Deciphering the implications of mitophagy-related signatures in clinical outcomes and microenvironment heterogeneity of clear cell renal cell carcinoma.

BACKGROUND: The role of mitophagy in various cancer-associated biological processes is well recognized. Nonetheless, the comprehensive implications of mitophagy in clear cell renal cell carcinoma (ccRCC) necessitate further exploration. METHODS: Based on the transcriptomic data encompassing 25 mitophagy-related genes (MRGs), we identified the distinct mitophage patterns in 763 ccRCC samples. Subsequently, a mitophage-related predictive signature with machine learning algorithms was constructed, designated as RiskScore, to quantify the individual mitophagy status in ccRCC patients. Employing multispectral immunofluorescence (mIF) and immunohistochemistry (IHC) staining, we detected the effect of PTEN-induced putative kinase 1 (PINK1) in the prognosis and immune microenvironment of ccRCC. RESULTS: Our analysis initially encompassed a comprehensive assessment of the expression profiling, genomic variations, and interactions among the 25 MRGs in ccRCC. Subsequently, the consensus clustering algorithm was applied to stratify ccRCC patients into three clusters with distinct prognostic outcomes, tumor microenvironment (TME) characteristics, and underlying biological pathways. We screened eight pivotal genes (CLIC4, PTPRB, SLC16A12, ENPP5, FLRT3, HRH2, PDK4, and SCD5) to construct a mitophagy-related predictive signature, which showed excellent prognostic value for ccRCC patients. Moreover, patient subgroups divided by the RiskScore showed contrasting expression levels of immune checkpoints (ICPs), abundance of immune cells, and immunotherapy response. Additionally, a nomogram was established with robust predictive power integrating the RiskScore and clinical features. Notably, we observed that PINK1 expression markedly correlated with favorable treatment response and advanced maturation stages of tertiary lymphoid structures, which potentially shed light on enhancing anti-tumor immunity of ccRCC. CONCLUSION: Collectively, this study initially developed a signature associated with mitophagy, which demonstrated an excellent ability to predict the clinical prognosis, TME characterization, and responsiveness to targeted therapy and immunotherapy for ccRCC patients. Of particular note is the pivotal role of PINK1 in mediating the treatment response and immune microenvironment for ccRCC patients.

Identification of sterile a-motif domain-containing 9-like as a potential biomarker in patients with cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is one of the most aggressive malignancies, accounting for approximately 75% of skin cancer-related fatalities annually. Sterile a-motif domain-containing 9-like (SAMD9L) has been found to regulate cell proliferation and suppress the neoplastic phenotype, but its specific role in SKCM remains unknown. To investigate the cancer-associated immunology of SKCM and the role of SAMD9L in tumor progression, we conducted an integrative bioinformatics analysis that revealed elevated expression levels of SAMD9L in SKCM. ROC curves and survival analyses confirmed the considerable diagnostic and prognostic abilities of SAMD9L. Moreover, a real-world cohort of 35 SKCM patients from the First Affiliated Hospital of Soochow University showed that higher expression levels of SAMD9L were associated with better prognosis. We performed validation experiments, including cell culture, generation of lentiviral-transfected SKCM cell lines, cell proliferation assay, and transwell assay, which demonstrated that down-regulation of SAMD9L significantly promoted proliferation and migration capacities of SKCM cells. Additionally, SAMD9L expression was found to be strongly linked to immune infiltration. Our results revealed a positive correlation between SAMD9L and XAF1 expression, suggesting that SAMD9L may serve as a prospective prognostic indicator of SKCM with co-expressed XAF1 gene. In summary, our findings indicate that SAMD9L may serve as a promising prognostic and therapeutic biomarker and play a critical role in tumor-immune interactions in SKCM.

Special issue "The advance of solid tumor research in China": Multi-omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response.

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8+ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.

A Multi-Omics Study on the Effect of Helicobacter Pylori-Related Genes in the Tumor Immunity on Stomach Adenocarcinoma.

Background: Helicobacter pylori (HP), a gram-negative spiral-shaped microaerophilic bacterium, colonizes the stomach of approximately 50% of the world's population, which is considered a risk factor for gastritis, peptic ulcers, gastric cancer, and other malignancies. HP is also considered carcinogenic since it involves the mutation and damage of multiple HP-related genes. Stomach adenocarcinoma (STAD) is a common stom5ach cancer with a poor prognosis and high risk of metastasis in the advanced stage. Therefore, an early diagnosis and targeted therapies are needed to ensure a better prognosis. In this study, a scoring system was constructed based on three HP infection-related candidate genes to enable a more accurate prediction of tumor progression and metastasis and response to immunotherapies. Methods: HP infection-induced mutation patterns of STAD samples from six cohorts were comprehensively assessed based on 73 HP-related genes, which were then correlated with the immune cell-infiltrating characteristics of the tumor microenvironment (TME). The risk signature was constructed to quantify the influence of HP infection on individual tumors. Subsequently, an accurate nomogram was generated to improve the clinical applicability of the risk signature. We conducted immunohistochemical experiments and used the Affiliated Hospital of Youjiang Medical University for Nationalities (AHYMUN) cohort data set with survival information to further verify the clinical value of this risk signature. Results: Two distinct HP-related mutation patterns with different immune cell-infiltrating characteristics (ICIC) and survival possibility were identified. We demonstrated that the evaluation of HP infection-induced mutation patterns of tumor could assist the prediction of stages, phenotypes, stromal activity, genetic diversity, and patient prognosis. A low risk score involved an increased mutation burden and activation of immune responses, with a higher 5-year survival rate and enhanced response to anti-PD-1/L1 immunotherapy, while a high risk score involved stromal activation and poorer survival. The efficiency of the risk signature was further evidenced by the nomogram. Conclusions: STAD patients with a low risk score demonstrated significant therapeutic advantages and clinical benefits. HP infection-induced mutations play a nonnegligible role in STAD development. Quantifying the HP-related mutation patterns of individual tumors will contribute to phenotype classification, guide more effective targeted and personalized therapies, and enable more accurate predictions of metastasis and prognosis.

Protumorigenic Role of Elevated Levels of DNA Polymerase Epsilon Predicts an Immune-Suppressive Microenvironment in Clear Cell Renal Cell Carcinoma.

Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival (p < 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4+ T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.

Genome-wide analyses of the prognosis-related mRNA alternative splicing landscape and novel splicing factors based on large-scale low grade glioma cohort.

Alternative splicing (AS) changes are considered to be critical in predicting treatment response. Our study aimed to investigate differential splicing patterns and to elucidate the role of splicing factor (SF) as prognostic markers of low-grade glioma (LGG). We downloaded RNA-seq data from a cohort of 516 LGG tumors in The Cancer Genome Atlas and analyzed independent prognostic factors using LASSO regression and Cox proportional regression to build a network based on the correlation between SF-related survival AS events. We collected 100 patients from our center for immunohistochemistry and analyzed survival using χ2 test and Cox and Kaplan-Meier analyses. A total of 9,616 AS events related to LGG were screened and identified as well as established related models. Through analyzing specific splicing patterns in LGG, we screened 16 genes to construct a prognostic model to stratify the risk of LGG patients. Validation revealed that the expression level of the prognostic model in LGG tissue was increased, and patients with high expression showed worse prognosis. In summary, we demonstrated the role of SFs and AS events in the progression of LGG, which may provide insights into the clinical significance and aid the future exploration of LGG-associated AS.

Involvement of p75NTR in the effects of Aß on L-type Ca2+ channel in cultured neuronal networks.

Ca2+ overload in neurons has been implicated in Alzheimer's Disease (AD). Upregulation of Ca2+ through L-type Ca2+ channels was known to be involved in the neurodegeneration induced by amyloid-ß (Aß) peptides in AD. However, little is known about the mechanism by which upregulation of L-type Ca2+ channel currents is linked to Aß-induced neuronal toxicity. In the present study, we found that the L-type Ca2+ current in transgenic AD mice (Tg2576) neurons is greater than in wild-type (WT) neurons, and this Ca2+ channel current change were rescued in Tg2576/p75NTR+/- (p75 neurotrophin receptor) neurons. We further examined the changes in the gating of L-type Ca2+ channels following Aß42 treatment, and the results showed that the L-type Ca2+ channel current was significantly increased by Aß42 treatment in WT hippocampal neurons. Blocking or decreasing the expression of p75NTR eliminated the influence of Aß42 on the L-type Ca2+ channel current in WT hippocampal neurons. We also evaluated how Aß42 affected the voltage-dependent activation and inactivation of L-type Ca2+ channels in cultured WT neurons. The results indicated that the half-maximal activation voltage (V1/2) was left shifted, and the half-inactivation voltage (V1/2) displayed a right shift in neuron treated by Aß42. Decreasing the expression of p75NTR eliminated the effect of Aß42 on voltage-dependent activation and inactivation of the L-type Ca2+ channel. These results indicate that Aß42 changes L-type Ca2+ channel currents by modulating the channel's activation and inactivation dynamics, while decreasing p75NTR expression can remove this effect.