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The relationship between lactate levels and multiple organ dysfunction in patients with severe heatstroke remains unclear. In this study, we aimed to elucidate the clinical significance of lactate in severe heatstroke prognosis and assess whether incorporating lactate in the SOFA score improves its predictive efficacy. This study was a multicenter retrospective cohort investigation included 275 patients. Logistic regression analysis was performed to examine the relationship between lactate levels and patient outcomes and complications, including acute kidney injury (AKI), disseminated intravascular coagulation (DIC), and myocardial injury. Further, receiver operating characteristic (ROC) curves and clinical decision curve analysis (DCA) were used to evaluate the predictive power of lactate and SOFA scores in severe heatstroke-associated death. Lastly, the Kaplan–Meier survival curve was employed to differentiate the survival rates among the various patient groups. After adjusting for confounding factors, lactate was demonstrated as an independent risk factor for death (OR = 1.353, 95% CI [1.170, 1.569]), AKI (OR = 1.158, 95% CI [1.007, 1.332]), DIC (OR = 1.426, 95% CI [1.225, 1.659]), and myocardial injury (OR = 2.039, 95% CI [1.553, 2.679]). The area under the curve (AUC) of lactate for predicting death from severe heatstroke was 0.7540, with a cutoff of 3.35. The Kaplan–Meier survival curve analysis showed that patients with elevated lactate levels had higher mortality rates. Additionally, the ROC curves demonstrated that combining lactate with the SOFA score provided better predictive efficacy than the SOFA score alone in patients with severe heatstroke (AUC: 0.9025 vs. 0.8773, DeLong test, P < 0.001). Finally, the DCA curve revealed a higher net clinical benefit rate for lactate combined with the SOFA score. Lactate is an independent risk factor for severe heatstroke-related death as well as a risk factor for AKI, DIC, and myocardial injury associated with severe heatstroke. Thus, combining lactate with the SOFA score can significantly improve its predictive efficacy in patients with severe heatstroke. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Compared to typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance. Methods: Differences in gene expression profiles between advanced and nonadvanced GISTs were comprehensively analyzed based on the Gene Expression Omnibus (GEO) dataset GSE136755. A protein–protein interaction (PPI) network was constructed to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events related to the target gene based on the GSE47911 dataset. Subsequently, immunohistochemistry and Kaplan–Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its function in the proliferation, apoptosis, and imatinib resistance of GIST/T1 cells. Results: In the current study, a total of 606 differentially expressed genes (DEGs) were screened based on the GSE136755 dataset, and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersecting hub gene, Aurora kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Analysis of the Oncomine and GEPIA databases revealed a pattern of elevated AURKA expression in most human malignances. Clinical assays demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation, inhibit cell apoptosis, and enhance imatinib resistance in GIST/T1 cells. Conclusions: These findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs. [ABSTRACT FROM AUTHOR]

The ADP‐ribosylation factor‐like proteins (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive. In this study, we systematically investigate the expression status, interactive relations, potential pathways, genetic variations and clinical values of ARLs in GC. We find that ARLs are significantly dysregulated in GC and involved in various cancer‐related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant clinical indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that ARL4C is highly correlated with TGF‐β1 signalling. Correspondingly, TGF‐β1 treatment dramatically increases ARL4C expression and ARL4C knockdown inhibits the phosphorylation level of Smads, downstream factors of TGF‐β1. Meanwhile, the coexpression of ARL4C and TGF‐β1 worsens the prognosis of GC patients. Our work comprehensively demonstrates the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC‐promoting effects of TGF‐β1. More importantly, we uncover the great promise of ARL4C‐targeted therapy in improving the efficacy of TGF‐β1 inhibitors for GC patients. [ABSTRACT FROM AUTHOR]

Background: Despite advances in early diagnosis and treatment, cancer remains the major cause of mortality in the world. The Tob/BTG antiproliferative (APRO) protein family is reported to participate in diverse human diseases. However, there’s little known about their expression and prognostic values in most human cancers. Methods: We performed a detailed cancer vs. normal analysis. The mRNA expression levels of APRO family in various cancers were analyzed via the Oncomine database. Moreover, the Kaplan-Meier Plotter and PrognScan databases were used to evaluate the prognostic values. Results: We observed that the mRNA expression levels of TOB1-2 and BTG2 were decreased in most cancers compared with normal tissues, while BTG3 was upregulated in most cancers. In survival analyses based on Kaplan-Meier Plotter, TOB1, BTG1 and BTG4 showed significant associations with survival outcome of different subtypes of breast cancer. Decreased BTG2 was related with poor relapse free survival (RFS) in all subtypes of breast cancer. Especially, besides RFS, reduced BTG2 also indicated worse overall survival and distant metastasis free survival in breast cancer patients who were classified as luminal A. Significant prognostic effects of the whole APRO family were also found in lung adenocarcinoma, but not in squamous cell lung carcinoma. In addition, potential correlations between some APRO family members and survival outcomes were also observed in ovarian, colorectal and brain cancer. Conclusions: Some members of APRO family showed significant expression differences between cancer and normal tissues, and could be prognostic biomarkers for defined cancer types. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the common malignancies worldwide. Slit-Robo GTPase-activating proteins (SRGAPs) have been shown to regulate the occurrence and development of various tumors. However, their specific roles in HCC remain elusive. The expression pattern, genetic alteration and prognostic value of SRGAPs in HCC are analyzed by bioinformatics tools. The biological functions of SRGAP2 in HCC cells are demonstrated by in vitro experiments. The high-throughput RNA sequencing is conducted to explore the underlying molecular mechanisms of SRGAP2 in HCC cells. The expression levels of SRGAP1 and SRGAP2 are significantly elevated in HCC tissues compared to the normal both in Oncomine and TCGA datasets, and SRGAP2 are dramatically upregulated both in mRNA and protein levels. Moreover, higher SRGAP2 is significantly related to the clinical stages of HCC. Meanwhile, SRGAP2 might be an independent prognostic indicator, as it correlates negatively with the clinical outcomes of HCC patients. Further SRGAP2-silencing experiments imply that SRGAP2 might remarkably promote the migration and invasion of HCC cells in an EMT-independent pattern. Based on the high-throughput RNA sequencing of SRGAP2-knockdown HCC cells, enrichment and network analyses demonstrate that SRGAP2 is closely associated with cellular metabolic signaling. Our study firstly illustrates the crucial role of SRGAP2 in the metastasis of HCC and explores its underlying molecular mechanisms. We identify SRGAP2 as a promising prognostic biomarker and a novel therapeutic target for HCC patients. [ABSTRACT FROM AUTHOR]