Search

Previous studies have demonstrated that circST6GALNAC6 is a tumor suppressor in bladder cancer. However, the role of circST6GALNAC6 in ferroptosis remains unclear. In the current study, ferroptosis was induced in bladder cancer cells by erastin. Functional experiments showed that overexpression of circST6GALNAC6 promoted ferroptosis of bladder cancer cells in vitro and in vivo. Mechanistic studies revealed that circST6GALNAC6 bound to the N-terminus of small heat shock protein 1 (HSPB1) and thus blocked the erastin-induced phosphorylation of HSPB1 at the Ser-15 site, a phosphorylation site in the protective response to ferroptosis stress. In addition, protein kinase C inhibited circST6GALNAC6-induced ferroptosis by increasing the overall phosphorylation level of HSPB1, further demonstrating the role of phosphorylation activation of HSPB1 in resistance to ferroptosis. Finally, the involvement of the HSPB1/p38 MAPK pathway in the downstream signal transduction of circST6GALNAC6 in bladder cancer ferroptosis regulation was determined. The regulatory mechanism of ferroptosis sensitivity dependent on circST6GALNAC6 expression levels in bladder cancer was revealed as circRNA regulation of various protein functions. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by occupying the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Therefore, enhancing the expression of circST6GALNAC6 to promote ferroptosis or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity is of considerable importance to the development and application of ferroptosis intervention methods in bladder cancer.

Introduction. Thoracoscopic minimally invasive surgery is the main method for the treatment of lung cancer. The reduction of surgical trauma can effectively reduce the intraoperative and postoperative inflammatory reaction. The aim of the study is to compare the intraoperative and postoperative inflammatory reactions in patients with non-small-cell lung cancer (NSCLC) treated by single-port thoracoscopic surgery and three-port thoracoscopic surgery. Methods. A total of 68 NSCLC patients (stages I and II) of thoracoscopic surgery were selected and randomly divided into two groups where they received either single-port thoracoscopic surgery or three-port thoracoscopic surgery. Intraoperative and postoperative serum inflammatory markers (C-reactive protein, CRP; serum amyloid A protein, SAA; and interleukin 6, IL-6) were detected using the enzyme-linked immunosorbent assay. Results. The CRP level of the single-port group was significantly lower than that of the three-port group during surgery, the first day after surgery, and third day after surgery ( P < 0.05 ). The level of IL-6 in the single-port group was significantly lower than that in the three-port group during surgery on the first and third days after surgery ( P < 0.05 ). The level of SAA in the single-port group was also significantly lower than that in the three-port group on the first and third days after surgery ( P < 0.05 ). Conclusion. Compared with three-port thoracoscopic surgery, single-port thoracoscopic surgery could reduce the inflammatory response and improve the recovery of NSCLC patients. Single-port thoracoscopic surgery is worthy of further promotion in the current treatment field of NSCLC in terms of reducing intraoperative and postoperative inflammatory reactions.

Purpose The present study aimed to assess the feasibility, safety and accuracy of navigated spinopelvic fixation with focus on S2-alar-iliac screws (S2AIS) and tricortical S1 pedicle screw implantation with the use of high-resolution three-dimensional intraoperative imaging and real-time spinal navigation. Methods Patients undergoing navigated intraoperative CT-based spinopelvic stabilization between January 2016 and September 2019 were included. Pelvic fixation was achieved by implantation of S2AIS or iliac screws (IS). S1 screws were implanted with the goal of achieving tricortical purchase. In all cases, instrumentation was performed with real-time spinal navigation and intraoperative screw positioning was assessed using intraoperative computed tomography (iCT), cone-beam CT (CBCT) and robotic cone-beam CT (rCBCT). Screw accuracy was evaluated based on radiographic criteria. To identify predictors of complications, univariate analysis was performed. Results Overall, 52 patients (85%) received S2AIS and nine patients (15%) received IS instrumentation. Intraoperative imaging and spinal navigation were performed with iCT in 34 patients, CBCT in 21 patients and rCBCT in six patients. A total number of 10/128 (7.8%) iliac screws underwent successful intraoperative correction due to misalignment. Tricortical purchase was successfully accomplished in 58/110 (53%) of the S1 screws with a clear learning curve in the course of time. S2AIS implantation was associated with significantly fewer surgical side infection-associated surgeries. Conclusions Real-time navigation facilitated spinopelvic instrumentation with increasing accuracy of S2AIS and tricortical S1 screws. Intraoperative imaging by iCT, CBCT or rCBCT permitted screw assessment with the chance of direct navigated revision of misplaced iliac screws to avoid secondary screw revision surgery.

BackgroundCalcific aortic valve disease (CAVD) is the most frequent pathogeny of aortic valve replacement in developed countries. Iron deposits are found in the intraleaflet hemorrhage (IH) areas of calcific aortic valves. Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron overload-dependent excessive lipid peroxidation. In this research, we attempted to clarify the role of ferroptosis in CAVD.MethodsThe level of ferroptosis in tissue and valvular interstitial cells (VICs) was assessed by the contents of 4-HNE, NADPH, ROS, and GSH, lipid peroxidation and mitochondrial morphology. The levels of calcification, iron accumulation and Slc7a11 expression in surgical aortic valve specimens were detected by Alizarin red or Von Kossa, Perl’s blue and immunohistochemical staining. The osteogenic differentiation of VICs was assessed by PCR and western blot analyses. Furthermore, RNA sequencing was used to detect potential differentially expressed genes between normal and osteogenic medium-treated (OM-treated) VICs.ResultsOur experiments demonstrated that ferroptosis occurred in the IH areas of calcific aortic valves. We also found that Slc7a11 was expressed at low levels in OM-treated VICs and IH areas. Finally, we demonstrated that iron promoted Slc7a11-deficient VICs osteogenic differentiation by aggravating ferroptosis in vitro.ConclusionIn conclusion, iron promotes Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro, thereby accelerating the progression of aortic valve calcification.StatementStatements and opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the Editor(s), Society, or publisher, and the Editor(s), Society, and publisher disclaim any responsibility or liability for such material.Brief SummaryIn this work, two novel notions have been proposed. First, we reported that ferroptosis participated in the progression of CAVD. Second, this is the first cytology experiment of valvular interstitial cells (VICs) to clarify the mechanism by which intraleaflet hemorrhage aggravates calve calcification. This research provides new ideas and targets for alleviating the progression of CAVD, especially in patients who have calcified aortic valves without severe stenosis.

Granulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM. Improving the Ability of Diagnosis and Treatment of Difficult Diseases

Background The prevalence of Fabry disease (FD) in Chinese patients with hypertrophic cardiomyopathy (HCM) is unclear. We aimed to evaluate the prevalence, clinical characteristics, and outcomes of FD in Chinese patients with HCM. Methods Of 217 patients with HCM, FD probands were screened by next-generation sequencing at Fuwai Hospital. Medical data from α-galactosidase A activity, electrocardiography, echocardiography, coronary angiography, cardiac magnetic resonance, pathological examination, and follow up was analyzed. Results Two FD probands were observed (0.93% of patients with HCM), both of which were diagnosed with symptomatic obstructive HCM at 49 years of age. One proband had a GLA mutation (c.887T>C [p.M296T]) with a late-onset cardiac variant, which was characterized by dual ventricular hypertrophy and conduction disease with a permanent pacemaker. The other patient had a GLA mutation (c.758T>C [p.I253T]) with a classic phenotype and dual ventricular hypertrophy, atrioventricular block, renal failure, and recurrent cerebral infarction. Both probands had late gadolinium enhancement mainly in the basal segment of the inferolateral wall. Follow up revealed no exertional symptoms or outflow obstruction after surgical septal myectomy in the two probands, and stable renal function was observed after 6 months of migalastat therapy in the later one. A family study revealed six female carriers and three sudden cardiac deaths. Conclusions FD is not uncommon in Chinese patients with HCM. Multiple organic involvement, dual ventricular hypertrophy, and conduction disease provide clinical clues for suspected FD, and early genetic screening is necessary. Surgical septal myectomy and migalastat improve the long-term prognosis of patients with FD.

Zulipikaer Abudureheman,1,&ast; Li Li,2,&ast; XueMei Zhong,2,&ast; JingRan Xu,2 Hui Gong,1 Subinuer Yilamujiang,1 Jie Ren,2 ChengXin Xie,2 AiFang Zheng,2 Dilala Tuerxun,2 Ayiguzali Abudukadeer,2 Paierda Aini,2 AiMin Xu,3 XiaoGuang Zou2 1Department of Clinical Research Center of Infectious Diseases (Pulmonary Tuberculosis), First People’s Hospital of Kashi, Kashi, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, First People’s Hospital of Kashi, Kashi, People’s Republic of China; 3Department of Clinical Laboratory, First People’s Hospital of Kashi, Kashi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: AiMin Xu; XiaoGuang Zou Email 519202069@qq.com; ZXGKS11@yeah.netBackground: Kashi city is situated near the Taklamakan desert and has a high incidence rate of chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the relationship between the SNP of the SREK1 gene locus rs74794265 and the susceptibility to COPD among the Uyghur population in Kashi, XinJiang, China.Methods: A total of 541 patients with COPD and 534 control subjects were included in this study. Sanger sequencing was used to analyze the SNP of the SREK1 gene locus rs74794265 site. The distribution of genotypes in different genetic models between the case and control group were analyzed by logistic regression analysis after adjusting for age, sex, and smoking history.Results: The SREK1 gene SNP locus rs74794265 included two genotypes, namely, C/C and C/T, of which C/C was the wildtype; The risk of COPD was significantly lower in patients with heterozygous C/T in rs74794265 [p=0.0236, OR=0.3677 (0.1547– 0.8742)], and the allele frequency of T was also significantly lower in the patient group [p=0.0245, OR=0.3728 (0.1577– 0.8811)]. The heterozygous C/T of rs74794265 among non-smoking COPD patients was significantly lower than other COPD patients [p=0.0298, OR=0.3217 (0.1156– 0.8949)], and there was no significant correlation of the heterozygous C/T genotype in smokers.Conclusion: We found that the rs74794265 heterozygous C/T genotype significantly reduces the risk of COPD. The C/T genotype is likely a protective factor for COPD in the Kashi region. We speculate that the occurrence of COPD in this area is probably more related to desert climate condition and genetic factors than smoking status.Keywords: COPD, SREK1 gene polymorphism, rs74794265 locus, Uyghur population

BACKGROUND: Vertebral artery stenosis (narrowing of the vertebral artery) is an important cause of posterior circulation ischaemic stroke. Medical treatment (MT) e.g. controlling risk‐factors and drug treatment, surgery, and endovascular treatment (ET) are the prevailing treatment strategies for symptomatic vertebral artery stenosis. ET consist s of percutaneous transluminal angioplasty (balloon catheter through the skin), with or without stenting. However, optimal management of people with symptomatic vertebral artery stenosis has not yet been established. OBJECTIVES: To assess the safety and efficacy of percutaneous transluminal angioplasty, with or without stenting, combined with MT, compared to MT alone, in people with episodes of cerebral ischaemia due to vertebral artery stenosis. SEARCH METHODS: We searched the Cochrane Stroke Group, MEDLINE, Embase, BIOSIS, and two other indexes in Web of Science, China Biological Medicine Database, Chinese Science and Technique Journals Database, China National Knowledge Infrastructure and Wanfang Data, as well as ClinicalTrials.gov trials register and the World Health Organization (WHO) International Clinical Trials Registry Platform to 23 July 2021. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared ET plus MT with MT alone in treating people aged 18 years or over with symptomatic vertebral artery stenosis. We included all types of ET modalities (e.g. angioplasty alone, balloon‐mounted stenting, and angioplasty followed by placement of a self‐expanding stent). MT included risk factor control, antiplatelet therapy, lipid‐lowering therapy, and individualised management for people with hypertension or diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened potentially eligible studies, extracted data, and assessed trial quality and risk of bias. We applied the GRADE approach to assess the certainty of evidence. The primary outcomes were 30‐day post‐randomisation death/stroke (short‐term outcome) and fatal/non‐fatal stroke after 30 days post‐randomisation to completion of follow‐up (long‐term outcome). MAIN RESULTS: We included three RCTs with 349 participants with symptomatic vertebral artery stenosis with a mean age of 64.4 years. The included RCTs were at low risk of bias overall. However, all included studies had a high risk of performance bias because blinding of the ET was not feasible. There was no significant difference in 30‐day post‐randomisation deaths/strokes between ET plus MT and MT alone (risk ratio (RR) 2.33, 95% confidence interval (CI) 0.77 to 7.07; 3 studies, 349 participants; low‐certainty evidence). There were no significant differences between ET plus MT and MT alone in fatal/non‐fatal strokes in the territory of the treated vertebral artery stenosis after 30 days post‐randomisation to completion of follow‐up (RR 0.51, 95% CI 0.26 to 1.01; 3 studies, 349 participants; moderate‐certainty evidence), ischaemic or haemorrhagic stroke during the entire follow‐up period (RR 0.77, 95% CI 0.44 to 1.32; 3 studies, 349 participants; moderate‐certainty evidence), death during the entire follow‐up period (RR 0.78, 95% CI 0.37 to 1.62; 3 studies, 349 participants; low‐certainty evidence), and stroke or transient ischaemic attack (TIA) during the entire follow‐up period (RR 0.65, 95% CI 0.39 to 1.06; 2 studies, 234 participants; moderate‐certainty evidence). AUTHORS' CONCLUSIONS: This Cochrane Review provides low‐ to moderate‐certainty evidence indicating that there are no significant differences in either short‐ or long‐term risks of stroke, death, or TIA between people with symptomatic vertebral artery stenosis treated with ET plus MT and those treated with MT alone.

Carotid endarterectomy (CEA) has been the standard therapy for carotid artery stenosis (CAS). Modified eversion carotid endarterectomy (mECEA) was recently introduced to treat CAS. However, the short-term safety and long-term efficacy of mECEA are still controversial among studies. This systematic review aims to summarize the current literatures about safety and efficacy of mECEA in treating CAS.A systematic review of mECEA was conducted in the main bibliographic databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Clinical studies on the safety and efficacy of mECEA in treating CAS with clinical results of transient ischemic attack (TIA), stroke, death, and restenosis were included.The initial search and screening found 15 references from the main databases, and 7 studies were finally included after full-text article assessment, which consisted of 3 single-arm studies and 4 comparative studies. The risks of postoperative complications including TIA, stroke, myocardial infarction (MI), and death ranged from 1.1% to 2%, 0% to 2.5%, 0% to 4.4%, and 0% to 2.32%, respectively. The mECEA was significantly related to lower risk of carotid artery occlusion, incision numbness, and shorter lengths of stay in hospital and average scar when separately compared with conventional CEA (cCEA), CEA with patch closure (pCEA), and eversion CEA (eCEA).The mECEA is a promising surgical option for CAS with acceptable clinical outcomes. In order to prove its safety and efficacy, future practices need to be conducted by more medical workers in more large-scale trials.

Objectives We apply a general case replacement framework for quantifying the robustness of causal inferences to characterize the uncertainty of findings from clinical trials. Study design and setting We express the robustness of inferences as the amount of data that must be replaced to change the conclusion and relate this to the fragility of trial results used for dichotomous outcomes. We illustrate our approach in the context of an RCT of hydroxychloroquine on pneumonia in COVID-19 patients and a cumulative meta-analysis of the effect of antihypertensive treatments on stroke. Results We developed the Robustness of an Inference to Replacement (RIR), which quantifies how many treatment cases with positive outcomes would have to be replaced with hypothetical patients who did not receive a treatment to change an inference. The RIR addresses known limitations of the Fragility Index by accounting for the observed rates of outcomes. It can be used for varying thresholds for inference, including clinical importance. Conclusion Because the RIR expresses uncertainty in terms of patient experiences, it is more relatable to stakeholders than P-values alone. It helps identify when results are statistically significant, but conclusions are not robust, while considering the rareness of events in the underlying data.

Objectives To evaluate the oncologic and functional results of scapular reconstruction after partial or total scapulectomy for chondrosarcoma. Materials and methods Twenty-one patients with chondrosarcoma who underwent partial or total scapulectomy between January 2005 and July 2019 were reviewed retrospectively. Results At a mean follow-up of 62.6 months (range, 13–123 months), four patients developed local recurrence, and three developed distant metastases, one of which developed both recurrence and metastasis. The overall survival rate of patients at 5 years was 84.6%, the disease-free survival rate was 69.3%, and the complication rate was 19% (4/21). The 1993 American Musculoskeletal Tumor Society (MSTS93) scores of patients in the partial scapulectomy group, total scapulectomy + humeral suspension group and prosthetic reconstruction group were 26.50 ± 1.38, 19.00 ± 2.58, and 21.38 ± 2.62, respectively. There was a statistically significant difference between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group ( P = 0.006 and 0.0336, respectively). The range of motion of the shoulder joint for forward flexion was 80.83° ± 11.14°, 51.25° ± 21.36°, and 52.50° ± 11.02°, respectively. The p-values for the comparison between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group were 0.0493 and 0.0174, respectively. And the range of motion of abduction was 75.00° ± 10.49°, 32.50° ± 11.90°, 41.88° ± 11.63°, respectively. Patients in the partial scapulectomy group had significantly better postoperative shoulder abduction function than the total scapulectomy + humeral suspension or prosthetic reconstruction group (P = 0.0035 and 0.0304, respectively). There was no significant difference in MSTS93 scores and flexion and abduction function of the shoulder joint in the upper extremity after total scapulectomy with humeral suspension or prosthetic reconstruction (P > 0.05). Conclusions Surgical treatment of chondrosarcoma of the scapula can achieve a satisfactory prognosis and shoulder function. Total scapulectomy followed by prosthetic reconstruction or humeral suspension are both feasible treatments.

During viral infection, sensing of viral RNA by retinoic acid–inducible gene-I–like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O -linked β-d- N -acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus–triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.

PURPOSE: We aimed (1) to determine the molecular diagnosis rate and the recurrent causative genes of patients with non-obstructive azoospermia (NOA) using targeted next-generation sequencing (NGS) panel screening and (2) to discuss whether these genes help in the prognosis for microsurgical testicular sperm extraction (micro-TESE). METHODS: We used NGS panels to screen 668 Chinese men with NOA. Micro-TESE outcomes for six patients with pathogenic mutations were followed up. Functional assays were performed for two NR5A1 variants identified: p.I224V and p.R281C. RESULTS: Targeted NGS panel sequencing could explain 4/189 (2.1% by panel 1) or 10/479 (2.1% by panel 2) of the patients with NOA after exclusion of karyotype abnormalities and Y chromosome microdeletions. Almost all mutations detected were newly described except for NR5A1 p.R281C and TEX11 p.M156V. Two missense NR5A1 mutations—p.R281C and p.I244V—were proved to be deleterious by in vitro functional assays. Mutations in TEX11, TEX14, and NR5A1 genes are recurrent causes of NOA, but each gene explains only a very small percentage (less than 4/668; 0.6%). Only the patient with NR5A1 mutations produced viable spermatozoa through micro-TESE, but other patients with TEX11 and TEX14 had poor micro-TESE prognoses. CONCLUSIONS: A targeted NGS panel is a feasible diagnostic method for patients with NOA. Because each gene implicated explains only a small proportion of such cases, more genes should be included to further increase the diagnostic rate. Considering previous reports, we suggest that only a few genes that are directly linked to meiosis can indicate poor micro-TESE prognosis, such as TEX11, TEX14, and SYCE1. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02154-9.

Protein ubiquitination has been reported to be involved in many biological processes that affect cancer cell growth or death. In this study, we identified differentially expressed E3s/DUB-related genes associated with the prognosis of lung adenocarcinoma and then constructed an E3s/DUB enzyme signature prediction model for the training group and validated its accuracy for prognosis prediction in the validation group. According to our constructed model, all patients were divided into the high- or low-risk group, and a comparison of the two groups revealed that the high-risk group had poorer survival and higher mortality than the low-risk group. The calculated risk score was also an independent prognostic factor when analyzed together with other clinical factors. To explore the functions of the signature genes, we predicted the substrate proteins with which they interact and then performed enrichment analysis. Interestingly, we found that the signature genes were enriched in multiple treatment resistance and immune-related pathways. Therefore, we continued to analyze immune infiltration in the samples and found a variety of differences in immune cell infiltration. According to our constructed model, these differences in immune cell infiltration may predict different immune statuses after grouping and are associated with worse prognosis in high-risk patients.

Rationale: Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Methods: Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Results: Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Conclusion: Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.

Herein, a series of novel

Macroautophagy/autophagy is a conserved lysosome-dependent metabolic recycling pathway. ULK1 plays an essential role in autophagy initiation through a complex formed with ATG13, RB1CC1/FIP200, and ATG101 in mammalian cells. However, while autophagy is triggered by nutrient starvation where it is essential for cell survival, such conditions lead to the rapid degradation of ULK1, indicating that autophagy must be tightly controlled. Nevertheless, the precise mechanisms regulating the ULK1 complex are still largely unknown. Here we reveal the critical roles played by two novel ULK1 complex binding proteins in autophagy regulation, TRIM27 and STK38L. We show that basal autophagy is maintained through TRIM27-mediated ubiquitination and proteasomal degradation of ULK1, whereas under starvation conditions, excessive autophagy is restrained by the combined actions of TRIM27 and STK38L. TRIM27 ubiquitinates and activates STK38L which in turn phosphorylates ULK1, delivering ULK1 in a permissive state for hyper-ubiquitination by TRIM27. Thus, TRIM27 and STK38L kinase act in concert as a rheostat to control ULK1 levels. We further demonstrate increased basal autophagy inlt;igt;trim27lt;/igt; knockout mice and establish physiological relevance in the context of breast cancer. Our study highlights the STK38L-TRIM27-ULK1 axis as a potential treatment avenue to explore for activating autophagy in various disease states.

Uncontrolled epithelial cell proliferation in the prostate transition zone and the hyper-accumulation of mesenchymal-like cells derived from the epithelial-mesenchymal transition (EMT) of prostatic epithelium are two key processes in benign prostatic hyperplasia (BPH). m

Lung diseases, such as asthma, chronic obstructive pulmonary diseases (COPD), and cystic fibrosis (CF), are among the leading causes of mortality and morbidity globally. They contribute to substantial economic burdens on society and individuals. Currently, only a few treatments are available to slow the development and progression of these diseases. Thus, there is an urgent unmet need to develop effective therapies to improve quality of life and limit healthcare costs. An increasing body of clinical and experimental evidence suggests that altered zinc and its regulatory protein levels in the systemic circulation and in the lungs are associated with these disease’s development and progression. Zinc plays a crucial role in human enzyme activity, making it an essential trace element. As a cofactor in metalloenzymes and metalloproteins, zinc involves a wide range of biological processes, such as gene transcription, translation, phagocytosis, and immunoglobulin and cytokine production in both health and disease. Zinc has gained considerable interest in these lung diseases because of its anti-inflammatory, antioxidant, immune, and metabolic modulatory properties. Here we highlight the role and mechanisms of zinc in the pathogenesis of asthma, COPD, CF, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, and pulmonary hypertension.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, and its abnormal metabolism affects the survival and prognosis of patients. Recent studies have found that NAD(P)H quinone oxidoreductase-1 (NQO1) played an important role in tumor metabolism and malignant progression. However, the molecular mechanisms by which NQO1 regulates lipid metabolism during HCC progression remain unclear. In this study, bioinformatics analysis and immunohistochemical results showed that NQO1 was highly expressed in HCC tissues and its high expression was closely related to the poor prognosis of HCC patients. Overexpression of NQO1 promoted the cell proliferation, epithelial-to-mesenchymal transition (EMT) process, and angiogenesis of HCC cells. Luciferase reporter assay further revealed that NQO1/p53 could induce the transcriptional activity of SREBP1, consequently regulating HCC progression through lipid anabolism. In addition, Snail protein was stabilized by NQO1/p53/SREBP1 axis and triggered the EMT process, and participated in the regulatory role of NQO1/p53/SREBP1 axis in HCC. Together, these data indicated that NQO1/SREBP1 axis promoted the progression and metastasis of HCC, and might be a potential therapeutic target for HCC.

Background Somatosensory deficits and abnormal pain sensitivity are highly prevalent among stroke survivors, which negatively impacts their quality of life and recovery process. However, the factors for pressure pain threshold (PPT) and somatosensory abnormalities in post-stroke elderly remain unknown. The aim of this study was to explore the effects of age, side and other functional conditions, such as spasticity and motor functions, on PPT and sensory abnormalities among elderly after stroke. Methods The cross-sectional study finally included 43 post-stroke elderly aged over 60 and assessed the PPT of 14 bilateral muscles widely located in the whole body by using a digital force gage. Meanwhile, spasticity, motor function, joint pain and activity of daily living (ADL) were evaluated by the Modified Ashworth scale, Fugl-Meyer, and Barthel Index, respectively. All participants were divided into higher-aged and lower-aged groups based on the median age of all of them. Results Higher age tended to be associated with higher sensitivity but not significant except for one upper limb muscle, and the affected side showed significantly higher PPTs than the unaffected side in three out of seven muscles (p p p Conclusions The age and side differences of mechanical pain sensitivity were found among post-stroke elderly. Older patients show higher sensitivity in both sides compared with the younger ones, and the affected side of the elder shows more somatosensory abnormalities, particularly hypoalgesia, than that of the younger ones. Post-stroke elderly in good functional conditions, such as normal muscle tone, better physical function and daily activities, and less joint pain, seems to have more equal pain sensitivity between both sides than those in poor conditions.

Background This study sought to define the risk factors for lymph node metastasis (LNM) of soft tissue sarcomas (STS) of the head, neck, and extremities, and the clinical significance of negative lymph node dissection (NLND). Methods STS patient data in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015 were extracted and pooled. Logistics regression analysis was used to identify risk factors for LNM, Cox proportional hazards and Fine–Grey’s models were used for survival analysis, and Propensity score matching analysis (PSM) was used to assess the impact of NLND on patient prognosis. Results A total of 3276 patients were enrolled in the study, of whom 283 (8.6%) developed LNM. Rhabdomyosarcoma had the highest rate of LNM (25.3%), followed by clear cell sarcoma (16.8%) and epithelioid sarcoma (12.4%), while leiomyosarcoma had the lowest rate of LNM (1.3%). Sex, tumor size, grade, histology, and site were significantly associated with LNM. For specific histologic subtypes of STS, NLND significantly improves overall survival (HR: 0.718, 95%CI 0.535–0.962; P = 0.026) and cancer-specific survival (HR: 0.699, 95%CI 0.506–0.967; P = 0.031) and reduces cancer-specific mortality (Gray’s test, P = 0.017). However, NLND did not improve overall survival (P = 0.46) or reduce cancer-specific mortality (Gray’s test, P = 0.772) of patients with leiomyosarcoma. Conclusions Histology is an independent risk factor for LNM in STS of the head, neck, and extremities. Prophylactic NLND treatment was necessary and had a clinical benefit for patients with STS who were at high risk for LNM but had no significant impact on the prognosis of patients with leiomyosarcoma.

Objective:In the USA, community-based food pantries provide free groceries to people struggling with food insecurity. Many pantries obtain food from regional food banks using an online shopping platform. A food bank introduced a visible nutrition rank (i.e. green, yellow or red) onto its platform. The hypothesis was that pantry orders would increase for the healthiest options (green) and decrease for the least healthy options (red).Design:Interrupted time series (ITS) analysis of a natural experiment. Monthly data included nutrition ranks of available inventory and itemised records of all products ordered during the 15-month baseline period and 14-month intervention.Setting:A New England food bank.Participants:The twenty-five largest food pantries in the network based on pounds of food ordered.Results:Descriptive analyses of 63 922 pantry ordering records before and after the visible ranks identified an increase in the proportion of green items ordered (39·3–45·4 %) and a decrease in the proportion of red items ordered (10·5–5·1 %). ITS analyses controlling for monthly changes in inventory available and pantry variables indicated that average monthly orders of green items increased by 1286 pounds (P < 0·001) and red orders decreased by 631 pounds (P = 0·045). Among the largest changes were increases in orders of fresh produce, brown rice, low-fat dairy and low-fat meats and decreases in orders of sugary juice drinks, canned fruit with added sugar, higher fat dairy and higher fat meats.Conclusions:This promising practice can support system-wide efforts to promote healthier foods within the food banking network.

Background:. Sleep disorders are common but under-researched symptoms in patients with multiple system atrophy (MSA). We investigated the frequency and factors associated with sleep-related symptoms in patients with MSA and the impact of sleep disturbances on disease severity. Methods:. This cross-sectional study involved 165 patients with MSA. Three sleep-related symptoms, namely Parkinson's disease (PD)-related sleep problems (PD-SP), excessive daytime sleepiness (EDS), and rapid eye movement sleep behavior disorder (RBD), were evaluated using the PD Sleep Scale-2 (PDSS-2), Epworth Sleepiness Scale (ESS), and RBD Screening Questionnaire (RBDSQ), respectively. Disease severity was evaluated using the Unified MSA Rating Scale (UMSARS). Results:. The frequency of PD-SP (PDSS-2 score of ≥18), EDS (ESS score of ≥10), and RBD (RBDSQ score of ≥5) in patients with MSA was 18.8%, 27.3%, and 49.7%, respectively. The frequency of coexistence of all three sleep-related symptoms was 7.3%. Compared with the cerebellar subtype of MSA (MSA-C), the parkinsonism subtype of MSA (MSA-P) was associated with a higher frequency of PD-SP and EDS, but not of RBD. Binary logistic regression revealed that the MSA-P subtype, a higher total UMSARS score, and anxiety were associated with PD-SP; that male sex, a higher total UMSARS score, the MSA-P subtype, and fatigue were associated with EDS; and that male sex, a higher total UMSARS score, and autonomic onset were associated with RBD in patients with MSA. Stepwise linear regression showed that the number of sleep-related symptoms (PD-SP, EDS, and RBD), disease duration, depression, fatigue, and total Montreal Cognitive Assessment score were predictors of disease severity in patients with MSA. Conclusions:. Sleep-related disorders were associated with both MSA subtypes and the severity of disease in patients with MSA, indicating that sleep disorders may reflect the distribution and degree of dopaminergic/non-dopaminergic neuron degeneration in MSA.

This systematic review and meta-analysis summarized the current literature to compare the safety and efficacy between first-pass effect (FPE) and multiple-pass effect (MPE) for thrombectomy in treatment of acute ischemic stroke (AIS). Major databases were searched for studies which reported clinical outcomes regarding successful or complete recanalization after first pass of mechanical thrombectomy in AIS. The assessment of bias was performed using different scales. I2 statistic was used to evaluate heterogeneity between reviewers. Subgroup, meta-regression, and sensitivity analyses were conducted to explore the source of heterogeneity. Visualization of funnel plots was used to evaluate publication bias. A total of 9 studies were eligible for final analysis. For successful recanalization (mTICI 2b-3), favorable outcomes were seen in 49.7% (95% confidence interval (CI): 40.5–58.9%) and 34.7% (95% CI: 26.8–42.7%) of FPE and MPE patients, respectively. Mortality at 3 months was 13.8% (95% CI: 10.8–16.9%) and 26.0% (95% CI: 17.7–34.2%), respectively. For complete recanalization (mTICI 2c-3), proportion of favorable outcomes were 62.7% (95% CI: 51.2–74.2%) and 47.7% (95% CI: 37.4–58.0%) in FPE and MPE; mortality was seen in 11.5% (95% CI: 4.9–18.2%) and 17.0% (95% CI: 5.2–28.7%), respectively. For AIS with successful recanalization, FPE had more favorable outcome (odds ratio (OR): 1.85, 95% CI: 1.48–2.30; p

Objective To characterize the inferior adrenal artery (IAA) pulsatility index (PI) in intrauterine growth–restricted (IUGR) fetuses without brain sparing. Methods Twenty-three IUGR fetuses with a normal Doppler cerebroplacental ratio (CPR) and 23 normal controls were included in this prospective cross-sectional study. The PI of the IAA was recorded using routine transabdominal Doppler ultrasound. The differences in Doppler characteristics, perinatal outcomes, and steroidogenesis in the umbilical vein at birth (adrenocorticotropic hormone [ACTH] and cortisol [F] levels) were compared between the 2 groups. The correlations between IAA-PI and steroidogenesis were assessed in the IUGR group. Results IAA-PI was significantly lower in IUGR fetuses than in normal controls (0.85 vs 1.18 at first scan, 0.78 vs 0.92 at last scan; both P < 0.001). The plasma F and ACTH levels in IUGR cases were significantly higher than those of the normal controls (18.2 vs 12.4 µg/dL and 280.5 vs 125.6 pg/mL for F and ACTH, respectively; both P < 0.001). There were negative correlations between IAA-PI and plasma F values and between IAA-PI and ACTH values in the IUGR group (r = −0.774 and −0.82 at first scan, r = −0.525 and −0.45 at last scan, respectively; P < 0.001). Conclusion Increased adrenal gland blood flow with concomitant increases in ACTH and F levels were observed in IUGR fetuses. IAA-PI is useful to assess early blood redistribution and may be beneficial for evaluating the steroidogenic response in high-risk pregnancies.

Backgroud To evaluate the relationship between omentin-1 and benign prostatic hyperplasia (BPH). BPH is the most common urological disease in elderly men worldwide. Lower serum omentin-1 levels were reported to be negatively associated with the incidence of inflammation, diabetes, obesity and metabolic syndrome, which all play a role in the development of BPH. To the best of our knowledge, the relationship between omentin-1 and BPH has not been investigated previously. Methods A total of 70 males participated in this study, including forty patients diagnosed with BPH and thirty healthy males. The anthropometric measurements and the biochemical parameters were measured in this study. We evaluated serum omentin-1 levels and the correlation with those data. We also test the gene expression of IL-8, IL-18 in BPH group using the TURP tissues. Results The serum omentin-1 levels were lower in the BPH patients than in the control group (27.95 ± 4.18 versus 32.03 ± 5.46, p p = 0.013) as well as the whole group (r = − 0.457, p Conclusion Omentin-1 may suppress the development of BPH and Lower serum omentin-1 levels in BPH patients might associated with higher prostate volume and higher IL-8 and IL-18 expression levels in their prostatic cells.

BACKGROUND Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia. CBAVD is mainly caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and is also related to the X-linked ADGRG2 (adhesion G protein-coupled receptor G2) gene. Genetic screening and counseling strategies for Chinese CBAVD populations remain controversial because the genetic background of CBAVD in Chinese population is largely unknown. OBJECTIVES In this study, we aimed to study the mutation spectrum of CFTR and ADGRG2 in a group of CBAVD patients and to evaluate sperm retrieval outcomes in a subset of CBAVD patients. MATERIALS AND METHODS Next-generation targeted sequencing was used to identify mutations in the CFTR and ADGRG2 genes in 38 CBAVD patients. In addition, we followed and analyzed nine of the 38 patients who were undergoing sperm retrieval surgery. RESULTS In total, 27 of 38 (71.05%) patients carried at least one likely pathogenic or pathogenic mutation in CFTR or ADGRG2. In addition to the IVS9-5T allele, 15 CFTR and 1 ADGRG2 mutations were identified, including 4 novel mutations. CFTR hot-spot mutations were not identified in our study. Spermatozoon was successfully obtained in all nine patients who underwent MESA or TESE surgery, but most patients had spermatozoa with relatively low motility and high abnormality rates. DISCUSSION AND CONCLUSION Except for the IVS9-5T allele, hot-spot mutations of CFTR may not exist in Chinese CBAVD patients. Therefore, next-generation targeted sequencing for whole CFTR and ADGRG2 gene may be the appropriate genetic testing method, and genetic counseling may be different from Caucasian populations. We observed a high success rate of sperm retrieval with relatively low motility and high abnormality rates in Chinese CBAVD patients. However, this is only a weak conclusion due to the small sample size.

Background The real-world exposure levels of non-therapeutic antibiotics and neonicotinoids in type 1 diabetes (T1D) children and their associations as environmental triggers through gut microbiota shifts remained unknown. We thus investigated the antibiotics and neonicotinoids’ exposure levels and their associations with gut microbiota in pediatric T1D. Methods Fifty-one newly onset T1D children along with 67 age-matched healthy controls were recruited. Urine concentrations of 28 antibiotics and 12 neonicotinoids were measured by mass spectrometry. Children were grouped according to the kinds of antibiotics’ and neonicotinoids’ exposures, respectively. The 16S rRNA of fecal gut microbiota was sequenced, and the correlation with urine antibiotics and neonicotinoids’ concentrations was analyzed. Results The overall detection rates of antibiotics were 72.5% and 61.2% among T1D and healthy children, whereas the neonicotinoids detection rates were 70.6% and 52.2% (P = 0.044). Children exposed to one kind of antibiotic or two or more kinds of neonicotinoids had higher risk of T1D, with the odd ratios of 2.579 and 3.911. Furthermore, co-exposure to antibiotics and neonicotinoids was associated with T1D, with the odd ratio of 4.924. Antibiotics or neonicotinoids exposure did not affect overall richness and diversity of gut microbiota. However, children who were exposed to neither antibiotics nor neonicotinoids had higher abundance of Lachnospiraceae than children who were exposed to antibiotics and neonicotinoids alone or together. Conclusion High antibiotics and neonicotinoids exposures were found in T1D children, and they were associated with changes in gut microbiota featured with lower abundance of butyrate-producing genera, which might increase the risk of T1D.

Single treatment often faces the problem that it cannot completely eradicate tumor and inhibit the tumor metastasis. In order to overcome this shortcoming, multi-modal tumor treatment has attracted widespread attention. In the present article, based on ascorbyl palmitate (PA) and l-arginine (l-Arg), a multifunctional nanocarrier is designed for synergetic treatment of tumor with photothermal and nitric oxide (NO) gas therapy. Firstly, PA and l-Arg were self-assembled to form novel functional micelles, PL, with high biosafety using electrostatic interaction and hydrogen bonding. The functional micelles could self-catalyze to produce NO at the tumor site. Then, Ag

Background The cartilage segmentation algorithms make it possible to accurately evaluate the morphology and degeneration of cartilage. There are some factors (location of cartilage subregions, hydrarthrosis and cartilage degeneration) that may influence the accuracy of segmentation. It is valuable to evaluate and compare the accuracy and clinical value of volume and mean T2* values generated directly from automatic knee cartilage segmentation with those from manually corrected results using prototype software. Method Thirty-two volunteers were recruited, all of whom underwent right knee magnetic resonance imaging examinations. Morphological images were obtained using a three-dimensional (3D) high-resolution Double-Echo in Steady-State (DESS) sequence, and biochemical images were obtained using a two-dimensional T2* mapping sequence. Cartilage score criteria ranged from 0 to 2 and were obtained using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). The femoral, patellar, and tibial cartilages were automatically segmented and divided into subregions using the post-processing prototype software. Afterwards, all the subregions were carefully checked and manual corrections were done where needed. The dice coefficient correlations for each subregion by the automatic segmentation were calculated. Results Cartilage volume after applying the manual correction was significantly lower than automatic segmentation (P P Conclusions Automatic segmentation of cartilage volume has a high dice coefficient correlation and it can provide accurate quantitative information about cartilage efficiently without individual bias. Advances in knowledge: Magnetic resonance imaging is the most promising method to detect structural changes in cartilage tissue. Unfortunately, due to the structure and morphology of the cartilages obtaining accurate segmentations can be problematic. There are some factors (location of cartilage subregions, hydrarthrosis and cartilage degeneration) that may influence segmentation accuracy. We therefore assessed the factors that influence segmentations error.

Objective. GIT1 is identified as a novel tumor oncogene in breast cancer. In this article, we aimed to explore the role of GIT1 in the progression of head and neck squamous cell carcinoma (HNSCC). Methods. GIT1 expression in HNSCC was detected by RT-qPCR, immunohistochemistry assay, and Western blot. HNSCC cell proliferation, migration, and invasion were examined by CCK-8 assay, Wound healing assay, and Transwell assay, respectively. Cell apoptosis was detected by flow cytometric analysis. Results. In our study, GIT1 was notably upregulated in HNSCC tissues and cells. Moreover, GIT1 expression level had positive corelation with pathological grade and nodal status of HNSCC. Functional experiments showed that knockdown of GIT1 restrained HNSCC proliferation, invasion, migration, and EMT and facilitated cell apoptosis. Furthermore, GIT1 knockdown was found to restrain HNSCC tumor growth and lung metastasis. Additionally, PI3K/AKT/mTOR signal pathway inhibitors suppressed the effect of GIT1 on HNSCC cell progression. Conclusion. GIT1 was upregulated in HNSCC and facilitated HNSCC cell progression by inducing PI3K/AKT/mTOR signal pathway. Therefore, we suggested that GIT1 might be a potential target for HNSCC treatment.

3-monochloro-1,2-propanediol (3-MCPD) is a food contaminant believed to be harmful to human health. Previous studies showed that 3-MCPD exerts toxic effects in multiple tissues, but whether 3-MCPD affects female reproductive function remained unknown. Here, using mouse gastric lavage models, we report that 3-MCPD exposure for four weeks affected body growth, decreased the ovary/body weight ratio, and increased atretic follicle numbers. Expression levels of follicular development-related factors decreased. Further studies found that ovaries from 3-MCPD exposed mice had activated the Transforming Growth Factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis. Increased TNF-α, IL-1 and NF-κB expression also indicated the occurrence of ovarian inflammation. Exposure to 3-MCPD stimulated the caspase pathway and enhanced granulosa cell apoptosis. Consistent with disrupted ovarian homeostasis, 3-MCPD exposure interfered with mitochondrial function, generated more reactive oxygen species, increased ferrous ion and lipid peroxidation levels, and resulted in decreased oocyte development potential. Collectively, these findings indicated that 3-MCPD exposure induced ovarian inflammation and fibrosis, and caused disorders of mitochondrial function and ferrous ion homeostasis in oocytes, which consequently disturbed follicle maturation and reduced oocyte quality.

Objective The study objective was to investigate the use of peripheral blood biomarkers as predictors of patient survival. The aim of this study was to identify the baseline peripheral blood biomarkers associated with clinical outcome in patients with early lung cancer (stage I-II) treated with surgery. Methods We included and analysed data from 376 patients with early-stage lung cancer who underwent a standard lobectomy. Univariate and multivariate Cox regression analyses were performed on all patients to assess the relationships between progression-free survival (PFS) and overall survival (OS) and the peripheral blood biomarker metrics measured before surgical treatment. The peripheral blood parameters included monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and dimeric fibrin fragment D (D-dimer). Results After univariate Cox regression analysis, low MLR, low NLR, low PLR and low D-dimer values were significantly associated with both better OS and PFS (all p p p Conclusion A baseline signature of low MLR, low NLR, low PLR, and low D-dimer values was associated with a better survival outcome for patients treated with surgery. Patients with more favourable results had better survival outcomes.

Background Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood. Methods U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results Here we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better “turn off” tumor growth. Conclusion Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion. Electronic supplementary material The online version of this article (10.1186/s13046-017-0628-8) contains supplementary material, which is available to authorized users.

Deep learning models can recognize the food item in an image and derive their nutrition information, including calories, macronutrients (carbohydrates, fats, and proteins), and micronutrients (vitamins and minerals). This technology has yet to be implemented for the nutrition assessment of restaurant food. In this paper, we crowdsource 15,908 food images of 470 restaurants in the Greater Hartford region on Tripadvisor and Google Place. These food images are loaded into a proprietary deep learning model (Calorie Mama) for nutrition assessment. We employ manual coding to validate the model accuracy based on the Food and Nutrient Database for Dietary Studies. The derived nutrition information is visualized at both the restaurant level and the census tract level. The deep learning model achieves 75.1% accuracy when compared with manual coding. It has more accurate labels for ethnic foods but cannot identify portion sizes, certain food items (e.g., specialty burgers and salads), and multiple food items in an image. The restaurant nutrition (RN) index is further proposed based on the derived nutrition information. By identifying the nutrition information of restaurant food through crowdsourced food images and a deep learning model, the study provides a pilot approach for large-scale nutrition assessment of the community food environment.

Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2–mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

Purpose This study investigated the clinical epidemiological characteristics of nitrous oxide (N2O) abusers in a hospital in China, which have not been systematically reported. Methods The characteristics of patients abusing N2O who were examined and treated at the Affiliated Hospital of Xuzhou Medical University from January 2017 to December 2020 were analyzed. Results A total of 61 patients (average age: 21.7 ± 3.2 years; 42 male and 19 female) were enrolled; 60.7% of the patients had an education level of high school or lower, and most (59.0%) had no stable occupation. The mean exposure time was 8.5 ± 7.7 months (range: 1–36 months). Only 52.5% of the abusers reported the physician of the relevant exposure history at the first time of visiting the doctor. The main clinical type was mixed (49.2%). The most common clinical manifestation was distal limb numbness (80.3%). The most frequent outcome was peripheral neuropathy (59%) and subacute combined degeneration (36%). Serum homocysteine level was elevated in 67.5% (27/40) of the patients, while 44.4% (20/45) showed reduced vitamin B12. Note that 61% (22/36) showed abnormal signals in the posterior or lateral funiculus of the spinal cord, and 97% (31/32) of the patients showed peripheral nerve damage by electromyography. In all cases, symptoms were alleviated after halting N2O intake and receiving nutritional neurotherapy. Conclusions N2O abuse can lead to nervous system damage, especially peripheral nerve and spinal cord damage. A full understanding of its clinical epidemiological characteristics is helpful for clinicians to make a timely and clear diagnosis., Long‐term abuse of N2O mainly leads to nervous system damage by affecting the metabolism of vitamin B12, which is seriously harmful to the health of some teenagers. There are certain rules and characteristics in the clinical and epidemiological characteristics. A full understanding of these characteristics is helpful for clinicians to make timely and accurate diagnosis and treatment.

Intracranial artery atherosclerotic stenosis (ICAS) is one of the most common causes of stroke. Endovascular therapy including balloon angioplasty alone (BA), balloon-mounted stent (BMS), or self-expanding stent (SES) was an important alternative to treat symptomatic ICAS refractory to medical treatment, while none of the three subtypes has been established to be the primary option. We conducted a systematic review and network meta-analysis to determine both the safety and efficacy and establish a hierarchy of different endovascular therapies on symptomatic ICAS. Major databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies comparing outcomes of three different endovascular approaches and other comparable non-endovascular therapies for symptomatic ICAS patients published from 1 January 2000 to 1 November 2021. Primary outcomes included short-term mortality or stroke rate (peri-procedural, or mean follow-up ≤ 3 months), and long-term mortality or stroke rate (mean follow-up ≥ 6 months). Pairwise and network meta-analyses based on the above systematic review were conducted. A total of 19 eligible studies involving 3386 patients treated with 4 different approaches (BA, SES, BMS, and medical treatment) were analyzed. For primary outcome, BA had the highest ranking (SUCRA value 78), followed by BMS (SUCRA value 21.5) and SES (SUCRA value 13.1). The short-term mortality or stroke rate was significantly lower in the BA group compared to SES (OR = 2.50; 95% CI 1.12 to 5.57; p = 0.026) or BMS (OR = 0.43; 95% CI 0.19 to 0.96; p = 0.038). Other primary and secondary outcomes were no different among all three types of endovascular therapy. Overall, the studies were of good methodological quality and the consistency was acceptable across all network meta-analyses. BA offers the highest level of safety outcomes in terms of short-term mortality or stroke in treating symptomatic patients with intracranial artery stenosis, compared to SES and BMS, which needs to be confirmed in future studies. Trial registration in PROSPERO database: CRD42018084055.

We aimed to assess the potential causal association between Parkinson's disease (PD) and ischemic stroke (IS) with Mendelian randomization methods. Summary statistics data from two large-scale genome-wide association studies (GWAS) for 33,674 PD cases and 40,585 IS cases were used in this study. We used inverse variance-weighted method for primary analysis, and four other Mendelian randomization methods (weighted median, MR-Egger regression methods, robust adjusted profile score, radial regression) to test whether PD was causal for IS and its subtypes. Analyses were bidirectional to assess reverse causality. Primary analysis showed PD had a significantly causal association with IS (OR 1.04; 95% CI, 1.02-1.07; p = 0.0019), and two subtypes of IS, cardioembolic stroke (OR 1.11; 95% CI, 1.06-1.18; p = 0.0001) and large artery stroke (OR 1.08; 95% CI, 1.01-1.15; p = 0.034), but not with small-vessel stroke (p = 0.180). The point estimates from sensitivity analyses were in the same direction. There was no strong evidence for a reverse causal association between PD and IS. Using multiple Mendelian randomization methods based on large-scale GWAS, PD is a potential cause of cardioembolic stroke and large artery stroke, but not small-vessel stroke. Ischemic stroke does not cause PD.

We aimed to evaluate the assessment and management of epilepsy with anxiety and depression, and their clinical practice based on a survey.A cross-sectional survey of epilepsy health professionals was undertaken in Zhejiang Province using the modified International League Against Epilepsy (ILAE) Psychology Task Force questionnaire. We recorded the characteristics of participants and the practice of screening, referral, and treatment for depression and anxiety disorders. A total of 146 participants joined in the survey, of which 76.0% were neurologists, and 69 participants were the member of the Zhejiang Association Against Epilepsy (ZAAE).This survey revealed that almost all participants (87.7%) agreed that screening for depression and anxiety in patients with epilepsy (PWEs) was very important; however, the frequency of screening was very low (41.1% of participants screened less than 10% of patients, and 34.2% participants screened between 10% and 30% of patients). A higher frequency of screening was reported in the member group and compared with that in the non-member group (P = 0.025). The main barrier to screening was the lack of time during clinic visits: 81.5% participants included screening questions as part of their clinical review. When anxiety/depression was diagnosed, the next step should be to refer patients to a psychiatrist (78.1%). No standardized procedures and lack of mental health specialists trained to assess and/or manage PWEs, were the main barriers to follow-up assessment and management. Lack of appropriately trained mental health specialists was also the main barrier to psychological treatment for depression and anxiety.This survey highlighted that epilepsy healthcare professionals in Zhejiang province agreed on the importance of screening for psychiatric comorbidities in PWEs; however, the screening and management were actually insufficient. Certain barriers to screening, referral, and treatment were presented and improvements were recommended.

Summary Background Understanding how environmental factors affect SARS-CoV-2 transmission could inform global containment efforts. Despite high scientific and public interest and multiple research reports, there is currently no consensus on the association of environmental factors and SARS-CoV-2 transmission. To address this research gap, we aimed to assess the relative risk of transmission associated with weather conditions and ambient air pollution. Methods In this global analysis, we adjusted for the delay between infection and detection, estimated the daily reproduction number at 3739 global locations during the COVID-19 pandemic up until late April, 2020, and investigated its associations with daily local weather conditions (ie, temperature, humidity, precipitation, snowfall, moon illumination, sunlight hours, ultraviolet index, cloud cover, wind speed and direction, and pressure data) and ambient air pollution (ie, PM2·5, nitrogen dioxide, ozone, and sulphur dioxide). To account for other confounding factors, we included both location-specific fixed effects and trends, controlling for between-location differences and heterogeneities in locations’ responses over time. We built confidence in our estimations through synthetic data, robustness, and sensitivity analyses, and provided year-round global projections for weather-related risk of global SARS-CoV-2 transmission. Findings Our dataset included data collected between Dec 12, 2019, and April 22, 2020. Several weather variables and ambient air pollution were associated with the spread of SARS-CoV-2 across 3739 global locations. We found a moderate, negative relationship between the estimated reproduction number and temperatures warmer than 25°C (a decrease of 3·7% [95% CI 1·9–5·4] per additional degree), a U-shaped relationship with outdoor ultraviolet exposure, and weaker positive associations with air pressure, wind speed, precipitation, diurnal temperature, sulphur dioxide, and ozone. Results were robust to multiple assumptions. Independent research building on our estimates provides strong support for the resulting projections across nations. Interpretation Warmer temperature and moderate outdoor ultraviolet exposure result in a slight reduction in the transmission of SARS-CoV-2; however, changes in weather or air pollution alone are not enough to contain the spread of SARS-CoV-2 with other factors having greater effects. Funding None.

Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines.GBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response.YM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals.YM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.

Objectives Kashgar prefecture is an important transportation and trade hub with a high incidence of tuberculosis. The following study analyzed the composition and differences in Mycobacterium tuberculosis (M.tb) lineage and specific tags to distinguish the lineage of the M.tb in Kashgar prefecture, thus providing a basis for the classification and diagnosis of tuberculosis in this area. Methods Whole-genome sequencing (WGS) of 161 M.tb clinical strains was performed. The phylogenetic tree was constructed using Maximum Likelihood (ML) based on single nucleotide polymorphisms (SNPs) and verified through principal component analysis (PCA). The composition structure of M.tb in different regions was analyzed by combining geographic information. Results M.tb clinical strains were composed of lineage 2 (73/161, 45.34%), lineage 3 (52/161, 32.30%) and lineage 4 (36/161, 22.36%). Moreover, the 3 lineages were subdivided into 11 sublineages, among which lineage 2 included lineage 2.2.2/Asia Ancestral 1 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 2 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 3 (18/73, 24.66%), and lineage 2.2.1-Modern Beijing (39/73, 53.42%). Lineage 3 included lineage 3.2 (14/52, 26.92%) and lineage 3.3 (38/52, 73.08%), while lineage 4 included lineage 4.1 (3/36, 8.33%), lineage 4.2 (2/36, 5.66%), lineage 4.4.2 (1/36, 2.78%), lineage 4.5 (28/36, 77.78%) and lineage 4.8 (2/36, 5.66%), all of which were consistent with the PCA results. One hundred thirty-six markers were proposed for discriminating known circulating strains. Reconstruction of a phylogenetic tree using the 136 SNPs resulted in a tree with the same number of delineated clades. Based on geographical location analysis, the composition of Lineage 2 in Kashgar prefecture (45.34%) was lower compared to other regions in China (54.35%-90.27%), while the composition of Lineage 3 (32.30%) was much higher than in other regions of China (0.92%-2.01%), but lower compared to the bordering Pakistan (70.40%). Conclusion Three lineages were identified in M.tb clinical strains from Kashgar prefecture, with 136 branch-specific SNP. Kashgar borders with countries that have a high incidence of tuberculosis, such as Pakistan and India, which results in a large difference between the M.tb lineage and sublineage distribution in this region and other provinces of China.

Background One critical variable in the time series analysis is the change point, which is the point where an abrupt change occurs in chronologically ordered observations. Existing parametric models for change point detection, such as the linear regression model and the Bayesian model, require that observations are normally distributed and that the trend line cannot have extreme variability. To overcome the limitations of the parametric model, we apply a nonparametric method, the Mann-Kendall-Sneyers (MKS) test, to change point detection for the state-level COVID-19 case time series data of the United States in the early outbreak of the pandemic. Methods The MKS test is implemented for change point detection. The forward sequence and the backward sequence are calculated based on the new weekly cases between March 22, 2020 and January 31, 2021 for each of the 50 states. Points of intersection between the two sequences falling within the 95% confidence intervals are identified as the change points. The results are compared with two other change point detection methods, the pruned exact linear time (PELT) method and the regression-based method. Also, an open-access tool by Microsoft Excel is developed to facilitate the model implementation. Results By applying the MKS test to COVID-19 cases in the United States, we have identified that 30 states (60.0%) have at least one change point within the 95% confidence intervals. Of these states, 26 states have one change point, 4 states (i.e., LA, OH, VA, and WA) have two change points, and one state (GA) has three change points. Additionally, most downward changes appear in the Northeastern states (e.g., CT, MA, NJ, NY) at the first development stage (March 23 through May 31, 2020); most upward changes appear in the Western states (e.g., AZ, CA, CO, NM, WA, WY) and the Midwestern states (e.g., IL, IN, MI, MN, OH, WI) at the third development stage (November 19, 2020 through January 31, 2021). Conclusions This study is among the first to explore the potential of the MKS test applied for change point detection of COVID-19 cases. The MKS test is characterized by several advantages, including high computational efficiency, easy implementation, the ability to identify the change of direction, and no assumption for data distribution. However, due to its conservative nature in change point detection and moderate agreement with other methods, we recommend using the MKS test primarily for initial pattern identification and data pruning, especially in large data. With modification, the method can be further applied to other health data, such as injuries, disabilities, and mortalities.