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Background Currently, obesity has been recognized to be an independent risk factor for osteoarthritis (OA), and the Metabolic Score for Visceral Fat (METS-VF) has been suggested to be potentially more accurate than body mass index (BMI) in the assessment of obesity. Nevertheless, the correlation of METS-VF with OA has not been obviously revealed yet. Therefore, this study aimed to delve into the potential relationship between METS-VF and OA. Methods By examining data from the NHANES (2009–2018), weighted multivariate logistic regression analyses were used for assessing the correlation between METS-VF and OA. Subgroup analyses were then performed to validate the findings. Moreover, the nonlinear relationship between the two was assessed by restricted cubic spline (RCS). Receiver operating characteristic (ROC) curves were plotted to examine the diagnostic accuracy of METS-VF versus previous obesity index for OA. Results This study involved 7639 participants. According to our results, METS-VF was notably related to an elevated risk of OA, regardless of the METS-VF and the trend of positive association was more pronounced with the elevating METS-VF level (p for trend < 0.05). Subgroup analyses showed that the positive association between METS-VF and prevalence of osteoarthritis persisted in all populations with different characteristics, confirming its validity in all populations. Besides, RCS results showed a significant non-linear relationship between METS-VF and OA (p-non-linear < 0.05). As indicated by the ROC curve analysis results, METS-VF was a superior predictor of OA to BMI and HC. Conclusions This study finds a possible nonlinear positive correlation between METS-VF and the risk of OA. In addition, METS-VF may serve as an indicator for the more accurate diagnosis of OA and provide a new way to further evaluate the relationship between visceral fat and OA.

BackgroundNumerous lung cancer risk prediction models have been developed and validated worldwide. It is imperative to offer a comprehensive overview and comparative analysis of their performances.MethodsWe conducted an extensive literature search to identify studies developing and/or validating lung cancer risk prediction models. Then we summarised and compared the external performance of these models, focusing on discriminative accuracy (C-index) and calibration performance (E:O ratio).ResultsAfter an initial screening of 10 210 articles, 35 studies on 21 distinct prediction models were identified, which used 42 different types of predictors spanning seven categories. Notable performance variations were observed in external validations. In North American cohorts, the C-index ranged from 0.60 to 0.87, with E:O ratios from 0.62 to 3.70. Among the European cohorts, the Trøndelag health study HUNT and CanPredict exhibited C-indices surpassing 0.870. Conversely, the Bach, lung cancer risk assessment tool (LCRAT), prostate, lung, colorectal and ovarian cancer screening (PLCO)m2012 and PLCOall2014 performed poorly in electronic health records of the Qresearch database subgroup, with C-indices falling below 0.60. PLCOm2012 reached the best E:O ratio of 1.00 (95% CI: 0.93 to 1.08) in the UK Biobank subgroup. In Asian cohorts, the C-index ranged from 0.54 to 0.87. Only three models, Korean Men, LCRAT and Liverpool lung project incidence risk model (LLPi), achieved a C-index exceeding 0.80. LCRAT demonstrated the best calibration, while Hoggart performed the worst.ConclusionsPerformance of lung cancer risk prediction models, despite being well developed and validated, varies in diverse populations. Significant regional imbalance persists in the development of these models. Rigorous external validation or recalibration study in the target population is crucial in accordance with the guidance prior to model implementation.PROSPERO registration numberCRD42022324602.

Background: With the development of population aging worldwide, sarcopenia and knee osteoarthritis (KOA), two age-related diseases, will continue to impose increasing medical and economic burdens on the society. Previous studies have discovered an association between the two, but the causality remains controversial, and it is difficult to eliminate confounding factors. Therefore, a Mendelian randomization (MR) study was conducted to overcome these confounding factors and investigate the causal relationship between sarcopenia and KOA. Objective: The present work focused on assessing the causality between KOA and sarcopenia, so as to provide new strategies to prevent and treat these two conditions in clinic. Methods: We registered the title with PROSPERO (ID: CRD42023421096). The two-sample bidirectional MR analysis was conducted in two steps, with sarcopenia being the exposure whereas KOA being the outcome in the first step, and vice versa in the second step. Genomewide association studies (GWAS) data on low hand-grip strength (n=256,523), walking pace (n=459,915), appendicular lean mass (ALM n=450,243), and KOA (n=403,124) were obtained from the UK Biobank. Methods such as the inverse variance weighted (IVW) and weighted median were utilized for assessing the causality of KOA with sarcopenia, and sensitivity analyses were also conducted. Results: In the main MR analysis using the IVW method, evidence suggested that low hand-grip strength, walking pace, and ALM had adverse effects on KOA (p-value 0.0001, odds ratio (OR) 1.4569, 95% confidence interval (CI) 1.2007-1.7677 for low hand-grip strength; p-value 0.0003, OR 1.1500, 95% CI 1.050-1.183 for ALM; p-value 5.29E-19, OR 0.0932, 95% CI 0.0553-0.1572 for walking pace). However, there was no causality of KOA with sarcopenia in the opposite direction. Conclusion: Our study suggests an obvious unidirectional causality of KOA with sarcopenia, and supports the notion that patients with sarcopenia are more susceptible to the development of KOA. Keywords: Mendelian randomization, sarcopenia, knee osteoarthritis

Weight loss is a firmly established negative survival factor for individuals with cancer, yet effective biomarkers and targeted therapies remain elusive. In this study, we collected skeletal muscle, noncancerous, and cancerous tissues using the Illumina EPIC array to identify conserved DNA methylation probes associated with weight loss following bariatric surgery. Next, the consistency of the probes is evaluated and then the probes are integrated into a generalizable pathway enrichment score. Our results emphasize the gene-centered design, identifying KCNB1 , PEAK1 , SCG5 , and TNIK as key targets of DNA methylation, as confirmed by mouse phenotype data and druggability resources. Moreover, an illustrative test of protein abundance in cell lines is conducted. Utilizing the Clinical Proteomic Tumor Analysis Consortium data, a positive correlation is established between the chromosomal instability scores and our generated score in tumor tissues. In addition, considering these correlation findings, the presence of identifiable methylation blocks in the co-occurring gain samples. Our findings also suggest that upstream molecular drivers may influence this pathway enrichment score, potentially leading to dysregulated methylation associated with weight loss. In summary, DNA methylation analysis not only identifies functional targets but also uncovers new gene-disease connections.

Introduction With the global aging population on the rise, age-related macular degeneration (AMD) poses a growing healthcare burden. Prior research hints at immune-mediated inflammatory diseases (IMIDs) potentially elevating AMD risk via diverse mechanisms. However, causality remains disputed as a result of confounding factors. Hence, our Mendelian randomization (MR) study aims to untangle this link, mitigating confounding effects to explore the IMID–AMD causal relationship. This study aims to investigate the causal relationship between IMIDs and AMD, providing new strategies for the prevention and treatment of AMD in clinical practice. Methods This study was registered with PROSPERO, CRD42023469815. We obtained data on IMIDs and AMD from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium. Rigorous selection steps were applied to screen for eligible instrumental single nucleotide polymorphisms (SNPs). We conducted univariate Mendelian randomization, inverse variance-weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger), and multivariate Mendelian randomization (MVMR) analyses. Various sensitivity analysis methods were employed to assess pleiotropy and heterogeneity. The aim was to explore the causal relationships between IMIDs and AMD. Results The MR analysis revealed that Crohn’s disease (CD) (IVW: odd ratios (OR) 1.05, 95% CI (confidence interval) 1.01–1.10, p  = 0.007), rheumatoid arthritis (RA) (IVW: OR 1.09, 95% CI 1.04–1.15, p  = 0.0001), and type 1 diabetes (T1D) (IVW: OR 1.05, 95% CI 1.02–1.09, p  = 0.001) were correlated with an elevated risk of AMD, while multiple sclerosis (MS) (IVW: OR 2.78E−18, 95% CI 2.23E−31 to 3.48E−05, p  = 0.008) appeared to be protective against AMD. These findings were supported by an array of MR analysis methodologies and the MVMR approach. Conclusion Our study results, based on MR, provide genetic evidence indicating a causal relationship between specific IMIDs and AMD. CD, RA, and T1D are factors increasing the risk of AMD, while MS may have a protective effect.

Background and objectives Immune checkpoint inhibitors (ICIs) bring cancer patients tumor control and survival benefits, yet they also trigger immune-related adverse effects (irAEs), notably checkpoint inhibitor-related pneumonitis (CIP), affecting about 5% of patients among whom 1–2% experiencing severe grade 3 or higher pneumonitis. Current research points to potential links with T cell subset dysfunction and autoantibody increase, but the specific mechanisms underlying different grades of CIP are understudied. Methods Herein, we employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) from CIP patients across varying severity levels, aiming to elucidate underlying immune environment and mechanisms of CIP progression at cellular and molecular levels. Findings Totally, 121,409 high qualified cells from BALF of 11 patients were annotated and categorized into five major cell types. Severe CIP (CIP-S) cases have a significant increase in the percentage of unreported epithelial cells in their bronchoalveolar lavage fluid compared with mild CIP (CIP-M) cases. These cells were defined as aberrant basaloid cells. They upregulated SOX9, increased the expression of CXCL3/5, recruited neutrophils, and activated the immune system. Additionally, macrophages in the CIP-S group had stronger antigen-presenting abilities and resulted in more CD8 + effective T cells infiltrated. Conclusions Utilizing single-cell sequencing of BALF, we discovered an enriched population of aberrant basaloid cells in CIP-S patients, which had not been previously reported. Aberrant basaloid cells may upregulate SOX9 via CXCL3/5-CXCR2 to recruit and activate neutrophils, and further activate the immune system, resulting in CIP-S. This finding could identify new targets for stratified treatment of CIP patients, holding promise of a novel approach for clinical guidance.

Objective Chronic kidney disease (CKD) and osteoarthritis (OA) represent two frequently seen disorders among the general population, and they share several similar risk factors. The present work focused on assessing the relation of CKD with OA. Methods This cohort study included 26,280 eligible participants aged ≥ 20 years who had valid data on CKD and OA from the National Health and Nutrition Examination Survey (NHANES) 2011–2020. The association between CKD and OA was studied by logistic regression, adjusting for demographics, body mass index (BMI), socioeconomic factors, physical activity, ever smoking, alcohol using, diabetes status and hypertension status. Results Among the participants of this study, 26.69% of OA patients had concurrent CKD, whereas this proportion was only 13.83% among non-OA patients.CKD was related to OA[OR:2.269 (95%CI:2.266–2.271), p  < 0.01] and the relation was of significance [OR:1.031 (95%CI:1.030–1.033), p  < 0.01] following adjustments. In subgroup analyses based on age, the relation between osteoarthritis and chronic kidney disease remained significant, and in the subgroup analyses based on gender the previously mentioned relation between OA and CKD showed opposite directions in men [OR:0.869(95%CI0.867-0.871), p  < 0.01] and women [OR:1.178(95%CI1.177-1.180), p  < 0.01]. Conclusions In the present 10-year large-scale national-wide survey, OA is closely related to CKD, and women with OA showed a higher risk of developing CKD compared to men. This study suggests that the relationship between OA and CKD deserves further investigation, and we suggest that patients with OA need to pay extra attention to their own kidney health.

Background Previous studies suggested that zinc finger protein 536 (ZNF536) was abundant in the central brain and regulated neuronal differentiation. However, the role of ZNF536 in cancer has remained unclear. Methods ZNF536 mutation, copy number alteration, DNA methylation, and RNA expression were explored using public portals. Data from The Cancer Genome Atlas (TCGA) were utilized to analyze pathways and tumor microenvironment (TME), with a focus on prognosis in both TCGA and immunotherapy pan-cancer cohorts. Methylated ZNF536 from small cell lung cancer (SCLC) cell lines were utilized to train with probes for conducting enrichment analysis. Single-cell RNA profile demonstrated the sublocalization and co-expression of ZNF536, and validated its targets by qPCR. Results Genetic alterations in ZNF536 were found to be high-frequency and a single sample could harbor different variations. ZNF536 at chromosome 19q12 exerted a bypass effect on CCNE1, supported by CRISPR data. For lung cancer, ZNF536 mutation was associated with longer survival in primary lung adenocarcinoma (LUAD), but its prognosis was poor in metastatic LUAD and SCLC. Importantly, ZNF536 mutation and amplification had opposite prognoses in Stand Up To Cancer-Mark Foundation (SU2C-MARK) LUAD cohort. ZNF536 mutation altered the patterns of genomic alterations in tumors, and had distinct impacts on the signaling pathways and TME compared to ZNF536 amplification. Additionally, ZNF536 expression was predominantly in endocrine tumors and brain tissues. High-dimensional analysis supported this finding and further revealed regulators of ZNF536. Considering that the methylation of ZNF536 was involved in the synaptic pathway associated with neuroendocrine neoplasms, demonstrating both diagnostic and prognostic value. Moreover, we experimentally verified ZNF536 upregulated neuroendocrine markers. Conclusions Our results showed that ZNF536 alterations in cancer, including variations in copy number, mutation, and methylation. We proved the involvement of ZNF536 in neuroendocrine regulation, and identified highly altered ZNF536 as a potential biomarker for immunotherapy.

Osteoarthritis (OA) is one of the major disabling human diseases. The related studies indicate a potential correlation between walking and OA. However, there is still a lack of evidence in genetics to support the correlation between walking and OA. Therefore, this study aimed to explore the relationship between walking and OA at the genetic level. The publicly available Genome Wide Association Study (GWAS) data were used, with inverse variance weighting (IVW, the random-effects model) as the main analysis method, whereas MR-Egger, Weighted median, Simple mode, and Weighted mode as the secondary analysis methods. In addition, Cochran's Q test, pleiotropy test, and MR-Egger intercept test were conducted to examine the heterogeneity and pleiotropy of the outcome. In the MR analysis, IVW results showed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and OA (KOA or HOA) (odds ratio (OR) = 0.3224, 95% confidence interval (CI): 0.1261 to 0.8243), and the difference was of statistical significance (P = 0.0181). Moreover, IVW results also revealed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and KOA (OR = 0.1396, 95% CI: 0.0484 to 0.4026), and the difference was statistically significant (P = 0.0003). However, IVW results did not demonstrate any statistical significance types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and HOA (OR = 1.2075, 95% CI: 0.1978 to 7.3727, P = 0.8381). From genetic studies, types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) is negatively correlated with knee osteoarthritis (KOA), but there is no clear evidence supporting its correlation with hip osteoarthritis (HOA).

Acute kidney injury (AKI) is a clinical syndrome that results from a rapid decline in renal structure or renal functional impairment with the main pathological feature of sublethal and lethal damage to renal tubular cells. However, many potential therapeutic agents cannot achieve the desired therapeutic effect because of their poor pharmacokinetics and short retention time in the kidneys. With the recent emergence and progress of nanotechnology, nanodrugs with unique physicochemical properties could prolong circulation time, enhance efficient targeted delivery, and elevate the accumulation of therapeutics that can cross the glomerular filtration barrier and indicate comprehensive application prospects in the prevention and treatment of AKI. In this review, various types of nanosystems (such as liposomes, polymeric nanosystems, inorganic nanoparticles and cell-derived extracellular vesicles) are designed and applied to improve the pharmacokinetics of drug formation, which could further relieve the burden on the kidneys caused by the final cumulative dose of drugs in conventional treatments. Moreover, the passive or active targeting effect of nanosystems can also reduce the total therapeutic dose and off-target adverse effects on other organs. Nanodelivery systems for treating AKI that alleviate oxidative stress-induced renal cell damage and regulate the inflammatory kidney microenvironment are summarized.