Leveraging diverse cell-death patterns to predict the clinical outcome of immune checkpoint therapy in lung adenocarcinoma:Based on muti-omics analysis and vitro assay

Advanced LUAD shows limited response to treatment including immune therapy.With the development of sequencing omics,it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers.Using GSE72094(n=386)and GSE31210(n=226)gene expression profile data in the GEO database,we identified genes associated with lung adenocarcinoma(LUAD)death using tools such as“edgeR”and“maftools”and visualized the characteristics of these genes using the“circlize”R package.We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods.By calculating the cell death index(CDI)of each individual,we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis(PCA)and Kaplan-Meier analysis.We also used the“ConsensusClusterPlus”tool for unsupervised clustering of LUAD subtypes based on model genes.In addition,we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses.We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort.Finally,we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments.The study utilized the TCGA-LUAD cohort(n=493)and identified 2,901 genes that are differentially expressed in patients with LUAD.Through KEGG and GO enrichment analysis,these genes were found to be involved in a wide range of biological pathways.The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores.By comparing the overall survival(OS)outcomes of patients with different CDI values,it was found that increased CDI levels were significantly associated with lower OS rates.In addition,the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct clusters with significant differences in OS timing.Finally,a prognostic indicator called CDI was established and its feasibility as an independent prognostic indicator was evaluated by Cox proportional risk regression analysis.The immunotherapy efficacy was more sensitive in the group with high expression of programmed cell death models.Relationship between programmed cell death(PCD)signature models and drug reactivity.After evaluating the median inhibitory concentration(IC50)of various drugs in LUAD samples,statistically significant differences in IC50 values were found in cohorts with high and low CDI status.Specifically,Gefitinib and Lapatinib had higher IC50 values in the high-CDI cohort,while Olaparib,Oxaliplatin,SB216763,and Axitinib had lower values.These results suggest that individuals with high CDI levels are sensitive to tyrosine kinase inhibitors and may be resistant to conventional chemotherapy.Therefore,this study constructed a gene model that can evaluate patient immunotherapy by using programmed cell death-related genes based on muti-omics.The CDI index composed of these programmed cell death-related genes reveals the heterogeneity of lung adenocarcinoma tumors and serves as a prognostic indicator for patients.

Evaluation of hybrid closed-loop insulin delivery system in type 1 diabetes in real-world clinical practice:One-year observational study

BACKGROUND In 2016,the Food and Drug Administration approved the first hybrid closed-loop(HCL)insulin delivery system for adults with type 1 diabetes(T1D).There is limited information on the impact of using HCL systems on patient-reported outcomes(PROs)in patients with T1D in real-world clinical practice.In this independent study,we evaluated glycemic parameters and PROs over one year of continuous use of Medtronic’s 670G HCL in real-world clinical practice.AIM To assess the effects of hybrid closed loop system on glycemic control and quality of life in adults with T1D.METHODS We evaluated 71 patients with T1D(mean age:45.5±12.1 years;59%females;body weight:83.8±18.7 kg,body mass index:28.7±5.6 kg/m2,A1C:7.6%±0.8%)who were treated with HCL at Joslin Clinic from 2017 to 2019.We measured A1C and percent of glucose time-in-range(%TIR)at baseline and 12 months.We measured percent time in auto mode(%TiAM)for the last two weeks preceding the final visit and assessed PROs through several validated quality-of-life surveys related to general health and diabetes management.RESULTS At 12 mo,A1C decreased by 0.3%±0.1%(P=0.001)and%TIR increased by 8.1%±2.5%(P=0.002).The average%TiAM was only 64.3%±32.8%and was not associated with A1C,%TIR or PROs.PROs,provided at baseline and at the end of the study,showed that the physical functioning submodule of 36Item Short-Form Health Survey increased significantly by 22.9%(P<0.001).Hypoglycemia fear survey/worry scale decreased significantly by 24.9%(P<0.000);Problem Areas In Diabetes reduced significantly by-17.2%(P=0.002).The emotional burden submodules of dietary diversity score reduced significantly by-44.7%(P=0.001).Furthermore,analysis of Clarke questionnaire showed no increase in awareness of hypoglycemic episodes.WHO-5 showed no improvements in subject’s wellbeing among participants after starting the 670G HCL system.Finally,analysis of Pittsburgh Sleep Quality Index showed no difference in sleep quality,sleep latency,or duration of sleep from baseline to 12 mo.CONCLUSION The use of HCL in real-world clinical practice for one year was associated with significant improvements in A1C,%TIR,physical functioning,hypoglycemia fear,emotional distress,and emotional burden related to diabetes management.However,these changes were not associated with time in auto mode.

Preclinical and clinical evidence of the association of colibactinproducing Escherichia coli with anxiety and depression in colon cancer

BACKGROUND The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent.The gut microbiota contributes to colorectal carcinogenesis(CRC),as demonstrated with colibactin-producing Escherichia coli(CoPEC).AIM To evaluate the association between CoPEC prevalence and anxiety-and depressive-like behaviors with both preclinical and clinical approaches.METHODS Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview.Results were compared according to the CoPEC colonization.In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain.Their behavior was assessed using the Elevated Plus Maze test,the Forced Swimming Test and the Behavior recognition system PhenoTyper®.RESULTS In a limited cohort,all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis,whereas only one patient(17%)without CoPEC did.This result was confirmed in C57BL6/J wildtype mice and in a CRC susceptibility mouse model(adenomatous polyposis colimultiple intestinal neoplasia/+).Mice exhibited a significant increase in anxiety-and depressive-like behaviors after chronic infection with a CoPEC strain.CONCLUSION This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.

Fecal microbiota transplantation for treatment of non-alcoholic fatty liver disease:Mechanism,clinical evidence,and prospect

The population of non-alcoholic fatty liver disease(NAFLD)patients along with relevant advanced liver disease is projected to continue growing,because currently no medications are approved for treatment.Fecal microbiota transplantation(FMT)is believed a novel and promising therapeutic approach based on the concept of the gut-liver axis in liver disease.There has been an increase in the number of pre-clinical and clinical studies evaluating FMT in NAFLD treatment,however,existing findings diverge on its effects.Herein,we briefly summarized the mechanism of FMT for NAFLD treatment,reviewed randomized controlled trials for evaluating its efficacy in NAFLD,and proposed the prospect of future trials on FMT.

Analysis of the Current Situation of Drug Clinical Trial Institutions in Shaanxi Province

To understand the current situation of institutional registration in Shaanxi Province after the implementation ofregistration system management in drug clinical trial institutions.Relevant information was collected on the“Announcement on the Accreditation of Drug Clinical Trial Institutions”issued by the National Medical Products Administration from 2005 to August 2022,the record management information system of drug and medical device clinical trial institutions,and the drug clinical trial registration and information publicity platform.A retrospective analysis was carried out in terms of institutional development,regional distribution,registered majors,principal investigators,and the number of drug clinical trials.After the implementation of institution registration,the number of drug clinical trial institutions in Shaanxi Province increased by 47.4%,884 principal investigators were registered,the number of registered majors expanded from 58 qualified to 117,and the professional scope increased by 50.4%.The policy of institution registration is conducive to promoting the rational use of medical resources and the development of drug clinical trial institutions and improving the healthy development of the pharmaceutical industry in Shaanxi Province.

Knowledge and Attitudes of Oncology Nurses Toward Clinical Trials-A Secondary Publication

Purpose:The purpose of this study was to identify the knowledge and attitudes of oncology nurses toward clinical trials and to provide evidence for the development of clinical trial education programs for oncology nurses.Methods:The study was conducted on 142 nurses who had more than six months of nursing experience working with cancer patients at a tertiary hospital in Seoul,Korea.A structured questionnaire was used to measure the knowledge and attitudes of oncology nurses toward clinical trials.Results:The participants scored an average of 15.03±3.52 out of 19 in terms of knowledge about clinical trials.In terms of attitudes toward clinical trials,the participants scored an average of 5.91±1.37 out of 8.There was a significant positive correlation between the knowledge and attitudes of the participants toward clinical trials(r=0.23,P=0.007).Conclusion:This study found that there was a relationship between the knowledge and attitudes of oncology nurses toward clinical trials.To improve the competency of oncology nurses and provide high-quality care to patients participating in clinical trials,more systematic and sustainable education is required.

Methylome and transcriptome data integration reveals potential roles of DNA methylation and candidate biomarkers of cow Streptococcus uberis subclinical mastitis

Background:Mastitis caused by different pathogens including Streptococcus uberis(S.uberis)is responsible for huge economic losses to the dairy industry.In order to investigate the potential genetic and epigenetic regulatory mecha‑nisms of subclinical mastitis due to S.uberis,the DNA methylome(whole genome DNA methylation sequencing)and transcriptome(RNA sequencing)of milk somatic cells from cows with naturally occurring S.uberis subclinical mastitis and healthy control cows(n=3/group)were studied.Results:Globally,the DNA methylation levels of CpG sites were low in the promoters and first exons but high in inner exons and introns.The DNA methylation levels at the promoter,first exon and first intron regions were nega‑tively correlated with the expression level of genes at a whole‑genome‑wide scale.In general,DNA methylation level was lower in S.uberis‑positive group(SUG)than in the control group(CTG).A total of 174,342 differentially methylated cytosines(DMCs)(FDR<0.05)were identified between SUG and CTG,including 132,237,7412 and 34,693 DMCs in the context of CpG,CHG and CHH(H=A or T or C),respectively.Besides,101,612 methylation haplotype blocks(MHBs)were identified,including 451 MHBs that were significantly different(dMHB)between the two groups.A total of 2130 differentially expressed(DE)genes(1378 with up‑regulated and 752 with down‑regulated expression)were found in SUG.Integration of methylome and transcriptome data with MethGET program revealed 1623 genes with signifi‑cant changes in their methylation levels and/or gene expression changes(MetGDE genes,MethGET P‑value<0.001).Functional enrichment of genes harboring≥15 DMCs,DE genes and MetGDE genes suggest significant involvement of DNA methylation changes in the regulation of the host immune response to S.uberis infection,especially cytokine activities.Furthermore,discriminant correlation analysis with DIABLO method identified 26 candidate biomarkers,including 6 DE genes,15 CpG‑DMCs and 5 dMHBs that discriminated between SUG and CTG.Conclusion:The integration of methylome and transcriptome of milk somatic cells suggests the possible involve‑ment of DNA methylation changes in the regulation of the host immune response to subclinical mastitis due to S.uberis.The presented genetic and epigenetic biomarkers could contribute to the design of management strategies of subclinical mastitis and breeding for mastitis resistance.

Effect of individualized nutrition interventions on clinical outcomes of pregnant women with gestational diabetes mellitus

BACKGROUND Gestational diabetes mellitus(GDM)can lead to excessive pregnancy weight gain(PWG),abnormal glucolipid metabolism,and delayed lactation.Therefore,it is necessary to provide appropriate and effective interventions for pregnant women with GDM.AIM To clarify the effects of individualized nutrition interventions on PWG,glucolipid metabolism,and lactation in pregnant women with GDM.METHODS The study population consisted of 410 pregnant women with GDM who received treatment at the Northern Jiangsu People's Hospital of Jiangsu Provinceand Yangzhou Maternal and Child Health Hospital between December 2020 and December 2022,including 200 who received routine in-terventions[control(Con)group]and 210 who received individualized nutrition interventions[research(Res)group].Data on PWG,glucolipid metabolism[total cholesterol,(TC);triglycerides(TGs);fasting blood glucose(FPG);glycosylated hemoglobin(HbA1c)],lactation time,perinatal complications(cesarean section,premature rupture of membranes,postpartum hemorrhage,and pregnancy-induced hypertension),and neonatal adverse events(premature infants,fetal macrosomia,hypo-glycemia,and respiratory distress syndrome)were collected for comparative analysis.RESULTS The data revealed markedly lower PWG in the Res group vs the Con group,as well as markedly reduced TG,TC,FPG and HbA1c levels after the intervention that were lower than those in the Con group.In addition,obviously earlier lactation and statistically lower incidences of perinatal complications and neonatal adverse events were observed in the Res group.CONCLUSION Individualized nutrition interventions can reduce PWG in pregnant women with GDM,improve their glucolipid metabolism,and promote early lactation,which deserves clinical promotion.

Prevalence of posttraumatic stress disorder following acute coronary syndrome and clinical characteristics of patients referred to cardiac rehabilitation

BACKGROUND Studies have demonstrated that patients who have experienced acute coronary syndrome(ACS)have an increased risk of developing posttraumatic stress disorder(PTSD)and experiencing worse survival outcomes than those who do not develop PTSD.Nevertheless,the prevalence rates of PTSD following ACS vary widely across studies,and it is noteworthy that in most cases,the diagnosis of PTSD was based on self-report symptom questionnaires,rather than being established by psychiatrists.Additionally,the individual characteristics of patients who develop PTSD after ACS can differ widely,making it difficult to identify any consistent patterns or predictors of the disorder.AIM To investigate the prevalence of PTSD among a large sample of patients undergoing cardiac rehabilitation(CR)after ACS,as well as their characteristics in comparison to a control group.METHODS The participants of this study are patients who have experienced ACS with or without undergoing percutaneous coronary intervention and are enrolled in a 3-wk CR program at the largest CR center in Croatia,the Special Hospital for Medical Rehabilitation Krapinske Toplice.Patient recruitment for the study took place over the course of one year,from January 1,2022,to December 31,2022,with a total of 504 participants.The expected average follow-up period for patients included in the study is about 18 mo,and currently ongoing.Using self-assessment questionnaire for PTSD criteria and clinical psychiatric interview,a group of patients with a PTSD diagnosis was identified.From the participants who do not have a PTSD diagnosis,patients who would match those with a PTSD diagnosis in terms of relevant clinical and medical stratification variables and during the same rehabilitation period were selected to enable comparability of the two groups.RESULTS A total of 507 patients who were enrolled in the CR program were approached to participate in the study.Three patients declined to participate in the study.The screening PTSD Checklist-Civilian Version questionnaire was completed by 504 patients.Out of the total sample of 504 patients,74.2%were men(n=374)and 25.8%were women(n=130).The mean age of all participants was 56.7 years(55.8 for men and 59.1 for women).Among the 504 participants who completed the screening questionnaire,80 met the cutoff criteria for the PTSD and qualified for further evaluation(15.9%).All 80 patients agreed to a psychiatric interview.Among them,51 patients(10.1%)were diagnosed with clinical PTSD by a psychiatrist according to Diagnostic and Statistical Manual of Mental Disorders criteria.Among the variables analyzed,there was a noticeable difference in the percentage of theoretical maximum achieved on exercise testing between the PTSD and non-PTSD groups.Non-PTSD group achieved a significantly higher percentage of their maximum compared to the PTSD group(P=0.035).CONCLUSION The preliminary results of the study indicate that a significant proportion of patients with PTSD induced by ACS are not receiving adequate treatment.Furthermore,the data suggest that these patients may exhibit reduced physical activity levels,which could be one of the possible underlying mechanisms in observed poor cardiovascular outcomes in this population.Identifying cardiac biomarkers is crucial for identifying patients at risk of developing PTSD and may derive benefits from personalized interventions based on the principles of precision medicine in multidisciplinary CR programs.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease

Parkinson’s disease(PD,OMIM#168600)is a common neurodegenerative disorder with a global prevalence of approximately 8.5 million.PD is characterized by four cardinal motor symptoms:bradykinesia,rigidity,resting tremor,and subsequently by postural instability.It usually involves non-motor symptoms such as rapid eye movement sleep disorder,dementia,anosmia,and autonomic dysfunction.The gene glucocerebrosidase 1(GBA1),which encodes the lysosomal enzyme glucocerebrosidase(GCase)(IUBMB:EC 3.2.1.45),shows strong linkage with PD;variants of GBA1 are the commonest genetic association with PD(Sidransky et al.,2009).Several mechanisms may underlie the relationship between GBA1 mutations/variants and the molecular pathology of PD(Figure 1A and B).

Development and application of hepatocellular carcinoma risk prediction model based on clinical characteristics and liver related indexes

BACKGROUND Hepatocellular carcinoma(HCC)is difficult to diagnose with poor therapeutic effect,high recurrence rate and has a low survival rate.The survival of patients with HCC is closely related to the stage of diagnosis.At present,no specific serolo-gical indicator or method to predict HCC,early diagnosis of HCC remains a challenge,especially in China,where the situation is more severe.AIM To identify risk factors associated with HCC and establish a risk prediction model based on clinical characteristics and liver-related indicators.METHODS The clinical data of patients in the Affiliated Hospital of North Sichuan Medical College from 2016 to 2020 were collected,using a retrospective study method.The results of needle biopsy or surgical pathology were used as the grouping criteria for the experimental group and the control group in this study.Based on the time of admission,the cases were divided into training cohort(n=1739)and validation cohort(n=467).Using HCC as a dependent variable,the research indicators were incorporated into logistic univariate and multivariate analysis.An HCC risk prediction model,which was called NSMC-HCC model,was then established in training cohort and verified in validation cohort.RESULTS Logistic univariate analysis showed that,gender,age,alpha-fetoprotein,and protein induced by vitamin K absence or antagonist-II,gamma-glutamyl transferase,aspartate aminotransferase and hepatitis B surface antigen were risk factors for HCC,alanine aminotransferase,total bilirubin and total bile acid were protective factors for HCC.When the cut-off value of the NSMC-HCC model joint prediction was 0.22,the area under receiver operating characteristic curve(AUC)of NSMC-HCC model in HCC diagnosis was 0.960,with sensitivity 94.40%and specificity 95.35%in training cohort,and AUC was 0.966,with sensitivity 90.00%and specificity 94.20%in validation cohort.In early-stage HCC diagnosis,the AUC of NSMC-HCC model was 0.946,with sensitivity 85.93%and specificity 93.62%in training cohort,and AUC was 0.947,with sensitivity 89.10%and specificity 98.49%in validation cohort.CONCLUSION The newly NSMC-HCC model was an effective risk prediction model in HCC and early-stage HCC diagnosis.

Cases studies of application of model-informed drug development in early phase clinical trials

Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.

Changes in the gut mycobiome in pediatric patients in relation to the clinical activity of Crohn's disease

BACKGROUND Numerous studies have shown that in Crohn’s disease(CD),the gut microbiota is of great importance in the induction and maintenance of inflammation in the gastrointestinal tract.Until recently,studies have focused almost exclusively on bacteria in the gut.Lately,more attention has been paid to the role of intestinal fungi.AIM To study the gut mycobiome analysis of pediatric patients with CD(in different stages of disease activity)compared to healthy children.METHODS Fecal samples were collected from patients:With active,newly diagnosed CD(n=50);active but previously diagnosed and treated CD(n=16);non-active CD and who were in clinical remission(n=39)and from healthy volunteers(n=40).Fungal DNA was isolated from the samples.Next,next generation sequencing(MiSeq,Illumina)was performed.The composition of mycobiota was correlated with clinical and blood parameters.RESULTS Candida spp.were overrepresented in CD patients,while in the control group,the most abundant genus was Saccharomyces.In CD patients,the percentage of Malassezia was almost twice that of the control(P<0.05).In active CD patients,we documented a higher abundance of Debaryomyces hansenii(D.hansenii)compared to the non-active CD and control(P<0.05)groups.Moreover,statistically significant changes in the abundance of Mycosphaerella,Rhodotorula,and Microidium were observed.The analyses at the species level and linear discriminant analysis showed that in each group it was possible to distinguish a specific species characteristic of a given patient population.Moreover,we have documented statistically significant correlations between:D.hansenii and patient age(negative);C.zeylanoides and patient age(positive);C.dubliniensis and calprotectin(positive);C.sake and calprotectin(positive);and C.tropicalis and pediatric CD activity index(PCDAI)(positive).CONCLUSION Mycobiome changes in CD patients,and the positive correlation of some species with calprotectin or PCDAI,give strong evidence that fungi may be of key importance in the development of CD.

Biofilm analyses and exoproduct release by clinical and environmental isolates of Burkholderia pseudomallei from Brazil

Objective:To characterize biofilm production by clinical(n=21)and environmental(n=11)isolates of Burkholderia pseudomallei and evaluate the production of proteases,hemolysins and siderophores.Methods:Initially,the 32 strains were evaluated for biofilm production in Müller-Hinton broth-1%glucose(MH-1%glucose)and BHI broth-1%glucose,using the crystal violet staining technique.Subsequently,growing(48 h)and mature(72 h)biofilms were evaluated by confocal microscopy.Finally,the production of proteases,hemolysins and siderophores by planktonic aggregates,growing biofilms and mature biofilms was evaluated.Results:All isolates produced biofilms,but clinical isolates had significantly higher biomass in both MH-1%glucose(P<0.001)and BHI-glucose 1%(P=0.005).The structural analyses by confocal microscopy showed thick biofilms,composed of multiple layers of cells,homogeneously arranged,with mature biofilms of clinical isolates presenting higher biomass(P=0.019)and thickness of the entire area(P=0.029),and lower roughness coefficient(P=0.007)than those of environmental isolates.Protease production by growing biofilms was significantly greater than that of planktonic(P<0.001)and mature biofilms(P<0.001).Hemolysin release by planktonic aggregates was higher than that of biofilms(P<0.001).Regarding siderophores,mature biofilms presented higher production than growing biofilms(P<0.001)and planktonic aggregates(P<0.001).Conclusions:Clinical isolates have higher production of biofilms than their environmental counterparts;protease and siderophores seem important for growth and maintenance of Burkholderia pseu­domallei biofilms.

Clinical significance of serum oxidative stress and serum uric acid levels before surgery for hepatitis B-related liver cancer

BACKGROUND The incidence and mortality of liver cancer are among the highest of all malignant tumors in China.The high recurrence rate after conventional hepatectomy is worrying.There is a lack of effective prognostic indicators for liver cancer.AIM To explore the clinical significance of preoperative serum oxidative stress and serum uric acid(UA)levels in hepatitis B-related liver cancer.METHODS The medical records of 110 hepatitis B-related liver cancer patients who under-went hepatectomy in Gansu Provincial Hospital were retrospectively analyzed.Recurrence in patients within 3 years after surgery was determined.The logistic regression model and Pearson or Spearman correlation were used to analyze the correlation between oxidative stress level and UA,and the recurrence of hepatitis B-related liver cancer.RESULTS Compared with the non-recurrence group,the levels of superoxide dismutase(SOD)and glutathione(GSH)in the recurrence group were lower and the levels of malondialdehyde(MDA)and UA were higher(all P<0.05).UA,SOD,MDA,and GSH were risk factors for postoperative recurrence in hepatitis B-related liver cancer patients(P<0.05).UA was positively correlated with MDA(r=0.395,P<0.001)and negatively correlated with GSH(r=-0.204,P=0.032).The area under the receiver operating characteristic curve(AUC)of SOD,MDA,GSH,and UA in predicting the prognosis was 0.276,0.910,0.199,and 0.784,respectively(all P<0.001).CONCLUSION The preoperative serum SOD,GSH,MDA,and UA levels had significant predictive effects on postoperative recurrence of hepatitis B-related liver cancer.

Clinical implications of forkhead box M1, cyclooxygenase-2, and glucose-regulated protein 78 in breast invasive ductal carcinoma

BACKGROUND Breast infiltrating ductal carcinoma(BIDC)represents the largest heterotypic tumor group,and an in-depth understanding of the pathogenesis of BIDC is key to improving its prognosis.AIM To analyze the expression profiles and clinical implications of forkhead box M1(FOXM1),cyclooxygenase-2(COX-2),and glucose-regulated protein 78(GRP78)in BIDC.METHODS A total of 65 BIDC patients and 70 healthy controls who presented to our hospital between August 2019 and May 2021 were selected for analysis.The peripheral blood FOXM1,COX-2,and GRP78 levels in both groups were measured and the association between their expression profiles in BIDC was examined.Additionally,we investigated the diagnostic value of FOXM1,COX-2,and GRP78 in patients with BIDC and their correlations with clinicopathological features.Furthermore,BIDC patients were followed for 1 year to identify factors influencing patient prognosis.RESULTS The levels of FOXM1,COX-2,and GRP78 were significantly higher in BIDC patients compared to healthy controls(P<0.05),and a positive correlation was observed among them(P<0.05).Receiver operating characteristic analysis demonstrated that FOXM1,COX-2,and GRP78 had excellent diagnostic value in predicting the occurrence of BIDC(P<0.05).Subsequently,we found significant differences in FOXM1,COX-2,and GRP78 levels among patients with different histological grades and metastasis statuses(with vs without)(P<0.05).Cox analysis revealed that FOXM1,COX-2,GRP78,increased histological grade,and the presence of tumor metastasis were independent risk factors for prognostic death in BIDC(P<0.001).CONCLUSION FOXM1,COX-2,and GRP78 exhibit abnormally high expression in BIDC,promoting malignant tumor development and closely correlating with prognosis.These findings hold significant research implications for the future diagnosis and treatment of BIDC.

Operational definitions and measurement of externalizing behavior problems:An integrative review including research models and clinical diagnostic systems

Measurement of externalizing disorders such as antisocial disorders,attentiondeficit/hyperactivity disorder or borderline disorder have relevant implications for the daily lives of people with these disorders.While the Diagnostic and Statistical Manual of Mental Disorders(DSM)and the International Classification of Diseases(ICD)have provided the diagnostic framework for decades,recent dimensional frameworks question the categorical approach of psychopathology,inherent in traditional nosotaxies.Tests and instruments develop under the DSM or ICD framework preferentially adopt this categorical approach,providing diagnostic labels.In contrast,dimensional measurement instruments provide an individualized profile for the domains that comprise the externalizing spectrum,but are less widely used in practice.Current paper aims to review the operational definitions of externalizing disorders defined under these different frameworks,revise the different measurement alternatives existing,and provide an integrative operational definition.First,an analysis of the operational definition of externalizing disorders among the DSM/ICD diagnostic systems and the recent Hierarchical Taxonomy of Psychopathology(HiTOP)model is carried out.Then,in order to analyze the coverage of operational definitions found,a description of measurement instruments among each conceptualization is provided.Three phases in the development of the ICD and DSM diagnosis systems can be observed with direct implications for measurement.ICD and DSM versions have progressively introduced systematicity,providing more detailed descriptions of diagnostic criteria and categories that ease the measurement instrument development.However,it is questioned whether the DSM/ICD systems adequately modelize externalizing disorders,and therefore their measurement.More recent theoretical approaches,such as the HiTOP model seek to overcome some of the criticism raised towards the classification systems.Nevertheless,several issues concerning this model raise mesasurement challenges.A revision of the instruments underneath each approach shows incomplete coverage of externalizing disorders among the existing instruments.Efforts to bring nosotaxies together with other theoretical models of psychopathology and personality are still needed.The integrative operational definition of externalizing disorders provided may help to gather clinical practice and research.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Emerging role of galectin 3 in neuroinflammation and neurodegeneration

Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.