Curcumin blunts epithelial-mesenchymal transition to alleviate invasion and metastasis of prostate cancer through the JARID1D demethylation.

Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

Decoding 11-Oxygenated Androgen Synthesis: Insights from Enzyme Gene Expression and LC‒MS/MS Quantification.

BACKGROUND: Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited. METHODS: We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC‒MS/MS) techniques were employed. RESULTS: Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. Sc-RNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC‒MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data. CONCLUSION: This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.

[Relationship Between Physical Activity and Depressive Symptoms Among Middle-Aged and Older Adults in Chengdu,Sichuan,China].

Objective To investigate the current status of physical activity and depressive symptoms among middle-aged and older adults in Chengdu,Sichuan and explore the relationship between physical activity and depressive symptoms. Methods Multi-stage proportional stratified random sampling was employed to select middle-aged and older adults aged ≥45 years as the participants,and face-to-face interviews were carried out to collect data.Logistic regression was adopted to explore the relationship between physical activity and depressive symptoms in middle-aged and older adults.The trend test was performed for the relationship between different levels of physical activity and depressive symptoms.The subgroup analysis and the test for multiplicative interactions were conducted for the relationship between physical activity and depressive symptoms. Results A total of 4376 middle-aged and older adults were included.Among them,14.58% (638/4376),25.98% (1137/4376),and 27.83% (1218/4376) had depressive symptoms,failed to reach the guideline-recommended standards of physical activity,and were at low levels of physical activity,respectively.There was a negative association between reaching guideline-recommended physical activity standard and depressive symptoms in middle-aged and older adults (OR=0.713,95%CI=0.589-0.861,P<0.001).In addition,moderate levels (OR=0.714,95%CI=0.586-0.871,P=0.001) and high levels of physical activity (OR=0.705,95%CI=0.548-0.906,P=0.006) had negative associations with the presence of depressive symptoms.The trend test revealed that the negative association between physical activity and depressive symptoms in middle-aged and older adults enhanced as the level of physical activity increased (Pfor trend=0.001).The subgroup analysis and the test for multiplicative interactions revealed that neither reaching guideline-recommended physical activity standards or not nor the physical activity level had an interaction with each of the subgroups (all Pfor interaction>0.05). Conclusion The current status of depressive symptoms among middle-aged and older adults in Chengdu,Sichuan needs to be ameliorated.A negative association existed between reaching the guideline-recommended physical activity standard and presence of depressive symptoms,and the negative association enhanced as the physical activity level elevated.

Widespread purplish-red plaques with plasma cell infiltrate: A rare type of lichen planus.

Diseases in which cutaneous plasma cell infiltrates predominate are rare and usually of unknown etiology, including those that transition from benign to malignant, such as cutaneous plasmacytosis, multicentric Castleman disease, and extramedullary plasmacytoma. These diseases may present as purplish, reddish-brown cutaneous plaques or nodules. Here, we report an exceptional case of lichen planus (LP) in which the patient had classic histopathological features, but the infiltrating inflammatory cells were plasma cells with restricted light chain expression. The patient presented with severe rashes, including purplish-red plaques and nodules, erythema, and erosions in the palmoplantar area, verrucous hyperplasia of the oral mucosa, and anonychia of the toes. These findings suggest a possible role of plasma cells with restricted light chain expression in the LP. Clinicians should closely follow patients for changes in their rash, perform repeat biopsies if necessary, and regularly conduct multisystemic evaluations.

Role of endogenous T1ρ and its dispersion imaging in differential diagnosis of cardiac amyloidosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) has demonstrated excellent performance in the diagnosis of cardiac amyloidosis (CA). However, misdiagnosis occasionally occurs because the morphological and functional features of CA are non-specific. This study was performed to determine the value of non-contrast CMR T1ρ in the diagnosis of CA. METHODS: This prospective study included 45 patients with CA, 30 patients with hypertrophic cardiomyopathy (HCM), and 10 healthy controls (HCs). All participants underwent cine (whole heart), T1ρ mapping, pre- and post-contrast T1 mapping imaging (three slices), and late gadolinium enhancement using a 3T whole-body MRI system. All participants underwent T1ρ at two spin-locking frequencies: 0Hz and 298Hz. ECV maps were obtained using pre- and post-contrast T1 maps. The myocardial T1ρ dispersion map, termed myocardial dispersion index (MDI), was also calculated. All parameters were measured in the left ventricular myocardial wall. Participants in the HC group were scanned twice on different days to assess the reproducibility of T1ρ measurements. RESULTS: Excellent reproducibility was observed upon evaluation of the coefficient of variation between two scans (T1ρ [298Hz]: 3.1%; T1ρ [0Hz], 2.5%). The ECV (HC: 27.4 ± 2.8% vs. HCM: 32.6 ± 5.8% vs. CA: 46 ± 8.9%; p < 0.0001), T1ρ [0Hz] (HC: 35.8 ± 1.7 ms vs. HCM: 40.0 ± 4.5 ms vs. CA: 51.4 ± 4.4 ms; p < 0.0001) and T1ρ [298Hz] (HC: 41.9 ± 1.6 ms vs. HCM: 48.8 ± 6.2 ms vs. CA: 54.4 ± 5.2 ms; p < 0.0001) progressively increased from the HC group to the HCM group, and then the CA group. The MDI progressively decreased from the HCM group to the HC group, and then the CA group (HCM: 8.8 ± 2.8 ms vs. HC: 6.1 ± 0.9 ms vs. CA: 3.4 ± 2.1 ms; p < 0.0001). For differential diagnosis, the combination of MDI and T1ρ [298Hz] showed the greatest sensitivity (98.3%) and specificity (95.5%) between CA and HCM, compared with the native T1 and ECV. CONCLUSIONS: The T1ρ and MDI approaches can be used as non-contrast CMR imaging biomarkers to improve the differential diagnosis of patients with CA.

Catalytic elevation effect of methylglyoxal on invertase and characterization of MGO modification products.

Reactive carbonyl species can modify digestive enzymes upon intake due to their electrophilic nature. This study evaluated the effects of methylglyoxal (MGO), glyoxal, acrolein, and formaldehyde on invertase, an enzyme presents in digestive tract. Unexpectedly, MGO enhanced, rather than inhibited, invertase activity. Moreover, MGO counteracted the inhibitory effects of the other three carbonyls on invertase activity. Kinetic analyses revealed that 150 mmolLexp.-1 MGO resulted in a 2-fold increase in the Km and a 3.3-fold increase in Vmax, indicating that MGO increased the turnover rate of sucrose while reducing the substrate binding affinity of invertase. Additionally, MGO induced dynamic quenching of fluorescence, reduced free amino groups, increased hydrophobicity, the content of Amadori products, fluorescent and nonfluorescent AGEs, and amyloid fibrils of invertase. The specific modifications responsible for the elevated activity of MGO on invertase require further investigation.

Reactions of 2-chloropropionyl chloride on Cu(100): C-Cl bond cleavage and formation of methylketene and its dimer.

X-ray photoelectron spectroscopy, reflection-absorption infrared spectroscopy, and temperature-programmed reaction/desorption have been employed to investigate the reaction of CH3-CHCl-C(=O)Cl on Cu (100), with the aid of density functional theory (DFT) calculations. Experimentally, CH3-CH=C=O (methylketene) is found to be the product from the dechlorination of CH3-CHCl-C(=O)Cl on Cu(100) at 120 K. The CH3-CH=C=O generated on the surface would dimerize to form 2,4-dimethylcyclobutane-1,3-dione below 180 K. In agreement with the experimental findings, our DFT molecular dynamics simulations demonstrate that the dechlorination of CH3-CHCl-C(=O)Cl, resulting in CH3-CH=C=O and two Cl atoms, occurs readily, completing within 0.6 ps at 300 K. The simulations also indicate that the cleavage of the CH-Cl bond precedes that of the C(=O)-Cl bond. The static DFT calculations suggest that the dimerization of CH3-CH=C=O primarily occurs through the coupling of two C=C bonds, which has a lower barrier of 38.08 kJ mol-1 compared to the 69.05 kJ mol-1 barrier for C=C + C=O coupling.

Positive cooperativity in synergistic activation of Wnt proteins.

BACKGROUND: Wnt proteins are crucial for embryonic development, stem cell growth, and tissue regeneration. Wnt signaling pathway is activated when Wnt proteins bind to cell membrane receptors. METHODS AND RESULTS: We employed a luciferase reporter assay in HEK293STF cells to measure Wnt protein-induced signaling. We observed that Wnt3a uniquely promotes the Wnt/ß-catenin pathway through positive cooperativity. Additionally, MFH-ND, a molecular mimic of Wnt ligands, markedly increased Wnt3a-induced signaling in a dose-responsive manner. This suggests that various Wnt ligands can synergistically enhance Wnt pathway activation. CONCLUSIONS: The study suggests the likelihood of various Wnt ligands coexisting in a single signalosome on the cell membrane, providing new insights into the complexities of Wnt signaling mechanisms.

Impact of omega-3 fatty acids on hypertriglyceridemia, lipidomics, and gut microbiome in patients with type 2 diabetes.

BACKGROUND: Fish oil (FO), a mixture of omega-3 fatty acids mainly comprising docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been recommended for patients with type 2 diabetes (T2D) and hypertriglyceridemia. However, its effects on lipidomic profiles and gut microbiota and the factors influencing triglyceride (TG) reduction remain unclear. METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 309 Chinese patients with T2D with hypertriglyceridemia (ClinicalTrials.gov: NCT03120299). Participants were randomly assigned (1:1) to receive either 4 g FO or corn oil for 12 weeks. The primary outcome was changes in serum TGs and the lipidomic profile, and the secondary outcome included changes in the gut microbiome and other metabolic variables. FINDINGS: The FO group had significantly better TG reduction (mean [95% confidence interval (CI)]: -1.51 [-2.01, -1.01] mmol/L) compared to the corn oil group (-0.66 [-1.15, -0.16] mmol/L, p = 0.02). FO significantly altered the serum lipid profile by reducing low-unsaturated TG species and increasing those containing DHA or EPA. FO had minor effects on gut microbiota, while baseline microbial features predicted the TG response to FO better than phenotypic or lipidomic features, potentially mediated by specific lipid metabolites. A total of 9 lipid metabolites significantly mediated the link between 4 baseline microbial variables and the TG response to FO supplementation. CONCLUSIONS: Our findings demonstrate differential impacts of omega-3 fatty acids on lipidomic and microbial profiles in T2D and highlight the importance of baseline gut microbiota characteristics in predicting the TG-lowering efficacy of FO. FUNDING: This study was funded by the National Nature Science Foundation.

Epigenetic dysregulated long non-coding RNAs in renal cell carcinoma based on multi-omics data and their influence on target drugs sensibility.

Purpose: Epigenetic modifications play a crucial role in cancer development, and our study utilized public data to analyze which leads to the discovery of significant epigenetic abnormalities in lncRNAs, offering valuable insights into prognosis and treatment strategies for renal carcinoma. Methods: Public data were obtained from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) database. The analysis of the online public data was all completed in R software. Results: We discovered a great number of epigenetic abnormalities of lncRNA in renal cancer, which is achieved by comparing the following modification and methylation of histone region changes on the promoter and enhancer of lncRNA: H3K27ac, H3K4me1, H3K4me3. As a result, 12 specific epigenetic disorders of lncRNA genes in renal cancer were identified. Finally, based on this lncRNA, we investigated the prognosis of renal cancer samples, among which 8 lncRNA can be seen as markers of prognosis in renal cancer, which had great prediction ability for ccRCC prognosis. Meanwhile, high risk score may pose response better to axitinib and nilotinib, but not sorafenib or sunitinib. Beyond, we observed an elevated level of risk score in immunotherapy non-responders. Further, biological enrichment and immuno-infiltration analysis was conducted to investigate the fundamental differences between patients categorized as high or low risk. Conclusion: Our research improves the understanding in the function of epigenetic dysregulated long non-coding RNAs in renal carcinoma.

Automatic cardiothoracic ratio calculation based on lung fields abstracted from chest X-ray images without heart segmentation.

Introduction: The cardiothoracic ratio (CTR) based on postero-anterior chest X-rays (P-A CXR) images is one of the most commonly used cardiac measurement methods and an indicator for initially evaluating cardiac diseases. However, the hearts are not readily observable on P-A CXR images compared to the lung fields. Therefore, radiologists often manually determine the CTR's right and left heart border points of the adjacent left and right lung fields to the heart based on P-A CXR images. Meanwhile, manual CTR measurement based on the P-A CXR image requires experienced radiologists and is time-consuming and laborious. Methods: Based on the above, this article proposes a novel, fully automatic CTR calculation method based on lung fields abstracted from the P-A CXR images using convolutional neural networks (CNNs), overcoming the limitations to heart segmentation and avoiding errors in heart segmentation. First, the lung field mask images are abstracted from the P-A CXR images based on the pre-trained CNNs. Second, a novel localization method of the heart's right and left border points is proposed based on the two-dimensional projection morphology of the lung field mask images using graphics. Results: The results show that the mean distance errors at the x-axis direction of the CTR's four key points in the test sets T1 (21 × 512 × 512 static P-A CXR images) and T2 (13 × 512 × 512 dynamic P-A CXR images) based on various pre-trained CNNs are 4.1161 and 3.2116 pixels, respectively. In addition, the mean CTR errors on the test sets T1 and T2 based on four proposed models are 0.0208 and 0.0180, respectively. Discussion: Our proposed model achieves the equivalent performance of CTR calculation as the previous CardioNet model, overcomes heart segmentation, and takes less time. Therefore, our proposed method is practical and feasible and may become an effective tool for initially evaluating cardiac diseases.

Hospitals' strategies to reduce costs and improve quality: survey of hospital leaders.

OBJECTIVES: Hospitals in the US operate under various value-based payment programs, but little is known regarding the strategies they use in this context to improve quality and reduce costs, overall or in voluntary programs including Bundled Payments for Care Improvement Advanced (BPCI-A). STUDY DESIGN: A survey was administered to hospital leaders at 588 randomly selected acute care hospitals, with oversampling of BPCI-A participants, from November 2020 to June 2021. Twenty strategies and 20 barriers were queried in 4 domains: inpatient, postacute, outpatient, and community resources for vulnerable patients. METHODS: Summary statistics were tabulated, and responses were adjusted for sampling strategy and nonresponse. RESULTS: There were 203 respondents (35%), of which 159 (78%) were BPCI-A participants and 44 (22%) were nonparticipants. On average, respondents reported implementing 89% of queried strategies in the inpatient domain, such as care pathways or predictive analytics; 65% of postacute strategies, such as forming partnerships with skilled nursing facilities; 84% of outpatient strategies, such as scheduling close follow-up to prevent emergency department visits/hospitalizations; and 82% of strategies aimed at high-risk populations, such as building connections with community resources. There were no differences between BPCI-A and non-BPCI-A hospitals in 19 of 20 care redesign strategies queried. However, 78.3% of BPCI-A-participating hospitals reported programs aimed at reducing utilization of skilled nursing and inpatient rehabilitation facilities compared with 37.6% of non-BPCI-A hospitals (P < .0001). CONCLUSIONS: Hospitals pursue a broad range of efforts to improve quality. BPCI-A hospitals have attempted to reduce use of postacute care, but otherwise the strategies they pursue are similar to other hospitals.

miR-106b-5p protects against drug-induced liver injury by targeting vimentin to stimulate liver regeneration.

Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR-106b-5p protects mice from liver injury. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR-106b-5p by dual luciferase reporter and siRNA assays. Furthermore, single-cell RNA-sequencing analysis of toosendanin-injured mouse liver revealed a cluster of Vim + hepatocytes; nonetheless declined following miR-106b-5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR-106b-5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR-106b-5p safeguards restorative tissue repair by targeting vimentin.

Transposon mutagenesis screen in Klebsiella pneumoniae identifies genetic determinants required for growth in human urine and serum.

Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.

Connecting Protein Millisecond Conformational Dynamics to Protein Thermal Stability.

The stability of protein folded states is crucial for its function, yet the relationship with the protein sequence remains poorly understood. Prior studies have focused on the amino acid composition and thermodynamic couplings within a single folded conformation, overlooking the potential contribution of protein dynamics. Here, we address this gap by systematically analyzing the impact of alanine mutations in the C-terminal ß-strand (ß5) of ubiquitin, a model protein exhibiting millisecond timescale interconversion between two conformational states differing in the ß5 position. Our findings unveil a negative correlation between millisecond dynamics and thermal stability, with alanine substitutions at seemingly flexible C-terminal residues significantly enhancing thermostability. Integrating spectroscopic and computational approaches, we demonstrate that the thermally unfolded state retains a substantial secondary structure but lacks ß5 engagement, recapitulating the transition state for millisecond dynamics. Thus, alanine mutations that modulate the stabilities of the folded states with respect to the partially unfolded state impact both the dynamics and stability. Our findings underscore the importance of conformational dynamics with implications for protein engineering and design.

Mapping of a novel locus Ra conferring extreme resistance against potato virus A in cultivated potato (Solanum tuberosum L.).

KEY MESSAGE: The Ra extreme resistance against potato virus A was mapped to the upper of chromosome 4 in tetraploid potato. Potato virus A (PVA) is one of the major viruses affecting potato worldwide and can cause serious disease symptoms and yield losses. Previously, we determined that potato cultivar Barbara harbors Rysto (genotype: Ryryryry) and Ra (genotype: Rararara) that each independently confer extreme resistance to PVA. In this study, employing a combination of next-generation sequencing and bulked-segregant analysis, we further located this novel Ra on chromosome 4 using a tetraploid BC1 potato population derived from a Ry-free progeny (Rararararyryryry) of Barbara (RarararaRyryryry) × F58050 (rararararyryryry). Using 29 insertion-deletion (InDel) markers spanning chromosome 4, Ra was delimited by the InDel markers M8-83 and M10-8 within a genetic interval of 1.46 cM, corresponding to a 1.86-Mb genomic region in the potato DM reference genome. The InDel marker M10-8, which is closely linked with the resistance against PVA in the Ry-free segregating populations, was then used to screen 43 selected Rysto-free tetraploid potato breeding clones. The phenotype to PVA was significantly correlated with the present/absent of the marker, albeit with a 9.3% false positive rate and a 14.0% false negative rate. These findings are of importance in furthering the cloning of Ra and employing the marker-assisted selection for PVA resistance.

A Comparison of Tranexamic Acid in Nasal Versus Sinus Surgeries: a Systematic Review and Meta-Analysis.

Nasal surgeries (e.g.: rhinoplasties, septoplasties) and sinus surgeries (e.g.: Functional Endoscopic Sinus Surgeries) are common procedures in Otorhinolaryngology. Tranexamic acid (TXA), an antifibrinolytic drug, has been increasingly utilized to reduce hemorrhage recently. While close in proximity anatomically, the bleeding nature of sinus and nasal surgeries may differ. We present the first meta-analysis that has reviewed both nasal and sinus surgery collectively and compares the two. Pubmed, Embase, Cochrane Library and WoS were searched until April 2023. Outcomes of interest include Boezart Scoring, clotting time, postoperative complications and surgical field quality. 27 Studies were assessed, of which 25 studies were evaluated quantitatively. Of the 27 studies, 15 studies involved Sinus surgery while 12 involved Nasal surgery. The use of tranexamic acid was notably beneficial in the evaluation of blood loss, reduction of operating time, surgical field quality and surgeon satisfaction. TXA has proven to be efficacious in both nasal and sinus surgeries to varying degrees. TXA has more effects in sinus surgeries compared to nasal surgeries in objective markers such as reducing blood loss and operating time, but the converse occurs for subjective markers such as surgeon satisfaction scores. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-024-04579-x.

Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

PURPOSE: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. METHODS: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. RESULTS: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. CONCLUSION: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

[Research progress of KCNJ5 gene in aldosterone-producing adenoma].

Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.