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关键词： Triggering receptor expressed on myeloid cell-1   myasthenia gravis   enzyme-linked immunosorbent assay   biomarker   T cell  

摘要： Triggering receptor expressed on myeloid cells-1 (TREM-1) and TREM-2, cell surface receptors involved in innate and adaptive immunity, exist in soluble (sTREM-1 and sTREM-2) and membrane-bound forms, with the soluble form serve as biomarkers in many immune diseases. However, the role of TREM-1 and TREM-2 in myasthenia gravis (MG) remains unclear. This study aims to investigate the expression of TREM-1 and TREM-2 in MG, as well as their potential role in the immunopathological mechanism of MG. We enrolled a total of 85 MG patients and 43 healthy controls (HC). Enzyme-linked immunosorbent assay and flow cytometry were used to quantify the expression of TREM-1 and TREM-2 in MG patients and HC. The levels of TREM-1 and TREM-2 mRNA of peripheral blood mononuclear cells were measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) in MG and HC. In vitro experiments were performed to explore the functional effects of intervening TREM-1 on CD4+T cells. We found that serum sTREM-1 levels were significantly elevated in MG patients Compared to HC, whereas sTREM-2 showed no difference. Additionally, sTREM-1 levels in MG patients positively correlated with disease severity and memory B-cell proportions. TREM-1 expression was reduced and most significantly on CD4+T and CD8+T cells in MG patients. Inhibition of TREM-1 inhibited Treg cell differentiation but had no significant effect on Th1, Th2, and Th17, indicating its pathogenic role in MG.

关键词： immune checkpoint inhibitors   pembrolizumab   nivolumab   melanoma   renal cell carcinoma   triple-negative breast cancer   early-stage cancer   Hungary   I10   C02  

摘要： AimAnti-PD-(L)1 agents, inhibitors of programmed cell death protein 1 (PD-1) or its ligand (PD-L1), are established therapies that improve cancer management as well as the disease and societal burden of specific metastatic and early-stage cancers. The aim of the study was to determine the impact of adopting anti-PD-(L)1 agents for the treatment of all eligible patients with early-stage cancers versus reserving anti-PD-(L)1 agents for patients with metastatic disease alone in *** study evaluated two scenarios, one where anti-PD-(L)1 agents were used to treat all eligible early-stage disease cases (ESD scenario) of melanoma (stage IIB-C and III), renal cell carcinoma (RCC), and triple-negative breast cancer (TNBC) versus a reference scenario where anti-PD-(L)1 agents were only used to treat metastatic disease cases in Hungary (2024-2033). A Markov-modeling approach estimated the health outcomes and productivity losses from each scenario from a societal perspective. Outcomes included recurrence-/event-/disease-free life-years, total life-years, quality-adjusted life-years (QALYs), productive years (patients and caregivers), recurrences/events, active treatments for metastatic disease, and deaths. The cumulative health and productivity impact of ESD treatment with anti-PD-(L)1 agents in Hungary was the difference in health and productivity outcomes between the ESD and reference scenarios for the time horizon of the *** treatment with anti-PD-(L)1 agents was estimated to increase recurrence-/event-/disease-free life-years (+13.8%), total life-years (+3.7%), and QALYs (+4.7%), as well as productive work years for patients (+39.6%) and caregivers (+27.6%). Concurrently, there would be fewer recurrences/events (-31.0%), active treatments for metastatic disease (-34.0%), post-recurrence deaths (-30.3%), and total deaths (-23.1%).ConclusionInvesting in anti-PD-(L)1 agents for early-stage disease may not only increase the life expectancy and QALYs

关键词： Land subsidence   machine learning   SHAP   features optimization  

摘要： Land subsidence constitutes a major geological hazard, especially in swiftly urbanizing areas. This study examines the principal cities of southwestern China (Chengdu and Chongqing), where comprehending the processes contributing to subsidence and forecasting future dangers is crucial. Nevertheless, contemporary research seldom highlights a systematic feature screening procedure. This study utilized SHAP values in place of the conventional random forest method to measure land subsidence characteristics and employed a neural network to forecast regions at risk of future susceptibility. The findings indicate that the BP neural network model (RMSE = 0.468, MAE = 0.219) surpassed the RF model (RMSE = 0.557, MAE = 0.310). Following feature improvement, the model's performance was enhanced, resulting in a more precise prediction, with the obtained factors aligning with prior research. This feature optimization technique can aid in the selection of input variables and offer a robust theoretical framework for addressing and alleviating urban land subsidence.

关键词： GM soybean   non-targeted metabolomics   substantial equivalence   omega-3 fatty acid  

摘要： The overexpression of the Physaria fendleri omega-3 fatty acid desaturase (PfFAD3-1) in soybean (Glycine max (L.) Merr.) substantially increases seed alpha-linolenic acid (18:3) content. To evaluate the compositional safety of PfFAD3-1 transgenic soybeans, we conducted a three-year, two-location field trial (Jeonju and Gunwi, Republic of Korea) and applied non-targeted metabolite profiling of polar and lipophilic metabolites. Multivariate analyses (PCA, PLS-DA) revealed that environmental factors (site and year) had a strong effect on seed metabolite composition. Volcano plot and variable importance in projection (VIP) analyses indicated that most metabolite differences between PfFAD3-1 lines and Kwangan (KA) varied across years and locations, reflecting gene - environment interactions. Importantly, the majority of metabolites in PfFAD3-1 lines remained within the natural variation range of non-GM reference cultivars, supporting substantial equivalence. The consistent deviation was an increase in beta-amyrin, a triterpenoid precursor of soyasaponins. LC - MS analysis further confirmed line- and environment-dependent increases in specific saponins, particularly soyasaponin I. Given the established safety of triterpenoids in soybean and the biological coherence of fatty acid - triterpenoid pathway cross-talk, these findings suggest that beta-amyrin accumulation represents an intended metabolic adjustment rather than an unintended effect. Collectively, our results demonstrate that non-targeted metabolomics complements conventional OECD-recommended compositional analyses, providing a robust framework for the safety assessment of nutritionally enhanced GM soybeans.

关键词： Rock fracture   Shear mechanical characteristics   Roughness index   DEM   Shear test  

摘要： Rough feature quantitatively described by the roughness indexes is the key to evaluating the shear mechanical characteristics of rock fractures in advance. However, the correspondence between roughness index and fracture shear mechanical characteristics has not been verified. In this study, the specific relationship between the roughness index theta*max/(C + 1) and the shear mechanical characteristics of rock fractures was discussed through numerical direct shear tests of fracture specimens based on the discrete element method (DEM). To explore this, rough rock fractures having the same theta*max/(C + 1) were established by adjusting the ten standard roughness profiles. The microscopic mechanics parameters of the rock and fracture in the numerical model were determined by calibrating the macroscopic parameters with physical model experiments. The test results show that fracture specimens with the same roughness grade exhibit varying shear mechanics indicators, with the degree of dispersion increasing as the roughness increases. However, due to differences in morphology, specimens with the same roughness grade exhibit distinct contact force distribution and failure characteristics. It has been observed that theta*max/(C + 1) can well reflect the roughness grade and even macroscopic shear properties of fractures when discretisation is not taken into account.

关键词： tuberculosis infection   1HP   rifapentine concentration   pediatrics   safety  

摘要： Background : One month of daily rifapentine plus isoniazid (1HP) is a new regimen for tuberculosis (TB) infection to lower the incidence of active TB. However, it has not been prescribed for Chinese children, and the optimal dosage of daily rifapentine for children remains controversial. We aimed to assess the feasibility and safety of 1HP in young Chinese children with TB infection and to provide evidence for extrapolating dosing strategies to children. Methods : An open-label, prospective, single-arm clinical trial was conducted among eligible participants (aged <= 14 years). Completion rate, safety, and rifapentine concentrations of the 1HP regimen were analyzed. Results : Eighty children were enrolled in our study;79 of the participants (98.75%) completed the treatment, with only 1 case of noncompletion (1.25%) in the age group 6-14 years because of rash. Five of 80 participants (6.25%) experienced grade >= 3 adverse events, with no serious adverse events or deaths reported. The relationship between rifapentine concentration (mg/L) and time (days) in children stratified by age and weight demonstrated the lowest rifapentine concentration in participants <= 2 years old and those weighing <= 15 kg when compared to the other subgroups. Conclusions : The 1HP regimen is safe and feasible for young Chinese children with TB infection. Weight-based daily rifapentine (10-15 mg/kg) might not be enough for young children, particularly for those aged <= 2 years or weighing <= 15 kg. Clinical Trials Registration : ChiCTR2200066411.

关键词： Apoptosis   spheroid   PAC-1   glioma   caspase  

摘要： Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer and is generally approached with palliative intent. Preclinical studies suggest that short-term fasting may be an effective tool for enhancing existing cancer therapies by disrupting the glucose-dependent, oncogenic phenotype of many cancers. In this study, we investigated whether a fasting-mimicking environment (FME) enhances the efficacy of an emerging proapoptotic drug, procaspase-activating compound 1 (PAC-1), in 2D and 3D GBM cell models. Ad libitum food consumption (Fed) and FME conditions were simulated in vitro by modifying glucose, ketone and serum concentrations. The FME conditions enhanced PAC-1 in U87-MG, T98G and 9L-GS monolayer experiments by significantly reducing the PAC-1 50% inhibitory concentration (IC50), delaying cell growth and increasing apoptosis. Similarly, in the 3D spheroid models, the minimum concentration of PAC-1 required to reduce U87-MG and 9L-GS spheroid area was lower in the FME conditions than the Fed conditions. Additionally, we discovered that serum restriction was primarily responsible for the FME-induced PAC-1 enhancement. These finding are the first to demonstrate that fasting-mimicking conditions sensitize 2D and 3D glioma cell models to PAC-1, supporting the use of short-term fasting as a low-cost and widely accessible strategy for enhancing cancer therapies.

关键词： antiretroviral therapy   developing countries   dolutegravir   RCT   second-line  

摘要： Background : Longer-term outcome data following second-line antiretroviral therapy initiation in resource-limited settings is limited, especially in regions where genotypic resistance is inaccessible. This analysis evaluated extended efficacy and tolerability data from the D2EFT study. Methods : D2EFT is a completed, multicenter, phase IIIB/IV, randomized, open-label trial in 14 low- and middle-income countries. People with human immunodeficiency virus (HIV) who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to 1 of ritonavir-boosted darunavir plus 2 nucleoside reverse transcriptase inhibitors (DRV/r + 2NRTIs), ritonavir-boosted darunavir plus dolutegravir (DTG + DRV/r), or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG + TDF/XTC), with or without pre-switch genotyping. Here we report virological suppression at 96 weeks, defined as HIV RNA <50 copies/mL in a modified intention-to-treat population. Results : Between November 2017 and January 2022, 1190 participants were screened, 828 were randomized, and 826 were included in the analysis. At week 96, the proportions of participants with HIV RNA <50 copies/mL were 191/251 (76.1%) in DRV/r + 2NRTIs, 215/251 (85.7%) in DTG + DRV/r, and 231/283 (81.6%) in DTG + TDF/XTC. The treatment differences (95% confidence intervals [CIs]) in proportions achieving virological suppression were 9.6% (2.7, 16.4) in DTG + DRV/r and 9.0% (1.4, 16.6) in DTG + TDF/XTC, compared to DRV/r + 2NRTIs. Intermediate or high-level dolutegravir resistance was identified in 3/27 (13%) of virological failures in individuals taking DTG + TDF/XTC but in no one taking DTG + DRV/r. No darunavir resistance was observed. Conclusions : After 96 weeks of follow-up, DTG + DRV/r and DTG + TDF/XTC demonstrated virological superiority over DRV/r + 2NRTIs after first-line NNRTI-failure. However, emerging dolutegravir resistance, which was observed only in indi