Background: Colorectal cancer (CRC), a prevalent malignancy of the gastrointestinal tract, ranks among the leading causes of cancer-related morbidity and mortality. Its clinical course is marked by high fatality and poor prognosis. Elucidating the mechanisms underlying CRC initiation and recurrence is therefore critical for identifying novel therapeutic targets. Methods: This study incorporated two datasets, TCGA-CRC and GSE17537. A total of 84 glutamine metabolism-related genes (GMRGs) were identified, and differential expression analysis was conducted using the TCGA-CRC dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to determine gene modules most strongly associated with GMRG scores. Single-cell RNA sequencing (scRNA-seq) was utilized to characterize key cellular clusters and to identify differentially expressed genes (DEGs) between high and low glutamine metabolism (GM) groups. Overlapping GMRGs were visualized using the ggVennDiagram package in R. A CRC risk prediction model was developed through Cox proportional hazards and LASSO regression analyses, with performance evaluated by ROC curves. Cell type enrichment across 64 immune and stromal populations was assessed via xCell, and intergroup differences were tested using the Wilcoxon rank-sum test. TIDE scores were used to estimate immunotherapy responsiveness, while oncoPredict facilitated drug sensitivity profiling. PCOLCE2 expression in CRC was validated by RT-qPCR and Western blotting. Its functional role was examined through CCK-8 assays, invasion and migration tests, flow cytometry, and glutamate quantification. Results: ScRNA-seq analysis identified two key cell populations and 437 DEGs associated with GM status. WGCNA pinpointed the MEgreen module as most significantly correlated with GMRG scores, encompassing 1075 genes. Integration of DEGs, module genes, and GM-related DEGs yielded 60 candidate genes for downstream analysis. A GMRG-based prognostic model comprising six genes (SRPX, CXCL1, GPX3, PCOLCE2, CLU, SEMA3E) demonstrated strong predictive performance. Prognostic gene expression correlated with immune and stromal infiltration patterns, as indicated by Spearman correlation analysis. The high-risk group exhibited diminished predicted response to immunotherapy (TIDE scores). Drug sensitivity analysis identified four compounds-Dasatinib-51, WH-4-023-56, TWS-119-366, and LDN-193189-478-with elevated efficacy in high-risk CRC cases. PCOLCE2 expression was significantly reduced in CRC tissues. Functional assays revealed that PCOLCE2 knockdown did not substantially affect cell proliferation but significantly impaired invasion and migration in CRC cells, increased apoptosis, and suppressed both glutamine uptake and glutamate production-highlighting its oncogenic role. Conclusion: Six GMRGs-SRPX, CXCL1, GPX3, PCOLCE2, CLU, and SEMA3E-were identified as key components of a robust prognostic model for CRC. These findings offer valuable insights into CRC pathogenesis and potential therapeutic strategies. Notably, this study provides the first evidence implicating PCOLCE2 as a tumor-promoting factor in CRC.

This research aimed to determine genes associated with M1 TAMs (tumour-associated macrophages) and to develop an M1 TAMs-related signature for predicting GC (Gastric cancer)'s prognosis and therapeutic effect. Based on the GC dataset in TCGA, we constructed a prognostic signature using M1 TAMs-related genes and validated it using data from the GEO dataset. To evaluate the predictive power of the signature, the survival curves, ROC curves, Cox regression analysis, nomograms and calibration curves were constructed. Differences in immune infiltration, immunotherapy response, and chemotherapy sensitivity between the two risk groups were also analysed. Furthermore, by jointly using the string database and Cytoscape software, we identified the hub gene that differed between the two risk groups. In the end, the expression and function of the identified hub gene were validated using fresh tissue specimens and GC cell lines. A six-gene risk signature was developed based on M1 TAMs-related genes. Furthermore, the ROC curve, nomogram, calibration plot of the nomogram and Cox regression analysis confirmed M1 TAMs co-expressed genes have a strong predictive performance of the six-gene risk signature. Immune infiltration analysis and the TIDE algorithm indicated that low-risk GC patients may be more suitable for immunotherapy. Finally, fibronectin 1 (FN1), the hub gene with the highest degree of interaction between high- and low-risk groups, indicated a significant correlation with survival differences in GC. Functional analysis demonstrated that FN1 promotes GC cell proliferation, invasion, migration and EMT. The risk signature of six M1 TAMs co-expressed genes can be used to evaluate the prognosis and treatment efficacy of patients with GC, providing a basis for selecting new therapies for patients. The FN1 gene is the hub gene with predictive value in this signature, and it is upregulated in GC and functions as an oncogene.

BACKGROUND:Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration. METHODS:Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis. RESULTS:HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed. CONCLUSIONS:Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.

Intestinal inflammatory disease (IBD) is a chronic intestinal disorder that includes Crohn’s disease and ulcerative colitis. In recent years, its incidence has been increasing, but there is still no breakthrough in its treatment. Cell death was divided into programmed and nonprogrammed cell death (PCD). PCD mainly includes ferroptosis, apoptosis, necroptosis, pyroptosis, and autophagy, while non-PCD refers to necrosis. Increasing evidence shows that PCD, such as ferroptosis and autophagy, plays an important regulatory role in intestinal diseases, which may be involved in the occurrence and progression of IBD and can be used as a therapeutic target for the disease. This article reviews recent studies on ferroptosis, apoptosis, necroptosis, pyroptosis, and autophagy associated with IBD, combs the regulatory mechanisms of PCD in IBD, and summarizes the corresponding therapeutic drugs and new materials, aiming to provide new directions and treatments for IBD research.

A novel copper-dependent mode of death, cuproptosis, has been newly identified. This study developed a cuproptosis score (CS) based on the cuproptosis model to analyse the association of CS with prognosis, immune cell infiltration, drug sensitivity and immunotherapy response in hepatocellular carcinoma (HCC) patients. A typing model of cuproptosis was constructed based on the expression of 19 cuproptosis-related genes (CRGs). A total of 485 samples were divided into high scoring group (HSG) and low scoring group (LSG) according to CS, and the drug sensitivity and responsiveness to immunotherapy were evaluated by combining the immunophenotype score (IPS), oncoPredict, the tumour immune dysfunction and rejection (TIDE). The use of weighted gene coexpression network analysis (WGCNA) identified key prognostic genes for cuproptosis. Western blotting was used to detect the expression level of the key gene. The CRG key gene glutaminase (GLS) is highly expressed in HCC, and patients with high expression of GLS have a poorer prognosis. Furthermore, cell function experiments, such as proliferation, migration and invasion assays, confirmed that GLS knockdown significantly changed the incidence and progression of HCC. This study suggests that new biological markers associated with cuproptosis can be used in the clinical diagnosis of HCC patients to predict prognosis and therapeutic targets.

A new mode of cell death, disulfidptosis, has been discovered. Clinical prognostic significance of disulfidptosis related pattern in hepatocellular carcinoma(HCC). In this study, a risk score model was established based on disulfidptosis model to analyze the role of risk score in clinical prognosis, immune cell infiltration, drug sensitivity and immunotherapy response. Disulfidptosis subtype were constructed based on the transcriptional profiles of 15 disulfidptosis-related genes(DRGs). All 601 samples were defined as high risk group(HRG) and low risk group(LRG) based on the disulfidptosis risk score. Drug sensitivity and response to immunotherapy were calculated by immunophenotypic score(IPS), tumor prediction, tumor immune dysfunction and rejection(TIDE). RT-qPCR was used to determine the mRNA level of disulfidptosis prognostic gene. Risk groups was identified as potential predictors of immune cell infiltration, drug sensitivity, and immunotherapy responsiveness. HRG may benefit from immunotherapy. Classification is very effective in predicting the prognosis and therapeutic effect of patients, and provides a reference for accurate individualized treatment. This study suggests that new biomarkers related to Disulfidptosis can be used in clinical diagnosis of liver cancer to predict prognosis and treatment targets.

Bladder cancer (BCa) stands as a significant malignancy within the genitourinary system. Notably, heat shock proteins (HSPs) exhibit elevated expression in cells subjected to environmental stresses and have been linked to the progression of many human malignancies. Among these, the functional implications and specific mechanism of HSPB8 in BCa have yet to be fully explored. In this study, we measured HSPB8 expression in both BCa tissues and various cell lines, further delving into its influence on cellular behaviors. Our observations pinpoint an upregulation of HSPB8 in BCa, a trend strongly associated with more advanced clinical manifestations. Suppressing HSPB8 exhibited marked reductions in cell proliferation and migration capabilities, while simultaneously amplifying apoptosis and inducing cell cycle arrest. Reinforcing these findings, our in vivo analyses using mouse models showed similar trends. Notably, upon HSPB8 knockdown, levels of specific proteins including eNOS (S1177), Hsp27 (S78/S82), PRAS40(T246), RSK1/2(S221/S227), and STAT3 (S727) decreased, with Hsp27 (S78/S82) and PRAS40(T246) experiencing the most profound drops. Furthermore, the application of an HSP27 inhibitor effectively reversed the phenotypes caused by increased HSPB8 expression. Collectively, our results suggest that elevated HSPB8 expression could act as a potential prognostic marker for BCa, and targeting HSPB8 might open new therapeutic avenues for treating this malignancy.

Compared with asymptomatic pulmonary cryptococcosis, secondary cutaneous cryptococcosis may be the first clinical manifestation of disseminated infection but it can be difficult to diagnose clinically. The clinical manifestation of cutaneous cryptococcosis is not pathognomonic, varying from nodules to ulcers and plaques, and frequently mimics other pathologies. This case highlights that an isolated tumour can be an initial manifestation of systemic cryptococcosis in a kidney transplant patient.

Stem-like CD8+ T cells represent the key subset responding to multiple tumor immunotherapies, including tumor vaccination. However, the signals that control the differentiation of stem-like T cells are not entirely known. Most previous investigations on stem-like T cells are focused on tumor infiltrating T cells (TIL). The behavior of stem-like T cells in other tissues remains to be elucidated. Tissue-resident memory T cells (TRM) are often defined as a non-circulating T cell population residing in non-lymphoid tissues. TILs carrying TRM features are associated with better tumor control. Here, we found that stem-like CD8+ T cells differentiated into TRMs in a TGF-β and tumor antigen dependent manner almost exclusively in tumor draining lymph node (TDLN). TDLN-resident stemlike T cells were negatively associated with the response to tumor vaccine. In other words, after tumor vaccine, TDLN stem-like T cells transiently lost TRM features, differentiated into migratory effectors and exerted tumor control.

Von Hippel-Lindau (VHL) is an important tumor suppressor, and its inactivation is a hallmark of inherited VHL disease and most sporadic clear cell renal cell carcinoma (ccRCC). VHL protein (pVHL) with missense point mutations are unstable and degraded by the proteasome because of the disruption of elongin binding. Deubiquitylase ovarian tumor domain-containing 6B (OTUD6B) had been documented to couple pVHL and elongin B to form stable VHL - elonginB - elonginC complex, which protects pVHL from degradation. However, whether OTUD6B governs the stability of pVHL wild type and the missense mutants in ccRCC remains largely elusive. Here, we reported that low OTUD6B level predicted poorer survival in ccRCC patients with VHL missense mutation, but not frameshift deletion and nonsense mutation. OTUD6B is able to interact with wild type pVHL and tumor-derived pVHL missense mutants, except for pVHL I151T, and decrease their ubiquitylation and proteasomal degradation in ccRCC cells. Functionally, we revealed that OTUD6B depletion enhanced cell migration and HIF-2α level in ccRCC cells in a pVHL dependent manner. In addition, OTUD6B depletion reduced the inhibitory effects of ectopic pVHL missense mutants on cell migration and HIF-2α level, except for pVHL I151T. Thus, we speculated that I151 residue might be one of key sites of pVHL binding to OTUD6B. These results suggested that OTUD6B is an important regulator for the stability of pVHL missense mutants, which provides a potential therapeutic strategy for ccRCC with VHL mutations.