Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

The emerging roles of glutamine amidotransferases in metabolism and immune defense.

Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.

Tumors cells with mismatch repair deficiency induce hyperactivation of pyroptosis resistant to cell membrane damage but are more sensitive to co-treatment of IFN-γ and TNF-α to PANoptosis.

Hypermutated neoantigens in cancers with DNA mismatch repair deficiency (dMMR) are prerequisites for favorable clinical responses to immune-checkpoint blockade (ICB) therapy. However, TMB is not significantly associated with favorable prognosis from Preclinical and clinical studies. It implies that except for TMB, other mechanisms should be needed to contribute to successful cancer immunotherapy. We found that the hyperactivation of PANoptotic effective molecules in dMMR tumor cells caused cell membrane damage, induced ESCRT-mediated membrane repair, and protected tumor cells from the damage caused by Triton X-100, while DNA mismatch repair proficient (pMMR) tumor cells were sensitive to Triton X-100 mediating cell membrane damage due to the lack of ESCRT-mediated membrane repair. There was hyperactivation of GSDMD, GSDME, and p-MLKL in dMMR tumor cells. Co-treatment of IFN-γ and TNF-α induced rapid death of dMMR tumor cells by inducing PANoptosis including pyroptosis, apoptosis, and no necrosis. pMMR tumor cells had defects in the PANoptosis pathway and were resistant to co-treatment of IFN-γ and TNF-α. In conclusion, we can activate immune cells to release IFN-γ and TNF-α to overcome resistance to ICB treatment.

Interaction of immune cells with renal cancer development: Mendelian randomization (MR) study.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent and extensively immune-infiltrated malignancy of the urinary system. Immune cells play a crucial role in both the progression and therapeutic interventions targeting RCC. Nevertheless, the interplay between RCC and immune cells remains understudied, lacking substantial evidence supporting their causal relationship. METHODS: For the purpose of investigating the causal connection between RCC and immune cell characteristics, a two-way two-sample Mendelian randomization (MR) analysis was carried out in this study. The aim was to determine whether specific immune cell traits have a causal impact on the risk of RCC. In order to achieve this, publicly accessible genetic data was utilized to examine and establish the potential relationship between 731 immune cell characteristics and the likelihood of developing RCC. Additionally, various techniques were applied to verify the reliability, variability, and presence of horizontal pleiotropy in the outcomes. RESULTS: We found a bidirectional causal relationship between RCC and immune cells according to the MR analysis results. It should be noted that CD4-CD8-T cells (OR = 1.61, 95%CI = 1.02-2.55, P = 4.07 × 10-2) pose a risk for RCC, whereas BAFF-R (OR = 0.69, 95%CI = 0.53-0.89, P = 5.74 × 10-3) and CD19 (OR = 0.59, 95%CI = 1.02-2.55, P = 4.07 × 10-2) on B cells act as protective factors. Furthermore, the presence of RCC reduces the levels of B cells (OR = 1.05, 95%CI = 1.01-1.09, P = 1.19 × 10-2) and CD8 + T cells (OR = 1.04, 95%CI = 1.00-1.08, P = 2.83 × 10-2). CONCLUSIONS: Our research illustrates the intricate correlation between immune cells and RCC, presenting novel insights for the prospective safeguarding against RCC risk and the exploration of fresh therapeutic targets.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Degradation of the emerging brominated flame retardant tetrabromobisphenol S using organo-montmorillonite supported nanoscale zero-valent iron.

The widespread occurrence of emerging brominated flame retardant tetrabromobisphenol S (TBBPS) has become a major environmental concern. In this study, a nanoscale zero-valent iron (nZVI) impregnated organic montmorillonite composite (nZVI-OMT) was successfully prepared and utilized to degrade TBBPS in aqueous solution. The results show that the nZVI-OMT composite was very stable and reusable as the nZVI was well dispersed on the organic montmorillonite. Organic montmorillonite clay layers provide a strong support, facilitate well dispersion of the nZVI chains, and accelerate the overall TBBPS transformation with a degradation rate constant 5.5 times higher than that of the original nZVI. Four major intermediates, including tribromobisphenol S (tri-BBPS), dibromobisphenol S (di-BBPS), bromobisphenol S (BBPS), and bisphenol S (BPS), were detected by high-resolution mass spectrometry (HRMS), indicating sequential reductive debromination of TBBPS mediated by nZVI-OMT. The effective elimination of acute ecotoxicity predicted by toxicity analysis also suggests that the debromination process is a safe and viable option for the treatment of TBBPS. Our results have shown for the first time that TBBPS can be rapidly degraded by an nZVI-OMT composite, expanding the potential use of clay-supported nZVI composites as an environmentally friendly material for wastewater treatment and groundwater remediation.

Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors.

Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

Comparison of anterior cervical diskectomy with fusion (ACDF) and laminoplasty treating multilevel cervical spondylotic myelopathy with developmental canal stenosis: a retrospective study.

PURPOSE: To evaluate clinical effectiveness and radiologic results of anterior cervical diskectomy with fusion (ACDF) comparing with laminoplasty (LP) in treating multilevel cervical spondylotic myelopathy (MCSM) with developmental canal stenosis (DCS). METHODS: This was a retrospective analysis of 41 patients who had MCSM with DCS treated with ACDF or LP from December 2018 to April 2023. Patients were split into ACDF and LP groups for comparison, and patients were further separated into subgroups based on whether or not a reserving canal space was present. The operation time, hemoglobin, hospital stay, modified Japanese Orthopaedic Association (mJOA) score, and visual analog scale (VAS) score were used to assess clinical efficacy. The C2-C7 Cobb angle, C2-C7 sagittal vertical axis, T1 slope, and cervical range of motion were applied to evaluate imaging changes. RESULTS: Of the 41 patients, 19 received ACDF, and 22 received LP. At the final follow-up, both groups' mJOA scores significantly improved, and the intercomparison showed no differences; the VAS score was much lower in the ACDF group but remained unchanged in the LP group. At the final follow-up, the C2-C7 Cobb angle and T1 slope had significantly increased in the ACDF group, while the LP group showed no change; the cervical range of motion had significantly decreased in both groups, with the ACDF group exhibiting a more marked reduction. Within the ACDF subgroup, there was no postoperative symptom improvement for those with reserving space, whereas there was postoperative symptom resolution for those with non-reserving space; however, postoperative symptom in the LP subgroup was resolved. CONCLUSIONS: Both ACDF and LP were efficacious for MCSM patients with DCS. While ACDF could improve cervical lordosis and alleviate neck pain more effectively, it can also result in cervical sagittal imbalance and decreased mobility. Furthermore, the recovery from LP was superior to that from ACDF for patients with reserving space. In contrast, the recovery from both decompression techniques was comparable for individuals in non-reserving space.

Advances and challenges of first-line immunotherapy for non-small cell lung cancer: A review.

The current use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has dramatically changed the clinical strategy for metastatic non-small cell lung cancer (mNSCLC). As a result of great achievements in clinical trials, 6 programmed death-1 inhibitors (sintilimab, camrelizumab, tislelizumab, pembrolizumab, cemiplimab, and nivolumab), 2 programmed death-ligand 1 inhibitors (sugemalimab and atezolizumab), and 1 cytotoxic T lymphocyte-associated antigen-4 inhibitor (ipilimumab) have been approved as first-line treatment for mNSCLC by the US Food and Drug Administration. Recently, research on ICIs has shifted from a large number of second-line to first-line settings in clinical trials. Results from first-line trials have shown that almost all driver-negative mNSCLC are treated with ICIs and significantly prolong patient survival; however, the low response rate and adverse reactions to immunotherapy remain to be addressed. Here, we summarize the use of ICIs, including monotherapy and combination therapy, in the first-line treatment of mNSCLC in recent years and discuss the low response rate and adverse reactions of ICIs as well as the challenges and expectations for the first-line treatment of mNSCLC in the future.

Bisphenol A promote the cell proliferation and invasion ability of prostate cancer cells via regulating the androgen receptor.

A synthetic organic substance called bisphenol A (BPA) is used to make polyester, epoxy resin, polyacrylate, and polycarbonate plastic. BPA exposure on a regular basis has increased the risk of developing cancer. Recent research has shown that there is a strong link between BPA exposure and a number of malignancies. We want to investigate any connections between BPA and prostate cancer in this work. The scores of bisphenols in the prostate cancer cohort were obtained using the ssGSEA algorithm. The analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was used to investigate probable pathways that are closely related to the genes tied to BPA. The BPA-based risk model was built using regression analysis. Additionally, the molecular docking method was employed to assess BPA's capacity to attach to important genes. Finally, we were able to successfully get the BPA cohort ratings for prostate cancer patients. Additionally, the KEGG enrichment study showed that of the malignancies linked to BPA, prostate cancer is the most highly enriched. In a group of men with prostate cancer, the BPA-related prognostic prediction model exhibits good predictive value. The BPA demonstrated strong and efficient binding to the androgen receptor, according to the molecular docking studies. According to cell proliferation and invasion experiments, exposing prostate cancer cells to BPA at a dosage of 10-7 uM could greatly enhance their ability to proliferate and invade.

Comprehensive analysis of the impact of emerging flame retardants on prostate cancer progression: The potential molecular mechanisms and immune infiltration landscape.

Emerging flame retardants have been used to replace traditional flame retardants, but their potential impact on cancer, especially prostate cancer, is not well understood. Our study aimed to explore the link between flame retardants and prostate cancer, and identify potential carcinogenic mechanisms among populations exposed to emerging flame retardants. We screened flame retardant interacting genes differentially expressed in prostate cancer patients and identified hub genes by protein-protein interaction (PPI) analysis based on the STRING database. Univariate and multivariate Cox regression analyses were performed to construct risk models and identify flame retardant-related prognostic genes. We calculated the proportion of immune cell infiltration to explore the potential mechanism of the prognostic gene, and verified the target cell population of the prognostic gene in the single-cell transcriptome dataset. Our study revealed a significant link between emerging flame retardants and prostate cancer. We constructed a risk model with good predictive ability for prostate cancer prognosis using TCGA dataset, and identified six flame retardant-related prognostic genes validated in the GSE70769 dataset. We found that the expression of M2 macrophages was up-regulated in patients with high expression of prognostic genes, and the single-cell dataset confirmed the expression of prognostic genes in macrophages. Our study confirms the link between emerging flame retardants and prostate cancer, and highlights the role of immune-related pathways in the high-risk population exposed to these flame retardants.

CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling.

Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.

Safety evaluation of PEGylated MNPs and p-PEGylated MNPs in SD rats.

Polyethylene glycol-coated magnetic nanoparticles (PEGylated MNPs) have demonstrated prominent advantages in cancer diagnosis and hyperthermia therapy. However, there is currently lack of standard mode and sufficient toxicity data for determining the delayed risk of PEGylated MNPs. Nevertheless, the toxicity potentials, especially those associated with the oxidative stress, were ubiquitously reported. In this study, PEGylated MNPs and p-PEGylated MNPs were administrated to SD (Sprague Dawley) rats by single intravenously injection, and various toxicity indicators were monitored till 56 days post-administration for a comprehensive toxicity evaluation. We revealed that both nanoparticles could be rapidly cleared from plasma and enter tissues, such as, liver, kidneys and spleen, and p-PEGylated MNP is less prone to be accumulated in the tissues, indicating a lower toxicity risk. PEGylated MNPs were more likely to up-regulate the expression levels of Th2 type cytokines and trigger inflammatory pathways, but no related pathological change was found. Both MNPs are not mutagenic, while recoverable mild DNA damage associated with the presence of nanoparticles might also be observed. This study demonstrated a research approach for the non-clinical safety evaluation of nanoparticles. It also provided comprehensive valuable safety data for PEGylated and p-PEGylated MNPs, for promoting the clinical application and bio-medical translation of such MNPs with PEG modifications in the cancer diagnosis and therapy.

OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis.

O-GlcNAc transferase (OGT) acts in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC.

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk.

Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159-1.583, P = 1.33 × 10 -4; rs2683524: OR = 1.378, 95% CI: 1.164-1.632, P = 2.03 × 10 -4; rs11540872: OR = 1.472, 95% CI: 1.193-1.815, P = 3.06 × 10 -4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer ( P trend = 2.87 × 10 -12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3' untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

Cuproptosis in ccRCC: key player in therapeutic and prognostic targets.

Background: Classical biomarkers have been used to classify clear cell renal cell carcinoma (ccRCC) patients in a variety of ways, and emerging evidences have indicated that cuproptosis is closely related to mitochondrial metabolism, thereby accelerating the development and progression of ccRCC. Nevertheless, the specific relationship between cuproptosis and the prognosis and treatment of ccRCC remains unclear. Methods: We comprehensively integrated several ccRCC patient datasets into a large cohort. Following that, we systematically analyzed multi-omics data to demonstrate the differences between two cuproptosis clusters. Results: We identified two cuproptosis clusters in ccRCC patients. Among the two clusters, cluster 1 patients showed favorable prognosis. We then confirmed the significant differences between the two clusters, including more typical cancer hallmarks were enriched in cluster 2 patients; cluster 2 patients were more susceptible to develop mutations and had a lower level of gistic score and mRNAsi. Importantly, both Tumor Immune Dysfunction and Exclusion analysis and subclass mapping algorithm showed that cuproptosis 1 patients were more susceptible to be responded to immunotherapy. In addition, a prognostic signature was successfully developed and also showed prominent predictive power in response to immunotherapy. Conclusion: As a result of our findings, we were able to classify ccRCC patients according to cuproptosis in a novel way. By constructing the cuproptosis clusters and developing the signature, patients with ccRCC could have a more accurate prognosis prediction and better immunotherapy options.

Integrative analysis of triphenyl phosphate: contextual interpretation of bladder cancer cohort.

In recent years, organophosphate ester flame retardants (OPFRs) have emerged as preferred alternatives to brominated flame retardants (BFRs) in materials such as building supplies, textiles, and furnishings. Simultaneously, a notable surge in bladder cancer incidences has been observed globally, particularly in developed nations, placing it as the 10th most prevalent cancer type. Among the extensive OPFRs, the linkage between triphenyl phosphate (TPP) and bladder cancer remains inadequately investigated. Hence, our study endeavors to elucidate this potential association. We sourced transcriptome profiles and TPP-related data from The Cancer Genome Atlas and Comparative Toxicogenomics databases. Using the ssGSEA algorithm, we established TPP-correlated scores within the bladder cancer cohort. Differentially expressed analysis enabled us to identify key genes in bladder cancer patients. We utilized the LASSO regression analysis, along with univariate and multivariate COX regression analyses to construct a prognostic prediction model. To uncover critical pathways involving key genes, we employed GSEA and GSVA enrichment analyses. Molecular docking analysis was performed to determine the binding capability between TPP and proteins. Our findings reveal that the TPP-centric risk model offers valuable prediction for bladder cancer cohorts. Furthermore, the reliability of this TPP-influenced risk model was verified through ROC curve analysis and survival studies. Intriguingly, TPP exposure appears to bolster the proliferation and invasiveness of bladder cancer cells. This study furnishes new insights into the possible benefits of minimizing TPP exposure for hindering bladder cancer progression.

MLKL regulates Cx43 ubiquitinational degradation and mediates neuronal necroptosis in ipsilateral thalamus after focal cortical infarction.

Necroptosis is known to play an important role in the pathophysiology of cerebral ischemia; however, its role in the occurrence of secondary thalamic injury after focal cerebral infarction and the mechanism about how mixed lineage kinase domain-like (MLKL) executes necroptosis in this pathophysiology are still unclear. In this study, Sprague-Dawley rats were subjected to distal branch of middle cerebral artery occlusion (dMCAO). The expression of MLKL, connexin 43 (Cx43) and Von Hippel-Lindau (VHL) in vitro and in vivo were assessed by Western blot. Bioinformatic methods were used to predict the potential binding sites where MLKL interacted with Cx43, and the ubiquitination degradation of Cx43 regulated by VHL. The interactions among MLKL, Cx43, VHL, and Ubiquitin were assessed by immunoprecipitation. Dye uptake assay were used to examine the Cx43 hemichannels. Intracellular Ca2+ concentration was measured using Fluo-4 AM. Overexpression and site-directed mutagenesis studies were used to study the mechanisms by which MLKL regulates Cx43 ubiquitinational degradation to mediate neuronal necroptosis. We found that MLKL and Cx43 were upregulated in the ventral posterolateral nucleus (VPN) of the ipsilateral thalamus after dMCAO. In the in vitro experiments MLKL and Cx43 were upregulated after TSZ-mediated necroptosis in SH-SY5Y cells. The interaction between MLKL and Cx43 inhibited the K48-linked ubiquitination of Cx43 in necroptotic SH-SY5Y cells. VHL is an E3 ubiquitin ligase for Cx43, and MLKL competes with VHL for binding to Cx43. Interaction of MLKL Ser454 with Cx43 can trigger the opening of Cx43 hemichannels, causing increased intracellular Ca2+, and cell necroptosis. This innovative study at animal models, cellular, and molecular levels is anticipated to clarify the roles of MLKL and Cx43 in thalamic damage after focal cortical infarction. Our findings may help identify novel targets for neurological recovery after cortical infarction.

Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.