Per- and polyfluoroalkyl substances (PFAS) exposure in plasma and their blood-brain barrier transmission efficiency-A pilot study.

Per- and polyfluoroalkyl substances (PFAS) have been shown to penetrate the blood-brain barrier (BBB) and accumulate in human brain. The BBB transmission and accumulation efficiency of PFAS, as well as the potential health risks from human co-exposure to legacy and emerging PFAS due to differences in transport efficiency, need to be further elucidated. In the present pilot study, 23 plasma samples from glioma patients were analyzed for 17 PFAS. The concentrations of PFAS in six paired brain tissue and plasma samples were used to calculate the BBB transmission efficiency of PFAS (RPFAS). This RPFAS analysis was conducted with utmost care and consideration amid the limited availability of valuable paired samples. The results indicated that low molecular weight PFAS, including short-chain and emerging PFAS, may have a greater potential for accumulation in brain tissue than long-chain PFAS. As an alternative to perfluorooctane sulfonic acid (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) exhibited brain accumulation potential similar to that of PFOS, suggesting it may not be a suitable substitute concerning health risk in brain. The BBB transmission efficiencies of perfluorooctanoic acid, PFOS, and 6:2 Cl-PFESA showed similar trends with age, which may be an important factor influencing the entry of exogenous compounds into the brain. A favorable link between perfluorooctane sulfonamide (FOSA) and the development and/or progression of glioma may be implicated by a strong positive correlation (r2 = 0.94; p < 0.01) between RFOSA and Ki-67 (a molecular marker of glioma). However, a causal relationship between RFOSA and glioma incidence were not established in the present study. The present pilot study conducted the first examination of BBB transmission efficiency of PFAS from plasma to brain tissue and highlighted the importance of reducing and/or controlling exposure to PFAS.

Modeled Pathways and Fluxes of PCB Dechlorination by Redox Potentials.

Dechlorination is one of the main processes for the natural degradation of polychlorinated biphenyls (PCBs) in an anaerobic environment. However, PCB dechlorination pathways and products vary with PCB congeners, types of functional dechlorinating bacteria, and environmental conditions. The present study develops a novel model for determining dechlorination pathways and fluxes by tracking redox potential variability, transforming the complex dechlorination process into a stepwise sequence. The redox potential is calculated via the Gibbs free energy of formation, PCB concentrations in reactants and products, and environmental conditions. Thus, the continuous change in the PCB congener composition can be tracked during dechlorination processes. The new model is assessed against four measurements from several published studies on PCB dechlorination. The simulation errors in all four measurements are calculated between 2.67 and 35.1% under minimum (n = 0) and maximum (n = 34) numbers of co-eluters, respectively. The dechlorination fluxes for para-dechlorination pathways dominate PCB dechlorination in all measurements. Furthermore, the model also considers multiple-step dechlorination pathways containing intermediate PCB congeners absent in both the reactants and the products. The present study indicates that redox potential might be an appropriate indicator for predicting PCB dechlorination pathways and fluxes even without prior knowledge of the functional dechlorinating bacteria.

Quantitative Proteomics Analysis Reveals the Potential Role of lncRNA FTX in Endothelial Cells.

OBJECTIVE: This study investigated the role of long non-coding RNAs (lncRNAs) FTX in vascular endothelial cells (ECs). METHODS: Transfection of FTX/Sh-FTX with lentivirus was used to construct gain and loss of function cell models in human umbilical vein endothelial cells (HUVECs). Liquid chromatography-mass spectrometry was used for quantitative proteomics analysis of differentially expressed proteins (DEPs). Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein interaction analysis were further conducted to investigate the key molecules and pathways that respond to lncRNA-FTX. RESULTS: In the proteomics analysis, 3308 quantifiable proteins were identified, 64 proteins were upregulated and 103 were downregulated when lncRNA FTX was overexpressed. Additionally, 100 proteins were upregulated and 147 were downregulated when lncRNA FTX was knocked down. Functional clustering analysis of DEPs demonstrated that lncRNA FTX was involved in multiple biological processes. Among them, the expression of complement 3 (C3), cartilage oligomeric matrix protein (COMP), faciogenital dysplasia 6 (FGD6), and tissue inhibitor of metalloproteinase 1 (TIMP1) was significantly upregulated when lncRNA FTX was knocked down, and significantly downregulated when lncRNA FTX was overexpressed. They are associated with inflammation, collagen deposition, angiogenesis, and regulation of liver stem cell differentiation, which may be associated with the occurrence and development of liver fibrosis. CONCLUSIONS: The study demonstrated that lncRNA FTX might play a potential role in ECs and contribute to the development of liver fibrosis. Thus, FTX may be a promising target for the prevention or reversal of liver fibrosis.

Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination.

Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies. Targeting ferroptosis as a novel approach to tumor treatment has gained attention. Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe2+ levels, and decreased glutathione levels in GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect. Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4. The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro. Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST. In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.

COLEC12 Promotes Tumor Progression and Is Correlated With Poor Prognosis in Gastric Cancer.

PURPOSE: Collectin subfamily member 12, a transmembrane scavenger receptor C-type lectin, is aberrantly expressed in various cancers. However, its physiological role in gastric cancer remains somewhat unclear. This study aimed to investigate the Collectin subfamily member 12 expression pattern in human gastric cancer and its role in gastric cancer progression. METHODS: The Kaplan-Meier method was used for survival analysis. The univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for progression-free survival and overall survival. The effects of Collectin subfamily member 12 on gastric cancer cell proliferation, migration, invasion, and apoptosis were detected through the cell counting kit-8 assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry analysis, respectively. Additionally, the correlation between Collectin subfamily member 12 expression and immune cell infiltration was analyzed through bioinformatics. RESULTS: Collectin subfamily member 12 was highly expressed in advanced gastric cancer (T3-T4, pathologic stage III-IV). High Collectin subfamily member 12 expression was correlated with a worse progression-free survival and overall survival in the gastric cancer patients. In vitro, cell line studies revealed that Collectin subfamily member 12 promoted gastric cancer cell proliferation, migration, and invasion and inhibited gastric cancer cell apoptosis. The bioinformatics analysis further demonstrated that the Collectin subfamily member 12 expression level positively correlated with infiltration of several immune cells, such as M2 macrophages, dendritic cells, neutrophils, and regulatory T cells, suggesting that Collectin subfamily member 12 may also play a role in suppressing tumor immune response in gastric cancer. CONCLUSIONS: Collectin subfamily member 12 was identified as a novel predictive marker and target for the clinical treatment of gastric cancer.

Combination of the triglyceride-glucose index and EuroSCORE II improves the prediction of long-term adverse outcomes in patients undergoing coronary artery bypass grafting.

AIMS: We aimed to investigate the independent and combined association of the triglyceride-glucose (TyG) index and EuroSCORE II with major adverse cardiovascular event (MACE) after coronary artery bypass grafting (CABG), and examine whether the addition of the TyG index improves the predictive performance of the EuroSCORE II. MATERIALS AND METHODS: This study included 1013 patients who underwent CABG. The primary endpoint was MACE, which was defined as the composite of all-cause death, repeat coronary artery revascularisation, non-fatal myocardial infarction and non-fatal stroke. The patients were grouped by the TyG index and EuroSCORE II tertiles and the combination of these risk indicators. RESULTS: During the follow-up, 211 individuals developed MACE. Elevated levels of the TyG index and EuroSCORE II were associated with an increased risk of MACE. The hazard ratio [95% confidence interval (CI)] was 3.66 (2.34-5.73) in patients with the highest tertile of the TyG index and EuroSCORE II. Compared with the EuroSCORE II alone, combining the TyG index with EuroSCORE II achieved a better predictive performance [C-statistic increased 0.032, p < 0.001; continuous net reclassification improvement (NRI) (95% CI): 0.364 (0.215-0.514), p < 0.001; integrated discrimination improvement (IDI) (95% CI): 0.015 (0.007-0.023), p < 0.001, Akaike's information criteria (AIC) and Bayesian information criterion (BIC) decreased, and the likelihood ratio test, p < 0.001]. CONCLUSIONS: The TyG index and EuroSCORE II are independently associated with poor prognosis. Furthermore, the TyG index is an important adjunct to the EuroSCORE II for improving risk stratification and guiding early intervention among post-CABG patients.

Triglyceride-glucose index in the prediction of adverse cardiovascular events in patients without diabetes mellitus after coronary artery bypass grafting: a multicenter retrospective cohort study.

BACKGROUND: The triglyceride-glucose (TyG) index has been evaluated as a reliable surrogate for insulin resistance (IR) and has been proven to be a predictor of poor outcomes in patients with cardiovascular diseases. However, data are lacking on the relationship of the TyG index with prognosis in nondiabetic patients who underwent coronary artery bypass grafting (CABG). Thus, the purpose of our current study was to investigate the potential value of the TyG index as a prognostic indicator in patients without diabetes mellitus (DM) after CABG. METHODS: This multicenter, retrospective cohort study involving 830 nondiabetic patients after CABG from 3 tertiary public hospitals from 2014 to 2018. Kaplan-Meier survival curve analysis was conducted followed by the log-rank test. Cox proportional hazards regression models were used to explore the association between the TyG index and major adverse cardiovascular events (MACEs). The incremental predictive power of the TyG index was evaluated with C-statistics, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: An incrementally higher TyG index was associated with an increasingly higher cumulative incidence of MACEs (log-rank test, p < 0.001). The hazard ratio (95% CI) of MACEs was 2.22 (1.46-3.38) in tertile 3 of the TyG index and 1.38 (1.18-1.62) per SD increase in the TyG index. The addition of the TyG index yielded a significant improvement in the global performance of the baseline model [C-statistic increased from 0.656 to 0.680, p < 0.001; continuous NRI (95% CI) 0.269 (0.100-0.438), p = 0.002; IDI (95% CI) 0.014 (0.003-0.025), p = 0.014]. CONCLUSIONS: The TyG index may be an independent factor for predicting adverse cardiovascular events in nondiabetic patients after CABG.

The metabolic score for insulin resistance in the prediction of major adverse cardiovascular events in patients after coronary artery bypass surgery: a multicenter retrospective cohort study.

BACKGROUND: The metabolic score for insulin resistance (METS-IR) is a simple, convenient, and reliable marker for resistance insulin (IR), which has been regarded as a predictor of cardiovascular disease (CVD) and cardiovascular events. However, few studies examined the relationship between METS-IR and prognosis after coronary artery bypass graft (CABG). This study aimed to investigate the potential value of METS-IR as a prognostic indicator for the major adverse cardiovascular events (MACE) in patients after CABG. METHOD: 1100 CABG patients were enrolled in the study, including 760 men (69.1%) and 340 women (30.9%). The METS-IR was calculated as Ln [(2 × FPG (mg/dL) + fasting TG (mg/dL)] × BMI (kg/m2)/Ln [HDL-C (mg/dL)]. The primary endpoint of this study was the occurrence of major adverse cardiovascular events (MACE), including a composite of all-cause death, non-fatal myocardial infarction (MI), coronary artery revascularization, and stroke. RESULT: The following-up time of this study was 49-101 months (median, 70 months; interquartile range, 62-78 months). During the follow-up period, there were 243 MACEs (22.1%). The probability of cumulative incidence of MACE increased incrementally across the quartiles of METS-IR (log-rank test, p < 0.001). Multivariate Cox regression analysis demonstrated a hazard ratio (95% CI) of 1.97 (1.36-2.86) for MACE in quartile 4 compared with participants in quartile 1. The addition of the METS-IR to the model with fully adjusting variables significantly improved its predictive value [C-statistic increased from 0.702 to 0.720, p < 0.001, continuous net reclassification improvement (NRI) = 0.305, < 0.001, integrated discrimination improvement (IDI) = 0.021, p < 0.001]. CONCLUSION: METS-IR is an independent and favorable risk factor for predicting the occurrence of MACE and can be used as a simple and reliable indicator that can be used for risk stratification and early intervention in patients after CABG.

The synergistic effect of the triglyceride-glucose index and serum uric acid on the prediction of major adverse cardiovascular events after coronary artery bypass grafting: a multicenter retrospective cohort study.

BACKGROUND: Elevated serum uric acid (SUA) is regarded as a risk factor for the development of cardiovascular diseases. Triglyceride-glucose (TyG) index, a novel surrogate for insulin resistance (IR), has been proven to be an independent predictor for adverse cardiac events. However, no study has specifically focused on the interaction between the two metabolic risk factors. Whether combining the TyG index and SUA could achieve more accurate prognostic prediction in patients undergoing coronary artery bypass grafting (CABG) remains unknown. METHODS: This was a multicenter, retrospective cohort study. A total of 1225 patients who underwent CABG were included in the final analysis. The patients were grouped based on the cut-off value of the TyG index and the sex-specific criteria of hyperuricemia (HUA). Cox regression analysis was conducted. The interaction between the TyG index and SUA was estimated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). The improvement of model performance yielded by the inclusion of the TyG index and SUA was examined by C-statistics, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The goodness-of-fit of models was evaluated using the Akaike information criterion (AIC), Bayesian information criterion (BIC) and χ2 likelihood ratio test. RESULTS: During follow-up, 263 patients developed major adverse cardiovascular events (MACE). The independent and joint associations of the TyG index and SUA with adverse events were significant. Patients with higher TyG index and HUA were at higher risk of MACE (Kaplan-Meier analysis: log-rank P < 0.001; Cox regression: HR = 4.10; 95% CI 2.80-6.00, P < 0.001). A significant synergistic interaction was found between the TyG index and SUA [RERI (95% CI): 1.83 (0.32-3.34), P = 0.017; AP (95% CI): 0.41 (0.17-0.66), P = 0.001; SI (95% CI): 2.13 (1.13-4.00), P = 0.019]. The addition of the TyG index and SUA yielded a significant improvement in prognostic prediction and model fit [change in C-statistic: 0.038, P < 0.001; continuous NRI (95% CI): 0.336 (0.201-0.471), P < 0.001; IDI (95% CI): 0.031 (0.019-0.044), P < 0.001; AIC: 3534.29; BIC: 3616.45; likelihood ratio test: P < 0.001). CONCLUSIONS: The TyG index interacts synergistically with SUA to increase the risk of MACE in patients undergoing CABG, which emphasizes the need to use both measures concurrently when assessing cardiovascular risk.

Recalibrating polyparameter linear free energy relationships and reanalyzing mechanisms for partition of nonionic organic compounds to low-density polyethylene passive sampler.

Equilibrium passive sampling techniques based on the low-density polyethylene (LDPE) film are increasingly used for determining the concentration of contaminants in water and air. Reliable models capable of predicting LDPE-water and LDPE-air partition coefficients (KiLDPEw and KiLDPEa) would be very useful. In previous studies, polyparameter linear free energy relationships (PP-LFERs) based on Abraham's solute descriptors were calibrated for LDPE-water and LDPE-air systems. Unfortunately, a portion of unreliable partition coefficients and solute descriptors were included in the calibration sets of these previous studies, leading to unexpected system parameters and predictive performance in the regression results. In this study, more reliable PP-LFERs were recalibrated for LDPE-water and LDPE-air systems (20‒25 °C) using carefully collected reliable partition coefficients and solute descriptors of various polar and nonpolar compounds (over one hundred and with low redundancy) from the literature, as well as the robust regression method. The PP-LFERs performed well with root-mean-square errors of 0.15-0.25 log units and successfully predicted KiLDPEw and KiLDPEa values spanning over 10 orders of magnitude for compounds with reliable descriptors. The partitioning mechanisms of compounds to LDPE were also reanalyzed and compared in detail with n-alkanes (C6-C16). Generally, LDPE is more prone to form dispersion interactions with solutes than n-alkanes, while it is more difficult to form cavities in LDPE. In addition, the crystallinity of LDPE is not the sole reason for the distinct constant terms presenting in PP-LFERs for LDPE-water and n-hexadecane-water systems.

Country-specific riverine contributions to marine plastic pollution.

Marine plastic debris are mainly derived from land-based sources, and the transport of plastics via global rivers is of great concern. Ample efforts have been made in estimating the land-based contributions of plastic to the global oceans, but quantifying country-specific (and per capita) riverine outflows is an important step toward the development of a globally integrated framework to mitigate marine plastic pollution. To estimate the country-specific riverine contributions to global marine plastic pollution, we built a River-to-Ocean model framework. In 2016, the median annual country-specific riverine plastic outflows and related per capita values for 161 countries varied between 0.76 and 103,000 metric tons (MT) and 0.83-248 g, respectively. India, China, and Indonesia were the top three contributors to riverine plastic outflows, whereas Guatemala, Philippines, and Colombia had the highest per capita riverine plastic outflows. The total riverine plastic outflow from 161 countries was in the range of 0.15-0.53 million MT annually, accounting for 0.4 %-1.3 % of the 40 million MT plastic waste generated yearly by more than seven billion humans. Population, plastic waste generation, and Human Development Index are the dominant factors influencing riverine plastic outflows to global oceans from individual countries. Our findings provide an important basis for launching effective plastic pollution management and control measures in global countries.

New insight on the correlation of immune landscapes with immune markers expression in different risk classification of gastrointestinal stromal tumors.

BACKGROUND: The immune landscapes of gastrointestinal stromal tumors (GISTs) are still unclear. We aimed to explore the immune status of GISTs with different recurrence risks and sought potential immunotherapeutic targets. METHODS: Immune cell infiltration and the expression of 93 tumor markers of 65 GISTs with different recurrence risks from public datasets were analyzed via bioinformatic methods. Infiltrating immune cell and OX40L expression of 417 patients from the Zhongshan cohort were analyzed by immunohistochemistry and immunofluorescence. The clinicopathological data of the patients were collected and the prognostic factors were analyzed by univariate and multivariate methods. RESULTS: Macrophages, T cells and NK cells were the most abundant immune cells in tumor microenvironment. OX40L was the only differentially expressed marker in high- and low-risk patients, as well as in patients with primary and recurrent GIST. The positive rate of OX40L in GIST was 54%. OX40L was highly expressed in patients with no metastasis, low mitotic index and relapse risk. The amount of CD68 + macrophages was the independent factor of OX40L expression. The OX40L expression was positively correlated with M2 and resting mast cells. OX40L co-located with CD4 + T cells, M2 and activated mast cells. Patients with high OX40L levels experienced more prolonged relapse-free survival (RFS). CONCLUSIONS: We first reported that GIST cells could express OX40L, patients with high OX40L experienced longer RFS. The colocalization of OX40L with immune cells indicates that OX40L could be a promising potential target for immunotherapy in GIST.

Quantitative proteomics analysis revealed the potential role of lncRNA Ftx in cardiomyocytes.

OBJECTIVE: This study aims to decode the proteomic signature of cardiomyocytes in response to lncRNA Ftx knockdown and overexpression via proteomic analysis, and to study the biological role of lncRNA Ftx in cardiomyocytes.  METHODS: The expression level of the lncRNA Ftx in cardiomyocytes cultured in vitro was intervened, and the changes in protein levels in cardiomyocytes were quantitatively detected by liquid chromatography-mass spectrometry. The key molecules and pathways of the lncRNA-Ftx response were further examined by GO, KEGG, and protein interaction analysis. RESULTS: A total of 2828 proteins are quantified. With a 1.5-fold change threshold, 32 upregulated proteins and 49 downregulated proteins are identified in the lncRNA Ftx overexpression group, while 67 up-regulated proteins and 54 down-regulated proteins are identified in the lncRNA Ftx knockdown group. Functional clustering analysis of differential genes revealed that the lncRNA Ftx is involved in regulating cardiomyocyte apoptosis and ferroptosis and improving cellular energy metabolism. In addition, Hub genes such as ITGB1, HMGA2, STAT3, GSS, and LPCAT3 are regulated downstream by lncRNA Ftx. CONCLUSION: This study demonstrates that lncRNA Ftx plays a vital role in cardiomyocytes and may be involved in the occurrence and development of various myocardial diseases. It provides a potential target for clinical protection of the myocardium and reversal of myocardial fibrosis.

Insufficient evidence to link human exposure to heavy metals with biomarkers of glioma.

Information on molecular mechanisms has implicated potential association between the concentrations of heavy metals and incidences of glioma, but experimental data on human brain tissue remain sparse. To address this data gap, 13 heavy metals were measured in 137 glioma and 35 non-glioma samples collected from 161 alive patients in Guangdong Province, China in 2019 - 2020. All target heavy metals were detected, suggesting they could cross the blood-brain barrier. Concentrations of Mn, Cu, and Zn were higher in glioma than in non-glioma samples, while those of Ni and Se were higher in non-glioma samples, probably suggesting that these five heavy metals are more prone to be altered by changing pathological conditions. In addition, Cu/Zn, Cr/Mn, Cr/Se, Ni/Se, Pb/Mn, and Pb/Se were statistically different between glioma and non-glioma samples by a difference test and a multiple logistic regression model. These concentration ratios may serve as chemical markers to assist pathological analysis for differentiating between tumor and healthy tissues. However, no direct link between heavy metal concentrations or concentration ratios and biomarkers of glioma (i.e., tumor grade, P53, and Ki-67) was observed. No sufficient evidence was obtained to implicate the role of heavy metals in inducing glioma, largely caused by the limited number of samples. Different concentrations and concentration ratios of heavy metals may be the consequence rather than the cause of pathological changes in brain tumors.

Predicted health and environmental hazards of liquid crystal materials via quantitative structure-property relationship modeling.

Liquid crystal materials (LCMs) are considered as emerging contaminants with high persistent and bioaccumulative potentials, but their toxicological effects are not well understood. To address this issue, a list of 1431 LCMs commercially available in the market was established through literature reviews and surveys of LCM suppliers. Toxicological properties of 221 target LCMs were derived from the Classification and Labeling Inventory by the European Chemicals Agency. More than 80 % of target LCMs likely pose adverse effects on human health or aquatic ecosystems. Two quantitative structure-property relationship (QSPR) models developed from the toxicological properties of LCMs achieved approximately 90 % accuracy in external data sets. The probability-based approach was more efficient in defining the applicability domain for the QSPR models than a range- or distance-based approach. The highest accuracy was achieved for chemicals within the probability-based applicability domain. The QSPR models were applied to predict health and environmental hazards of 1210 LCMs that had not been notified to the Classification and Labeling Inventory, and 301 and 94 LCMs were recognized as posing potential hazards to human health and the environment, respectively. The present study highlights the potential detrimental effects of LCMs and offers a specific in silico technique for screening hazardous LCMs.

Glioma is associated with exposure to legacy and alternative per- and polyfluoroalkyl substances.

Data on the occurrences of legacy and alternative per- and polyfluoroalkyl substances (PFASs) in glioma are scarce. It remains unclear if PFASs exposure is related to the prevalence of glioma. A total of 137 glioma and 40 non-glioma brain tissue samples from patients recruited from the Nanfang Hospital, South China were analyzed for 17 PFAS compounds. Perfluorohexanoic acid, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorooctane sulfonamide (FOSA), and 6:2 chlorinated polyfluorinated ether sulfonate were frequently detected (> 60 %) in glioma. The total concentrations (range; median) of 17 PFASs in glioma (0.20-140; 3.1 ng g-1) were slightly higher than those in non-glioma (0.35-32; 2.2 ng g-1), but without statistical significance. The PFAS concentrations in males were statistically higher (p < 0.05) than those in females. Elevated glioma grades were associated with higher concentrations of PFOA, PFOS, and FOSA. Positive correlations were observed between PFAS concentrations (especially for PFOA) and Ki-67 or P53 expression, pathological molecular markers of glioma. Our findings suggested that exposure to PFASs might increase the probability to develop glioma. This is the first case study demonstrating associations between PFASs exposure and brain cancer. More evidences and potential pathogenic mechanisms warranted further investigations.

RNA m5C regulator-mediated modification patterns and the cross-talk between tumor microenvironment infiltration in gastric cancer.

The effect of immunotherapy strategy has been affirmed in the treatment of various tumors. Nevertheless, the latent role of RNA 5-methylcytosine (m5C) modification in gastric cancer (GC) tumor microenvironment (TME) cell infiltration is still unclear. We systematically explore the m5C modification patterns of 2,122 GC patients from GEO and TCGA databases by 16 m5C regulators and related these patterns to TME characteristics. LASSO Cox regression was employed to construct the m5Cscore based on the expression of regulators and DEGs, which was used to evaluate the prognosis. All the GC patients were divided into three m5C modification clusters with distinct gene expression characteristics and TME patterns. GSVA, ssGSEA, and TME cell infiltration analysis showed that m5C clusters A, B, and C were classified as immune-desert, immune-inflamed, and immune-excluded phenotype, respectively. The m5Cscore system based on the expression of eight genes could effectively predict the prognosis of individual GC patients, with AUC 0.766. Patients with a lower m5Cscore were characterized by the activation of immunity and experienced significantly longer PFS and OS. Our study demonstrated the non-negligible role of m5C modification in the development of TME complexity and inhomogeneity. Assessing the m5C modification pattern for individual GC patients will help recognize the infiltration characterization and guide more effective immunotherapy treatment.

Clinicopathological and therapeutic analysis of PDGFRA mutated gastrointestinal stromal tumor.

BACKGROUND: Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutation has causes a rare subgroup of gastrointestinal stromal tumor (GIST) and not too much attention has been paid on it until the appearance of Avapritinib. This study aims to explore the clinicopathological features, therapy and prognosis of PDGFRA-mutant GIST for better understanding and clinical practice. METHOD: 119 PDGFRA-mutant GIST patients were retrospectively collected from 2038 patients who underwent genetic testing. Kaplan-Meier method was used. RESULTS: The incidence rate of PDGFRA-mutant GIST in our center was 5.8 %, with 79 males, 40 females, and a median age of 57 (25⁃80) years old. All the tumors were in the stomach, among which 60 were epithelioid type, 25 were spindle type and 34 were mixed type. There were 13 cases of exon 12 mutation and 106 cases of exon 18 mutation including 83 cases of D842V mutation (69.7 %). During a median follow⁃up of 49.6 (range, 1⁃154) months, progression could be observed in 12 patients with gene mutation at the codon 842 of exon 18, another case was V561D mutation in exon 12. The 5-year diseases⁃free survival (DFS) was 90.1 %, which was associated with the loss of CD34 expression (P＜0.001). Patients in D842V group showed a marginal worse prognosis than those in non-D842V group (P = 0.163). According to the NIH criteria, high risk group showed a poorer prognosis than non-high risk group (P = 0.003), however, there were no significant differences among the three non-high risk groups (P = 0.495, P = 0.652). Among 13 advanced patients, 5 cases (treated with Avapritinib) achieved partial remission. CONCLUSION: PDGFRA-mutant GIST mostly derived from stomach, with a relative indolent behavior. D842V mutation and lose of CD34 expression were adverse prognostic factors. Avapritinib can effectively control advanced patients in a certain period of time.

Treatment of gastric cancer with dermatomyositis as the initial symptom: Two case reports and review of literature.

BACKGROUND: Dermatomyositis (DM) is a rare autoimmune disease involving the connective tissue. The association between DM and gastric cancer remains unclear. Patients with DM have an increased risk of cancer and higher mortality. It requires immunosuppressive therapy, heightened surveillance, and immunologic response to internal malignancy. CASE SUMMARY: Two cases of gastric cancer with DM as the first symptom in Zhongshan Hospital, Fudan University (Shanghai, China) were reported. Two patients had a typical skin rash. The rash in the first patient involved mainly bilateral upper limbs and neck, while the second patient manifested rash associated mainly with the face, neck, and back. Both manifested muscle weakness in the extremities and elevated serum creatine kinase. Radical resection of the tumor dramatically improved DM-related symptoms in the two patients. The literature review showed that gastric cancer is more commonly associated with DM in middle-aged and older male populations. CONCLUSION: The findings suggest the need for comprehensive screening for malignant tumors in patients with DM refractory to long-term pharmacotherapy or hormone manipulation.

THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are characterized by activating mutations of c-KIT or PDGFRa receptor tyrosine kinases (RTKs). Despite the clinical success of tyrosine kinase inhibitors (TKIs), more than half of GIST patients develop resistance due to a second mutation. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of CDK-activating kinase (CAK), and it plays an important role in the regulation of cell cycle transitions and gene transcription. THZ1, a CDK7 inhibitor, exhibits a dose-dependent inhibitory effect in various cancers. METHODS: Data from the public GEO database and tissue microarray were used to analyse the gene expression levels of CDKs in GISTs. The impact of CDK7 knockdown and the CDK7 inhibitor THZ1 on GIST progression was investigated in vitro using CCK-8, colony formation, and flow cytometry assays and in vivo using a xenograft mouse model. RNA sequencing was performed to investigate the mechanism of GIST cell viability impairment mediated by THZ1 treatment. RESULTS: Our study demonstrated that CDK7 is relatively overexpressed in high-risk GISTs and predicts a poor outcome. A low concentration of THZ1 exhibited a pronounced antineoplastic effect in GIST cells in vivo and in vitro. Moreover, THZ1 exerted synergistic anticancer effects with imatinib. THZ1 treatment resulted in transcriptional modulation by inhibiting the phosphorylation of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII). c-KIT, an oncogene driver of GIST, was transcriptionally repressed by THZ1 treatment or CDK7 knockdown. Transcriptome sequencing analysis showed that OSR1 acts as a downstream target of CDK7 and regulates c-KIT expression. Taken together, our results highlight elevated CDK7 expression as a predictor of poor outcome in GIST and present the combination of CDK7 and RTK inhibitors as a potent therapeutic strategy to improve the efficacy of GIST treatment. Video abstract.