanced Production of Reactive Oxygen Species in Cells at Spread-Out Bragg Peak under Proton Beam Radiation. This study investigates the radiobiological effects of gold nanoparticles (GNPs) as radiosensitizers for proton beam therapy (PBT). Specifically, we explore the enhanced production of reactive oxygen species (ROS) in GNP-loaded tumor cells irradiated by a 230 MeV proton beam in a spread-out Bragg peak (SOBP) zone obtained by a passive scattering system. Our findings indicate that the radiosensitization enhancement factor is 1.24 at 30% cell survival fraction, 8 days after 6 Gy proton beam irradiation. Since protons deposit the majority of their energy at the SOBP region and interact with GNPs to induce more ejected electrons from the high-Z GNPs, these ejected electrons then react with water molecules to produce excessive ROS that can damage cellular organelles. Laser scanning confocal microscopy reveals the excessive ROS induced inside the GNP-loaded cells immediately after proton irradiation. Furthermore, the damage to cytoskeletons and mitochondrial dysfunction in GNP-loaded cells caused by the induced ROS becomes significantly severe, 48 h after proton irradiation. Our biological evidence suggests that the cytotoxicity of GNP-enhanced ROS production has the potential to increase the tumoricidal efficacy of PBT. | no data |
Proportion of CD4+CD25+ regulatory T cell is increased in the patients with ovarian carcinoma. To study the frequency of the CD4+CD25+ regulatory T cells (Tregs) in the patients with ovarian carcinoma and its possible mechanism. The percentages of CD4+CD25+ Tregs in the peripheral blood lymphocytes (PBLs), tumor infiltrating lymphocytes (TILs) and tumor associated lymphocytes (TALs) from 13 patients with ovarian carcinoma and in the PBLs from 14 healthy women were determined by flow cytometry. The expression of CD69 on CD4+PBLs from the patients was detected. PBLs from healthy women were cultured in complete RPMI 1640 containing the supernatant from SKOV3 cell line with or without PHA (phytohemagglutinin) stimulation for 72 hours, then the percentage of CD4+CD25+ T cells was detected. CD4+CD25+ Tregs in the PBLs from patients with ovarian carcinoma were significantly increased compared with those from the control. The percentage of CD4+CD25+ Tregs in TILs was higher than that in PBLs and TALs from the patients, but not significantly. The expression of CD69 on CD4+PBLs from the patients was negative. The percentages of CD4+CD25+ T cells in PBLs cultured with SKOV3 supernatant elevated significantly compared with those without supernatant whether PHA was added or not (P=0.001 and 0.001, respectively). There is an increasing of the proportion of CD4+CD25+ Tregs in PBLs, TILs and TALs of the patients with ovarian carcinoma, which probably results from up-regulation of soluble factor secreted by ovarian carcinoma cells. | ovarian cancer |
Protective effect of anthocyanins from black soybean seed coats on UVB-induced apoptotic cell death in vitro and in vivo. UVB radiation proves to be one of the most relevant environmental risks because of its hazardous effects, such as premature skin aging and especially skin photocarcinogenesis. Anthocyanins, water-soluble pigments present in plants, are known to be powerful antioxidants that help protect plants from UV damage. In this study, we aimed at investigating the protective effect of anthocyanins from black soybean [Glycine max (L.) Merr] seed coats on UVB-induced apoptosis, and furthermore, we investigated the molecular mechanism responsible for regulation of apoptosis in vitro and in vivo. Pretreatment with anthocyanins reduced UVB-induced reactive oxygen species levels and inhibited UVB-induced apoptotic cell death through the prevention of caspase-3 pathway activation and reduction of proapoptotic Bax protein levels. UVB irradiation induced apoptotic cell death, which was inhibited by topical application of anthocyanins in hairless mice. It is concluded that anthocyanins from the seed coat of black soybeans may be useful compounds to modulate UVB-induced photoaging. | skin cancer |
Side effects of oncologic therapies in the pediatric central nervous system: update on neuroimaging findings. The need for early, accurate diagnosis of central nervous system (CNS) complications occurring during and after pediatric cancer treatment is growing because of the improvement in overall survival rates related to innovative and aggressive oncologic therapies. An elevated degree of suspicion is needed to recognize the radiologic features of these CNS complications. Radiologists need familiarity with the early and late side effects of cancer therapy in the pediatric CNS (eg, toxic effects, infection, endocrine or sensory dysfunction, neuropsychologic impairment, second malignancies), in order to accelerate the imaging diagnosis and minimize as much as possible the associated morbidity. Acquisition of knowledge about these complications will enable the development of more appropriate therapeutic trials and more effective patient surveillance and will lead to an improved quality of life by decreasing the long-term sequelae in survivors. | brain cancer |
Relationship between Oral Health Status and Postoperative Fever among Patients with Lung Cancer Treated by Surgery: A Retrospective Cohort Study. A retrospective observational study using an oral bacteria counter was conducted to evaluate the trends in the number of oral bacteria in the perioperative period of lung cancer patients and to verify the relationship between oral health status and postoperative fever. All patients received perioperative oral management (POM) by oral specialists between April 2012 and December 2018 at Kagawa Prefectural Central Hospital, Kagawa, Japan prior to lung cancer surgery. Bacteria counts from the dorsum of the tongue were measured on the day of pre-hospitalization, pre-operation, and post-operation, and background data were also collected retrospectively. In total, 441 consecutive patients were enrolled in the study. Bonferroni's multiple comparison test showed significantly higher oral bacteria counts at pre-hospitalization compared to pre- and post-operation (p < 0.001). Logistic regression analysis showed that body mass index, performance status, number of housemates, number of teeth, and white blood cell count at pre-operation were significantly associated with postoperative fever. The study showed that POM can reduce the level of oral bacterial counts, that the risk of postoperative complications is lower with dentulous patients, and that appropriate POM is essential for prevent of complications. Therefore, POM may play an important role in perioperative management of lung cancer patients. | lung cancer |
Decoy receptor 3: an endogenous immunomodulator in cancer growth and inflammatory reactions. Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to 'decoy' function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via 'non-decoy' action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, 'switch-on' of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while 'switch-off' of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo. | multi cancer |
Lymphatic mapping and sentinel lymphadenectomy in early stage breast carcinoma. The rate of axillary lymph node metastases is low in early stage breast carcinoma and axillary lymph node dissection is controversial in the treatment of these patients. Intraoperative lymphatic mapping technique is suggested for the identification of metastatic lymph nodes. Intraoperative lymphatic mapping was performed on 60 clinical stage I and II patients who were treated at Ankara Oncology Hospital between 1996-1998. Patent blue dye was injected in all cases, as the tumor was totally excised before mastectomy, into the surrounding breast tissue at four different quadrants. Presence of metastases were examined on stained lymph nodes (sentinel lymph node: SLN) by frozen-section. Modified radical mastectomy was performed including level I, II, III lymph node dissection. Metastases were evaluated on the remnants of frozen-section tissues and unstained lymph nodes (nonsentinel lymph node: nSLN) in axilla on hematoxyline-eosin stained slides and by immunohistochemistry. Forty-nine (81.6%) SLNs were identified among 60 cases. In 18 (36.7%) of these 49 patients, metastases were detected in SLNs by frozen section. In one case micrometastasis was detected in the remnants of frozen-section by immunohistochemistry though it was negative with hematoxyline-eosin. There were no metastases in nSLNs of 27 cases whose SLNs's frozen-sections were tumor free. In 3 cases SLNs were negative but metastases were detected in nSLNs (false negative: 6.1%). There were no local or systemic complications due to injections of dye. Selective lymph node dissections can be performed on early stage breast cancer patients by means of lymphatic mapping. This minimally invasive technique identifies metastatic axillary lymph nodes with a high degree of accuracy, so we can suggest that, non-metastatic patients can be treated without axillary dissection. | breast cancer |
Methylseleninic acid is a novel suppressor of aromatase expression. Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens by aromatase, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women. Although aromatase inhibitors have been used as a first-line therapy for estrogen receptor-positive breast cancer in postmenopausal women, their potential as breast cancer chemopreventive agents has been limited due to toxicities and high costs. It is therefore imperative to develop new aromatase-inhibiting/suppressing agents with lower toxicities and lower costs for breast cancer chemoprevention, especially in obese postmenopausal women. The expression of the aromatase gene, CYP19, is controlled in a tissue-specific manner by the alternate use of different promoters. In obese postmenopausal women, increased peripheral aromatase is primarily attributed to the activity of the glucocorticoid-stimulated promoter, PI.4, and the cAMP-stimulated promoter, PII. In the present study, we show that methylseleninic acid (MSA), a second-generation selenium compound, can effectively suppress aromatase activation by dexamethasone, a synthetic glucocorticoid, and forskolin, a specific activator of adenylate cyclase. Unlike the action of aromatase inhibitors, MSA suppression of aromatase activation is not mediated via direct inhibition of aromatase enzymatic activity. Rather, it is attributable to a marked downregulation of promoters PI.4- and PII-specific aromatase mRNA expression, and thereby a reduction of aromatase protein. Considering the low-cost and low-toxicity nature of MSA, our findings provide a strong rationale for the further development of MSA as a breast cancer chemopreventive agent for obese postmenopausal women. | breast cancer |
Soluble Urokinase Plasminogen Activator Receptor (suPAR) Concentrations are Elevated in Patients with Neuroendocrine Malignancies. Neuroendocrine neoplasia (NEN) comprises heterogeneous tumors that are challenging to diagnose and, especially in cases of poorly differentiated (G3) NEN, are associated with very limited survival. Novel biomarkers allowing an early diagnosis as well as an optimal selection of suitable treatment options are urgently needed to improve the outcome of these patients. Recently, alterations of soluble urokinase-type plasminogen activator receptor (suPAR) serum levels were described in various types of cancers. However, the role of circulating suPAR as a biomarker in patients with NEN is unknown. In this study, we measured suPAR serum levels in a large and well-characterized cohort of 187 patients with NEN (neuroendocrine carcinomas (NEC) n = 30; neuroendocrine tumors (NET), n = 157) as well as 44 healthy controls. suPAR concentrations were significantly elevated in patients compared to controls. However, suPAR concentrations were independent of tumor-related factors such as the proliferation activity according to Ki-67, tumor grading, TNM (TNM classification of malignant tumors) stage, somatostatin receptor expression or clinical features such as functional or nonfunctional disease and the presence of tumor relapse. Interestingly, suPAR concentrations in NET patients were similar when compared to those measured in NEC patients. In contrast to previous results from other malignancies, in our analysis suPAR levels were not a significant predictor of overall survival. In conclusion, our data suggests that suPAR serum concentrations are elevated in NEN patients but do not allow prediction of outcome. | rare cancer |
Pulmonary resection for metastases from hepatocellular carcinoma. Pulmonary metastasectomy has become the standard therapy for various metastatic malignancies to the lungs; however, few data have been available about lung metastasectomy for hepatocellular carcinoma. To confirm the role for resection of pulmonary metastases for such tumors, we reviewed our institutional experience. Between 1993 and 2005, 12 patients with pulmonary metastases from hepatocellular carcinomas underwent complete pulmonary resection. All patients had undergone curative resection of their primary hepatocellular carcinomas and also had obtained or had obtainable locoregional control of their primaries. Various perioperative variables were investigated retrospectively to analyze the possible prognostic factors for overall survival and pulmonary metastases-free survival after pulmonary metastasectomy. Nine patients were male and three were female (median age, 53 (range, 43-80) years). Overall survival rate after metastasectomy was 80.8%, 57.7%, and 28.9% at 1, 2, and 5 years, respectively. Pulmonary metastases-free survival rate was 64.2%, 32.1%, and 21.4% at 1, 2, and 5 years, respectively. Five patients presented recurrences in the remaining liver before pulmonary metastases, but hepatic recurrences at this interval did not affect an overall survival after pulmonary metastasectomies. Two patients had undergone living-related liver transplantation. The maximum tumor size of the pulmonary metastasis < 3 cm was the only favorable prognostic factor for overall survival (P = 0.0006), whereas there was no significant prognostic factor for pulmonary metastases-free survival. Pulmonary metastasectomy for hepatocellular carcinoma in selected patients was well justified when the maximum tumor size was <3 cm. | liver cancer |
Discussion of relationships among changes of pathological indicators, postoperative lymphedema of the upper limb, and prognosis of patients with breast cancer. Objectives: The present study aimed to discuss the impacts of changes to pathological indicators of patients with breast cancer upon the incidence of postoperative lymphedema of the upper limb and prognosis. Methods: 2597 female patients with breast cancer who received surgical treatment in our hospital were enrolled in the present study to evaluate the incidence of these patients' postoperative lymphedema of the upper limb. Results: For patients with breast cancer, the incidence of postoperative lymphedema of the upper limb was related to T stage of breast cancer, lymph node metastasis, the number of metastatic lymph nodes, pTNM stage, and pathological types of breast cancer (P<0.05). Lymph node metastasis was an independent risk factor of lymphedema of the upper limb; lymph node metastasis and Ki-67 expression level were independent factors that impacted pathologic complete response rate of neoadjuvant chemotherapies. Patients' mortality was correlated to pathological and molecular subtypes, Ki-67 expression level, ER expression level, PR expression level, and pTNM stage (P<0.05), among which the pTNM stage, Ki-67 expression level, and PR expression level were independent factors that affected prognosis of patients with breast cancer. Conclusion: Patients with lymph node metastasis were more prone to lymphedema of the upper limb, while it was easier for those whose Ki-67 expression level was high and who were not subject to lymph node metastasis to get a pathological complete response after receiving neoadjuvant chemotherapies. The prognosis was poorer among patients whose progesterone receptors were negative and Ki-67 expression levels were high at the advanced pTNM stage. | breast cancer |
Survival of colorectal cancer in Iran. Colorectal cancer is the fourth cause of cancer after stomach, bladder, prostate in men and second cause after breast in women in Iran. It is estimated that 4,000 new cases occur each year with 1,150 deaths annually. The present study aimed to determine survival of colorectal cancers in Iran in a national manner. The data from national cancer registry department of the Ministry of Health and Medical Education (MOH and ME) were used as the main source of incident colorectal cancer information in Iran from March 2000 to March 2005. One and five year survival proportions were 88% and 45% for females versus 86% and 39% for men. The median overall survival for colorectal cancer in Iran was 3.5 years with a 95 % confidence interval of 3.2-3.8 years. The worst survival status was found for patients less than 20 and more than 80 years old. The overall 5 year survival for colorectal cancer in Iran (41%) is comparable even with some developed countries but it is far from those with advanced health care systems, or community based screening programs. Thus at the policy level, application of an appropriate national cancer control program and management guidelines should be under consideration. | colorectal cancer |
A predictive and prognostic model for metastasis risk and prognostic factors in gastrointestinal signet ring cell carcinoma. This study aimed to predict metastasis risk and identify prognostic factors of gastrointestinal signet ring cell carcinoma (SRCC) using data from the SEER database, the largest cancer dataset in North America. Data were obtained from the SEER database, covering 17 cancer registries from 2004 to 2020. Demographic and clinical data included sex, age, race, tumor location, size, pathological grade, stage, overall survival time, and treatment modalities. Statistical analyses were conducted using SPSS and R software. Propensity Score Matching (PSM) ensured comparable baseline characteristics between gastric cancer (GC) and colorectal cancer (CRC) groups. LASSO regression analysis identified predictors of metastasis, leading to the construction of predictive models using the lrm function in R. Nomograms were visualized with the "rms" package and assessed via ROC curves, calibration curves, and decision curve analysis (DCA). Cox regression analyses identified prognostic indicators for overall survival (OS), and Kaplan-Meier curves compared OS between high-risk and low-risk groups. From 2004 to 2020, 7680 SRCC patients were identified, including 4980 GC and 2700 CRC patients. CRC patients were older and had larger tumors, higher staging, and worse differentiation. Nomograms demonstrated good discriminative ability, with AUCs of 0.704 and 0.694 for GC, and 0.694 and 0.701 for CRC in training and validation cohorts, respectively. The DCA curve indicates that this predictive model has a high gain in predicting metastasis and OS. The nomograms effectively predicted metastasis risk and OS in metastatic SRCC patients, offering clinical utility in stratifying patients and guiding treatment decisions, thereby enhancing personalized treatment approaches. | gastric cancer |
Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation. Progestin regulation of gene expression was assessed in the progestin-dependent murine tumor line C4HD which requires MPA, a synthetic progestin, for in vivo growth and expresses high levels of progesterone receptor (PR). By using suppressive subtractive hybridization, caveolin-1 was identified as a gene whose expression was increased with in vivo MPA treatment. By Northern and Western blot analysis, we further confirmed that caveolin-1 mRNA and protein expression increased in MPA-treated tumors as compared with untreated tumors. When primary cultures of C4HD cells were treated in vitro with MPA, caveolin-1 levels also increased, effect that was abolished by pre-treatment with progestin antagonist RU486. In addition, MPA promoted strong caveolin-1 promoter transcriptional activation both in mouse and human breast cancer cells. We also showed that MPA regulation of caveolin-1 expression involved in activation of two signaling pathways: MAPK and PI-3K. Short-term MPA treatment of C4HD cells led to tyrosine phosphorylation of caveolin-1 protein, where Src was the kinase involved. Additionally, we showed that MPA-induced association of caveolin-1 and PR, which was detected by coimmunoprecipitation and by confocal microscopy. Finally, we proved that MPA-induced proliferation of C4HD cells was inhibited by suppression of caveolin-1 expression with antisense oligodeoxynucleotides to caveolin-1 mRNA. Furthermore, we observed that inhibition of caveolin-1 expression abrogated PR capacity to induced luciferase activity from a progesterone response element-driven reporter plasmid. Comprehensively, our results demonstrated for the first time that caveolin-1 expression is upregulated by progestin in breast cancer. We also demonstrated that caveolin-1 is a downstream effector of MPA that is partially responsible for the stimulation of growth of breast cancer cells. | breast cancer |
A rational approach to pulmonary screening in newly diagnosed head and neck cancer. The purpose of this study was to determine the detection rate of lung metastasis or a synchronous lung primary tumor in patients with newly diagnosed head and neck mucosal squamous cell carcinoma (SCC) and to determine factors that are associated with positive findings. This was a prospective cohort study of 102 patients with head and neck mucosal SCC diagnosed in a tertiary cancer center. Chest x-rays and a CT scan of the thorax were performed. An indeterminate nodule on CT scan was followed with either a repeat scan to assess progression or a CT-guided needle biopsy. Metastasis or synchronous lung primary tumor were determined by CT scan. The findings were correlated with age, sex, duration of symptoms, site of primary tumor, grade of tumor, T classification, and N classification. A CT scan of the thorax showed abnormalities or suspicious nodules in 20 patients (19.6%). With either follow-up scans or CT-guided biopsy, 10 patients were eventually proven to have pulmonary metastasis and one a synchronous lung primary tumor. Of those eleven patients (10.8%), seven had normal chest x-ray. Eight (72.7%) of 11 patients with a positive CT scan had N2 or N3 disease in contrast to 32 (35.2%) of 91 patients with a normal CT scan (p = .02). Seven patients (63.6%) with a positive CT scan had T4 disease, whereas 34 (37.4%) with a normal CT scan had T4 disease (p = .08). Primary tumors arising in the oropharynx, hypopharynx, and supraglottis had a greater risk of a positive CT scan than tumors arising in the oral cavity, glottis, or unknown sites (OR = 5.4; 95% CI, 1.3-21.9). Age, sex, duration of symptoms, and grade of disease did not predict a positive CT scan. The detection rate of lung metastasis or a synchronous lung primary tumor by CT scan is 10.8%. We recommend the use of CT scans of the thorax in screening the lungs of newly diagnosed patients with T4 and/or N2 or N3 oropharyngeal, hypopharyngeal, and supraglottic SCC. | head and neck cancer |
Effect of mobile phone app-based training on the quality of life for women with breast cancer. The study purpose was to determine the effects on quality of life (QoL) of a mobile phone app-based training for supportive care of women with breast cancer who were using adjuvant endocrine hormonal therapy. The study is based on a randomized pre-post test design. Participants were randomly assigned to either a control group that received routine care or an intervention group that received routine care plus access to the mobile phone app-based training support for 12 weeks. QoL and symptom distress were measured before intervention (T0), and after 12 weeks (T1) of intervention. This study is the application of two modality combinations: the mobile app-based patient education (1) and web-based management application (2). The mobile app-based training also provided basic information about breast cancer, symptom diary and lifestyle recommendations (adequate and balanced nutrition, regular physical activity, deal with stress effectively). QoL of the treatment group after intervention increased and distress level was lower compared to the control group; these results were statistically significant. The majority of the patients reported that the mobile application was "informative and useful". This demonstrated that the mobile app is an effective intervention for supportive care in women with breast cancer. The mobile app-based training, which is an innovative intervention, is recommended as a supportive care initiative for women with breast cancer. | breast cancer |
Radiation-induced liver disease in the era of SBRT: a review. Stereotactic Body Radiotherapy (SBRT) in liver tumors allows ablative radiation doses in tumors preserving the liver tissue. However, liver is a parallel organ allowing high doses in a small region to preserve its function. If this is not possible, radio-induced liver toxicity is produced. Radio-induced liver toxicity or radio-induced liver disease (RILD) is the most serious toxicity in liver radiotherapy. In this review, we analyzed published literature on PubMed and MEDLINE. We included papers in English language with information about RILD characteristics, diagnostic, risk factors, pathophysiology, and treatment. All citations were evaluated for relevant content and validation. The study of RILD is fundamental before the implementation of liver SBRT. Radio-induced liver toxicity is a complication that can be fatal for patients. This is a diagnosis of exclusion and it is essential that experts in the treatment of hepatic SBRT know about it and anticipate its development. The study and development of molecular or imaging biomarkers could be key in their diagnosis and prevention. | liver cancer |
The microenvironment of pituitary adenomas: biological, clinical and therapeutical implications. The microenvironment of pituitary adenomas (PAs) includes a range of non-tumoral cells, such as immune and stromal cells, as well as cell signaling molecules such as cytokines, chemokines and growth factors, which surround pituitary tumor cells and may modulate tumor initiation, progression, invasion, angiogenesis and other tumorigenic processes. The microenvironment of PAs has been actively investigated over the last years, with several immune and stromal cell populations, as well as different cytokines, chemokines and growth factors being recently characterized in PAs. Moreover, key microenvironment-related genes as well as immune-related molecules and pathways have been investigated, with immune check point regulators emerging as promising targets for immunotherapy. Understanding the microenvironment of PAs will contribute to a deeper knowledge of the complex biology of PAs, as well as will provide developments in terms of diagnosis, clinical management and ultimately treatment of patients with aggressive and/or refractory PAs. | no data |
Anaplastic ganglioglioma of the brainstem in an adult. Gangliogliomas are neoplasms with neuronal and glial components. The most common location is the temporal lobe and for that reason those patients have seizures as the major complaint. Gangliogliomas with anaplastic features are uncommon. A 33-year-old man presented with a two-year history of progressively worsening right-sided weakness and contractures. Physical examination demonstrated right-sided weakness and contractures involving the upper and lower extremities. Magnetic resonance demonstrated multiple nodules involving the tegmental pons with a small projection into the prepontine cistern on the left, midbrain tegmentum on the left in the subthalamic region. The patient was studied by MRI on T1WI, T2WI, FLAIR, DWI, and magnetic resonance spectroscopy. He underwent a craniotomy and biopsy of the mass. Histological examination of the specimen revealed glial proliferation. Based on these findings the pathologic diagnosis was anaplastic ganglioglioma. Only one previous report of an anaplastic astrocytoma in the cerebello-pontine angle in an adult has been published. In children three cases were reported, only one with magnetic resonance. Our case showed multiple nodular structures hypointense on T1 and hyperintense on T2 and FLAIR with enhancement on T1 after injection of paramagnetic contrast. Only in this contribution T2 value were diffusion-weighted and ADC characteristics and (1)H spectroscopy analyzed. | brain cancer |
Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. Male breast cancer (MBC) is an uncommon malignancy. We have previously reported that the expression of the Hippo transducers TAZ/YAP and their target CTGF was associated with inferior survival in MBC patients. Preclinical evidence demonstrated that Axl is a transcriptional target of TAZ/YAP. Thus, we herein assessed AXL expression to further investigate the significance of active TAZ/YAP-driven transcription in MBC. For this study, 255 MBC samples represented in tissue microarrays were screened for AXL expression, and 116 patients were included. The association between categorical variables was verified by the Pearson's Chi-squared test of independence (2-tailed) or the Fisher Exact test. The relationship between continuous variables was tested with the Pearson's correlation coefficient. The Kaplan-Meier method was used for estimating survival curves, which were compared by log-rank test. Factors potentially impacting 10-year and overall survival were verified in Cox proportional regression models. AXL was positively associated with the TAZ/CTGF and YAP/CTGF phenotypes (P = 0.001 and P = 0.002, respectively). Patients with TAZ/CTGF/AXL- or YAP/CTGF/AXL-expressing tumors had inferior survival compared with non-triple-positive patients (log rank P = 0.042 and P = 0.048, respectively). The variables TAZ/CTGF/AXL and YAP/CTGF/AXL were adverse factors for 10-year survival in the multivariate Cox models (HR 2.31, 95%CI:1.02-5.22, P = 0.045, and HR 2.27, 95%CI:1.00-5.13, P = 0.050). Nearly comparable results were obtained from multivariate analyses of overall survival. The expression pattern of AXL corroborates the idea of the detrimental role of TAZ/YAP activation in MBC. Overall, Hippo-linked biomarkers deserve increased attention in this rare disease. J. Cell. Physiol. 232: 2246-2252, 2017. © 2016 Wiley Periodicals, Inc. | breast cancer |
The Dural Dark-Side Approach for falcine and tentorial meningioma: A surgical series of five patients. Falcine or tentorial meningioma can be complex to resect. When large meningiomas are located in eloquent areas, a direct ipsilateral surgical approach may cause brain injury and postoperative neurological deficits. In this series, 5 patients were surgically treated using a contralateral transfalcine or transtentorial approach to minimize brain retraction. This strategy was called the Dural Dark-Side Approach (DDSA). The aim was to analyze the quality of tumor resection and postoperative outcome. In our department, from June 2018 to January 2020, 5 patients underwent microsurgical DDSA for resection of 4 falcine and 1 tentorial meningioma. All tumors were selected on the following two criteria: large>40mm diameter tumor, with surrounding functional cortex. Clinical and radiologic data were retrospectively analyzed. Mean follow-up was 20 months. No patients required use of a rigid retractor during surgery. Gross total resection was performed in 3 patients and near-total resection in 2. All patients had favorable neurologic outcome. Postoperative MRI showed no ipsilateral or contralateral brain lesions. This series suggested that meticulous DDSA allows excellent resection in selected large falcine or tentorial meningioma. The approach offered a safe and effective surgical corridor without injuring the surrounding healthy parenchyma. | brain cancer |
Role of Narrow Band Imaging Endoscopy in Preoperative Evaluation of Laryngeal Leukoplakia: A Review of the Literature. Leukoplakia is a precancerous lesion considered to be within the spectrum of histopathological results from parakeratosis, through stages of dysplasia to invasive cancer. Narrow band imaging (NBI) endoscopy has been introduced to improve early diagnosis of benign and malignant laryngeal lesions. The aim of this literature review was to evaluate the accuracy of preoperative evaluation of vocal fold leukoplakia with NBI endoscopy in comparison with histology. A systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using 3 different databases: PubMed, Embase, and Scopus. The included articles in the systematic review were identified combining each of the following terms: "narrow band imaging" OR "NBI," [AND] with each of these terms: "laryngeal leukoplakia," OR "vocal fold leukoplakia," OR "vocal cord leukoplakia." The articles that fully met the inclusion criteria were 5 case series, conducted between January 2010 and February 2018, and published between 2017 and 2019. The selected articles included 312 patients (86% males and 14% females), affected by 382 vocal cord leukoplakia, evaluated with NBI endoscopy and that underwent surgical microlaryngoscopy with biopsy. Based on the studies included in the review, accuracy of NBI in predicting malignancy within leukoplakia ranged from 81% to 97.8%, demonstrating to be an accurate method to predict the risk of malignant transformation of vocal fold leukoplakia. Narrow band imaging can help otolaryngologists in the decision-making process on the necessity to perform a biopsy and transoral surgery or long-term follow-up. Larger studies are necessary to confirm the high association of NBI evaluation of the epithelium surrounding the leukoplakia with the histological diagnosis. | head and neck cancer |
Recent advances in medicinal chemistry and pharmaceutical technology--strategies for drug delivery to the brain. This paper provides a mini-review of some recent approaches for the treatment of brain pathologies examining both medicinal chemistry and pharmaceutical technology contributions. Medicinal chemistry-based strategies are essentially aimed at the chemical modification of low molecular weight drugs in order to increase their lipophilicity or the design of appropriate prodrugs, although this review will focus primarily on the use of prodrugs and not analog development. Recently, interest has been focused on the design and evaluation of prodrugs that are capable of exploiting one or more of the various endogenous transport systems at the level of the blood brain barrier (BBB). The technological strategies are essentially non-invasive methods of drug delivery to malignancies of the central nervous system (CNS) and are based on the use of nanosystems (colloidal carriers) such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, polymeric micelles and dendrimers. The biodistribution of these nanocarriers can be manipulated by modifying their surface physico-chemical properties or by coating them with surfactants and polyethylene-glycols (PEGs). Liposomes, surfactant coated polymeric nanoparticles, and solid lipid nanoparticles are promising systems for delivery of drugs to tumors of the CNS. This mini-review discusses issues concerning the scope and limitations of both the medicinal chemistry and technological approaches. Based on the current findings, it can be concluded that crossing of the BBB and drug delivery to CNS is extremely complex and requires a multidisciplinary approach such as a close collaboration and common efforts among researchers of several scientific areas, particularly medicinal chemists, biologists and pharmaceutical technologists. | brain cancer |
α-Mangostin and lawsone methyl ether in tooth gel synergistically increase its antimicrobial and antibiofilm formation effects in vitro. α-Mangostin (α-MG) and lawsone methyl ether (LME) show antimicrobial and anti-biofilm activities. The objectives of this study were to develop a herbal tooth gel containing α-MG and LME plus fluoride and determine its antimicrobial, anti-biofilm formation, anti-cancer, anti-inflammatory, wound healing, and enamel microhardness effects. Antimicrobial assays against Streptococcus mutans, Porphyromonas gingivalis, and Candida albicans were performed. The microbes' ultrastructural morphology was assessed using Transmission Electron Microscopy. The effect on microbial biofilm formation was tested by a broth microdilution. Cell viability was assessed with MTT assay. The anti-inflammatory effect was investigated by measuring inhibition of nitric oxide production. Enamel microhardness was measured via Vickers microhardness testing. The enamel chemical composition was investigated with Fourier Transform Spectrometer. The enamel surface morphology and fluoride content were examined by Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy. The results show synergistic effects of α-MG and LME on antimicrobial activity and antibiofilm formation without cytotoxicity at a therapeutic dose. At a higher dose, the tooth gel inhibited proliferation of cancer cell line. Enamel microhardness was increased after brushing with the tooth gel plus fluoride. A large amount of fluoride was detected on the enamel surface. The tooth gel containing α-MG and LME synergized its antimicrobial activity and antibiofilm formation and inhibited oral cancer cell proliferation. Incorporating fluoride into the tooth gel increased enamel microhardness. Thus, the herbal tooth gel containing α-MG and LME plus fluoride may be useful for preventing dental caries and promoting oral health. | no data |
Concurrent paclitaxel, carboplatin, and radiation therapy for locally advanced non-small cell lung cancer. Combination chemotherapy plus radiation therapy for non-small cell lung cancer has several theoretical advantages: the potential of chemotherapy to radiosensitize tumors, the possibility of improved local control due to combined treatment, and the opportunity for spatial cooperation, attacking disease both locally and systemically and thus potentially increasing response and, ultimately, survival. The combination of radiotherapy plus standard chemotherapy (etoposide plus cisplatin) has yielded limited success; therefore, new and novel chemotherapies have been sought. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the prototype of a novel class of drugs, the taxanes, has proven feasible both alone and with other agents in combined-modality regimens with radiation. Concurrent paclitaxel/carboplatin/radiotherapy appears to offer a relatively safe and more active regimen to control local and metastatic non-small cell lung cancer than the current standard. This report reviews the range of experience with paclitaxel-based combined-modality therapy. | lung cancer |
Enantioselective NHC-Catalyzed [3+3] Annulation of α-Bromoenals with 2-Aminobenzimidazoles. A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido[1,2-a]benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies indicated that the formed pyrimido[1,2-a]benzimidazole exhibited moderate cytotoxic activity against tumor cells. | no data |
High-resolution genome-wide copy-number analyses identify localized copy-number alterations in Ewing sarcoma. Ewing sarcoma family tumors are aggressive sarcomas of childhood and adolescence with continuing poor outcomes. Decades of research on the characteristics of the often solitary-known oncogenic-genomic aberration in Ewing sarcoma family tumors, namely a TET-ETS fusion, have provided little advancement in the understanding of the molecular pathogenesis of Ewing sarcoma or treatment thereof. In this study, the high-resolution single-nucleotide polymorphism technology was used to identify additional/secondary copy-number alterations (CNAs) in Ewing sarcoma that might elucidate the aggressive biology of this sarcoma. We compared paired constitutional and tumor DNA samples. Commonly known genomic alterations including gain of 1q and chromosome 8 were the most frequently detected changes in this study. In addition, deletions and loss of heterozygosity were identified in 10q, 11p, and 17p. Furthermore, tumor-specific CNAs were identified not only in genes previously known to be of interest, including CDKN2A, but also in genes not previously associated with Ewing sarcoma, including SOX6 and PTEN. Selected array-based findings were confirmed by fluorescence in situ hybridization, immunohistochemical studies, or sequencing. The results highlight an unexpected level of cytogenetic complexity associated with several of the samples, 2 of which contained TP53 mutations. In summary, our high-resolution genome-wide copy-number data identify several novel CNAs associated with Ewing sarcoma, which are promising targets for novel therapeutic strategies in this aggressive sarcoma. | rare cancer |
Beyond pancreatic cancer: irinotecan and gemcitabine in solid tumors and hematologic malignancies. Non-platinum combinations including gemcitabine and irinotecan (Gemzar; Eli Lilly and Company, Indianapolis, IN) for the management of a variety of malignancies have started to emerge. Gemcitabine and irinotecan are well-tolerated single agents, each with a broad spectrum of antitumor activity. Preclinical data suggests synergy for the two drugs when used in combination. A phase I trial has defined a well-tolerated combination regimen using both drugs on a day-1, -8 schedule every 3 weeks. Phase II data suggest activity for the combination in pancreatic cancer, and a phase III trial of the two-drug combination versus gemcitabine alone is underway in previously untreated pancreatic cancer patients. Other phase II trials evaluating the impact of this combination on a variety of other tumors, such as non-small cell lung, small cell lung, breast, colorectal, and non-Hodgkin's lymphoma, are either forthcoming or in progress. Semin Oncol 28 (suppl 10):34-43. | multi cancer |
Rumex vesicarius L. boosts the effectiveness of sorafenib in triple-negative breast cancer by downregulating BCl2, mTOR, and JNK, and upregulating p21 expression. Triple-negative breast cancer (TNBC) is characterized by poor prognosis, rapid progression, serious clinical behavior, an elevated risk of metastasis, and resistance to standard treatments. Traditional medicine practitioners value Rumex vesicarius L. (RMV) for a variety of reasons, including the plant's antioxidant capabilities. Our study's goals were to ascertain the efficacy of RMV alone and in combination with sorafenib (SOR) against the aggressive TNBC cell line (MDA-MB-231) and use in vitro and in silico analysis to deduce the fundamental mechanism of action. In the current study, molecular operating environment (MOE, 2019.0102) software was used for performing molecular docking. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to determine the cytotoxicity of RMV, SOR or RMV/SOR combination against the TNBC cell line MDA-MB-231 cells. The effects of RMV, SOR, and RMV and SOR combining on mRNAs expressions of the target genes including mTOR, p21, JNK, and BCl2 were evaluated. In TNBC cells, the relative expressions of mRNAs of the genes were examined by using real-time quantitative polymerase chain reaction (RT-qPCR). In our experiments, we discovered that both RMV extracts alone and in combination with SOR considerably reduced cancer cell proliferation (IC50 = 0.83 and 0.19 μM, respectively). Additionally, the expression of the tumor suppressor gene p21 was elevated whereas the expression of the invasion and anti-apoptosis genes BCl2, mTOR, and JNK were significantly decreased after treatment with RMV and SOR. Based on in silico analysis, it was found that RMV extract contains bioactive chemicals with a high affinity for inhibiting JNK and VEGFR-2. In conclusion, in vitro and in silico investigations show that the RMV extract improves the anticancer efficiency of SOR through molecular processes involving the downregulation of mTOR, BCl2, and JNK1 and overexpression of p21 tumor suppressor gene. Finally, we suggest conducting additional in vivo investigations on RMV and its bioactive components to verify their potential in cancer therapy. | breast cancer |
Factors Associated with College Women's Personal and Parental Decisions to be Vaccinated Against HPV. The human papillomavirus (HPV) is a public health concern because of its association with cancer. HPV vaccine rates among college students remains low. This is a critical catch-up age for individuals to receive the HPV vaccine and research shows parents still play a role in college students' medical decision-making. Therefore, the purpose of this study was to examine factors related to college women making a solo decision to initiate the HPV vaccination in comparison to making a joint parent-daughter decision. Data collected using an internet-delivered questionnaire were analyzed from 799 college women who had initiated or completed the HPV vaccination. Multinomial logistic regression was performed to compare study variables on who decided the participant should be vaccinated (self-decision, parent-only decision, joint parent-daughter decision). Participants who were older (OR 1.68, p < 0.001) and sexually active (OR 4.97, p < 0.001) were significantly more likely to have made a solo decision to be vaccinated. Participants who completed the HPV vaccination (OR 0.33, p < 0.001) and those who talked with a parent about the HPV vaccine (OR 0.12, p < 0.001) were significantly less likely to have made a solo decision to be vaccinated. Findings indicate joint parent-daughter decisions may improve HPV vaccination cycle completion. | no data |
Effects of PEG-liposomal oxaliplatin on apoptosis, and expression of Cyclin A and Cyclin D1 in colorectal cancer cells. Oxaliplatin is one of the agents used against colorectal cancer. Using PEG-liposome encapsulated oxaliplatin may enhance the accumulation of drugs in tumor cells, inducing apoptosis. However, the mechanism of action of PEG-liposome encapsulated oxaliplatin remains unclear. SW480 human colorectal cancer cells were treated with empty PEG-liposomes, free oxaliplatin or PEG-liposomal oxaliplatin. Cell cycle and apoptosis were assessed using fluorescence confocal microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end-labeling (TUNEL). Western blotting was used to analyze the expression of pro-apoptotic, anti-apoptotic and cyclin proteins. We found that PEG-liposomal oxaliplatin induced a stronger apoptotic response than empty PEG-liposomes or free oxaliplatin. Moreover, expression of Cyclin D1 increased, whereas expression of Cyclin A decreased after treatment with PEG-liposomal oxaliplatin. Furthermore, the cell cycle was arrested in the G1 phase. The results presented here indicate that PEG-liposome entrapment of oxaliplatin enhances the anticancer potency of the chemotherapeutic agent. The effect of PEG-liposomal oxaliplatin on apoptosis of SW480 human colorectal cancer cells may be through regulation of expression of Cyclin A or Cyclin D1, as well as pro-apoptotic and anti-apoptotic proteins. | colorectal cancer |
Imaging of cranial nerves: a pictorial overview. The human body has 12 pairs of cranial nerves that control motor and sensory functions of the head and neck. The anatomy of cranial nerves is complex and its knowledge is crucial to detect pathological alterations in case of nervous disorders. Therefore, it is necessary to know the most frequent pathologies that may involve cranial nerves and recognize their typical characteristics of imaging. Cranial nerve dysfunctions may be the result of pathological processes of the cranial nerve itself or be related to tumors, inflammation, infectious processes, or traumatic injuries of adjacent structures. Magnetic resonance imaging (MRI) is considered the gold standard in the study of the cranial nerves. Computed tomography (CT) allows, usually, an indirect view of the nerve and is useful to demonstrate the intraosseous segments of cranial nerves, the foramina through which they exit skull base and their pathologic changes. The article is a complete pictorial overview of the imaging of cranial nerves, with anatomic and pathologic descriptions and great attention to illustrative depiction. We believe that it could be a useful guide for radiologists and neuroradiologists to review the anatomy and the most important pathologies that involve cranial nerves and their differential diagnosis. | head and neck cancer |
Cold atmospheric plasma jet effects on V79-4 cells. The effects of cold plasmas are due to charged particles, reactive oxygen species (ROS), reactive nitrogen species (RNS), UV photons, and intense electric field. In order to obtain a more efficient action on mammalian cells (useful for cancer therapy), we used in our studies chemically activated cold plasma (He and O2 gas mixture). V79-4 cells were exposed to plasma jet for different time periods (30, 60, 90, 120 and 150s), using different combinations of helium and oxygen inputs (He:2.5l/min + 02:12.5ml/min; He:2.51/min + O2:25ml/min; He:2.51/min + O2:37.5 ml/min). Using MTT test we demonstrated that plasma jet induced cell viability decrease in all cases. The effect of chemically activated cold plasma--apoptosis or necrosis--depends on gas mixture and treatment period. Taking into account that ROS density in cell microenvironment is related to O2 percent in the gas mixture and treatment period, we can presume that cell death is due to ROS produced in plasma jet. | no data |
Autoreactivity against interleukin 6 as a risk factor in elderly patients with colorectal carcinoma. Aging results in both decreased immunity to exogenous antigens and increased autoreactivity. We suggest that the increased autoreactivity against tumor-releasing cachectic cytokine and postsurgical hypercytokinemia are involved in the cause of increased morbidity and mortality in elderly patients with colorectal cancer. Eighty-three patients with colorectal cancer admitted to a university hospital were studied prospectively. Surgical specimens of primary colorectal cancer were harvested and peripheral venous blood samples were obtained perioperatively. The tissue concentrations of interleukin (IL) 1beta and IL-6 were determined. Serial determinations of serum concentrations of IL-6, IL-6 soluble receptor, and C-reactive protein were performed. Nutritional status was assessed by the creatinine height index. The tumor IL-6 content was the independent factor that influenced the creatinine height index in the elderly patients, whereas Dukes classification was the only independent factor that influenced the creatinine height index in the younger patients. The elderly patients showed an exaggerated C-reactive protein response and increased IL-6 soluble receptor consumption independent of the tumor IL-6 content and postoperative IL-6 response. This immunologic disturbance was followed by a significant (P = .03) delay in the normalization of activated neutrophils, which seemed to be associated with postoperative fatal complications in the elderly patients. Autoreactivity against intrinsic IL-6 was increased and seemed to be associated with poor clinical outcomes in elderly patients. To prevent fatal complications, adequate nutritional support early in treatment and attenuation of the neutrophil-related hyperinflammatory sequence by controlling the IL-6 soluble receptor affinity should be advocated. | colorectal cancer |
Natural antisense transcript TPM1-AS regulates the alternative splicing of tropomyosin I through an interaction with RNA-binding motif protein 4. LncRNAs play a vital role in alternative splicing of target genes. However, the mechanisms underlying lncRNAs involvement in splicing are poorly understood. In the present study, we identified a previously uncharacterized lncRNA, which is denoted as TPM1-AS, is reverse-transcribed from the fourth intronic region of the tropomyosin I (TPM1). In situ hybridization and RNA immunoprecipitation assays demonstrated that TPM1-AS was located in the nucleus and interacted with RNA-binding motif protein 4 (RBM4) in human esophageal cancer cells. TPM1-AS overexpression or RBM4 knockdown decreased endogenous exon 2a expression of TPM1, resulting in specifically down-regulation of TPM1variant V2 and V7 in human esophageal cancer cells. Mechanismly, the interaction of TPM1-AS with RBM4 hindered binding of RBM4 to TPM1 pre-mRNA and inhibited RBM4 to promote endogenous exon 2a inclusion of TPM1. Importantly, overexpression of TPM1-AS inhibited migration and filopodium formation, whereas TPM1variant V2 and V7 promoted these behaviors of human esophageal cancer cells. Taken together, the results suggest that a natural antisense TPM1-AS regulates the alternative splicing of TPM1 through an interaction with RBM4 and involves in TPM1-mediated filopodium formation and migration of cancer cells. | no data |
pT3 N0 Laryngeal Squamous Cell Carcinoma: Oncologic Outcomes and Prognostic Factors of Surgically Treated Patients. To assess the disease control, survival rates, and prognostic factors of exclusive surgical treatment for patients with pT3 N0 laryngeal squamous cell carcinoma (LSCC). Multicentric retrospective cohort study. Multicentric retrospective case series of previously untreated patients with pT3 R0N0 LSCC, who received exclusive surgery between 2011 and 2019. Tumor location; subsite involvement; grading; and lymphatic, vascular, and perineural invasion were reported. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were measured. Fifty-four patients (mean age 67.1; male sex 83.3%; mean follow-up period 37 months) underwent total laryngectomy (48.1%) or partial laryngectomy (51.9%). Ipsilateral or bilateral neck dissection was performed in 46 (85.2%) cases. Perineural invasion was more frequent in case of supraglottic involvement than glottic involvement (85.7% vs. 14.3%, P = .03). Five (9.3%) patients experienced recurrence (3 local recurrences, 1 nodal recurrence, 1 distant recurrence). Rate of recurrence differed between glottic (0%), supraglottic (80%), and transglottic (20%) tumors (P = .01), with a lower risk yielded by glottic involvement (odds ratio [OR], 0.05, 95% confidence interval [95% CI], 0.01-0.56, P = .01). A higher risk was recorded in case of perineural invasion (OR, 66.0, 95% CI, 1.41-3085.3, P = .03). The OS, DSS, and DFS were 79.6%, 96.3%, and 90.7%, without differences regarding the type of surgery. The DFS was lower in case of supraglottic involvement when compared to purely glottic LSCC (83.9% vs. 100%, P = 0.02). Exclusive surgery is a safe option for patients with pT3 R0N0 LSCC. Adjuvant treatments or closer follow-up monitoring might be considered in case of supraglottic involvement or perineural invasion. 4 Laryngoscope, 131:2262-2268, 2021. | head and neck cancer |
Heterogeneous nuclear ribonucleoprotein K upregulates the kinetochore complex component NUF2 and promotes the tumorigenicity of colon cancer cells. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a multi-functional protein involved in transcription, mRNA splicing, mRNA stabilization and translation. Although hnRNP K has been suggested to play a role in the development of many cancers, its molecular function in colorectal cancer has remained elusive. Here we show that hnRNP K plays an important role in the mitotic process in HCT116 colon cancer cells. Furthermore, we demonstrate that hnRNP K directly transactivates the NUF2 gene, the product of which is a component of the NDC80 kinetochore complex and which is known to be critical for a stable spindle microtubule-kinetochore attachment. In addition, knockdown of both hnRNP K and NUF2 caused failure in metaphase chromosome alignment and drastic decrease in the growth of colon cancer cells. These results suggest that the hnRNP K-NUF2 axis is important for the mitotic process and proliferation of colon cancer cells and that this axis could be a target for the therapy of colon cancer. | colorectal cancer |
Future prospects for oncolytic therapy. Viruses have been engineered to replicate selectively in cancer cells, based on a number of innovative principles. Several of these viruses have entered clinical trials and have proven relatively safe, and have shown evidence of efficacy. However, further research is required to enable these agents to function systemically. This might involve attempts to suppress immune responses to virus antigens, and re-targeting of viruses to favor tumor infection and increased potency. When these barriers are overcome, oncolytic viruses could enter the mainstream of clinical oncology. | blood cancer |
Differential regulation of NPY and SP receptor expression in STRO-1+ve PDLSCs by inflammatory cytokines. The aims of this study were to investigate neuropeptide receptor expression regulation on STRO-1 +ve periodontal ligament stem cells (PDLSCs) in response to inflammatory cytokines and to investigate a potential osteogenic effect of neuropeptides. Nerve fibres innervating the periodontal tissues in humans contain several neuropeptides including neuropeptide Y and substance P. The role of neuropeptide receptors on PDLSCs, including their response to the local inflammatory environment of periodontitis, is currently unknown. A homogenous population of STRO-1 +ve PDLSCs was prepared by immunomagnetic separation of cells obtained by the tissue out-growth method from healthy premolar teeth from a single donor. Regulation of gene expression of the neuropeptide Y Y1 receptor and substance P receptor tachykinin receptor 1 was investigated. A potential osteogenic effect of neuropeptide Y and substance P was also investigated by measuring alkaline phosphatase (ALP) activity, Alizarin red staining and quantifying osteogenic gene expression. Treatment of STRO-1 +ve PDLSCs with tumour necrosis factor-alpha or interleukin 1-beta up-regulated the expression of the neuropeptide Y's Y1 receptor, but down-regulated substance P's receptor. Significantly increased ALP activity was observed in STRO-1 +ve PDLSCs treated with neuropeptide Y but not substance P. Further studies showed that neuropeptide Y had a modest osteogenic effect on cells at both a functional level and a gene level. Expression of the neuropeptide Y Y1 receptor gene on STRO-1 +ve PDLSCs was sensitive to local inflammatory cytokines. Treatment of cells with neuropeptide Y was found to produce a modest enhanced osteogenic effect. | no data |
Cervical cytology in vulnerable pregnant women. To identify the prevalence of abnormal Papanicolau (Pap) smears in pregnancy in a vulnerable urban family practice, determine the percentage of abnormal Pap smears that persist into the postpartum period, and identify associated risk factors. A retrospective chart review of all prenatal patients (N = 192) from a large urban family practice in upstate New York from 2000 to 2004. Descriptive statistic analysis was performed on demographic information, risk factors for abnormal Pap smears, and disposition of the patients. This study provides information on the risk factors associated with abnormal Pap smears in pregnancy in a population at high risk. A significant relationship was seen between a positive marijuana toxicology screen and an abnormal Pap smear. In addition, the younger the patient age, the higher the probability of having a positive toxicology result. As expected, human papillomavirus (HPV) was the only sexually transmitted infection associated with an abnormal Pap smear in those that had reflex testing with liquid based cytology. Patients with primary care providers were much more likely to return for cervical cancer screening within 1 year of previous testing. There are many barriers to screening and prevention for cervical cancer in vulnerable populations. Newer technologies with HPV testing have helped to identify those women at highest risk for cervical cancer. Implementing strategies among healthcare providers to avoid missed opportunities for screening, assessment and education of risk factors, and offering vaccination against HPV are needed. Empowering women may begin to reduce disparities through the development of educational programs that reduce cultural and linguistic barriers to screening and awareness that socioeconomic factors may be impediments to care and adherence. | cervical cancer |
Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues. | no data |
Antimicrobial susceptibility patterns and characterization of clinical isolates of Staphylococcus aureus in immunocompromised cancer patients undergoing chemotherapy in Pakistan. Cancer patients undergoing chemotherapy are highly prone to infections because of suppression of their immune system. in the present study, the activity of fluoroquinolones, cephalosporins, glycopeptides and oxazolidinones was evaluated in Staphylococcus aureus strains by broth dilution method according to Clinical and laboratory Standards institute (ClSi), USA guidelines. the frequency of methicillin-resistant S. aureus (mRSA) and methicillin-sensitive S. aureus (mSSA) strains was 67% and 33% respectively. The MIC(50 )and MIC(90 )of isolates were ciprofloxacin 8 and 32 microg/ml for mRSA, 8 and 16 microg/ml for mSSA, levofloxacin 8 and 16 microg/ml for mRSA and mSSA, gatifloxacin 4 and 16 microg/ml for mRSA and 4 and 8 microg/ml for mSSA. MIC(50 )and MIC(90 )of vancomycin and linzolid were 1 and 2 microg/ml, 2 and 4 microg/ml for both mRSA and mSSA strains respectively. this study shows a high prevalence of and resistance in mRSA. However, vancomycin and linezolid were highly active and could be used for treating mRSA infections. | no data |
Cytogenotoxic effects of Adenium obesum seeds extracts on breast cancer cells. The extracts prepared from various areal parts of the Adenium obesum (Forssk.) Roem. & Schult. (Family: Apocynaceae) including leaves, fruit and seeds ethanolic extracts and seed aqueous extract were evaluated against MCF-7 cells in order to investigate its potential of cytogenotoxicity and induction of apoptosis. The ethanolic seeds extract had comparatively higher cytotoxicity (IC50 ∼ 337 µg/ml). Further, apoptosis and DNA damaging potential of seeds ethanolic extract was analyzed by applying multiple sub-lethal concentrations and durations. Flow cytometry results revealed that maximum percentage of early apoptosis (37%) and late apoptosis (35%) were observed after 12 h exposure in concentrations 200 µg/ml and 300 µg/ml, respectively. Similarly, the higher effect of extract in terms of DNA damage by alkaline comet assay was registered after 12 h treatment at concentrations 200 and 300 µg/mL. The calculated total damage score (TDS) for these concentrations were 614 and 617, respectively. The above findings indicate that A. obesum ethanolic seeds extracts has cytogenotoxic properties that could be further explored for the potential source of chemotherapeutic lead against cancer. | breast cancer |
Acute phase markers for the differentiation of infectious and malignant pleural effusions. Acute-phase markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), have been studied in inflammatory and malignant disorders. We examined the diagnostic value of these markers for the differentiation among parapneumonic, tuberculous and malignant effusions. We studied 124 patients with pleural effusions, classified as exudates [total (n=97), parapneumonic (n=15), tuberculous (n=25), malignant (n=57)] and transudates due to congestive heart failure (n=27). CRP, IL-6 and TNF-alpha were measured in pleural fluid and serum. Pleural fluid CRP was higher in parapneumonic compared to tuberculous and malignant effusions, providing 100% sensitivity for a cut-off point of 5.3mg/dL. IL-6 was higher in both parapneumonic and tuberculous compared to malignant effusions. TNF-alpha was higher in tuberculous compared to malignant effusions, providing 96.0% sensitivity, and 93.0% specificity for a cut-off point of 88.1 pg/mL. Pleural fluid CRP levels were lower than serum in all groups, probably reflecting systemic inflammation, whereas IL-6 and TNF-alpha were higher in pleural fluid indicating local production. Our data suggest that these markers may provide useful information for the differentiation of infectious and malignant effusions in clinical practice. However, further studies are needed for the validation of these findings in usual clinical circumstances. | no data |
Macrophages and therapeutic resistance in cancer. How neoplastic cells respond to therapy is not solely dependent on the complexity of the genomic aberrations they harbor but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments. Therefore, therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways identified so far whereby macrophages mediate therapeutic responses. | multi cancer |
Carcinoid and other neuroendocrine tumors of the colon and rectum. Neuroendocrine tumors (NETs) are found throughout the intestinal tract and arise from the Kulchitsky cells located in the crypts of Lieberkühn. They are classified by site of origin and by degree of differentiation, with well-differentiated lesions representing those tumors formerly referred to as carcinoid tumors. The focus of this review is NETs of the appendix, colon, and rectum. The clinical presentation of these tumors is dependent on the primary site and many are discovered incidentally, either during screening or during the investigation of nonspecific abdominal complaints. Treatment is primarily via surgical removal as the response to chemotherapy has been traditionally poor. A noted exception to this has been with treatment of the carcinoid syndrome, which occurs almost exclusively in patients with liver metastases and is due to the release of bioactive peptides and amines directly into the systemic circulation. The use of somatostatin congeners to block the release of these substances has greatly ameliorated the devastating symptoms of this condition. Postresection follow-up is advocated, but specific recommendations are lacking an evidentiary basis. NETS, particularly those of the small bowel, colon, and appendix, are seen in association with other synchronous or metachronous malignancies, often of the gastrointestinal tract. However, the utility of subsequent screening and surveillance is unproven. | colorectal cancer |
The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma. The identity of cancer cells is defined by the interplay between genetic, epigenetic transcriptional and post-transcriptional variation. A lot of this variation is present in RNA-seq data and can be captured at once using reference-free, k-mer analysis. An important issue with k-mer analysis, however, is the difficulty of distinguishing signal from noise. Here, we use two independent lung adenocarcinoma datasets to identify all reproducible events at the k-mer level, in a tumor versus normal setting. We find reproducible events in many different locations (introns, intergenic, repeats) and forms (spliced, polyadenylated, chimeric etc.). We systematically analyze events that are ignored in conventional transcriptomics and assess their value as biomarkers and for tumor classification, survival prediction, neoantigen prediction and correlation with the immune microenvironment. We find that unannotated lincRNAs, novel splice variants, endogenous HERV, Line1 and Alu repeats and bacterial RNAs each contribute to different, important aspects of tumor identity. We argue that differential RNA-seq analysis of tumor/normal sample collections would benefit from this type k-mer analysis to cast a wider net on important cancer-related events. The code is available at https://github.com/Transipedia/dekupl-lung-cancer-inter-cohort. | lung cancer |
Spinal tumors in children. Spinal tumors are rare in the pediatric population, presenting many specific peculiarities when compared to adults. We have performed a broad narrative review to describe the most common spinal tumors in children, discussing their main characteristics and management options. The authors have performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Multimodality radiological studies (plain films, 3D computed tomography scan and magnetic resonance imaging) are necessary for proper evaluation and differential diagnosis of spinal tumors in children. In selected cases nuclear medicine imaging is used to improve the chances of a more accurate diagnosis. As a general rule, a fine needle biopsy is recommended after radiological evaluation to confirm the tumor's histology. Primary bone tumors can be divided into benign bone tumors, mostly represented by vertebral hemangiomas, osteoid osteomas, osteoblastomas, aneurismal bone cysts, and eosinophilic granulomas, and malign or aggressive tumors, such as Ewing's or osteogenic sarcomas. Secondary bone tumors (spinal metastases) comprise different tumor histologies, and treatment is mainly based on tumor's radiosensitivity. The characteristics and treatment options of the main spinal tumors are discussed in details. Spinal tumors in children are rare lesions that demand a thorough understanding of their main characteristics for their proper management. Understanding the nuances of spinal tumors in children is of paramount importance for improving outcomes and chances of cure. | rare cancer |
Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. Chemotherapy is a reasonable alternative to cystectomy in patients with invasive and advanced bladder cancer. However, bladder cancer cells often develop drug resistance to these therapies, and ~ 50% of patients with advanced bladder cancer do not respond to chemotherapy. Recent studies have shown that long non-coding RNA (lncRNA) is involved in the development of chemoresistance. Here we investigated the role of the urothelial cancer-associated 1 (UCA1) lncRNA in cisplatin resistance during chemotherapy for bladder cancer. We showed that cisplatin-based chemotherapy results in up-regulation of UCA1 expression in patients with bladder cancer. Similarly, UCA1 levels are increased in cisplatin-resistant bladder cancer cells. Over-expression of UCA1 significantly increases the cell viability during cisplatin treatment, whereas UCA1 knockdown reduces the cell viability during cisplatin treatment. UCA1 inhibition also partially overcomes drug resistance in cisplatin-resistant T24 cells. Furthermore, we showed that UCA1 positively regulates expression of wingless-type MMTV integration site family member 6 (Wnt6) in human bladder cancer cell lines. UCA1 and Wnt6 expression is also positively correlated in vivo. Up-regulation of UCA1 activates Wnt signaling in a Wnt6-dependent manner. We finally demonstrate that UCA1 increases the cisplatin resistance of bladder cancer cells by enhancing the expression of Wnt6, and thus represents a potential target to overcome chemoresistance in bladder cancer. | bladder cancer |
Prognostic potential of KLOTHO and SFRP1 promoter methylation in head and neck squamous cell carcinoma. Hypermethylation in the CpG island promoter regions of tumor suppressors is known to play a significant role in the development of HNSCC and the detection of which can aid the classification and prognosis of HNSCC. This study aims to profile the methylation patterns in a panel of key genes including CDKN2A, CDKN2B, KLOTHO (KL), RASSF1A, RARB, SLIT2, and SFRP1, in a group of HNSCC samples from Saudi Arabia. The extent of methylation in these genes is determined using the MethyLight assay and correlated with known clinicopathological parameters in our samples of 156 formalin-fixed and paraffin-embedded HNSCC tissues. SLIT2 methylation had the highest frequency (64.6%), followed by RASSF1A (41.3%), RARB (40.7%), SFRP1 (34.9), KL (30.7%), CKDN2B (29.6%), and CKDN2A (29.1%). KL and SFRP1 methylation were more predominant in nasopharyngeal tumors (P = 0.001 and P = 0.031 respectively). Kaplan Meier analysis showed that patients with moderately differentiated tumors who display SFRP1 methylation have significantly worse overall survival in comparison with other samples. In contrast, better clinical outcomes were seen in patients with KL methylation. In conclusion, our findings suggest that the detection of frequent methylation in SFRP1 and KL genes' promoters could serve as prognostic biomarkers for HNSCC. | head and neck cancer |
Modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mutation in the cecum and colon of big blue rats by conjugated linoleic acid and 1,2-dithiole-3-thione. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent mutagen and suspected human carcinogen present in cooked protein-rich food. It preferentially induced colon tumors in male rats and mammary tumors in female rats. In the present study, the in vivo antimutagenic efficacy of two dietary compounds, conjugated linoleic acid (CLA) and 1,2-dithiole-3-thione (DTT), against PhIP was explored using 1acI transgenic Big Blue rats. Five- or six-week-old male Big Blue rats were fed a diet containing CLA (0.5%, wt/wt) or DTT (0.005%, wt/wt) starting one week before exposure to 200 ppm PhIP for 61 days. PhIP treatment induced a approximately 8- to 16-fold increase in the mutation frequency (MF) in the colon. The induced MF was significantly lower in the cecum than in the proximal and distal colon (approximately 52 x 10(-5) vs. 100 x 10(-5), p < 0.008). CLA and DTT significantly reduced the PhIP-induced MF in the distal colon (p < 0.05) by 14% and 24%, respectively. The frequency of -1 frameshift mutations was lower in the distal colon of CLA- or DTT-treated rats. This protective effect was not observed in the cecum or in the proximal colon. In contrast, the PhIP-induced MF in the cecum (specifically, the frequency of -1 frameshifts and GC-->TA transversions) was elevated by 43% after treatment with CLA. In conclusion, CLA and DTT modulate PhIP-induced mutagenesis in a tissue-specific manner, and different modulation pathways are employed by CLA and DTT. | colorectal cancer |
Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes. Sonic hedgehog (Shh) signaling is important in the growth and differentiation of many cell types and recently has been reported to play a role in T cell development in the thymus. This prompted us to investigate whether or not Shh contributes to the clonal expansion of peripheral CD4(+) T cells. In this study, we demonstrate that Shh and other components of the signaling pathway patched, smoothened, and Gli1 (glioma-associated oncogene) are expressed in peripheral CD4(+) T cells. The addition of the biologically active amino-terminal Shh peptide had no effect on resting CD4(+) T cells, but significantly enhanced proliferation of anti-CD3/28 Ab-activated CD4(+) T cells. This was not due to antiapoptotic effects, but by promoting entry of T cells into the S-G(2) proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G(2) phase, suggesting that endogenously produced Shh plays a physiological role in the clonal expansion of T cells. Furthermore, we have observed a significant up-regulation of Shh and Gli1 (glioma-associated oncogene) mRNA in activated CD4(+) T cells with or without addition of exogenous Shh, which corresponds with maximal CD4(+) T cell proliferation, whereas bcl-2 was only up-regulated in activated cells in the presence of Shh. Our findings suggest that endogenously produced Shh may play a role in sustaining normal CD4(+) T cell proliferation and exogenously added Shh enhances this response. | no data |
Lipid metabolism in cartilage and its diseases: a concise review of the research progress. The homeostasis of the vertebrate body depends on anabolic and catabolic activities that are closely linked the inside and outside of the cell. Lipid metabolism plays an essential role in these metabolic activities. Although a large amount of evidence shows that normal lipid metabolism guarantees the conventional physiological activities of organs in the vertebrate body and that abnormal lipid metabolism plays an important role in the occurrence and deterioration of cardiovascular-related diseases, such as obesity, atherosclerosis, and type II diabetes, little is known about the role of lipid metabolism in cartilage and its diseases. This review aims to summarize the latest advances about the function of lipid metabolism in cartilage and its diseases including osteoarthritis, rheumatoid arthritis, and cartilage tumors. With the gradual in-depth understanding of lipid metabolism in cartilage, treatment methods could be explored to focus on this metabolic process in various cartilage diseases. | no data |
Engineered Near-Infrared Fluorescent Protein Assemblies for Robust Bioimaging and Therapeutic Applications. Fluorescent proteins are investigated extensively as markers for the imaging of cells and tissues that are treated by gene transfection. However, limited transfection efficiency and lack of targeting restrict the clinical application of this method rooted in the challenging development of robust fluorescent proteins for in vivo bioimaging. To address this, a new type of near-infrared (NIR) fluorescent protein assemblies manufactured by genetic engineering is presented. Due to the formation of well-defined nanoparticles and spectral operation within the phototherapeutic window, the NIR protein aggregates allow stable and specific tumor imaging via simple exogenous injection. Importantly, in vivo tumor metastases are tracked and this overcomes the limitations of in vivo imaging that can only be implemented relying on the gene transfection of fluorescent proteins. Concomitantly, the efficient loading of hydrophobic drugs into the protein nanoparticles is demonstrated facilitating the therapy of tumors in a mouse model. It is believed that these theranostic NIR fluorescent protein assemblies, hence, show great potential for the in vivo detection and therapy of cancer. | no data |
Understanding the Mechanism of Direct Activation of AMP-Kinase: Toward a Fine Allosteric Tuning of the Kinase Activity. Mammalian AMP-activated protein kinase (AMPK) is a Ser/Thr protein kinase with a key role as a sensor in cellular energy homeostasis. It has a major role in numerous metabolic disorders, such as type 2 diabetes, obesity, and cancer, and hence it has gained progressive interest as a potential therapeutic target. AMPK is a heterotrimeric enzyme composed by an α-catalytic subunit and two regulatory subunits, β and γ. It is regulated by several mechanisms, including indirect activators such as metformin and direct activators such as compound A-769662. The crystal structure of AMPK bound to A-769662 has been recently reported, suggesting a hypothetical allosteric mechanism of AMPK activation assisted by phosphorylated Ser108 at the β-subunit. Here, we have studied the direct activation mechanism of A-769662 by means of molecular dynamics simulations, suggesting that the activator may act as a glue, coupling the dynamical motion of the β-subunit and the N-terminal domain of the α-subunit, and assisting the preorganization of the ATP-binding site. This is achieved through the formation of an allosteric network that connects the activator and ATP-binding sites, particularly through key interactions formed between αAsp88 and βArg83 and between βpSer108 and αLys29. Overall, these studies shed light into key mechanistic determinants of the allosteric regulation of this cellular energy sensor, and pave the way for the fine-tuning of the rational design of direct activators of this cellular energy sensor. | no data |
Advanced usage of Ti3C2Tx MXenes for photothermal therapy on different 3D breast cancer models. Globally, breast cancer is the most diagnosed invasive cancer among women. Current therapies (e.g., chemotherapy) show numerous limitations due to the lack of selectivity and involved side effects, which urgently asks for novel approaches with enhanced tumor-killing efficacy. We previously demonstrated that MXenes, new bioactive nanomaterials with promising photophysical properties, are capable to increase the efficiency of the targeted breast cancer photothermal therapy (PTT). In this work, we investigated the effect of few- and multi-layer Ti3C2Tx MXenes mediated-PTT on two different 3D reliable breast cancer models such as conventional and bio-printed spheroids. We performed PTT on both cancer models using a non-toxic MXene concentration of 50 µg/mL. After PTT, a significant reduction in the cell viability along with a notable increase in reactive oxygen species (ROS) was observed. Moreover, we studied the effect of PTT on the migration of macrophages and endothelial cells toward cancer regions in both 3D models. Our results indicate that PTT mediated by both few- and multi-layer MXenes significantly modulates the tumor progression through cells' death by increasing the temperature, which holds particularly true for the bio-printed model. | breast cancer |
Effect of N-acetylcysteine on the murine model of colitis induced by dextran sodium sulfate through up-regulating PON1 activity. Reactive oxygen species (ROS) are increased in inflammatory bowel disease (IBD) and have been implicated as mediators of intestinal inflammation. We investigated the hypothesis that N-acetylcysteine (NAC) as a glutathione (GSH) precursor attenuates disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model. A colitis model was induced by adding 5% DSS into the drinking water for 7 days. BALB/c mice were injiciatur enema with saline, 5-ASA, N-acetylcysteine, respectively, and free drinking water as control group. DSS-treated mice developed severe colitis as shown by bloody diarrhea, weight loss, and pathologic involvement. Colon lengths were significantly decreased in DSS-treated mice with decreased GSH activity too (P < 0.01). ROS in the colon, the level of interleukin 1 beta (IL-1 beta) in colonic mucosa, serum tumor necrosis factor a (TNF-alpha), MPO, and MDA were significantly increased in DSS-treated animals (P < 0.01), with decreased PON1 activity (P < 0.01). However, NAC significantly decreased colonic MPO activity, ROS, TNF-alpha and IL-1 beta levels and increased PON1 activity and GSH concentration. Moreover, NAC attenuated the macroscopic colonic damage and the histopathologic changes-induced by DSS while similar to 5-ASA group. These results suggest that NAC may be effective in the treatment of colitis through its up-regulating PON1 and scavenging oxygen-derived free radicals. | colorectal cancer |
Ovarian cancer screening in the general population. During the last year, population screening trials from the USA and Japan have reported on the effectiveness of transvaginal ultrasound screening in the early detection of ovarian cancer. Although the data are not from randomized trials, it is consistent with an impact of screening on mortality. A randomized control trial to definitively answer this question is now underway in the UK. This study also addresses the issues of target population, compliance, health economics and physical and psychological morbidity of screening. | ovarian cancer |
Outcomes of invasive mediastinal nodal staging versus positron emission tomography staging alone for early-stage non-small cell lung cancer treated with stereotactic body radiation therapy. The benefit of invasive mediastinal nodal staging (IMNS) in addition to positron emission tomography-computed tomography (PET/CT) is undefined for early stage non-small cell lung cancer (NSCLC). This multi-institutional investigation aimed to evaluate outcomes and patterns of failure in patients staged with PET/CT with or without additional IMNS. Two academic centers assessed all consecutive patients staged with PET/CT for early-stage, primary lung NSCLC (cT1-2aN0M0) treated with SBRT. Local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes. Overall, 180 patients (199 lesions) were staged with PET/CT alone and 56 patients (58 lesions) underwent additional IMNS. Among patients receiving IMNS, 52 (93%) underwent EBUS and 4 (7%) underwent mediastinoscopy. At a median follow-up of 33.5 months (range, 1.9-80.9 months), there was no significant difference in LRFS (37 vs. 47 months, p=0.309), NRFS (34 vs. 42 months p=0.370), DMFS (36 vs. 47 months, p=0.234) or OS (37 vs. 47 months, p=0.236) between patients undergoing PET/CT-only versus PET/CT+IMNS staging, respectively. Receipt of IMNS did not correlate with any outcome on either univariate or multivariate analysis (p>0.05). Patterns of failure in both groups were similar, including crude isolated nodal failure rates (8% PET/CT-only versus 14% PET+IMNS group, p=0.202). Patients undergoing IMNS had similar survival and patterns of recurrence as those receiving PET/CT alone. Further study, ideally prospectively, is needed to determine which subgroups might benefit from IMNS. | lung cancer |
The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy. Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the MYC locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. MYC gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, MYC copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and MYC knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy. SIGNIFICANCE: Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting MYC gain in pretreatment tumors as a potential marker of therapy resistance. | no data |
Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression. Tumor-infiltrating lymphocytes (TIL) are an important component of the tumor environment. Their role in tumor growth and progression has been debated for decades. Today, emphasis has shifted to beneficial effects of TIL for the host and to therapies optimizing the benefits by reducing immune suppression in the tumor microenvironment. Evidence indicates that when TILs are present in the tumor as dense aggregates of activated immune cells, tumor prognosis and responses to therapy are favorable. Gene signatures and protein profiling of TIL at the population and single-cell levels provide clues not only about their phenotype and numbers but also about TIL potential functions in the tumor. Correlations of the TIL data with clinicopathological tumor characteristics, clinical outcome, and patients' survival indicate that TILs exert influence on the disease progression, especially in colorectal carcinomas and breast cancer. At the same time, the recognition that TIL signatures vary with time and cancer progression has initiated investigations of TIL as potential prognostic biomarkers. Multiple mechanisms are utilized by tumors to subvert the host immune system. The balance between pro- and antitumor responses of TIL largely depends on the tumor microenvironment, which is unique in each cancer patient. This balance is orchestrated by the tumor and thus is shifted toward the promotion of tumor growth. Changes occurring in TIL during tumor progression appear to serve as a measure of tumor aggressiveness and potentially provide a key to selecting therapeutic strategies and inform about prognosis. | multi cancer |
Trends and Patterns of Primary Hepatic Carcinoma in Saudi Arabia. Primary hepatic carcinoma (PHC) is the 4th most common malignancy among males at King Faisal Specialist Hospital and Research center (KFSH & RC) and in Saudi Arabia. There has been a steady increase in the number of PHC cases since 1975 at KFSH & RC and the burden of hepatic carcinomas is growing in Saudi Arabia. The aim of this study is to explore the changing trends and patterns of PHCs at KFSH & RC and conduct a comparative analysis with local, regional and global trends. Cancer incidence data was obtained from the King Faisal Specialist Hospital and Research Center Tumor Registry program as per the American College of Surgeons standards. Clinico-epidemiological data of 1174 liver cancer patients from KFSH & RC during 2000 to 2014 and Saudi Cancer Registry (SCR) between 2001-2015 with total of 5,796 cases was reviewed. Trends, patterns of occurrence and other prognostic factors of interest were sub-stratified by gender, age, stage, and grade. Temporal trends indicated a rising incidence of PHC from 2001 to 2014 in Saudi Arabia; from 323 cases in 2001 to 376 cases in 2015 as per SCR. A total of 2,779 new cases of PHC were seen at KFSH & RC between 1975 and 2014; the rate of PHC increased from 60 cases in 2004 to 80 cases in 2014. Majority of liver cancers were hepatocellular carcinomas (79.3%) followed by cholangiocarcinoma (11%), and hepatoblastoma (4.7%) with significantly higher incidence among males with a male to female ratio of 2:1 (p <0.01). The highest incidence by age was at 6th and 7th decade of life. Majority of patients were diagnosed in localized stage (44.6%) and had a past medical history (28.2%) of hepatitis (p < 0.001). The most common treatment for liver cancer at KFSH & RC was surgery (26.7%) followed by transplant (9.5%). Despite improvement in preventive measures, incidence rates of PHC has increased during the last decade with marked regional variation. Etiology of this escalating trend is multifactorial; predominantly, chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), heavy alcohol consumption, obesity, diabetes, and tobacco smoking. This exponential increase may also be due to early detection and diagnosis due to expanding health care delivery in the Kingdom. Further studies are indicated to comprehend the rising trends at the molecular and genetic levels. | liver cancer |
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