Mitigation and mechanism of low dose linoleic acid on depression caused by disorder of gut microbiome.

OBJECTIVES: Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated. METHODS: Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin-eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively. RESULTS: The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain. DISCUSSION: LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.

Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer.

BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Antioxidant peptides, the guardian of life from oxidative stress.

Reactive oxygen species (ROS) are produced during oxidative metabolism in aerobic organisms. Under normal conditions, ROS production and elimination are in a relatively balanced state. However, under internal or external environmental stress, such as high glucose levels or UV radiation, ROS production can increase significantly, leading to oxidative stress. Excess ROS production not only damages biomolecules but is also closely associated with the pathogenesis of many diseases, such as skin photoaging, diabetes, and cancer. Antioxidant peptides (AOPs) are naturally occurring or artificially designed peptides that can reduce the levels of ROS and other pro-oxidants, thus showing great potential in the treatment of oxidative stress-related diseases. In this review, we discussed ROS production and its role in inducing oxidative stress-related diseases in humans. Additionally, we discussed the sources, mechanism of action, and evaluation methods of AOPs and provided directions for future studies on AOPs.

Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.

Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of energy metabolism pathways for the treatment of cancer. Numerous studies and clinical trials have demonstrated the efficacy of nutritional therapy in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing treatment outcomes, prolonging survival, and improving the overall quality of life of patients. This review article comprehensively examines nutritional therapy strategies that specifically address tumor energy metabolism. Moreover, it explores the intricate interplay between energy metabolism and the gut microbiota in the context of nutritional therapy. The findings aim to provide valuable insights for future clinical research endeavors in this field.

A Rapidly Dissolvable Microneedle Patch with Tip-Accumulated Antigens for Efficient Transdermal Vaccination.

Dissolvable microneedles (DMNs) are an attractive alternative for vaccine delivery due to their user-friendly, skin-targeted, and minimally invasive features. However, vaccine waste and inaccurate dosage remain significant issues faced by DMNs, as the skin's elasticity makes it difficult to insert MNs completely. Here, a simple and reliable fabrication method are introduced based on two-casting micromolding with centrifugal drying to create a rapidly DMN patch made of hyaluronic acid. Ovalbumin (OVA), as the model antigens, is concentrated in the tip parts of the DMNs (60% of the needle height) to prevent antigen waste caused by skin elasticity. The time and temperature of the initial centrifugal drying significantly affect antigen distribution within the needle tips, with lower temperature facilitating antigen accumulation. The resulting DMN patch is able to penetrate the skin with enough mechanical strength and quickly release antigens into the skin tissue within 3 min. The in vivo study demonstrates that immunization of OVA with DMNs outperforms conventional vaccination routes, including subcutaneous and intramuscular injections, in eliciting both humoral and cellular immunity. This biocompatible DMN patch offers a promising and effective strategy for efficient and safe vaccination.

A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice.

BACKGROUND: High-fat diet (HFD) consumption is an important reason for promoting depression, but the mechanism is unclear. The present study aims to explore the relationship between metabolic disturbance and HFD-induced depression-like behaviors. METHODS: Depression models were established by HFD consumption and chronic unpredictable mild stress (CUMS) in mice. Enzyme-linked immunosorbent assay, western blotting, real-time polymerase chain reaction, gas chromatography and metabolomic analysis were undertaken to investigate the 5-hydroxytryptamine (5-HT) system, neuroinflammation and to identify altered lipid metabolic pathways. RESULTS: Depression-like behaviors, impaired 5-HT neurotransmission and disordered lipid metabolism were observed upon HFD consumption. Despite a similar reduction of high-density lipoprotein cholesterol in CUMS and HFD group, high levels of body low-density lipoprotein cholesterol in the HFD group could help distinguish HFD from CUMS. Levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and inflammation-related metabolites were increased in HFD mice, so a link between depression and inflammation was postulated. Different metabolites were enriched in the two groups. The linoleic acid (LA) metabolic pathway and expression of fatty acid desaturase (FADS)1 and FADS2 (key enzymes in LA metabolic pathway) were enhanced significantly in HFD mice compared with the control group. LIMITATIONS: Causality analyses for HFD and inflammation-related features were not undertaken. CONCLUSIONS: HFD-induced depression-like behaviors was characterized by more severely disordered metabolism of lipids (especially in the LA metabolic pathway) and increased levels of inflammatory mediators, which might be the reasons for the disturbance of serotonergic system in hippocampus.

Rationally Designed Nonapeptides with Great Skin Photoprotective Effect through Producing Type 1 Collagen and Blocking the mTOR Pathway.

Ultraviolet (UV), as the most common environmental stress factor to human skin, causes redox imbalance and leads to photoaging and the development of cancer. In this work, we screened a nonapeptide (PWH) with good activities of antioxidant, promoting the secretion of type 1 collagen (COL-1) and repairing damaged skin from a series of rationally designed novel short peptides. PWH could alleviate UV-A-induced oxidative stress, restrain pro-inflammatory cytokine production, protect mitochondrial function, and maintain autophagy activity. We also first indicated that inhibiting the PI3K/AKT/mTOR signaling pathway and restoration of autophagy activity might delay the photoaging process in skin cells. Topical applications of PWH were further demonstrated to exhibit significant protection in full-wavelength UV-induced skin aging in mice models both in the prophylaxis and treatment way. In addition, given the good stability and without unwanted toxicity and anaphylaxis, PWH could be a promising candidate for cosmetics and pharmaceuticals.

Hydrophobicity Determines the Bacterial Killing Rate of α-Helical Antimicrobial Peptides and Influences the Bacterial Resistance Development.

Rapid antimicrobial action is an important advantage of antimicrobial peptides (AMPs) over antibiotics, which is also a reason for AMPs being less likely to induce bacterial resistance. However, the structural parameters and underlying mechanisms affecting the bacterial killing rate of AMPs remain unknown. In this study, we performed a structure-activity relationship (SAR) study using As-CATH4 and 5 as templates. We revealed that hydrophobicity, rather than other characteristics, is the critical structural parameter determining the bacterial killing rate of α-helical AMPs. With the hydrophobicity increase, the action rates of AMPs including bacterial binding, lipopolysaccharides neutralization, and outer and inner membrane permeabilization increased. Additionally, the higher hydrophobic AMPs with enhanced bacterial killing rates possess better in vivo therapeutic potency and a lower propensity to induce bacterial resistance. These findings revealed the importance of the bacterial killing rate for AMPs and are of great significance to the design and optimization of AMP-related drugs.

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1.

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene­knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low­density lipoprotein cholesterol (LDL­C) and high­density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of ß­cell islets was evaluated by using the insulin resistance index (HOMA­IR) and pancreatic ß­cell secretion index (HOMA­ß). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA­IR decreased since VEGFB was knocked down. Western blotting and RT­qPCR results revealed that the expression levels of VEGFR1 and neuropilin­1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

Reducing VEGFB accelerates NAFLD and insulin resistance in mice via inhibiting AMPK signaling pathway.

OBJECTIVE: Vascular endothelial growth factor B (VEGFB) was regarded to improve lipid metabolism and reduce obesity-related hyperlipidemia. Whether VEGFB participates in lipid metabolism in nonalcoholic fatty liver disease (NAFLD) has not been clear yet. This study investigated the involvement of VEGFB in lipid metabolism and insulin resistance via the AMPK signaling pathway in NAFLD. METHODS: We constructed the animal and cell model of NAFLD after VEGFB gene knockout to detect liver damage and metabolism in NAFLD. Bioinformatics analysis of VEGFB and the AMPK signaling pathway relative genes to verify the differential proteins. And mRNA levels of NAFLD fatty acid metabolism-related genes were detected. RESULTS: After the systemic VEGFB knockout mice were fed with high fat, the body fat, serum lipoprotein, NAFLD score, and insulin resistance were increased. Animal and cell experiments showed that the expression levels of phosphorylated proteins of CaMKK2 and AMPK decreased, the expression of proteins related to AMPK/ACC/CPT1 signaling pathway decreased, and the target genes CPT1α and Lcad decreased accordingly, reducing fatty acid oxidation in hepatocyte mitochondria; The expression of AMPK/SREBP1/Scd1 signaling pathway relative proteins increased, ACC1 and FAS increased correspondingly, which increased lipid synthesis in the endoplasmic reticulum. CONCLUSION: VEGFB can participate in lipid metabolism and insulin resistance of NAFLD through the AMPK signaling pathway.

Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug-resistant infections.

Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are important effector immune defense molecules in multicellular organisms. AMPs exert their antimicrobial activities through several mechanisms; thus far, induction of drug resistance through AMPs has been regarded as unlikely. Therefore, they have great potential as new generation antimicrobial agents. To date, more than 30 AMP-related drugs are in the clinical trial phase. In recent years, studies show that some AMPs and conventional antibiotics have synergistic effects. The combined use of AMPs and antibiotics can kill drug-resistant pathogens, prevent drug resistance, and significantly improve the therapeutic effects of antibiotics. In this review, we discuss the progress in synergistic studies on AMPs and conventional antibiotics. An overview of the current understanding of the functional scope of AMPs, ongoing clinical trials, and challenges in the development processes are also presented.

Defensing role of novel piscidins from largemouth bass (Micropterus salmoides) with evidence of bactericidal activities and inducible expressional delineation.

Micropterus salmoides is an economical important species of freshwater-cultured fish, the in-depth knowledge of its immune system is in urgent development to cope with serious infectious diseases. Piscidin is an important antimicrobial peptide (AMP) family existing in almost all teleosts. However, no piscidin has been reported in largemouth bass. In this study, three novel piscidins (MSPiscidin-1, -2, and -3) were firstly identified and characterized from the largemouth bass. The predicted mature peptides of MSPiscidin-1, -2, and -3 (consists of 24, 27, 25 amino acid residues, respectively) all adopted an amphipathic α-helical conformation representative of cationic AMPs that are important for membrane permeabilization and antibacterial activity. MSPiscidin-2 and -3 indeed displayed strong, broad-spectrum, and highly efficient antimicrobial activities in vitro against aquatic pathogens, but MSPiscidin-1 didn't show direct antimicrobial activity. MSPiscidin-2 and -3 killed bacteria mainly by inducing membrane permeabilization, in addition, they also can interact with bacterial genomic DNA, which might influence the DNA replication and transcription. Besides, MSPiscidin-2 and -3 could effectively inhibit the formation of the bacterial biofilm and eliminate the preformed biofilms. In vivo, MSPiscidin-1-3 genes showed an inducible expression pattern in the tested tissues upon Vibrio harveyi infection, which further indicated the key roles of piscidins in innate immunity in largemouth bass. Overall, this study will supplement the understanding of M. salmoides innate immune system and provide candidates for the design of novel peptide antibacterial agents used in aquaculture.

Evaluating the reparative effects and the mechanism of action of docosahexaenoic acid on azithromycin-induced lipid metabolism dysfunction.

To explore the reparative effects of DHA on the gut microbiome disturbance and dysfunctional lipid metabolism caused by long-term antibiotic therapy, it was tested on an azithromycin (AZI) mouse antibiotic model. Thirty specific-pathogen-free BALB/c mice (SPF grade, half male and half female) were randomly separated into three groups (n = 10, 5 male and 5 female): control group (CK), azithromycin natural recovery group (AZI) and DHA group (DHA). High-throughput sequencing and bioinformatics methods were used to analyze the gut microbiome. ELASE kits were used to measure blood lipid, lipids in the liver, and bile salt hydrolase (BSH) levels in feces. Gas chromatography and UPLC-MS/MS were employed to detect DHA and bile acids contents in liver, respectively. Real-time polymerase chain reaction (RT-PCR) was used to measure the expression of key enzymes involved in lipid metabolism. Long-term AZI treatment led to dyslipidemia, gut microbiome disturbance and anxious behaviors in the mouse model. DHA was found to significantly improve the dyslipidemia and anxiety-like behaviors induced by AZI. DHA had no effect on the structure of gut microbiome and bile acids contents but increased the content of the metabolic enzyme BSH in gut microbiota and normalized the expression of enzymes involved in lipid metabolism.

SPETS: Secure and Privacy-Preserving Energy Trading System in Microgrid.

Recently, the development of distributed renewable energy resources, smart devices, and smart grids empowers the emergence of peer-to-peer energy trading via local energy markets. However, due to security and privacy concerns in energy trading, sensitive information of energy traders could be leaked to an adversary. In addition, malicious users could perform attacks against the energy market, such as collusion, double spending, and repudiation attacks. Moreover, network attacks could be executed by external attackers against energy networks, such as eavesdropping, data spoofing, and tampering attacks. To tackle the abovementioned attacks, we propose a secure and privacy-preserving energy trading system (SPETS). First, a permissioned energy blockchain is presented to perform secure energy transactions between energy sellers and buyers. Second, a discrete-time double auction is proposed for energy allocation and pricing. Third, the concept of reputation scores is adopted to guarantee market reliability and trust. The proposed energy system is implemented using Hyperledger Fabric (HF) where the chaincode is utilized to control the energy market. Theoretical analysis proves that SPETS is resilient to several security attacks. Simulation results demonstrate the increase in sellers' and buyers' welfare by approximately 76.5% and 26%, respectively. The proposed system ensures trustfulness and guarantees efficient energy allocation. The benchmark analysis proves that SPETS consumes few resources in terms of memory and disk usage, CPU, and network utilization.

[Molecular design, pharmacology and toxicology optimization of antimicrobial peptide from Hydrophis cyanocinctus, Hc-CATH].

Based on the cathelicidin family antimicrobial peptide Hc-CATH derived from sea snake, the Hc-16 and Hc-15 of 16 and 15 amino acid residues, were designed. By using CCK8, minimal inhibitory concentration, ELISA and bio-layer interferometry assays, their cytotoxicity, antibacterial activity, anti-inflammatory activity, and LPS neutralization activity was examined. Compared with Hc-15, Hc-16 had lower cytotoxicity and better broad-spectrum antibacterial activity against pathogens including clinically resistant bacteria, with the minimum inhibitory concentration of only 4.69 µg/mL. Hc-16 inhibited the expression of inflammatory cytokines of TNF-α and IL-6 induced by LPS, so as to significantly reduce the inflammatory response induced by infection. In addition, structure-activity relationship studies have shown that the phenylalanine at the C- and N-terminals of Hc-16 played a crucial role in its antibacterial and anti-inflammatory activity. Altogether, the designed Hc-16 has an excellent prospect to be developed into a novel antibiotic.

A clinical variable-based nomogram could predict the survival for advanced NSCLC patients receiving second-line atezolizumab.

OBJECTIVE: A nomogram model based on clinical variables was conducted to predict the survival in patients with non-small cell lung cancer (NSCLC) receiving second-line atezolizumab. METHODS: Four hundred and twenty-four patients with NSCLC receiving atezolizumab from OAK study were regarded as the training cohort. Next, a nomogram model based on clinical variables in the training cohort was established to predict the survival of patients receiving atezolizumab. The concordance index, area under curve (AUC), and calibration plots were used to assess the performance of the nomogram model. In addition, 144 patients with NSCLC receiving atezolizumab from POPLAR study were regarded as the test cohort to validate the nomogram model. Using Kaplan-Meier and log-rank test, we compared the survival difference between the high- and low-risk groups, atezolizumab and docetaxel treatment groups, respectively. RESULTS: We successfully constructed a nomogram model based on different variable scores for predicting the survival in NSCLC patients receiving atezolizumab using the training cohort. According to risk score, patients receiving atezolizumab were divided into the high- and low-risk groups. Importantly, in the training cohort, patients had worse overall survival (OS) in high-risk group compared with the low-risk group (median survival: 252.3 vs. 556.9 days; p < 0.0001). As expected, in the test cohort, the high-risk patients also showed a worse OS (median survival: 288.8 vs. 529.3 days, p = 0.0003). In addition, all the patients from the training and test cohorts could be found the OS benefit from atezolizumab compared with docetaxel (all, p < 0.05). CONCLUSIONS: The clinical variable-based nomogram model could predict the survival benefit for NSCLC patients receiving second-line atezolizumab.

Effects of high-fat diet on the formation of depressive-like behavior in mice.

Depression is an important global health issue that is associated with serious physical and mental health consequences. The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression. Here, we aim to evaluate the effects of high-fat diet (HFD) consumption on depressive-like behaviors. BALB/c mice were grouped randomly: control, chronic restraint stress (CRS), HFD and CRS + HFD groups. The depressive-like behavior was evaluated using behavioral tests. The serotonin content in murine brain tissue and blood lipid concentrations were detected by ELISA. The fatty acid content in the liver, adipose tissue of epididymis, brain tissue, and serum of mice was determined by gas chromatography (GC). Expression of the fatty acid synthesis pathway-related enzymes at the mRNA level was analyzed by qRT-PCR. The results indicated that a high-fat diet could promote depressive-like behavior. In comparison with regular feeding, concentrations of blood lipids were significantly changed in the HFD group. Correlation analysis implied that high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were closely related to depressive-like behavior. Based on fatty acid analysis, the palmitoleic acid, linoleic acid, oleic acid, and arachidonic acid content was remarkably changed in mice with depressive-like behavior. In addition, acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid desaturase 1 (FADS1), and fatty acid desaturase 2 (FADS2) expression, which are involved in de novo fatty acid synthesis, desaturation of fatty acids, and arachidonic acid synthesis, were strengthened in HFD mice with depressive-like behavior. Therefore, we postulated that the disorder of lipid metabolism induced by HFD consumption accelerated the development of depressive-like behavior.

Repurposing existing medications for coronavirus disease 2019: protocol for a rapid and living systematic review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has no confirmed specific treatments. However, there might be in vitro and early clinical data as well as evidence from severe acute respiratory syndrome and Middle Eastern respiratory syndrome that could inform clinicians and researchers. This systematic review aims to create priorities for future research of drugs repurposed for COVID-19. METHODS: This systematic review will include in vitro, animal, and clinical studies evaluating the efficacy of a list of 34 specific compounds and 4 groups of drugs identified in a previous scoping review. Studies will be identified both from traditional literature databases and pre-print servers. Outcomes assessed will include time to clinical improvement, time to viral clearance, mortality, length of hospital stay, and proportions transferred to the intensive care unit and intubated, respectively. We will use the GRADE methodology to assess the quality of the evidence. DISCUSSION: The challenge posed by COVID-19 requires not just a rapid review of drugs that can be repurposed but also a sustained effort to integrate new evidence into a living systematic review. TRIAL REGISTRATION: PROSPERO 2020 CRD42020175648.

A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy.

BACKGROUND: Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. METHODS: Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0. RESULTS: A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. CONCLUSIONS: As an early index that can reflect the tissue's radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future's clinical work.

Helicobacter pylori causes delayed gastric emptying by decreasing interstitial cells of Cajal.

Helicobacter pylori (HP) infection is one of the most frequent bacterial infections in humans and is associated with the pathogenesis of gastric motility disorders such as delayed gastric emptying (DGE). Although HP infection is considered to delay gastric emptying, there has been little research on the underlying mechanism. Gastric motility involves interactions among gastrointestinal hormones, smooth muscle, enteric and extrinsic autonomic nerves and interstitial cells of Cajal (ICCs), and ICCs play an important role in gastrointestinal motility. Mutation or loss of stem cell factor (SCF) expression is known to reduce the number of ICCs or alter the integrity of the ICC network, contributing to gastrointestinal dysmotility. The aim of the present study was to investigate whether a reduction in ICCs contributes to the DGE caused by HP. A mouse model of HP infection was established and gastric emptying was compared between HP-infected and uninfected mice using the bead method. In addition, ICC counts and SCF expression levels in gastric tissue were evaluated using immunohistochemistry and western blotting, respectively. The results revealed that gastric emptying was significantly slower, the number of ICCs in gastric tissue was significantly reduced and the protein level of SCF in gastric tissue was significantly decreased in HP-infected mice compared with uninfected mice. Therefore, it may be concluded that HP reduced the number of ICCs by decreasing the expression of SCF protein in gastric tissue, thereby causing DGE.