Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3ß.

BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.

HIF-1A as a prognostic biomarker related to invasion, migration and immunosuppression of cervical cancer.

Background: The incidence of cervical cancer ranks second among malignant tumors in women, exerting a significant impact on their quality of life and overall well-being. The hypoxic microenvironment plays a pivotal role in the initiation and progression of tumorigenesis. The present study aims to investigate the fundamental genes and pathways associated with the hypoxia-inducible factor (HIF-1A) in cervical cancer, aiming to identify potential downstream targets for diagnostic and therapeutic purposes. Methods: We obtained dataset GSE63514 from the Comprehensive Gene Expression Database (GEO). The dataset comprised of 24 patients in the normal group and 28 patients in the tumor group. Gene set difference analysis (GSVA) and gene set enrichment analysis (GSEA) were used to identify the genes related to HIF-1A expression and the specific signaling pathways involved.The association between HIF-1A and tumor immune infiltration was examined in the TCGA dataset. The WGCAN network was constructed to identify key genes within the blue module, and subsequent gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to determine the pathways and functional annotations associated with HIF-1A. The protein interaction network of the HIF-1A gene was obtained from the STRING database and visualized using Cytoscape in the meantime.The function of HIF-1A and its related gene expression were verified in vivo. Results: HIF-1A was a risk factor in both univariate and multivariate Cox regression analysis of cervical cancer patients. A total of 344 genes significantly correlated with the expression of HIF-1A were identified through correlation analysis, and the genes exhibiting the strongest correlation were obtained. The major signaling pathways involved in HIF-1A encompass TNF-α/NF-κB, PI3K/AKT/MTOR, TGF-ß, JAK-STAT, and various other signaling cascades. Reinforced by qRT-PCR, we identified Integrin beta-1 (ITGB1), C-C motif chemokine ligand 2 (CCL2), striatin 3 (STRN3), and endothelin-1 (EDN1) as pivotal downstream genes influenced by HIF-1A. HIF-1A is associated with immune infiltration of natural killer (NK) cells, mast cells, CD4+T cells, M0 macrophages, neutrophils, follicular helper T cells, CD8+T cells, and regulatory T cells (Treg). HIF-1A is associated with sensitivity to chemotherapy drugs. The identification of the HIF-1A pathway and its function primarily focuses on cytoplasmic translation, aerobic respiration, cellular respiration, oxidative phosphorylation, thermogenesis, among others. The results of in vivo experiments have confirmed that HIF-1A plays a crucial role in promoting the migration and invasion of cervical cancer cells. Moreover, the overexpression of HIF-1A led to an upregulation in the expressions of ITGB1, CCL2, STRN3, and EDN1. Conclusions: The role of HIF-1A in cervical cancer was determined through a combination of bioinformatics analysis and experimental validation. The genes potentially implicated in the tumorigenesis mechanism of HIF-1A were identified. These findings has the potential to enhance our comprehension of the progression of cervical cancer and offer promising therapeutic targets for its clinical management.

Dysfunction of Akt/FoxO3a/Atg7 regulatory loop magnifies obesity-regulated muscular mass decline.

BACKGROUND: Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of Atg7 gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity remain uncertain. The study aimed to elucidate the role and underly mechanism of Atg7 action in the context of obesity-induced muscle mass decline. METHODS: In this study, we established a murine model of high-fat diet-induced obesity (DIO) and introduced adeno-associated virus delivery of short hairpin RNA to knock down Atg7 (shAtg7) into the gastrocnemius muscle. We then examined the expressions of Atg7 and myoprotein degradation markers in the gastrocnemius tissues of obese patients and mice using immunofluorescence and western blotting techniques. To further investigate the effects of Atg7, we assessed skeletal muscle cell diameter and the myoprotein degradation pathway in C2C12 and HSkMC cells in the presence or absence of Atg7. Immunofluorescence staining for MyHC and western blotting were utilized for this purpose. To understand the transcriptional regulation of Atg7 in response to myoprotein degradation, we conducted luciferase reporter assays and chromatin immunoprecipitation experiments to examine whether FoxO3a enhances the transcription of Atg7. Moreover, we explored the role of Akt in Atg7-mediated regulation and its relevance to obesity-induced muscle mass decline. This was accomplished by Akt knockdown, treatment with MK2206, and GST pulldown assays to assess the interaction between Atg7 and Akt. RESULTS: After 20 weeks of being on a high-fat diet, obesity was induced, leading to a significant decrease in the gastrocnemius muscle area and a decline in muscle performance. This was accompanied by a notable increase in Atg7 protein expression (p < 0.01). Similarly, in gastrocnemius tissues of obese patients when compared to nonobese individuals, there was a significant increase in both Atg7 (p < 0.01) and TRIM63 (p < 0.01) levels. When palmitic acid was administered to C2C12 cells, it resulted in increased Atg7 (p < 0.01), LC3Ⅱ/Ⅰ (p < 0.01), and p62 levels (p < 0.01). Additionally, it promoted FoxO3a-mediated transcription of Atg7. The knockdown of Atg7 in the gastrocnemius partially reversed DIO-induced muscle mass decline. Furthermore, when Atg7 was knocked down in C2C12 and HSkMC cells, it mitigated palmitic acid-induced insulin resistance, increased the p-Akt/Akt ratio (p < 0.01), and reduced TRIM63 (p < 0.01). Muscular atrophy mediated by Atg7 was reversed by genetic knockdown of Akt and treatment with the p-Akt inhibitor MK2206. Palmitic acid administration increased the binding between Atg7 and Akt (p < 0.01) while weakening the binding of PDK1 (p < 0.01) and PDK2 (p < 0.01) to Akt. GST pulldown assays demonstrated that Atg7 directly interacted with the C-terminal domain of Akt. CONCLUSION: The consumption of a high-fat diet, along with lipid-induced effects, led to the inhibition of Akt signaling, which, in turn, promoted FoxO3a-mediated transcription, increasing Atg7 levels in muscle cells. The excess Atg7 inhibited the phosphorylation of Akt, leading to a cyclic activation of FoxO3a and exacerbating the decline in muscle mass regulated by obesity. Consequently, Atg7 serves as a regulatory point in determining the decline in muscle mass induced by obesity.

MicroRNA-152 specifically targets kinesin family member 14 to suppress the advancement of bladder cancer cells via PI3K/AKT pathway.

BACKGROUND: Kinesin family member 14 (KIF14) overexpression has been linked to tumor progression and metastasis in different malignancies, but its precise molecular mechanism in bladder cancer (BLCA) remains unclear. METHODS: The expression of KIF14 in BLCA and its relationship with clinical outcomes were assessed. Functional investigations on KIF14 were conducted using CCK-8, Transwell experiment, colony formation, scratch motility assays, and flow cytometry. We examined the downstream route of KIF14 and identified its upstream regulatory factor through luciferase reporter experiments and bioinformatics tools. RESULTS: Our findings demonstrated that increased KIF14 expression was associated with poor survival prognosis in BLCA patients. Deletion of KIF14 affected cell cycle progression, induced apoptosis, and inhibited cell growth, migration, and invasion. GSEA analysis revealed a strong association between KIF14 expression and the PI3K/AKT signaling pathway. Further research showed that KIF14 deletion decreased the levels of p-PI3K, p-AKT, FOXM1, and CCNB1. We also found that has-miR-152-3p (miR-152) suppressed BLCA cell growth by post-transcriptionally regulating KIF14 expression. CONCLUSIONS: Our findings suggest that targeting KIF14 could alter the PI3K/AKT and FOXM1-CCNB1 axis, leading to growth inhibition, cell cycle arrest, and induction of apoptosis in BLCA cells. Additionally, miR-152 directly regulates KIF14 expression at the post-transcriptional level. Overall, KIF14 represents a promising therapeutic target for BLCA clinical therapy.

Combined influence of nutritional and inflammatory status and depressive symptoms on mortality among US cancer survivors: Findings from the NHANES.

BACKGROUND: Inflammation and nutrition and depression are interrelated, and both are related to changes in mortality rates. We investigated the association of nutritional and inflammation index or depressive symptoms with the risk of all-cause mortality or cause-specific mortality among cancer survivors. METHODS: A prospective cohort of a nationally representative sample of cancer survivors, aged 40 years or older (n = 2331; weighted population, 15 248 255; 67.6 ± 11.0 years; 50.6 % males), were recruited from the US National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Advanced lung cancer inflammation index (ALI) reflected inflammation and nutritional status and Patient Health Questionnaire 9 (PHQ-9) demonstrated depressive symptoms. The independent and joint associations of ALI and PHQ-9 score with mortality outcomes were examined among cancer survivors and Cox regression analysis based on weights was used to calculate the relative risk. RESULTS: We identified 605 all-cause deaths (cancer, 204; non-cancer, 401) over a median of 6.2 years of follow-up (15,385 person-years; interquartile range, 3.3-9.8 years). High ALI was observed to be consistently associated with lower risks of all-cause (hazard ratio [HR], 0.516; 95 % CI, 0.400-0.667) and non-cancer (HR, 0.414; 95 % CI, 0.291-0.588) mortality compared with low ALI in a series of adjusted models. Meanwhile, lower PHQ-9 score (0-4) was associated with lower risks of all-cause (HR, 0.686; 95 % CI, 0.521-0.903) and non-cancer (HR, 0.686; 95 % CI, 0.474-0.992) mortality compared with higher PHQ-9 score (≥10). Furthermore, joint analyses showed that high ALI was associated with a decreased risk of death among cancer survivors who were not depressive. Specifically, survivors with high ALI but not depressive symptoms had the lowest overall (HR, 0.404; 95 % CI, 0.228-0.715) risks. CONCLUSION: In this cohort study, we observed impact of nutritional and inflammatory status and depressive symptoms on mortality among cancer survivors, with the lowest risks of death from both all causes and non-cancer being noted among the combination of high level ALI with no depression.

Proscillaridin A inhibits lung cancer cell growth and motility through downregulation of the EGFR-Src-associated pathway.

First-generation tyrosine kinase inhibitors (TKIs) have been associated with good responses in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations. However, this therapeutic strategy inevitably promotes resistance to TKIs. This study aimed to investigate the functional role and mechanism of proscillaridin A in NSCLC with or without EGFR mutations. Cellular function assays showed that proscillaridin A could inhibit cell proliferation, migration and invasion in vitro independent of EGFR mutation status. Real-time PCR of the human chromosome 17 α-satellite region revealed that proscillaridin A significantly suppressed tumour micrometastasis in vivo. In immunofluorescence experiments, we found that proscillaridin A decreased filopodia length in NSCLC cells. Furthermore, proscillaridin A also downregulated EGFR-Src-mediated cytoskeleton-related pathways, including FAK-paxillin signalling, which has been shown to promote cell filopodia formation by regulating small G-proteins. Therefore, we used the GST-PBD pull-down assay to demonstrate that proscillaridin A could decrease Cdc42 activity. Moreover, survival analyses of 591 lung adenocarcinoma patients from the GEO database indicated that the expression levels of Src and paxillin and the risk score of the gene signature based on these two factors were negatively correlated with overall survival and could be used as independent prognostic factors. In conclusion, we speculate that proscillaridin A inhibits lung cancer cell growth and motility by regulating EGFR-Src-associated pathways.

Association between intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid (n-3 PUFA DHA) and reduced risk of ovarian cancer: A systematic Mendelian Randomization study.

BACKGROUND & AIMS: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. METHODS: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. RESULTS: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. CONCLUSION: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.

Knockdown of kinesin family member 4A inhibits cell proliferation, migration, and invasion while promoting apoptosis of urothelial bladder carcinoma cells.

BACKGROUND: Kinesin family member 4A (KIF4A) is upregulated in a variety of cancers. However, its expression and potential downstream targets in urothelial bladder carcinoma (UBC) remain unclear. METHODS: Expression data of KIF4A in UBC and noncancerous tissues were downloaded from the GEPIA database. Cell proliferation, migration, invasion, and apoptosis of T24 and 5637 UBC cells were examined using wound healing, transwell, colony formation, CCK-8, and flow cytometry assays. KIF4A and potential downstream genes were analyzed using qRT-PCR, western blot analysis, and immunohistochemistry. RESULTS: In UBC samples, KIF4A expression was significantly higher than in corresponding noncancerous samples. UBC patients with high KIF4A expression had poor cancer-specific survival and overall survival. Knockdown of KIF4A significantly inhibited proliferation and promoted apoptosis of UBC cells, accompanied by dephosphorylation of AKT and increased the protein level of proapoptotic factors. Additionally, knockdown of KIF4A reduced migration and invasion of UBC cells whereas overexpression of KIF4A exhibited opposite effects, along with altered protein level in epithelial-mesenchymal transition-related genes. Furthermore, overexpression of YAP1 promoted KIF4A expression whereas knockdown of YAP1 suppressed KIF4A expression in UBC cells. Alternatively, KIF4A knockdown reduced YAP1 nuclear protein level whereas KIF4A overexpression suppressed YAP1 phosphorylation and facilitated YAP1 nuclear translocation. CONCLUSIONS: KIF4A upregulation correlates with poor prognosis of UBC. Knockdown of KIF4A inhibits proliferation, migration, and invasion of UBC cells while inducing apoptosis possibly through dephosphorylation of AKT, changes in EMT-related genes, and interaction with YAP1.

Insight into the causality between basal metabolic rate and endometrial and ovarian cancers: Analysis utilizing systematic Mendelian randomization and genetic association data from over 331,000 UK biobank participants.

BACKGROUND: Observational studies have demonstrated that basal metabolic rate (BMR) is associated with the risk of endometrial cancer (EC) and ovarian cancer (OC). However, it is unclear whether these associations reflect a causal relationship. OBJECTIVE: To reveal the causality between BMR and EC and OC, we performed the first comprehensive two-sample Mendelian randomization (MR) analyses. METHODS: Genetic variants were used as proxies of BMR. GWAS summary statistics of BMR, EC and OC were obtained from the UK Biobank Consortium, Endometrial Cancer Association Consortium and Ovarian Cancer Association Consortium respectively. The inverse variance weighted method was employed as the main approach for MR analysis. A series of sensitivity analyses were implemented to validate the robustness and reliability of the results. RESULTS: BMR was significantly related to an increased risk of EC (ORSD  = 1.49; 95% CI: 1.29-1.72; p-Value < .001) and OC (ORSD  = 1.21; 95% CI: 1.08-1.35; p-Value < .001). Furthermore, the stratified analysis indicated that BMR was positively associated with endometrioid endometrial cancer (EEC) (ORSD  = 1.45; 95% CI, 1.23-1.70; p-Value < .001), clear cell ovarian cancer(CCOC) (ORSD  = 1.89; 95% CI:1.35-2.64; p-Value < .001) and endometrioid ovarian cancer risk (EOC) (ORSD  = 1.45; 95% CI: 1.12-1.88; p-Value = .005). However, there were no significant associations of BMR with invasive mucinous ovarian cancer (IMOC), high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC). The robustness of the above results was further verified in sensitivity analyses. CONCLUSION: The MR study provided etiological evidence for the positive association of BMR with the risk of EC, EEC, OC, CCOC and EOC. But this study did not provide enough evidence suggesting the causal associations of BMR with IMOC, HGSOC and LGSOC.

Pain Incidence and Associated Risk Factors among Cancer Patients within 72 Hours after Surgery: A Large Retrospective Analysis.

BACKGROUND: A fundamental principle of pain management is to determine the distribution and causes of pain. However, relevant data among postoperative cancer patients based on a large amount of data remain sparse. OBJECTIVE: We aimed to investigate the incidence of postoperative pain in cancer patients and to explore the associated risk factors. METHODS: We retrospectively collected information on postoperative pain-evaluation records of cancer patients who underwent surgery between 1 January 2014 and 31 December 2019. Descriptive statistics were presented, and multinominal logistic regression analysis was performed to explore the risk factors associated with postoperative pain. RESULTS: Among the 11,383 patients included in the study, the incidence of mild/moderate to severe pain at the 24th hour after surgery was 74.9% and 18.3%, respectively. At the 48th and 72nd hour after surgery, the incidence of mild pain increased slightly, while the incidence of moderate to severe pain continued to decrease. Female patients experienced a higher risk of pain (ORs: 1.37-1.58). Undergoing endoscopic surgery was associated with a higher risk of pain (ORs: 1.40-1.56). Patients with surgical sites located in the respiratory system had a higher risk of pain compared to in the digestive system (ORs: 1.35-2.13), and other patients had a relatively lower risk of pain (ORs: 0.11-0.61). CONCLUSION: The majority of cancer patients experienced varying degrees of postoperative pain but may not receive adequate attention and timely treatment. Female, young age and endoscopic surgery were associated with increased pain risk, and effective identification of these high-risk groups had positive implications for enhanced postoperative pain management.

Identification and quantitation of the novel insecticide sulfoxaflor and its metabolites in floral nectar from Salvia splendens Ker Gawl. (Lamiaceae).

Sulfoxaflor is a new systemic insecticide developed as a replacement for older neonicotinoids which are known to be toxic to pollinators. However, its metabolism in nectar and effect on nectar biosynthesis have not been investigated. After soil and foliar application, sulfoxaflor and its main metabolites in soil, leaf and Salvia splendens nectar, were measured by liquid chromatography coupled with triple quadrupole mass spectrometer (LC-MS/MS). The chemical composition between the clean and sulfoxaflor spiked nectar were also compared. The activities of two possible sulfoxaflor detoxifying enzymes in S. splendens nectar, nitrile hydratase and glutathione-s-transferase, were measured by LC-MS and spectrophotometry. S. splendens nectar proteome was investigated by high-resolution orbitrap-based MS/MS to screen for sulfoxaflor detoxifying relevant proteins. S. splendens could absorb sulfoxaflor through root or leaf surface and secrete a proportion of sulfoxaflor along with its metabolites into the nectar. After soil application, sulfoxaflor's low toxic metabolite X11719474 was dominant in the nectar and reached an average concentration of 8905 ppb. However, after foliar application, sulfoxaflor was dominant over its metabolites in the nectar. S. splendens nectar has no nitrile hydratase and glutathione-s-transferase activity and none of the 106 proteins identified in the nectar were predicted to function in detoxifying sulfoxaflor. Soil and foliar sulfoxaflor application can result in different profiles of sulfoxaflor and its metabolites presented in the nectar. However, sulfoxaflor had no effects on S. splendens nectar secretion and chemical composition and cannot be directly detoxified by components in the nectar.

Synergism between the metabolic syndrome components and cancer incidence: results from a prospective nested case-control study based on the China Health and Retirement Longitudinal Study (CHARLS).

OBJECTIVES: Synergism between the metabolic syndrome (MetSyn) components and cancer incidence still remains inconclusive. We aimed to investigate the unique or joint role of MetSyn components in cancer onset. DESIGN: We conducted a prospective nested case-control study based on the China Health and Retirement Longitudinal Study. SETTING: An ongoing national representative longitudinal study included follow-up survey of people aged 45 years and older and their partners living in private households in China. PARTICIPANTS: There were 17 708 individuals included at baseline. A total of 306 incident cancers was identified during the follow-up. For every case, we used incidence-density sampling to match three concurrent cancer-free controls by age, sex, and both duration and calendar time of follow-up. Exposure of interest was any MetSyn diagnosis at baseline. RESULTS: We observed elevation in cancer risk associated with MetSyn in a significant way when the number of MetSyn components was over three (OR: 1.88; 95% CI: 1.19 to 2.97), or when components contained any of elevated triglycerides (OR: 1.61; 95% CI: 1.05 to 2.48), reduced high-density lipoprotein (HDL) cholesterol (OR: 2.33; 95% CI: 1.40 to 3.86) or elevated blood pressure (OR: 1.65; 95% CI: 1.04 to 2.59) after consistent multiple adjustments in different models. The highest cancer risk was in the female reproductive system and breast cancer (OR: 4.22; 95% CI: 1.62 to 10.95) followed by digestive system (OR: 1.67; 95% CI: 1.11 to 2.53). Sensitivity analyses showed similar results after first follow-up was excluded. However, any unique MetSyn component was not associated with increased cancer risk. Interestingly, the reduced HDL was observed to be widely associated with over twofold increased risk of cancer, only when together with other MetSyn components. CONCLUSION: MetSyn components, in a collaborative manner rather than its unique component, were associated with elevated cancer risk. Not only obesity but even subtle metabolic disturbances may give rise to cancer.

Comparing Long-Term Survival Outcomes for Muscle-Invasive Bladder Cancer Patients Who Underwent with Radical Cystectomy and Bladder-Sparing Trimodality Therapy: A Multicentre Cohort Analysis.

Background: Although radical cystectomy (RC) is the clinical practice guideline-recommended treatment of muscle-invasive bladder cancer (MIBC), bladder-sparing trimodality therapy (TMT) has emerged as a valid treatment option. Findings comparing the survival outcomes for MIBC patients who underwent RC and TMT are inconclusive. Objective: We designed a large hospital-based multicohort study to compare the effectiveness of TMT with RC. Methods: Information on deaths was jointly retrieved from EMR (electronic medical record), cause of death registry, and chronic disease surveillance as well as study-specific questionnaire. To avoid the systematical difference between patients who received two modalities, RC-MIBC cohort was propensity score-matched to TMT-MIBC cohort, and the Cox proportional hazard regression was used to calculate the overall survival (OS) and disease-specific survival (DSS). Results: There were 891 MIBC patients treated with RC and another 891 MIBC patients who underwent with TMT in the propensity score matching. Comparable effectiveness between two modalities was observed for DSS (HR, 1.20; 95% confidence interval (CI), 0.94 to 1.49) and OS (HR, 1.17; 95% CI, 0.91 to 1.43) according to multiple adjustment after a median follow-up of approximately 9.3 years. However, a relatively higher mortality rate around 5 years after TMT treatment was found compared to RC (HR, 1.26; 95% CI, 1.01 to 1.53). The respective 5-year OS rates were 69% and 73% for TMT cohort and RC cohort, respectively. Conclusions: Our findings supported that MIBC patients with TMT yielded survival outcomes comparable to MIBC patients who underwent RC overall. Treatment options should be suggested considering patients' age and willingness.

Hormone replacement therapy in relation to the risk of colorectal cancer in women by BMI: a multicentre study with propensity score matching.

BACKGROUND: Epidemiological evidence about hormone replacement therapy and colorectal carcinogenesis by demographic and clinical traits remains unclear. We aimed to assess this postulated association in a large multicentre study and further explore the modification effect by BMI and others. METHODS: We retrospectively collected records of women diagnosed with colorectal cancer (CRC) at the age of 50 years and older during 2014-2017 and their HRT dispensing prior to CRC diagnosis in three tertiary hospitals in China. CRC cases were matched with controls at a ratio of 1:3 using nearest neighbour propensity scores matching to better control for the remaining imbalance between groups, which generated a total of 824 cases with 2472 controls. RESULTS: Our study confirmed the inversed association between colorectal cancer risk and hormone replacement therapy (OR, 0.62; 95% CI, 0.54-0.75), which was more prominent among women having multiple HRT dispenses (OR, 0.60; 95% CI, 0.52-0.76). Furthermore, significant associations were consistently observed for the short-term (OR, 0.69; 95% CI, 0.57-0.88), middle-term (OR, 0.51; 95% CI, 0.41-0.66), and long-term HRT users (OR, 0.70; 95% CI, 0.43-0.90). Estrogen-related regimen reduced CRC risk more than progestogen-only. We, for the first time, found that the modifying effect of BMI on HRT use and CRC risk was in different ways when BMI was categorized by a medium level of 27. CONCLUSION: Our findings mainly suggest that there might be a different mechanism for the reversed association between HRT and colorectal tumorigenesis by BMI level, providing thoughts on clinical treatment of CRC.

The effects of mechanical insufflation-exsufflation on lung function and complications in cardiac surgery patients: a pilot study.

BACKGROUND: Postoperative positive pressure lung expansion is associated with decreased pulmonary complications and improved clinical outcomes. The aim of the present study was to compare the differences in post-operative pulmonary complications and clinical outcomes between two groups of study subjects who underwent cardiac surgery; one included subjects who received mechanical insufflation-exsufflation (MI-E) and the other included subjects who received intermittent positive pressure breathing (IPPB) therapy. METHODS: This retrospective study included 51 subjects, who underwent cardiac surgery in an intensive care unit of a tertiary hospital during the time period from June 2017 to February 2018. After liberation from mechanical ventilation, the subjects received lung expansion therapy by means of two types of positive pressure devices, MI-E (n = 21) or IPPB (n = 30). The pulmonary complications, lung function, and clinical outcomes were compared between the two groups. RESULTS: Subjects in both groups displayed similar baseline characteristics and underwent similar types of surgical procedures. Compared to subjects who received non-oscillatory therapy, those who received MI-E therapy had higher post-operative force vital capacity (58.4 ± 4.74% vs. 46.0 ± 3.70%, p = 0.042), forced expiratory volume in one second (62.4 ± 5.23% vs. 46.8 ± 3.83%, p = 0.017), and peak flow rate (67.1 ± 5.53 L vs. 55.7 ± 4.44 L p = 0.111). However, the incidence of chest pain was higher in the MI-E group (n = 13, 61.9%) than in the IPPB group (n = 4, 16.7%; odds ratio, 0.123, 95% confidence interval, 0.03-0.45; p = 0.002). The length of hospital and ICU stay, development of atelectasis, pneumonia, and pleural effusion were similar in both the groups. CONCLUSION: Both IPPB and MI-E therapies have similar effects on preventing post-operative complications in cardiac surgery patients. However, compared to IPPB therapy, MI-E therapy was associated with better-preserved pulmonary function and higher incidence of chest pain.

Jaridon 6, a new diterpene from Rabdosia rubescens (Hemsl.) Hara, can display anti-gastric cancer resistance by inhibiting SIRT1 and inducing autophagy.

Tumor resistance is the main cause of treatment failure and is associated with many tumor factors. Jaridon 6, a new diterpene extracted from Rabdosia rubescens (Hemsl.) Hara, which has been previously extracted by our research team, has been tested having more obvious advantages in resistant tumor cells. However, its mechanism is unclear. In this study, we studied the effect and the specific mechanism of Jaridon 6 in resistant gastric cancer cells. Cytotoxicity test, colony test, western blotting, and nude test verified the anti-drug resistance ability of Jaridon 6 in the MGC803/PTX and MGC803/5-Fu cells. Jaridon 6 has shown obvious inhibitory effects in the sirtuin 1 (SIRT1) enzyme test. Transmission electron microscopy and immunofluorescence tests further proved the autophagic action of Jaridon 6. Jaridon 6 could inhibit the proliferation of the resistant gastric cancer cell in vivo and in vitro. Jaridon 6 inhibited SIRT1 enzyme and induced autophagy by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway. Thus, it may be considered for treating gastric cancer resistance by individual or combined administration, as an SIRT1 inhibitor and autophagy inducer.

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression.

It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

Identification of Specific Endobronchial Ultrasound Features to Differentiate Sarcoidosis From Other Causes of Lymphadenopathy.

OBJECTIVES: We hypothesized that specific endobronchial ultrasound (EBUS) features may differentiate sarcoidosis from other causes of lymphadenopathy. METHODS: We conducted this retrospective observational study from January 2014 to January 2019 to analyze patients with intrathoracic lymphadenopathy who underwent EBUS-guided transbronchial needle aspiration. Ultrasound features, including nodal size, margin, echogenicity, the presence or absence of calcification, a central hilar structure, the coagulation necrosis sign, nodal conglomeration, and the septal vessel sign in the color Doppler mode were recorded and compared between 3 groups. RESULTS: Of the 90 included patients, 15 had a diagnosis of tuberculosis; 56 had a diagnosis of sarcoidosis; and 19 had a diagnosis of malignant lymph nodes by EBUS-guided transbronchial needle aspiration. The presence of nodal conglomeration (94.6% versus 60.0% versus 5.3%; P < .001), the septal vessel sign in the color Doppler mode (55.4% versus 13.3% versus 15.8%; P = .002), and a distinct margin (73.2% versus 13.3% versus 47.4%; P < .001) were significantly higher in the sarcoidosis group than in the tuberculosis lymphadenopathy and malignant lymph node groups. The presence of the coagulation necrosis sign (8.9% versus 93.3% versus 31.6%; P < .001) was significantly lower in the sarcoidosis group than in tuberculosis lymphadenopathy and malignant lymph node groups. A multivariate analysis showed that the presence of nodal conglomeration, the absence of coagulation necrosis, and the presence of the septal vessel sign in the color Doppler mode were independent predictive factors for the diagnosis of sarcoidosis. CONCLUSIONS: The presence of nodal conglomeration, the absence of coagulation necrosis, and the presence of the septal vessel sign in the color Doppler mode in lymph nodes on EBUS are predictive of sarcoidosis.

Distinguishing lupus lymphadenitis from Kikuchi disease based on clinicopathological features and C4d immunohistochemistry.

OBJECTIVES: Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. METHODS: We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). RESULTS: Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P<10-7], and capillaries/venules [5/19 (26%) vs 7/81 (9%); P=0.048] and trabecular/hilar vessels [11/18 (61%) vs 8/81 (10%); P<10-4] in the viable area was more common in LL. During validation, both the risk stratification criteria and machine learning models were superior to conventional histological criteria. CONCLUSIONS: Integrating clinicopathological and C4d findings could distinguish LL from KD.

Risk of Death in Colorectal Cancer Patients with Multi-morbidities of Metabolic Syndrome: A Retrospective Multicohort Analysis.

PURPOSE: The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities. MATERIALS AND METHODS: We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort. RESULTS: A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis. CONCLUSION: Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.