Revealing the potential of solute carrier family 31 (copper transporters), member 1: Insights into its role in bladder cancer progression and therapeutic implications.

Introduction: Bladder cancer represents a significant public health concern with diverse genetic alterations influencing disease onset, progression, and therapy response. In this study, we explore the multifaceted role of Solute Carrier Family 31 Member 1 (SLC31A1) in bladder cancer, a pivotal gene involved in copper homeostasis. Methods: Our research involved analyzing the SLC31A1 gene expression via RT-qPCR, promoter methylation via targeted bisulfite sequencing, and mutational status via Next Generation Sequencing (NGS) using the clinical samples sourced by the local bladder cancer patients. Later on, The Cancer Genome Atlas (TCGA) datasets were utilized for validation purposes. Moreover, prognostic significance, gene enrichment terms, and therapeutic drugs of SLC31A1 were also explored using KM Plotter, DAVID, and DrugBank databases. Results: We observed that SLC31A1 was significantly up-regulated at both the mRNA and protein levels in bladder cancer tissue samples, suggesting its potential involvement in bladder cancer development and progression. Furthermore, our investigation into the methylation status revealed that SLC31A1 was significantly hypomethylated in bladder cancer tissues, which may contribute to its overexpression. The ROC analysis of the SLC31A1 gene indicated promising diagnostic potential, emphasizing its relevance in distinguishing bladder cancer patients from normal individuals. However, it is crucial to consider other factors such as cancer stage, metastasis, and recurrence for a more accurate evaluation in the clinical context. Interestingly, mutational analysis of SLC31A1 demonstrated only benign mutations, indicating their unknown role in the SLC31A1 disruption. In addition to its diagnostic value, high SLC31A1 expression was associated with poorer overall survival (OS) in bladder cancer patients, shedding light on its prognostic relevance. Gene enrichment analysis indicated that SLC31A1 could influence metabolic and copper-related processes, further underscoring its role in bladder cancer. Lastly, we explored the DrugBank database to identify potential therapeutic agents capable of reducing SLC31A1 expression. Our findings unveiled six important drugs with the potential to target SLC31A1 as a treatment strategy. Conclusion: Our comprehensive investigation highlights SLC31A1 as a promising biomarker for bladder cancer development, progression, and therapy.

Construction and Validation of a MRI­Based Radiomic Nomogram to Predict Overall Survival in Patients with Local Advanced Cervical Cancer: A Multicenter Study.

BACKGROUND: Cervical cancer is the fourth most common cancer among women. Radiomics has emerged as a new approach providing valuable information for cancer management. The aim of this study was to construct a radiomics nomogram to accurately predict survival outcomes in patients with locally advanced cervical cancer. METHODS: This retrospective study enrolled a total of 582 locally advanced cervical cancer patients from three center (training cohort: n = 228; internal validation cohort: n = 98; external validation cohort: n = 256). Radiomic features were extracted from pretreatment MRI images. Least absolute shrinkage and selection operator logistic regression were applied to select radiomic features and calculated the radiomic scores. Univariate and multivariate Cox proportional hazards regression analyses were used to identify the independent prognostic clinic-radiological factors for cervical cancer, which were incorporated into the nomogram. RESULTS: A total of six radiomic features were found to be associated with overall survival (OS) of locally advanced cervical cancer patients. The AUC of radiomic scores in the training cohort was 0.634-0.708 for the training cohort, 0.725-0.762 for internal validation cohort and 0.788-0.881 for the external validation cohort. Age, parametrial invasion, and radiomic score were the independent prognostic indicators for cervical cancer patients (Age: HR=1.041, 95% CI=1.012-1.071, p = 0.006; Parametrial invasion: HR=4.755, 95% CI=1.493-15.144, p = 0.008; HR=2.324, 95% CI=1.050-5.143, p = 0.037). The nomogram model incorporating these factors showed favorable discrimination in predicting the overall survival rates of cervical cancer patients, with the AUC values of 0.809, 0.808, and 0.862 for 1-, 2-, and 3-year predictions. The decision curve analysis (DCA) indicated that the nomogram model achieved the highest clinical net benefit across the entire range of reasonable threshold probabilities. CONCLUSION: The nomogram, incorporating clinicopathological factors and radiomic features derived from MRI images, showed satisfactory discrimination in predicting the OS rates of locally advanced cervical cancer patients.

Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague-Dawley Rats.

The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5'-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5'-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5'-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

Comparison of neurally adjusted ventilatory assist and synchronized intermittent mandatory ventilation in preterm infants after patent ductus arteriosus ligation: a retrospective study.

OBJECTIVE: This study aimed to compare the efficacy of neurally adjusted ventilatory assist (NAVA) to synchronized intermittent mandatory ventilation (SIMV) in preterm infants requiring mechanical ventilation after patent ductus arteriosus (PDA) ligation. METHODS: A retrospective analysis was conducted on intubated preterm infants who underwent PDA ligation at our hospital from July 2021 to January 2023. Infants were divided into NAVA or SIMV groups based on the ventilation mode after surgery. RESULTS: Fifty preterm infants were included. During treatment, peak inspiratory pressure (PIP) and mean airway pressure (MAP) were lower with NAVA compared to SIMV (PIP: 19.1 ± 2.9 vs. 22.4 ± 3.6 cmH2O, P < 0.001; MAP: 9.1 ± 1.8 vs. 10.9 ± 2.7 cmH2O, P = 0.002). PaO2 and PaO2/FiO2 were higher with NAVA (PaO2: 94.0 ± 11.7 vs. 84.8 ± 15.8 mmHg, P = 0.031; PaO2/FiO2: 267 [220-322] vs. 232 [186-290] mmHg, P = 0.025). Less sedation was required with NAVA (midazolam: 1.5 ± 0.5 vs. 1.1 ± 0.3 µg/kg/min, P < 0.001). CONCLUSION: Compared to SIMV, early use of NAVA post PDA ligation in preterm infants was associated with decreased PIP and MAP. Early NAVA was also associated with reduced sedation needs and improved oxygenation. However, further studies are warranted to quantify the benefits of NAVA ventilation.

A prognostic model for hepatocellular carcinoma patients based on polyunsaturated fatty acid-related genes.

OBJECTIVE: Polyunsaturated fatty acids (PUFAs) have attracted increasing attention for their role in liver cancer development. The objective of this study is to develop a prognosis prediction model for patients with liver cancer based on PUFA-related metabolic gene characteristics. METHOD: Transcriptome data and clinical data were obtained from public databases, while gene sets related to PUFAs were acquired from the gene set enrichment analysis (GSEA) database. Univariate Cox analysis was conducted on the training set, followed by LASSO logistic regression and multivariate Cox analysis on genes with p < .05. Subsequently, the stepwise Akaike information criterion method was employed to construct the model. The high- and low-risk groups were divided based on the median score, and the model's survival prediction ability, diagnostic efficiency, and risk score distribution of clinical features were validated. The above procedures were also validated in the validation set. Immune infiltration levels were evaluated using four algorithms, and the immunotherapeutic potential of different groups was explored. Significant enrichment pathways among different groups were selected based on the GSEA algorithm, and mutation analyses were conducted. Nomogram prognostic models were constructed by incorporating clinical factors and risk scores using univariate and multivariate Cox regression analysis, validated through calibration curves and clinical decision curves. Additionally, sensitivity analysis of drugs was performed to screen potential targeted drugs. RESULTS: We constructed a prognostic model comprising eight genes (PLA2G12A, CYP2C8, ABCCI, CD74, CCR7, P2RY4, P2RY6, and YY1). Validation across multiple datasets indicated the model's favorable prognostic prediction ability and diagnostic efficiency, with poorer grading and staging observed in the high-risk group. Variations in mutation status and pathway enrichment were noted among different groups. Incorporating Stage, Grade, T.Stage, and RiskScore into the nomogram prognostic model demonstrated good accuracy and clinical decision benefits. Multiple immune analyses suggested greater benefits from immunotherapy in the low-risk group. We predicted multiple targeted drugs, providing a basis for drug development. CONCLUSION: Our study's multifactorial prognostic model across multiple datasets demonstrates good applicability, offering a reliable tool for personalized therapy. Immunological and mutation-related analyses provide theoretical foundations for further research. Drug predictions offer important insights for future drug development and treatment strategies. Overall, this study provides comprehensive insights into tumor prognosis assessment and personalized treatment planning.

Identification of GMFG as a novel biomarker in IgA nephropathy based on comprehensive bioinformatics analysis.

Background: IgA nephropathy (IgAN) stands as the most prevalent form of glomerulonephritis and ranks among the leading causes of end-stage renal disease worldwide. Regrettably, we continue to grapple with the absence of dependable diagnostic markers and specific therapeutic agents for IgAN. Therefore, this study endeavors to explore novel biomarkers and potential therapeutic targets in IgAN, while also considering their relevance in the context of tumors. Methods: We gathered IgAN datasets from the Gene Expression Omnibus (GEO) database. Subsequently, leveraging these datasets, we conducted an array of analyses, encompassing differential gene expression, weighted gene co-expression network analysis (WGCNA), machine learning, receiver operator characteristic (ROC) curve analysis, gene expression validation, clinical correlations, and immune infiltration. Finally, we carried out pan-cancer analysis based on hub gene. Results: We obtained 1391 differentially expressed genes (DEGs) in GSE93798 and 783 DGEs in GSE14795, respectively. identifying 69 common genes for further investigation. Subsequently, GMFG was identified the hub gene based on machine learning. In the verification set and the training set, the GMFG was higher in the IgAN group than in the healthy group and all of the GMFG area under the curve (AUC) was more 0.8. In addition, GMFG has a close relationship with the prognosis of malignancies and a range of immune cells. Conclusions: Our study suggests that GMFG could serve as a promising novel biomarker and potential therapeutic target for both IgAN and certain types of tumors.

Diaphragm ultrasonography as a monitor in assessing antagonistic effect of sugammadex on rocuronium in patients with Child-Pugh grades A and B.

Background: Although diaphragm ultrasound can be used for detecting residual neuromuscular blockade post-surgery, there exists notable dearth in contemporary research exploring the correlation between preoperative Child-Pugh classification and the effectiveness of sugammadex in reversing rocuronium-induced blockade as evaluated by diaphragmatic ultrasonography. Methods: This was a prospective, double-blind, non-randomized controlled clinical trial conducted on patients scheduled for laparoscopic liver resection surgery. The participants were categorized into two groups, A and B, based on their preoperative Child-Pugh classification. Prior to anesthesia induction, baseline diaphragm thickness was evaluated using ultrasonography. Throughout the surgical procedure, a deep neuromuscular blockade was maintained with rocuronium. Post-surgery, sugammadex (2 mg/kg) was intravenously administered to patients in both groups upon reaching a train-of-four ratio of 0.2. Diaphragm thickness was assessed at 0, 10, and 30 min, as well as 2 h after extubation, to analyze thickening fractioning (TF) and thickness recovery fractioning (TRF). Results: No significant differences in TF or TRF were observed between the two groups at 0, 10, and 30 min, as well as 2 h after extubation. Furthermore, there were no significant variances in hemodynamic stability following sugammadex administration. However, patients in the Child-Pugh B group experienced a significantly prolonged time from sugammadex administration to tracheal extubation (19 ± 8.0 min vs. 11 ± 6.1 min) and an extended post-anesthesia care unit stay (123 ± 28.3 min vs. 103 ± 26.0 min) compared to those in the Child-Pugh A group. Conclusion: The preoperative Child-Pugh grades may not exhibit a significant association with the reversal effect of sugammadex on rocuronium, as evaluated through diaphragmatic ultrasonography. Clinical trial registration: Registered in the ClinicalTrials.gov (NCT05028088) on July 18, 2021.

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

A prognostic nomogram for predicting breast cancer survival based on mammography and AJCC staging.

Rationale and objectives: To develop a prognostic nomogram using mammography data and AJCC staging to predict breast cancer survival. Materials and methods: A prognostic nomogram was created using data from 1000 women diagnosed with breast cancer at a medical cancer center in Taiwan between 2011 and 2015. The variables included age at diagnosis (≤60 or > 60 years), mammography purpose (screening or diagnostic), mammography modality (digital mammogram or digital breast tomosynthesis), and the 7th American Joint Committee on Cancer (AJCC) stage. The outcome predicted was breast cancer-related mortality. The nomogram utilized Kaplan-Meier analysis for all subsets and Cox proportional hazards regression analysis for prediction. The nomogram's accuracy was internally validated using the concordance index and receiver operating characteristic (ROC) curve analysis, focusing on 3-year and 5-year survival predictions. Results: Participants' mean age at breast cancer diagnosis was 54 years (SD = 11.2 years). The 1-year, 3-year, and 5-year overall survival (OS) rates were found to be 99.7%, 95.3%, and 91.4%, respectively. The bootstrap-corrected concordance indices indicated the following: nomogram, 0.807 and AJCC, 0.759. A significant difference was observed between the nomogram's area under the curve (AUC) and the AJCC stage in predicting the probability of 5-year survival (p = 0.005). A nomogram, constructed based on mammography and AJCC, demonstrated excellent calibration through internal validation using bootstrapping. Conclusion: The utilization of a nomogram that incorporates mammography data and the AJCC registry data has been demonstrated to be a reliable predictor of breast cancer survival.

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study.

Background: Currently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA. Methods: We retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism. Results: Our findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA (P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (ORIVW: 0.622, 95% CI: 0.438-0.883, FDR = 0.045) and elevated serum levels of X-11538 (ORIVW: 0.442, 95% CI: 0.250-0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections (Vibrio cholerae and Helicobacter pylori) as well as the mTOR signaling pathway. Conclusion: In conclusion, our study demonstrates that Family Rikenellaceae and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process.

Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

Comprehensive Analysis of the Associations of LOXL1-4 with Prognosis and Immune Infiltration in Breast Cancer.

Objective: Invasive breast cancer (BRCA) poses a major challenge to women's health due to its high incidence and poor prognosis. Dysregulated Lysine oxidase-like (LOXL) family genes are implicated in tumor progression across malignancies. Understanding the role of Lysine oxidase-like (LOXL) family genes in BRCA is crucial for advancing treatment strategies. Methods: TIMER, Oncomine, TNMplot, TCGA, GTEx and GEPIA datasets were used to investigate LOXL1-4 expression in breast cancer. The UALCAN and HPA datasets were utilized to detect the protein levels of LOXL1-4 in BRCA. Kaplan-Meier Plotter was used to analyze the prognostic values of LOXL1-4 in BRCA patients. Gene ontology (GO) and KEGG pathway enrichment analyses, conducted through DAVID 6.8 and R, revealed potential biological functions. TIMER was used to explore the link between LOXL1-4 expression and tumor immune infiltration. The cBioPortal dataset was used to analyze LOXL1-4 alterations and CNV-survival links in breast cancer. GSCA was used to assess LOXL1-4's correlations with immune infiltration. LOXL1-4's links to the eight immune checkpoint genes were analyzed using R's pheatmap. Results: Our study revealed that aberrant expression of LOXL1/2/4 in BRCA significantly affects relapse-free survival (RFS), overall survival (OS), and distant metastasis-free survival (DMFS), particularly highlighting the prognostic importance of LOXL4. LOXL1-4 displayed substantial relationships with the tumor immune microenvironment and immune cell infiltration. Furthermore, copy number variations (CNVs) of LOXL1-4 are significantly associated with immune infiltration in BRCA, particularly LOXL2 CNV, which significantly impacts OS and progression-free survival (PFS). Conclusion: The correlation between LOXL1-4 expression, prognosis, and immune infiltration in BRCA underscores their potential as biomarkers for prognosis and targets for immunotherapy.

B-cell intrinsic regulation of antibody mediated immunity by histone H2A deubiquitinase BAP1.

Introduction: BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, through its direct catalytic activity on the repressive epigenetic mark histone H2AK119ub, as well as on several other substrates. BAP1 is also a highly important tumor suppressor, expressed and functional across many cell types and tissues. In recent work, we demonstrated a cell intrinsic role of BAP1 in the B cell lineage development in murine bone marrow, however the role of BAP1 in the regulation of B cell mediated humoral immune response has not been previously explored. Methods and results: In the current study, we demonstrate that a B-cell intrinsic loss of BAP1 in activated B cells in the Bap1 fl/fl Cγ1-cre murine model results in a severe defect in antibody production, with altered dynamics of germinal centre B cell, memory B cell, and plasma cell numbers. At the cellular and molecular level, BAP1 was dispensable for B cell immunoglobulin class switching but resulted in an impaired proliferation of activated B cells, with genome-wide dysregulation in histone H2AK119ub levels and gene expression. Conclusion and discussion: In summary, our study establishes the B-cell intrinsic role of BAP1 in antibody mediated immune response and indicates its central role in the regulation of the genome-wide landscapes of histone H2AK119ub and downstream transcriptional programs of B cell activation and humoral immunity.

[Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss].

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics（ACMG） variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA（p. Ser1176Valfs*14）, a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del（p. Leu2481Glufs*86） and c. 10250_10252del（p. Ser3417del）,a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ（CAP-Ⅱ） and 5 on the Speech Intelligibility Rating（SIR）. Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

Association between sleep apnea-specific hypoxic burden and severity of coronary artery disease.

PURPOSE: Sleep apnea-specific hypoxic burden (SASHB) is a polysomnographic metric that comprehensively measures the degree of nocturnal desaturation caused by obstructive sleep apnea. This research was conducted to elucidate the relationship between SASHB and coronary artery disease (CAD) severity. METHODS: We carried out a prospective study of hospitalized patients with CAD of unstable angina who were expected to undergo invasive coronary angiography at Beijing Anzhen Hospital from February to September 2023. SASHB values were calculated using a self-programmed C + + program. Multivariable logistic regression analysis was applied to identify the association between SASHB and the prevalence of severe CAD, documented by the Gensini Score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) Score. RESULTS: This study enrolled 137 patients with a median age of 59 years, 96 (70.1%) of whom were male. A total of 125 (91.2%) patients had coronary stenosis of ≥ 50% in at least one location. Patients with a high SASHB of ≥ 18% min/h had a significantly higher Gensini Score (32.0 vs. 18.5, P = 0.002) and SYNTAX Score (14.0 vs. 7.0, P = 0.002) than those with a low SASHB. After adjusting for multiple covariates, a high SASHB was significantly associated with the prevalence of severe CAD, determined by a Gensini Score ≥ 21 (OR 2.67, P = 0.008) or a SYNTAX Score > 22 (OR 4.03, P = 0.016). CONCLUSION: Our findings revealed a robust and independent association between SASHB and CAD severity in patients with unstable angina, highlighting the potential value of SASHB as a predictor of risk and a target for interventions aimed at preventing cardiovascular diseases. TRIAL REGISTRATION: Chinese Clinical Trial Registry No. ChiCTR2300067991 on February 2, 2023.

Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

BACKGROUND/AIM: One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. PATIENTS AND METHODS: Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. RESULTS: In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. CONCLUSION: Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Fatty acid metabolism-related molecular subtypes and a novel model for predicting prognosis in bladder cancer patients.

This study aims to develop fatty acid metabolism-related molecular subtypes and construct a fatty acid metabolism-related novel model for bladder cancer (BCa) by bioinformatic profiling. Genome RNA-seq expression data of BCa samples from the TCGA database and GEO database were downloaded. We then conducted consensus clustering analysis to identify fatty acid metabolism-related molecular subtypes for BCa. Univariate and multivariate Cox regression analysis were performed to identify a novel prognostic fatty acid metabolism-related prognostic model for BCa. Finally, we identified a total of three fatty acid metabolismrelated molecular subtypes for BCa. These three molecular subtypes have significantly different clinical characteristics, PD-L1 expression levels, and tumor microenvironments. Also, we developed a novel fatty acid metabolism-related prognostic model. Patients with low-risk score have significantly preferable overall survival compared with those with high-risk score in the training, testing, and validating cohorts. The area under the ROC curve (AUC) for overall survival prediction was 0.746, 0.681, and 0.680 in the training, testing and validating cohorts, respectively. This model was mainly suitable for male, older, high-grade, cluster 2-3, any TCGA stage, any N-stage, and any T-stage patients. Besides, we selected FASN as a hub gene for BCa and further qRT-PCR validation was successfully conducted. In conclusion, we developed and successfully validated a novel fatty acid metabolism-related prognostic model for predicting outcome for BCa patients.

IGFBP5, as a Prognostic Indicator Promotes Tumor Progression and Correlates with Immune Microenvironment in Glioma.

Background: Insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in multiple human cancers, including glioma. Despite this, it remains unclear what role it plays in glioma. The aim of the present study was to analyze whether IGFBP5 could be used as a predictor of prognosis and immune infiltration in glioma. Methods: Glioma patients' clinical information was collected from the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), Rembrandt, and Gravendeel databases. The diagnostic and prognostic roles of IGFBP5 were assessed by the Kaplan-Meier survival curves, diagnostic receiver operating characteristic (ROC) curves, nomogram model, Cox regression analysis and Enrichment analysis by R software. Moreover, the correlation between IGFBP5 expression and immune cell infiltration, and immune checkpoint genes was conducted. Immunohistochemistry staining, CCK8, colony formation, scratch and transwell assays and western blot were used to interrogate the expression and function of IGFBP5 in glioma. Results: IGFBP5 levels were obviously increased in glioma with higher malignancy and predicted poor outcomes by Univariate and multivariate Cox analysis. The biological function analysis revealed that IGFBP5 correlated closely with immune signatures. Moreover, IGFBP5 expression was associated with tumor infiltration of B cells, T cells, macrophages, and NK cells. IGFBP5 affected glioma cell proliferation, migration, and invasion probably involved in the epithelial-to-mesenchymal transition (EMT) and Hippo-YAP signaling pathway. Further study showed that IGFBP5 induced the expression of PD-L1 and CXCR4. Conclusions: IGFBP5 as an oncogene is a useful biomarker of prognosis and correlates with progression and immune infiltration in glioma.