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Transmembrane domain-containing 7 (CMTM7) is a protein located at the plasma membrane. It plays a role in regulating the development and immune microenvironment of tumor cells. However, the impact of CMTM7 on hepatocellular carcinoma (HCC) is not well understood. To better understand the role of CMTM7 in HCC, the correlations of CMTM7 with clinical characteristics, patient prognosis, chronic inflammation, and immune cell infiltration were analyzed using tissue microarray slides, sequencing datasets and various analysis tools (Web). The bulk sequencing analysis indicated that elevated expression of CMTM7 appears to promote chronic inflammation, immunosuppression, M2 macrophage infiltration, a diminished response to cancer immunotherapy, and an unfavorable clinical prognosis in patients with hepatocellular carcinoma (HCC). Further investigation through single-cell RNA sequencing and multiple fluorescence staining demonstrated that CMTM7 serves as a molecular marker for M2 macrophages and is associated with T cell exhaustion as well as highly plastic stem-like characteristics. We propose that CMTM7 may represent a novel immune checkpoint for HCC patients experiencing suboptimal therapeutic outcomes. Utilizing the Connectivity Map and AutoDock Vina, we predicted two potential compounds targeting CMTM7—fasudil and arachidonyltrifluoromethane—as promising therapeutic candidates. Collectively, these findings suggest that CMTM7-positive macrophages play significant roles in establishing an immunosuppressive tumor microenvironment while promoting highly plastic and stem-like traits in HCC cells, ultimately contributing to poor prognostic outcomes.

ObjectiveTo investigate the potential of prophylactic closure of mucosal defects to prevent adverse events following endoscopic resection of superficial layers of the gastrointestinal (GI) wall.DesignSystematic review and meta-analysis.Data sourcesWe searched PubMed, Embase, Web of Science and the Cochrane Library for studies eligible for inclusion in our meta-analysis from inception to February 2022.Data extraction and synthesisWe compared the effects of closure versus non-closure of mucosal defects with respect to adverse events including delayed bleeding, delayed perforation and postpolypectomy coagulation syndrome (PPCS). We used a random-effects model for all analyses. Subgroup analyses were performed based on gastrointestinal sites, surgical procedures and study designs.ResultsIn total, this study includes 11 383 patients from 28 studies. For delayed bleeding, closure group was associated with a lower incidence (Risk Ratio [RR]: 0.40, 95% Confidence interval [CI]: 0.30 to 0.53, p<0.001; I2=25%) and consistent results were observed in the subgroups. Also, for delayed perforation, a combined analysis of all sites and surgical methods showed a protective effect of prophylactic closure of mucosal defects (RR: 0.42, 95% CI: 0.22 to 0.82, p=0.01; I2=0%). Similar results were observed in the subgroup analyses, despite the wide CIs. Regarding the PPCS, neither the pooled RRs nor the subgroup analyses showed significant differences.ConclusionProphylactic closure of mucosal defects is beneficial in reducing the incidence of delayed bleeding and delayed perforation after endoscopic resection, but there is no significant difference in reducing the incidence of PPCS.

Background Recent studies have demonstrated the pivotal role of pathogenic Th17 cells during the target organ damage in systemic lupus erythematosus (SLE). Therefore, identifying Th17-related precision therapeutic targets is essential for developing effective treatments. Methods Potential targets of a novel alkaloid compound, Dehydrocorydaline (DHC), in SLE were investigated using integrated network pharmacology and molecular docking. The therapeutic efficacy of DHC was evaluated in vivo using a lupus-prone mouse model and in vitro via pathogenic Th17 polarization assays. Mechanistic studies were conducted using transcriptional analysis, cell thermal shift assay (CETSA), microscale thermophoresis (MST), and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). Results This study demonstrates the therapeutic potential of DHC in SLE. Network pharmacology analysis identified mTOR signaling and Th17 cell polarization as key potential targets and pathways of DHC. In vivo, DHC treatment selectively reduced the frequencies of Th17 cells, inhibited serum IL-17A levels, restored glomerular filtration rate (GFR), and attenuated renal damage in lupus mice. Molecular docking, CETSA, and MST results suggested a direct interaction between DHC and mTOR. In vitro, DHC inhibited the phosphorylation of mTOR and STAT3 during pathogenic Th17 differentiation. Pharmacological activation of mTOR reversed the inhibitory effects of DHC on STAT3 activation and Th17 differentiation. Mechanistically, DHC blocked the mTOR-dependent STAT3 nuclear translocation and  Rorc  transcription during Th17 polarization. Conclusion DHC attenuates renal damage in SLE by suppressing the Th17 response via the mTOR/STAT3/RORγt axis. This finding represents a novel therapeutic strategy for addressing the unmet clinical needs in SLE. Graphical Abstract

Metabolic reprogramming driven by oncogenes plays a critical role in promoting and sustaining multiple steps of gastric cancer metastasis. However, the key metabolic driver of metastasis that can lead to the development of targeted therapies for preventing and treating metastatic gastric cancer remains elusive. Here, it is identified that the transmembrane guanylate cyclase, natriuretic peptide receptor 1 (NPR1), promoted gastric cancer lymph node metastasis by activating lipid droplet lipolysis and enhancing mitochondrial oxidative phosphorylation (OXPHOS). Clinical analysis reveals that elevated NPR1 protein level is correlated with increased lymph node metastasis and shorter patient survival. Functionally, NPR1 induced lipolysis of stored lipid droplets, releasing bioavailable fatty acids that are imported into mitochondria to upregulate OXPHOS, thus fueling the energy required for the metastasis of gastric cancer cells. Mechanistically, NPR1 activates protein kinase cGMP‐dependent 1 (PRKG1 or PKG), which directly bound to and activated hormone‐sensitive lipase (HSL) by phosphorylation at residues Ser855 and Ser951, thereby increasing lipolysis. Furthermore, targeted delivery of NPR1 siRNA using engineered exosome mimetics effectively suppressed gastric cancer metastasis. Taken together, these findings elucidate the NPR1‐driven metabolic mechanism underlying gastric cancer metastasis and suggest NPR1 as a promising therapeutic target for patients with metastatic gastric cancer. NPR1 induces lipolysis of stored lipid droplet and enhances mitochondrial oxidative phosphorylation to fuel gastric cancer metastasis. Specifically, NPR1‐mediated activation of PKG directly phosphorylates and activates HSL at Ser855 and Ser951, thereby driving lipolytic processes. Targeting NPR1 with siNPR1‐loaded engineered exosome mimetics offers a potential therapeutic strategy to inhibit gastric cancer metastasis.

Gastric cancer is the third leading cause of cancer death worldwide. In this study, we tried to clarify the function of KLF5 in gastric cancer. Copy number variation (CNV) and the expression of KLF5 were interrogated in public datasets. The clinical significance of KLF5 amplification and gene expression in gastric cancer were evaluated. The function of KLF5 in cell proliferation was studied in gastric cancer cell lines and organoids. We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation. In addition, higher KLF5 expression correlated with more locally invasive gastric cancer and higher T stage. Next, a KLF5 gene expression signature was curated. The genes in the signature were involved in cell development, cell cycle regulation, cell death, suggesting potential roles played by KLF5. Functional studies using siRNAs revealed that KLF5 was essential for the proliferation of gastric cancer cells. Finally, using gastric organoid models, we revealed that the proliferation of organoids was significantly inhibited after the down regulation of KLF5. Our study revealed that KLF5 was amplified and over-expressed in gastric cancer, and it may play an oncogene-like role in gastric cancer by supporting cell proliferation.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically 1 , 2 . This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells 3 . However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy. Lactylation of NBS1 by TIP60 promotes homologous recombination-driven DNA repair and resistance to chemotherapy in cancer cells and links altered cancer cell metabolism to increase genome stability.

The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.

Abstract Background Carbohydrate drinking 2–3 hours before surgery has been widely adopted in colorectal operations. However, there is little direct evidence regarding its application in gastric cancer surgery. We aimed to evaluate the gastric residual volume, safety, and effectiveness of drinking 250 mL of 5% glucose solution 2–3 hours before elective gastric cancer surgery. Methods We conducted an investigator-initiated, multicenter, randomized–controlled, parallel group, and equivalence trial. Eighty-eight patients with gastric adenocarcinoma were randomized into study or control group. Patients in the control group followed the traditional routine of 6–8 hours preoperative fasting, while those in the study group drank 250 mL of 5% glucose solution 2–3 hours before surgery. Immediately following tracheal intubation, gastric contents were aspirated through gastroscopy. The primary outcome was preoperative gastric residual volume. Results Eighty-three patients were eventually analysed in the study (42 in the study group and 41 in the control group). Two groups were comparable at baseline characteristics. There were no statistical differences in residual gastric fluid volumes (35.86 ± 27.13 vs 27.70 ± 20.37 mL, P = 0.135) and pH values (2.81 ± 1.99 vs 2.66 ± 1.68, P = 0.708) between the two groups. Preoperative discomfort was significantly more decreased in the study group than in the control group (thirst score: 1.49 ± 1.23 vs 4.14 ± 2.07, P < 0.001; hunger score: 1.66 ± 1.18 vs 3.00 ± 2.32, P = 0.007). There was no statistical difference in the incidence of postoperative complications (19.05% vs 17.07%, P = 0.815). Conclusions Drinking 250 mL of 5% glucose solution 2–3 hours before surgery in elective gastric cancer patients shows benefits in lowering thirst and hunger scores without increasing gastric residual volume and perioperative complications.

Kinase inhibitors (KIs) are mainstays of targeted cancer therapy, but their clinical utility is frequently limited by cardiotoxicity. A systematic resource to explore the underlying causal mechanisms is urgently needed. We present the KICDB (Kinase Inhibitor Cardiotoxicity Database), a comprehensive and interactive web server. KICDB is built upon a framework integrating large-scale transcriptomics meta-analysis with causal inference. This database centralizes the findings from a comprehensive meta-analysis of 26 kinase inhibitors (KIs) across 7 studies (n=5291) identified 8,907 significant gene expression changes in human cardiomyocytes. To establish causality, we performed a two-pronged Mendelian randomization (MR) analysis testing hundreds of downstream genes and a panel of 43 key kinase proteins against 46 cardiovascular outcomes. This large-scale analysis revealed 26 significant causal associations, implicating novel molecular mediators in KI-induced cardiotoxicity. KICDB serves as a valuable and accessible platform for the cardio-oncology community. By integrating transcriptomic signatures with causal inference data, the database empowers researchers to formulate mechanistic hypotheses, accelerate biomarker validation, and guide the design of future cardioprotective strategies. URL: https://zhang-lab-database.shinyapps.io/KICDB/ We developed KICDB, a comprehensive and publicly accessible web server, to systematically investigate the causal mechanisms of KI-induced cardiotoxicity. KICDB integrates a large-scale meta-analysis of transcriptomic data from 26 KIs with a robust Mendelian randomization (MR) framework to move beyond correlation and infer causality. The analysis identified 8,907 significant gene expression changes and 26 significant causal associations between KI-associated genes and 46 cardiovascular outcomes.