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Abstract Porphyromonas gingivalis (P. gingivalis), the main pathogen responsible for periodontitis, is linked to systemic disorders via the oral-gut axis. Short-chain fatty acids (SCFAs) are vital for gut health, but their role in P. gingivalis-induced gut disorders remains unclear. This study utilized metabolomics and 16 S rRNA sequencing to explore gut microbiota and SCFAs levels in P. gingivalis-induced periodontitis mouse models. Significant changes were observed in gut, including a reduction in SCFAs-producing bacteria, such as Lactobacillus, Ligilactobacillus, Allobucalum, and a notable decrease in Firmicutes and Actinobacteriota. The intestinal permeability tests and histological analyses revealed that periodontitis led to epithelial inflammation, reduced mucin secretion, and compromised gut barrier integrity. In vitro experiments with Caco-2 cells co-cultured with P. gingivalis showed that the bacterium disrupted cellular junctions by impairing autophagy, specifically through the ATG5-LC3 pathway, leading to decreased expression of tight junction proteins and reduced SCFA absorption. Remarkably, rapamycin treatment both in vitro and in vivo restored gut barrier function by enhancing autophagy, increasing tight junction protein expression, and promoting SCFAs absorption via MCT1 and SMCT1, alongside GPR43/GPR109a pathway activation. These findings reveal autophagy’s novel role in regulating SCFAs metabolism in P. gingivalis-induced gut dysbiosis, offering insights for preventing and treating periodontitis-related systemic diseases.

Abstract The mechanical rock-crushing efficiency is directly influenced by rock properties and joint structure. Tipped-hob is widely used in the construction of shafts. By analyzing the motion of tipped-hob and the mechanical properties of granite and sandstone, numerical rock samples with different mechanical properties were built to investigate the influences of rock properties and joint structure on rock-crushing efficiency using a single ring of tipped cutter. The results revealed correlations between compressive strength, tensile strength, hardness, brittleness, specific energy consumption, and the vibration of thrusting forces. It was suggested that the spacing, dip angle, and continuity of joints have a significant impact on the failure patterns and crack propagation in the process of rock fragmentation, as well as on the vibration frequency and amplitude of breaking-force of cutter and the specific energy consumption. This research is crucial for controlling the stability of drilling machine during shaft sinking by drilling method.

Abstract In order to obtain the pattern of variation of PM2.5concentrations in the atmosphere in Nanchang City, we build a Support Vector Regression(SVR) with modified Whale Optimization Algorithm(WOA) hybrid model (namely mWOA-SVR model) that can predict the PM2.5concentration. Firstly, according to the Pearson correlation coefficient (PCC) method to examine the dynamic relationship between air pollutants and meteorological factors together with them, PM10, SO2and CO were selected as air pollutant concentration characteristics, while daily maximum and minimum temperatures, and wind power levels were selected as meteorological characteristics; then, using modified WOA algorithm for parameter selection of SVR model, four sets of better parameter combinations were found; finally, the mWOA-SVR model was built by the four sets parameters to predict PM2.5concentration. The results show that the prediction accuracy of mixed mWOA-SVR model with pollutant concentration plus weather factors as the feature was higher than single pollutant concentration.

Abstract To evaluate the efficacy of neuronavigation-assisted stereotactic drilling drainage compared with that of craniotomy in the treatment of massive intracerebral haemorrhage (ICH) in elderly patients. This was a randomized, controlled, blind endpoint clinical study. Elderly patients with massive ICH treated at our neurosurgery department, without the formation of brain herniation preoperatively, all underwent neurosurgical intervention. Patients were randomly assigned to two groups: the minimally invasive surgery (MIS) group, which received neuronavigation-assisted stereotactic drilling drainage, and the craniotomy haematoma removal surgery (CHRS) group. Patient characteristics, surgical anaesthesia methods, surgery duration, intraoperative bleeding volume, duration of ICU stay duration of hospital stay, complications, and modified Rankin scale (mRS) scores at 90 days posttreatment were compared between the two groups. Statistical analysis was performed on the collected data. A total of 67 patients were randomly assigned, with 33 (49.25%) in the MIS group and 34 (50.75%) in the CHRS group. Compared with the CHRS group, the MIS group had advantages, including the use of local anaesthesia, shorter surgery duration, less intraoperative bleeding, shorter ICU stay, and fewer complications (P 0.05). For elderly patients with massive ICH without brain herniation, stereotactic drilling drainage is a simple surgical procedure that can be performed under local anaesthesia. Patients treated with this approach seem to have better outcomes than those treated with craniotomy. In clinical practice, neuronavigation-assisted stereotactic drilling drainage is recommended for surgical treatment in elderly patients with massive ICH without brain herniation. Clinical trial registration number: NCT04686877

Abstract Killer cell lectin-like receptor B1 (KLRB1) is implicated in cancer progression and immunity. In this study, we aimed to evaluate the expression levels of KLRB1 in lung adenocarcinoma (LUAD) and analyze the relationship between KLRB1 expression levels, LUAD progression, and the tumor immune microenvironment. KLRB1 levels in LUAD were analyzed using data from the TCGA and XENA databases. Additionally, the diagnostic values of KLRB1 were analyzed in patients with LUAD. Survival and meta-analyses were employed to investigate the relationship between KLRB1 levels and other prognostic factors in patients with LUAD. Bioinformatics and cellular experiments were used to understand the functions and mechanisms of KLRB1. In addition, correlation analysis was used to investigate the relationship between KLRB1 levels and the immune microenvironment in LUAD. Reduced KLRB1 expression in LUAD was found to positively correlate with tumor size, distant metastasis, pathological stage, age, overall survival, diagnostic value, and disease-specific survival in patients with LUAD (P

Abstract Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to β3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.

Abstract Background Droplet digital PCR (ddPCR) is widely applied to monitor measurable residual disease (MRD). However, there are limited studies on the feasibility of ddPCR-MRD monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially targeting multiple molecular markers simultaneously. Methods Our study collected samples from patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in complete remission after allo-HSCT between January 2018 and August 2021 to evaluate whether posttransplant ddPCR-MRD monitoring can identify patients at high risk of relapse. Results Of 152 patients, 58 (38.2%) were MRD positive by ddPCR within 4 months posttransplant, with a median variant allele frequency of 0.198%. The detectable DTA mutations (DNMT3A, TET2, and ASXL1 mutations) after allo-HSCT were not associated with an increased risk of relapse. After excluding DTA mutations, patients with ddPCR-MRD positivity had a significantly higher cumulative incidence of relapse (CIR, 38.7% vs. 9.7%, P

Abstract Background To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR. Results Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors. Conclusions Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.

Background Metabolic syndrome (MetS) has been shown to have a negative impact on prostate cancer (PCa). However, there is limited research on the effects of MetS on testosterone levels in metastatic prostate cancer (mPCa). Objective This study aims to investigate the influence of MetS, its individual components, and composite metabolic score on the prognosis of mPCa patients, as well as the impact on testosterone levels. Additionally, it seeks to identify MetS-related risk factors that could impact the time of decline in testosterone levels among mPCa patients. Methods A total of 212 patients with mPCa were included in the study. The study included 94 patients in the Non-MetS group and 118 patients in the combined MetS group. To analyze the relationship between MetS and testosterone levels in patients with mPCa. Additionally, the study aimed to identify independent risk factors that affect the time for testosterone levels decline through multifactor logistic regression analysis. Survival curves were plotted by the Kaplan-Meier method. Results Compared to the Non-MetS group, the combined MetS group had a higher proportion of patients with high tumor burden, T stage ≥ 4, and Gleason score ≥ 8 points (P < 0.05). Patients in the combined MetS group also had higher lowest testosterone values and it took longer for their testosterone to reach the lowest level (P < 0.05). The median progression-free survival (PFS) time for patients in the Non-MetS group was 21 months, while for those in the combined MetS group it was 18 months (P = 0.001). Additionally, the median overall survival (OS) time for the Non-MetS group was 62 months, whereas for the combined MetS group it was 38 months (P < 0.001). The median PFS for patients with a composite metabolic score of 0–2 points was 21 months, 3 points was 18 months, and 4–5 points was 15 months (P = 0.002). The median OS was 62 months, 42 months, and 29 months respectively (P < 0.001). MetS was found to be an independent risk factor for testosterone levels falling to the lowest value for more than 6 months. The risk of testosterone levels falling to the lowest value for more than 6 months in patients with MetS was 2.157 times higher than that of patients with Non-MetS group (P = 0.031). Patients with hyperglycemia had a significantly higher lowest values of testosterone (P = 0.015). Additionally, patients with a BMI ≥ 25 kg/m2 exhibited lower initial testosterone levels (P = 0.007). Furthermore, patients with TG ≥ 1.7 mmol/L experienced a longer time for testosterone levels to drop to the nadir (P = 0.023). The lowest value of testosterone in the group with a composite metabolic score of 3 or 4–5 was higher than that in the 0–2 group, and the time required for testosterone levels to decrease to the lowest value was also longer (P < 0.05). Conclusion When monitoring testosterone levels in mPCa patients, it is important to consider the impact of MetS and its components, and make timely adjustments to individualized treatment strategies.

Summary: Background: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. Methods: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists’ detection performance. Findings: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p 0.99), and it detected 2 cases that had been missed by radiologists. Interpretation: The developed DL model can accurately detect colorectal cancer and improve radiologists’ detection performance, showing its potential as an effective computer-aided detection tool. Funding: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

Abstract Background Cementoblasts on the tooth-root surface are responsible for cementum formation (cementogenesis) and sensitive to Porphyromonas gingivalis stimulation. We have previously proved transcription factor CXXC-type zinc finger protein 5 (CXXC5) participates in cementogenesis. Here, we aimed to elucidate the mechanism in which CXXC5 regulates P. gingivalis-inhibited cementogenesis from the perspective of mitochondrial biogenesis. Methods In vivo, periapical lesions were induced in mouse mandibular first molars by pulp exposure, and P. gingivalis was applied into the root canals. In vitro, a cementoblast cell line (OCCM-30) was induced cementogenesis and submitted for RNA sequencing. These cells were co-cultured with P. gingivalis and examined for osteogenic ability and mitochondrial biogenesis. Cells with stable CXXC5 overexpression were constructed by lentivirus transduction, and PGC-1α (central inducer of mitochondrial biogenesis) was down-regulated by siRNA transfection. Results Periapical lesions were enlarged, and PGC-1α expression was reduced by P. gingivalis treatment. Upon apical inflammation, Cxxc5 expression decreased with Il-6 upregulation. RNA sequencing showed enhanced expression of osteogenic markers, Cxxc5, and mitochondrial biogenesis markers during cementogenesis. P. gingivalis suppressed osteogenic capacities, mitochondrial biogenesis markers, mitochondrial (mt)DNA copy number, and cellular ATP content of cementoblasts, whereas CXXC5 overexpression rescued these effects. PGC-1α knockdown dramatically impaired cementoblast differentiation, confirming the role of mitochondrial biogenesis on cementogenesis. Conclusions CXXC5 is a P. gingivalis-sensitive transcription factor that positively regulates cementogenesis by influencing PGC-1α-dependent mitochondrial biogenesis. Video Abstract

Abstract Affected by differences in the pharmacokinetics (PK) of lenalidomide, the toxicity of lenalidomide varies among different patients, with serious toxicity leading to dose reduction or discontinuation. The differences in the PK of lenalidomide may be related to factors such as patients’ physiological characteristics, pathological characteristics and gene polymorphisms etc., which may also affect its toxicity. The aim of this study is to establish a population pharmacokinetic (PPK) model of lenalidomide and explore factors associated with the adverse events (AEs) of lenalidomide from a PK perspective. Blood samples were collected by opportunistic blood collection. Drug concentrations were determined by using HPLC/MS and genotype of ABCB1 3435 C > T (rs1045642), ABCB1 1236 A > G (rs1128503) and ABCB1 2677 A > C/T (rs2032582) was tested by the first-generation DNA sequencing technology. NONMEM software and SPSS 26.0 software were used respectively to establish PPK model of lenalidomide and explore the correlation between PK parameters and the incidence of serious AEs of lenalidomide. 51 patients were enrolled in the PPK study, and one-compartment model with first-order absorption and elimination agreed well with the observed data. The significant covariate affecting lenalidomide apparent volume of distribution (V/F) were the gene polymorphism of ABCB1 3435 C > T and diet. Safety studies could be conducted in 39 patients. The V/F value in patients suffering from serious AEs was significantly higher than that in others ( median = 67.04 L vs 37.17 L, P = 0.033). According to the covariates screened, the incidence of serious AEs was higher in patients with genotype CT or TT at ABCB1 3435 C > T locus than that in patients with genotype CC (P = 0.039). Additionally, V/F value was the highest in patients carrying genotype TT with postprandial medication, in whom the incidence of serious AEs was higher than others (P = 0.037). In conclusion, the genotype of ABCB1 3435 C > T locus and diet had pharmacokinetically relevant impact on lenalidomide, which may also be related to the incidence of serious AEs. Patients with gene variants of CT or TT at ABCB1 3435 C > T locus may be more susceptible to serious AEs, and monitoring of adverse reactions should be particularly strengthened in patients who carried genotype TT with postprandial medication.

Abstract Hepatocellular carcinoma (HCC) is a prevalent malignancy and there is a lack of effective biomarkers for HCC diagnosis. Living organisms are complex, and different omics molecules interact with each other to implement various biological functions. Genomics and metabolomics, which are the top and bottom of systems biology, play an important role in HCC clinical management. Fatty acid metabolism is associated with malignancy, prognosis, and immune phenotype in cancer, which is a potential hallmark in malignant tumors. In this study, the genes and metabolites related to fatty acid metabolism were thoroughly investigated by a dynamic network construction algorithm named EWS-DDA for the early diagnosis and prognosis of HCC. Three gene ratios and eight metabolite ratios were identified by EWS-DDA as potential biomarkers for HCC clinical management. Further analysis using biological analysis, statistical analysis and document validation in the discovery and validation sets suggested that the selected potential biomarkers had great clinical prognostic value and helped to achieve effective early diagnosis of HCC. Experimental results suggested that in-depth evaluation of fatty acid metabolism from different omics viewpoints can facilitate the further understanding of pathological alterations associated with HCC characteristics, improving the performance of early diagnosis and clinical prognosis.

Abstract With the rapid urbanization process in China, there has been a significant development of urban underground spaces. The pipe-jacking method has gained popularity in various projects due to its advantages such as short construction period, adaptability to different soil conditions, and minimal excavation disturbance. This study focuses on a tunnel project involving double-hole rectangular pipe-jacking under an expressway. Utilizing FLAC software, a three-dimensional numerical model was created to analyze the impact of double-hole pipe-jacking construction on surface settlement and deformation of the expressway. The simulation results were validated by comparing them with field monitoring data. The study also investigated the impact of different construction parameters, such as excavation sequence and the angle of underpassing the expressway, on surface settlement. Additionally, the surface settlement curve at the slope bottom of the expressway exhibits asymmetric distribution and an offset center in the settlement trough. It is recommended to carry out the construction of double-hole pipe-jacking in the sequence of "big first and then small". Furthermore, when the included angle between the expressway and the jacking axis is 90°, the impact on surface settlement is minimized. This research provides valuable insights for the construction of double-hole pipe-jacking underpass structures in tunnel engineering.

Abstract. Background:. Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China. Methods:. Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders. Results:. During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR = 0.78, 95% confidence interval [CI]: 0.71–0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m2 ≤ BMI < 24.0 kg/m2); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68–0.89) and 0.69 (95% CI: 0.59–0.79) compared with their counterparts, respectively. Conclusions:. High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.

Abstract Background Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). Methods This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. Results In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. Conclusions This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios. Graphical Abstract

Abstract Herein, a novel Ag NP substrate doped with Au nanobipyramids was designed and fabricated via a convenient procedure of galvanic reaction for the identification and classification of amphetamine-type stimulants (ATS) in oral fluids in combination with surface enhanced Raman scattering (SERS). The substrate was shown to have a three-dimensional nanostructure, high SERS activity, and good stability. In combination with SERS, the Ag NP substrate doped with Au nanobipyramids was able to detect ultra-low traces of ATS, including amphetamine, methylamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethylamphetamine (MDMA) in oral fluid with limit of detection (LOD) and limit of determination quantitation (LOQ) as low as 10–9 mg/mL, which is much better than the current spectroscopic techniques. The equations between concentration and peaks intensity for quantitative analysis displied good doublelogarithmic linear relations and reliability figures of merit at nanogram concentration level in compartion with GC–MS method. The approach can be broadly applied to the ultra-low trace detection of ATS in oral fluid and would be particularly useful for the analyses of nitrogenous organic compounds.

While numerous studies have revealed the impact of different bullying behaviors, such as victimization and perpetration, on the psychological development of adolescents, the exploration of the correlates of positive/negative bystander behaviors and their potential underlying mechanisms remains scarce in China. The present study aims to compare the relationships between mental health and positive versus negative bystander behavior and to clarify whether self-efficacy and coping styles mediate the relationships between mental health and bullying dynamics. The current study was conducted on 11,734 students from 18 secondary schools in Suzhou, China (Meanage = 15.00, SDage = 1.47; 53.8% boys). The information on bullying victimization, perpetration, positive/negative bystander behaviors, as well as self-efficacy, coping styles and mental health variables (including depression, anxiety, sleep disturbance, suicide risk), were collected. Negative bystander behavior was positively associated with mental health problems, while positive bystander behavior was negatively associated with these factors. Also, further analysis showed that coping styles and self-efficacy mediated the relationship between different bullying behaviors and mental health outcomes. The results highlighted the comparison of the correlates of positive and negative bystander behaviors, which were comparably crucial to those of victims and perpetrators for prevention and intervention efforts. Promoting adaptive coping styles and self-efficacy to buffer the deleterious psychological consequences of bullying behavior in adolescents was also important.

Abstract Background Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. Methods This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. Results Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug–related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. Conclusions FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. Trial registration ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

ObjectiveThis study comprehensively evaluated the causal relationship between different types of statins use and knee/hip osteoarthritis (OA) using a two-sample and multivariate Mendelian randomization (MR) method.MethodsMR analysis was conducted using publicly available summary statistics data from genome-wide association studies (GWAS) to assess the causal associations between total statins use (including specific types) and knee/hip OA. The primary analysis utilized the inverse variance-weighted (IVW) method, with sensitivity analysis conducted to assess robustness. Multivariable MR (MVMR) analysis adjusted for low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI).ResultsThe MR analysis revealed a significant inverse association between genetically predicted total statins use and the risk of knee OA (OR = 0.950, 95%CI: 0.920-0.982, p = 0.002) as well as hip OA (OR = 0.932, 95%CI: 0.899-0.966, p ConclusionThis study provides compelling evidence of the close relationship between statin use and a reduced risk of knee/hip OA, particularly with atorvastatin and simvastatin. LDL-C and IDL-C may mediate these effects. These findings have important implications for the clinical prevention and treatment of knee/hip OA.

BackgroundThe long non-coding RNA cancer susceptibility candidate (CASC) has abnormal expression in lung cancer tissues and may correlate with lung cancer prognosis. This study aimed to comprehensively evaluate the association between CASC expression and the cancer prognosis.MethodsPubMed, Embase, Web of Science, Google Scholar, Cochrane Library, and China National Knowledge Infrastructure databases were searched until April 1, 2023, to obtain the relevant literature. Studies that met the predefined eligibility criteria were included, and their quality was independently assessed by 2 investigators according to the Newcastle-Ottawa Scale (NOS) score. Detailed information was obtained, such as first author, year of publication, and number of patients. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted and grouped to assess the relationship between CASC expression and cancer prognosis. The dichotomous data was merged and shown as the odds ratio (OR) with a 95% CI was extracted to assess the relationship between CASC expression and clinicopathological parameters.ResultsA total of 12 studies with 746 patients with lung cancer were included in the meta-analysis. The expression levels of lncRNA CASC2 and CASC7 were decreased, while those of CASC9, 11, 15, and 19 were induced in lung cancer tissues compared with paracancerous tissues. In the population with low CASC expression (CASC2 and CASC7), high CASC expression indicated a good lung cancer prognosis (HR = 0.469; 95% CI, 0.271-0.668). Conversely, in the population with high CASC expression (CASC9, 11, 15, and 19), high CASC expression predicted a poor lung cancer outcome (HR = 1.910; 95% CI, 1.628-2.192). High CASC expression also predicted worse disease-free survival (DFS) (HR = 2.803; 95% CI, 1.804-6.319). Combined OR with 95% CI revealed an insignificant positive association between high CASC expression and advanced TNM stage (OR = 1.061; 95% CI, 0.775-1.454), LNM (OR = 0.962; 95% CI, 0.724-1.277), tumor size (OR = 0.942; 95% CI, 0.667-1.330), and histological grade (OR = 1.022; 95% CI, 0.689-1.517).ConclusionThe CASC expression levels negatively correlate with lung cancer prognosis. Therefore, CASC expression may serve as a prognostic marker and a potential therapeutic target for lung cancer.

To tackle the global water imbalance problem, a multitude of inter-basin water transfer projects have been built worldwide in recent decades. Nevertheless, given the complexity and safety challenges associated with project operation, effective emergency decision-making is crucial for addressing unforeseen incidents. Hence, this research has developed a two-stage emergency decision-making framework to tackle the uncertainty in the development trends of emergencies in inter-basin water transfer projects. (1) The first stage mainly utilizes case-based reasoning techniques to extract historical case information and disposal plans for inter-basin water transfer projects. Subsequently, a holistic similarity model is built by employing structural similarity and local attribute similarity algorithms to identify highly similar historical cases. (2) The second stage involves the optimization and adjustment of decision-making plans based on the dynamic evolution characteristics of emergencies. It utilizes the theory of decision-makers regret psychology and combines it with practical case studies to verify the scientific rationality of the method. This enables it to achieve effective multidimensional expression and rapid matching of scenarios, satisfying the decision-making requirements of "scenario response". Finally, this study compares the results obtained from this method with those computed using the traditional TOPSIS method and fuzzy comprehensive evaluation method, further validating its feasibility and effectiveness. In practice, this method can provide effective support for decision-makers work.

In this study, we proposed an efficient algorithm (X-LD) for estimating linkage disequilibrium (LD) patterns for a genomic grid, which can be of inter-chromosomal scale or of small segments. Compared with conventional methods, the proposed method was significantly faster, dropped from O(nm2) to O(n2m)—n the sample size and m the number of SNPs, and consequently we were permitted to explore in depth unknown or reveal long-anticipated LD features of the human genome. Having applied the algorithm for 1000 Genome Project (1KG), we found (1) the extended LD, driven by population structure, universally existed, and the strength of inter-chromosomal LD was about 10% of their respective intra-chromosomal LD in relatively homogeneous cohorts, such as FIN, and to nearly 56% in admixed cohort, such as ASW. (2) After splitting each chromosome into upmost of more than a half million grids, we elucidated the LD of the HLA region was nearly 42 folders higher than chromosome 6 in CEU and 11.58 in ASW; on chromosome 11, we observed that the LD of its centromere was nearly 94.05 folders higher than chromosome 11 in YRI and 42.73 in ASW. (3) We uncovered the long-anticipated inversely proportional linear relationship between the length of a chromosome and the strength of chromosomal LD, and their Pearson’s correlation was on average over 0.80 for 26 1KG cohorts. However, this linear norm was so far perturbed by chromosome 11 given its more completely sequenced centromere region. Uniquely chromosome 8 of ASW was found most deviated from the linear norm than any other autosomes. The proposed algorithm has been realized in C++ (called X-LD) and is available at https://github.com/gc5k/gear2, and can be applied to explore LD features in any sequenced populations.

Abstract Background It is known that measuring the triglyceride glucose (TyG) index and TyG-related parameters [triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC), and triglyceride glucose-waist to height ratio (TyG-WHtR)] can predict diabetes; this study aimed to compare the predictive value of the baseline TyG index and TyG-related parameters for the onset of diabetes at different future periods. Methods We conducted a longitudinal cohort study involving 15,464 Japanese people who had undergone health physical examinations. The subject’s TyG index and TyG-related parameters were measured at the first physical examination, and diabetes was defined according to the American Diabetes Association criteria. Multivariate Cox regression models and time-dependent receiver operating characteristic (ROC) curves were constructed to examine and compare the risk assessment/predictive value of the TyG index and TyG-related parameters for the onset of diabetes in different future periods. Results The mean follow-up period of the current study cohort was 6.13 years, with a maximum of 13 years, and the incidence density of diabetes was 39.88/10,000 person-years. In multivariate Cox regression models with standardized hazard ratios (HRs), we found that both the TyG index and TyG-related parameters were significantly and positively associated with diabetes risk and that the TyG-related parameters were stronger in assessing diabetes risk than the TyG index, with TyG-WC being the best parameter (HR per SD increase: 1.70, 95% CI 1.46, 1.97). In addition, TyG-WC also showed the highest predictive accuracy in time-dependent ROC analysis for diabetes occurring in the short-term (2–6 years), while TyG-WHtR had the highest predictive accuracy and the most stable predictive threshold for predicting the onset of diabetes in the medium- to long-term (6–12 years). Conclusions These results suggest that the TyG index combined with BMI, WC, and WHtR can further improve its ability to assess/predict the risk of diabetes in different future periods, where TyG-WC was not only the best parameter for assessing diabetes risk but also the best risk marker for predicting future diabetes in the short-term, while TyG-WHtR may be more suitable for predicting future diabetes in the medium- to long-term.

Background NLRP12-associated autoinflammatory disease (NLRP12-AID) is an autosomal dominant autoinflammatory disorder caused by variants of NLRP12 gene. We aimed to report a cohort of Chinese adult patients with NLRP12-AID and summarised phenotypes and genotypes.Methods Twenty patients were diagnosed with NLRP12-AID after performing whole-exome sequencing and were included in our cohort. Demographic information, clinical data and treatment response were collected and evaluated. A literature review of NLRP12-AID was performed, and the clinical features and mutated sites were summarised and compared with our cohort.Results Among the 20 NLRP12-AID patients, the main clinical features of NLRP12-AID included fever, cutaneous rash, arthralgia/arthritis, pharyngitis/tonsillitis, lymphadenopathy, myalgia and abdominal pain/diarrhoea. Thirteen NLRP12 variants were detected as F402L, G39V, R1030X, R7G, E24A, Q90X, A218V, A259V, W581X, G729R, R859W, c.-150T>C and c.*126G>C. Glucocorticoids were used in 14 patients, immunosuppressive agents in 13, and tocilizumab in 2. Seventeen patients had good responses to therapy. When compared with 50 NLRP12-AID patients from other countries, Chinese patients had fewer variants in exon 3, higher incidences of cutaneous rash, pharyngitis/tonsillitis and lymphadenopathy. Among all these 70 NLRP12-AID patients, patients carrying non-exon-3 variants had higher frequencies of ocular involvement, pharyngitis/tonsillitis, headache and lymphadenopathy than those with exon-3 variants.Conclusion This is the largest cohort of NLRP12-AID in the world and seven novel variants of NLRP12 were identified. Chinese adult patients of NLRP12-AID had more non-specific symptoms such as pharyngitis/tonsillitis and lymphadenopathy when compared with patients from other countries, for which the less occurrence of exon-3 variants might be one possible reason.

Abstract Background Spermatogenesis associated serine rich 2 like (SPATS2L) was highly expressed in homoharringtonine (HHT) resistant acute myeloid leukemia (AML) cell lines. However, its role is little known in AML. The present study aimed to investigate the function of SPATS2L in AML pathogenesis and elucidate the underlying molecular mechanisms. Methods Overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) were used to evaluate the prognostic impact of SPATS2L for AML from TCGA database and ourcohort. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. The changes of proteins were assessed by Western blot(WB). A xenotransplantation mice model was used to evaluate in vivo growth and survival. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML. Results SPATS2L expression increased with increasing resistance indexes(RI) in HHT-resistant cell lines we had constructed. Higher SPATS2L expression was observed in intermediate/high-risk patients than in favorable patients. Meanwhile, decreased SPATS2L expression was observed in AML patients achieving complete remission (CR). Multivariate analysis showed high SPATS2L expression was an independent poor predictor of OS, EFS, RFS in AML. SPATS2L knock down (KD) suppressed cell growth, induced apoptosis, and suppressed key proteins of JAK/STAT pathway, such as JAK2, STAT3, STAT5 in AML cells. Inhibiting SPATS2L expression markedly enhanced the pro-apoptotic effects of traditional chemotherapeutics (Ara-c, IDA, and HHT). Conclusions High expression of SPATS2L is a poor prognostic factor in AML, and targeting SPATS2L may be a promising therapeutic strategy for AML patients.

Background Though the previous genome-wide association studies found the association between HLA alleles and rosacea in the European populations, the data is lacking among the Asians. Moreover, neutrophils are important in the immune-related mechanism of rosacea, and dyslipidemia is closely related to rosacea. We aimed to explore the association between HLA genes and rosacea in Chinese rosacea patients, as well as the mediation effect of neutrophils, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) on the relationship between HLA genes and rosacea.Methods A total of 249 rosacea and 150 controls were ranked by the international investigator global rosacea severity scores. HLA genes, neutrophils, HDL, and LDL were detected. And their mediation effects on the relationship between HLA and rosacea risk or severity were analysed.Results HLA-DQB1*03:03 allele (OR = 41.89, 95% CI: 9.80 ∼ 179.09, p = 4.7*10−7), HLA-DQB1*04:02 allele (OR = 0.16, 95% CI: 0.03 ∼ 0.81, p = 0.026) and HLA-DQB1*03:03/05:02 genotype (OR = 5.57, 95% CI: 1.13 ∼ 27.52, p = 0.0351) were significantly associated with rosacea. Moreover, HLA-DQB1*03:03 allele (b = 1.434, SE = 0.217, p = 2.0*10−10), HLA-DQB1*05:01 allele (b = 0.894, SE = 0.33520, p = 0.008) and HLA-DQB1*03:03/06:01 genotype (b = 0.998, SE = 0.472, p = 0.040) were positively associated with rosacea severity. Furthermore, we found both neutrophils and HDL, instead of LDL, have mediation effects on the relationship between HLA-DQB1*03:03 and risk or severity of rosacea.Conclusions We discovered novel susceptible HLA alleles for rosacea in the Chinese population, and disclosed the mediation effect of neutrophils and HDL on the relationship between HLA-DQB1 and rosacea, implying a possible correlation between rosacea and inflammatory or metabolic factors, providing hints for future studies in the mechanism of rosacea. Key messagesHLA-DQB1*03:03 allele, HLA-DQB1*04:02 allele and HLA-DQB1*03:03/05:02 genotype were significantly associated with rosacea.HLA-DQB1*03:03 allele, HLA-DQB1*05:01 allele and HLA-DQB1*03:03/06:01 genotype were positively associated with rosacea severity.Neutrophils and HDL have mediation effects on the relationship between HLA-DQB1*03:03 and risk or severity of rosacea.

Abstract Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. Methods In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. Results Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. Conclusions LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy.

Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic datasets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than threefold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed the best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

Abstract. Background:. Changes in thyroid hormone levels are commonly recognized characters among the elderly, which were reported to potentially influence incident frailty. Therefore, we examined the cross-sectional associations of thyroid hormones (THs) with frailty as well as the five components characterizing frailty (fatigue, resistance, ambulation, number of illnesses, and loss of weight) among the oldest-old. Methods:. Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District, Beijing, participated in our recruitment campaign between April 2019 and May 2020. The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight) and a positive score for each frailty subdomain. Demographic information (age, sex, marital status, and educational status), comorbidities, and details on the participants’ lifestyles were recorded. Serum THs including free triiodothyronin (fT3), triiodothyronine (T3), free thyroxine (fT4), and thyroxine (T4) and thyroid stimulating hormone (TSH) levels were also measured at the beginning of our study. Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains. Results:. Among the total 487 subjects at enrollment, 60 (12.23%) of them were diagnosed with subclinical hypothyroidism and 110 (22.59%) of the total population scored positive for frailty. Logistic regression analyses adjusted for all potential confounders, showed that frailty was significantly associated with the serum TSH concentration (odds ratio [OR]: 1.06), fT3 concentration (OR: 0.54), and subclinical hypothyroidism score (OR: 2.18). The association between fT4 and frailty was absent in our observational study. The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty. Conclusion:. Subclinical hypothyroidism, higher TSH level, lower fT3 level, and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old, suggesting a relevant role of thyroid function in aging. Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.

Abstract Background Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity. Methods The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins. Results APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway. Conclusion Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.

Objective No consensus exists regarding the association between pemphigus and thyroid disease. To explore the relationship between the two conditions by synthesizing the existing data. Methods We performed this review based on PubMed, Embase and Web of Science (from inception to 2022) and used the Newcastle-Ottawa scale for assessing the quality of studies. The outcome was represented by pooled odds ratios (ORs) with 95% confidence intervals (CI). And the publication bias and sensitivity analyses were developed. Results Our analyze finally included six studies containing 17,567 pemphigus patients. Overall, we revealed that pemphigus is significantly associated with hypothyroidism (OR 1.70, 95% CI 1.54–1.87), while not with thyroid cancer (OR 0.93, 95% CI 0.41–2.11) and autoimmune thyroid disease (AITD) (OR 1.64, 95% CI 0.91–2.95). In subgroup analyses, pemphigus was also not associated with Graves’ disease (OR 0.97, 95% CI 0.63–1.49) and Hashimoto’s thyroiditis (OR 1.32, 95% CI 0.88–1.97). Conclusion Our results reveal a significant association between pemphigus and hypothyroidism. Considering other relevant studies, we also speculate that the prevalence of AITD is higher in pemphigus patients than in the general population.

Abstract Background Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. Methods The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. Results In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74–0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57–0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69–0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55–0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . Conclusions By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.

Objective To explore the relationship between the serum concentration of IL-17 and the pathogenesis of psoriasis. Methods ampere database was established through literature search, and meta-analysis was used to evaluate the effect indicator of the included literatures. Results 5 articles were included in the study, and the quality evaluation score was 6–7 points by the Newcastle-Ottawa Scale (NOS) criteria. There was heterogeneity in the standardized mean difference (SMD) between the two groups (I 2 = 98.63%). The random effect model analysis showed that the combined SMD = 2.11, 95%CI (0.79, 3.43), the effect size between studies was statistically significant (z = 3.13, p = 0.00). Conclusion There was a statistical difference in serum IL-17 concentration between the case group and the control group. The serum concentration of IL-17 in the case group was higher than that in the control group.

Objective To explore the role of blood glucose, blood lipids, and androgen receptor gene (CAG)n genotype in the pathogenesis of osteoporosis in Chinese Han men and to provide theoretical value for screening people susceptible to osteoporosis. Methods Patients who visited the First Affiliated Hospital of Chengdu Medical College from February 2021 to October 2021 were selected as research subjects to measure bone density by double-energy X-ray, osteoporosis patients as osteoporosis group (40 patients), and non-osteoporosis patients as the control group (40 patients). The STR method detected the repeat times of the androgen receptor gene (CAG)n in the two groups. The repeat times ≤22 were the SS genotype, and >22 were the LL genotype. Meanwhile, the patient’s age, body mass index (BMI), blood glucose, blood lipids, calcium, phosphorus, and alkaline phosphatase examined on day one after admission were collected, and the statistical analysis was performed using SPSS 26.0. Results The results of the univariate analysis showed that there was no significant difference in age, calcium, phosphorus, alkaline phosphatase, and glycosylated hemoglobin between the two groups (P > 0.05). There were significant differences in average blood glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, and genotype frequency (P < 0.05). The multivariate logistic regression analysis results showed significant differences in total cholesterol and genotype frequency between the two groups (P < 0.05). Conclusion Androgen receptor LL genotype and elevated total cholesterol may be the risk factors for osteoporosis in older men of Han nationality.

ObjectiveTo reveal the relationship between Body Mass Index(BMI), type 2 diabetes, and bone mineral density(BMD) using a mendelian randomization (MR) approach.MethodsGWAS data on BMI, type 2 diabetes, and BMD were selected from the IEU GWAS database at the University of Bristol.Univariable, multivariable, and mediated MR analyses were used to explore the relationship between BMI, type 2 diabetes, and BMD. beta(β) values were given, and three methods, including inverse variance weighting, MR-Egger regression, and weighted median, were used in this analysis.ResultsUnivariable mendelian randomization (UVMR) results showed that BMI and type 2 diabetes were positively associated with BMD. However, the association between BMI and BMD was insignificant in the multivariable Mendelian randomization (MVMR) analysis, while that between type 2 diabetes and BMD remained significant. Mediated MR analysis indicated that type 2 diabetes mediated the regulation of BMD by BMI.ConclusionThis study provides evidence supporting a positive causal association between BMI, type 2 diabetes, and BMD. Type 2 diabetes acts as a mediator in the regulation of BMD by BMI, indicating that both BMI and type 2 diabetes exert a protective influence on BMD.

Abstract Background Hypertrophic scar (HTS) is a fibrotic disorder of skins and may have repercussions on the appearance as well as functions of patients. Recent studies related have shown that competitive endogenous RNA (ceRNA) networks centering around miRNAs may play an influential role in HTS formation. This study aimed to construct and validate a three-miRNA (miR-422a, miR-2116-3p, and miR-3187-3p) ceRNA network, and explore its potential functions. Methods Quantitative real‑time PCR (qRT‑PCR) was used to compare expression levels of miRNAs, lncRNAs, and genes between HTS and normal skin. Target lncRNAs and genes of each miRNA were predicted using starBase as well as TargetScan database to construct a distinct ceRNA network; overlapping target lncRNAs and genes of the three miRNAs were utilized to develop a three-miRNA ceRNA network. For every network, protein–protein interaction (PPI) network analysis was performed to identify its hub genes. For each network and its hub genes, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to explore their possible functions. Results MiR-422a, miR-2116-3p, and miR-3187-3p were all downregulated in HTS tissues and fibroblasts. MiR-422a-based ceRNA network consisted of 101 lncRNAs with 133 genes; miR-2116-3p-centered ceRNA network comprised 85 lncRNAs and 978 genes; miR-3187-3p-derived ceRNA network encompassed 84 lncRNAs as well as 1128 genes. The three-miRNA ceRNA network included 2 lncRNAs with 9 genes, where MAPK1, FOSL2, ABI2, KPNA6, CBL, lncRNA-KCNQ1OT1, and lncRNA-EBLN3P were upregulated. According to GO and KEGG analysis, these networks were consistently related to ubiquitination. Three ubiquitination-related genes (CBL, SMURF2, and USP4) were upregulated and negatively correlated with the expression levels of the three miRNAs in HTS tissues. Conclusions This study identified a three-miRNA ceRNA network, which might take part in HTS formation and correlate with ubiquitination.

Purpose We aimed to establish a cholesterogenic gene signature to predict the prognosis of young breast cancer (BC) patients and then verified it using cell line experiments. Methods In the bioinformatic section, transcriptional data and corresponding clinical data of young BC patients (age ≤ 45 years) were downloaded from The Cancer Genome Atlas (TCGA) database for training set. Differentially expressed genes (DEGs) were compared between tumour tissue (n = 183) and normal tissue (n = 30). By using univariate Cox regression and multi COX regression, a five-cholesterogenic-gene signature was established to predict prognosis. Subgroup analysis and external validations of GSE131769 from the Gene Expression Omnibus (GEO) were performed to verify the signature. Subsequently, in experiment part, cell experiments were performed to further verify the biological roles of the five cholesterogenic genes in BC. Results In the bioinformatic section, a total of 97 upregulated genes and 124 downregulated cholesterogenic genes were screened as DEGs in the TCGA for training the model. A risk scoring signature contained five cholesterogenic genes (risk score = −1.169 × GRAMD1C −0.992 × NFKBIA + 0.432 × INHBA + 0.261 × CD24 −0.839 × ACSS2) was established, which could differentiate the prognosis of young BC patients between high-risk and low-risk group (

Abstract The activation of DNA‐dependent kinase (DNA‐PKcs) upon DNA damage contains a cascade of reactions, covering acetylation by TIP60, binding with Ku70/80, and autophosphorylation. However, how cells regulate TIP60‐mediated acetylation of DNA‐PKcs and the following DNA‐PKcs activation upon DNA damage remains obscure. This present study reported that TIP60 is hyper‐SUMOylated in normal conditions, but upon irradiation‐induced DNA damage, small ubiquitin‐like modifier (SUMO)‐specific protease 3 (SENP3)‐mediated deSUMOylation of TIP60 promoted its interaction with DNA‐PKcs to form the TIP60‐DNA‐PKcs complex. We show that TIP60 SUMOylation is reduced quickly in response to DNA damage and the deSUMOylation of TIP60 by SENP3 is required for DNA‐PKcs acetylation and its autophosphorylation. Comet and γH2AX immunofluorescence assay showed that knockdown of SENP3 impaired DNA damage repair. Using the NHEJ report system, we found that knockdown of SENP3 affected the efficiency of NHEJ. Further exploration using clonogenic survival assay, cell viability assay and cytoflow assay suggested that leaking SENP3 increased the sensitivity of tumour cells to serval DNA damage treatment. Overall, our findings revealed a previously unidentified role of SENP3 in regulating DNA‐PKcs activity and DNA damage repair.

Abstract Acute lung injury (ALI), which could be induced by multiple factors such as lipopolysaccharide (LPS), refer to clinical symptoms of acute respiratory failure, commonly with high morbidity and mortality. Reportedly, active ingredients from green tea have anti-inflammatory and anticancer properties, including epigallocatechin-3-gallate (EGCG). In the present study, protein kinase C alpha (PRKCA) is involved in EGCG protection against LPS-induced inflammation and ALI. EGCG treatment attenuated LPS-stimulated ALI in mice as manifested as improved lung injury scores, decreased total cell amounts, neutrophil amounts and macrophage amounts, inhibited the activity of MPO, decreased wet-to-dry weight ratio of lung tissues, and inhibited release of inflammatory cytokines TNF-α, IL-1β, and IL-6. PRKCA mRNA and protein expression showed to be dramatically decreased by LPS treatment while reversed by EGCG treatment. Within LPS-stimulated ALI mice, PRKCA silencing further aggravated, while PRKCA overexpression attenuated LPS-stimulated inflammation and ALI through MAPK signaling pathway. PRKCA silencing attenuated EGCG protection. Within LPS-induced RAW 264.7 macrophages, EGCG could induce PRKCA expression. Single EGCG treatment or Lv-PRKCA infection attenuated LPS-induced increases in inflammatory factors; PRKCA silencing could reverse the suppressive effects of EGCG upon LPS-stimulated inflammatory factor release. In conclusion, EGCG pretreatment inhibits LPS-induced ALI in mice. The protective mechanism might be associated with the inhibitory effects of PRKCA on proinflammatory cytokine release via macrophages and MAPK signaling pathway.

Abstract Background Cigarette smoking constitutes a major lifestyle risk factor for osteoporosis and hip fracture. It is reported to impair the outcome of many clinical procedures, such as wound infection treatment and fracture healing. Importantly, although several studies have already demonstrated the negative correlation between cigarette consume and impaired bone homeostasis, there is still a poor understanding of how does smoking affect bone health, due to the lack of an adequately designed animal model. Our goal was to determine that cigarette smoke exposure impairs the dynamic bone remodeling process through induction of bone resorption and inhibition of bone formation. Methods We developed cigarette smoke exposure protocols exposing mice to environmental smoking for 10 days or 3 months to determine acute and chronic smoke exposure effects. We used these models, to demonstrate the effect of smoking exposure on the cellular and molecular changes of bone remodeling and correlate these early alterations with subsequent bone structure changes measured by microCT and pQCT. We examined the bone phenotype alterations in vivo and ex vivo in the acute and chronic smoke exposure mice by measuring bone mineral density and bone histomorphometry. Further, we measured osteoclast and osteoblast differentiation gene expression levels in each group. The function changes of osteoclast or osteoblast were evaluated. Results Smoke exposure caused a significant imbalance between bone resorption and bone formation. A 10-day exposure to cigarette smoke sufficiently and effectively induced osteoclast activity, leading to the inhibition of osteoblast differentiation, although it did not immediately alter bone structure as demonstrated in mice exposed to smoke for 3 months. Cigarette smoke exposure also induced DNA-binding activity of nuclear factor kappaB (NFκB) in osteoclasts, which subsequently gave rise to changes in bone remodeling-related gene expression. Conclusions Our findings suggest that smoke exposure induces RANKL activation-mediated by NFκB, which could be a “smoke sensor” for bone remodeling.

Abstract Background Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML). Methods The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis. Results In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1. Conclusion Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.

Abstract Mannan-binding lectin-associated serine protease-2 (MASP-2) has been reported to play an important role as a key enzyme in the lectin pathway of the complement system. The objectives of our study were to determine whether the single-nucleotide polymorphism (SNPs) of MASP2 and the gene-tea drinking interaction were associated with the susceptibility to TB. In total, 503 patients and 494 healthy controls were contained. Three SNPs (rs12142107, rs12711521, and rs7548659) were genotyped. The association between the SNPs and susceptibility to TB were investigated by conducting multivariate unconditional logistic regression analysis. The gene-tea drinking interactions were analyzed by the additive model of marginal structural linear odds models. Both genotype AC + AA at rs12711521 of MASP2 genes and genotype GT + GG at rs7548659 of MASP2 genes were more prevalent in the TB patient group than the healthy control group (OR: 1.423 and 1.439, respectively, P

Thermally processed Buthus martensii Karsch scorpion is an important traditional Chinese medical material that has been widely used to treat various diseases in China for over one thousand years. Our recent work showed that thermally processed Buthus martensii Karsch scorpions contain many degraded peptides; however, the pharmacological activities of these peptides remain to be studied. Here, a new degraded peptide, BmTX4-P1, was identified from processed Buthus martensii Karsch scorpions. Compared with the venom-derived wild-type toxin peptide BmTX4, BmTX4-P1 missed some amino acids at the N-terminal and C-terminal regions, while containing six conserved cysteine residues, which could be used to form disulfide bond-stabilized α-helical and β-sheet motifs. Two methods (chemical synthesis and recombinant expression) were used to obtain the BmTX4-P1 peptide, named sBmTX4-P1 and rBmTX4-P1. Electrophysiological experimental results showed that sBmTX4-P1 and rBmTX4-P1 exhibited similar activities to inhibit the currents of hKv1.2 and hKv1.3 channels. In addition, the experimental electrophysiological results of recombinant mutant peptides of BmTX4-P1 indicated that the two residues of BmTX4-P1 (Lys22 and Tyr31) were the key residues for its potassium channel inhibitory activity. In addition to identifying a new degraded peptide, BmTX4-P1, from traditional Chinese scorpion medicinal material with high inhibitory activities against the hKv1.2 and hKv1.3 channels, this study also provided a useful method to obtain the detailed degraded peptides from processed Buthus martensii Karsch scorpions. Thus, the study laid a solid foundation for further research on the medicinal function of these degraded peptides.

Objectives Our study aimed to assess the association between the Dietary Inflammatory Index (DII) and depression in the elderly over 55 years in Northern China.Methods We analysed the data of 2022 Chinese adults aged 55 and over from a community-based neurological disease cohort study from 2018 to 2019. A validated semiquantitative food frequency questionnaire was used to assess eating habits at the time of inclusion. Multiple logistic regression was used for analysis, and social demographics, lifestyle and health-related factors were adjusted.Results Among the included population, the prevalence of depression was 23.39%. Mean (SD) and range of the DII in the included population were 1.70 (1.42) and −5.20 to +5.68. The risk of depression was significantly higher in participants in the most pro-inflammatory group (quartile 4) than in the participants in the most anti-inflammatory group (quartile 1) (OR 1.53; 1.37 to 1.82; p-trend=0.01). The subgroup analysis of body mass index (BMI) showed that there is a significant association between DII and the risk of depression in overweight and obese people (p＜0.05). The restricted cubic spline results show that the OR value of depression possesses an upward trend with the increase of the DII score.Conclusions Aged patients with depression present a higher potential for dietary inflammation. Pro-inflammatory diets might increase the risk of depressive symptoms. Further research in different populations is crucial to confirm the association between DII and depression.

Abstract Background Vascular endothelial growth factor (VEGF)-targeted therapy is effective in patients with ovarian cancer. Whether adipose tissue (AT) could predict the efficacy of VEGF receptor (VEGFR) inhibitors in ovarian cancer is unknown. We aimed to evaluate the ability of distinct AT depots to predict the efficacy of apatinib, a VEGFR inhibitor, in recurrent ovarian cancers included in the AEROC trial. Methods The AEROC was a single-arm phase 2 trial of apatinib and oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer. Apatinib was administered continuously, and oral etoposide was administered every 21 days for a maximum of six cycles. This was a post hoc study based on the AEROC trial. Areas of visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) were measured using computed tomography scan at baseline to assess their association with the objective response rate, progression-free survival, and overall survival. Results Of the 35 treated patients, 31 patients with at least one post-baseline efficacy assessment by computed tomography scan were included in this study. After adjusting for apatinib exposure, high VAT (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.03–0.90, P = 0.037) and SAT (OR, 0.16; 95% CI, 0.03–0.87, P = 0.034) were significantly associated with a higher objective response rate. Further, decreased risks of disease progression and death were associated with high VAT (hazard ratio [HR], 0.39; 95% CI, 0.17–0.92, P = 0.031, and HR, 0.12; 95% CI, 0.04–0.40, P

Summary: Background: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has killed millions of people worldwide. The current crisis has created an unprecedented demand for rapid test of SARS-CoV-2 infection. Methods: Reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a fast and convenient method to amplify and identify the transcripts of a targeted pathogen. However, the sensitivity and specificity of RT-LAMP were generally regarded as inferior when compared with the gold standard RT-qPCR. To address this issue, we combined bioinformatic and experimental analyses to improve the assay performance for COVID-19 diagnosis. Findings: First, by experimental screening as well as high-throughput sequencing studies, we discovered new primer features that impacted LAMP sensitivity and specificity. These features were then used to build an improved bioinformatics algorithm to design LAMP primers targeting SARS-CoV-2. We further rigorously validated these new assays for their efficacy and specificity. We demonstrated that multiplexed RT-LAMP assay could directly detect as low as 1.5 copies/µL of SARS-CoV-2 particles in saliva, without the need of RNA isolation. We further tested this ultra-sensitive and specific RT-LAMP assay using saliva samples from COVID-19 patients. Clinical validation results indicated that the new RT-LAMP assay was comparable to standard RT-qPCR in overall assay sensitivity and specificity. Interpretation: In summary, our new LAMP primer design algorithm along with the validated assays provide a fast and reliable method for the diagnosis of COVID-19 cases. Funding: National Institutes of Health.

Abstract Background Microsurgical replantation has become the most favorable treatment option for scalp avulsion. However, the accurate prediction of postoperative replant viability remains challenging. Case presentation In this article, we showed that (indocyanine green angiography, ICGA) can provide a much more precise prediction of replant necrosis than conventional clinical assessment in a rare case of complete scalp avulsion with prolonged ischemia time. Conclusion Clinical assessment of replant survival may be misleading in cases of complex tissue injuries and prolonged ischemic stress. This case provides insight into the promising utility of ICGA as an important adjuvant tool to better assess tissue perfusion and viability in scalp avulsion and possibly other types of replantation.

People may experience media vicarious traumatization due to frequent exposure to media coverage of disasters. Currently, the influential relationship between personality traits and media vicarious traumatization still lacks systematic and in-depth research. Based on the MU5735 airplane crash, this study explored the effects of configurations of personality traits on media vicarious traumatization by analyzing data from 331 Chinese university students (Mage = 22.63 years, SD = 2.67, range = 18 to 29, n = 186 male and n = 145 female) using Fuzzy-set Qualitative Comparative Analysis (fsQCA). The results revealed that five combinations of the Big Five personality traits could lead to media vicarious traumatization, the combinations of configurations are: (1) high conscientiousness, high agreeableness, and high neuroticism; (2) high conscientiousness, high extraversion, and high agreeableness; (3) high extraversion, high neuroticism, low conscientiousness, and low agreeableness; (4) high openness, high extraversion, high agreeableness, and high neuroticism; (5) high extraversion, high agreeableness, low openness, and low neuroticism. Furthermore, sociodemographic variables (gender, age, and education) interacted with personality traits and also resulted in different configurations of media vicarious traumatization. This study indicates the asymmetric relationships between personality traits and media vicarious traumatization, identifies the vulnerable groups to facilitate targeted trauma interventions for university students according to different configurations, and provides a reference for public psychological relief efforts in emergencies.