MSCs biomimetic ultrasonic phase change nanoparticles promotes cardiac functional recovery after acute myocardial infarction.

Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.

BACKGROUND: Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients. METHODS: In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1. FINDINGS: Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib. CONCLUSIONS: Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC. FUNDING: This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.

Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases.

Background: The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases. Methods: Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety. Results: The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed. Conclusion: Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment.

Global burden of chronic kidney disease in adolescents and young adults, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.

Background: The global status of chronic kidney disease (CKD) is underestimated, particularly the burden on adolescents and young adults (early-onset, aged 15-39). Objective: We aim to investigate the pattern and trend of early-onset CKD from 1990 to 2019. Methods: We analyzed age-specific rates of early-onset CKD incidence, death, and disability-adjusted life years (DALY) using Global Burden of Disease Study 2019 data. We examined the global, regional, national, gender-based, age group-based, and temporal changes of early-onset CKD burden from 1990 to 2019, as well as proportional DALY attributions of various risk factors. Results: From 1990 to 2019, the global age-specific incidence rate (per 100,000 population) significantly increased from 25.04 (95% confidence interval 18.51, 31.65) to 32.21 (23.73, 40.81) for early-onset CKD. However, the global age-specific death rate significantly decreased from 2.96 (2.76, 3.15) to 2.86 (2.61, 3.11), and the age-specific DALY rate remained stable. Regarding sociodemographic indexes (SDI), countries with middle SDI had the highest incidence rates and the fastest increasing trends, while those with low and low-middle SDI experienced the highest death and DALY rates. Women had a generally higher age-specific incidence rate than men, whereas men showed higher age-specific death and DALY rates. In addition, the burdens of CKD increased with age among adolescents and young adults. Moreover, the main attributable risk factors for DALY of early-onset CKD were high systolic blood pressure (SBP), fasting plasma glucose (FPG), and body mass index (BMI). Conclusion: The age-specific incidence rate of early-onset CKD increased significantly from 1990 to 2019, and the age-specific DALY rate remained stable. High SBP, high FPG, and high BMI were the primary risk factors. Targeted prevention and healthcare measures should be developed considering age, gender, and region.

Investigating the protective effect of loganin in ovariectomy­induced bone loss through network pharmacology and molecular docking.

Loganin, a major iridoid glycoside derived from Cornus officinalis, exerts strong anti-inflammatory property. The present study aimed to investigate the underlying mechanism of loganin to reduce estrogen deficiency-induced bone loss through a combination of network pharmacology, molecular docking and in vivo validation. First, the drug targets and structural interactions of loganin with osteoclasts on postmenopausal osteoporosis (PMOP) were predicted through network pharmacology and molecular docking. An ovariectomized (OVX) mouse model was established to experimentally validate loganin's anti-PMOP efficacy, supported by its protective effect on bone destruction and excessive inflammatory cytokines. The top 10 core targets of loganin generated by a protein-protein interaction network were the following: GAPDH, VEGFA, EGFR, ESR1, HRAS, SRC, FGF2, HSP90AA1, PTGS2 and IL-2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that loganin suppressed PMOP via mediating inflammation, bone formation, IL-17 signaling pathway and NF-κB signaling pathway. Molecular docking results indicated strong binding between loganin and core targets, in which the binding energy was approximately -5.2 and -7.4 kcal/mol. In vivo mouse model revealed that loganin inhibited the expression of pro-osteoclastic markers, such as tartrate-resistant acid phosphatase, C-terminal telopeptide, TNF-α and IL-6, enhanced the secretion of bone formation markers, such as procollagen type I intact n-terminal pro-peptide and IL-10, and improved bone micro-structure (bone volume/tissue volume and trabecular number), representative of the anti-resorptive effect mediated by loganin. In summary, the present study combined network pharmacology and molecular docking to predict the underlying mechanism of loganin against PMOP, validated by the in vivo mouse model showing that loganin attenuated OVX-induced bone loss by inhibiting inflammation.

QTL detection for grain shape and fine mapping of two novel locus qGL4 and qGL6 in rice.

Rice grain size and grain weight, which have a great influence on rice quality and yield, are complex quantitative traits that are mediated by grain length (GL), grain width (GW), length-to-width ratio (LWR), and grain thickness (GT). In this study, the BC1F2 and BC1F2:3 populations derived from a cross between two indica rice varieties, Guangzhan 63-4S (GZ63-4S) and Dodda, were used to locate quantitative trait loci (QTL) related to grain size. A total of 30 QTL associated with GL, GW and LWR were detected, of which six QTL were scanned repeatedly in both populations. Two QTL, qGL4 and qGL6, were selected for genetic effect validation and were subsequently fine mapped to 2.359 kb and 176 kb, respectively. LOC_Os04g52240 (known as OsKS2/OsKSL2), which encoding an ent-beyerene synthase and as the only gene found in 2.359 kb interval, was proposed to be the candidate for qGL4. Moreover, the grains of qGL4 homozygous mutant plants generated by the CRISPR-Cas9 system became shorter and wider. In addition, the qGL4 allele from GZ63-4S contributes to the increase of yield per plant. Our study not only laid the foundation for further functional study of qGL4 and map-based cloning of qGL6, but also provided genetic resources for the development of high yield and good quality rice varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01502-8.

Resveratrol Protects Müller Cells Against Ferroptosis in the Early Stage of Diabetic Retinopathy by Regulating the Nrf2/GPx4/PTGS2 Pathway.

The aim of this study was to investigate the anti-ferroptotic effect of resveratrol (RSV) on retinal Müller cells (RMCs) in the early stages of diabetic retinopathy (DR) via the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/prostaglandin-endoperoxide synthase 2 (PTGS2). The retina was obtained from normal and diabetic Sprague-Dawley rats or wild-type and Nrf2 knockout (KO) diabetic mice, with or without RSV (10 mg/kg/d) treatment for 12 weeks. RMCs transfected with or without SiNrf2 were cultured with high glucose and RSV (20 mM). The retinal neurofunctional changes were measured by electroretinogram (ERG). The retinal inner nuclear layer cell mitochondrial morphological changes were detected by transmission electron microscopy. The cell viabilities were measured by cell counting kit-8 (CCK-8) assay. The levels of Fe2+, malonic dialdehyde (MDA), and glutathione (GSH) were measured by colorimetric method. The expression of Nrf2, GPx4, and PTGS2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry. In vivo, RSV inhibited retinal neurofunctional changes and mitochondrial morphological changes; decreased Fe2+, MDA, and PTGS2; and increased GSH, Nrf2, and GPx4 in retina of DM rats. In vitro, RSV decreased MDA and PTGS2 and increased cell viability, GSH, Nrf2, and GPx4. In vivo and vitro, the role of Nrf2-regulated signaling pathway in anti-ferroptosis by RSV was further confirmed using Nrf2 KO mice and pre-transfected SiNrf2 in RMCs. These findings indicated that RSV is a potential therapeutic option for DR and that Nrf2/GPx4/PTGS2 plays a role in the anti-ferroptosis mechanism of RSV on RMCs.

Research of multi-label text classification based on label attention and correlation networks.

Multi-Label Text Classification (MLTC) is a crucial task in natural language processing. Compared to single-label text classification, MLTC is more challenging due to its vast collection of labels which include extracting local semantic information, learning label correlations, and solving label data imbalance problems. This paper proposes a model of Label Attention and Correlation Networks (LACN) to address the challenges of classifying multi-label text and enhance classification performance. The proposed model employs the label attention mechanism for a more discriminative text representation and uses the correlation network based on label distribution to enhance the classification results. Also, a weight factor based on the number of samples and a modulation function based on prediction probability are combined to alleviate the label data imbalance effectively. Extensive experiments are conducted on the widely-used conventional datasets AAPD and RCV1-v2, and extreme datasets EUR-LEX and AmazonCat-13K. The results indicate that the proposed model can be used to deal with extreme multi-label data and achieve optimal or suboptimal results versus state-of-the-art methods. For the AAPD dataset, compared with the suboptimal method, it outperforms the second-best method by 2.05% ∼ 5.07% in precision@k and by 2.10% ∼ 3.24% in NDCG@k for k = 1, 3, 5. The superior outcomes demonstrate the effectiveness of LACN and its competitiveness in dealing with MLTC tasks.

Efficacy and Safety of Iparomlimab, an Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors: A Phase 1c Study.

INTRODUCTION: Iparomlimab (QL1604) is a humanized immunoglobulin G4 mAb against programmed cell death protein 1 (PD-1). Here, we report the preliminary efficacy, safety, pharmacokinetics, and immunogenicity of iparomlimab in patients with advanced solid tumors. METHODS: In this open-label, phase 1c study, patients with advanced or metastatic solid tumors, either failed or had no standard therapies available, were enrolled and received intravenous iparomlimab at 3 mg/kg once every 3 weeks. The primary efficacy endpoint was the objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: Between July 20, 2020, and September 6, 2021, 71 patients were enrolled and received at least one dose of iparomlimab. The ORR was 9.9% (7/71) and disease control rate was 36.6% (26/71). Median duration of response of all responders was 10.7 months [95% confidence interval (CI), 1.4-not estimable]. Additionally, the median time to progression, progression-free survival, and overall survival were 1.4 months (95% CI, 1.4-2.8), 1.4 months (95% CI, 1.4-2.7), and 9.7 months (95% CI, 7.2-15.3), respectively. A total of 52 (73.2%) patients experienced treatment-related adverse events (TRAEs) (grade ≥ 3, 19.7%). The most common TRAE (≥ 10%) was anemia (18.3%). A total of 20 (28.2%) experienced immune-related adverse events (grade ≥ 3, 7.0%). TRAEs leading to discontinuation of study drug occurred in 4 (5.6%) patients, including immune-mediated myocarditis (2 patients), Guillain-Barré syndrome (1 patient), and diarrhea (1 patient). CONCLUSIONS: Iparomlimab showed preliminary clinical activity and had a manageable safety profile in patients with advanced solid tumors. These results support further investigation of iparomlimab as monotherapy or in combination therapy in advanced solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05801094. Retrospectively registered in 2023-03-24.

Schizophrenia and type 2 diabetes risk: a systematic review and meta-analysis.

Objectives: The metabolic syndrome in patients with schizophrenia has consistently been a challenge for clinicians. Previous studies indicate that individuals with schizophrenia are highly prone to developing type 2 diabetes mellitus (T2DM). In recent years, a continuous stream of new observational studies has been reported, emphasizing the pressing need for clinicians to gain a more precise understanding of the association between schizophrenia and T2DM. The objective of this meta-analysis is to integrate new observational studies and further explore the potential link between schizophrenia and the risk of T2DM. Methods: We conducted a comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science using medical subject headings (MeSH) and relevant keywords. The risk of bias in cohort studies and case-control studies was assessed using the Newcastle-Ottawa Scale (NOS), while cross-sectional studies were evaluated using the Agency for Healthcare Research and Quality scale (AHRQ), scoring was based on the content of the original studies. A fixed-effects model was employed if P > 0.1 and I2 ≤ 50%, indicating low heterogeneity. Conversely, a random-effects model was utilized if I2 > 50%, indicating substantial heterogeneity. Publication bias was assessed using funnel plots and Egger's test. Statistical analyses were carried out using Stata statistical software version 14.0. Results: This meta-analysis comprised 32 observational studies, involving a total of 2,007,168 patients with schizophrenia and 35,883,980 without schizophrenia, published from 2004 to 2023. The pooled analysis revealed a significant association between a history of schizophrenia and an increased risk of T2DM (Odds Ratio [OR] = 2.15; 95% Confidence Interval [CI]: 1.83-2.52; I2 = 98.9%, P < 0.001). Stratified by gender, females with schizophrenia (OR = 2.12; 95% CI: 1.70-2.64; I2 = 90.7%, P < 0.001) had a significantly higher risk of T2DM than males (OR = 1.68; 95% CI: 1.39-2.04; I2 = 91.3%, P < 0.001). Regarding WHO regions, EURO (OR = 2.73; 95% CI: 2.23-3.35; I2 = 97.5%, P < 0.001) exhibited a significantly higher risk of T2DM compared to WPRO (OR = 1.72; 95% CI: 1.32-2.23; I2 = 95.2%, P < 0.001) and AMRO (OR = 1.82; 95% CI: 1.40-2.37; I2 = 99.1%, P < 0.001). In terms of follow-up years, the >20 years subgroup (OR = 3.17; 95% CI: 1.24-8.11; I2 = 99.4%, P < 0.001) showed a significantly higher risk of T2DM than the 10-20 years group (OR = 2.26; 95% CI: 1.76-2.90; I2 = 98.6%, P < 0.001) and <10 years group (OR = 1.68; 95% CI: 1.30-2.19; I2 = 95.4%, P < 0.001). Conclusions: This meta-analysis indicates a strong association between schizophrenia and an elevated risk of developing diabetes, suggesting that schizophrenia may function as an independent risk factor for T2DM. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023465826.

Comprehensive analysis of the relationship between yield stress and dewatering performance in sludge conditioning: Insights from various treatment methods.

Understanding the relationship between sludge yield stress (σy) and dewatering performance is essential for optimizing sludge conditioning processes. This study systematically investigates the effects of various conditioning methods-including thermal hydrolysis (TH), freezing/thawing (FT), anaerobic digestion (AD), polyaluminum chloride (PAC), polyacrylamide (PAM), and Fenton treatment (Fenton)-on sludge yield stress and its correlation with dewatering efficiency. Using linear regression, partial least squares regression (PLSR), and correlation heatmap analyses, we reveal significant variations in the correlation between σy and dewatering indexes, including moisture content (Mc), capillary suction time (CST), and bound water proportion (Wb/Wt), depending on the conditioning method and intensity. Under FT and PAM conditioning, σy shows a strong negative linear correlation with dewatering performance, with Pearson's r values exceeding -0.880, indicating that a decrease in σy corresponds to improved dewatering efficiency. Conversely, AD conditioning exhibits a positive linear correlation, with r values up to 0.993, suggesting that an increase in σy correlates with reduced dewatering efficiency. For TH, PAC, and Fenton treatments, the correlation between σy and dewatering metrics is highly sensitive to changes in treatment intensity. In the PLSR analysis, the VIP values, which quantify the importance of each predictor variable, indicate that Wb/Wt in TH conditioning (VIP = 1.649) and CST in PAC (VIP = 1.309) and Fenton (VIP = 1.299) conditioning strongly influence σy. This study highlights the significant impact of conditioning methods and intensities on the correlation between σy and dewatering performance. While σy provides valuable insights as a predictive indicator, its predictive power is limited in more complex conditioning scenarios. Therefore, optimizing conditioning intensity and incorporating multiple rheological parameters are essential for achieving superior sludge dewatering outcomes.

New insights into acinic cell carcinoma of the breast: clinicopathology, origin of histology, molecular features, prognosis, and treatment.

Acinic cell carcinoma (AciCC) of the breast is a rare malignant epithelial neoplasm, with approximately 60 cases reported in the literature. It predominantly affects women and exhibits significant histological heterogeneity. The diagnosis of breast AciCC is primarily based on the presence of eosinophilic and/or basophilic granular cytoplasm and markers of serous acinar differentiation. Despite being considered a low-grade variant of conventional triple-negative breast cancer (TNBC), over 25% of patients with breast AciCC have adverse clinical outcomes. Additionally, in early research, microglandular adenosis (MGA) and atypical MGA were considered potential precursors for various breast cancers, including intraductal carcinoma, invasive ductal carcinoma, adenoid cystic carcinoma, metaplastic carcinoma, and AciCC. Similarly, some studies have proposed that breast AciCC should be considered a type of carcinoma developing in MGA with acinic cell differentiation rather than a distinct entity. Therefore, the pathogenesis of breast AciCC has not yet been clarified. Moreover, to the best of our knowledge, the literature has not summarized the latest prognosis and treatment of breast AciCC. In this review, we synthesized the current literature and the latest developments, aiming at exploring the clinicopathology, histological origin, molecular features, prognosis, and treatment of breast AciCC from a novel perspective.

Chlorquinaldol Alleviates Lung Fibrosis in Mice by Inhibiting Fibroblast Activation through Targeting Methionine Synthase Reductase.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.

Design, Synthesis, and Antiviral and Fungicidal Activities of 4-Oxo-4H-quinolin-1-yl Acylhydrazone Derivatives.

To discover novel antiviral agents, based on the high antiviral activity of (4-oxo-4H-quinolin-1-yl)-acetic acid hydrazide (C), a series of 4-oxo-4H-quinoline acylhydrazone derivatives were designed, synthesized, and first evaluated for their antiviral and fungicidal activities. Most acylhydrazone derivatives exhibited moderate to good antiviral activities in vivo. The inactive, curative, and protective activities of compounds 4 (51.2, 47.6, and 46.3%), 11 (49.6, 43.0, and 45.2% at 500 mg/L), and 17 (47.1, 49.2, and 44.1%) were higher than those of ribavirin (39.2, 38.0, and 40.8%) at 500 mg/L. Molecular docking showed that compound 4 exhibited a stronger affinity to TMV coat protein (TMV-CP) than ribavirin, with a binding energy (-6.89 kcal/mol) slightly lower than that of ribavirin (-6.08 kcal/mol). Microscale thermophoresis showed that compound 4 (K d = 0.142 ± 0.060 µM) exhibited a strong binding ability to TMV-CP, superior to that of ribavirin (K d = 0.512 ± 0.257 µM). The results of transmission electron microscopy showed that compound 4 hindered the self-assembly and growth of TMV. The antifungal activities of most compounds were moderate at 50 mg/L, among which compounds 12 and 21 exhibited a 72.1 and 76.5% inhibitory rate against Physalospora piricola, respectively. Meanwhile, compound 16 exhibited a 60% inhibitory rate against Cercospora arachidicola Hori at 50 mg/L.

Altered brain function in treatment-resistant depression patients: A resting-state functional magnetic resonance imaging study.

BACKGROUND: It has been established that there are functional changes in the brain of treatment-resistant depression (TRD) patients, but previous studies of functional connectivity (FC) usually involved selection of regions of interest based on accumulated a priori knowledge of the disorder. In this study, we combine amplitude of low-frequency fluctuation (ALFF) and FC; this approach, based on the abnormal ALFF, may provide some insights into the neural basis of the disease in terms of fMRI signals of low-frequency fluctuations. METHODS: A total of 16 TRD patients, who visited the Qingdao Mental Health Center, Shandong Province, China between March 2023 and January 2024, along with 16 normal subjects, were enrolled into this study for functional imaging. In this study, we first explored the ALFF changes of TRD patients at a baseline resting state. Second, we selected the regions that were significantly changed in the ALFF as seeds and calculated the regional activity and functional connectivity (FC) of these regions using a seed-based approach. We also calculated correlations between the percent change in the PDQ-5D scores and ALFF values in brain regions with differing activity for TRD patients. RESULTS: During the baseline resting state, by using the ALFF, we found a significantly decreased or increased ALFF in the TRD patients relative to the controls. These regions were located in the left/right postcentral gyrus (PoCG.L/PoCG.R), right cuneus(CUN.R). We found that the ALFF values of the right hippocampus (HIP.R) in the TRD group were negatively correlated with the PDQ-5D score. Then, we selected these brain regions as seeds to investigate the FC changes in brains of TRD patients. We found abnormal functional connectivity in left/right middle frontal gyrus(MFG.L/MFG.R), the right Inferior frontal gyrus, opercular part (IFGoperc.R), the left/right Anterior cingulate and paracingulate gyri (ACC.L/ACC.R), the right supramarginal gyrus (SMG.R), and the right Calcarine fissure and surrounding cortex (CAL.R). CONCLUSION: We found a larger range of altered brain regions in TRD patients compared to healthy controls, especially in the central executive network (CEN), salience network (SN) and default mode network (DMN).

Bipolar disorder: Construction and analysis of a joint diagnostic model using random forest and feedforward neural networks.

Background: To construct a diagnostic model for Bipolar Disorder (BD) depressive phase using peripheral tissue RNA data from patients and combining Random Forest with Feedforward Neural Network methods. Methods: Datasets GSE23848, GSE39653, and GSE69486 were selected, and differential gene expression analysis was conducted using the limma package in R. Key genes from the differentially expressed genes were identified using the Random Forest method. These key genes' expression levels in each sample were used to train a Feedforward Neural Network model. Techniques like L1 regularization, early stopping, and dropout layers were employed to prevent model overfitting. Model performance was then validated, followed by GO, KEGG, and protein-protein interaction network analyses. Results: The final model was a Feedforward Neural Network with two hidden layers and two dropout layers, comprising 2345 trainable parameters. Model performance on the validation set, assessed through 1000 bootstrap resampling iterations, demonstrated a specificity of 0.769 (95 % CI 0.571-1.000), sensitivity of 0.818 (95 % CI 0.533-1.000), AUC value of 0.832 (95 % CI 0.642-0.979), and accuracy of 0.792 (95 % CI 0.625-0.958). Enrichment analysis of key genes indicated no significant enrichment in any known pathways. Conclusion: Key genes with biological significance were identified based on the decrease in Gini coefficient within the Random Forest model. The combined use of Random Forest and Feedforward Neural Network to establish a diagnostic model showed good classification performance in Bipolar Disorder.

Sarcopenia as a prognostic factor in patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization plus sorafenib.

INTRODUCTION: Loss of skeletal muscle volume is an important aspect of sarcopenia in hepatocellular carcinoma (HCC) patients treated by surgical resection, transcatheter arterial chemoembolization (TACE), or sorafenib. PURPOSE: This study determined the influence of sarcopenia and other laboratory results on survival in patients with HCC treated with TACE plus sorafenib. METHODS: The patients were divided into two groups based on the presence of sarcopenia. The skeletal muscle index was calculated by normalizing the cross-sectional muscle area at the L3 level on an abdominal computed tomography scan before embolization according to the patient's height. The clinical characteristics of the two groups were then compared. The progression-free survival (PFS) and overall survival (OS) rates after treatment were determined. RESULTS: Sarcopenia was present in 75 of the 102 (74%) patients with HCC included in this study. The albumin, prealbumin, and cholinesterase levels were lower in those with sarcopenia. The OS (P = 0.001) and PFS (P = 0.008) were significantly prolonged in the nonsarcopenia group compared to the sarcopenia group. Sarcopenia, ECOG (≥2), and prealbumin (<180 mg/L) were significantly associated with PFS. Sarcopenia, ECOG (≥2), Child-Pugh B, BCLC stage C, prealbumin (<180 mg/L), and cholinesterase (<5,320 U/L) were significantly associated with OS. The prognostic factors for OS included sarcopenia, ECOG (≥2), and cholinesterase (<5,320 U/L), whereas only ECOG (≥2) was identified as a prognostic factor for PFS. CONCLUSION: Sarcopenia may be an indicator of poor clinical outcome in patients with HCC receiving TACE plus sorafenib.

Incidence of endometrial cancer in BRCA mutation carriers.

OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps.

BACKGROUND AND AIMS: Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. METHODS: NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. RESULTS: Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. CONCLUSIONS: This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

Two hub genes of bipolar disorder, a bioinformatics study based on the GEO database.

Bipolar disorder is a mood illness that affects many people. It has a high recurrence frequency and will cause significant damage to the patient's social function. At present, the pathogenesis of BD is not clear. The National Center for Biotechnology Information (NCBI) established and maintained the Gene Expression Omnibus (GEO) database, a gene expression database. For bioinformatics analysis, researchers can obtain expression data from the internet. At present, the samples of the dataset used in the research of BD are mostly from brain tissue, and the data containing blood samples are rarely used. GEO databases (GSE46416, GSE5388, and GSE5389) were used to retrieve public data, and utilizing the online tool GEO2R, differentially expressed genes (DEGs) were retrieved. The common DEGs between the samples of patients with BD and the samples of the normal population were screened by Venn diagrams. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to perform functional annotation and pathway enrichment analysis of DEGs. A protein-protein interaction network (PPI) was built to investigate hub genes on this basis. There were 117 up-regulated DEGs and 38 down-regulated DEGs discovered, with two hub genes [SRC, CDKN1A] among the up-regulated DEGs. These two hub genes were also highly enriched in the oxytocin signaling pathway, proteoglycans in cancer and bladder cancer, according to KEGG analysis. The results of the receiver operating characteristic curve (ROC) of SRC and CDKN1A in the three datasets strongly suggested that SRC and CDKN1A were potential diagnostic markers of BD. The results strongly suggest that SRC and CDKN1A are related to the pathogenesis of BD.