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BackgroundDisheveled, EGL-10, and pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a component of GTPase-activating protein (GAP) activity toward the RAG complex 1 (GATOR1) protein, which is an inhibitor of the amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). With the wide application of whole exome sequencing (WES), more and more variations in DEPDC5 were uncovered in FFEVF families.MethodsA family with a proband diagnosed with familial focal epilepsy with variable foci (FFEVF) was involved in this study. Whole exome sequencing (WES) was performed in the proband, and Sanger sequencing was used to confirm the variation carrying status of the family members. Mini-gene splicing assay was performed to validate the effect on the alternative splicing of the variation.ResultsA novel variant, c.1217 + 2T>A, in DEPDC5 was identified by WES in the proband. This splicing variant that occurred at the 5′ end of intron 17 was confirmed by mini-gene splicing assays, which impacted alternative splicing and led to the inclusion of an intron fragment. The analysis of the transcribed mRNA sequence indicates that the translation of the protein is terminated prematurely, which is very likely to result in the loss of function of the protein and lead to the occurrence of FFEVF.ConclusionThe results suggest that c.1217 + 2T>A variations in DEPDC5 might be the genetic etiology for FFEVF in this pedigree. This finding expands the genotype spectrum of FFEVF and provides new etiological information for FFEVF.

Abstract Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Background and objectives: Strokes will result in decreased in cortical excitability and changed in the balance between the affected and unaffected hemispheres. Previous studies have focused on cortical changes in healthy subjects during swallowing, while they remain unknown in patients with stroke at different locations. Thus, the purpose of this study was to research cortical activation patterns of swallowing in patients with dysphagia and healthy subjects by the functional near-infrared spectroscopy (fNIRS). We also focus on the comparability of brain activation areas associated with swallowing between patients with different stroke locations and healthy subjects. Methods: total of 104 participants were invited to our study, involving 86 patients with dysphagic unilateral hemispheric stroke and 18 age and sex matched healthy controls. The stroke patients were categorized into patients with left unilateral stroke lesions (n = 30), patients with right unilateral stroke lesions (n = 32) and patients with brainstem injury (n = 24) according to different stroke sites. All patients underwent a series of clinical swallowing function assessments, such as the Fiberoptic endoscopic dysphagia severity scale (FEDSS), penetration-aspiration scale (PAS) of Rosenbek, the gugging swallowing screen (GUSS) and the functional oral Intake scale (FOIS) after informed consent has been signed. All participants received the fNIRS system assessment. Results: The results showed that extensive areas of the cerebral cortex activated during the swallowing tasks in healthy participants (P

Economic policy uncertainty (EPU) reduces energy consumption and the use of pollution intensive commodities, which not only relieves environmental degradation, but also hinders investment in renewable energy and R&D, and leading to environmental degradation. Geopolitical risks (GPRs) result in a sharp drop in economic growth and energy consumption, and hinder environmental degradation. In addition, they can bring about a decrease in R&D, innovation and renewable energy, and will further exacerbate environmental degradation. By using the monthly data from Jan. 2000 to Dec. 2017 of China, a five-variable time varying parameter stochastic volatility vector auto regression model (TVP-VAR) of EPU, GPRs, industrial added value growth rate, crude oil growth rate and ecological footprint (EFOOT) is established. According to the results of the model, the conclusions can be drawn as follows : (1) EFOOT has a positive feedback on EPU in short, medium and long term, marking the investment effect of EPU is greater than consumption effect. (2) EFOOT has a negative feedback on GPRs in short, medium and long term. (3) The utilization characterized by the growth rate of industrial added value and crude oil has a negative impact on EFOOT. It is worth noting with the steady improvement of China’s economy, the further improvement of economic strength and the high attention to environmental protection from 2015, the impact of EPU and GPRs on the EFOOT began to weaken.

Multiple primary malignant neoplasms (MPMNs) are defined as multiple tumors with different pathogenic origins. MPMNs are rare, but the morbidity rate is on the rise. With the development of anti-tumor treatments, such as targeted therapy and immunotherapy, the overall survival of cancer patients has been significantly prolonged, leading to an increased number of patients with MPMNs. A crucial aspect of MPMNs management is deciding how to schedule further treatments according to individual tumor risk. This process involves a multidisciplinary physician team to ensure favorable outcomes. Herein we report a 60-year-old male who developed four different malignancies, including esophageal squamous cell carcinoma, upper urinary tract urothelial carcinoma, mediastinal small cell lung cancer, and left lung squamous cell carcinoma over 20 years and received appropriate treatment of each cancer with long survival.

BackgroundThe most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), has a worse prognosis and a higher probability of relapse since there is a narrow range of treatment options. Identifying and testing potential therapeutic targets for the treatment of TNBC is of high priority.MethodsUsing a transcriptional signature of triple-negative breast cancer collected from Gene Expression Omnibus (GEO), CMap was utilized to reposition compounds for the treatment of TNBC. CCK8 and colony formation experiments were performed to detect the effect of the candidate drug on the proliferation of TNBC cells. Meanwhile, transwell and wound healing assay were implemented to detect cell metastasis change caused by the candidate drug. Moreover, the proteomic approach was presently ongoing to evaluate the underlying mechanism of the candidate drug in TNBC. Furthermore, drug affinity responsive target stability (DARTS) coupled with LC-MS/MS was carried out to explore the potential drug target candidate in TNBC cells.ResultsWe found that the most widely used medication, eugenol, reduced the growth and metastasis of TNBC cells. According to the underlying mechanism revealed by proteomics, eugenol could inhibit TNBC cell proliferation and metastasis via the NOD1-NF-κB signaling pathway. DARTS experiment further revealed that eugenol may bind to NF-κB in TNBC cells.ConcludesOur findings pointed out that eugenol was a potential candidate drug for the treatment of TNBC.

BackgroundAt present, the effect of Tai Chi (TC) on lower limb function in patients with Parkinson’s disease (PD) is controversial. Therefore, we conducted a meta-analysis on the influence of TC on lower limb function in PD patients.MethodsAccording to the PRISMA guidelines, seven databases were searched. Randomized controlled trials (RCTS) were selected and screened according to inclusion and exclusion criteria. We assessed the quality of the studies using the Cochrane Risk of Bias tool and then extracted the characteristics of the included studies. The random effect model was adopted, and heterogeneity was measured by I2 statistic.ResultsA total of 441 articles were screened, and 10 high-quality RCTs were with a total of 532 patients with PD met Our inclusion criteria. Meta-analysis showed that compared To control groups TC improved several outcomes. TC significantly improved motor function (SMD = −0.70; 95% CI = −0.95, −0.45; p

Holothurian glycosaminoglycan (hGAG) is extracted from the body wall of the sea cucumber, and previous studies have shown many unique bioactivities of hGAG, including antitumor, anti-angiogenesis, anti coagulation, anti thrombosis, anti-inflammation, antidiabetic effect, antivirus, and immune regulation. The effects of 3W and 5W molecular weights hGAG with hematoporphyrin derivative-photodynamic therapy (HPD-PDT) on lung cancer were investigated. Human lung adenocarcinoma A549 cells were divided into 6 groups: control group, 3W molecular weight hGAG group, 5W molecular weight hGAG group, HPD-PDT group, 3W molecular weight hGAG + HPD-PDT group, and 5W molecular weight hGAG + HPD-PDT group. Cell morphology was observed under inverted phase contrast microscope. Cell proliferative activity was detected by CCK8 and cell apoptosis was assayed by Hoechst33258 staining and flow cytometry. The results showed that two different molecular weights hGAG could inhibit proliferation, promote apoptosis rates of A549 cells, and enhance the sensitivity of A549 cells to HPD-PDT. The combined use of hGAG and HPD-PDT has synergistic inhibitory effects on A549 cells, and the effects of 3W molecular weight hGAG are better than that of 5W molecular weight hGAG.

To develop a short-term follow-up CT-based radiomics approach to predict response to immunotherapy in advanced non-small-cell lung cancer (NSCLC) and investigate the prognostic value of radiomics features in predicting progression-free survival (PFS) and overall survival (OS). We first retrospectively collected 224 advanced NSCLC patients from two centers, and divided them into a primary cohort and two validation cohorts respectively. Then, we processed CT scans with a series of image preprocessing techniques namely, tumor segmentation, image resampling, feature extraction and normalization. To select the optimal features, we applied the feature ranking with recursive feature elimination method. After resampling the training dataset with a synthetic minority oversampling technique, we applied the support vector machine classifier to build a machine-learning-based classification model to predict response to immunotherapy. Finally, we used Kaplan-Meier (KM) survival analysis method to evaluate prognostic value of rad-score generated by CT-radiomics model. In two validation cohorts, the delta-radiomics model significantly improved the area under receiver operating characteristic curve from 0.64 and 0.52 to 0.82 and 0.87, respectively (P

Abstract. The study was to investigate the clinical characteristics and significance of antinuclear antibody (ANA) cytoplasmic patterns in ANCA-associated vasculitis (AAV) from Southwest China. A retrospective study including 232 AAV patients from Peoples Hospital of Deyang City was performed. These included 115 patients with ANA cytoplasmic pattern as observation group and 117 patients without ANA cytoplasmic pattern as control group. Chest involvement (60.00 vs 46.15, P = .035), cardiovascular involvement (5.21 vs 29.91, P

BackgroundA number of publications have examined the relation between blood group and female infertility including ovarian reserve, recurrent miscarriage, and live birth. However, there is a lack of literature investigating joint mother/father ABO blood type in a large cohort. This study aimed to investigate the association between couple combinations for ABO blood groups and assisted reproductive technology (ART) outcomes in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodsThis retrospective cohort study included 30,717 couples who underwent IVF cycles between 2010 and 2019. The clinical outcomes of IVF treatment were the primary outcome. History of spontaneous miscarriage, embryo quality, and birth sex, weights, defects rate were also studied.ResultsThere was no difference in the baseline demographics between the blood type groups. There was a statistically significant positive association between the combination of female blood type AB and male blood type AB with biochemical pregnancy, clinical pregnancy, and live birth rate (OR 1.36; 95% CI, 1.05–1.78; P = 0.02 and OR 1.31; 95% CI, 1.0–1.68; P = 0.031 and OR 1.28; 95% CI, 1.01–1.63; P = 0.041 respectively). No statistically significant difference was observed between joint mother/father ABO blood types and high-quality embryo rate, early abortion rate, birth sex, birth weights, and birth defect rate.ConclusionsOur findings suggest that the success rate of IVF/ICSI cycles in parent mating AB blood type is higher than that in other blood type combination groups.

Background: The gut microbiota plays important roles in modulating host metabolism. Previous studies have demonstrated differences in the gut microbiome of T2D and prediabetic individuals compared to healthy individuals, with distinct disease-related microbial profiles being reported in groups of different age and ethnicity. However, confounding factors such as anti-diabetic medication hamper identification of the gut microbial changes in disease development. Method: We used a combination of in-depth metagenomics and metaproteomics analyses of faecal samples from treatment-naïve type 2 diabetic (TN-T2D, n = 77), pre-diabetic (Pre-DM, n = 80), and normal glucose tolerant (NGT, n = 97) individuals to investigate compositional and functional changes of the gut microbiota and the faecal content of microbial and host proteins in Pre-DM and treatment-naïve T2D individuals to elucidate possible host-microbial interplays characterizing different disease stages. Findings: We observed distinct differences characterizing the gut microbiota of these three groups and validated several key features in an independent TN-T2D cohort. We also demonstrated that the content of several human antimicrobial peptides and pancreatic enzymes differed in faecal samples between three groups. Interpretation: Our findings suggest a complex, disease stage-dependent interplay between the gut microbiota and the host and point to the value of metaproteomics to gain further insight into interplays between the gut microbiota and the host. Fund: The study was supported by the National Natural Science Foundation of China (No. 31601073), the National Key Research and Development Program of China (No. 2017YFC0909703) and the Shenzhen Municipal Government of China (No. JCYJ20170817145809215). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Keywords: Metagenomics, Metaproteomics, Prediabetes, Treatment-naïve type 2 diabetes

Background: Vascular dementia (VD), as the second-largest type of dementia, is a serious stage of vascular cognitive impairment. It is significant to conduct retrospective epidemiological studies to characterize further the disease for public health. This study estimated the prevalence of VD among the population aged 18 yr and older in China. Methods: Epidemiological investigations on VD published in journals and covering the period from 1999 to 2019 were identified manually and online by using Chinese databases (such as Chinese BioMedical Literature Database, Chinese National Knowledge Infrastructure database, Chinese science-technology databases, and the Chinese Wanfang and Chongqing VIP database) and English databases (such as PubMed, Elsevier Science Bibliographic Databases and Cochrane library). Studies were included if the diagnostic criteria for VD are clear and the quality of the included literature was evaluated using the quality evaluation criteria of epidemiological research methods. A random-effects model was employed according to the statistical test of homogeneity. Results: Twenty-six studies met the inclusion criteria, including 100,923 subjects and 977 VD patients. The pooled prevalence of VD was 0.96% (95% [confidence interval, CI] 0.63%~2.1%). The prevalence of VD increased with increasing age. There was a higher prevalence of VD in the northeast China population, in urban areas and males. Conclusion: We stratified the included studies based on age, location, gender, and geographical distribution for prevalence. The prevalence of VD has slowly risen since 1999. It is obviously different between the North & South and urban &rural districts. While there are many benefits of systematic reviews, the methods presented have inherent limitations.

Objective: To study the effect of therapeutic exercise on knee osteoarthritis after injection of botulinum toxin type A, hyaluronate or saline. Methods: Sixty participants with knee osteoarthritis were randomly assigned to 3 groups: injection of saline (control) (group A), botulinum toxin type A (group B), or hyaluronate (group C). All participants received therapeutic exercise. Western Ontario and McMaster Universities Osteoarthritis Index questionnaire score, visual analogue scale pain scale, and Medical Outcomes Study 36-item Health Survey were conducted at baseline, and at the end of the 4th and 8th weeks. Results: At end of the 4th and 8th weeks, the scores on the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire and visual analogue scale were higher in the control group. There were significant differences in Physical Component Summary-36 and Mental Component Summary-36 scores between the 3 groups (p

Eleven dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)naphthalene derivatives as anticancer agents through regulating cell autophagy were designed and synthesized. The anticancer activity results indicated that most compounds manifested obvious un-toxic effect on GES-1 and L-02 with IC50 from 0.58 to 1.41 mM. Among them, (S,Z)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 4-(3,4-dihydroisoquinolin-2(1 H)-yl)-4-oxobut-2-enoate (compound 4i) could induce cancer cells apoptosis. Further experiments showed that autophagy played an important role in the pro-apoptotic effect of this compound. Preliminary mechanism indicated that this compound could inhibit phosphoinositide 3-kinase/protein kinase B and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway by mediating apoptosis in an autophagy-dependent manner.

In recent years, with the rapid development of economy, China’s labor relations are constantly changing, and the demands of workers for interests are increasing. In addition, with the outbreak of COVID-19, enterprises are facing severe challenges under both external and internal pressure. In view of this, relying on AI technology and professional personnel, Wish Magic provides consultation and service of labor laws and regulations for people or enterprises in need of relevant help, mediates labor disputes and strives for legitimate interests through online AI keyword search and offline VIP face-to-face expert consultation.

Exploring labor rights on the cognition of relationship with labor dispute is not only from the direct role of workers and HR, but also from the fight for labor rights of college students. However, many labor disputes in labor process are mainly related to labor rights. Therefore, we explore the relationship between labor rights and labor disputes, use neural network analysis and questionnaire survey method, and execute AI combining with big data analysis tools to collect first-hand data from two aspects of college students, workers in the industry, HR and labor dispatch personnel. Finally, the results show that: (1) there is a negative correlation between social security and labor disputes; (2) there is a negative correlation between labor safety and labor disputes; (3) there is a negative correlation between wages and labor disputes; (4) there is a negative correlation between labor contract signing and labor disputes; (5) there is a positive correlation between rights awareness and labor disputes.

Interleukins are a group of immunomodulatory proteins that mediate a variety of immune reactions in the human body. To investigate the association between interleukin gene polymorphisms and recurrent pregnancy loss (RPL), we reviewed 21 studies from MEDLINE, EMBASE, OVID SP and PubMed to evaluate RPL-related interleukin gene polymorphisms. Meta-analysis was performed on 12 of the polymorphisms, and a review included the others. Our integrated results indicated that IL-1β (-511C/T) (P = 0.02, 95% CI 0.77[0.62,0.96]), IL-6 (-634C/G) (P

Objective: To investigate the different effects of lipopolysaccharide (LPS) mediating early and late activated THP-1 macrophages (Mφ) on ECV304 endothelial cell dysfunction: dysregulation of secretion of VEGF and proliferation, and migration of ECV304. Methods: The inflammatory Mφ was divided into early phase (2 h) group and late phase (24 h) group according the different exposure time to LPS. Then the inflammatory Mφ and ECV304 were co-cultured via transwell chambers in both non-contacting and contacting systems. The levels of VEGF were determined by ELISA, and the proliferation index and apoptosis of ECV304 were analyzed by FACSCalibur. The migration of ECV304 was tested by modified Boyden chamber assay. Results: The level of VEGF and the proliferation of ECV304 cell were increased more apparently in early-phase Mφ-treated group. But the proportion of early apoptotic and late apoptotic/necrotic cells in late-phase Mφ-treated group were higher than that of the former. Migration rate of ECV304 was enhanced in early-phase Mφ-treated group. All those effects were more significant in contacting system comparing with no-contacting system. Conclusion: Early-activated macrophages (mediated by LPS) could increase the secretion of VEGF and promote the proliferation and migration of ECV304; while the late-activated macrophages could promote/enhance the apoptosis of ECV304 more significant in contacting system when (it was) compared with no-contacting system.