Revealing the pathogenesis of gastric intestinal metaplasia based on the mucosoid air-liquid interface.

BACKGROUND: Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies. METHOD: The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells. RESULT: Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway. CONCLUSION: The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence, such as Crohn's disease and ulcerative colitis. The accurate etiology and pathogenesis of IBD remain unclear, and it is generally believed that it is related to genetic susceptibility, gut microbiota, environmental factors, immunological abnormalities, and potentially other factors. Currently, the mainstream therapeutic drugs are amino salicylic acid agents, corticosteroids, immunomodulators, and biological agents, but the remission rates do not surpass 30-60% of patients in a real-life setting. As a consequence, there are many studies focusing on emerging drugs and bioactive ingredients that have higher efficacy and long-term safety for achieving complete deep healing. This article begins with a review of the latest, systematic, and credible summaries of the pathogenesis of IBD. In addition, we provide a summary of the current treatments and drugs for IBD. Finally, we focus on the therapeutic effects of emerging drugs such as microRNAs and lncRNAs, nanoparticles-mediated drugs and natural products on IBD and their mechanisms of action.

Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.

OBJECTIVES: The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase: producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics. METHODS: To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC. RESULTS: The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations. CONCLUSIONS: Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.

Causal associations between thyroid cancer and IgA nephropathy: a Mendelian randomization study.

BACKGROUND: The incidence of kidney disease caused by thyroid cancer is rising worldwide. Observational studies cannot recognize whether thyroid cancer is independently associated with kidney disease. We performed the Mendelian randomization (MR) approach to genetically investigate the causality of thyroid cancer on immunoglobulin A nephropathy (IgAN). METHODS AND RESULTS: We explored the causal effect of thyroid cancer on IgAN by MR analysis. Fifty-two genetic loci and single nucleotide polymorphisms were related to thyroid cancer. The primary approach in this MR analysis was the inverse variance weighted (IVW) method, and MR‒Egger was the secondary method. Weighted mode and penalized weighted median were used to analyze the sensitivity. In this study, the random-effect IVW models showed the causal impact of genetically predicted thyroid cancer across the IgAN risk (OR, 1.191; 95% CI, 1.131-1.253, P < 0.001). Similar results were also obtained in the weighted mode method (OR, 1.048; 95% CI, 0.980-1.120, P = 0.179) and penalized weighted median (OR, 1.185; 95% CI, 1.110-1.264, P < 0.001). However, the MR‒Egger method revealed that thyroid cancer decreased the risk of IgAN, but this difference was not significant (OR, 0.948; 95% CI, 0.855-1.051, P = 0.316). The leave-one-out sensitivity analysis did not reveal the driving influence of any individual SNP on the association between thyroid cancer and IgAN. CONCLUSION: The IVW model indicated a significant causality of thyroid cancer with IgAN. However, MR‒Egger had a point estimation in the opposite direction. According to the MR principle, the evidence of this study did not support a stable significant causal association between thyroid cancer and IgAN. The results still need to be confirmed by future studies.

Short sleep duration and atrial fibrillation risk: A comprehensive analysis of observational cohort studies and genetic study.

BACKGROUND: Previous observational studies are inconclusive on whether an association exists between short sleep duration and the high risk of developing atrial fibrillation (AF). Understanding their potential association would be of great clinical significance. Thus, in this study, we aimed to explore their causal relationship. METHODS AND RESULTS: We meta-analyzed the association between short sleep duration and the risk of developing AF by including six observational studies. Based on genetic susceptibility analysis using the mendelian randomization (MR) method, we identified 16 genetic loci that might link short sleep duration and the high risk of developing AF. Meta-analysis showed a significant association between short sleep duration and a higher risk of developing AF (RR = 1.06, 95% CI 1.02-1.11, P = 0.005). However, the fixed-effect and random-effect inverse variance weighted (IVW) models using the MR method showed a non-obvious effect of short sleep duration on the risk of developing AF (OR, 0.979; 95% CI, 0.880-1.089, P = 0.693; OR, 0.979; 95% CI, 0.857-1.117, P = 0.750, respectively). Other models, also showed no statistical difference. No heterogeneity or asymmetry was observed, as Cochran's Q test showed. The leave-one-out sensitivity analysis demonstrated good robust results, which were not subject to directional pleiotropy. CONCLUSION: Meta-analysis and MR analysis demonstrated inconsistent results on the relationship between short sleep duration and a high risk of developing AF. Specifically, while meta-analysis confirmed that short sleep duration increases the risk of developing AF, MR analysis did not support a causal association between genetically determined short sleep and risk of AF.

Mapping of qChalk1 controlling grain chalkiness in japonica rice.

BACKGROUND: Rice grain chalkiness is an undesirable characteristic that affects grain quality. The aim of this study was to map QTLs controlling grain chalkiness in japonica rice. METHODS AND RESULTS: In this study, two japonica rice cultivars with similar grain shapes but different grain chalkiness rates were crossed and the F2 and BC1F2 populations were subjected to QTL-seq analysis to map the QTLs controlling the grain chalkiness rate. QTL-seq analysis revealed SNP index differences on chromosome 1 in both of the segregating populations. Using polymorphic markers between the two parents, QTL mapping was conducted on 213 individual plants in the BC1F2 population. QTL mapping confined a QTL controlling grain chalkiness, qChalk1, to a 1.1 Mb genomic region on chromosome 1. qChalk1 explained 19.7% of the phenotypic variation. CONCLUSION: A QTL controlling grain chalkiness qChalk1 was detected in both F2 and BC1F2 segregating populations by QTL-Seq and QTL mapping methods. This result would be helpful for further cloning of the genes controlling grain chalkiness in japonica rice.

Electroacupuncture Alleviates 46-Trinitrobenzene Sulfonic Acid-Induced Visceral Pain via the Glutamatergic Pathway in the Prefrontal Cortex.

Visceral pain caused by inflammatory bowel disease (IBD) greatly diminishes the quality of life in affected patients. Yet, the mechanism of how IBD causes visceral pain is currently not fully understood. Previous studies have suggested that the central nervous system (CNS) and gut-brain axis (GBA) play an important role in IBD-inducing visceral pain. As one of the treatments for IBD, electroacupuncture (EA) has been used to treat various types of pain and gastrointestinal diseases in clinical practice. However, whether EA relieves the visceral pain of IBD through the gut-brain axis has not been confirmed. To verify the relationship between visceral pain and CNS, the following experiments were conducted. 1H-NMR analysis was performed on the prefrontal cortex (PFC) tissue obtained from IBD rat models to determine the link between the metabolites and their role in EA treatment against visceral pain. Western blot assay was employed for detecting the contents of glutamate transporter excitatory amino acid transporters 2 (EAAT2) and the glutamate receptor N-methyl-D-aspartate (NMDA) to verify whether EA treatment can alleviate neurotoxic symptoms induced by abnormal increases of glutamate. Study results showed that the glutamate content was significantly increased in the PFC of TNBS-induced IBD rats. This change was reversed after EA treatment. This process was associated with increased EAAT2 expression and decreased expression of NMDA receptors in the PFC. In addition, an increase in intestinal glutamic-metabolizing bacteria was observed. In conclusion, this study suggests that EA treatment can relieve visceral pain by reducing glutamine toxicity in the PFC, and serves an alternative clinical utility.

Rescue Robots for the Urban Earthquake Environment.

Robotics have important applications in the field of disaster medical rescue. The deployment of urban rescue robots at the earthquake site can help shorten response time, improve rescue efficiency and keep rescue personnel away from danger. This discussion introduces the performance of some robots in actual rescue scenarios, focuses on the current research status of robots that can provide medical assistance, and analyzes the merits and shortcomings of each system. Based on existing studies, the limitations and development directions of urban rescue robots are also discussed.

Wuzi Yanzong Pill for the treatment of male infertility: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The incidence of male infertility is increasing worldwide, and has become an important problem that plagues many married couples. Half of the infertility cases have induced by male infertility. Wuzi Yanzong Pill is a traditional Chinese herbal formula used in treating spermatorrhea, premature ejaculation, erectile dysfunction, lumbago and male sterility widely. Therefore, in this systematic review, we design to evaluate the effectiveness and safety of Wuzi-Yanzong Pill for the treatment of male infertility. METHODS: The English and Chinese literature published before June 30, 2020 will be searched in PubMed, EMBASE, Cochrane library, and Chinese literature in China National Knowledge Infrastructure, Chinese biomedical document service system, VIP Chinese Science and Technology Journal Database, WANFANG data. All related randomized controlled trials that meet the eligibility criteria will be included and other studies will be excluded. We will search literature with text keywords "male infertility" or "sperm" or "semen" and "Wuzi Yanzong Pill" or "Wuziyangzong" or "WZYZ". Progressive motility, sperm concentration, sperm morphology, sperm viability, sperm DNA fragmentation, sperm number per ejaculate, pregnancy rates will be evaluated. RevMan 5.3 and Stata 14.0 will be used to conduct this systematic review. The preferred reporting items for systematic reviews and meta-analysis protocols statement is followed in this protocol and the PRISMA statement will be followed in the completed systematic review. CONCLUSION: The efficacy and safety of Wuzi Yanzong Pill in the treatment of male infertility will be e evaluated. The results of this review may provide some help for the clinician's decision.

The effect of varicocele repair for sperm DNA fragmentation: A protocol for systematic review and meta-analysis.

INTRODUCTION: Sperm DNA integrity has been considered as one of the important determinants of normal fertilization and embryonic development in natural and assisted pregnancy. It is difficult for men with high levels of sperm DNA fragmentation (SDF) in semen to conceive their partners naturally and assist in conception. The studies have found that the level of SDF in the semen of patients with varicocele (VC) was on the high side. In recent years, the effect of VC surgery on DNA fragmentation index has attracted the attention of researchers. In this study, we will evaluate the effectiveness of VC repair as a way to alleviate SDF and improve male fertility. METHODS AND ANALYSIS: Electronic databases including English databases (PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, China Biology Medicine Database, Wanfang Database, VIP Database) will be searched from their inception to December 2020 to recognize related studies. All the randomized controlled trials of microsurgical varicocelectomy for the management of VC patients will be included. The potential outcome will include improvement in SDF, oxidative stress markers (reactive oxygen species, nitric oxide, and lipid peroxidation products), sperm chromatin compaction, other advanced sperm function characteristics, follow-up of fertility results. We will conduct this study strictly according to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: The study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings on April 5th of 2021. CONCLUSION: This systematic review will provide more evidence to assess whether varicocelectomy is an effective intervention for patients with SDF. The results will be published in a public issue journal and offer the urologists help to make clinical decisions. ETHICS AND DISSEMINATION: Formal ethical approval is not required in this protocol. We will collect and analyze data based on published research. Since this research does not involve patients, personal privacy will not be affected. The results of this review will be distributed to peer-reviewed journals or submitted to relevant conferences. PROTOCOL REGISTRATION NUMBER: INPLASY202070119.

The effect of nebivolol on erectile function in the cases with coronary artery bypass surgery: A protocol for a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Erectile dysfunction is a common disease. It affects the quality of life of both husband and wife and its prevalence is higher in patients with overt cardiovascular disease or cardiovascular risk factors. In recent years, multiple studies confirm that nebivolol exerts protective effects on erectile function against the disruptive effects of cardiopulmonary bypass in patients undergoing coronary artery bypass grafting, but its quality and efficacy have not been systematically evaluated. Therefore, it is necessary to carry out a systematic review and meta-analysis to fully evaluate the efficacy and safety of nebivolol on erectile function in the cases with coronary artery bypass grafting. METHODS AND ANALYSIS: Chinese and English literature of nebivolol on erectile function in the cases with coronary artery bypass surgery published before August 31, 2020 will be comprehensive searched in PubMed, Cochrane Library, EMBASE, WANFANG, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journal Database, Chinese biomedical document service system, and Clinicaltrials.gov. Only randomized controlled trials that meet the eligibility criteria will be included. Two researchers will independently complete literature screening, data extraction and assess the risk of bias, and the third investigator will handle disagreements. Our main evaluation includes 2 outcome indicators including the international index of erectile function 5 score and adverse events. RevMan 5.3 and Stata 14.0 will be used to conduct this systematic review. The preferred reporting items for systematic reviews and meta-analysis protocols (PRISMA-P) statement is followed in this protocol and the PRISMA statement will be followed in the completed systematic review. CONCLUSION AND DISSEMINATION: The efficacy and safety of nebivolol on erectile function in the cases with coronary artery bypass grafting will be evaluated. We will publish the results of this systematic review in peer-reviewed journals to provide new evidence to clinicians. ETHICS AND DISSEMINATION: Ethical approval is not required as the review is a secondary study based on published literature. The results will be published in a public issue journal to provide evidence-based medical evidence for urologists and andrologists to make better clinical decisions. REGISTRATION INFORMATION: INPLASY202060110.

Efficacy of microsurgical varicocelectomy in the treatment of premature ejaculation: A protocol for systematic review and meta-analysis.

INTRODUCTION: Premature ejaculation (PE) is the most common type of sexual disorder among men which comprises a great of problems. Varicocele is defined as the dilation of the pampiniform venous plexus draining the testicle. At present, selective serotonin reuptake inhibitors antidepressants, topical anesthetics, tramadol, phosphodiesterase type 5 inhibitors are the common alternative strategy to improve PE. However, these therapeutic measures have several shortcomings and side effects. Recently, the correlation between varicocele and PE has attracted the attention of some researchers. A few studies consider microsurgical varicocelectomy can be a new remedy for PE. But it is still absent enough a great deal of convincing evidence. The study will assess the effectiveness and safety of the microsurgical varicocelectomy treatment in PE patients. METHODS AND ANALYSIS: Electronic databases including English databases (PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, China Biology Medicine Database, Wanfang Database, VIP Database) will be searched from their inception to December 2020 to recognize related studies. All the randomized controlled trials of microsurgical varicocelectomy for the management of PE patients will be included. The potential outcome will include intravaginal ejaculation latency time, Chinese index of sexual function for premature ejaculation-5, visual analogue score, premature ejaculation diagnostic tool, success treatment rate, serum testosterone levels. We will conduct this study strictly according to the Cochrane Handbook for systematic reviews of interventions. RESULTS: The current study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings in the February 28, 2021. CONCLUSION: This systematic review will provide more evidence to assess whether microsurgical varicocelectomy is an effective intervention for patients with PE. The results will be published in a public issue journal and offer the urologists and andrologists help to make clinical decisions. ETHICS AND DISSEMINATION: Formal ethical approval is not required in this protocol. We will collect and analyze data based on published studies, and since there are no patients involved in this study, individual privacy will not be under concerns. The results of this review will be disseminated to peer-reviewed journals or submit to related conferences. PROTOCOL REGISTRATION NUMBER: INPLASY202060058.

Serum vitamin D levels and type 2 diabetic erectile dysfunction: A protocol for systematic review and meta-analysis.

INTRODUCTION: Diabetic erectile dysfunction (DED) has gradually become a worldwide problem. Due to the mechanism of DED is not clear, it is impossible to treat it pertinently. Recently, some studies have shown that vitamin D is associated with DED, type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED), but there is no systematic review and meta-analysis on the relationship between vitamin D and DED. METHODS AND ANALYSIS: The databases of English databases (PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, China Biology Medicine Database, Wanfang Database, VIP Database) will be retrieved. The search strategy that will be run in the PubMed and tailored to the other database when necessary is presented in . RevMan 5.3 and Stata 11.0 will be used for Systematic Review and Meta-analysis. This protocol reported under the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, and we will report the systematic review by following the PRISMA statement.(Table is included in full-text article.) RESULTS:: Through a systematic review, and meta-analysis when necessary, we can obtain the relationship between vitamin D and DED. We will share our findings in the third quarter of 2021. CONCLUSION: The association between serum vitamin D levels and type 2 diabetic erectile dysfunction will be assessed. Besides, the results of this review may provide some help for clinicians to make decisions. ETHICS AND DISSEMINATION: Ethical approval is not required as the review is a secondary study based on published literature. The results will be published in a public issue journal to provide evidence-based medical evidence for urologists and andrologists to make better clinical decisions. PROTOCOL REGISTRATION NUMBER: INPLASY202040164.

The efficacy and safety comparison of PD-1/PD-L1 antibody, chemotherapy and supportive treatment for pretreated advanced esophagogastric cancer: a network meta-analysis.

BACKGROUND: Immunotherapy is important for the treatment of esophagogastric cancer. The purpose of this study is to compare the efficacy and safety of PD-(L)1 antibody, chemotherapy, and supportive treatment in the management of pretreated advanced esophagogastric cancer. METHODS: The randomized controlled trials were identified by searching electronic databases including PubMed, Cochrane Library and Embase database. The network meta-analysis (NMA) was carried out using software R 3.3.2. Main outcomes including overall survival (OS), progression-free survival (PFS), all grades and serious treatment-related adverse events (TRAEs) were extracted and analyzed. The ranking results for all outcomes were performed to identify the best treatments. RESULTS: Seven high-quality RCTs involving 1,891 patients were taken into analysis. Compared with supportive treatment, PD-(L)1 antibody and chemotherapy both had a significantly longer OS time. Chemotherapy could obvious improve PFS than supportive treatment, but it had more all grades and serious TRAEs than PD-(L)1 antibody and supportive treatment. No significant difference was found in other comparisons. The probabilities of rank plot showed that PD-(L)1 antibody was the best in the outcome of OS. Chemotherapy ranked first in PFS and ranked last in all grades and serious TRAEs. CONCLUSIONS: According to our results, PD-(L)1 antibody had excellent survival benefits and tolerable TRAEs for pretreated advanced esophagogastric cancer. It might be a suitable potential choice, especially for patients with high PDL1 CPS or with gastroesophageal junction cancer.

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors.

Tubulin polymerisation inhibitors exhibited an important role in the treatment of patients with prostate cancer. Herein, we reported the medicinal chemistry efforts leading to a new series of benzothiazoles by a bioisosterism approach. Biological testing revealed that compound 12a could significantly inhibit in vitro tubulin polymerisation of a concentration dependent manner, with an IC50 value of 2.87 µM. Immunofluorescence and EBI competition assay investigated that compound 12a effectively inhibited tubulin polymerisation and directly bound to the colchicine-binding site of ß-tubulin in PC3 cells. Docking analysis showed that 12a formed hydrogen bonds with residues Tyr357, Ala247 and Val353 of tubulin. Importantly, it displayed the promising antiproliferative ability against C42B, LNCAP, 22RV1 and PC3 cells with IC50 values of 2.81 µM, 4.31 µM, 2.13 µM and 2.04 µM, respectively. In summary, compound 12a was a novel colchicine site tubulin polymerisation inhibitor with potential to treat prostate cancer.