Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Functional Group-driven Competing Mechanism in Electrochemical Reaction and Adsorption/Desorption Processes toward High-capacity Aluminum-Porphyrin Batteries.

Nonaqueous organic aluminum batteries are considered as promising high-safety energy storage devices due to stable ionic liquid electrolytes and Al metals. However, the stability and capacity of organic positive electrodes are limited by their inherent high solubility and low active organic molecules. To address such issues, here porphyrin compounds with rigid molecular structures present stable and reversible capability in electrochemically storing AlCl2+. Comparison between the porphyrin molecules with electron-donating groups (TPP-EDG) and with electron-withdrawing groups (TPP-EWG) suggests that EDG is responsible for increasing both HOMO and LUMO energy levels, resulting in decreased redox potentials. On the other hand, EWG is associated with decreasing both HOMO and LUMO energy levels, leading to promoted redox potentials. EDG and EWG play critical roles in regulating electron density of porphyrin π bond and electrochemical energy storage kinetics behavior. The competitive mechanism between electrochemical redox reaction and de/adsorption processes suggests that TPP-OCH3 delivers the highest specific capacity ~171.8 mAh g-1, approaching a record in the organic Al batteries.

Enzyme-powered, label-free DNA walker for Uracil-DNA glycosylase detection at single-cell level.

Uracil-DNA glycosylase (UDG) plays a crucial role in the removal of damaged uracil bases, thereby upholding genetic stability and integrity. An enzyme-powered, label-free DNA walker was devised for UDG activity detection. Initially, a label-free DNA track, incorporating a gold nanoparticle (AuNP), multiple hairpin structures, and various swing arms, was engineered for walking mechanism. The hairpin structure was meticulously crafted to include a G-quadruplex sequence, enabling the generation of a label-free fluorescence signal. The swing arm remained inert in the absence of UDG, but became activated upon the introduction of UDG, thereby initiating the enzyme-powered walking process and generating significant dissociative G-quadruplex sequences. By integrating a selective fluorescent dye into the design, an enhanced label-free fluorescence response was achieved. The proposed DNA walker presented a direct and label-free approach for UDG detection, demonstrating exceptional sensitivity with a detection limit of 0.00004 U/mL. Using the uracil glycosylase inhibitor (UGI) as an inhibitory model, inhibitor assay was conducted with satisfactory precision. Furthermore, successful analysis of cellular UDG at the single-cell level was accomplished. Consequently, the developed DNA walker serves as a label-free, selective, and sensitive tool for UDG activity assessment, showing great potential for applications in disease diagnosis, inhibitor screening, and biomedical investigations.

Mild hypothermia pretreatment improves hepatic ischemia-reperfusion injury: A systematic review and meta-analysis of animal experiments.

BACKGROUND AND AIM: Mild hypothermia in hepatic ischemia-reperfusion injury is increasingly being studied. This study aimed to conduct a systematic evaluation of the effectiveness of mild hypothermia in improving hepatic ischemia-reperfusion injury. METHODS: We systematically searched CNKI, WanFang Data, PubMed, Embase, and Web of Science for original studies that used animal experiments to determine how mild hypothermia(32-34°C) pretreatment improves hepatic ischemia-reperfusion injury(in situ 70% liver IR model). The search period ranged from the inception of the databases to May 5, 2023. Two researchers independently filtered the literature, extracted the data, and assessed the risk of bias incorporated into the study. The meta-analysis was performed using RevMan 5.4.1 and Stata 15 software. RESULTS: Eight randomized controlled trials (RCTs) involving a total of 117 rats/mice were included. The results showed that the ALT levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [Standardized Mean Difference (SMD) = -5.94, 95% CI(-8.09, -3.78), P<0.001], and AST levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [SMD = -4.45, 95% CI (-6.10, -2.78), P<0.001]. The hepatocyte apoptosis rate in the mild hypothermia pretreatment group was significantly lower than that in the normothermic control group [SMD = -6.86, 95% CI (-10.38, -3.33), P<0.001]. Hepatocyte pathology score in the mild hypothermia pretreatment group was significantly lower than that in the normothermic control group [SMD = -4.36, 95% CI (-5.78, -2.95), P<0.001]. There was no significant difference in MPO levels between the mild hypothermia preconditioning group and the normothermic control group [SMD = -4.83, 95% CI (-11.26, 1.60), P = 0.14]. SOD levels in the mild hypothermia preconditioning group were significantly higher than those in the normothermic control group [SMD = 3.21, 95% CI (1.27, 5.14), P = 0.001]. MDA levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [SMD = -4.06, 95% CI (-7.06, -1.07) P = 0.008]. CONCLUSION: Mild hypothermia can attenuate hepatic ischemia-reperfusion injury, effectively reduce oxidative stress and inflammatory response, prevent hepatocyte apoptosis, and protect liver function.

Development of Novel N-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.

Peritoneal fluid indocyanine green test for diagnosis of gut leakage in anastomotic leakage rats and colorectal surgery patients.

BACKGROUND: Application of indocyanine green (ICG) fluorescence has led to new developments in gastrointestinal surgery. However, little is known about the use of ICG for the diagnosis of postoperative gut leakage (GL). In addition, there is a lack of rapid and intuitive methods to definitively diagnose postoperative GL. AIM: To investigate the effect of ICG in the diagnosis of anastomotic leakage in a surgical rat GL model and evaluate its diagnostic value in colorectal surgery patients. METHODS: Sixteen rats were divided into two groups: GL group (n = 8) and sham group (n = 8). Approximately 0.5 mL of ICG (2.5 mg/mL) was intravenously injected postoperatively. The peritoneal fluid was collected for the fluorescence test at 24 and 48 h. Six patients with rectal cancer who had undergone laparoscopic rectal cancer resection plus enterostomies were injected with 10 mL of ICG (2.5 mg/mL) on postoperative day 1. Their ostomy fluids were collected 24 h after ICG injection to identify the possibility of the ICG excreting from the peripheral veins to the enterostomy stoma. Participants who had undergone colectomy or rectal cancer resection were enrolled in the diagnostic test. The peritoneal fluids from drainage were collected 24 h after ICG injection. The ICG fluorescence test was conducted using OptoMedic endoscopy along with a near-infrared fluorescent imaging system. RESULTS: The peritoneal fluids from the GL group showed ICG-dependent green fluorescence in contrast to the sham group. Six samples of ostomy fluids showed green fluorescence, indicating the possibility of ICG excreting from the peripheral veins to the enterostomy stoma in patients. The peritoneal fluid ICG test exhibited a sensitivity of 100% and a specificity of 83.3% for the diagnosis of GL. The positive predictive value was 71.4%, while the negative predictive value was 100%. The likelihood ratios were 6.0 for a positive test result and 0 for a negative result. CONCLUSION: The postoperative ICG test in a drainage tube is a valuable and simple technique for the diagnosis of GL. Hence, it should be employed in clinical settings in patients with suspected GL.

Recombinant human protein TCFL5-activated NRSN2-AS1 promotes esophageal cancer progression via the microRNA-874-5p/RELT regulatory axis.

The incidence of esophageal cancer continues to increase worldwide. Current therapeutic approaches have limited efficacy, so in order to search for better markers of the disease, it is necessary to further elucidate its molecular pathogenesis. Regulation of gene expression by long non-coding Rnas plays a role in many diseases, however the role in esophageal cancer is unclear. The aim of this study was to elucidate the role and regulatory mechanism of long non-coding RNA NRSN2-AS1 in the progression of esophageal cancer. By real-time quantitative PCR, immunohistochemistry, RNA interference, western blotting, and double luciferase reporter gene analysis, we found that NRSN2-AS1 was up-regulated in esophageal cancer tissues and cell lines, and was closely related to disease stage and prognosis. Functional studies have shown that the silencing of NRSN2-AS1 inhibits the proliferation of esophageal cancer cells, induces apoptosis, and prevents cell migration and invasion. In mouse models, NRSN2-AS1 also promoted tumor growth. The transcription factor TCFL5 upregulates the transcription of NRSN2-AS1, which acts as a sponge for microRNA(miR)-874-5p, thereby upregulating the expression of the oncogene RELT. Activation of the NRSN2-AS1/miR-874-5p/RELT regulatory axis was validated in vivo.

Predictive value of CXCL1+_FAP+ phenotype in CAFs for distant metastasis and its correlation with PD-L1 expression in locoregionally advanced nasopharyngeal carcinoma patients.

OBJECTIVE: There is a lack of effective biomarkers for predicting the distant metastasis in nasopharyngeal carcinoma (NPC). We aimed to explore the expression of FAP+Cancer-associated fibroblasts (CAFs) derived CXCL1 in NPC and its predictive values for distant metastasis and correlation with PD-L1 expression. MATERIALS AND METHODS: A total of 345 patients with locoregionally advanced NPC were retrospectively enrolled (the training cohort: the validation cohort = 160:185). Co-expression of CXCL1 and FAP and the expression of PD-L1 were detected by multi-immunofluorescence staining and immunohistochemistry, respectively. The primary end-point was distant metastasis-free survival (DMFS). The Kaplan-Meier method was used to calculate the survival. The Cox proportional hazards model was used to assess prognostic risk factors. RESULTS: A novel CXCL1+_FAP+ phenotype in CAFs was identified in NPC and then used to divide patients into low and high risk groups. Both in the training cohort and validation cohort, patients in the high risk group had poorer DMFS, overall survival (OS), progression-free survival (PFS) and locoregional relapse-free survival (LRFS) than patients in the low risk group. Multivariate analysis revealed CXCL1+_FAP+ phenotype was an independent prognostic factor for DMFS, OS, PFS and LRFS. Further results showed patients in the high risk group had higher PD-L1 expression than those in the low risk group. CONCLUSION: Our study showed CXCL1+_FAP+ phenotype in CAFs could effectively classified locoregionally advanced NPC patients into different risk groups for distant metastasis and might be a potential biomarker for anti-PD-1/PD-L1 immunotherapy.

Acetylation model predicts prognosis of patients and affects immune microenvironment infiltration in epithelial ovarian carcinoma.

BACKGROUND: Epithelial ovarian carcinoma (EOC) is a prevalent gynaecological malignancy. The prognosis of patients with EOC is related to acetylation modifications and immune responses in the tumour microenvironment (TME). However, the relationships between acetylation-related genes, patient prognosis, and the tumour immune microenvironment (TIME) are not yet understood. Our research aims to investigate the link between acetylation and the tumour microenvironment, with the goal of identifying new biomarkers for estimating survival of patients with EOC. METHODS: Using data downloaded from the tumour genome atlas (TCGA), genotypic tissue expression (GTEx), and gene expression master table (GEO), we comprehensively evaluated acetylation-related genes in 375 ovarian cancer specimens and identified molecular subtypes using unsupervised clustering. The prognosis, TIME, stem cell index and functional concentration analysis were compared among the three groups. A risk model based on differential expression of acetylation-related genes was established through minimum absolute contraction and selection operator (LASSO) regression analysis, and the predictive validity of this feature was validated using GEO data sets. A nomogram is used to predict a patient's likelihood of survival. In addition, different EOC risk groups were evaluated for timing, tumour immune dysfunction and exclusion (TIDE) score, stemness index, somatic mutation, and drug sensitivity. RESULTS: We used the mRNA levels of the differentially expressed genes related to acetylation to classify them into three distinct clusters. Patients with increased immune cell infiltration and lower stemness scores in cluster 2 (C2) exhibited poorer prognosis. Immunity and tumourigenesis-related pathways were highly abundant in cluster 3 (C3). We developed a prognostic model for ten differentially expressed acetylation-related genes. Kaplan-Meier analysis demonstrated significantly worse overall survival (OS) in high-risk patients. Furthermore, the TIME, tumour immune dysfunction and exclusion (TIDE) score, stemness index, tumour mutation burden (TMB), immunotherapy response, and drug sensitivity all showed significant correlations with the risk scores. CONCLUSIONS: Our study demonstrated a complex regulatory mechanism of acetylation in EOC. The assessment of acetylation patterns could provide new therapeutic strategies for EOC immunotherapy to improve the prognosis of patients.

The role of P2X4R in regulating CA1 hippocampal synaptic impairment in LPS-induced depression.

AIM: To study the role of the P2X4 receptor (P2X4R) in regulating hippocampal synaptic impairment in lipopolysaccharide (LPS)-induced depression. METHODS: A rat model of depression was established by LPS injection. P2X4R expression was inhibited by 5-(3-bromophenyl)-1, 3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD). Depressive symptoms were identified through behavioral tests. P2X4R and cytokine mRNA levels were measured by qRT-PCR, while synaptic protein levels were measured by Western blotting. Synaptic ultrastructure was assessed by transmission electron microscopy, and the colocalization of brain-derived neurotrophic factor (BDNF) with microglia, astrocytes, and neurons was determined by double immunofluorescence staining. RESULTS: Injection of 5-BDBD alleviated LPS-induced depressive symptoms. LPS injection significantly increased the mRNA levels of P2X4R and proinflammatory cytokines in the hippocampus, especially in the CA1 region. The levels of synaptic proteins (BDNF, PSD95, and synapsin I) in the CA1 region were significantly lower than those in the other two regions of the hippocampus, and the synaptic ultrastructure in the hippocampal CA1 region was significantly altered. As expected, the Pearson's correlation R and the overlap coefficient R for the hippocampal colocalization of IBA-1 with BDNF were decreased, and 5-BDBD injection reversed these trends. Injection of 5-BDBD increased hippocampal BDNF mRNA expression. CONCLUSIONS: P2X4R may induce synaptic impairment in the hippocampal CA1 region by influencing microglial BDNF expression in the context of LPS-induced depression in rats.

High-quality reference genome of cowpea beetle Callosobruchus maculatus.

Callosobruchus maculatus is one of the most competitive stored grain pests, which causes a great loss to agricultural economy. However, due to an inadequacy of high-quality reference genome, the molecular mechanisms for olfactory and hypoxic adaptations to stored environments are unknown and require to be revealed urgently, which will contribute to the detection and prevention of the invasive pests C. maculatus. Here, we presented a high-quality chromosome-level genome of C. maculatus based on Illumina, Nanopore and Hi-C sequencing data. The total size was 1.2 Gb, and 65.17% (797.47 Mb) of it was identified to be repeat sequences. Among assembled chromosomes, chromosome 10 was considered the X chromosome according to the evidence of reads coverage and homologous genes among species. The current version of high-quality genome provides preferable data resources for the adaptive evolution research of C. maculatus.

Altered tumor microenvironment heterogeneity of penile cancer during progression from non-lymphatic to lymphatic metastasis.

BACKGROUND: Lymphatic metastasis is the major challenge in the treatment of penile cancer. The prognosis of individuals with lymphatic metastasis is extremely poor. Therefore, early identification of disease progression and lymphatic metastasis is an urgent task for researchers in penile cancer worldwide. METHODS: In this study, using single-cell RNA sequencing, an immune landscape was established for the cancer ecosystem based on 46,861 cells from six patients with penile cancer (four with lymphatic metastasis [stage IV] and two without lymphatic metastasis [stage I]). Using bulk RNA sequencing, the discrepancy between the cancers and their respective metastatic lymph nodes was depicted based on seven patients with penile cancer. RESULTS: The interaction between epithelial cells, fibroblasts, and endothelial cells, and the functional cooperation among invasion, epithelial-mesenchymal transition, and angiogenesis were found to be important landscapes in the penile cancer ecosystem, playing important roles in progression of cancer and lymph node metastasis. CONCLUSIONS: This study is the first to investigate the altered tumor microenvironment heterogeneity of penile cancer as it evolves from non-lymphatic to lymphatic metastasis and provides insights into the mechanisms underlying malignant progression, the premetastatic niche, and lymphatic metastasis in penile cancer.

Active monitoring of antifungal adverse events in hospitalized patients based on Global Trigger Tool method.

Background: The increasing prevalence of fungal infections necessitates broader use of antifungal medications. However, the prevalence of adverse drug events (ADEs) restricts their clinical application. This study aimed to develop a reliable ADEs trigger for antifungals to enable proactive ADEs monitoring, serving as a reference for ADEs prevention and control. Methods: This investigation comprises two phases. Initially, the trigger was established via a literature review, extraction of relevant items, and refinement through Delphi expert consultation. Subsequently, the validity of the trigger was assessed by analyzing hospital records of antifungal drug users from 1 January 2019 to 31 December 2020. The correlation between each trigger signal and ADEs occurrence was examined, and the sensitivity and specificity of the trigger were evaluated through the spontaneous reporting system (SRS) and Global Trigger Tool (GTT). Additionally, risk factors contributing to adverse drug events (ADEs) resulting from antifungal use were analyzed. Results: Twenty-one preliminary triggers were refined into 21 final triggers after one expert round. In the retrospective analysis, the positive trigger rate was 65.83%, with a positive predictive value (PPV) of 28.75%. The incidence of ADEs in inpatients was 28.75%, equating to 44.58 ADEs per 100 admissions and 33.04 ADEs per 1,000 patient days. Predominant ADEs categories included metabolic disturbances, gastrointestinal damage, and skin rashes. ADEs severity was classified into 36 cases at grade 1, 160 at grade 2, and 18 at grade 3. The likelihood of ADEs increased with longer stays, more positive triggers, and greater comorbidity counts. Conclusion: This study underscores the effectiveness of the GTT in enhancing ADEs detection during antifungal medication use, thereby confirming its value as a monitoring tool.

Adult Neurogenesis, Context Encoding, and Pattern Separation: A Pathway for Treating Overgeneralization.

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Characteristics and source apportionment of black carbon the urban and desert underlying surfaces.

The spatial distribution of black carbon (BC) concentrations was highly variable across different underlying surfaces. Differences in meteorological conditions and emission sources led to great temporal and spatial variations in BC characteristics. As the most important absorbing aerosol, BC can affect radiation, clouds, and surface snow. BC mass concentrations were measured using a seven channel aethalometer (AE-33) in the Urumqi and Taklimakan Deserts from January to December 2022. The aethalometer data, potential source contribution function (PSCF), and concentration-weighted trajectory (CWT) models were used to analyse the variation characteristics, potential sources, and affected areas. Results showed that the BC concentrations in the Taklamakan Desert and Urumqi were in the range of 0-500 ng·m-3, accounting for 66.20 % and 59.50 % of the total, respectively. The backward trajectory simulation of BC mass concentration in the tower and Urumqi using the HYSPLIT model found that the airflow trajectories in the tower in summer corresponded to the BC concentration in the following order: trajectory 4 > trajectory 3 > trajectory 2 > trajectory 1, and trajectory 4 originated from the Turpan airflow accounting for 46.19 % of the total, which corresponded to the highest BC concentration of 621.73 ng·m-3. The trajectories of the airflow in Urumqi in summer corresponded to the BC concentration in the order of high to low, and the BC concentration in summer corresponded to the highest concentration in the Turpan airflow. BC concentrations arranged from high to low were trajectory 1 > trajectory 5 > trajectory 3 > trajectory 4 > trajectory 2. Trajectories 3, 4, and 5 airflow directions were the same, and the airflow trajectory accounted for 47.48 %, corresponding to BC concentrations of 599.82 ng·m-3, 579.99 ng·m-3, and 555.85 ng·m-3, respectively. Tower in the spring compared with other seasons of the CWT value of >400 ng·m-3 had the widest coverage, and Urumqi had more source areas contributing to moderate pollution concentration weights in winter (400 ng·m-3 < CWT < 800 ng·m-3). The conclusions of this study provide a scientific basis for regional environmental management and the formulation of air pollution measures in Xinjiang.

Examining the influence of body fat distribution on standing balance and functional performance in overweight female patients with degenerative lumbar disease.

Introduction: Degenerative lumbar disease (DLD) is a prevalent disorder that predominantly affects the elderly population, especially female. Extensive research has demonstrated that overweight individuals (categorized by body fat distribution) have a higher susceptibility to developing DLD and an increased risk of falling. However, there is limited research available on the standing balance and functional performance of overweight females with DLD. Aims: To determine the impact of body fat distribution on standing balance and functional performance in overweight females with DLD. Methods: This cross-sectional study evaluated thirty females with DLD were categorized into three types of body fat distribution based on body mass index (BMI) and waist-hip ratio, specifically as android-type, gynoid-type, and normal weight groups. In addition, a control group of ten age-matched females with normal weight was recruited. The Visual Analogue Scale, Roland Morris Disability Questionnaire, Cobb angle (Determined using x-ray), and body composition (Determined using the InBody S10), were conducted only on the DLD groups. All participants were assessed standing balance in the anteroposterior and mediolateral directions. The functional assessments included timed-up-and-go and 5-times-sit-to-stand tests. Results: There were 10 people in each group. Android-type (Age = 65.00 ± 6.34 years; BMI = 26.87 ± 2.05 kg/m2), Gynoid-type (Age = 65.60 ± 4.99 years; BMI = 26.60 ± 1.75 kg/m2), Normal weight (Age = 65.70 ± 5.92 years; BMI = 22.35 ± 1.26 kg/m2), and Control (Age = 65.00 ± 5.23 years; BMI = 22.60 ± 1.12 kg/m2). The android-type group had higher body fat, visceral fat, and lower muscle mass (p < 0.05), along with an increased Cobb angle (p < 0.05). They showed greater ellipse area, total excursion, and mean distance in the anteroposterior direction (p < 0.05). During the functional performance assessments, the android-type group had longer durations in both the 5-times-sit-to-stand and timed-up-and-go tasks (p < 0.05). Conclusion: Our study found that android-type overweight individuals showed postural instability, reduced functional performance, and insufficient lower limb muscle strength and mass. These findings might help physical therapists in planning interventions, as they imply that patients with DLD may require specific types of standing balance training and lower extremities muscle-strengthening based on their body fat distribution. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05375201.

Evaluation of pathological response to neoadjuvant chemotherapy in locally advanced cervical cancer.

Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Deciphering m6A methylation in monocyte-mediated cardiac fibrosis and monocyte-hitchhiked erythrocyte microvesicle biohybrid therapy.

Rationale: Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of m6A modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. m6A modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-ß1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Results: Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing m6A modification on MyD88 and TGF-ß1 mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-ß1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Conclusion: Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting m6A modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.

Integrative profiling of untreated primary membranous nephropathy at the single-cell transcriptome level.

Background: Primary membranous nephropathy (PMN) is an autoimmune kidney disease. Despite the identification of certain autoantigens, the etiology and pathophysiology of PMN are still largely unknown. Methods: Five patients with biopsy-proven PMN were enrolled in this study. Their blood, kidney and urine samples were collected respectively to profile cellular, molecular and immunological alterations by using single-cell RNA sequencing (scRNA-seq). Experimental verifications were also implemented in kidney tissue. Results: In the peripheral blood mononuclear cell (PBMC) samples, portions of B cells and plasma cells were increased in PMN patients. Cell-cell communication analysis suggests that APRIL (a proliferation-inducing ligand from B cells) might be a potential molecule that regulates the activity of plasma cells. In the kidney samples, scRNA-seq analysis showed that the infiltration of T cells, as well as the myeloid cells, appears abundant compared with healthy controls, suggesting that immune cells are actively recruited to kidney. Furthermore, we observed an enhanced interaction between inflammatory cells and podocytes, which might contribute to kidney injury. Accordingly, scRNA-seq analysis of urinary samples is partially reminiscent of the kidney cell landscape, especially T cells and myeloid cells, suggesting monitoring urinary samples is a promising method to monitor PMN development. Additionally, integrative analysis across the blood, kidney and urine identified LTB, HERP1, ANXA1, IL1RN and ICAM1 as common regulators of PMN. Finally, immune repertoire in PBMC also showed an elevated diversity of clonal type, implying the existence of autoreactive T-cell receptor/B-cell receptor. Conclusion: Our study comprehensively profiled the transcriptomic landscapes of blood, kidney and urine in patients with PMN using scRNA-seq. We depicted the alterations including cell compositions and cell-cell communication in PMN. These results offer important clues with regard to the diagnosis and pathogenesis of PMN and potential intervention of PMN progression.

The anti-tumor activity of tangeretin in esophageal squamous cell carcinoma by inhibiting GLI2-mediated transcription of GPNMB.

Tangeretin (Tan), a citrus flavonoid, possesses a strong anti-tumor efficacy in various human cancers. However, the precise role of Tan in the development of esophageal squamous cell carcinoma (ESCC) remains unclear. RNA sequencing (RNA-seq) analysis was performed to observe the Tan-related genes in Tan-treated TE-1 cells. The direct relationship between GLI family zinc finger 2 (GLI2) and the promoter of glycoprotein non-metastatic melanoma protein B (GPNMB) was predicted by bioinformatics analysis and validated by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Cell survival after Tan treatment was assessed by CCK8 assay. Gene expression levels were evaluated by a qRT-PCR, western blot, or immunofluorescence method. Cell migration and invasion were detected by wound-healing and transwell assays. The function of Tan in vivo was examined using xenograft studies. Our data indicated anti-migration and anti-invasion functions of Tan in ESCC cells in vitro. Tan also diminished tumor growth in vivo. Mechanistically, Tan diminished the expression and transcriptional activity of GLI2 in ESCC cells. Silencing of GLI2 resulted in decreased expression of GPNMB by inhibiting GPNMB transcription via the binding site at the GPNMB promoter at position +(1539-1550). Moreover, Tan down-regulated GPNMB expression in ESCC cells, and re-expression of GPNMB reversed anti-migration and anti-invasion functions of Tan in ESCC cells. Our findings uncover anti-migration and anti-invasion effects of Tan in ESCC cells by down-regulating GPNMB by suppressing GLI2-mediated GPNMB transcription, providing new evidence that Tan can function as a therapeutic agent against ESCC.