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Abstract Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients’ quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection.

Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague—Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of wogonin in different rat biological samples. After i.v. dosing of wogonin at different levels (10, 20 and 40 mg/kg) the elimination half-life was approximately 14 min, the AUC0-∞ increased in a dose disproportional manner from 112.13 mg/L·min for 10 mg/kg to 758.19 mg/L·min for 40 mg/kg, indicating a non linear pharmacokinetic profile. After i.g. dosing at 100 mg/kg, plasma levels of wogonin peaked at 28 min with a Cmax value of 300 ng/mL and a very low oral bioavailability (1.10%). Following i.v. single dose (20 mg/kg), wogonin was detected in all examined tissues (including testis) with the highest levels in kidney and liver. Approximately 21% of the administered dose was excreted as unchanged drug (mainly via non-biliairy fecal route (16.33%). Equilibrium dialysis was used to evaluate plasma protein binding of wogonin at three concentrations (0.1, 0.5 and 2 µg/mL). Results indicated a very high protein binding degree (over 90%), reducing substantially the free fraction of the compound.

Abstract Background The effects of lipid‐lowering drugs [including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] on hyperlipidaemia have been established. Some may have treatment effects beyond their reported properties, offering potential opportunities for drug repurposing. Epidemiological studies have reported conflicting findings on the relationship between lipid‐lowering medication use and sarcopenia risk. Methods We performed a two‐sample Mendelian randomization (MR) study to investigate the causal association between the use of genetically proxied lipid‐lowering drugs (including statins, ezetimibe, and PCSK9 inhibitors, which use low‐density lipoprotein as a biomarker), and sarcopenia risk. The inverse‐variance weighting method was used with pleiotropy‐robust methods (MR–Egger regression and weighted median) and colocalization as sensitivity analyses. Results According to the positive control analysis, genetically proxied inhibition in lipid‐lowering drug targets was associated with a lower risk of coronary heart disease [PCSK9 (OR, 0.67; 95% CI, 0.61 to 0.72; P = 7.7E‐21); 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR; OR, 0.68; 95% CI, 0.57 to 0.82; P = 4.6E‐05), and Niemann–Pick C1‐like 1 (NPC1L1; OR, 0.53; 95% CI, 0.40 to 0.69; P = 3.3E‐06)], consistent with drug mechanistic actions and previous trial evidence. Genetically proxied inhibition of PCSK9 (beta, −0.040; 95% CI, −0.068 to −0.012; P = 0.005) and circulating PCSK9 levels (beta, −0.019; 95% CI, −0.033 to −0.005; P = 0.006) were associated with reduced appendicular lean mass (ALM) with concordant estimates in terms of direction and magnitude. Validation analyses using a second instrument for PCSK9 yielded consistent results in terms of direction and magnitude [(PCSK9 to ALM; beta, −0.052; 95% CI, −0.074 to −0.032; P = 7.1E‐7); (PCSK9 protein to ALM; beta, −0.060; 95% CI, −0.106 to −0.014; P = 0.010)]. Genetically proxied inhibition of PCSK9 gene expression in the liver may be associated with reduced ALM (beta, −0.013; 95% CI, −0.035 to 0.009; P = 0.25), consistent with the results of PCSK9 drug‐target and PCSK9 protein MR analyses, but the magnitude was less precise. No robust association was found between HMGCR inhibition (beta, 0.048; 95% CI, −0.015 to 0.110; P = 0.14) or NPC1L1 (beta, 0.035; 95% CI, −0.074 to 0.144; P = 0.53) inhibition and ALM, and validation and sensitivity MR analyses showed consistent estimates. Conclusions This MR study suggested that PCSK9 is involved in sarcopenia pathogenesis and that its inhibition is associated with reduced ALM. These findings potentially pave the way for future studies that may allow personalized selection of lipid‐lowering drugs for those at risk of sarcopenia.

Abstract Background Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long‐term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. Methods In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4‐week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Results Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2‐year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12‐month progression‐free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2‐55.6), with an 18‐month PFS rate of 37.8% (95% CI, 22.7‐52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3‐36.9), and the 24‐month OS rate was 47.8% (95% CI, 31.7‐62.3). Age > 50 years, programmed death‐ligand 1 (PD‐L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. Conclusion Long‐term survival follow‐up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first‐line platinum‐based chemotherapy. No new safety signals were noted with long‐term treatment.

The heavy metal, cadmium (Cd) is an increasingly serious issue in agricultural ecosystems, mediating bottom-up effects on plants, herbivores and natural enemies. We measured how Cd modifies interactions between tomato Solanum lycopersicum, western flower thrips Frankliniella occidentalis, and the predatory bug Orius sauteri by examining Cd effects on the growth of tomato, the fitness of western flower thrips, and the survival and behavior of predators. The photosynthetic parameters of Pn (net photosynthetic rate), Gs (stomatal conductance), Ci (intercellular CO2 concentration), and Tr (transpiration rate) of tomato plants significantly decreased with the increase of Cd concentration. The total survival number of western flower thrips fed on tomato plants treated with different concentrations of Cd was significantly lower than that of the control, and sex ratios (female/male) gradually increased with the increase of Cd concentration. The numbers of thrips predated by O. sauteri on tomato plants treated with high concentrations of Cd (2.0 or 4.0 mg/L) were significantly reduced by the second day. Cadmium was accumulated and bioconcentrated in the roots, stems, leaves of tomato plants, and transferred to F. occidentalis, and O. sauteri. Cadmium translocated in significant quantities from roots to the stems and leaves of tomato plants, and from the tomato leaf to F. occidentalis. However, there was minimal (non-significant) transfer of Cd from F. occidentalis to O. sauteri. The presence of Cd significantly reduced the growth of tomato plants, the fitness of F. occidentalis, and the predation efficiency of O. sauteri. Collectively, Cd can mediate bottom-up effects on tomato, thrip, and predatory bug along food chain, potentially interrupting pest biological control in tomato in heavy metal-contaminated ecosystems.

Background Cervical cancer remains a global health challenge. The identification of new immunotherapeutic targets may provide a promising platform for advancing cervical cancer treatment.Objective This study aims to investigate the role of CUB domain-containing protein 1 (CDCP1) in cervical cancer progression and evaluate its potential as a therapeutic target.Methods We performed comprehensive analyses using patient cohorts and preclinical models to examine the association between CDCP1 expression and cervical cancer prognosis. Then in immunodeficient and immunocompetent mouse models, we further investigated the impact of CDCP1 on the tumor immune microenvironment, focusing on its effects on tumor-infiltrating T cells, including cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Mechanistic studies were performed to elucidate the pathways involved in CDCP1-mediated immune modulation, in particular its interaction with the T cell receptor CD6 and the activation of the JAK-STAT signaling pathway.Results Our results show that CDCP1 overexpression is associated with poor prognosis and T cell infliction in cervical cancer. Specifically, it affects the activity of CTLs and Tregs. Mechanistically, CDCP1 binds to CD6 and inhibits the JAK-STAT pathway of T cells. The study further demonstrates that targeting CDCP1 with the inhibitor 8-prenylnaringenin (8PN) effectively suppresses tumor growth in vivo and enhances antitumor immunity.Conclusions CDCP1 plays a critical role in cervical cancer progression by modulating the tumor immune microenvironment. Targeting CDCP1 offers a promising therapeutic strategy to improve the outcome of patients with cervical cancer.

Aim: To discover novel methylation-related differentially expressed genes (MRDEGs) for cervical cancer, with a focus on their potential for early diagnosis and prognostic assessment. Materials & methods: We integrated data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. TCGA-MRDEGs were identified by analyzing differentially methylated genes (DMGs) and their correlation with gene expression. We examined GEO datasets GSE39001, GSE9750, and GSE46306 for GEO-MRDEGs. Overlapping MRDEGs were subjected to overall survival (OS) analysis to identify prognostic markers. The expression and methylation levels of these genes were validated in a total of 30 tissue samples, comprising 20 from cervical cancer patients and 10 from normal cervical tissues, using qRT-PCR and MassARRAY EpiTYPER Assay. Results: A total of 314 TCGA-MRDEGs and 40 GEO-MRDEGs were identified. Intersection analysis yielded 10 overlapping MRDEGs. Notably, NOVA1, GSTM5, TRHDE, and CXCL12 were found to have reduced expression and increased methylation in cervical cancer, which correlated with poor prognosis. The methylation status and expression levels of these genes were confirmed in tissue specimens. Conclusion: We identified four MRDEGs as potential prognostic biomarkers for cervical cancer. Their clinical utility is highlighted, but further validation in larger cohorts is required to establish their clinical significance.

Abstract Background Previous studies have demonstrated the association between food security and cardiometabolic diseases (CMDs), yet none have investigated trends in prevalence of CMDs by food security status in the United States (US). Methods Serial cross-sectional analysis of the US nationally representative data from National Health and Nutrition Examination Survey (1999–2018) was conducted among adults aged 20 years or older. Food security status was defined by the US Household Food Security Survey Module (full, marginal, low, and very low food security). We estimated the age-adjusted prevalence of CMDs including obesity, hypertension, diabetes, and coronary heart disease by food security status. Racial and ethnic disparities in age-adjusted prevalence of CMDs by food security status were also assessed. Results A total of 49,738 participants were included in this analysis (weighted mean age 47.3 years; 51.3% women). From 1999 to 2018, the age-adjusted prevalence of CMDs was lower in full food secure group as compared with other groups. For example, trends in hypertension decreased from 49.7% (47.5-51.8%) to 45.9% (43.8-48.0%) (P-trend = 0.002) among the full and from 54.2% (49.9-58.5%) to 49.7% (46.8-52.6%) (P-trend = 0.02) among the marginal but remained stable among the low at 49.7% (47.9-51.6%) and among the very low at 51.1% (48.9-53.3%) (P-interaction = 0.02). Prevalence of diabetes increased from 8.85% (8.15-9.60%) to 12.2% (11.1-13.5%) among the full (P-trend

The straight part of the corrugated steel plate (CSP) pipe-arch structure in soil may cause local buckling instability due to insufficient load-bearing capacity. Recently, composite CSP pipe-arch has been widely utilized to enhance structural stability, and their stability needs to be thoroughly investigated. This paper studies the local buckling stability problem of the straight part of composite CSP pipe-arch in soil by simplifying the soil support and introducing the inter-layer bonding effect. Based on elastic stability theory, a theoretical mechanical model of composite CSP pipe-arch was proposed. The Rayleigh–Ritz method and the semi-combined composite structure stiffness approximation were used to derive the critical buckling conditions for the straight part of the composite CSP pipe-arch. Through numerical calculation and influencing factors analysis, it is concluded that the critical buckling load of the straight part of the composite CSP pipe-arch structure is affected by the elastic modulus, thickness, Poisson’s ratio, rotational restraint stiffness and side length of the straight part of the material. In particular, it is found that as the inter-layer bonding coefficient increases, the critical buckling load is improved, while the critical buckling wave number is mainly influenced by the width of the straight part, elastic modulus, and inter-layer bonding coefficient. Additionally, we discussed the coupling effect of several key parameters on the stability of the structure. The results of this study offer theoretical foundations and guidance for the application of composite CSP pipe-arch in soil engineering, such as culverts, tunnels, and pipeline transportation.

In underground spaces, corrugated steel plate (CSP) pipe-arches may experience local buckling instability, which can subsequently lead to the failure of the entire structure. Recently, sandwich CSP pipe-arches have been used to enhance the stability of embedded engineering outcomes, and their buckling behaviors require in-depth research. In this paper, we establish a theoretical model by simplifying soil support and using Hoff sandwich plate theory to focus on the local buckling stability of the straight segment in embedded sandwich CSP pipe-arches using the Rayleigh–Ritz method. Through stability analysis, the instability criteria for embedded sandwich CSP pipe-arches are analytically determined. Numerical calculations reveal that the critical buckling load of a sandwich CSP pipe-arch is affected by several factors, including the elastic modulus, thickness, Poisson’s ratio, rotational constraint stiffness, and the length of the straight segment. Specifically, increasing the thickness of the sandwich CSP pipe-arch can substantially enhance the critical buckling load. Meanwhile, the wavenumber is affected by the elastic modulus and the length of the straight segment. The analytical results are in agreement with those obtained from finite element analysis. These findings provide a theoretical basis and guidance for the application of sandwich CSP pipe-arches in fields such as subway stations, tunnel construction, underground passages, and underground parking facilities.

The defining attribute of self-excited motion is its capability to extract energy from a stable environment and regulate it autonomously, making it an extremely promising innovation for microdevices, autonomous robotics, sensor technologies, and energy generation. Based on the concept of an automobile, we propose a light-fueled self-propulsion of liquid crystal elastomer-engined automobiles in zero-energy mode. This system utilizes a wheel comprising a liquid crystal elastomer (LCE) turntable as an engine, a wheel with conventional material and a linkage. The dynamic behavior of the self-propulsion automobile under steady illumination is analyzed by integrating a nonlinear theoretical model with an established photothermally responsive LCE model. We performed the analysis using the fourth-order Runge–Kutta method. The numerical findings demonstrate the presence of two separate motion patterns in the automobile system: a static pattern and a self-propulsion pattern. The correlation between the energy input and energy dissipation from damping is essential to sustain the repetitive motion of the system. This study delves deeper into the crucial requirements for initiating self-propulsion and examines the effect of critical system parameters on the motion of the system. The proposed system with zero-energy mode motions has the advantage of a simple structural design, easy control, low friction and stable kinematics, and it is very promising for many future uses, including energy harvesting, monitoring, soft robotics, medical devices, and micro- and nano-devices.

Summary: Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer.

Summary: Background: Sintilimab is an antibody against programmed cell death protein 1. We assessed the efficacy and safety of sintilimab plus albumin-bound (nab)-paclitaxel for the treatment of recurrent or metastatic cervical cancer. Methods: This multicenter, open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT04341883) enrolled patients with recurrent or metastatic cervical cancer who progressed after at least one line of systemic therapy. The patients received sintilimab 200 mg and nab-paclitaxel 260 mg/m2 body surface area every 3 weeks. The primary endpoint was objective response rate (ORR) assessed by investigators per Response Evaluation Criteria in Solid Tumors version 1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Findings: From January 13, 2020 to February 21, 2022, 27 patients were enrolled and received treatment. Median patient age was 50 years (range, 34–68 years). By data cut-off (May 22, 2022), in intention-to-treat population, ORR was 44.4% (95% CI, 24.4%–64.5%). The disease control rate was 88.9% (95% CI, 70.8%–97.6%). Median PFS was 5.2 months (95% CI, 2.7–7.7 months). Median DoR was 3.8 months (95% CI, 0.7–6.9 months), and median OS was 13.1 months (95% CI, 5.8–20.4 months). Treatment-related grade 3 or 4 adverse events (AEs) occurred in 44.4% of the patients, and the most common AEs were decreased neutrophil count (22.2%), decreased white blood cell count (14.8%), and anemia (7.4%). The most common potential immune-related AEs were grade 1–2 hypothyroidism (18.5%), neutropenia (11.1%), and rash (7.4%). Interpretation: Sintilimab plus nab-paclitaxel treatment shows promising antitumor activity and manageable toxicity in patients with advanced cervical cancer. Larger randomized controlled trials are required for validation. Funding: Innovent Biologics Co., Ltd.; Csps Holdings Co., Ltd.

Abstract Background There is growing interest regarding vitamin D and its potential role in gestational diabetes mellitus (GDM). We aimed to assess maternal vitamin D status in early pregnancy and its relationships with the risk of GDM in a Chinese population in Shanghai. Methods The retrospective cohort study included a total of 7816 pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) during 24–28 weeks of gestation. Participants’ demographic information including maternal age, prepregnancy body mass index (BMI), gestational age, parity, season of blood collection, serum 25-hydroxy vitamin D [25(OH)D] data and other blood biomarker data at 6 to 14 weeks of gestation were retrospectivly extracted from the medical records in the hospital information system. Results In the cohort, the prevalence of GDM was 8.6% and the prevalence of vitamin D deficiency and insufficiency in early pregnancy was 53.1 and 38.5%, respectively. The mean value of the serum 25(OH)D concentration was 19.6±7.5 ng/mL. The restricted cubic splines model showed an inverted J-shaped relationship in which the risk of GDM decreased when the 25(OH)D concentrations were ≥ 20 ng/mL. Logistic model analysis showed that 25(OH)D concentrations ≥ 30 ng/mL significantly decreased the risk of GDM (odds ratio = 0.63, 95% confidence interval: 0.45-0.89; P = 0.010) compared with 25(OH)D concentrations < 20 ng/ml. Conclusions In early pregnancy, vitamin D deficiency and insufficiency were very common, and a high level of vitamin D showed protective effects against the incidence risk of GDM.

Abstract Background Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic disease that involves the infiltration of IgG4-positive plasma cells in multiple organs. Kimura disease (KD) presents as subcutaneous masses on the head and neck, frequently accompanied by eosinophilia and high immunoglobulin E (IgE) levels. Here, we report a rare case of concurrence of IgG4-RD and KD with manifestations of asthma, pulmonary embolism, and central diabetes insipidus accompanied by lung carcinoma. Case presentation A 65-year-old Chinese male with an eight-year history of KD was admitted to our hospital with complaints of dyspnea and expectoration for one month. Laboratory examination showed a considerable elevation in the serum eosinophil count and total IgE and IgG4 levels. Chest enhanced computed tomography showed filling defects in the right pulmonary artery and a nodule in the left inferior lobe. Pancreatic enhanced magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography showed a swollen pancreatic tail and local stricture of the pancreatic duct section of the common bile duct. Enhanced MRI of the pituitary gland showed thickening of the pituitary stalk. Additionally, immunohistochemistry of the specimens collected eight years prior revealed IgG4-positive cells. Following the diagnosis of IgG4-RD with KD, glucocorticoids with immunosuppressants were initiated; there was a prompt improvement in the patient’s condition. One-year post-discharge, the patient underwent wedge-shaped resection of the lung due to enlargement of the pulmonary nodule, and the pathology revealed lung squamous carcinoma. Conclusions This case presents a rare clinical condition in which the concurrence of IgG4-RD and KD causes various rare manifestations including asthma, pulmonary embolism, central diabetes insipidus, and complicated lung carcinoma. This highlights the importance of monitoring for malignancies in IgG4-RD patients during follow-up.

Abstract Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

Abstract Background Keratoconus (KC) is a complex, non-inflammatory corneal degenerative disease. Although numerous studies have analyzed the correlation of SNP rs1324183, which located in MPDZ-NF1B gene, and KC in different populations, only few findings were repeated. In this study, to evaluate the association between rs1324183 and KC in a new independent Chinese population, we performed a replication study of the significantly associated rs1324183. Methods In total of 114 unrelated KC patients and 88 unrelated controls were recruited from Ningxia, China. We detected the genotypes and alleles of rs1324183 using PCR technology and Sanger sequencing and also analyzed the association between this locus and KC, its clinical parameters by statistical methods. Results The frequency of genotype AA (11, 9.6%) and genotypes containing allele A (47, 41.2%) of rs1324183 in KC were both higher than those of the control group. And genotype AA of rs1324183 conferred a higher risk of KC (OR > 1). Moreover, corneal parameter Belin/Ambrósio enhanced ectasia display final D value (BAD-D) had significant correlation (p = 0.002) with AA genotype of rs1324183 in KC. Conclusions Our replication study indicates that the results of rs1324183 associated with KC in our population is robust and further better illustrates the significance of BAD-D as a diagnostic indicator for KC. rs1324183 should be considered as the first genetic mark of KC risk in its future diagnosis.

Background Disparities in cardiovascular disease (CVD) outcomes persist across the United States. Social determinants of health play an important role in driving these disparities. The current study aims to identify the most important social determinants associated with CVD mortality over time in US counties. Methods and Results The authors used the Agency for Healthcare Research and Quality's database on social determinants of health and linked it with CVD mortality data at the county level from 2009 to 2018. The age‐standardized CVD mortality rate was measured as the number of deaths per 100 000 people. Penalized generalized estimating equations were used to select social determinants associated with county‐level CVD mortality. The analytic sample included 3142 counties. The penalized generalized estimating equation identified 17 key social determinants of health including rural–urban status, county's racial composition, income, food, and housing status. Over the 10‐year period, CVD mortality declined at an annual rate of 1.08 (95% CI, 0.74–1.42) deaths per 100 000 people. Rural counties and counties with a higher percentage of Black residents had a consistently higher CVD mortality rate than urban counties and counties with a lower percentage of Black residents. The rural–urban CVD mortality gap did not change significantly over the past decade, whereas the association between the percentage of Black residents and CVD mortality showed a significant diminishing trend over time. Conclusions County‐level CVD mortality declined from 2009 through 2018. However, rural counties and counties with a higher percentage of Black residents continued to experience higher CVD mortality. Median income, food, and housing status consistently predicted higher CVD mortality.

Abstract Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in cervical cancer (CCa) remains largely unknown. Herein, we demonstrated that a circRNA derived from the TADA2A gene (hsa_circ_0043280) was significantly downregulated in CCa and that this reduction in expression was correlated with a poor prognosis. Furthermore, our results demonstrated that hsa_circ_0043280 functions as a tumor suppressor to inhibit tumor growth and metastasis in CCa. Mechanistically, hsa_circ_0043280 competitively sponges miR-203a-3p and prevents miR-203a-3p from reducing the levels of PAQR3. Collectively, our results demonstrate that hsa_circ_0043280 plays a pivotal role in the development and metastasis of CCa, thus suggesting that hsa_circ_0043280 has significant potential as a prognostic biomarker and a therapeutic target for CCa.

Background: A novel braided nasal stent is an effective alternative to nasal packing after septoplasty that can be used to manage the mucosal flap after septoplasty and expand the nasal cavity. This study aimed to investigate the influence of design parameters on the mechanical properties of the nasal stent for optimal performance.Methods: A braided nasal stent modeling method was proposed and 27 stent models with a range of different geometric parameters were built. The compression behavior and bending behavior of these stent models were numerically analyzed using a finite element method (FEM). The orthogonal test was used as an optimization method, and the optimized design variables of the stent with improved performance were obtained based on range analysis and weight grade method.Results: The reaction force and bending stiffness of the braided stent increased with the wire diameter, braiding density, and external stent diameter, while wire diameter resulted as the most important determining parameter. The external stent diameter had the greatest influence on the elongation deformation. The influence of design parameters on von-Mises stress distribution of bent stent models was visualized. The stent model with geometrical parameters of 25 mm external diameter, 30° braiding angle, and 0.13 mm wire diameter (A3B3C3) had a greater reaction force but a considerably smaller bending stiffness, which was the optimal combination of parameters.Conclusion: Firstly, among the three design parameters of braided stent models, wire diameter resulted as the most important parameter determining the reaction force and bending stiffness. Secondly, the external stent diameter significantly influenced the elongation deformation during the compression simulation. Finally, 25 mm external diameter, 30° braiding angle, and 0.13 mm wire diameter (A3B3C3) was the optimal combination of stent parameters according to the orthogonal test results.

We describe the case of a young patient with a borderline mucinous ovarian tumor that progressed into ipsilateral ovarian anaplastic carcinoma in only 3 months with metastasis to the contralateral ovary and extensive spread in the pelvic and abdominal regions. The mucinous tumor harbored micro-foci of intraepithelial carcinoma, but no mural nodules, microinvasion, or invasive adenocarcinoma were detected. Notably, a rupture on the ovarian mass and low-grade pseudomyxoma peritonei were present. Next-generation sequencing identified an identical KRAS mutation in the mucinous tumor and anaplastic carcinoma, while the latter had KRAS gene amplification and CDKN2A, MPL and TP53 mutations. These findings indicate the anaplastic carcinoma might have arisen via recurrence, malignant transformation and dedifferentiation of the former low-grade mucinous tumor. We consider that the mass rupture and pseudomyxoma peritonei were high-risk factors for recurrence, while genetic mutations were key drivers of progression. Accordingly, such cases may benefit from active surgical treatment and early chemotherapy.

Basement excavation may induce deformations of the adjacent tunnels. The response of existing tunnels to basement excavation considering the critical unloading ratio is rarely studied. In this study, a three-dimensional numerical model is established to investigate basement–tunnel interaction. Then, the numerical model is validated by simulating the centrifuge model test. Thereafter, the influences of basement geometry and tunnel location relative to the basement on the vertical deformation of the tunnel are studied. The results show that the vertical deformation of the tunnel increases linearly with the unloading ratio, which describes the degree of excavation depth above the tunnel. But there exists a critical unloading ratio of 0.6, beyond which the vertical deformation of the tunnel increases significantly. On this basis, an empirical model is proposed to predict the vertical deformation of the tunnel considering the unloading ratio.

Abstract Background The adverse effects of particulate air pollution on heart rate variability (HRV) have been reported. However, it remains unclear whether they differ by the weight status as well as between wake and sleep. Methods A repeated-measure study was conducted in 97 young adults in Beijing, China, and they were classified by body mass index (BMI) as normal-weight (BMI, 18.5–24.0 kg/m2) and obese (BMI ≥ 28.0 kg/m2) groups. Personal exposures to fine particulate matter (PM2.5) and black carbon (BC) were measured with portable exposure monitors, and the ambient PM2.5/BC concentrations were obtained from the fixed monitoring sites near the subjects’ residences. HRV and heart rate (HR) were monitored by 24-h Holter electrocardiography. The study period was divided into waking and sleeping hours according to time-activity diaries. Linear mixed-effects models were used to investigate the effects of PM2.5/BC on HRV and HR in both groups during wake and sleep. Results The effects of short-term exposure to PM2.5/BC on HRV were more pronounced among obese participants. In the normal-weight group, the positive association between personal PM2.5/BC exposure and high-frequency power (HF) as well as the ratio of low-frequency power to high-frequency power (LF/HF) was observed during wakefulness. In the obese group, personal PM2.5/BC exposure was negatively associated with HF but positively associated with LF/HF during wakefulness, whereas it was negatively correlated to total power and standard deviation of all NN intervals (SDNN) during sleep. An interquartile range (IQR) increase in BC at 2-h moving average was associated with 37.64% (95% confidence interval [CI]: 25.03, 51.51%) increases in LF/HF during wakefulness and associated with 6.28% (95% CI: − 17.26, 6.15%) decreases in SDNN during sleep in obese individuals, and the interaction terms between BC and obesity in LF/HF and SDNN were both statistically significant (p

Spiking Neural Networks (SNNs) are often considered the third generation of Artificial Neural Networks (ANNs), owing to their high information processing capability and the accurate simulation of biological neural network behaviors. Though the research for SNNs has been quite active in recent years, there are still some challenges to applying SNNs to various potential applications, especially for robot control. In this study, a biologically inspired autonomous learning algorithm based on reward modulated spike-timing-dependent plasticity is proposed, where a novel rewarding generation mechanism is used to generate the reward signals for both learning and decision-making processes. The proposed learning algorithm is evaluated by a mobile robot obstacle avoidance task and experimental results show that the mobile robot with the proposed algorithm exhibits a good learning ability. The robot can successfully avoid obstacles in the environment after some learning trials. This provides an alternative method to design and apply the bio-inspired robot with autonomous learning capability in the typical robotic task scenario.

[Objectives] This Study was conducted lO observe ihe protective effect of Pratia extract on acute liver injury in mice. Methods] Mice were randomly divided into 6 groups according to lxxly weight, 10 in each group: normal control group, elhanol-induced/CCl., liver injury model, low-dose, middle-dose and high-dose Pratia extract groups, and hifendatatum group. Except the blank group, other groups were given 50% eihauol intragaslrically at a dose of 12 ml/kg to cause acute alcoholic liver injury, or inlraperitoneally injected with 10% CC14 soybean oil solution to cause acute CC14 liver injury. The serum ALT and AST activity were measured as well as liver SOD and MUA concentrations. [Results] Pratia exlracl effectively reduced serum ALT and AST, decreased MDA content and increased liver tissue SOD activity. [Conclusions] Pratia extract has certain protective effect on acute liver injury. [ABSTRACT FROM AUTHOR]

Abstract Background The demand for assessing health-related quality of life (HRQoL) in chronic otitis media (COM) is increasing globally. The currently available Chinese-language patient-reported outcome measurement (PROM) specific for COM includes merely a limited range of related symptoms and dimensions. Hence, in this study, we aim to translate, culturally adapt, and validate the Zurich Chronic Middle Ear Inventory (ZCMEI-21) in Chinese, to enable a comprehensive evaluation of the patients’ subjective health outcome in COM. Methods We sampled and surveyed 223 COM patients at three tertiary referral centers in China, using the Chinese translation of ZCMEI-21 (ZCMEI-21-Chn) and the EQ-5D questionnaire, a generic measure of HRQoL. Confirmatory factor analysis (CFA) was performed to investigate the structural model fit to the dataset. Cronbach’s α and test-retest reliability coefficient were calculated to establish reliability, and correlation was tested between ZCMEI-Chn scores and EQ-5D scores for convergent validity. Results A total of 208 adult patients with COM were included, with a mean age of 46 years (SD 14 years) and a male proportion of 41% (85/208). A modified bifactor model with ωH of 0.65 and ECV of 0.47 was found to fit the scale scores, indicating fair general factor saturation and multidimensionality of the instrument. ZCMEI-21-Chn demonstrated good reliability (Cronbach’s α = 0.88, test-retest reliability = 0.88). The total scores of ZCMEI-21-Chn had a moderate correlation with a question directly addressing HRQoL (r = 0.40, p

Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening.Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated.Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening.Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.

BackgroundEarly diagnosis and effective intervention are the keys to delaying the progression of Alzheimer’s Disease (AD). Therefore, we aimed to identify new biomarkers for the early diagnosis of AD through bioinformatic analysis and elucidate the possible underlying mechanisms.Methods and ResultsGSE1297, GSE63063, and GSE110226 datasets from the GEO database were used to screen the highly differentially expressed genes. We identified a potential biomarker, Platelet activating factor receptor (PTAFR), significantly upregulated in the brain tissue, peripheral blood, and cerebrospinal fluid of AD patients. Furthermore, PTAFR levels in the plasma and brain tissues of APP/PS1 mice were significantly elevated. Simultaneously, PTAFR could mediate the inflammatory responses to exaggerate the microenvironment, particularly mediated by the microglia through the IL10-STAT3 pathway. In addition, PTAFR was a putative target of anti-AD compounds, including EGCG, donepezil, curcumin, memantine, and Huperzine A.ConclusionPTAFR was a potential biomarker for early AD diagnosis and treatment which correlated with the microglia-mediated microenvironment. It is an important putative target for the development of a novel strategy for clinical treatment and drug discovery for AD.

Endometrial cancer (EC) is one of the most common gynecological malignancies in women, accompanied by the increasing incidence and decreasing age of onset. Pyroptosis plays an important role in the occurrence and development of malignant tumors. However, the relationship between pyroptosis-related genes and tumor prognosis remains unclear. In this study, analyzing the expression levels and survival data of 33 pyroptosis-related genes in the Cancer Genome Atlas (TCGA) between normal samples and tumor samples, we obtained six pyroptosis-related prognostic differentially expressed genes (DEGs). Then, through the least absolute shrinkage and selection operator (LASSO) regression analysis, a gene signature composed of six genes (GPX4, GSDMD, GSDME, IL6, NOD2 and PYCARD) was constructed and divided patients into high- and low-risk groups. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally has lower immune infiltrating cells and less active immune function. In short, we constructed and validated a pyroptosis-related gene signature to predict the prognosis of EC, which is correlated to immune infiltration and proposed to help the precise diagnosis and therapy of EC.

Background. In developed countries, the most common gynecologic malignancy is endometrial carcinoma (EC), making the identification of EC biomarkers extremely essential. As a natural enzyme, butyrylcholinesterase (BCHE) is found in hepatocytes and plasma. There is a strong correlation between BCHE gene mutations and cancers and other diseases. The aim of this study was to analyze the role of BCHE in patients with EC. Methods. A variety of analyses were conducted on The Cancer Genome Atlas (TCGA) data, including differential expression analysis, enrichment analysis, immunity, clinicopathology, and survival analysis. The Gene Expression Omnibus (GEO) database was used to validate outcomes. Using R tools, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) analyses revealed the potential mechanisms of BCHE in EC. Sangerbox tools were used to delve into the relations between BCHE expression and tumor microenvironment, including microsatellite instability (MSI), tumor neoantigen count (TNC), and tumor mutation burden (TMB). BCHE’s genetic alteration analysis was conducted by cBioPortal. In addition, the Human Protein Atlas (HPA) was used to validate the outcomes by immunohistochemistry, and an analysis of the protein-protein interaction network (PPI) was performed with the help of the STRING database. Results. Based on our results, BCHE was a significant independent prognostic factor for patients with EC. The prognosis with EC was affected by age, stage, grade, histological type, and BCHE. GSEA showed that BCHE was closely related to pathways regulating immune response, including transforming growth factor-β (TGF-β) signaling pathways and cancer immunotherapy through PD1 blockade pathways. The immune analysis revealed that CD4+ regulatory T cells (Tregs) were negatively correlated with BCHE expression and the immune checkpoint molecules CD28, ADORA2A, BTNL2, and TNFRSF18 were all significantly related to BCHE. BCHE expression was also associated with TMB by genetic alteration analysis. Conclusions. Identifying BCHE as a biomarker for EC might help predict its prognosis and could have important implications for immunotherapy.

With over 350,000 cases occurring each year, out-of-hospital cardiac arrest (OHCA) remains a severe public health concern in the United States. The correct and timely use of automated external defibrillators (AEDs) has been widely acknowledged as an effective measure to improve the survival rate of OHCA. While general guidelines have been provided by the American Heart Association (AHA) for AED deployment, the lack of detailed instructions hindered the adoption of such guidelines under dynamic scenarios with various time and space distributions. Formulating the AED deployment as a location optimization problem under budget and resource constraints, we proposed an overlayed spatio-temporal optimization (OSTO) method, which accounted for the spatiotemporal heterogeneity of potential OHCAs. To highlight the effectiveness of the proposed model, we applied the proposed method to Washington DC using user-generated anonymized mobile device location data. The results demonstrated that optimization-based planning provided an improved AED coverage level. We further evaluated the effectiveness of adding additional AEDs by analyzing the cost-coverage increment curve. In general, our framework provides a systematic approach for municipalities to integrate inclusive planning and budget-limited efficiency into their final decision-making. Given the high practicality and adaptability of the framework, the OSTO is highly amenable to different healthcare facilities’ deployment tasks with flexible demand and resource restraints.