Correlation between the neuroendocrine axis,microbial species,inflammatory response,and gastrointestinal symptoms in irritable bowel syndrome

BACKGROUND This study examines the complex relationships among the neuroendocrine axis,gut microbiome,inflammatory responses,and gastrointestinal symptoms in patients with irritable bowel syndrome(IBS).The findings provide new insights into the pathophysiology of IBS and suggest potential therapeutic targets for improving patient outcomes.AIM To investigate the interactions between the neuroendocrine axis,gut microbiome,inflammation,and gastrointestinal symptoms in patients with IBS.METHODS Patients diagnosed with IBS between January 2022 and January 2023 were selected for the study.Healthy individuals undergoing routine check-ups during the same period served as the control group.Data were collected on neuroendocrine hormone levels,gut microbiome profiles,inflammatory biomarkers,and gastrointestinal symptomatology to analyze their interrelations and their potential roles in IBS pathogenesis.RESULTS IBS patients exhibited significant dysregulation of the neuroendocrine axis,with altered levels of cortisol,serotonin,and neuropeptides compared to healthy controls.The gut microbiome of IBS patients showed reduced diversity and specific alterations in bacterial genera,including Bifidobacterium,Lactobacillus,and Faecalibacterium,which were associated with neuroendocrine disturbances.Additionally,elevated levels of inflammatory markers,such as C-reactive protein,interleukin-6,and tumor necrosis factor-α,were observed and correlated with the severity of gastrointestinal symptoms like abdominal pain,bloating,and altered bowel habits.CONCLUSION The findings suggest that targeting the neuroendocrine axis,gut microbiome,and inflammatory pathways may offer novel therapeutic strategies to alleviate symptoms and improve the quality of life in IBS patients.

Micro-alloying of Zn and Ca in vacuum induction casted bioresorbable Mg system:Perspectives on corrosion resistance,cytocompatibility,and inflammatory response

There is an increasing interest in biodegradable materials,such as magnesium,for orthopaedic implants.This is driven by their potential to address challenges like stress shielding and the need for secondary removal surgery.In this study,biodegradable magnesium alloys were produced using the Vacuum Induction Casting technique.The impact of micro-alloying Zn and Ca in Mg-xZn-0.2Ca(x=0.1,0.2,0.3,and 0.4 wt%)alloys on corrosion resistance,cytocompatibility,and early-stage inflammatory response was investigated.XRD and SEM-EDS analysis confirmed the presence of Ca_(2)Mg_(6)Zn_(3)secondary phases in all alloys.The Mg-0.3Zn-0.2Ca alloy exhibited the lowest corrosion rate and an elastic modulus of 36.8 GPa,resembling that of natural bone.Electrochemical measurements indicated a correlation between grain size and secondary phase volume fraction in explaining corrosion behaviour.In vitro degradation in simulated body fluid(SBF)for 21 days showed hydroxyapatite formation on alloy surfaces,aligning with electrochemical studies.In vitro cytotoxicity tests demonstrated the cytocompatibility of all alloys,with Mg-0.3Zn-0.2Ca having the highest cell viability over a 6-day cell culture.Investigation into the inflammatory response with RAW-Blue macrophages revealed the anti-inflammatory properties of Mg-0.3Zn-0.2Ca alloys.Micro-alloying with 0.3 wt%Zn and 0.2 wt%Ca enhanced mechanical properties,corrosion resistance,cytocompatibility,and immunomodulatory properties.This positions the Mg-0.3Zn-0.2Ca alloy as a promising biodegradable implant for bone fixation applications.

Preoperative systemic inflammatory response index as a prognostic marker for distal cholangiocarcinoma after pancreatoduodenectomy

BACKGROUND The relationship between preoperative inflammation status and tumorigenesis as well as tumor progression is widely acknowledged.AIM To assess the prognostic significance of preoperative inflammatory biomarkers in patients with distal cholangiocarcinoma(dCCA)who underwent pancreat-oduodenectomy(PD).METHODS This single-center study included 216 patients with dCCA after PD between January 1,2011,and December 31,2022.The individuals were categorized into two sets based on their systemic inflammatory response index(SIRI)levels:A low SIRI group(SIRI<1.5,n=123)and a high SIRI group(SIRI≥1.5,n=93).Inflam-matory biomarkers were evaluated for predictive accuracy using receiver operating characteristic curves.Both univariate and multivariate Cox proportional hazards analyses were performed to estimate SIRI for overall survival(OS)and recurrence-free survival(RFS).RESULTS The study included a total of 216 patients,with 58.3%being male and a mean age of 65.6±9.6 years.123 patients were in the low SIRI group and 93 were in the high SIRI group after PD for dCCA.SIRI had an area under the curve value of 0.674 for diagnosing dCCA,showing better performance than other inflammatory biomarkers.Multivariate analysis indicated that having a SIRI greater than 1.5 independently increased the risk of dCCA following PD,leading to lower OS[hazard ratios(HR)=1.868,P=0.006]and RFS(HR=0.949,P<0.001).Additionally,survival analysis indicated a significantly better prognosis for patients in the low SIRI group(P<0.001).CONCLUSION It is determined that a high SIRI before surgery is a significant risk factor for dCCA after PD.

Systemic inflammatory response index is a predictor of prognosis in gastric cancer patients: Retrospective cohort and meta-analysis

BACKGROUND The systemic inflammatory response index(SIRI)has been demonstrated to make a significant difference in assessing the prognosis of patients with different solid neoplasms.However,research is needed to ascertain the accuracy and reliability of applying the SIRI to patients who undergo robotic radical gastric cancer sur-gery.AIM To validate the applicability of the SIRI in assessing the survival of gastric cancer patients and evaluate the clinical contribution of preoperative SIRI levels to predicting long-term tumor outcomes in patients,who received robotic radical gastric cancer surgery.METHODS Initially,an exhaustive retrieval was performed in the PubMed,the Cochrane Library,EMBASE,Web of Science,and Scopus databases to identify relevant studies.Subsequently,a meta-analysis was executed on 6 cohort studies iden-tifying the value of the SIRI in assessing the survival of gastric cancer patients.Additionally,the clinical data of 161 patients undergoing robotic radical gastric cancer surgery were retrospectively analyzed to evaluate their clinicopathological characteristics and relevant laboratory indicators.The association between preoperative SIRI levels and 5-year overall survival(OS)and disease-free survival(DFS)was assessed.RESULTS The findings demonstrated an extensive connection between SIRI values and the outcome of patients with gastric cancer.Preoperative SIRI levels were identified as an independent hazard feature for both OS and DFS among those who received robotic surgery for gastric cancer.SIRI levels in gastric cancer patients were observed to be associated with the presence of comorbidities,T-stage,carcinoembryonic antigen levels,the development of early serious postoperative complications,and the rate of lymph node metastasis.CONCLUSION SIRI values are correlated with adverse in the gastric cancer population and have the potential to be utilized in predicting long-term oncological survival in patients who undergo robotic radical gastric cancer surgery.

Inflammatory responses in esophageal mucosa before and after laparoscopic antireflux surgery

BACKGROUND Currently,the primary treatment for gastroesophageal reflux is acid suppression with proton pump inhibitors,but they are not a cure,and some patients don’t respond well or refuse long-term use.Therefore,alternative therapies are needed to understand the disease and develop better treatments.Laparoscopic anti-reflux surgery(LARS)can resolve symptoms of these patients and plays a significant role in evaluating esophageal healing after preventing harmful effects.Successful LARS improves typical gastroesophageal reflux symptoms in most patients,main-ly by reducing the exposure time to gastric contents in the esophagus.Amelio-ration of the inflammatory response and a recovery response in the esophageal epithelium is expected following the cessation of the noxious attack.AIM To explore the role of inflammatory biomolecules in LARS and assess the time required for esophageal epithelial recovery.METHODS Of 22 patients with LARS(pre-and post/5.8±3.8 months after LARS)and 25 healthy controls(HCs)were included.All subjects underwent 24-h multichannel intraluminal impedance-pH monitoring and upper gastrointestinal endoscopy,during which esophageal biopsy samples were collected using endoscopic tech-niques.Inflammatory molecules in esophageal biopsies were investigated by reverse transcription-polymerase chain reaction and multiplex-enzyme-linked immunosorbent assay.RESULTS Post-LARS samples showed significant increases in proinflammatory cytokines[interleukin(IL)-1β,interferon-γ,C-X-C chemokine ligand 2(CXCL2)],anti-inflammatory cytokines[CC chemokine ligand(CCL)11,CCL13,CCL17,CCL26,CCL1,CCL7,CCL8,CCL24,IL-4,IL-10],and homeostatic cytokines(CCL27,CCL20,CCL19,CCL23,C-CL25,CXCL12,migration inhibitory factor)compared to both HCs and pre-LARS samples.CCL17 and CCL21 levels were higher in pre-LARS than in HCs(P<0.05).The mRNA expression levels of AKT1,fibroblast growth factor 2,HRAS,and mitogen-activated protein kinase 4 were significantly decreased post-LARS vs pre-LARS.CCL2 and epidermal growth factor gene levels were significantly increased in the pre-LARS compared to the HCs(P<0.05).CONCLUSION The presence of proinflammatory proteins post-LARS suggests ongoing inflammation in the epithelium.Elevated homeostatic cytokine levels indicate cell balance is maintained for about 6 months after LARS.The anti-inflam-matory response post-LARS shows suppression of inflammatory damage and ongoing postoperative recovery.

Mufangji tang ameliorates pulmonary arterial hypertension through improving vascular remodeling,inhibiting inflammatory response and oxidative stress,and inducing apoptosis

Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.

Antagonistic Effects of N-acetylcysteine on Mitogen-activated Protein Kinase Pathway Activation, Oxidative Stress and Inflammatory Responses in Rats with PM2.5 Induced Lung Injuries

Objective To evaluate the antagonistic effects of N-acetylcysteine(NAC)on mitogen-activated protein kinases(MAPK)pathway activation,oxidative stress and inflammatory responses in rats with lung injury induced by fine particulate matter(PM2.5).Methods Forty eight male Wistar rats were randomly divided into six groups:blank control group(C1),water drip control group(C2),PM2.5 exposed group(P),low-dose NAC treated and PM2.5 exposed group(L),middle-dose NAC treated and PM2.5 exposed group(M),and high-dose NAC treated and PM2.5 exposed group(H).PM2.5 suspension(7.5 mg/kg)was administered tracheally once a week for four times.NAC of 125 mg/kg,250 mg/kg and 500 mg/kg was delivered intragastrically to L,M and H group respectively by gavage(10 ml/kg)for six days before PM2.5 exposure.The histopathological changes and human mucin 5 subtype AC(MUC5AC)content in lung tissue of rats were evaluated.We investigated IL-6 in serum and bronchoalveolar lavage fluid(BALF)by Enzyme-linked immunosorbent assay(ELISA),MUC5AC in lung tissue homogenate by ELISA,glutathione peroxidase(GSH-PX)in serum and BALF by spectrophotometry,and the expression of p-ERK1/2,p-JNK1/2 and p-p38 proteins by Western blot.All the measurements were analyzed and compared statistically.Results Lung tissue of rats exposed to PM2.5 showed histological destruction and increased mucus secretion of bronchial epithelial cells.Rats receiving NAC treatment showed less histological destruction and mucus secretion.Of P,L,M and H group,MUC5AC in lung tissue,IL-6 in serum and BALF were higher than controls(C1 and C2)(all P<0.05),with the highest levels found in the P group and a decreasing trend with increase of NAC dose.The activity of GSH-PX in serum and BALF of PM2.5 exposed rats(P,L,M and H)was lower than that of controls(all P<0.05),with higher activities found in NAC treated rats(L,M,and H),and an increasing trend with increase of NAC dose.The expressions of p-ERK1/2,p-JNK1/2 and p-p38 proteins in PM2.5 exposed lung tissue(P,L,M and H)was higher than controls(all P<0.05),with decreased levels and dose dependent downregulation found in NAC treated rats.Conclusion NAC can antagonize major MAPK pathway activation,lung oxidative stress and inflammatory injury induced by PM2.5 in rats.

A theory for three-dimensional response of micropolar plates

Through combined applications of the transfer-matrix method and asymptotic expansion technique,we formulate a theory to predict the three-dimensional response of micropolar plates.No ad hoc assumptions regarding through-thickness assumptions of the field variables are made,and the governing equations are two-dimensional,with the displacements and microrotations of the mid-plane as the unknowns.Once the deformation of the mid-plane is solved,a three-dimensional micropolar elastic field within the plate is generated,which is exact up to the second order except in the boundary region close to the plate edge.As an illustrative example,the bending of a clamped infinitely long plate caused by a uniformly distributed transverse force is analyzed and discussed in detail.

Computed tomography radiomic features and clinical factors predicting the response to first transarterial chemoembolization in intermediate-stage hepatocellular carcinoma

Background:According to clinical practice guidelines,transarterial chemoembolization(TACE)is the standard treatment modality for patients with intermediate-stage hepatocellular carcinoma(HCC).Early prediction of treatment response can help patients choose a reasonable treatment plan.This study aimed to investigate the value of the radiomic-clinical model in predicting the efficacy of the first TACE treatment for HCC to prolong patient survival.Methods:A total of 164 patients with HCC who underwent the first TACE from January 2017 to September 2021 were analyzed.The tumor response was assessed by modified response evaluation criteria in solid tumors(mRECIST),and the response of the first TACE to each session and its correlation with overall survival were evaluated.The radiomic signatures associated with the treatment response were identified by the least absolute shrinkage and selection operator(LASSO),and four machine learning models were built with different types of regions of interest(ROIs)(tumor and corresponding tissues)and the model with the best performance was selected.The predictive performance was assessed with receiver operating characteristic(ROC)curves and calibration curves.Results:Of all the models,the random forest(RF)model with peritumor(+10 mm)radiomic signatures had the best performance[area under ROC curve(AUC)=0.964 in the training cohort,AUC=0.949 in the validation cohort].The RF model was used to calculate the radiomic score(Rad-score),and the optimal cutoff value(0.34)was calculated according to the Youden’s index.Patients were then divided into a high-risk group(Rad-score>0.34)and a low-risk group(Rad-score≤0.34),and a nomogram model was successfully established to predict treatment response.The predicted treatment response also allowed for significant discrimination of Kaplan-Meier curves.Multivariate Cox regression identified six independent prognostic factors for overall survival,including male[hazard ratio(HR)=0.500,95%confidence interval(CI):0.260–0.962,P=0.038],alpha-fetoprotein(HR=1.003,95%CI:1.002–1.004,P<0.001),alanine aminotransferase(HR=1.003,95%CI:1.001–1.005,P=0.025),performance status(HR=2.400,95%CI:1.200–4.800,P=0.013),the number of TACE sessions(HR=0.870,95%CI:0.780–0.970,P=0.012)and Rad-score(HR=3.480,95%CI:1.416–8.552,P=0.007).Conclusions:The radiomic signatures and clinical factors can be well-used to predict the response of HCC patients to the first TACE and may help identify the patients most likely to benefit from TACE.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Probiotics: Shaping the gut immunological responses

Probiotics are live microorganisms exerting beneficial effects on the host’s health when administered in adequate amounts.Among the most popular and adequately studied probiotics are bacteria from the families Lactobacillaceae,Bifidobacteriaceae and yeasts.Most of them have been shown,both in vitro and in vivo studies of intestinal inflammation models,to provide favorable results by means of improving the gut microbiota composition,promoting the wound healing process and shaping the immunological responses.Chronic intestinal conditions,such as inflammatory bowel diseases(IBD),are characterized by an imbalance in microbiota composition,with decreased diversity,and by relapsing and persisting inflammation,which may lead to mucosal damage.Although the results of the clinical studies investigating the effect of probiotics on patients with IBD are still controversial,it is without doubt that these microorganisms and their metabolites,now named postbiotics,have a positive influence on both the host’s microbiota and the immune system,and ultimately alter the topical tissue microenvironment.This influence is achieved through three axes:(1)By dis-placement of potential pathogens via competitive exclusion;(2)by offering protection to the host through the secretion of various defensive mediators;and(3)by supplying the host with essential nutrients.We will analyze and discuss almost all the in vitro and in vivo studies of the past 2 years dealing with the possible favorable effects of certain probiotic genus on gut immunological responses,highlighting which species are the most beneficial against intestinal inflammation.

Inflammation: Complexity and significance of cellular and molecular responses

Inflammation is a multifaceted cellular and molecular response triggered by injury,infection,or various pathological conditions.Serving as a protective defense mechanism,the inflammatory response involves clinical signs like redness,swelling,pain,and increased body temperature.Immune cells,notably neutrophils and macrophages,play key roles in orchestrating this response.The delicate balance between proinflammatory and anti-inflammatory mediators,including cytokines and chemokines,regulates the inflammatory cascade.While acute inflammation is crucial for tissue repair,chronic inflammation may indicate an imbalance,contributing to conditions like autoimmune diseases.Understanding these mechanisms is vital for developing therapeutic strategies and managing chronic diseases.

Thermo-hydro-poro-mechanical responses of a reservoir-induced landslide tracked by high-resolution fiber optic sensing nerves

Thermo-poro-mechanical responses along sliding zone/surface have been extensively studied.However,it has not been recognized that the potential contribution of other crucial engineering geological interfaces beyond the slip surface to progressive failure.Here,we aim to investigate the subsurface multiphysics of reservoir landslides under two extreme hydrologic conditions(i.e.wet and dry),particularly within sliding masses.Based on ultra-weak fiber Bragg grating(UWFBG)technology,we employ specialpurpose fiber optic sensing cables that can be implanted into boreholes as“nerves of the Earth”to collect data on soil temperature,water content,pore water pressure,and strain.The Xinpu landslide in the middle reach of the Three Gorges Reservoir Area in China was selected as a case study to establish a paradigm for in situ thermo-hydro-poro-mechanical monitoring.These UWFBG-based sensing cables were vertically buried in a 31 m-deep borehole at the foot of the landslide,with a resolution of 1 m except for the pressure sensor.We reported field measurements covering the period 2021 and 2022 and produced the spatiotemporal profiles throughout the borehole.Results show that wet years are more likely to motivate landslide motions than dry years.The annual thermally active layer of the landslide has a critical depth of roughly 9 m and might move downward in warmer years.The dynamic groundwater table is located at depths of 9e15 m,where the peaked strain undergoes a periodical response of leap and withdrawal to annual hydrometeorological cycles.These interface behaviors may support the interpretation of the contribution of reservoir regulation to slope stability,allowing us to correlate them to local damage events and potential global destabilization.This paper also offers a natural framework for interpreting thermo-hydro-poro-mechanical signatures from creeping reservoir bank slopes,which may form the basis for a landslide monitoring and early warning system.

Effects of Rosa roxburghii&edible fungus fermentation broth on immune response and gut microbiota in immunosuppressed mice

With the rise of probiotics fermentation in food industry,fermented foods have attracted worldwide attention.In this study,protective effects of Rosa roxburghii&edible fungus fermentation broth(REFB)on immune function and gut health in Cyclophosphamide induced immunosuppressed mice were investigated.Results showed that REFB could improve the immune organ index,and promote the proliferation and differentiation of splenic T lymphocytes.In addition,it attenuated intestinal mucosal damage and improved intestinal cellular immunity.REFB administration also up-regulated the expression of IL-4,INF-γ,TNF-α,T-bet and GATA-3 mRNA in small intestine.Furthermore,administration of REFB modulated gut microbiota composition and increased the relative abundance of beneficial genus,such as Bacteroides.It also increased the production of fecal short-chain fatty acids.These indicate that REFB has the potential to improve immunity,alleviate intestinal injury and regulate gut microbiota in immunosuppressed mice.

Prognostic value of preoperative prognostic nutritional index and its associations with systemic inflammatory response markers in patients with stage Ⅲ colon cancer

Background: The prognostic nutritional index(PNI) has been widely applied for predicting survival outcomes of patients with various malignant tumors. Although a low PNI predicts poor prognosis in patients with colorectal cancer after tumor resection, the prognostic value remains unknown in patients with stage Ⅲ colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy. This study aimed to investigate the prognostic value of PNI in patients with stage III colon cancer.Methods: Medical records of 274 consecutive patients with stage Ⅲ colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December2013 were reviewed. The optimal PNI cutoff value was determined using receiver operating characteristic(ROC) curve analysis. The associations of PNI with systemic inflammatory response markers, including lymphocyte-to-monocyte ratio(LMR), neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), and C-reactive protein(CRP)level, and clinicopathologic characteristics were assessed using the Chi square or Fisher's exact test. Correlation analysis was performed using Spearman's correlation coefficient. Disease-free survival(DFS) and overall survival(OS)stratified by PNI were analyzed using Kaplan-Meier method and log-rank test, and prognostic factors were identified by Cox regression analyses.Results: The preoperative PNI was positively correlated with LMR(r= 0.483, P < 0.001) and negatively correlated with NLR(r =-0.441, P < 0.001), PLR(r =-0.607, P < 0.001), and CRP level(r =-0.333, P < 0.001). A low PNI(≤49.22)was significantly associated with short OS and DFS in patients with stage ⅢC colon cancer but not in patients with stage ⅢA/ⅢB colon cancer.In addition, patients with a low PNI achieved a longer OS and DFS after being treated with6-8 cycles of adjuvant chemotherapy than did those with < 6 cycles. Multivariate analyses revealed that PNI was independently associated with DFS(hazard ratios 2.001; 95% confidence interval 1.157-3.462; P = 0.013).Conclusion: The present study identified preoperative PNI as a valuable predictor for survival outcomes in patients with stage Ⅲ colon cancer receiving curative tumor resection followed by adjuvant chemotherapy.

Time-domain dynamic constitutive model suitable for mucky soil site seismic response

Soil nonlinear behavior displays noticeable effects on the site seismic response.This study proposes a new functional expression of the skeleton curve to replace the hyperbolic skeleton curve.By integrating shear modulus and combining the dynamic skeleton curve and the damping degradation coefficient,the constitutive equation of the logarithmic dynamic skeleton can be obtained,which considers the damping effect in a soil dynamics problem.Based on the finite difference method and the multi-transmitting boundary condition,a 1D site seismic response analysis program called Soilresp1D has been developed herein and used to analyze the time-domain seismic response in three types of sites.At the same time,this study also provides numerical simulation results based on the hyperbolic constitutive model and the equivalent linear method.The results verify the rationality of the new soil dynamic constitutive model.It can analyze the mucky soil site nonlinear seismic response,reflecting the deformation characteristics and damping effect of the silty soil.The hysteresis loop area is more extensive,and the residual strain is evident.

Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses

AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY ) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by mea-suring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by downregulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4 + CD25 + Foxp3 + regulatory T cells (TGF-β, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05). CONCLUSION: MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD.

Effect of glutarnate on inflammatory responses of intestine and brain after focal cerebral ischemia

AIM: To study the modulation of glutamate on post-ischemic intestinal and cerebral inflammatory responses in a ischemic and excitotoxic rat model.METHODS: Adult male rats were subjected to bilateral carotid artery occlusion for 15 min and injection of monosodium glutamate intraperitoneally, to decapitate them at selected time points. Tumor necrosis factor alpha (TNF-α) level and nuclear factor kappa B (NF-κB) activity were determined by enzyme-linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA), respectively.Hemodynamic parameters were monitored continuously during the whole process of cerebral ischemia and reperfusion.RESULTS: Monosodium glutamate (MSG) treated rats displayed statistically significant high levels of TNF-α in cerebral and intestinal tissuess within the first 6 h of ischemia. The rats with cerebral ischemia showed a minor decrease of TNF-α production in cerebral and intestinal tissuess. The rats with cerebral ischemia and treated with MSG displayed statistically significant low levels of TNF-α in cerebral and intestinal tissues. These results correlated significantly with NF-κB production calculated at the same intervals. During experiment, the mean blood pressure and heart rates in all groups were stable.CONCLUSION: Glutamate is involved in the mechanism of intestinal and cerebral inflammation responses. The effects of glutamate on cerebral and intestinal inflammatory responses after ischemia are up-regulated at the transcriptional level,through the NF-κB signal transduction pathway.

Computed tomography-based nomogram of Siewert type Ⅱ/Ⅲ adenocarcinoma of esophagogastric junction to predict response to docetaxel, oxaliplatin and S-1

BACKGROUND Neoadjuvant chemotherapy(NAC)has become the standard care for advanced adenocarcinoma of esophagogastric junction(AEG),although a part of the patients cannot benefit from NAC.There are no models based on baseline computed tomography(CT)to predict response of Siewert type II or III AEG to NAC with docetaxel,oxaliplatin and S-1(DOS).AIM To develop a CT-based nomogram to predict response of Siewert type II/III AEG to NAC with DOS.METHODS One hundred and twenty-eight consecutive patients with confirmed Siewert type II/III AEG underwent CT before and after three cycles of NAC with DOS,and were randomly and consecutively assigned to the training cohort(TC)(n=94)and the validation cohort(VC)(n=34).Therapeutic effect was assessed by disease-control rate and progressive disease according to the Response Evaluation Criteria in Solid Tumors(version 1.1)criteria.Possible prognostic factors associated with responses after DOS treatment including Siewert classification,gross tumor volume(GTV),and cT and cN stages were evaluated using pretherapeutic CT data in addition to sex and age.Univariate and multivariate analyses of CT and clinical features in the TC were performed to determine independent factors associated with response to DOS.A nomogram was established based on independent factors to predict the response.The predictive performance of the nomogram was evaluated by Concordance index(C-index),calibration and receiver operating characteristics curve in the TC and VC.RESULTS Univariate analysis showed that Siewert type(52/55 vs 29/39,P=0.005),pretherapeutic cT stage(57/62 vs 24/32,P=0.028),GTV(47.3±27.4 vs 73.2±54.3,P=0.040)were significantly associated with response to DOS in the TC.Multivariate analysis of the TC also showed that the pretherapeutic cT stage,GTV and Siewert type were independent predictive factors related to response to DOS(odds ratio=4.631,1.027 and 7.639,respectively;all P<0.05).The nomogram developed with these independent factors showed an excellent performance to predict response to DOS in the TC and VC(C-index:0.838 and 0.824),with area under the receiver operating characteristic curve of 0.838 and 0.824,respectively.The calibration curves showed that the practical and predicted response to DOS effectively coincided.CONCLUSION A novel nomogram developed with pretherapeutic cT stage,GTV and Siewert type predicted the response of Siewert type II/III AEG to NAC with DOS.

In vivo and in vitro protective effect of arginine against intestinal inflammatory response induced by Clostridium perfringens in broiler chickens

Background:Necrotic enteritis is a widespread disease in poultry caused by Clostridium perfringens.We previously reported that dietary arginine supplementation protected the intestinal mucosa of broiler chickens with necrotic enteritis,but the related protective mechanisms remain unclear.The in vivo trial was designed as a 2×2 factorial arrangement to evaluated the effects of arginine supplementation on inflammatory responses,arginine transporters,arginine catabolism and JAK-STAT signalling pathway in broiler chickens challenged with C.perfringens or without C.perfringens.Furthermore,we validated the in vivo results using intestinal epithelial cells of chicken embryos.Results:C.perfringens infection markedly increased gut gross pathological and histopathological lesion scores,promoted liver C.perfringens invasion,reduced serum arginine levels,and elevated jejunal mucosal lysozyme activities(P<0.05),but these effects were significantly reversed by arginine supplementation in vivo(P<0.05).The challenge significantly increased serum procalcitonin levels,jejunal mucosal iNOS activities and jejunal IL-6,TGF-β3,cationic amino acid transporter(CAT)-1,and CAT-3 mRNA expression(P<0.05),whereas arginine supplementation significantly reduced jejunal IFN-γ,IL-1β,IL-6,IL-10,TGF-β3,and CAT-3 mRNA expression(P<0.05).Arginine supplementation significantly attenuated the C.perfringens challenge-induced increases in jejunal i NOS,arginase 2,arginine decarboxylase,arginine:glycine amidinotransferase,JAK1,JAK3,STAT1,and STAT6 mRNA expression(P<0.05).The in vitro experiment showed that C.perfringens challenge markedly increased cellular cytotoxicity and the mRNA expression of IL-1β,IL-8,IL-10,CAT-1 and CAT-3(P<0.05),which were significantly reversed by 50μmol/L and/or400μmol/L arginine pre-treatment(P<0.05).Conclusions:Arginine prevented C.perfringens challenge-induced circulated arginine deficiency,normalized intestinal arginine transport and catabolism,down-regulated JAK-STAT signalling pathway and attenuated the inflammatory response,which exerted protective effects on the intestine of broiler chickens.