Unveiling the unique role of TSPAN7 across tumors: a pan-cancer study incorporating retrospective clinical research and bioinformatic analysis.

BACKGROUND: TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear. METHODS: Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients' survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7. RESULTS: In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155-27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients' survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified. CONCLUSION: TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.

Ferredoxin 1: a gatekeeper in halting lung adenocarcinoma progression through activation of the GPRIN2 signaling pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly lethal form of lung cancer. Despite advancements in treatments, managing LUAD is still challenging due to its aggressive behavior. Recent studies indicate that various molecular pathways, including the dysregulation of ferredoxin 1 (FDX1), play roles in LUAD progression. FDX1, a crucial protein in cellular redox reactions and energy metabolism, has been linked to several cancers. However, its exact role in the development of LUAD is not yet fully understood. METHODS: We investigated the role of ferredoxin 1 (FDX1) in LUAD progression through analysis of its expression in LUAD tissues and its impact on patient survival. Functional assays were performed to assess the effects of FDX1 overexpression on LUAD cell proliferation, migration, and invasion. A xenograft model was employed to evaluate the tumorigenesis potential of LUAD cells with FDX1 overexpression. Mechanistic insights into FDX1 regulation were gained through depletion experiments targeting the G protein-regulated inducer of neurite outgrowth 2 (GPRIN2)/PI3K signaling pathway. RESULTS: FDX1 expression was down-regulated in LUAD tissues, correlating with shorter patient survival. Overexpression of FDX1 suppressed LUAD cell proliferation, migration, and invasion in vitro, and inhibited tumorigenesis in vivo. Mechanistically, the GPRIN2/PI3K signaling pathway was implicated in FDX1 regulation, as depletion of GPRIN2 reversed the effects of FDX1 overexpression on cellular functions. CONCLUSIONS: Our findings highlight FDX1 as a potential tumor suppressor in LUAD, acting through modulation of the GPRIN2/PI3K signaling pathway. These results suggest FDX1 as a promising therapeutic target for LUAD treatment, warranting further investigation into its clinical relevance.

Microwave ablation combined with PD-L1 blockade synergistically promotes Cxcl9-mediated antitumor immunity.

Although microwave ablation (MWA) is an important curative therapy in colorectal cancer liver metastasis, recurrence still occurs clinically. Our previous studies have shown that the expression of programmed cell death 1 ligand 1 (PD-L1) is upregulated following MWA, suggesting that MWA combined with anti-PD-L1 treatment can serve as a promising clinical therapeutic strategy against cancer. Using MWA-treated preclinical mice models, MWA combined with αPD-L1 treatment decreased tumor growth and prolonged overall survival (OS). Furthermore, through flow cytometry and single-cell RNA sequencing analysis, we determined that the MWA plus αPD-L1 therapy significantly suppressed CD8+ T cell exhaustion and enhanced their effector function. A significant increase in γ-interferon (IFN-γ) stimulated transcription factors, specifically Irf8, was observed. This enhancement facilitated the polarization of tumor-associated macrophages (TAM1s and TAM2s) through the nuclear factor-κB/JAK-STAT1 signaling pathway. Furthermore, the combination therapy stimulated the production of CXC motif chemokine ligand (CXCL9) by TAM1s and tumor cells, potentially increasing the chemotaxis of CD8 T cells and Th1 cells. Knocking out Cxcl9 in MC38 tumor cells or using CXCL9 blockade enhanced tumor growth of untreated tumors and shortened OS. Taken together, our study showed that blocking the IFN-γ-Cxcl9-CD8+ T axis promoted tumor progression and discovered a potential involvement of IRF8-regulated TAMs in preventing T cell exhaustion. Collectively, we identified that the combination of MWA with anti-PD-L1 treatment holds promise as a therapeutic strategy to rejuvenate the immune response against tumors. This merits further exploration in clinical studies.

TIGIT Blockade Reshapes the Tumor Microenvironment Based on the Single-cell RNA-Sequencing Analysis.

SUMMARY: Immune checkpoint blockade therapy is a pivotal approach in treating malignant tumors. TIGIT has emerged as a focal point of interest among the diverse targets for tumor immunotherapy. Nonetheless, there is still a lack of comprehensive understanding regarding the immune microenvironment alterations following TIGIT blockade treatment. To bridge this knowledge gap, we performed single-cell sequencing on mice both before and after the administration of anti-TIGIT therapy. Our analysis revealed that TIGIT was predominantly expressed on T cells and natural killer (NK) cells. The blockade of TIGIT exhibited inhibitory effects on Treg cells by downregulating the expression of Foxp3 and reducing the secretion of immunosuppressive cytokines. In addition, TIGIT blockade facilitated the activation of NK cells, leading to an increase in cell numbers, and promoted cDC1 maturation through the secretion of XCL1 and Flt3L. This activation, in turn, stimulated the TCR signaling of CD8 + T cells, thereby enhancing their antitumor effect. Consequently, anti-TIGIT therapy demonstrated substantial potential for cancer immunotherapy. Our research provided novel insights into future therapeutic strategies targeting TIGIT for patients with cancer.

Health insurance as a moderator in the relationship between financial toxicity and medical cost-coping behaviors: Evidence from patients with lung cancer in China.

OBJECTIVE: This study investigates the relationship between financial toxicity and medical cost-coping behaviors (MCCB) in Chinese patients with lung cancer, with a particular focus on the moderating role of health insurance. METHODS: We surveyed 218 patients with lung cancer and assessed their Comprehensive Score for Financial Toxicity (COST) and self-reported MCCB. Patients were categorized into Urban Employee's Basic Medical Insurance (UEBMI) group and Urban-Rural Resident Basic Medical Insurance Scheme (URRBMI) groups by their medical insurance, and matched for socioeconomic, demographic, and disease characteristics via propensity score. RESULTS: Significant different characteristics were noted between UEBMI patients and URRBMI patients. Patients with UEBMI had higher COST scores but lower levels of MCCB compared to URRBMI patients in the original dataset. After data matching, multivariate logit regression analysis showed that better financial toxicity was associated with lower levels of MCCB (OR = 0.95, 95% CI: 0.92-0.99). Health insurance type did not have a direct association with cost-coping behaviors, but an interaction was observed between health insurance type and financial toxicity. Among patients with URRBMI, better financial toxicity was associated with lower levels of cost-coping behaviors (OR = 0.89, 95% CI: 0.83-0.95). Patients with UEBMI had a lower probability of engaging in any cost-coping behaviors in situations of worse financial toxicity compared to patients with URRBMI. CONCLUSION: The findings suggest that financial toxicity is correlated with MCCB in Chinese patients with lung cancer. The type of health insurance, specifically UEBMI and URRBMI, plays a moderating role in this relationship. Understanding these dynamics is essential for developing targeted interventions and policies to mitigate financial toxicity and improve patients' management of medical costs.

Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

Identification of a novel stemness-related signature with appealing implications in discriminating the prognosis and therapy responses for prostate cancer.

PURPOSE: Cancer stemness represents the tumor-initiation and self-renewal potentials of cancer stem cells. It is involved in prostate cancer progression and resistance to therapy. Herein, we aimed to unveil the stemness features, establish a novel prognostic model, and identify potential therapeutic targets. METHODS: 26 stemness-related signatures were obtained from StemChecker. The expression profiles and clinical traits of TCGA-PRAD were obtained from TCGA and cBioPortal, respectively. GSE5446 and GSE70769 cohorts were acquired from GEO. PRAD_MSKCC cohort was also retrieved via the cBioPortal. The consensus clustering method was used for stemness subclusters classification. WGCNA was used to identify hub genes related to the stemness subcluster. The most important feature was explored in vitro. RESULTS: Prostate cancer patients of TCGA-PRAD were divided into two subclusters (C1 and C2) based on the enrichment scores of the 26 stemness-related signatures. C1 was characterized by decreased survival, rich infiltrations of M0 macrophages and regulatory T cells, minimum sensitivity to chemotherapy, and a low response to immunotherapy. Hub genes of the red module with the highest correlation with C1 were subsequently identified by WGCNA and subjected to stemness-related risk model construction based on the machine-learning framework. Prostate cancer patients with high stemness scores had unfavorable prognosis, immunosuppressive tumor microenvironment, minimum sensitivity to chemotherapy, and a low response to immunotherapy. MXD3, the most important factor of the model, can regulate the stemness traits of prostate cancer cells. CONCLUSIONS: Our study depicted the stemness landscapes of prostate cancer and characterized two subclusters with diverse prognoses and tumor immune microenvironments. A stemness-risk signature was developed and demonstrated prospective implications in predicting prognosis and precision medicine.

The crosstalk between anoikis and epithelial-mesenchymal transition and their synergistic roles in predicting prognosis in colon adenocarcinoma.

Anoikis and epithelial-mesenchymal transition (EMT) are significant phenomena occurring in distant metastasis of colon adenocarcinoma (COAD). A comprehensive understanding of their crosstalk and the identification of key genes are vital for treating the distant metastasis of COAD. The objective of this study was to design and validate accurate prognostic predictors for COAD patients based on the anoikis and EMT processes. We obtained gene signatures from various databases and performed univariate and multivariate Cox regression analyses, principal component analysis (PCA). The COAD patients were categorized into the worst prognosis group, the Anoikis Potential Index (API) Low + EMT Potential Index (EPI) High group and the others group. Then we utilized gene set enrichment analysis (GSEA) to identify differentially expressed genes and to establish a prognostic risk model. The model classified patients into high- or low-risk groups, with patients in the high-risk group displaying worse survival status. A nomogram was established to predict overall survival rates, demonstrating high specificity and sensitivity. Additionally, we connected the risk model to the tumor microenvironment (TME) using single-sample GSEA and the MCP counter tool, as well as evaluated the sensitivity to common chemotherapeutic drugs, such as Gefitinib and Gemcitabine. Lastly, cell and tissue experiments suggested a positive correlation among anoikis resistance, EMT, and liver/lung metastasis of COAD. This is the first study to comprehensively analyze the crosstalk between anoikis and EMT and offers new therapeutic targets for COAD metastasis patients.

Metformin improves sheep sperm cryopreservation via vitalizing the AMPK pathway.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a key regulator of sperm function and physiological metabolism. Metformin, an inexpensive and effective antioxidant, is known to play an important role in the activation of AMPK. Therefore metformin has potential to improve sperm cryopreservation. The aim of this study was to investigate the effect of metformin during semen cryopreservation of sheep and to find the most effective concentration in freezing extender. Semen were cryopreserved with extender containing different concentrations of metformin (0, 0.25, 0.5, 1.0, 2.0 and 4.0 mmol/L). Sperm motility, acrosome integrity and plasma membrane integrity were measured after semen freezing and thawing. All results showed that sperm quality was significantly increased in the 1.0 mmol/L metformin-treated group compared with the control group (P < 0.05). In addition, the study showed that metformin effectively reduced the content of malondialdehyde (MDA) and reactive oxygen species (ROS), and increased the activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and total antioxidant capacity (T-AOC) of freeze-thawed sperm (P < 0.05). The optimal concentration of metformin was 1.0 mmol/L. Moreover, the results showed that AMPK was localized in the acrosome region, junction and midsection of sperm, and p-AMPK was distributed in the post-acrosomal region, junction and midsection. Western blot analysis indicated that 1.0 mmol/L metformin stimulated the phosphorylation of AMPK in sperm. Further results showed that 1.0 mmol/L metformin significantly increased the mitochondrial membrane potential (ΔΨm), ATP content, glucose uptake and lactate efflux of post-thawed sperm through the AMPK pathway, improved sperm quality, and increased the cleavage rate of in vitro fertilization (P < 0.05).

Combining expression of RNF43 and infiltration level of CD163+ tumor associated macrophage predicts prognosis of clear cell renal cell carcinoma.

Searching for reliable indicators for evaluating prognosis diagnosed with clear cell renal cell carcinoma (ccRCC) is crucial for improving clinical therapies. However, current researches have looked mainly at the prognostic value of a single intratumoral indicator, neglecting tumor-infiltrating immune cells (TIICs) in the microenvironment. This study examined whether the integration of Ring finger protein 43 (RNF43) expression and CD163+ tumor-associated macrophage (TAM) infiltration in combination with clinical indexes forecast ccRCC patient outcome with relatively high accuracy. Firstly, the expression of RNF43 and CD163 were detected with immunohistochemistry. Totally, 346 ccRCC patients were random separated evenly into training and validation datasets to make further analyses. We found that RNF43 expression was negatively correlated with infiltration level of CD163+ TAM in ccRCC, which was closely associated with the TNM stage and outcome of these patients. The multiple regression analysis demonstrated that RNF43, CD163, and TNM stage could function as independent risk factors in overall survival (OS) and progression-free survival (PFS) prediction of ccRCC. Furthermore, a better postoperative prognosis index for ccRCC patients was obtained by combining RNF43 and CD163+ TAMs, which assessed with time-dependent C-index analyses and a nomogram. Consequently, combining RNF43 and CD163+ TAMs along with TNM stage acquired robust accuracy in forecasting outcome of patients with ccRCC. In conclusion, combining intratumoral RNF43 expression, CD163+ TAM infiltration, and TNM stage could significantly enhance the veracity in forecasting postoperative outcomes.

NGF regulates sertoli cell growth and prevents LPS-induced junction protein damage via PI3K/AKT/NFκB signaling.

Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease; however, whether and how NGF regulates Sertoli cell function remains unclear. Here, we aimed to assess the effect of NGF on the growth of Sertoli cells isolated from the testes of dairy goats and evaluate if NGF has a protective effect on these cells. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment. In addition, qPCR results suggested that Sertoli cell apoptosis was inhibited after NGF treatment. To investigate the protective effect of NGF on Sertoli cells under pathological inflammatory conditions, LPS was used to induce inflammatory response in Sertoli cells. Post-treatment, the entangled filamentous pseudopodia of the cells loosened and no longer spanned adjacent cells. The expression of several junction proteins (ZO-1, occludin, CX-43, ß-catenin, and N-cadherin), which was down-regulated after inflammatory response induction, was restored following NGF treatment. LPS-induced changes in cytotoxicity and transepithelial electrical resistance were reversed and the intercellular connections became tighter after NGF treatment. We further demonstrated that NGF prevented the inflammatory response of Sertoli cells via the PI3K/AKT/NFκB signaling pathway, similar to the effect of the PI3K-inhibitor, LY294002, which is modified by the PI3K activator, 740Y-P. These results provide insights for devising strategies for protecting the male reproductive system and curing or preventing associated pathological conditions.

Aldolase A promotes cell proliferation and cisplatin resistance via the EGFR pathway in gastric cancer.

BACKGROUND: Gastric cancer is the third leading cause of cancer-related mortality worldwide, and the 5-year survival rate remains poor, globally. Overexpression of Aldolase A (ALDOA) has been linked to tumor cell proliferation and metastasis in numerous cancer types, including pancreatic, colorectal, hepatocellular carcinoma, and lung cancer. Although the significance of ALDOA as a potential biomarker in GC prognosis has been reported, its potential role and possible mechanism of ALDOA in GC cell sensitivity to chemotherapy remains to be elucidated. METHODS: The GEPIA platform and clinical samples were used to investigate ALDOA expression in GC tumors and neighboring normal tissues. The CCK8 and colony formation tests were used to examine whether ALDOA increased GC cell proliferation and decreased resistance to the chemotherapy drug cisplatin. Furthermore, the underlying molecular mechanisms were elucidated. RESULTS: Overexpression of ADOLA was seen in GC tumors and GC cells. Prognostic markers, i.e., invasion depth, tumor size, and metastasis of lymph node were all negatively impacted by ADOLA overexpression. Following ADOLA knockdown, in vitro proliferation of AGS cells was decreased and drug resistance was reduced. Conversely, ADOLA overexpression exhibited an inverse effect in MKN45 cells. ALDOA knockdown dramatically slowed the development of GC tumors in in vivo experiments. Mechanistically, ADOLA regulated the activity of epidermal growth factor receptor (EGFR), its downstream molecue the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) signaling pathway in GC cells. Moreover, in the absence of EGFR, ALDOA overexpression had no effect on GC cell growth. CONCLUSION: In the EGFR signaling pathway, ADOLA boosted the proliferation and cisplatin resistance of GC cells, making it a viable GC therapeutic target.

LAG3 blockade coordinates with microwave ablation to promote CD8+ T cell-mediated anti-tumor immunity.

BACKGROUND: The immune checkpoint inhibitors (ICIs) combined with other therapeutic strategies have shown exciting results in various malignancies, and ICIs have now become the gold standard for current cancer treatment. In several preclinical and clinical investigations, ablation coupled with immunotherapy has proved to be quite effective. Our previous studies have shown that ablation coupled with ICI is a potential anti-cancer regimen for colorectal cancer liver metastases (CRLM). Furthermore, we have reported that following microwave ablation (MWA), the expression of LAG3 is up-regulated in tumor microenvironment (TME), indicating that LAG3 is implicated in the regulation of immunosuppressive immune response, and combination therapy of MWA and LAG3 blockade can serve as a promising therapeutic strategy against cancer. METHODS: The expression of LAG3 was investigated in this study utilizing a preclinical mouse model treated with MWA. Moreover, we monitored the tumor development and survival in mice to assess the anti-cancer effects of MWA alone or in combination with LAG3 blockade. Flow cytometry was also used to phenotype the tumor-infiltrating lymphocytes (TILs) and CD8+ T cell effector molecules. We finally analyzed the single-cell RNA sequencing (scRNA-seq) data of infiltrating CD45+ immune cells in the tumors from the MWA alone and MWA combined with LAG3 blockade groups. RESULTS: After MWA, the expression of LAG3 was up-regulated on sub-populations of TILs, and introducing LAG3 blockade to MWA postponed tumor development and extended survival in the MC38 tumor model. Flow cytometry and scRNA-seq revealed that LAG3 blockade in combination with MWA markedly boosted the proliferation and the function of CD8+ TILs, leading to altered myeloid cells in the TME. CONCLUSION: Combination therapy of LAG3 blockade and MWA was a unique therapeutic regimen for some solid tumors, and such combination therapy might reprogram the TME to an anti-tumor manner.

Impacts of price changes on public hospital reforms in China: evidence from 25 million patients at tertiary hospitals.

China's public hospital price change reform was progressively piloted at urban-level tertiary hospitals in 2015, aiming to adjust the healthcare expenditure structure, reorient public hospitals towards social objectives and control inflated healthcare expenditure. This study investigates the impacts of price changes on inpatient expenditure, service quantity, quality and efficiency and whether the impacts varied in different specialities, treatments and hospitals. A difference-in-differences analysis was conducted using data from 25 million patients from 124 nationally representative tertiary hospitals between 2013 and 2018. The study analyses changes in total expenditure, drug, medical services and diagnostic test/medical consumables expenditure per admission, the use of antibiotics, performed surgery, readmission within 30 days and length of stay (LOS). These factors are examined before and after adjusting the price changes for demographic, socioeconomic and clinical covariates. The price changes decreased drug expenditure per admission (-13.5%, P < 0.001, USD 96.6) and increased medical services expenditure per admission (30.9%, P < 0.001, USD 153.3). They also reduced the LOS (-1.2%, P = 0.019, 0.1 days) while not significantly affecting total expenditure per admission, diagnostic test/medical consumables per admission and the use of antibiotics, surgery performed and readmission rates. In heterogeneity analysis, price changes reform increased efficiency in major diagnostic categories (MDCs) with high drug share and improved quality in nonoperating room surgical groups and hospitals with high drug share; however, it increased total expenditure in MDCs with low drug share or surgical groups. China's public hospital price change reform generally adjusted the inpatient expenditure structure and reduced the LOS in tertiary public hospitals. Sufficient compensation from medical services and government subsidies that minimize the income effects may be the key to the success of price change reform.

The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma.

BACKGROUND: As an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined. METHODS: Immunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model. RESULTS: We found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion. CONCLUSION: Our study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.

Prenatal di-(2-ethylhexyl) phthalate exposure induced myocardial cytotoxicity via the regulation of the NRG1-dependent ErbB2/ErbB4-PI3K/AKT signaling pathway in fetal mice.

Environmental sanitation of maternal contact during pregnancy is extremely important for the development of different fetal tissues and organs. In particular, during early pregnancy, any adverse exposure may cause abnormal fetal growth or inhibit the development of embryogenic organs. The potential risks of phthalate exposure, which affects the development of humans and animals, are becoming a serious concern worldwide. However, the specific molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP)-induced cardiotoxicity in fetal mice remains unclear. In this study, animal models of DEHP gavage at concentrations of 250, 500, and 1000 mg/kg/day within 8.5-18.5 days of pregnancy were established. The cell proliferation, survival, and apoptosis rates were evaluated using CCK8, EdU, TUNEL and flow cytometry. The molecular mechanism was assessed via transcriptome sequencing, immunohistochemistry, immunofluorescence, reverse transcription-quantitative polymerase chain reaction, and Western blot analysis. In vivo, DEHP increased apoptosis, decreased Ki67 and CD31 expression, reduced heart weight and area, slowed down myocardial sarcomere development, and caused cardiac septal defect in fetal mice heart. Transcriptome sequencing showed that DEHP decreased NRG1 expression and downregulated the ErbB2/ErbB4-PI3K/AKT signaling pathway-related target genes. In vitro, primary cardiomyocytes were cultured with DEHP at a concentration of 150 µg/mL combined with ErbB inhibitor (AG1478, 10 µmol/L) and/or NRG1 protein (100 ng/mL) for 72 h. After DEHP intervention, the expression of NRG1 and the phosphorylation level of ErbB2, ErbB4, PI3K, and AKT decreased, and the apoptosis-related protein levels increased. Moreover, the apoptosis rate increased. After adding exogenous NRG1, the phosphorylation level of the NRG1/ERbB2/ERbB4-PI3K/AKT pathway increased, and the apoptosis-related protein levels decreased. Further, the apoptosis rate reduced. Interestingly, after exposure to DEHP and AG1478 + NRG1, the anti-apoptotic effect of NRG1 and cardiomyocyte proliferation decreased by inhibiting the NRG1/ERbB2/ERbB4-PI3K/AKT pathway. Hence, the NRG1-dependent regulation of the ERbB2/ERbB4-PI3K/AKT signaling pathway may be a key mechanism of DEHP-induced myocardial cytotoxicity.

Heterogeneity of tumor microenvironment is associated with clinical prognosis of non-clear cell renal cell carcinoma: a single-cell genomics study.

Non-clear renal cell carcinomas (nccRCCs) are less frequent in kidney cancer with histopathological heterogeneity. A better understanding of the tumor biology of nccRCC can provide more effective treatment paradigms for different subtypes. To reveal the heterogeneity of tumor microenvironment (TME) in nccRCC, we performed 10x sing-cell genomics on tumor and normal tissues from patients with papillary renal cell carcinoma (pRCC), chromophobe RCC (chrRCC), collecting duct carcinoma (CDRCC) and sarcomatoid RCC (sarRCC). 15 tissue samples were finally included. 34561 cells were identified as 16 major cell clusters with 34 cell subtypes. Our study presented the sing-cell landscape for four types of nccRCC, and demonstrated that CD8+ T cells exhaustion, tumor-associated macrophages (TAMs) and sarcomatoid process were the pivotal factors in immunosuppression of nccRCC tissues and were closely correlated with poor prognosis. Abnormal metabolic patterns were present in both cancer cells and tumor-infiltrating stromal cells, such as fibroblasts and endothelial cells. Combined with CIBERSORTx tool, the expression data of bulk RNA-seq from TCGA were labeled with cell types of our sing-cell data. Calculation of the relative abundance of cell types revealed that greater proportion of exhausted CD8+ T cells, TAMs and sarRCC derived cells were correlated with poor prognosis in the cohort of 274 nccRCC patients. To the best of our knowledge, this is the first study that provides a more comprehensive sight about the heterogeneity and tumor biology of nccRCC, which may potentially facilitate the development of more effective therapies for nccRCC.

Direct and indirect associations between childhood socioeconomic status and cognitive function in the middle-aged and older adults in China.

OBJECTIVES: To investigate whether childhood socioeconomic status (SES) is associated with cognitive function, and what factors might mediate the associations. METHOD: Using data from the China Health and Retirement Longitudinal Study (CHARLS) and within frameworks of the latency model, the pathway model and the accumulation model, we quantified direct and indirect pathways between childhood SES and cognitive function for Chinese middle-aged and older adults aged 45+ by structural equations modeling. RESULTS: We found significant direct, indirect and total effects of childhood SES on cognitive function at baseline. The indirect effects were mediated through educational attainment, household consumption, smoking behaviors and social engagement. At follow-ups, cognitive enhancement can be made by indirect pathways through educational attainment, improvement of household consumption and social engagement. CONCLUSION: Our results supported the latency model, the pathway model and the accumulation model when considering pathways linking childhood SES to cognitive function. The findings underscored the value of taking early interventions to improve SES and cognitive function, especially among those with low childhood SES.

Nutritional Risk, Health Outcomes, and Hospital Costs Among Chinese Immobile Older Inpatients: A National Study.

Purpose: Evidence of the impact of nutritional risk on health outcomes and hospital costs among Chinese older inpatients is limited. Relatively few studies have investigated the association between clinical and cost outcomes and nutritional risk in immobile older inpatients, particularly those with neoplasms, injury, digestive, cardiac, and respiratory conditions. Methods: This China-wide prospective observational cohort study comprised 5,386 immobile older inpatients hospitalized at 25 hospitals. All patients were screened for nutritional risk using the Nutrition Risk Screening (NRS 2002). A descriptive analysis of baseline variables was followed by multivariate analysis (Cox proportional hazards models and generalized linear model) to compare the health and economic outcomes, namely, mortality, length of hospital stay (LoS), and hospital costs associated with a positive NRS 2002 result. Results: The prevalence of a positive NRS 2002 result was 65.3% (n = 3,517). The prevalence of "at-risk" patients (NRS 2002 scores of 3+) was highest in patients with cardiac conditions (31.5%) and lowest in patients with diseases of the respiratory system (6.9%). Controlling for sex, age, education, type of insurance, smoking status, the main diagnosed disease, and Charlson comorbidity index (CCI), the multivariate analysis showed that the NRS 2002 score = 3 [hazard ratio (HR): 1.376, 95% CI: 1.031-1.836] were associated with approximately a 1.5-fold higher likelihood of death. NRS 2002 scores = 4 (HR: 1.982, 95% CI: 1.491-2.633) and NRS scores ≥ 5 (HR: 1.982, 95% CI: 1.498-2.622) were associated with a 2-fold higher likelihood of death, compared with NRS 2002 scores <3. An NRS 2002 score of 3 (percentage change: 16.4, 95% CI: 9.6-23.6), score of 4 (32.4, 95% CI: 24-41.4), and scores of ≥ 5 (36.8, 95% CI 28.3-45.8) were associated with a significantly (16.4, 32.4, and 36.8%, respectively) higher likelihood of increased LoS compared with an NRS 2002 scores <3. The NRS 2002 score = 3 group (17.8, 95% CI: 8.6-27.7) was associated with a 17.8%, the NRS 2002 score = 4 group (31.1, 95% CI: 19.8-43.5) a 31.1%, and the NRS 2002 score ≥ 5 group (44.3, 95% CI: 32.3-57.4) a 44.3%, higher likelihood of increased hospital costs compared with a NRS 2002 scores <3 group. Specifically, the most notable mortality-specific comorbidity and LoS-specific comorbidity was injury, while the most notable cost-specific comorbidity was diseases of the digestive system. Conclusions: This study demonstrated the high burden of undernutrition at the time of hospital admission on the health and hospital cost outcomes for older immobile inpatients. These findings underscore the need for nutritional risk screening in all Chinese hospitalized patients, and improved diagnosis, treatment, and nutritional support to improve immobile patient outcomes and to reduce healthcare costs.