Crk mediates Csk-Hippo signaling independently of Yap tyrosine phosphorylation to induce cell extrusion.

Src family kinases (SFKs), including Src, Fyn and Yes, play important roles in development and cancer. Despite being first discovered as the Yes-associated protein, the regulation of Yap by SFKs remains poorly understood. Here, through single-cell analysis and genetic lineage tracing, we show that the pan-epithelial ablation of C-terminal Src kinase (Csk) in the lacrimal gland unleashes broad Src signaling but specifically causes extrusion and apoptosis of acinar progenitors at a time when they are shielded by myoepithelial cells from the basement membrane. Csk mutants can be phenocopied by constitutively active Yap and rescued by deleting Yap or Taz, indicating a significant functional overlap between Src and Yap signaling. Although Src-induced tyrosine phosphorylation has long been believed to regulate Yap activity, we find that mutating these tyrosine residues in both Yap and Taz fails to perturb mouse development or alleviate the Csk lacrimal gland phenotype. In contrast, Yap loses Hippo signaling-dependent serine phosphorylation and translocates into the nucleus in Csk mutants. Further chemical genetics studies demonstrate that acute inhibition of Csk enhances Crk/CrkL phosphorylation and Rac1 activity, whereas removing Crk/CrkL or Rac1/Rap1 ameliorates the Csk mutant phenotype. These results show that Src controls Hippo-Yap signaling through the Crk/CrkL-Rac/Rap axis to promote cell extrusion.

Effects of Bony Pelvic and Prostate Dimensions on Surgical Difficulty of Robot-Assisted Radical Prostatectomy: An Original Study and Meta-analysis.

BACKGROUND: Due to the deep location of the prostate within the pelvic cavity, procedures of robot-assisted radical prostatectomy (RARP) might be challenged by the prostate size and the limited pelvic cavity space. This study aimed to investigate the roles of bony pelvic and prostate dimensions in RARP procedures by an original study coupled with a meta-analysis. METHODS: In the original study, patients undergoing multiport RARP between 2021 and 2022 were consecutively assessed. The associations of anatomic features with operative time (OT), estimated blood loss (EBL), and positive surgical margin (PSM) were evaluated using linear and logistic regression analyses as well as restricted cubic spline (RCS) analysis. Based on machine-learning algorithms, this study established predictive models for surgical difficulty and interpreted the model using SHapley Additive exPlanation (SHAP). In the meta-analysis, three databases were searched for eligible studies. Quantitative syntheses were subsequently performed. RESULTS: Overall, 219 patients were enrolled in the original study. Prostate volume (PV) and the prostate volume-to-pelvic cavity index (PCI) ratio (PV-to-PCI ratio) were significantly associated with longer OT (P < 0.05). In the RCS models, U-shaped associations were observed between the prostate anteroposterior diameter (PAD) and OT, and between the prostate height (PH) and EBL, and an L-shaped association was observed between the anteroposterior diameter of the pelvic inlet (API) and EBL. The XGBoost model was superior to the logistic regression model in predicting prolonged OT. The meta-analysis demonstrated that greater PV was significantly associated with longer OT (ß = 0.20; 95% confidence interval [CI] 0.12-0.27; odds ratio [OR] = 1.05; 95% CI 1.00-1.11), and a smaller PV could increase the risk of PSM (OR = 0.82; 95% CI 0.77-0.88). CONCLUSIONS: A large prostate within a narrow and deep pelvis might suggest increased surgical difficulty of RARP. The size of the pelvic inlet also had a great impact on RARP. For PAD and PH, there seemed to be an optimal range with the lowest surgical difficulty. Machine-learning models based on the XGBoost algorithm could be successfully applied to predict the surgical difficulty of RARP.

PFDA promotes cancer metastasis through macrophage M2 polarization mediated by Wnt/ß-catenin signaling.

Perfluoroundecanoic acid (PFDA) is extensively utilized in the textile and food processing industries and may have a tumor-promoting effect by modulating the tumor microenvironment. Macrophages play crucial roles in tumor microenvironment as key regulators of tumor immunity. However, further investigation is needed to elucidate how PFDA interacts with macrophages and contributes to tumor progression. In this study, we treated the macrophage cell line RAW264.7 with various concentrations of PFDA and found that RAW264.7 transitioned into an M2 tumor-promoting phenotype. Through bioinformatic analysis and subsequent verification of molecular assays, we uncovered that PFDA could activate ß-catenin and enhance its nuclear translocation. Additionally, it was also observed that inhibiting ß-catenin nuclear translocation partly attenuated RAW264.7 M2 polarization induced by PFDA. The conditioned medium derived from PFDA-pretreated RAW264.7 cells significantly promoted the migration and invasion abilities of human ovarian cancer cells. Furthermore, in vivo studies corroborated that PFDA-pretreated RAW264.7 could promote tumor metastasis, which could be mitigated by pretreatment with the ß-catenin inhibitor ICG001. In conclusion, our study demonstrated that PFDA could promote cancer metastasis through regulating macrophage M2 polarization in a Wnt/ß-catenin-dependent manner.

Association between dietary vitamin C intake/blood level and risk of digestive system cancer: a systematic review and meta-analysis of prospective studies.

Experimental studies have shown that vitamin C has anti-cancer effects, but previous meta-analyses have indicated that the role of vitamin C in digestive system cancers (DSCs) is controversial. In this study, a systematic review and meta-analysis of the relationship between dietary intake/plasma concentration of vitamin C and the risk of DSC was conducted, evaluating 32 prospective studies with 1 664 498 participants. Dose-response and subgroup analyses were also performed. Systematic literature searches were performed in PubMed, EMBASE and Web of Science databases until 9th September 2023. Vitamin C intake significantly reduced DSCs risk (RR = 0.88, 95% confidence interval (CI) 0.83 to 0.93). The subgroup analyses showed the risks of oral, pharyngeal, and esophageal (OPE) cancers (0.81, 0.72 to 0.93), gastric cancer (0.81, 0.68 to 0.95), and colorectal cancer (0.89, 0.82 to 0.98) were negatively correlated with vitamin C intake, and the effect of vitamin C was different between colon cancer (0.87, 0.77 to 0.97) and rectal cancer (1.00, 0.84 to 1.19). However, plasma vitamin C concentration was only inversely associated with gastric cancer risk (0.74, 0.59 to 0.92). Dose-response analysis revealed that 250 and 65 mg day-1 vitamin C intakes had the strongest protective effect against OPE and gastric cancers respectively. These estimates suggest that vitamin C intake could significantly reduce gastrointestinal cancer incidence, including OPE, gastric, and colon cancers. Plasma vitamin C has a significant reduction effect on the incidence of gastric cancer only, but additional large-scale clinical studies are needed to determine its impact on the incidence of DSCs.

Ratio of hemoglobin to red cell distribution width: an inflammatory predictor of survival in AIDS-related DLBCL.

Background: Despite the introduction of combined antiretroviral therapy, AIDS-related diffuse large B-cell lymphoma (AR-DLBCL) remains a prominent cancer among individuals living with HIV with a suboptimal prognosis. Identifying independent prognostic markers could improve risk stratification. Methods: In this multicenter retrospective cohort study spanning years 2011 to 2019, 153 eligible patients with AR-DLBCL were examined. Overall survival (OS) factors were analyzed using Kaplan-Meier curves, and univariate and multivariate Cox proportional hazards models. The discriminatory ability of the risk score was evaluated by examining the area under the receiver operating characteristic curve. Results: The study included 153 patients with a median age of 47 years (interquartile range [IQR] 39-58), 83.7% of whom were men. The median follow-up was 12.0 months (95% confidence interval [CI], 8.5-15.5), with an OS rate of 35.9%. Among the potential inflammatory markers examined, only the ratio of hemoglobin (g/dL) to red cell distribution width (%) (Hb/RDW) emerged as an independent prognostic parameter for OS in the training (hazard ratios [HR] = 2.645, 95% CI = 1.267-5.522, P = 0.010) and validation cohorts (HR = 2.645, 95% CI = 1.267-5.522, P = 0.010). A lower Hb/RDW ratio was strongly correlated with adverse clinical factors, including advanced Ann Arbor stage, increased extranodal sites, reduced CD4 count, elevated lactate dehydrogenase levels, poorer Eastern Cooperative Oncology Group performance status (ECOG PS), and a higher International Prognostic Index (IPI) score. The addition of the Hb/RDW ratio to the IPI produced a highly discriminatory prognostic composite score, termed Hb/RDW-IPI. Conclusion: We identified a cost-effective and readily available inflammatory biomarker, the Hb/RDW ratio, as an independent predictor of outcomes in patients with AR-DLBCL. Its integration into the IPI score partially improves prognostic accuracy.

Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated LC3B transcription in NSCLC.

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of LC3B transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and LC3B, which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC.

PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway.

BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice. RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells' ability to resist chemotherapy and metastasize. CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.

Prognostic Model and Nomogram for Early-Onset Adenoid Cystic Carcinoma of Head and Neck: A Retrospective SEER-Based Analysis.

BACKGROUND: Adenoid cystic carcinoma of head and neck (ACCHN) is an uncommon head and neck cancers, whose predilection age is 40 to 60. Some studies have revealed that early-onset cancers, such as colorectal cancers and esophageal adenocarcinoma, might present some unique clinicopathological features and have different prognosis with late-onset ones. However, little is known about the early-onset ACCHN. This study aimed to develop a prognostic nomogram for overall survival (OS) of patients younger than 40 with ACCHN. METHODS: Cases with ACCHN from 1975 to 2016 were retrieved from SEER-18 program. Demographic, clinical, and survival outcomes data of patients were identified for further analysis. The caret package was used to randomly divide early-onset patients into a training cohort and a validation cohort. A prognostic nomogram was constructed based on the univariate and multivariate Cox analysis. The discriminative ability and calibration power of the nomogram was evaluated by the concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve. RESULTS: A total of 5858 cases with ACCHN were selectively retrieved from SEER program in this study. The number of patients younger than 40, which was defined as early-onset ACCHN in this study, was 825. Based on the outcomes of multivariate analysis, tumor size, chemotherapy, surgery, and stage were selected for the construction of nomogram to predict 10-year OS. The C-index was 0.792 (95%CI 0.760-0.823) and 0.776 (95%CI 0.720-0.832) in the training and validation set, respectively. The area under the ROC curve values were 0.875 (95%CI 0.810-0.940) and 0.833(95%CI 0.754-0.912). The calibration plot indicated that this nomogram had proper calibration in both the training and validation cohorts. CONCLUSION: A novel prognostic nomogram for early-onset ACCHN was constructed and validated in this study. This nomogram could be applied for assisting clinicians to more accurately assess the prognosis of young patients, which might facilitate clinical decision-making and subsequent follow-up.

A promising prognostic model for predicting survival of patients with HIV-related diffuse large B-cell lymphoma in the cART era.

BACKGROUND: Optimization of risk stratification is important for facilitating prognoses and therapeutic decisions regarding diffuse large B-cell lymphoma (DLBCL). However, a simple and applicable prognostic tool is lacking for individuals with human immunodeficiency virus (HIV)-related DLBCL in the era of combined antiretroviral therapy (cART). METHODS: This retrospective multicenter observational study included 147 HIV-related DLBCL patients with histologically confirmed DLBCL from 2013 to 2020. The total group was divided into training (n = 78) and validation (n = 69) cohorts to derive the best prognostic score. Clinicopathological and characteristic biomarkers correlated with clinical outcomes were analyzed. RESULTS: Age, Ann Arbor stage, lactate dehydrogenase (LDH) ratio, bulky disease, and red blood cell distribution width (RDW) ratio retained robust independent correlations with overall survival (OS) in multivariate analysis. A new and practical prognostic model was generated and externally validated, classifying patients into three categories with significantly different survival rates. Moreover, the new index outperformed the International Prognostic Index (IPI) score (area under the curve values of 0.94 vs. 0.81 in the training cohort and 0.85 vs. 0.74 in the validation cohort, C-indices of 0.80 vs. 0.70 in the training cohort and 0.74 vs. 0.70 in the validation cohort, and integrated discrimination improvement values of 0.203 in the training cohort and 0.175 in the validation cohort) and was better at defining intermediate- and high-risk groups. The calibration curves performed satisfactorily for predicting 3-year OS in the training and validation cohorts. CONCLUSIONS: We developed and validated a simple and feasible prognostic model for patients with HIV-related DLBCL that had more discriminative and predictive accuracy than the IPI score for risk stratification and individualized treatment in the cART era.

MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage.

Peritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.

Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan.

BACKGROUND: Infective endocarditis (IE) is an important cause of morbidity and mortality in pediatric patients with heart disease. Little literature has explored differences in the presentation of endocarditis in children with and without heart disease. This study aimed to compare the clinical outcomes and determine the risk of in-hospital death in the study population. METHODS: Data were retrospectively collected from 2001 to 2019 from the Chang Gung Research Database (CGRD), which is the largest collection of multi-institutional electronic medical records in Taiwan. Children aged 0-20 years with IE were enrolled. We extracted and analyzed the demographic and clinical features, complications, microbiological information, and outcomes of each patient. RESULTS: Of the 208 patients with IE, 114 had heart disease and 94 did not. Compared to those without heart disease, more streptococcal infections (19.3% vs. 2.1%, p < 0.001) and cardiac complications (29.8% vs. 6.4%, p < 0.001) were observed in patients with heart disease. Although patients with heart disease underwent valve surgery more frequently (43.9% vs. 8.5%, p < 0.001) and had longer hospital stays (28.5 vs. 12.5, p = 0.021), their mortality was lower than that of those without heart disease (3.5% vs. 10.6%, p = 0.041). Thrombocytopenia was independent risk factor for in-hospital mortality in pediatric patients with IE (OR = 6.56, 95% CI: 1.43-40.37). CONCLUSION: Among pediatric patients diagnosed with IE, microbiological and clinical features differed between those with and without heart disease. Platelet counts can be used as a risk factor for in-hospital mortality in pediatric patients with IE.

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling.

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013-2016 data. We treated human ovarian cancer cells with 0-1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

Idiopathic Mesenteric Phlebosclerosis: A Single-Institute Experience in Taiwan.

BACKGROUND: Idiopathic mesenteric phlebosclerosis is a rare condition with unclear pathogenesis. This study aimed to investigate the clinical features, diagnostic modalities, treatments, and outcomes of idiopathic mesenteric phlebosclerosis patients in Taiwan. METHODS: Idiopathic mesenteric phlebosclerosis patients diagnosed by the typical characteristic of tree-like mesenteric venous calcifications on plain abdominal radiography or computed tomography between January 1992 and July 2021 were retrospectively analyzed. RESULTS: Totally, 36 idiopathic mesenteric phlebosclerosis patients were enrolled (50% females; mean age, 61.6 years). Among the included patients, 26 (72.2%) and 10 (27.7%) were symptomatic and asymptomatic, respectively. Abdominal pain (61.1%) accounted for the majority of all symptoms, followed by fever, diarrhea, and bloody stools. Our results showed that 83.3% of patients had at least 1 risk factor, whereas 16.6% of patients had none. Moreover, among the included patients, 36.1%, 44.4%, 50.0%, 38.8%, and 8.3% had cardiovascular disease, chronic renal disease, cancer, chronic liver disease, and diabetes mellitus, respectively. Our findings showed 94.4% of patients were diagnosed via abdominal computed tomography and plain abdominal radiography, whereas 5.6% of patients were diagnosed via plain abdominal radiography. The ascending colon was the most commonly involved site (100%). Our findings showed that 91.6% of patients experienced good recovery after conservative treatment, except for the 3 who died of sepsis and respiratory failure. By contrast, 8.3% of idiopathic mesenteric phlebosclerosis patients underwent colectomy. The average follow-up duration was 62.5 months. CONCLUSIONS: Idiopathic mesenteric phlebosclerosis remains a rare disease in Taiwan. Plain abdominal radiography and computed tomography can be utilized for establishing a definite diagnosis. Conservative treatment is usually adequate for most patients, with surgical treatment only indicated for severe cases.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer. / USH2Açªå˜å’Œå ¶ä»–å ³é”®é©±åŠ¨åŸºå› çªå˜äºšåž‹ä¸Žå ç–«æ£€æŸ¥ç‚¹æŠ‘åˆ¶å‰‚åœ¨è‚ºç™Œæ‚£è€ ä¸­ä¸´åºŠè”ç³»çš„å ³è”ç ”ç©¶.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01|‒|1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49|‒|2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48|‒|1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39|‒|1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32|‒|0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38|‒|0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75|‒|8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88|‒|6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Toxicogenomics scoring system: TGSS, a novel integrated risk assessment model for chemical carcinogenicity prediction.

BACKGROUND: Given the increasing exposure of humans to environmental chemicals and the limitations of conventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. OBJECTIVES: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets. METHODS: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts. RESULTS: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 ×10-5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts. CONCLUSION: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

Association between Different Types of Tea Consumption and Risk of Gynecologic Cancer: A Meta-Analysis of Cohort Studies.

Plenty of studies have shown that tea has an effect of inhibiting gynecologic tumors. However, there still remained controversy of the association between tea and gynecologic tumors in epidemiological studies. In this study, PubMed, Embase, and Cochrane Database were used to search the literature from 1 January 1960 to 26 December 2022 to investigate the association between tea intake and gynecologic cancer risk. In total, 19 cohort studies with 2,020,980 subjects and 12,155 gynecological tumor cases were retrieved. The pooled relative risk (RR) of gynecologic tumor for tea intake was 1.00 (95% CI: 0.96-1.04). RRs were 0.94 (95% CI: 0.88-1.01) for ovarian cancer, 1.02 (95% CI: 0.97-1.07) for endometrial cancer, and 1.06 (95% CI: 0.91-1.23) for cervical cancer. Subgroup analyses were adopted based on the tea type and geographic location. Interestingly, significant preventive impact of non-herbal tea on ovarian cancer (pooled relative risk: 0.67; 95% CI: 0.55-0.81) was found, especially for black tea (pooled relative risk: 0.64; 95% CI: 0.51-0.80). Dose-response analysis indicated that although it is not statistically significant, a decreasing trend of ovarian cancer risk could be observed when the tea consumption was 1.40 to 3.12 cups/day. In conclusion, our findings suggested that ovarian cancer, but not other gynecologic cancers, could possibly be prevented by drinking non-herbal tea. In addition, the preventive impact of green tea on gynecologic cancer seemed to be relatively weak and needs further cohorts to validate it.

Extracellular Vesicle-Packaged circATP2B4 Mediates M2 Macrophage Polarization via miR-532-3p/SREBF1 Axis to Promote Epithelial Ovarian Cancer Metastasis.

Ovarian cancer is one of the most common gynecologic malignancies with a highly immunosuppressive tumor microenvironment (TME) and poor prognosis. Circular RNA (circRNA) is a type of noncoding RNA with high stability, which has been shown to play an important role in biological processes and TME reprogramming in a variety of tumors. The biological function of a novel circRNA, circATP2B4, in epithelial ovarian cancer (EOC) was detected and evaluated. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of extracellular vesicles (EV)-packaged circATP2B4. Macrophage uptake of circATP2B4 was determined by EVs tracing. Dual luciferase reporter, FISH, Western blotting, and flow cytometry assays were used to investigate the interactions between circATP2B4 and miR-532-3p as well as sterol regulatory element-binding factor 1 (SREBF1) expression in macrophages. CircATP2B4 was upregulated in EOC tissues and positively correlated with ovarian cancer progression. Functionally, circATP2B4 promoted carcinogenic progression and metastasis of EOC both in vitro and in vivo. Mechanistically, EV-packaged circATP2B4 in EOC could be transmitted to infiltrated macrophages and acted as competing endogenous RNA of miR-532-3p to relieve the repressive effect of miR-532-3p on its target SREBF1. Furthermore, circATP2B4 induced macrophage M2 polarization by regulating the miR-532-3p/SREBF1/PI3Kα/AKT axis, thereby leading to immunosuppression and ovarian cancer metastasis. Collectively, these data indicate that circATP2B4-containing EVs generated by EOC cells promoted M2 macrophages polarization and malignant behaviors of EOC cells. Thus, targeting EVs-packaged circATP2B4 may provide a potential diagnosis and treatment strategy for ovarian cancer.

An oxidative stress-related prognostic signature for indicating the immune status of oral squamous cell carcinoma and guiding clinical treatment.

Oral squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide and presents high mortality. Oxidative stress, caused by reactive oxygen species accumulation, plays a crucial role in tumorigenesis, cancer progression, and drug resistance. Nevertheless, the specific prognostic and clinical values of oxidative stress-related genes (OSGs) in OSCC remain unclear. Here, we developed an oxidative stress-related prognostic signature according to mRNA expression data from The Cancer Genome Atlas (TCGA) database and evaluated its connections with the prognosis, clinical features, immune status, immunotherapy, and drug sensitivity of OSCC through a series of bioinformatics analyses. Finally, we filtered out six prognostic OSGs to construct a prognostic signature. On the basis of both TCGA-OSCC and GSE41613 cohorts, the signature was proven to be an independent prognostic factor with high accuracy and was confirmed to be an impactful indicator for predicting the prognosis and immune status of patients with OSCC. Additionally, we found that patients with high-risk scores may obtain greater benefit from immune checkpoint therapy compared to those with low-risk scores, and the risk score presented a close interaction with the tumor microenvironment and chemotherapy sensitivity. The prognostic signature may provide a valid and robust predictive tool that could predict the prognosis and immune status and guide clinicians to develop personalized therapeutic strategies for patients with OSCC.

Peripheral blood mononuclear cell microRNAs are novel biomarkers for diagnosing and monitoring Crohn's disease.

Crohn's disease is a recurrent, progressive, immune-mediated inflammatory disease and merely manifests non-specific symptoms at early stage. In this study, we isolated peripheral blood mononuclear cells (PBMCs) to determine whether PBMC miRNAs are reliable biomarkers for Crohn's disease diagnosing and monitoring. 5 Crohn's disease patients and 5 healthy controls were recruited to find differentially expressed miRNAs by next generation sequencing. Candidate PBMC miRNAs were further validated by qRT-PCR in another cohort consisting of 86 Crohn's disease patients and 39 healthy controls. We found PBMC miR-582-5p could diagnose Crohn's disease with the area under receiver operating characteristic curve (AUROC) of 0.701(95%CI 0.606-0.796, p < .001). While PBMC miR-96-5p was significantly higher in active Crohn's disease and correlated with both clinical (ρ = 0.376, p < .001) and endoscopic activity (ρ = 0.512, p = .015). Furthermore, PBMC miR-96-5p had a better performance in recognizing active Crohn's disease with AUROC of 0.727 (95%CI 0.609-0.844, p = .001) than C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin. In conclusion, PBMC miR-582-5p may be further utilized as a diagnostic biomarker, while miR-96-5p may be a novel and valuable biomarker in monitoring disease activity.