Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma.

The main challenge in treating stomach adenocarcinoma (STAD) is chemotherapy resistance, which is characterized by changes in the immune microenvironment. Disulfidptosis, a novel form of programmed cell death, is involved in STAD but its mechanism is not fully understood. Long non-coding RNAs (LncRNAs) may play a role in regulating disulfidptosis and influencing the immune microenvironment and chemotherapy resistance in STAD. This study aims to establish disulfidptosis-related lncRNA (DRL) features and explore their significance in the immune microenvironment and chemotherapy resistance in STAD patients. By analyzing RNA sequencing and clinical data from STAD patients and extracting disulfidptosis-related genes, we identified DRLs through co-expression, single-factor and multi-factor Cox regression, and Lasso regression analyses. We also investigated differences in the immune microenvironment, immune function, immune checkpoint gene expression, and chemotherapy resistance between different risk groups using various algorithms. A prognostic risk model consisting of 2 DRLs was constructed, with a strong predictive value for patient survival, outperforming other clinical-pathological factors in predicting 3-year and 5-year survival. Immune-related analysis revealed a strong positive correlation between T cell CD4+ cells and risk score across all algorithms, and higher expression of immune checkpoint genes in the high-risk group. In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.

Disulfidptosis-related lncRNA signatures assess immune microenvironment and drug sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is associated with a high mortality rate, where resistance to immunotherapy and chemotherapy plays a crucial role. A newly identified form of cell death called disulfidptosis shows promise, but its biological mechanism in HCC remains uncertain. In this study, a prognostic model was developed for Disulfidptosis-related long non-coding RNAs (DRLs) from 370 HCC patients sourced from TCGA-LIHC, utilizing five key features: AC026356.1, AC073254.1, PXN-AS1 expression, AC026412.3, and AC099066.2. High-risk HCC patients had lower survival, CD4+ T cell infiltration, and elevated immune checkpoint gene expression. Furthermore, based on the features of DRLs, HCC was classified into three subtypes. Notably, patients belonging to different subtypes demonstrated varying overall survival rates, immune cell infiltration patterns, and sensitivity to immune therapy. Moreover, the novel DRL AC026412.3 (HR = 40.207) emerged as the most significant prognostic factor, exhibiting high expression across all HCC cells. Elevated expression of AC026412.3 promoted HCC cell proliferation and induced resistance to gefitinib. In conclusion, we have discovered five DRLs and constructed a prognostic risk model. Our findings validate the correlation between DRL-related prognostic models, tumor subtypes, and the HCC immune microenvironment along with its implications for immunotherapy. Moreover, further investigation into the molecular mechanisms of key biomarkers like AC026412.3 in the future will contribute significantly to advancing our comprehension of HCC's pathogenesis and drug resistance mechanisms.

Solanine induces ferroptosis in colorectal cancer cells through ALOX12B/ADCY4 molecular axis.

OBJECTIVES: Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Solanine is a phytochemical extracted from traditional Chinese medicine with widely reported anticancer effects. Here, we investigated the potential role of solanine in regulating ferroptosis in CRC cells and scrutinized the molecular mechanism. METHODS: Cell growth and cytotoxicity were examined using CCK-8 proliferation assay and lactate dehydrogenase assay. Oxidative stress was determined by measuring glutathione (GSH), malondialdehyde, and reactive oxygen species (ROS) levels. Subcellular changes in mitochondria were examined by transmission electron microscopy. Gene and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein-protein interaction was determined by co-immunoprecipitation. KEY FINDINGS: Solanine arrested cell proliferation in CRC cells and induced typical ferroptotic changes. Solanine treatment promoted ROS production, lipid peroxidation, and cell membrane disruption, while the cellular level of antioxidant GSH was reduced upon solanine treatment. ALOX12B was identified as a molecular mediator of solanine to promote ferroptosis. Solanine treatment upregulated ALOX12B levels and silencing ALOX12B could suppress solanine-induced ferroptosis. Further, ADCY4 was found to physically associate with ALOX12B and maintain ALOX12B protein stability. Silencing ADCY4 destabilized ALOX12B and attenuated solanine-induced ferroptosis. CONCLUSIONS: Our data demonstrated the ferroptosis-inducing effect of solanine in CRC cells, and revealed ALOX12B/ADCY4 molecular axis as the ferroptosis mediator of solanine. Solanine may synergize with existing ferroptosis inducer as an anticancer strategy in CRC, which warrants further validation in animal experiments.

Long-Term Outcomes of Iron Deficiency Before and After Bariatric Surgery: a Systematic Review and Meta-analysis.

PURPOSE: This study reviews the prevalence of iron deficiency (ID) in bariatric surgery candidates and the long-term outcomes of the prevalence of ID after bariatric surgery. MATERIALS AND METHODS: A systematic literature search and meta-analysis were performed in PubMed for articles published by August 31, 2022, including these search terms: bariatric surgery, metabolic surgery, weight loss surgery, obesity surgery, sleeve gastrectomy, gastric banding, gastric bypass, duodenal switch, duodenojejunal bypass, iron, iron deficiency, sideropenia, and hypoferritinemia. Fifty-seven studies examining a total of 26,328 patients with morbidly obese were included in this meta-analysis finally. RESULTS: The results showed a prevalence of 17% of ID in bariatric surgery candidates and a prevalence of 14%, 17%, 26%, 34%, 23%, 38%, and 23% of ID at 1-, 2-, 3-, 4-, 5-, 8-, and 10-year follow-up after bariatric surgery, respectively. Additionally, the results showed a prevalence of 15%, 19%, 35%, 38%, 29%, 30%, and 23% of ID at 1-, 2-, 3-, 4-, 5-, 8-, and 10-year follow-up after Roux-en-Y gastric bypass, respectively; a prevalence of 12%, 12%, 15%, 31%, and 17% of ID at 1-, 2-, 3-, 4-, and 5-year follow-up after sleeve gastrectomy, respectively; and a prevalence of 19% of ID at 1-year follow-up after anastomosis gastric bypass. CONCLUSION: As a result, preoperative evaluation and correction of ID may lead to better outcomes for bariatric surgery candidates. ID is also common in patients after bariatric procedures, especially RYGB. Long-term, even lifelong, medical and nutritional monitoring and tailored interventions are critical.

HS6ST1 overexpressed in cancer-associated fibroblast and inhibited cholangiocarcinoma progression.

BACKGROUD: Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumor microenvironment, which play an important role in tumor progression. However, the mechanism is unclear. AIMS: To investigate the role of CAFs with HS6ST1-overexpression in cell migration and invasion effects. METHODS: Human primary CAFs were isolated and identified from intrahepatic cholangiocarcinoma. mRNA profiles differences between CAFs and NFs were examined by using transcriptome sequencing. Using Transwell® migration assays, ICCA cells (RBE and HUCCT1) with NF-CM, CAF-CM, CAFsNC-CM, and CAFsHS6ST1-CM were analyzed. Immunohistochemical staining were used to analyze the expression of HS6ST1 in CAF in 152 patients with ICCA. Overall survival (OS) was compared based on CAF HS6ST1 expression were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Successfully isolated CAFs is positive staining with αSMA, FSP-1, FAP, and PDGFR-ß. Transcriptome sequencing showed that differently expressed genes were enriched in the function of the extracellular matrix and chemokine signaling pathway. HS6ST1 is differentially expressed between CAFs and NFs, and associated with the migration and invasion of ICCA cells. Moreover, HS6ST1 positive expression of CAFs predicted unfavorable prognosis in patients with intrahepatic cholangiocarcinoma and showed correlation with the presence of lymph node metastasis. CONCLUSION: HS6ST1 is new possibilities for targeting the CAFs to reduce cholangiocarcinoma growth and metastasis.