The role of immune metabolism in skin cancers: implications for pathogenesis and therapy.

The skin is a complex organ that serves as a critical barrier against external pathogens and environmental impact. Recent advances in immunometabolism have highlighted the intricate link between cellular metabolism and immune function, particularly in the context of skin cancers. This review aims to provide a comprehensive overview of the key metabolic pathways and adaptations that occur in immune cells during homeostasis and activation, and explore how metabolic reprogramming contributes to the pathogenesis of specific skin cancers. We discuss the complex interplay between tumor cells and infiltrating immune cells, which shapes the tumor microenvironment and influences disease outcomes. The review delves into the role of various metabolic pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, in the regulation of immune cell function and their impact on the development and progression of skin cancers. Furthermore, we examine the potential of targeting metabolic pathways as a therapeutic strategy in skin cancers and discuss the challenges and future perspectives in this rapidly evolving field. By understanding the metabolic basis of skin immune responses, we can develop novel, personalized therapies for the treatment of skin cancers, ultimately improving patient outcomes and quality of life. The insights gained from this review will contribute to the growing body of knowledge in immunometabolism and its application in the management of skin cancers, paving the way for more effective and targeted interventions in the future.

Advancing primate surveillance with image recognition techniques from unmanned aerial vehicles.

Using unmanned aerial vehicles (UAVs) for surveys on thermostatic animals has gained prominence due to their ability to provide practical and precise dynamic censuses, contributing to developing and refining conservation strategies. However, the practical application of UAVs for animal monitoring necessitates the automation of image interpretation to enhance their effectiveness. Based on our past experiences, we present the Sichuan snub-nosed monkey (Rhinopithecus roxellana) as a case study to illustrate the effective use of thermal cameras mounted on UAVs for monitoring monkey populations in Qinling, a region characterized by magnificent biodiversity. We used the local contrast method for a small infrared target detection algorithm to collect the total population size. Through the experimental group, we determined the average optimal grayscale threshold, while the validation group confirmed that this threshold enables automatic detection and counting of target animals in similar datasets. The precision rate obtained from the experiments ranged from 85.14% to 97.60%. Our findings reveal a negative correlation between the minimum average distance between thermal spots and the count of detected individuals, indicating higher interference in images with closer thermal spots. We propose a formula for adjusting primate population estimates based on detection rates obtained from UAV surveys. Our results demonstrate the practical application of UAV-based thermal imagery and automated detection algorithms for primate monitoring, albeit with consideration of environmental factors and the need for data preprocessing. This study contributes to advancing the application of UAV technology in wildlife monitoring, with implications for conservation management and research.

Cervical facet joint degeneration, facet joint angle and paraspinal muscle degeneration are correlated with degenerative cervical spondylolisthesis at C4/5: a propensity score-matched study.

BACKGROUND CONTEXT: Prior studies have hypothesized that degenerative cervical spondylolisthesis (DCS) may be influenced by loss of stability due to disc, facet joint or cervical alignment. Meanwhile, it is commonly believed that the facet joints and paraspinal muscles participate in maintaining cervical spine stability. However, the impact of paraspinal muscle morphology and detailed facet joint features on DCS requires further investigation. PURPOSE: To compare facet joint characteristics, disc degeneration and muscle morphology between patients with DCS and those without DCS. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Consecutive surgical patients with degenerative cervical spondylosis from June 2016 to August 2023 were recruited. OUTCOME MEASURES: DCS was assessed on X-ray based on the translation distance. Cervical facet joint degeneration (CFD), the facet joint angle on the axial plane (FA-A) and the facet joint angle on the sagittal plane (FA-S), and facet joint tropism (FT) were measured on computerized tomography (CT). Paraspinal muscle degeneration was assessed on magnetic resonance imaging (MRI) including by the adjusted cross-sectional area (aCSA), the functional aCSA, the fat infiltration ratio (FI%). The Pfirrmann grade of the cervical disc was also evaluated. METHODS: Demographic and clinical data were compared in matched and unmatched cohorts. Disc degeneration, muscle degeneration and facet joint characteristics, including FA, FT and CFD, were compared between patients with and without DCS. Furthermore, the degree of CFD was compared with that of adjacent segments in both groups. Additionally, logistic regression was performed to determine independent risk factors for DCS. Finally, the receiver operating characteristic (ROC) curve, area under the curve (AUC) and cutoff value for the risk factors were calculated. RESULTS: A total of 431 surgical patients were propensity score matched for age, sex and BMI, and 146 patients were included in the final analysis, with 73 patients in the DCS group and 73 patients in the non-DCS group. DCS patients exhibited more severe CFD at C4/5 (segment with spondylolisthesis). Additionally, DCS was generally associated with more severe CFD, a more horizontal FA-S, more FT and worse paraspinal muscle health but similar disc degeneration. In addition, anterior spondylolisthesis was related to more severe CFD and decreased functional aCSA of the flexors and extensors. Finally, more severe CFD, a more horizontal FA-S and a higher FI% on deep extensor were revealed to be risk factors for DCS, with cutoff values of 1.5, 44.5̊, and 37.1%, respectively. CONCLUSIONS: This study demonstrated that CFD, the FA and FT and parasipnal muscle degeneration were associated with DCS. And may provide novel insight into the pathogenesis and nature history of DCS and suggest the evolution of degeneration in the cervical spine.

Genomic profiling of a multi-lineage and multi-passage patient-derived xenograft biobank reflects heterogeneity of ovarian cancer.

Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/ß-catenin signaling contribute to acquired DDRi drug resistance.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Glutamine Mitigates Oxidative Stress-Induced Matrix Degradation, Ferroptosis, and Pyroptosis in Nucleus Pulposus Cells via Deubiquitinating and Stabilizing Nrf2.

Aims: Intervertebral disc degeneration (IDD) is closely related to low back pain, which is a prevalent age-related problem worldwide; however, the mechanism underlying IDD is unknown. Glutamine, a free amino acid prevalent in plasma, is recognized for its anti-inflammatory and antioxidant properties in various diseases, and the current study aims to clarify the effect and mechanism of glutamine in IDD. Results: A synergistic interplay was observed between pyroptosis and ferroptosis within degenerated human disc specimens. Glutamine significantly mitigated IDD in both ex vivo and in vivo experimental models. Moreover, glutamine protected nucleus pulposus (NP) cells after tert-butyl hydroperoxide (TBHP)-induced pyroptosis, ferroptosis, and extracellular matrix (ECM) degradation in vitro. Glutamine protected NP cells from TBHP-induced ferroptosis by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitin-proteasome degradation and inhibiting lipid oxidation. Innovation and Conclusions: A direct correlation is evident in the progression of IDD between the processes of pyroptosis and ferroptosis. Glutamine suppressed oxidative stress-induced cellular processes, including pyroptosis, ferroptosis, and ECM degradation through deubiquitinating Nrf2 and inhibiting lipid oxidation in NP cells. Glutamine is a promising novel therapeutic target for the management of IDD.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPKα lactylation in intervertebral disc degeneration.

Regulating metabolic disorders has become a promising focus in treating intervertebral disc degeneration (IDD). A few drugs regulating metabolism, such as atorvastatin, metformin, and melatonin, show positive effects in treating IDD. Glutamine participates in multiple metabolic processes, including glutaminolysis and glycolysis; however, its impact on IDD is unclear. The current study reveals that glutamine levels are decreased in severely degenerated human nucleus pulposus (NP) tissues and aging Sprague-Dawley (SD) rat nucleus pulposus tissues, while lactate accumulation and lactylation are increased. Supplementary glutamine suppresses glycolysis and reduces lactate production, which downregulates adenosine-5'-monophosphate-activated protein kinase α (AMPKα) lactylation and upregulates AMPKα phosphorylation. Moreover, glutamine treatment reduces NP cell senescence and enhances autophagy and matrix synthesis via inhibition of glycolysis and AMPK lactylation, and glycolysis inhibition suppresses lactylation. Our results indicate that glutamine could prevent IDD by glycolysis inhibition-decreased AMPKα lactylation, which promotes autophagy and suppresses NP cell senescence.

Application of a Magnetic Resonance Imaging-Based Lumbar Vertebral Bone Quality Scoring System in Patients with Degenerative Lumbar Scoliosis.

BACKGROUND: Although dual-energy X-ray absorptiometry is still the gold standard for diagnosing osteoporosis, it can lead to inaccurate bone mineral density measurements due to lumbar degeneration and scoliosis. Many researchers have investigated diagnostic methods for osteoporosis in patients with degenerative lumbar scoliosis (DLS). This study aimed to investigate the differences between conventional vertebral bone quality (VBQ) scores and modified VBQ scores in patients with DLS and the influence of lumbar scoliosis on VBQ scores. METHODS: We retrospectively collected the clinical and radiological data of 68 patients with DLS admitted to Sun Yat-sen Memorial Hospital from July 2018 to April 2023. The patients were classified into one of 2 groups based on the T score of the left femoral neck. VBQ scores relative to cerebrospinal fluid at different levels, VBQ scores on different planes and single-level VBQ scores were compared. Receiver operating characteristic analysis was also performed. Different modified VBQ scores were compared between the moderate scoliosis group (10°

Bone mineral density in patients with primary ovarian insufficiency: A systematic review and Meta-Analysis.

INTRODUCTION: Premature menopause is a major complication of primary ovarian insufficiency (POI), and this loss is closely relates to bone mineral density (BMD). Previous research has indicated potential associations between BMD and POI. This study set out to provide the first systematic literature review and meta-analysison account of BMD content among women with POI. METHODS: Studies including women with POI and controls were eligible from PubMed, Embase, Cochrane Library and Web of Science databases (from their inception to April 2022). Two reviewers independently evaluated study eligibility. The meta-analysis was performed using the DerSimonian and Laird random effects model. RESULTS: Ten studies featuring 578 women with POI and 480 controls were selected. BMD content of femur neck (SMD:-0.76; 95 % CI: -1.20 to -0.31; P = 0.0008), the BMD content of nondominating forearm (SMD:-0.67; 95 % CI: -1.15 to -0.18; P = 0.007) were significantly decreased in women with POI. However, no differences were seen in other regions (lumbar spine, total hip, hipneck). DISCUSSION: The results of this study indicate that BMD content altered in patients with primary ovarian insufficiency. An implication of this is the possibility that hormone replacement therapy to minimize the prevalence of fracture morbidity and mortality associated with osteopenia in patients with POI.

Identification of HSP90B1 in pan-cancer hallmarks to aid development of a potential therapeutic target.

Heat shock proteins play crucial roles in various biochemical processes, encompassing protein folding and translocation. HSP90B1, a conserved member of the heat shock protein family, growing evidences have demonstrated that it might be closely associated with cancer development. In the present study, we employed multi-omics analyses and cohort validations to explore the dynamic expression of HSP90B1 in pan-cancer and comprehensively evaluate HSP90B1 as a novel biomarker that hold promise for precision cancer diagnostics and therapeutics. The results suggest HSP90B1 was highly expressed in various kinds of tumors, often correlating with a poor prognosis. Notably, methylation of HSP90B1 emerged as a protective factor in several cancer types. In immune infiltration analysis, the expression of HSP90B1 in most tumors showed a negative association with CD8 + T cells. HSP90B1 expression was positively correlated with microsatellite instability and tumor mutational burden. HSP90B1 expression was also discovered to be positively correlated with tumor metabolism, cell cycle-related pathways and the expression of immune checkpoint genes. The expression of HSP90B1 was mainly negatively correlated with immunostimulatory genes and positively correlated with immunosuppressive genes, as well as strongly correlated with chemokines and their receptor genes. In addition, the HSP90B1 inhibitor PU-WS13 demonstrated significant efficacy in suppressing cancer cell proliferation in both leukemic and solid tumor cells, and remarkably reduced the expression of the cancer cell surface immune checkpoint PD-L1. The single-cell RNA sequencing analysis further highlighted that HSP90B1 was significantly higher in tumor cells compared to surrounding cells, revealing a potential target therapeutic window. Taken together, HSP90B1 emerges as a promising avenue for breakthroughs in cancer diagnosis, prognosis and therapy. This study provides a rationale for HSP90B1 targeted cancer diagnosis and therapy in future.

Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance.

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor ß pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.

MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC.

BACKGROUND: Although the clinical application of PARP inhibitors has brought hope to ovarian cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance monitoring of PARP inhibitors. RESULTS: By cfDNA detecting during Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, we found the presence of MRE11:p.K464R mutation was strongly associated with acquired Olaparib resistance. Structural analysis revealed that the MRE11:p.K464R mutation is situated at a critical site where the MRE11 protein interacts with other biomolecules, leading to potential structural and functional abnormalities of MRE11 protein. Functionally, MRE11:p.K464R mutation enhanced the tolerance of Olaparib by reducing the DNA damage. Mechanistically, MRE11:p.K464R mutation improved the efficiency of DNA damage repair and induce Olaparib resistance by enhancing its binding activity with the interacting proteins (including RAD50 and RPS3). Among them, the enhanced binding of MRE11:p.K464R mutation to RAD50/RPS3 facilitated non-homologous end joining (NHEJ) repair in tumor cells, thereby expanding the scope of research into acquired resistance to PARP inhibitors. CONCLUSIONS: Our findings provide a theoretical basis for MRE11:p.K464R mutation as a specific indicator of resistance monitoring in Olaparib treatment, and the exploration of its resistance mechanism provides a novel insights for the formulation of combination ther therapies after Olaparib resistance.

Pan-cancer analysis of IFN-γ with possible immunotherapeutic significance: a verification of single-cell sequencing and bulk omics research.

Background: Interferon-gamma (IFN-γ), commonly referred to as type II interferon, is a crucial cytokine that coordinates the tumor immune process and has received considerable attention in tumor immunotherapy research. Previous studies have discussed the role and mechanisms associated with IFN-γ in specific tumors or diseases, but the relevant role of IFN-γ in pan-cancer remains uncertain. Methods: TCGA and GTEx RNA expression data and clinical data were downloaded. Additionally, we analyzed the role of IFN-γ on tumors by using a bioinformatic approach, which included the analysis of the correlation between IFN-γ in different tumors and expression, prognosis, functional status, TMB, MSI, immune cell infiltration, and TIDE. We also developed a PPI network for topological analysis of the network, identifying hub genes as those having a degree greater than IFN-γ levels. Result: IFN-γ was differentially expressed and predicted different survival statuses in a majority of tumor types in TCGA. Additionally, IFN-γ expression was strongly linked to factors like infiltration of T cells, immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors, as well as tumor purity, functional statuses, and prognostic value. Also, prognosis, CNV, and treatment response were all substantially correlated with IFN-γ-related gene expression. Particularly, the IFN-γ-related gene STAT1 exhibited the greatest percentage of SNVs and the largest percentage of SNPs in UCEC. Elevated expression levels of IFN-γ-related genes were found in a wide variety of tumor types, and this was shown to be positively linked to drug sensitivity for 20 different types of drugs. Conclusion: IFN-γ is a good indicator of response to tumor immunotherapy and is likely to limit tumor progression, offering a novel approach for immunotherapy's future development.

Is there an association between the lunar phases and hospital admission for different episode types in bipolar disorder? A retrospective study in northern China.

The effects of the moon on mental activities remain contentious. Few studies have investigated associations between lunar phases and different types of bipolar disorder (BD) episodes. In the current study, 7,452 patients with BD from three hospitals were enrolled. Patients were divided into two groups on the basis of episode types, and the effects of lunar phase were examined for each type. The cosinor analysis revealed moon-related rhythmicity in admissions for BD in a period of 14.75 days. There were fewer admissions around the new moon and the full moon. There was no significant difference between different groups in acrophase. There was possibly a temporal lag between the onset of BD and hospitalization. Thus, it is too early to draw firm conclusions about the impact of lunar phases on BD. Sleep might be a middle way from moon effect to admissions of BD. These results have implications for future disease prevention strategies and research.

Rosuvastatin suppresses TNF-α-induced matrix catabolism, pyroptosis and senescence via the HMGB1/NF-κB signaling pathway in nucleus pulposus cells.

Intervertebral disc degeneration is mainly caused by irregular matrix metabolism in nucleus pulposus cells and involves inflammatory factors such as TNF-α. Rosuvastatin, which is widely used in the clinic to reduce cholesterol levels, exerts anti-inflammatory effects, but whether rosuvastatin participates in IDD remains unclear. The current study aims to investigate the regulatory effect of rosuvastatin on IDD and the potential mechanism. In vitro experiments demonstrate that rosuvastatin promotes matrix anabolism and suppresses catabolism in response to TNF-α stimulation. In addition, rosuvastatin inhibits cell pyroptosis and senescence induced by TNF-α. These results demonstrate the therapeutic effect of rosuvastatin on IDD. We further find that HMGB1, a gene closely related to cholesterol metabolism and the inflammatory response, is upregulated in response to TNF-α stimulation. HMGB1 inhibition or knockdown successfully alleviates TNF-α-induced ECM degradation, senescence and pyroptosis. Subsequently, we find that HMGB1 is regulated by rosuvastatin and that its overexpression abrogates the protective effect of rosuvastatin. We then verify that the NF-κB pathway is the underlying pathway regulated by rosuvastatin and HMGB1. In vivo experiments also reveal that rosuvastatin inhibits IDD progression by alleviating pyroptosis and senescence and downregulating HMGB1 and p65. This study might provide new insight into therapeutic strategies for IDD.

MicroRNA-155 suppressed cholesterol-induced matrix degradation, pyroptosis and apoptosis by targeting RORα in nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is associated with low back pain, yet its inherent mechanism remains obscure. Hypercholesteremia was regarded as a risk factor for IDD, and our previous study showed that cholesterol accumulation could elicit matrix degradation in the nucleus pulposus (NP). MicroRNA-155 (miR-155) was substantiated as protective in IDD, but its role in cholesterol-induced IDD was unclear. The present study investigated whether miR-155 could mediate cholesterol-related IDD and its internal mechanisms. In vivo experiments revealed high-fat diet-induced hypercholesteremia in wild-type (WT) mice along with the occurrence of IDD, whereas Rm155LG transgenic mice showed milder NP degeneration, as evidenced by Saffron O-fast green (SF) staining and immunohistochemistry (IHC). Meanwhile, IHC showed that NLRP3 and Bax expression was also suppressed in Rm155LG mice. In vitro studies using Western blotting (WB) and immunofluorescence (IF) confirmed that the miR-155 mimic could alleviate cholesterol-induced matrix degradation, apoptosis and pyroptosis in NP. Moreover, RORα was upregulated in severely degenerated NP compared to mild IDD. It was also noted that RORα was suppressed in Rm155LG mice. In this study, we demonstrated that miR-155 could target RORα and that inhibition of RORα could prevent cholesterol-induced matrix degradation, apoptosis, and pyroptosis in NP, indicating the protective effect of miR-155 in cholesterol-induced IDD by targeting RORα.

BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors.

BACKGROUND: Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers. METHODS: We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry. RESULTS: We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance. CONCLUSIONS: We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.

Comprehensive landscape of the IPAF inflammasomes in pan-cancer: A bulk omics research and single-cell sequencing validation.

BACKGROUND: IPAF (ICE-protease Activating Factor) is a nucleotide-binding/leucine-rich repeat (NLR) protein known as the cysteine-associated recruitment domain 12 (CARD12). Previous studies only discuss the role of IPAF inflammasomes in specific tumors. The role of IPAF inflammasomes in pan-cancer is still unclear. Therefore, we performed a comprehensive analysis of IPAF inflammasome in 33 tumors. METHODS: We used databases like The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) from the UCSC XENA (http://xena.ucsc.edu/) to retrieve and analyze gene expression. The influence of IPAF inflammasome on the prognosis of tumor patients was analyzed using univariate Cox regression analysis and Kaplan-Meier survival analysis. Furthermore, we conducted the following analysis: Single-sample gene set enrichment analysis, single-cell level functional state analysis, single-cell sequencing, immune cell infiltration analysis, and tumor immune dysfunction and exclusion (TIDE) score. RESULTS: First, the differential expression of IPAF inflammasome-related genes (IPAF-RGs) in 33 tumors were analyzed. The results revealed that IPAF-RGs were significantly and differentially expressed in eight tumors. The prognostic significance of IPAF inflammasome scores was different in different tumors. A positive correlation was observed between IPAF inflammasomes scores and CD8+ T cells in most tumors. Further analysis revealed that IPAF inflammasome might affect tumor immunity mainly by mediating effector T cell recruitment via the expression of chemokines such as CXCL9, CXCL10, and CCL5. The analysis of TIDE and IPAF inflammasome scores revealed a significant negative correlation between IPAF inflammasome and TIDE scores in 11 tumors. CONCLUSION: A pan-cancer analysis of IPAF inflammasome in various tumors was performed. The results highlight the potential value of IPAF inflammasome in response to immunotherapy in patients and provide a new direction for future immunotherapy.

BRD9 Inhibition Attenuates Matrix Degradation and Pyroptosis in Nucleus Pulposus by Modulating the NOX1/ROS/NF-κB axis.

Intervertebral disc degeneration (IDD) is considered to be the leading cause of low back pain (LBP). The progression of IDD is closely related to the inflammatory microenvironment, which results in extracellular matrix degradation and cell death. One of the proteins, which have been shown to participate in the inflammatory response, is the bromodomain-containing protein 9 (BRD9). This study aimed to investigate the role and mechanism of BRD9 in regulating IDD. The tumor necrosis factor-α (TNF-α) was used to mimic the inflammatory microenvironment in vitro. Western blot, RT-PCR, immunohistochemistry, immunofluorescence, and flow cytometry were used to demonstrate the effect of BRD9 inhibition or knockdown on matrix metabolism and pyroptosis. We found that the expression of BRD9 was upregulated as IDD progressed. BRD9 inhibition or knockdown alleviated TNF-α-induced matrix degradation, reactive oxygen species (ROS) production, and pyroptosis in rat nucleus pulposus cells. Mechanistically, RNA-seq was used to investigate the mechanism of BRD9 in promoting IDD. Further investigation revealed that BRD9 regulated NOX1 expression. Inhibition of NOX1 could abrogate matrix degradation, ROS production, and pyroptosis caused by BRD9 overexpression. In vivo, the radiological and histological evaluation showed that the pharmacological inhibition of BRD9 alleviated IDD development in rat IDD model. Our results indicated that BRD9 could promote IDD via the NOX1/ROS/ NF-κB axis by inducing matrix degradation and pyroptosis. Targeting BRD9 may be a potential therapeutic strategy in treating IDD.