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ObjectivesTumor grading is important for prognosis of pancreatic ductal adenocarcinoma (PDAC). In this study, we developed preoperative clinical-radiomics nomograms using features from contrast-enhanced CT (CECT), to discriminate high-grade and low-grade PDAC and predict overall survival (OS).MethodsIn this single-center, retrospective study conducted from February 2014 to April 2021, consecutive PDAC patients who underwent CECT and had pathologically identified grading were randomized to training (n=200) and test (n=84) cohorts for development of model to predict histological grade based on radiomics scores from CECT (HGrad). Another 42 patients were used as external validation cohort of HGrad. A nomogram (HGnom) was constructed using radiomics score, CA12-5 and smoking to predict histological grade. A second nomogram (Pnom) was constructed using radiomics score, CA12-5, TNM, adjuvant treatment, resection margin and microvascular invasion to predict OS in radical resection patients (217 of 284).ResultsAmong 326 patients, 122 were high-grade (120 poorly differentiated and 2 undifferentiated). The HGrad yielded AUCs of 0.75 (95% CI: 0.64, 0.85) and 0.76 (95% CI: 0.60, 0.91) in test and validation cohorts. The HGnom achieved AUCs of 0.77 (95% CI: 0.66, 0.87), and the predicted grades calibrated well with actual grades (P=.13). OS was different between the grades predicted by radiomics scores (P=.01). The integrated AUC of the Pnom for predicting OS was 0.80 (95% CI: 0.75, 0.88).ConclusionCompared with the HGrad using features from CECT, the HGnom demonstrated higher performance for predicting histological grade. The Pnom helped identify patients with high survival outcome in pancreatic ductal adenocarcinoma.

Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 μM, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors.

Objectivegastrointestinal stromal tumors (GISTs) with KIT exon 11 deletions have more malignant clinical outcomes. A radiomics model was constructed for the preoperative prediction of KIT exon 11 deletion in GISTs.MethodsOverall, 126 patients with GISTs who underwent preoperative enhanced CT were included. GISTs were manually segmented using ITK-SNAP in the arterial phase (AP) and portal venous phase (PVP) images of enhanced CT. Features were extracted using Anaconda (version 4.2.0) with PyRadiomics. Radiomics models were constructed by LASSO. The clinical-radiomics model (combined model) was constructed by combining the clinical model with the best diagnostic effective radiomics model. ROC curves were used to compare the diagnostic effectiveness of radiomics model, clinical model, and combined model. Diagnostic effectiveness among radiomics model, clinical model and combine model were analyzed in external cohort (n=57). Statistics were carried out using R 3.6.1.ResultsThe Radscore showed favorable diagnostic efficacy. Among all radiomics models, the AP-PVP radiomics model exhibited excellent performance in the training cohort, with an AUC of 0.787 (95% CI: 0.687-0.866), which was verified in the test cohort (AUC=0.775, 95% CI: 0.608-0.895). Clinical features were also analyzed. Among the radiomics, clinical and combined models, the combined model showed favorable diagnostic efficacy in the training (AUC=0.863) and test cohorts (AUC=0.851). The combined model yielded the largest AUC of 0.829 (95% CI, 0.621–0.950) for the external validation of the combined model. GIST patients could be divided into high or low risk subgroups of recurrence and mortality by the Radscore.ConclusionThe radiomics models based on enhanced CT for predicting KIT exon 11 deletion mutations have good diagnostic performance.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematological diseases and a high risk for transformation to acute myeloid leukemia (AML). The identification of key genetic alterations in MDS has enhanced our understanding of the pathogenesis and evolution. In recent years, it has been found that both innate and adaptive immune signaling are activated in the hematopoietic niche of MDS with aberrant cytokine secretion in the bone marrow microenvironment. It is also clear that immune dysregulation plays an important role in the occurrence and progression of MDS, especially the destruction of the bone marrow microenvironment, including hematopoiesis and stromal components. The purpose of this review is to explore the role of immune cells, the immune microenvironment, and cytokines in the pathogenesis of MDS. Insights into the mechanisms of these variants may facilitate the development of novel effective treatments to prevent disease progression.

Abstract The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.

Ebola virus (EBOV) infection leads to staggeringly high mortality rate. Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa. In this study, we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo. Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein (GPcl), disrupting GPcl interaction with viral receptor Niemann-Pick C1, thus blocking the fusion of viral and cellular membranes. Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl. More importantly, since berbamine hydrochloride has been used in clinic to treat leukopenia, it holds great promise of being quickly repurposed as an anti-EBOV drug.

Abstract. Background:. Cell competition is an important feature in pancreatic cancer (PC) progression, but the underlying mechanism remains elusive. This study aims to explore the role of exosomes derived from normal pancreatic ductal epithelial cells involved in PC progression. Methods:. PC cells and pancreatic stellate cells (PSCs) were treated with exosomes isolated from pancreatic ductal epithelial cells. Cell proliferation was assessed by CCK8 assays. Cell migration and invasion were assessed by Transwell assays. PC and matched adjacent non-tumor tissue specimens were obtained from 46 patients pathologically diagnosed with PC at Peking University First Hospital from 2013 to 2017. Tissue miR-485-3p and p21-activated kinase-1 (PAK1) expression was examined by real-time polymerase chain reaction (RT-PCR), and the relationship of the two was analyzed using Pearman's product-moment correlation. The clinical significance of miR-485-3p was analyzed using the Chi-square test, Wilcoxon rank-sum test, and Fisher exact probability, respectively. The binding of miR-485-3p to PAK1 5′-untranslated region (5′-UTR) was examined by luciferase assay. PC cells were xenografted into nude mice as a PC metastasis model. Results:. Exosomes from pancreatic ductal epithelial cells suppressed PC cell migration and invasion as well as the secretion and migration of PSCs. MiR-485-3p was enriched in the exosomes of pancreatic ductal epithelial cells but deficient in those of PC cells and PSCs, in accordance with the lower level in PSCs and PC cells than that in pancreatic ductal cells. And the mature miR-485-3p could be delivered into these cells by the exosomes secreted by normal pancreatic duct cells, to inhibit PC cell migration and invasion. Clinical data analysis showed that miR-485-3p was significantly decreased in PC tissues (P

Abstract Background Pancreatic cancer remains among the most prevalent and aggressive forms of cancer. While immunotherapeutic treatment strategies have shown some promise in affected patients, the benefits of these interventions have been limited by insufficient tumor infiltration by activated T cells. Results Here, Titanium diselenide (TiSe2) nanosheets were synthesized with good stability. When exposed to ultrasound (US), the TiSe2 nanosheets served as a reliable nano-sensitizer capable of inducing large amounts of reactive oxygen species (ROS) mediating sonodynamic therapy (SDT) under hypoxic and normoxic conditions. The tumor-released TAAs induced by TiSe2 nanosheet-mediated SDT promoted immunogenic cell death (ICD) conducive to the maturation of dendritic cells (DCs), and cytokine secretion and the subsequent activation and infiltration of T cells into the tumor. Combining TiSe2-mediated SDT with anti-PD-1 immune checkpoint blockade treatment led to the efficient suppression of the growth of both primary tumor and distant tumor, while simultaneously preventing lung metastasis. These improved immunotherapeutic and anti-metastatic outcomes were associated with activated systematic antitumor immune responses, including the higher levels of DC maturation and cytokine secretion, the increased levels of CD8+ T cells and the decreased levels of Treg cells infiltrated in tumors. Conclusion TiSe2 can be used as a sonosensitizer with good efficacy and high safety to mediate efficient SDT. The combination treatment strategy comprised of TiSe2-mediated SDT and PD-1 blockade activate anti-tumor immune responses effectively thorough inducing ICD, resulting in the inhibition the growth and metastasis of tumor. The combination therapy holds promise as a novel immunotherapy-based intervention strategy for pancreatic cancer patients.

Abstract Purpose This study aimed to investigate air leakage during invasive mechanical ventilation (IMV) in a pediatric intensive care unit (PICU) and explore potential risk factors. Methods We conducted a retrospective cohort study of children who underwent IMV in a single-center PICU in a tertiary referral hospital. Air leakage risk factors and factors associated with an improved outcome were assessed. Results A total of 548 children who underwent IMV were enrolled in this study. Air leakage occurred in 7.5% (41/548) of the cases in the PICU. Air leakage increased the duration of IMV and hospitalization time. Multivariate logistic regression analysis showed a higher risk of air leakage during IMV for PICU patients with acute respiratory dyspnea syndrome (ARDS) (OR = 4.38), a higher pediatric critical illness score (PCIS) (OR = 1.08), or a higher peak inspiratory pressure (PIP) (OR = 1.08), whereas the risk was lower for patients with central respiratory failure (OR = 0.14). The logistic model had excellent predictive power for air leakage, with an area under the curve of 0.883 and tenfold cross-validation. Patients aged between 1 and 6 years who were diagnosed with measles or pneumonia and had a low positive end-expiratory pressure (PEEP) or high PaO2/FiO2 ratio were associated with improved outcomes. Patients diagnosed with central respiratory failure or congenital heart diseases were associated with less desirable outcomes. Conclusions Patients with ARDS, a higher PCIS at admission or a higher PIP were at higher risk of air leakage.

SARS- CoV-2 hijacks ACE2 for cell entry. Here, the authors report that dynamic SUMOylation modulates the TOLLIP-directed selective autophagic degradation of ACE2 and suggest SUMOylation inhibition as a potential intervention against SARS-CoV-2 infection.

Abstract Background As a member of RNA-binding protein, CDKN2AIP has been shown to play a critical role in stem cell pluripotency and somatic differentiation. Recent studies indicate that Cdkn2aip is essential for spermatogonial self-renewal and proliferation through the activating Wnt-signaling pathway. However, the mechanisms of how Cdkn2aip regulate spermatogenesis is poorly characterized. Results We discovered that the CDKN2AIP was expressed in spermatocyte as well as spermatids and participated in spermiogenesis. Cdkn2aip −/− mice exhibited multiple sperm head defects accompanied by age dependent germ cell loss that might be result of protamine replacement failure and impaired SUN1 expression. Loss of Cdkn2aip expression in male mice resulted in synapsis failure in 19% of all spermatocytes and increased apoptosis due to damaged DNA double-strand break (DSB) repair and crossover formation. In vitro, knockdown of Cdkn2aip was associated with extended S phase, increased DNA damage and apoptosis. Conclusions Our findings not only identified the importance of CDKN2AIP in spermiogenesis and germ cell development, but also provided insight upon the driving mechanism.

Background & Aims: Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Methods: Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. Results: CT radiomics correlated with CD8+ T cells (r = –0.72–0.71, p = 0.004–0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = –0.58–0.57, p = 0.020–0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09–3.81; p = 0.011–0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p

Herpes simplex virus 1 (HSV-1) is a widely distributed virus. HSV-1 is a growing public health concern due to the emergence of drug-resistant strains and the current lack of a clinically specific drug for treatment. In recent years, increasing attention has been paid to the development of peptide antivirals. Natural host-defense peptides which have uniquely evolved to protect the host have been reported to have antiviral properties. Cathelicidins are a family of multi-functional antimicrobial peptides found in almost all vertebrate species and play a vital role in the immune system. In this study, we demonstrated the anti-HSV-1 effect of an antiviral peptide named WL-1 derived from human cathelicidin. We found that WL-1 inhibited HSV-1 infection in epithelial and neuronal cells. Furthermore, the administration of WL-1 improved the survival rate and reduced viral load and inflammation during HSV-1 infection via ocular scarification. Moreover, facial nerve dysfunction, involving the abnormal blink reflex, nose position, and vibrissae movement, and pathological injury were prevented when HSV-1 ear inoculation-infected mice were treated with WL-1. Together, our findings demonstrate that WL-1 may be a potential novel antiviral agent against HSV-1 infection-induced facial palsy.

IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major strategy to cure patients with acute lymphoblastic leukemia (ALL). The aim of this study was to evaluate whether isolated flow cytometry (FCM)-positive central nervous system (CNS) involvement before allo-HSCT is clinically significant.MethodsThe effects of isolated FCM-positive CNS involvement prior to transplantation on the outcomes of 1406 ALL patients with complete remission (CR) were retrospectively investigated.ResultsPatients were classified into isolated FCM-positive CNS involvement (n=31), cytology-positive CNS involvement (n = 43), and negative CNS involvement (n = 1332) groups. Among the three groups, the 5-year cumulative incidence of relapse (CIR) values were 42.3%, 48.8%, and 23.4%, respectively (P

Due to the low viscosity of water, water-lubricated bearings are susceptible to significant wear and noise in demanding operating conditions. It has been demonstrated that a small quantity of secondary lubricating medium can improve the lubrication performance of water-lubricated contact surfaces and achieve the purpose of temporary risk aversion. As a further step, the feasibility of the proposed idea is experimentally validated on a water-lubricated bearing test bench. A numerical model that couples the N–S equation and the VOF model is then developed to investigate the behavior of the flow field lubricated by pure water and water with a small quantity of the secondary lubricating medium. This model provides the predictions of important quantities such as the load-carrying capacity, the secondary lubricating medium volume fraction and the contact pressure under different lubricated conditions. The results show that the secondary lubricating medium can enter into the contact region and improve the lubrication performance of water-lubricated bearings, especially at lower shaft rotational speeds. Therefore, the feasibility of our proposed idea is verified, which provides a promising approach to reduce the wear and friction of water-lubricated bearings when they encounter short-time severe working conditions.

In this work, a fixed-time leader-following event-triggered (ET) consensus problem for multi-agent systems (MASs) with external disturbances is investigated. A distributed observer is developed to achieve the estimated state of the leader. By means of the observation information, the consensus error system for multi-agents is reformulated into a tracking error system, wherein individual follower agent aims to track the leader agent. Building upon Lyapunov technology and fixed-time stability theory, a new ET protocol is introduced to mitigate communication wastes. Notably, the proposed controller incorporates a strong robust fixed-time control form with lower complexity, and a reliable dynamic triggering condition also ensures the excellent performance of the system. Rigorous demonstrations underscore the stability and robustness of the ET method, while guaranteeing the avoidance of Zeno behavior. Finally, several numerical simulations are provided to underscore the efficacy of the proposed protocols.

The FY-3E satellite plasma analyzer marks China’s first detection of the characteristics, occurrence, and development of the typical plasma environment in the dawn–dusk orbit space. It provides data source support for operational space weather alerts and forecasts, helps ensure the in-orbit safety of the satellite, and accumulates space environment detection data for space environment modeling and space physics research. This paper gives a detailed introduction to the detection technology adopted by the FY-3E satellite plasma analyzer. We calibrated its performance through a calibration experiment and then analyzed and compared it with similar instruments in China. It is indicated that the instrument is capable of measuring an ion energy spectrum of 24 eV~32 keV and an electron energy spectrum of 23.7 eV~31.6 keV, its field of view reaches 180° × 90°, and the inversed measurement range of spacecraft absolute potential is better than −30 kV~+30 kV. All these contribute to a notably improved technology for plasma and satellite potential detection of China’s LEO satellites.

A meta-analysis of wheat aphid populations obtained from 120 studies from 1970 to 2017 reveals that pest loads increased in China but decreased in Europe and suggests this is due to differences in pesticide use, fertilization, land use, and natural enemies.

Abstract Pine wilt disease (PWD) is a worldwide forest disease caused by pine wood nematode (PWN). In this article, we investigated the composition, organization, correlation, and function of the endophytic microbial community in Pinus massoniana field with and without PWN. Samples were taken from branches, upper, middle, and lower trunks, as well as soil, from both healthy and infected trees. The results showed that the fungal diversity of healthy pines is around 1.1 times that of infected pines, while the bacterial diversity is about 0.75 times that of infected pines at the OTUs level. An increase of the abundance of pathogenic fungus such as Saitozyma, Graphilbum, Diplodia, Candida, Pseudoxanthomonas, Dyella and Pantoea was witnessed in infected pines according to the result of LEfSe. Furthermore, Ophiostoma and saprophytic fungus such as Entomocorticium, ganoderma, tomentella, entomocorticium were exclusively prominent in infected pines, which were substantially and highly connected with other species (p

A method for the simultaneous determination of 24 sulfonamide antibiotics including sulfamethazine, sulfaguanidine, sulfanilamide and so on in fish products was established by QuEChERS coupled with ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS). The optimal experimental conditions were determined by optimizing the chromatographic and mass spectrometric conditions and the QuEChERS pre-treatment technique. The samples were extracted by acetonitrile under ultrasonication, and then purified by C18 and anhydrous MgSO4. The solvent was detected by UPLC-MS/MS after filtering through 0.20 μm microporous membrane. The separation was performed on an Eclipse XDB-C18 column (4.6 mm × 100 mm, 1.8 μm) using acetonitrile −0.1% formic acid aqueous solution as the mobile phase, and determined with positive ion mode of electrospray ionization (ESI) under multiple reaction monitoring (MRM). Then the matrix matching external standard method was used for quantitative analysis. The results indicated that the 24 sulfonamide antibiotics showed good linearity in the respective linear range with the correlation coefficients (r) higher than 0.999. The average recoveries at three spiked levels of 5, 10 and 50 µg/kg ranged from 80.0% to 116.4% with the relative standard deviation (RSD) of 0.8%~9.4% (n=7). Moreover, the limits of detection (LOD) were 0.01~0.48 µg/kg and the limits of quantification (LOQ) were 0.02~1.59 µg/kg. The method was simple, rapid, selective and sensitive for the high-throughput detection of 24 sulfonamide antibiotics in fish products.

Abstract Aims This study aimed to develop and validate the psychometric properties of Information Needs Questionnaire for Differentiated Thyroid Cancer (INQ‐DTC) in DTC patients with radioactive iodine (RAI) therapy. Design Mixed methods. Methods Using qualitative methods, we developed the initial questionnaire from a personal perspective of information needs of 15 patients with DTC. We used a formal Delphi consensus process to help assess the initial questionnaire and provide recommendations for its application. Totally, 230 DTC patients with RAI therapy were selected for the process of validation. Results The final version of INQ‐DTC contains 33 items. The total Cronbach's alpha coefficient was 0.945, the total split‐half reliability was 0.822, and the test‐retest value was 0.984 for the overall score. Exploratory factor analysis extracted 5 factors, which could explain 61.86% of the total variance. The Scale‐level content validity index (S‐CVI) was 0.928, and 0.929 for the item‐level content validity index (I‐CVI).

Summary: Whether hypervariable region 1 (HVR1)-targeting antibodies elicited during natural hepatitis C virus (HCV) infection contribute to virus clearance and what is the mechanism underlying remain unclear. Here, we demonstrated that treatment of HCV-infected hepatoma Huh7.5 cells with the IgGs purified from 2 of 28 (7.1%) chronic hepatitis C (CHC) patients efficiently controlled the infection, for which genotype 1b HVR1 (1bHVR1)-binding antibody was critical. Moreover, we found that 1bHVR1 peptide was superior to 2aHVR1 in rabbit immunization to elicit antibodies neutralizing genotypes 1a, 2a, 3a, and 4a. The neutralization effect of 1bHVR1 IgG could be augmented by HH-1, an antibody constructed from CHC memory B cells but without binding to HVR1 peptide. Mechanistic studies showed that 1bHVR1 antisera and IgGs disrupted the interaction of E2-SR-B1 receptor. This study highlights the neutralizing activity of HVR1 antibody elicited by CHC patients and generated by HVR1-immunization against the established infections of multiple HCV genotypes.

Owing to their antitumor and major histocompatibility complex (MHC)-independent capacities, γδ T cells have gained popularity in adoptive T-cell immunotherapy in recent years. However, many unknowns still exist regarding γδ T cells, and few clinical data have been collected. Therefore, this review aims to describe all the main features of the applications of γδ T cells and provide a systematic view of current γδ T-cell immunotherapy. Specifically, this review will focus on how γδ T cells performed in treating cancers in clinics, on the γδ T-cell clinical trials that have been conducted to date, and the role of γδ T cells in the pharmaceutical industry.

IntroductionThe study aimed to explore the association of serum 25(OH)D3 and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and to determine whether the effect of vitamin D (VD) is mediated by activation of the peroxisome proliferator-activated receptor α (PPARα) pathway.MethodsThe study contained a case-control study, in vivo and in vitro experiments. A case-control study was conducted to compare serum parameters between NAFLD patients and controls and to evaluate the association of 25(OH)D3 and NAFLD. In vivo study, male Wistar rats were randomly divided into control and model groups, fed a standard chow diet and a high-fat diet (HFD), respectively, for 7 weeks to generate an NAFLD model. Then, the rats were treated with VD and a PPARα antagonist (MK886) for 7 weeks. Tissue and serum were collected and assessed by biochemical assays, morphological analysis, histological analysis, and western blot analysis. In vitro, HepG2 cells were incubated with oleic acid (OA) to induce steatosis, which was evaluated by staining. HepG2 cells were pretreated with MK886 followed by calcitriol treatment, and differences in lipid metabolism-related proteins were detected by western blot.ResultsNAFLD patients were characterized by impaired liver function, dyslipidemia, and insulin resistance. Serum 25(OH)D3 was negatively associated with alanine aminotransferase (ALT) in NAFLD. VD deficiency was a risk factor for patients with no advanced fibrosis. Adequate VD status (25(OH)D3 >20 ng/mL) had a protective effect in patients after adjustment for confounding variables. NAFLD rats showed hyperlipidemia with severe hepatic steatosis, systematic inflammation, and lower serum 25(OH)D3. VD treatment ameliorated hepatic steatosis both in NAFLD rats and OA-induced HepG2 cells. Further, MK886 inhibited the anti-steatosis effect of VD.ConclusionThe study revealed that an adequate VD level may act as a protective factor in NAFLD and that VD may alleviate hepatic steatosis via the PPARα signaling pathway.

IntroductionThis study aimed to investigate the feasibility of predicting progression-free survival (PFS) in breast cancer patients using pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) radiomics signature and clinical parameters.MethodsBreast cancer patients who underwent 18F-FDG PET/CT imaging before treatment from January 2012 to December 2020 were eligible for study inclusion. Eighty-seven patients were randomly divided into training (n = 61) and internal test sets (n = 26) and an additional 25 patients were used as the external validation set. Clinical parameters, including age, tumor size, molecularsubtype, clinical TNM stage, and laboratory findings were collected. Radiomics features were extracted from preoperative PET/CT images. Least absolute shrinkage and selection operators were applied to shrink feature size and build a predictive radiomics signature. Univariate and multivariate Cox proportional hazards models and Kaplan-Meier analysis were used to assess the association of rad-score and clinical parameter with PFS. Nomograms were constructed to visualize survival prediction. C-index and calibration curve were used to evaluate nomogram performance.ResultsEleven radiomics features were selected to generate rad-score. The clinical model comprised three parameters: clinical M stage, CA125, and pathological N stage. Rad-score and clinical-model were significantly associated with PFS in the training set (P< 0.01) but not the test set. The integrated clinical-radiomics (ICR) model was significantly associated with PFS in both the training and test sets (P< 0.01). The ICR model nomogram had a significantly higher C-index than the clinical model and rad-score in the training and test sets. The C-index of the ICR model in the external validation set was 0.754 (95% confidence interval, 0.726–0.812). PFS significantly differed between the low- and high-risk groups stratified by the nomogram (P = 0.009). The calibration curve indicated the ICR model provided the greatest clinical benefit.ConclusionThe ICR model, which combined clinical parameters and preoperative 18F-FDG PET/CT imaging, was able to independently predict PFS in breast cancer patients and was superior to the clinical model alone and rad-score alone.

The rapid emergence of highly transmissible SARS-CoV-2 variants poses serious threat to the efficacy of vaccines and neutralizing antibodies. Thus, there is an urgent need to develop new and effective inhibitors against SARS-CoV-2 and future outbreaks. Here, we have identified a series of glycopeptide antibiotics teicoplanin derivatives that bind to the SARS-CoV-2 spike (S) protein, interrupt its interaction with ACE2 receptor and selectively inhibit viral entry mediated by S protein. Computation modeling predicts that these compounds interact with the residues in the receptor binding domain. More importantly, these teicoplanin derivatives inhibit the entry of both pseudotyped SARS-CoV-2 Delta and Omicron variants. Our study demonstrates the feasibility of developing small molecule entry inhibitors by targeting the interaction of viral S protein and ACE2. Together, considering the proven safety and pharmacokinetics of teicoplanin as a glycopeptide antibiotic, the teicoplanin derivatives hold great promise of being repurposed as pan-SARS-CoV-2 inhibitors.

Abstract Background High tissue and blood eosinophils are linked to poor treatment outcome in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, the difference between the patients with different level of blood or tissue eosinophilia in relation to disease control is still lacking. Objectives This study aimed to characterize patients with CRSwNP with intensely high eosinophil level. Methods A retrospective study of CRSwNP patients underwent endoscopic sinus surgery was conducted. The patients were subdivided with various cut‐off values of blood and tissue eosinophils. Tissue eosinophils of ≥50% and 10%–20% were defined as intensely high tissue eosinophils (IH‐tissue‐eos) and high tissue eosinophils (H‐tissue‐eos), respectively. Blood eosinophils of ≥0.6 × 109/L and 0.2 × 109/L–0.3 × 109/L were defined as intensely high blood eosinophils (IH‐blood‐eos) and high blood eosinophils (H‐blood‐eos). Clinical characteristics, Lund‐Mackay score (LMS), and disease control status were compared between subgroups. Results A total of 302 patients were enrolled. There was a trend toward a higher rate of uncontrolled disease when the patients subdivided by blood eosinophil cut‐off values ranged from 0.1 × 109/L to 0.6 × 109/L. The controlled patients accounted for 27%, 36%, 22%, and 31%, and the uncontrolled patients 46%, 32%, 52%, and 31% of patients in IH‐tissue‐eos, H‐tissue‐eos, IH‐blood‐eos, and H‐blood‐eos subgroup, respectively. The percentages of patients in the three categories of control were not significantly different between IH‐tissue‐eos and H‐tissue‐eos subgroups. By contrast, the IH‐blood‐eos subgroup had higher percentages of current smoker and asthma, preoperative LMS and tissue eosinophil percentage, and showed a trend toward a higher rate of uncontrolled subjects compare with the H‐blood‐eos subgroup. Conclusion CRSwNP patients with IH‐blood‐eos (≥0.6 × 109/L) may be possibly associated with a poorer disease control than those with levels near the threshold of blood eosinophilia (0.2 × 109/L–0.3 × 109/L). Further larger, preferably prospective studies are needed to confirm this relationship. Level of Evidence: 4.

Abstract Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.

The Dahai Pb-Zn mining area is located in the northwestern Pb-Zn district in northeastern Yunnan Province in the Sichuan-Yunnan-Guizhou Pb-Zn metallogenic triangle (SYGT), east of the Xiaojiang fault. Numerous Pb-Zn deposits (spots) occur in clastic rocks in this area. In this study, the Maliping, Laoyingqing, and Jinniuchang Pb-Zn deposits, representative clastic rocks in the Dahai mining area, were selected as research objects. The results of H-O-S-Sr-Pb isotope analyses show that the three deposits mainly formed through the mixing of a basinal brine with a hydrothermal fluid derived from deep within the underlying (deformed) basement, and brines leached organic matter from wall rocks. The δ34S values range from −2.62–30.30‰. The S isotope results show two different sources of reduced S: one in the Laoyingqing deposit derived from the S reduction generated by the pyrolysis of sulfur-bearing organic matter in the carbonaceous slate of the Kunyang Group, and the second in the Maliping and Jinniuchang deposits derived from the S reduction generated by the thermochemical sulfur reduction (TSR) of seawater sulfate in the Lower Cambrian Yuhucun Formation and Sinian Dengying Formation. The Pb isotope results show that the Pb sources of the three deposits are derived from basement rocks (Kunyang Group) with a small portion derived from Devonian–Permian carbonate rocks and Dengying Formation dolomite, both of which have undergone homogenization during mineralization. The Sr content varied from 0.09629 to 0.2523 × 10−6, and the study shows that the main source of Sr is a mixture of ore-forming fluid flowing through basement rocks (Kunyang Group) and through sedimentary cover. However, most of the Sr in the Maliping deposit is derived from marine carbonate, and in the Laoyingqing deposit, it is provided by basement rocks (Kunyang Group). Based on a comparative study of the deposits, the Pb-Zn deposits in the clastic rocks of the Dahai mining area and the SYGT belong to the same metallogenic system and were formed under the same metallogenic geological background. Finally, a unified metallogenic model of the two types of fluid migration and mixed mineralization of the Pb-Zn deposit in clastic rocks of the Dahai mining area is proposed. The metallogenic model provides a basis for the study of the Pb-Zn metallogenic system and guidance for deep and peripheral prospecting in this area.

Magnesium (Mg) plays a crucial role in crop growth, but how Mg supply level affects root growth and nutrient absorption in vegetable crops with different genotypes has not been sufficiently investigated. In this study, the responses of tomato (Solanum lycopersicum L.) and cucumber (Cucumis sativus L.) crops to different levels of Mg supply were explored. Four levels of Mg treatment (i.e., 0.2, 1.0, 2.0, 3.0 mmol/L) were applied under hydroponic conditions, denoted as Mg0.2, Mg1, Mg2, and Mg3, respectively. The results showed that with increasing Mg levels, the plant biomass, root growth, and nutrient accumulation in both vegetable crops all increased until reaching their maximum values under the Mg2 treatment and then decreased. The total biomass per tomato plant of Mg2 treatment was 30.9%, 14.0%, and 14.0% higher than that of Mg0.2, Mg1, and Mg3 treatments, respectively, and greater increases were observed in cucumber plant biomass (by 54.3%, 17.4%, and 19.9%, respectively). Compared with the Mg0.2 treatment, the potassium (K) and calcium (Ca) contents in various plant parts of both crops remarkably decreased under the Mg3 treatment. This change was accompanied by prominently increased Mg contents in various plant parts and para-hydroxybenzoic acid and oxalic acid contents in root exudates. Irrespective of Mg level, plant biomass, root growth, nutrient accumulation, and root exudation of organic acids were all higher in tomato plants than in cucumber plants. Our findings indicate that excessive Mg supply promotes the roots to exude phenolic acids and hinders the plants from absorbing K and Ca in different genotypes of vegetable crops despite no effect on Mg absorption. A nutritional deficiency of Mg stimulates root exudation of organic acids and increases the types of exuded organic acids, which could facilitate plant adaption to Mg stress. In terms of root growth and nutrient absorption, tomato plants outperform cucumber plants under low and medium Mg levels, but the latter crop is more tolerant to Mg excess.

In order to achieve the effective computer recognition of the She ethnic clothing from different regions through the extraction of color features, this paper proposes a She ethnic clothing classification method based on the Flower Pollination Algorithm-optimized color feature fusion and Convolutional Neural Network (FPA-CNN). The method consists of three main steps: color feature fusion, FPA optimization, and CNN classification. In the first step, a color histogram and color moment features, which can represent regional differences in She ethnic clothing, are extracted. Subsequently, FPA is used to perform optimal weight fusion, obtaining an optimized ratio. Kernel principal component analysis is then applied to reduce the dimensionality of the fused features, and a CNN is constructed to classify the She ethnic clothing from different regions based on the reduced fused features. The results show that the FPA-CNN method can effectively classify the She ethnic clothing from different regions, achieving an average classification accuracy of 98.38%. Compared to SVM, BP, RNN, and RBF models, the proposed method improves the accuracy by 11.49%, 7.7%, 6.49%, and 3.92%, respectively. This research provides a reference and guidance for the effective recognition of clothing through the extraction of color features.

The axle box bearing is a crucial component of high-speed electric multiple units (EMU) and is exposed to harsh working conditions, making it susceptible to subsurface-induced rolling contact fatigue (RCF) under long-term alternating stress. The objective of this paper is to develop a damage-coupled elastic–plastic constitutive model that can accurately predict the RCF life of EMU axle box bearings made from AISI 52100 bearing steel. The total damage is divided into elastic damage related to the shear stress range and plastic damage associated with plastic deformation. Material parameters are determined based on experimental data from the literature, and validation is conducted to ensure the validity of the model. Finally, the RCF behavior of the EMU axle box bearing, including crack initiation, crack propagation, and spalling, is simulated, and reasonable results are obtained. This study provides valuable insights into the RCF behavior of EMU axle box bearings and contributes to the accurate prediction of the fatigue life.

Abstract Objectives To assess volumetric DCE-MRI radiomics nomogram in predicting response to neoadjuvant chemotherapy (nCT) in EC patients. Methods This retrospective analysis of a prospective study enrolled EC patients with stage cT1N + M0 or cT2-4aN0-3M0 who received DCE-MRI within 7 days before chemotherapy, followed by surgery. Response assessment was graded from 1 to 5 according to the tumor regression grade (TRG). Patients were stratified into responders (TRG1 + 2) and non-responders (TRG3 + 4 + 5). 72 radiomics features and vascular permeability parameters were extracted from DCE-MRI. The discriminating performance was assessed with ROC. Decision curve analysis (DCA) was used for comparing three different models. Results This cohort included 82 patients, and 72 tumor radiomics features and vascular permeability parameters acquired from DCE-MRI. mRMR and LASSO were performed to choose the optimized subset of radiomics features, and 3 features were selected to create the radiomics signature that were significantly associated with response (P

The plant UV-B photoreceptor UV RESISTANCE LOCUS 8 (UVR8) exists as a homodimer in its inactive ground state. Upon UV-B exposure, UVR8 monomerizes and interacts with a downstream key regulator, the CONSTITUTIVE PHOTOMORPHOGENIC 1/SUPPRESSOR OF PHYA (COP1/SPA) E3 ubiquitin ligase complex, to initiate UV-B signaling. Two WD40 proteins, REPRESSOR OF UV-B PHOTOMORPHOGENESIS 1 (RUP1) and RUP2 directly interact with monomeric UVR8 and facilitate UVR8 ground state reversion, completing the UVR8 photocycle. Here, we reconstituted the RUP-mediated UVR8 redimerization process in vitro and reported the structure of the RUP2-UVR8W285A complex (2.0 Å). RUP2 and UVR8W285A formed a heterodimer via two distinct interfaces, designated Interface 1 and 2. The previously characterized Interface 1 is found between the RUP2 WD40 domain and the UVR8 C27 subregion. The newly identified Interface 2 is formed through interactions between the RUP2 WD40 domain and the UVR8 core domain. Disruption of Interface 2 impaired UV-B induced photomorphogenic development in Arabidopsis thaliana. Further biochemical analysis indicated that both interfaces are important for RUP2-UVR8 interactions and RUP2-mediated facilitation of UVR8 redimerization. Our findings suggest that the two-interface-interaction mode is adopted by both RUP2 and COP1 when they interact with UVR8, marking a step forward in understanding the molecular basis that underpins the interactions between UVR8 and its photocycle regulators.

Abstract Background To evaluate the effect of the single energy metal artifact reduction (SEMAR) algorithm with a multidetector CT (MDCT) for knee tumor prostheses. Methods First, a phantom of knee tumor prosthesis underwent a MDCT scan. The raw data was reconstructed by iterative reconstruction (IR) alone and IR plus SEMAR. The mean value of the CT number and the image noise were measured around the prosthesis at the stem level and articular level. Second, 95 consecutive patients with knee tumor prostheses underwent MDCT scans. The raw data were also reconstructed by the two methods. Periprosthetic structures were selected at the similar two levels. Four radiologists visually graded the image quality on a scale from 0 to 5. Additionally, the readers also assessed the presence of prosthetic complication and tumor recurrence on a same scale. Results In the phantom, when the SEMAR was used, the CT numbers were closer to normal value and the noise of images using soft and sharper kernel were respectively reduced by up to 77.1% and 43.4% at the stem level, and by up to 82.2% and 64.5% at the articular level. The subjective scores increased 1 ~ 3 points and 1 ~ 4 points at the two levels, respectively. Prosthetic complications and tumor recurrence were diagnosed in 66 patients. And the SEMAR increased the diagnostic confidence of prosthetic complications and tumor recurrence (4 ~ 5 vs. 1 ~ 1.5). Conclusions The SEMAR algorithm can significantly reduce the metal artifacts and increase diagnostic confidence of prosthetic complications and tumor recurrence in patients with knee tumor prostheses.

Background: We describe the molecular epidemiology and resistance patterns of blaOXA-48 Klebsiella pneumoniae and Escherichia coli in Taiwan. Methods: In this multicenter surveillance study from January 2012 to August 2015, the identified blaOXA-48 Enterobacteriaceae isolates were subjected to antibiotics susceptibility testing. PCR method was used for detecting concomitant other beta-lactamases. Outer membrane porins were analyzed. Genetic relatedness and molecular epidemiology of the isolates were determined through pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Plasmid incompatibility was determined using PCR-based replicon typing. Results: Forty-three blaOXA-48 K. pneumoniae and two E. coli isolates were analyzed. The annual incidence of blaOXA-48 K. pneumoniae isolates from 2012 to 2015 were 0%, 1.1%, 2.4%, and 7.6%, respectively. Forty-three (95.5%) of 45 isolates were non-susceptible to broad-spectrum beta-lactams (ceftriaxone, ceftazidime, cefepime, piperacillin/tazobactam), Forty-two (93.3%) of the 45 isolates showed resistance against all tested carbapenems (imipenem, meropenem, doripenem, and ertapenem). Molecular characterization revealed that they co-produced at least one extended-spectrum beta-lactamases or AmpC beta-lactamases, with at least one outer membrane porin loss. Thirty-eight (88.3%) of the 43 K. pneumoniae isolates belonged to ST11. PFGE analysis of 43 K. pneumoniae isolates revealed dissemination of multiple clones. Six of the 12 tested K. pneumoniae representatives of different pulso-types belonged to IncA/C. Conclusion: Concomitant loss of porins and production of other beta-lactamases renders the blaOXA-48-producing isolates in Taiwan a high-level carbapenem resistance and broad resistance against many beta-lactam antibiotics. Following dissemination of multiple clones of blaOXA-48 K pneumoniae ST 11, a trend of increased blaOXA-48 prevalence was noted.

Abstract Background Melanoma is an extremely aggressive type of skin cancer and experiencing a expeditiously rising mortality in a current year. Exploring new potential prognostic biomarkers and therapeutic targets of melanoma are urgently needed. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma. Methods Gene expression data and corresponding clinical informations of melanoma patients as well as sequence data of normal controls are collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Quantitative real-time PCR (qRT-PCR) analysis was carried out to detect the RNA expression of IGF2BP3 in A375 cell line, melanoma tissues, and normal tissues. Western blot, cell proliferation, and migration assays were performed to assess the ability of IGF2BP3 in A375 cell line. Results Differently expressed m6A regulators between tumor samples and normal samples were analyzed. A three-gene prognostic signature including IGF2BP3, RBM15B, and METTL16 was constructed, and the risk score of this signature was identified to be an independent prognostic indicator for melanoma. In addition, IGF2BP3 was verified to promote melanoma cell proliferation and migration in vitro and associate with lymph node metastasis in clinical samples. Moreover, risk score and the expression of IGF2BP3 were positively associated with the infiltrating immune cells and these hub genes made excellent potential drug targets in melanoma. Conclusion We identified the genetic changes in m6A regulatory genes and constructed a three-gene risk signature with distinct prognostic value in melanoma. This research provided new insights into the epigenetic understanding of m6A regulators and novel therapeutic strategies in melanoma.

Measurement(s) venture capitalist • Affiliation Technology Type(s) digital curation Factor Type(s) year Sample Characteristic - Location China Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14811009

Summary: Oligodendrocyte spheroids (OL-spheroids) containing oligodendrocytes and neurons provide an accessible system to dissect demyelinating diseases and test therapeutic treatment. However, generation of human OL-spheroids is still technically challenging and time-consuming until now. Here, we presented evidence that overexpression of SOX10 and OLIG2 (SO) in human embryonic stem cells (hESCs)-derived ventral forebrain neural progenitors is sufficient to produce forebrain pre-oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) within 20–40 days. More importantly, optimizing this procedure by overexpression of SO in ventral forebrain spheroids, we successfully generated OL-spheroids with pre-OLs, mature OLs, and neurons 40 days after OL-induction. We further demonstrated oligodendrocyte-neuron interactions and obvious axon myelination in OL-spheroids. Finally, over 30% cells developed into mature oligodendrocytes with forebrain identity and myelinate axons in mouse brain 3 months after transplantation. This study provides a strategy to generate forebrain OL-spheroids rapidly and efficiently which would facilitate development of new therapeutics for demyelinating disorders.

Long-interspersed element 1 (LINE-1) is an autonomous non-LTR retrotransposon. Its replication can cause mutation and rearrangement of host genomic DNA, which may result in serious genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we reported that CCHC-type zinc-finger protein ZCCHC3 can repress LINE-1 retrotransposition, and this activity is closely related to its zinc-finger domain. Further studies show that ZCCHC3 can post-transcriptionally diminish the LINE-1 RNA level. The association of ZCCHC3 with both LINE-1 RNA and ORF1 suggests that ZCCHC3 interacts with LINE-1 RNP and consequently causes its RNA degradation. These data demonstrate collectively that ZCCHC3 contributes to the cellular control of LINE-1 replication.

BackgroundMen who have sex with men (MSM) are at high risk for HIV infection. Accurate estimation of the population size and monitoring the risk sexual behavioral change of MSM is of great importance to develop targeted HIV prevention and interventions. ObjectiveThe goal of the research was accurate estimation of the population size and monitoring the risk sexual behavioral change of MSM. MethodsStreet interception investigation methods were conducted among males aged 16 years and older in selected sites in Shenzhen in 2014 and 2019. A population survey was used to estimate the population size of MSM. Logistic regression analysis was applied to evaluate the difference in behavioral characteristics in MSM from 2014 to 2019. ResultsIn this study, we surveyed 10,170 participants in 2014, of whom 448 (4.41%, 95% CI 4.01%-4.80%) participants were men who have ever had sex with another man (MSMe) and 229 (2.25%, 95% CI 1.96%-2.54%) were men who had sex with another man in the previous 6 months (MSMa). A total of 10,226 participants were surveyed in 2019, of which 500 (4.90%, 95% CI 4.47%-5.31%) and 208 (2.03%, 95% CI 1.76%-2.31%) participants were MSMe and MSMa, respectively. The results showed that the population size of MSM who are active (MSMa) in Shenzhen was 155,469 (2.29%, 95% CI 2.28%-2.30%) in 2014 and 167,337 (2.05%, 95% CI 2.04%-2.06%) in 2019. It was estimated that there were about 12,005,445 (2.04%, 95% CI 2.04%-2.04%) MSMa in China in 2019. Compared with 2014, the MSMa in 2019 were more likely to seek sex partners through mobile phone apps and less likely to have male and female sex partners in addition to having inconsistent condom use and more than 6 sex partners in the previous 6 months. ConclusionsIn Shenzhen, the proportion of MSMa among the general male population was lower in 2019 than in 2014, and the prevalence of HIV risk behavior was reduced in 2019. Although the preferred platform to find male sex partners among MSM has changed, intervention with high–HIV risk MSM could still help to reduce HIV risk behaviors among the whole MSM group. Because MSM prefer to seek sex partners through mobile phone apps, further study is needed to strengthen internet interventions with high–HIV risk MSM to curb the spread of HIV.

Gastric cancer (GC) is the third-leading cause of cancer mortality worldwide. The aim of this study was to develop a nomogram that estimates 1-year, 3-year, and 5-year survival probability of GC patients after D2 gastrectomy combined with adjuvant chemotherapy. The results showed that median age is 58 (range: 18-85) years in the training cohort and 59 (range: 32-85) years in the validation cohort. On multivariate analysis, four factors were found to be significantly associated with worse overall survival (OS): late TNM stage, positive resection margin, preoperative carcinoembryonic antigen (CEA) level, and single chemotherapy regimens compared with multiple chemotherapy regimens. All of these findings were validated in the validation cohort. Furthermore, the four factors were included in the final nomogram for the prediction of 1-year, 3-year, and 5-year survival probability, with accurate calibration and reasonable discrimination (C-index = 0.676 for training cohort, and C-index = 0.664 for validation cohort). The AUC values analyzed by the ROC analysis demonstrated a good predictive accuracy of the nomogram for OS (1-year, 3-year, and 5-year OS were 94.43%, 77.42%, and 73.03% in the training cohort, respectively; 96.95%, 81.54%, and 73.41% in the validation cohort, respectively). In conclusion, the proposed nomogram may be used to objectively and accurately predict survival probability of GC patients in a multi-institutional clinical setting.

Autophagy-related genes have a vital effect on colorectal cancer (CRC) by affecting genomic stability and regulating immune responses. However, the associations between genetic variants in autophagy-related genes and CRC outcomes for chemotherapy therapy remain unclear. The Cox regression model was used to evaluate the associations between single-nucleotide polymorphisms (SNPs) in autophagy-related genes and overall survival (OS) and progression-free survival (PFS) of CRC patients. The results were corrected by the false discovery rate (FDR) correction. We used the logistic regression model to investigate the associations of SNPs with the disease control rate (DCR) of patients. Gene expression analysis was explored based on an in-house dataset and other databases. The associations between gene expression and infiltrating immune cells were evaluated using the Tumor Immune Estimation Resource (TIMER) database. We observed that ATG2B rs17094017 A > T was significantly associated with increased OS (HR = 0.65, 95% CI = 0.50-0.86, P = 2.54×10-3), PFS (HR = 0.76, 95% CI = 0.62-0.93, P = 7.34×10-3), and DCR (OR = 0.60, 95% CI = 0.37-0.96, P = 3.31×10-2) of CRC patients after chemotherapy. The expression of ATG2B was down-expressed in CRC tissues than in adjacent normal tissues. Moreover, ATG2B expression influenced the infiltration of CD8+ T cells, CD4+ T cells, B cells, and T cell receptor signaling pathways, which may inhibit the occurrence of CRC by affecting the immune system. This study suggests that genetic variants in the autophagy-related gene ATG2B play a critical role in predicting the prognosis of CRC prognosis undergoing chemotherapy.

Introduction The self-harm of young people can cause tremendous distress to their parents/carers and impair parents’ ability to provide care. At the same time, parents play an essential role in supporting their child during the management and treatment of self-harm. The synthesis of evidence about parental experiences and needs can inform mental health practice and the development of interventions to provide better care to young people who self-harm and their parents.Methods and analysis A comprehensive search will be conducted across several information sources, including multiple electronic databases (eg, PubMed, Embase, CINAHL, PsycINFO, ProQuest, CNKI, Wanfang, VIP and SinoMed), grey literature, the websites of specific organisations and hand-searched reference lists of all the relevant studies. Qualitative studies published in English or Chinese and focusing on the lived experiences of parents whose child self-harms will be included. Two reviewers will independently screen all the retrieved articles according to the flow diagram proposed by PRISMA (the Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Two independent reviewers will then appraise the methodological quality of all the included articles using the JBI (Joanna Briggs Institute) critical appraisal checklist for qualitative research. The meta-aggregation approach will be used to synthesise the findings of the included qualitative studies, and the level of confidence in the synthesised findings will be assessed using the Confidence in the Qualitative synthesised finding approach.Ethics and dissemination No additional ethical clearance is required since this review is a secondary analysis of published primary studies. The findings will be disseminated through publication in a peer-reviewed journal and conference presentations.PROSPERO registration number CRD42021265525.