Ferroptosis Is Crucial for Cisplatin Induced Sertoli Cell Injury via N6-Methyladenosine Dependent Manner.

PURPOSE: This study aimed to investigate the effect of the N6-methyladenosine (m6A) dependent ferroptosis on cisplatininduced Sertoli cell injury. MATERIALS AND METHODS: A cisplatin exposure mouse model was established by intraperitoneal injection of cisplatin in our study. TM4 cell lines was used for in vitro study. Ferroptosis was detected according to metabolomic analysis and a series of assays, including malondialdehyde, glutathione, and glutathione disulfide concentration detection, 2',7'-dichlorodihydrofluorescein diacetate and BODIPY 581/591 C11 probe detection, and transmission electron microscope imaging. Key ferroptosis-related genes were identified via transcriptomic analysis, western blot and immunohistochemistry. The m6A modification was demonstrated via m6A RNA immunoprecipitation and luciferase reporter assays. Immune cell infiltration was detected by mass cytometry, and verified by flow cytometry and immunofluorescence. RESULTS: Ferroptosis, but not other types of programmed cell death, is a significant phenomenon in cisplatin-induced testis damage and Sertoli cell loss. Ferroptosis induced by cisplatin in Sertoli cell/TM4 cell is GPX4 independent but is regulated by SLC7A11 and ALOX12. Both SLC7A11 and ALOX12 are regulated via m6A dependent manner by METTL3. Furthermore, overexpressed ALOX12-12HETE pathway may result in macrophage polarization and inflammatory response in cisplatin exposure testis. CONCLUSIONS: Cisplatin-induced Sertoli cell injury via ferroptosis and promoted ferroptosis in an m6A dependent manner. m6A modification of both SLC7A11 and ALOX12 mRNA could result in ferroptosis in our in vitro model. Further, overexpressed ALOX12 can cause more production of 12-HETE, which may be responsible for testis inflammation caused by cisplatin.

Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

Unveiling hormone-stimulated gene mechanisms in prostate cancer: A prognostic model, immune infiltration analysis, and drug sensitivity study.

Hormones promote the progression of prostate cancer (PRCA) through the activation of a complex regulatory network. Inhibition of hormones or modulation of specific network nodes alone is insufficient to suppress the entire oncogenic network. Therefore, it is imperative to elucidate the mechanisms underlying the occurrence and development of PRCA in order to identify reliable diagnostic markers and therapeutic targets. To this end, we used publicly available data to analyze the potential mechanisms of hormone-stimulated genes in PRCA, construct a prognostic model, and assess immune infiltration and drug sensitivity. The single-cell RNA-sequencing data of PRCA were subjected to dimensionality reduction clustering and annotation, and the cells were categorized into two groups based on hormone stimulus-related scores. The differentially expressed genes between the two groups were screened and incorporated into the least absolute shrinkage and selection operator machine learning algorithm, and a prognostic model comprising six genes (ZNF862, YIF1A, USP22, TAF7, SRSF3, and SPARC) was constructed. The robustness of the model was validation through multiple methods. Immune infiltration scores in the two risk groups were calculated using three different algorithms. In addition, the relationship between the model genes and immune cell infiltration, and that between risk score and immune cell infiltration were analyzed. Drug sensitivity analysis was performed for the model genes and risk score using public databases to identify potential candidate drugs. Our findings provide novel insights into the mechanisms of hormone-stimulated genes in PRCA progression, prognosis, and drug screening.

Bladder Cancer: Immunotherapy and Pelvic Lymph Node Dissection.

Bladder cancer, a common malignancy of the urinary system, is routinely treated with radiation, chemotherapy, and surgical excision. However, these strategies have inherent limitations and may also result in various side effects. Immunotherapy has garnered considerable attention in recent years as a novel therapeutic approach. It harnesses and activates the patient's immune system to recognize and eliminate cancer cells, which not only prolongs therapeutic efficacy but also minimizes the toxic side effects. Several immune checkpoint inhibitors and cancer vaccines have been developed for the treatment of bladder cancer. Whereas blocking immune checkpoints on the surface of tumor cells augments the effect of immune cells, immunization with tumor-specific antigens can elicit the production of anti-tumor immune effector cells. However, there are several challenges in applying immunotherapy against bladder cancer. For instance, the efficacy of immunotherapy varies considerably across individual patients, and only a small percentage of cancer patients are responsive. Therefore, it is crucial to identify biomarkers that can predict the efficacy of immunotherapy. Pelvic lymph nodes are routinely dissected from bladder cancer patients during surgical intervention in order to remove any metastatic tumor cells. However, some studies indicate that pelvic lymph node dissection may reduce the efficacy of immunotherapy by damaging the immune cells. Therefore, the decision to undertake pelvic lymph node removal should be incumbent on the clinical characteristics of individual patients. Thus, although immunotherapy has the advantages of lower toxic side effects and long-lasting efficacy, its application in bladder cancer still faces challenges, such as the lack of predictive biomarkers and the effects of pelvic lymph node dissection. Further research is needed to explore these issues in order to improve the efficacy of immunotherapy for bladder cancer.

The role of PKP1 in tumor progression in melanoma: Analysis of a cell adhesion-related model.

The incidence rate of melanoma varies across regions, with Europe, the United States, and Australia having 10-25, 20-30, and 50-60 cases per 1 00 000 people. In China, patients with melanoma exhibit different clinical manifestations, pathogenesis, and outcomes. Current treatments include surgery, adjuvant therapy, and immune checkpoint inhibitors. Nonetheless, complications may arise during treatment. Melanoma development is heavily reliant on cell adhesion molecules (CAMs), and studying these molecules could provide new research directions for metastasis and progression. CAMs include the integrin, immunoglobulin, selectin, and cadherin families, and they affect multiple processes, such as maintenance, morphogenesis, and migration of adherens junction. In this study, a cell adhesion-related risk prognostic signature was constructed using bioinformatics methods, and survival analysis was performed. Plakophilin 1 (PKP1) was observed to be crucial to the immune microenvironment and has significant effects on melanoma cell proliferation, migration, invasion, and the cell cycle. This signature demonstrates high reliability and has potential for clinical applications.

Ovarian cancer treatment and natural killer cell-based immunotherapy.

Background: Ovarian cancer (OC) is one of the malignant tumors that poses a serious threat to women's health. Natural killer (NK) cells are an integral part of the immune system and have the ability to kill tumor cells directly or participate indirectly in the anti-tumor immune response. In recent years, NK cell-based immunotherapy for OC has shown remarkable potential. However, its mechanisms and effects remain unclear when compared to standard treatment. Methods: To explore the value of NK cell-based immunotherapy in the treatment of OC, we conducted a literature review. In comparison to standard treatment, our focus was primarily on the current anti-tumor mechanisms, the clinical effect of NK cells against OC, factors affecting the structure and function of NK cells, and strategies to enhance the effectiveness of NK cells. Results: We found that NK cells exert their therapeutic effects in OC through mechanisms such as antibody-dependent cell cytotoxicity, perforin release, and granule enzyme secretion. They also secrete IFN-γ and TNF-α or engage in Fas/FasL and TRAIL/TRAILR pathways, mediating the death of OC cells. In clinical trials, the majority of patients experienced disease stability with mild side effects after receiving NK cell-based immunotherapy, but there is still a lack of high-quality research evidence regarding its clinical effectiveness. OC and prior experience with standard treatments have an effect on NK cells, and it may be considered to maximize NK cell effects through the modulation of the tumor microenvironment or combination with other therapies. Conclusions: In this review, we have summarized the current evidence of NK cell applications in the treatment of OC. Furthermore, factors and strategies that influence and enhance the role of NK cell immunotherapy are discussed.

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma.

BACKGROUND: Alternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level. METHODS: We adopted a gap analysis to screen for significant differential AS events (DASEs) associated with BLCA. DASEs with prognostic value for OS and the disease-free interval (DFI) were identified by Cox analysis. In addition, a differential AS network and AS clusters were identified using unsupervised cluster analysis. We examined differences in the sensitivity to chemotherapy and immunotherapy between BLCA patients with high and low overall survival (OS) risk. RESULTS: An extensive number of DASEs (296) were found to be clinically relevant in BLCA. A prognosis model was established based prognostic value of OS and DFI. CUGBP elav-like family member 2 (CELF2) was identified as a hub splicing factor for AS networks. We also identified AS clusters associated with OS using unsupervised cluster analysis, and we predicted that the effects of cisplatin and gemcitabine chemotherapy would be different between high- and low-risk groups based on OS prognosis. CONCLUSION: We completed a comprehensive analysis of AS events in BLCA at the genome-wide level. The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.