Combined Influence of Insulin Resistance and Inflammatory Biomarkers on Type 2 Diabetes:A Population-based Prospective Cohort Study of Inner Mongolians in China

This prospective study was designed to examine the combined influence of insulin resistance（IR）and inflammatory biomarker levels on type 2 diabetes mellitus（T2DM）among 1,903Inner Mongolians.

Current advances in circulating inflammatory biomarkers in atherosclerosis and related cardio-cerebrovascular diseases

Atherosclerosis (AS) is a systemic chronic disease affecting both the coronary and cerebral arteries. Inflammation plays a key role in the initiation and progression of AS, and numerous inflammatory factors have been proposed as potential biomarkers. This article reviews recent research in studies on major circulating inflammatory biomarkers to identify surrogates that may reflect processes associated with AS development and the risk of AS-related vascular events, such as Von Willebrand factor, lectin-like oxidized low-density-lipoprotein receptor-1, soluble urokinase plasminogen activator receptor, regulated upon activation, normal T-cell expressed and secreted, and microparticles, which may provide new perspectives for clinical AS evaluation and risk stratification.

Biomarkers in inflammatory bowel diseases:Current status and proteomics identification strategies

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.

Pan-immune-inflammation value as a prognostic biomarker for colon cancer and its variation by primary tumor location

BACKGROUND A growing body of research indicates significant differences between left-sided colon cancers(LCC)and right-sided colon cancers(RCC).Pan-immune-inflammation value(PIV)is a systemic immune response marker that can predict the prognosis of patients with colon cancer.However,the specific distinction between PIV of LCC and RCC remains unclear.AIM To investigate the prognostic and clinical significance of PIV in LCC and RCC patients.METHODS This multicenter retrospective cohort study included 1510 patients with colon cancer,comprising 801 with LCC and 709 with RCC.We used generalized lifting regression analysis to evaluate the relative impact of PIV on disease-free survival(DFS)in these patients.Kaplan-Meier analysis,as well as univariate and multivariate analyses,were used to examine the risk factors for DFS.The correlation between PIV and the clinical characteristics was statistically analyzed in these patients.RESULTS A total of 1510 patients{872 female patients(58%);median age 63 years[interquartile ranges(IQR):54-71];patients with LCC 801(53%);median follow-up 44.17 months(IQR 29.67-62.32)}were identified.PIV was significantly higher in patients with RCC[median(IQR):214.34(121.78-386.72)vs 175.87(111.92-286.84),P<0.001].After propensity score matching,no difference in PIV was observed between patients with LCC and RCC[median(IQR):182.42(111.88-297.65)vs 189.45(109.44-316.02);P=0.987].PIV thresholds for DFS were 227.84 in LCC and 145.99 in RCC.High PIV(>227.84)was associated with worse DFS in LCC[PIV-high:Adjusted hazard ratio(aHR)=2.39;95%confidence interval:1.70-3.38;P<0.001]but not in RCC(PIV-high:aHR=0.72;95%confidence interval:0.48-1.08;P=0.114).CONCLUSION These findings suggest that PIV may predict recurrence in patients with LCC but not RCC,underscoring the importance of tumor location when using PIV as a colon cancer biomarker.

Prognostic impact of inflammatory and nutritional biomarkers in pancreatic cancer

Pancreatic cancer is usually associated with a poor prognosis.Surgery is the main curative treatment but pancreatic operations are aggressive and new tools that help clinicians to predict surgical and prognostic outcomes are necessary.Lu et al recently published a retrospective,single centre cohort study evaluating the impact of seven nutritional and inflammatory markers in pancreatic cancer surgical patients:The albumin-to-globulin ratio,prognostic nutritional index(PNI),systemic immune-inflammation index(SII),neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),nutritional risk index,and the geriatric nutritional risk index.A significant correlation was found between the PNI,SII,NLR,and PLR and a hospital discharge of less than 15 days.In a univariable analysis,PNI,SII,NLR and PLR were significantly related to recurrence-free survival and,in a multivariable analysis PNI was associated with overall survival.Various meta-analyses corroborate the results in terms of prognosis but individual studies are discordant on their usefulness.Besides,the cut-off values for these markers vary significantly between studies and there are no clinical trials comparing them to identify the most relevant ones.These are limitations when implementing nutritional and inflammatory biomarkers into clinical practice and further studies are needed in order to answer these questions.

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Neutrophil Count, Platelet Indices, CRP and Their Association with Disease Activity of Juvenile Idiopathic Arthritis (JIA): A Study from Bangladesh

Background: Chronic inflammation of the joints in JIA patients is associated with raised levels of serum inflammatory biomarkers, which vary according to disease activity. Neutrophil count, platelet count, mean platelet volume (MPV), platelet distribution width (PDW), ESR and CRP are the essential markers to evaluate the disease activity status of JIA patients. Objectives: To assess neutrophil count, platelet count, MPV, PDW, CRP and Juvenile Arthritis Disease Activity Score (JADAS) in JIA patients and determine their association at the initial visit and six months after treatment. Methods: This prospective observational study was conducted from March 2019 to December 2020 in the department of paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Fifty newly diagnosed JIA cases fulfilling the ILAR classification criteria were included in the study. Disease activity was assessed by JADAS 27. JADAS 27 and inflammatory biomarkers were measured at the initial visit and six months of treatment and these were compared. Results: Mean neutrophil count, platelet count, and CRP significantly decreased at follow-up after six months of treatment. MPV and PDW were increased after six months compared to the initial visit, and the change was significant. Mean JADAS 27 also decreased significantly at follow-up. Neutrophil count, Platelet indices and CRP had a significant association with JADAS 27. Conclusion: In this study, neutrophil count, platelet indices, and CRP after six months of treatment were improved. A significant association of JADAS 27 was found with platelet indices, neutrophil count and CRP.

Value of Preoperative Neutrophil-to-Lymphocyte Ratio in Predicting Prognosis of Surgically Resectable Urinary Cancers: Systematic Review and Meta-Analysis

Objective Accumulated evidence has suggested that there is a close association between preoperative neutrophilto-lymphocyte ratio(NLR)and prognosis of various malignant tumors.However,the relationship between NLR and surgically resectable urinary cancers remains contradictory.Therefore,we performed this systematic review and meta-analysis to explore whether preoperative NLR could predict the prognosis of surgically resectable urinary cancers.Methods After searching the Embase,PubMed/MEDLINE and Cochrane databases and screening the articles,we finally included 25 studies involving 15950 patients.Hazard ratios(HRs)and their 95%confidence intervals(CIs)were extracted to assess the association between preoperative NLR and the overall survival(OS)and cancerspecific survival(CSS)of surgically resectable urinary cancers.Results The pooled results revealed that an elevated preoperative NLR could predict a worse OS(HR=1.40,95%CI:1.26–1.54,P<0.001)and CSS(HR=1.43,95%CI:1.27–1.59,P<0.001)in urinary cancers.In addition,our analyses also suggested that high preoperative NLR was associated with worse prognosis in renal cell carcinoma(OS:HR=2.06,95%CI:1.54–2.76,P=0.131;CSS:HR=2.46,95%CI:1.46–4.16,P=0.178),upper tract urothelial carcinoma(OS:HR=1.91,95%CI:1.50–2.42,P=0.616;CSS:HR=1.84,95%CI:1.41–2.39,P=0.001),bladder cancer(OS:HR=1.09,95%CI:1.02–1.17,P<0.001;CSS:HR=1.05,95%CI:1.01–1.09,P=0.163)and prostate cancer(OS:HR=1.69,95%CI:1.19–2.41,P=0.714).Regardless of the participants’race or the cutoff value of the preoperative NLR,the results remained valid.Conclusion Elevated preoperative NLR could predict a worse prognosis in surgically resectable urinary cancers,namely,renal cell carcinoma,bladder cancer,prostate cancer and upper tract urothelial carcinoma.

The Correlation Between Decreased Ornithine Level and Alleviation of Rheumatoid Arthritis Patients Assessed by a Randomized,Placebo-Controlled,Double-Blind Clinical Trial of Sinomenine

Sinomenine(SIN)is commonly used as part of rheumatoid arthritis(RA)therapy in China,but there is still no published evidence of the efficacy of SIN monotherapy.This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients.In this 24 week,randomized,placebo-controlled,double-blind clinical trial,people with mild to moderate RA were randomly assigned(1:1:1,stratified by hospital)to receive SIN(120 mg,twice daily),methotrexate(MTX)(10 mg per week),or SIN+MTX therapy.The primary outcome was the proportion of patients who achieved a 50%improvement in the American College of Rheumatology(ACR50)criteria at week 24 and who showed improvement according to the clinical disease activity index(CDAI).In this prospective subgroup analysis,we also assessed whether the 24-week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine.Of the 135 enrolled participants,38,39,and 36 patients were treated with SIN,MTX,and SIN+MTX,respectively.In the SIN-treated group,52.63%of patients achieved ACR50 after 24-weeks of treatment,which was comparable to the results in the MTX-treated and SIN+MTX-treated groups.Hepatic and gastrointestinal disorders were the main adverse events;however,the ratio of patients suffering from hepatic disorder in the SIN group(1/38)was much lower than that in the MTX(10/39)and SIN+MTX(8/36)groups.A total of 221 serum samples were collected at the four follow-up time points in the three treatments,and the levels of ornithine,citrulline,and arginine were obtained through ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF/MS).The serum ornithine level decreased after the 24-week treatment along with a decrease in disease activity,and may reflect therapeutic responses with a sensitivity value of 80%.In conclusion,SIN revealed a comparable efficacy to MTX for treating RA patients,but with fewer side effects.In addition,the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA,which shows the value of this measure as an assessment indicator of drugs in treating RA.

Personal predictive model based on systemic inflammation markers for estimation of postoperative pancreatic fistula following pancreaticoduodenectomy

BACKGROUND Postoperative pancreatic fistula(PF)is a serious life-threatening complication after pancreaticoduodenectomy(PD).Our research aimed to develop a machine learning(ML)-aided model for PF risk stratification.AIM To develop an ML-aided model for PF risk stratification.METHODS We retrospectively collected 618 patients who underwent PD from two tertiary medical centers between January 2012 and August 2021.We used an ML algorithm to build predictive models,and subject prediction index,that is,decision curve analysis,area under operating characteristic curve(AUC)and clinical impact curve to assess the predictive efficiency of each model.RESULTS A total of 29 variables were used to build the ML predictive model.Among them,the best predictive model was random forest classifier(RFC),the AUC was[0.897,95%confidence interval(CI):0.370–1.424],while the AUC of the artificial neural network,eXtreme gradient boosting,support vector machine,and decision tree were between 0.726(95%CI:0.191–1.261)and 0.882(95%CI:0.321–1.443).CONCLUSION Fluctuating serological inflammatory markers and prognostic nutritional index can be used to predict postoperative PF.

Association of vitamin D receptor gene polymorphism(VDR)with vitamin D deficiency,metabolic and inflammatory markers in Egyptian obese women

Vitamin D deficiency might contribute to the pathogenesis of metabolic syndrome and could cause immune disturbance.The aim of this study is to analyze the associations between Vitamin D receptor(VDR)gene polymorphism,serum 25-hydroxy vitamin D,metabolic and inflammatory biomarkers in Egyptian obese women.The study included 201 obese women with vitamin D deficiency and 249 obese matched age healthy controls with sufficient vitamin D levels.Their age ranged between 25 and 35 years.Inflammatory biomarkers(interleukin-6 and C-reactive protein)and serum 25(OH)D were measured by enzyme-linked immunosorbent assay.Insulin resistance(IR)was determined by the homeostasis model assessment of insulin resistance(HOMA-IR).Vitamin D receptor(VDR)gene polymorphisms of FokI,ApaI,and TaqI were studied by PCR using the restriction fragment length polymorphism(RFLP)technique.Obese women with vitamin D deficiency had significant higher values of inflammatory and metabolic parameters compared to controls.Multivariable-logistic regression showed associations between 25(OH)D deficiency and metabolic components when comparing cases with controls.Moreover,cases carrying polymorphic alleles showed significant lower levels of serum 25(OH)D and higher HOMA-IR,blood pressure levels and lipid parameters compared to those with the wild type homozygote in obese cases with vitamin D deficiency.Vitamin D deficiency in Egyptian obese women with vitamin D deficiency is associated with abnormal metabolic components and abnormal inflammatory biomarkers.Moreover,VDR polymorphisms play important role in immune and inflammation status.