Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.

Overview of the immunological mechanisms in hepatitis B virus reactivation:Implications for disease progression and management strategies

Hepatitis B virus(HBV)reactivation is a clinically significant challenge in disease management.This review explores the immunological mechanisms underlying HBV reactivation,emphasizing disease progression and management.It delves into host immune responses and reactivation’s delicate balance,spanning innate and adaptive immunity.Viral factors’disruption of this balance,as are interac-tions between viral antigens,immune cells,cytokine networks,and immune checkpoint pathways,are examined.Notably,the roles of T cells,natural killer cells,and antigen-presenting cells are discussed,highlighting their influence on disease progression.HBV reactivation’s impact on disease severity,hepatic flares,liver fibrosis progression,and hepatocellular carcinoma is detailed.Management strategies,including anti-viral and immunomodulatory approaches,are critically analyzed.The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation.In conclusion,this compre-hensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation.With a dedicated focus on understanding its implic-ations for disease progression and the prospects of efficient management stra-tegies,this article contributes significantly to the knowledge base.The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches,ultimately enhancing disease management and elevating patient outcomes.The dynamic landscape of management strategies is critically scrutinized,spanning anti-viral and immunomodulatory approaches.The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Hypothetical hypoxia-driven rapid disease progression in hepatocellular carcinoma post transarterial chemoembolization:A case report

BACKGROUND Transarterial chemoembolization(TACE)is widely performed for intermediatestage or unresectable hepatocellular carcinoma(HCC),but approximately half of patients do not respond to TACE treatment.We describe a case of rapidly progressing of HCC after TACE and provide a possible hypothesis for this condition.The finding may contribute to identifying patients who obtain less benefit from TACE,thus avoiding the unnecessary waste of medical resources and treatment during the golden hour window.CASE SUMMARY A 61-year-old woman had been diagnosed with chronic hepatitis B infection and HCC at Barcelona Clinic Liver Cancer stage B,which had been treated by segmental hepatectomy 14 mo ago.The tumor recurred in the two months after surgery.She received an initial TACE and then underwent systemic therapy with lenvatinib 8 mg daily due to an increased level of alpha-fetoprotein(AFP)after the first TACE.However,the tumor continued to progress with an increased level of AFP,and she underwent a second TACE,after which the tumor volume did not obviously decrease on the contrast-enhanced computed tomography image.One month later,she had a third TACE to control the residual HCC tumors.Two weeks after that,the HCC had increased dramatically with tea-colored urine and yellowish skin turgor.Eventually,the patient refused further treatment and went into hospice care.CONCLUSION Intense hypoxia induced by TACE can trigger rapid disease progression in infiltrative HCC patients with a large tumor burden.

Prediction for risk of disease progression among hospitalized COVID-19 patients

Objective:The COVID-19 pandemic poses a significant threat to global health.Given the lack of studies on risk factors for COVID-19 progression at present,this study aimed to build a predictive model to predict the progression risk among hospitalized COVID-19 patients.Methods:We extracted data from 1074 mild and moderate COVID-19 patients from Electronic Health Records(EHRs)in a designated Wuhan hospital including demographic characteristics and clinical and laboratory information.Disease progression was defined as progressing to severe critical illness after admission.The LASSO regression was used to select the predicted variables and a logistic regression model was applied to build the predictive model.Nomogram was used to show the results.Results:Seven variables were included in the predictive model:age per 10 years(OR,1.15;95%CI,1.03-1.29),lactate dehydrogenase(OR,1.73;95%CI,1.14-2.62),neutrophil-to-lymphocyte ratio(OR,2.07;95%CI,1.42-3.02),eosinophil count(OR,2.10;95%CI,1.20-3.69),albumin(OR,2.37;95%CI,1.65-3.45),hemoglobin(OR,1.50;95%CI,1.10-2.05),D-dimer(OR,1.63;95%CI,1.19-2.23).The mean area under the receiver operating characteristic curve of the predictive model was 0.72(95%CI,0.69-0.76).Conclusions:This study built a predictive model that could effectively predict the progression risk among hospitalized COVID-19 patients.

Neuroflament light and heterogeneity of disease progression in amyotrophic lateral sclerosis:development and validation of a prediction model to improve interventional trials

Background:Interventional trials in amyotrophic lateral sclerosis(ALS)sufer from the heterogeneity of the disease as it considerably reduces statistical power.We asked if blood neuroflament light chains(NfL)could be used to antici‑pate disease progression and increase trial power.Methods:In 125 patients with ALS from three independent prospective studies-one observational study and two interventional trials-we developed and externally validated a multivariate linear model for predicting disease pro‑gression,measured by the monthly decrease of the ALS Functional Rating Scale Revised(ALSFRS-R)score.We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis:NfL levels,sex,age,site of onset,body mass index,disease duration,ALSFRS-R score,and monthly ALSFRS-R score decrease since disease onset.We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials.We analyzed the impact on trial power in mixed-efects models and compared the performance of the NfL model with two currently used predictive approaches,which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period(lead-in)or since disease onset(ΔFRS).Results:Among the parameters provided,the NfL levels(P<0.001)and the interaction with site of onset(P<0.01)contributed signifcantly to the prediction,forming a robust NfL prediction model(R=0.67).Model application in the trial cohorts confrmed its applicability and revealed superiority over lead-in andΔFRS-based approaches.The NfL model improved statistical power by 61%and 22%(95%confdence intervals:54%-66%,7%-29%).Conclusion:The use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could signif‑cantly increase the trial power.NCT00868166,registered March23,2009;NCT02306590,registered December 2,2014.

Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas.The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated.In this observational study,we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases(LBDs)and Alzheimer disease(AD),shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration.We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival.Disease progression in LBDs correlated positively with poly(ADP-Ribose)and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts,indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes.Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine(8-oxo-d G)and myeloperoxidase concentrations in the striatum,suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism ofβ-amyloid entering the mitochondria and subsequent free radicals generation.Patients with lower striatal 8-oxo-d G and myeloperoxidase levels had a survival advantage in AD.The age of onset also affected disease progression.Tissue requests for the postmortem biochemistry,genetics,and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center(ADRC)Biospecimens Committee(ethics approval reference number:T1705,approval date:August 6,2019).Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health&Safety Biological Safety Committee(approval code:3739,approval date:February 25,2020).Radioactive Material Authorization was approved by the Washington University Environmental Health&Safety Radiation Safety Committee(approval code:1056,approval date:September 18,2019).

Comparison of cognitive and UHDRS measures in monitoring disease progression in Huntington’s disease: a 12-month longitudinal study

Progressive cognitive decline is a feature of Huntington’s disease(HD),an inherited neurodegenerative movement disorder.Comprehensive neuropsychological testing is the‘gold standard’to establish cognitive status but is often impractical in time-constrained clinics.The study evaluated the utility of brief cognitive tests(MMSE and MoCA),UHDRS measures and a comprehensive neuropsychological tests battery in monitoring short-term disease progression in HD.Twenty-two manifest HD patients and 22 matched controls were assessed at baseline and 12-month.A linear mixed-effect model showed that although the HD group had minimal change in overall global cognition after 12 months,they did show a significant decline relative to the control group.The controls exhibited a practice effect in most of the cognitive domain scores over time.Cognitive decline at 12-month in HD was found in the executive function domain but the effect of this on global cognitive score was masked by the improvement in their language domain score.The varying practice effects by cognitive domain with repeated testing indicates the importance of comparing HD patients to control group in research trials and that cognitive progression over 12 months in HD should not be judged by changes in global cognitive score.The three brief cognitive tests effectively described cognition of HD patients on cross-sectional analysis.The UHDRS cognitive component,which focuses on testing executive function and had low variance over time,is a more reliable brief substitute for comprehensive neuropsychological testing than MMSE and MoCA in monitoring cognitive changes in HD patients after 12 months.

Location-based prediction model for Crohn’s disease regarding a novel serological marker,anti-chitinase 3-like 1 autoantibodies

BACKGROUND Defective neutrophil regulation in inflammatory bowel disease(IBD)is thought to play an important role in the onset or manifestation of IBD,as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens.Like neutrophils in the context of innate immune responses,immunoglobulin A(IgA)as an acquired immune response partakes in the defense of the intestinal epithelium.Under normal conditions,IgA contributes to the elimination of microbes,but in connection with the loss of tolerance to chitinase 3-like 1(CHI3L1)in IBD,IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms.The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target,the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear.AIM To determine the predictive potential of Ig subtypes of a novel serological marker,anti-CHI3L1 autoantibodies(aCHI3L1)in determining the disease phenotype,therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients.METHODS Sera of 257 Crohn’s disease(CD)and 180 ulcerative colitis(UC)patients from a tertiary IBD referral center of Hungary(Division of Gastroenterology,Department of Internal Medicine,Faculty of Medicine,University of Debrecen)were assayed for IgG,IgA,and secretory IgA(sIgA)type aCHI3L1 by enzyme-linked immunosorbent assay using recombinant CHI3L1,along with 86 healthy controls(HCONT).RESULTS The IgA type was more prevalent in CD than in UC(29.2%vs 11.1%)or HCONT(2.83%;P<0.0001 for both).However,sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT(39.3%and 32.8%vs 4.65%,respectively;P<0.0001).The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement(P<0.0001 and P=0.038,respectively)in patients with CD.Complicated disease behavior at sample procurement was associated with aCHI3L1 sIgA positivity(57.1%vs 36.0%,P=0.009).IgA type aCH3L1 was more prevalent in patients with frequent relapse during the disease course in the CD group(46.9%vs 25.7%,P=0.005).In a group of patients with concomitant presence of pure inflammatory luminal disease and colon involvement at the time of diagnosis,positivity for IgA or sIgA type aCH3L1 predicted faster progression towards a complicated disease course in time-dependent models.This association disappeared after merging subgroups of different disease locations.CONCLUSION CHI3L1 is a novel neutrophil autoantigenic target in IBD.The consideration of antibody classes along with location-based prediction may transform the future of serology in IBD.

Treatment of refractory anti-melanoma differentiation-associated gene 5 anbibody-positive dermatomyositis complicated by rapidly progressing interstitial pulmonary disease:Two case reports

BACKGROUND Anti-melanoma differentiation-associated gene 5 antibody-positive(anti-MDA5 Ab+)dermatomyositis complicated with rapidly progressive interstitial lung disease(anti-MDA5 Ab+DM-RP-ILD)has an unclear underlying mechanism with no recommended unified treatment plan.Herein,one of the cases that we report(Case 2)was successfully treated with tocilizumab despite having lung infection.CASE SUMMARY Case 1 was a 30-year-old woman who was admitted due to recurrent rash for 5 mo,fever and cough for 1 mo,and chest tightness for 3 d.She was diagnosed with non-myopathic dermatomyositis(anti-MDA5 Ab+)and interstitial pneumonia,and was treated with the combination of hormone therapy and cyclophosphamide followed by oral tacrolimus.Case 2 was a 31-year-old man admitted due to systemic rash accompanied by muscle weakness of limbs for more than 1 mo,and chest tightness and dry cough for 4 d.He was diagnosed with dermatomyositis(anti-MDA5 Ab+)and acute interstitial pneumonia with Pneumocystis jirovecii and Aspergillus fumigatus infections and was treated with hormone therapy(without cyclophosphamide)and the combination of tocilizumab and tacrolimus.The condition of both patients eventually improved and they were discharged and showed clinically stable condition at the latest follow-up.CONCLUSION Tocilizumab could be a salvage treatment for patients with anti-MDA5 Ab+DMRP-ILD who are refractory to intensive immunosuppression.

Advanced diffusion magnetic resonance imaging in patients with Alzheimer’s and Parkinson’s diseases

The prevalence of neurodegenerative diseases is increasing as human longevity increases. The objective biomarkers that enable the staging and early diagnosis of neurodegenerative diseases are eagerly anticipated. It has recently become possible to determine pathological changes in the brain without autopsy with the advancement of diffusion magnetic resonance imaging techniques. Diffusion magnetic resonance imaging is a robust tool used to evaluate brain microstructural complexity and integrity, axonal order, density, and myelination via the micron-scale displacement of water molecules diffusing in tissues. Diffusion tensor imaging, a type of diffusion magnetic resonance imaging technique is widely utilized in clinical and research settings;however, it has several limitations. To overcome these limitations, cutting-edge diffusion magnetic resonance imaging techniques, such as diffusional kurtosis imaging, neurite orientation dispersion and density imaging, and free water imaging, have been recently proposed and applied to evaluate the pathology of neurodegenerative diseases. This review focused on the main applications, findings, and future directions of advanced diffusion magnetic resonance imaging techniques in patients with Alzheimer's and Parkinson's diseases, the first and second most common neurodegenerative diseases, respectively.

Progression and Regression of Abdominal Aortic Aneurysms in Mice

Objective:Abdominal aortic aneurysm(AAA)is a significant medical problem with a high mortality rate.Nevertheless,the underlying mechanism for the progression and regression of AAA is unknown.Methods:Experimental model of AAA was first created by porcine pancreatic elastase incubation around the infrarenal aorta of C57BL/6 mice.Then,AAA progression and regression were evaluated based on the diameter and volume of AAA.The aortas were harvested for hematoxylin-eosin staining(HE),orcein staining,sirius red staining,immunofluorescence analysis and peris’prussian blue staining at the indicated time point.Finally,P-aminopropionitrile monofumarate(BAPN)was used to explore the underlying mechanism of the regression of AAA.Results:When we extended the observation period to 100 days,we not only observed an increase in the AAA diameter and volume in the early stage,but also a decrease in the late stage.Consistent with AAA diameter and volume,the aortic thickness showed the same tendency based on HE staining.The elastin and collagen content first degraded and then regenerated,which corresponds to the early deterioration and late regression of AAA.Then,endogenous up-regulation of lysyl oxidase(LOX)was detected,accompanying the regression of AAA,as detected by an immunofluorescent assay.BAPN and LOX inhibitor considerably inhibited the regression of AAA,paralleling the degradation of elastin lamella and collagen.Conclusion:Taken together,we tentatively conclude that endogenous re-generation of LOX played an influential role in the regression of AAA.Therefore,regulatory factors on the generation of LOX exhibit promising therapeutic potential against AAA.

Analysis on the status quo and influencing factors of fear of disease progress in 120 patients ’ spouse after bladder cancer surgery

Objective:To investigate the status quo of fear of disease progressi on in postoperative patients’spouse of bladder cancer and analyze its influencing factors.Methods:Postoperative patients’spouse of bladder cancer of a cancer hospital in Tianjin were selected as the research objects by the convenience sampling method.The general data questionnaire,spouse fear of disease progression scale and self-efficacy scale were used to investigate.Multiple linear regression was used to analyze the influencing factors of the fear of the disease progression in the postoperative pa tients’spouse of bladder cancer.Results:The score of fear of disease progression was(35.75±9.86).The results of multiple linear regression analysis showed that the spouse’s age,medical payment method,occupational status and self-efficacy were the main influencing factors for the spouse’s fear of disease progression after bladder cancer(P<0.05),which accounted for 55%of the total variation.Conclusion:The spouse’s fear of disease progression in patients with bladder cancer is at a moderate lev el,and age,medical payment method,occupational status and self-efficacy are the main influencing factors.It is suggested that clinical medical staff focus on young,rural cooperative medical care,self-financed,in-service,and unemployed,low self-eff icacy of postoperative bladder cancer patients'spouses.A series of psychological counseling and health education should be given to help the patient spouse correctly understand and deal with diseases,reduce the patients’spouses of negative emotions,im prove the patients’spouses of self-efficacy,and reduce the spouse fear level of disease progression.

Association of non-alcoholic fatty liver disease and COVID-19: A literature review of current evidence

The coronavirus disease 2019(COVID-19)pandemic has swept through nations,crippled economies and caused millions of deaths worldwide.Many people diagnosed with COVID-19 infections are often found to develop liver injury,which,in a small portion of patients,progresses to severe liver disease.Liver injury in the form of elevated transaminases,hyperbilirubinemia and alterations in serum albumin has been observed to be higher in patients with severe forms of the disease.Those who already have insult to the liver from chronic disease,such as nonalcoholic fatty liver disease(NAFLD)may be at the greatest disadvantage.The severity of COVID-19 also seems to be driven by the presence of NAFLD and other co-morbidities.About 25%of the global population has NAFLD.With such a widespread prevalence of NAFLD,understanding the disease progression of COVID-19 and the occurrence of liver injury in this vulnerable population assumes great significance.In this review,we present an overview of COVID-19 infection in patients with NAFLD.

Role of serum β2-microglobulin, glycosylated hemoglobin, and vascular endothelial growth factor levels in diabetic nephropathy

BACKGROUND Diabetic nephropathy(DN)is a common complication of type 1 and type 2 diabetes that can lead to kidney damage and high blood pressure.Increasing evidence support the important roles of microproteins and cytokines,such asβ2-microglobulin(β2-MG),glycosylated hemoglobin(HbA1c),and vascular endothelial growth factor(VEGF),in the pathogenesis of this disease.In this study,we identified novel therapeutic options for this disease.AIM To analyze the guiding significance ofβ2-MG,HbA1c,and VEGF levels in patients with DN.METHODS A total of 107 patients with type 2 diabetes mellitus complicated with nephropathy and treated in our hospital from May 2018 to February 2021 were included in the study.Additionally,107 healthy individuals and 107 patients with simple diabetes mellitus were selected as the control groups.Changes inβ2-MG,HbA1c,and VEGF levels in the three groups as well as the different proteinuria exhibited by the three groups were examined.RESULTS Changes inβ2-MG,HbA1c,and VEGF levels in the disease,healthy,and simple diabetes groups were significantly different(P<0.05).The expression of these factors from high to low were evaluated in different groups by pairwise comparison.In the disease group,high to low changes inβ2-MG,HbA1c,and VEGF levels were noted in the massive proteinuria,microproteinuria,and normal urinary protein groups,respectively.Changes in these factors were positively correlated with disease progression.CONCLUSION The expression of serumβ2-MG,HbA1c,and VEGF was closely correlated with DN progression,and disease progression could be evaluated by these factors.

Impact of delay from transperineal biopsy to radical prostatectomy upon objective measures of cancer control

Objective:Treatment delays in prostate cancer have been characterised,although not explicitly in men undergoing transperineal prostate biopsies.We aimed to determine if delays to radical prostatectomy correlate with adverse outcomes using a contemporary population-based cohort of men diagnosed by transperineal biopsies.Methods:This study analysed men with prostate cancer of the International Society for Urological Pathology grade group≥2,diagnosed by transperineal prostate biopsies who underwent prostatectomy,using the prospectively data from 1 January 2014 to 30 June 2018 Prostate Cancer Outcomes Registry-Victoria.Data were analysed according to stratified demographic and disease characteristics.Time intervals from biopsy(28,60,90,120,and 270 days)were compared using odds ratios and regression analyses for proportion of upgrading,early biochemical recurrence,pT3 disease at prostatectomy,and positive surgical margins.Results:In total,2008 men were analysed.There were 306(16.7%)men with upgrading,151(8.4%)with biochemical recurrence,1068(54.1%)with pT3 disease,and 464(23.1%)with positive surgical margins(percentages excluded patients with missing data).All adverse outcomes studied were significantly associated with higher prostate-specific antigen and grade at diagnosis.Delays of 120-270 days did not adversely alter the incidence of Gleason upgrading,pT3,or recurrence.Delays(most frequent 60-89 days,28%)were associated with positive surgical margins but not monotonically.Regression modelling demonstrated no increased likelihood of most adverse outcomes for up to 270 days.Conclusion:Men with prostate cancer of grade group≥2 diagnosed through transperineal biopsy may wait up to 270 days for a prostatectomy without a greater likelihood of upgrading,pT3 disease,positive surgical margins,or biochemical recurrence.

Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy

Colorectal cancer represents the third most diagnosed malignancy in the world.The liver is the main site of metastatic disease,affected in 30%of patients with newly diagnosed disease.Complete resection is considered the only potentially curative treatment for colorectal liver metastasis(CRLM),with a 5-year survival rate ranging from 35%to 58%.However,up to 80%of patients have initially unresectable disease,due to extrahepatic disease or bilobar multiple liver nodules.The availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease,improving long-term outcomes,and accessing tumor biology.In recent years,response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic factor.Some studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the disease.Even if disease progression during chemotherapy represents an independent negative prognostic factor,some patients may still benefit from surgery,given the role of this modality as the main treatment with curative intent for patients with CRLM.In selected cases,based on size,the number of lesions,and tumor markers,surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.

Molecular mechanisms and novel therapeutic strategies of BCG-unresponsive non-muscle invasive bladder cancer: Emerging immunotherapy has become a new choice?

Objective:THigh-risk non-invasive bladder cancer(NMIBC)has a high rate of recurrence and disease progression.At present,there are still insufficient effective prevention and treatment methods,especially for patients who have failed BCG treatment.This article reviews the research progress of the molecular mechanism of BCG unresponsive NMIBC,and summarizes the current status and prospects of emerging therapeutic strategies represented by immunotherapy,providing a theoretical basis for the immunotherapy of BCG non-reactive NMIBC.Methods:We searched the PubMed and CNKI journal full-text database search system for keywords"non-muscle invasive bladder cancer,BCG unresponsive,disease recurrence,disease progression,and immunotherapy"with 126 English and 538 Chinese articles.The literature,as well as the relevant clinical research in ClinicalTrials.gov,were integrated together to obtain the results.Results:Immunotherapy was performed in various types of tumors,and the use of immunotherapeutic drugs with different oncotargets administered alone,sequentially or in combination for the treatment of BCG-unresponsive NMIBC have achieved favorable effects,and more Clinical research is still ongoing.Conclusion:Immunotherapy is currently the most promising treatment for cancer,and it is indispensable for patients with NMIBC,both biologically and clinically.We look forward to more laboratory and clinical research in immunotherapy in the future.

IL-17A in Ovarian Cancer

Ovarian cancer is the most common malignant disease leading to death among women. IL (interleukin)-17A is the most well-studied member of the IL-17 family, and has been demonstrated to play a critical role in host defenses against various microbial pathogens, as well as against tissue inflammation. T-helper (Th)17 cells that produce interleukin (IL)-17A are of particular importance, because IL-17A exerts a wide variety of biological functions, particularly related to inflammation and the resultant carcinogenesis, as well as immune suppression in patients with cancer, and IL-17A-targeted therapy has been proven to be effective in the treatment of some autoimmune diseases. The pathogenic features of Th17 and IL-17A cells in cancer are still controversial, and Th17 cells appear to promote disease progression, as well as be present in the vicinity of many types of malignant diseases. In cancer patients, MDSC (myeloid-derived suppressor cells), one of the major immunosuppressive immature cells, and VEGF (vascular endothelial growth factor) are reported to correlate each other and strongly connected to IL-17-driven inflammation and malnutrition. In the present review, the latest advances are presented about the basic features of IL-17A and Th17. The function of IL-17A has not been clarified especially in ovarian cancer. This review overview the basic features of IL-17A and the functions in ovarian cancer as well as in other malignant and non-malignant diseases. Increasing our understanding of the interactions between IL-17A and ovarian cancer could lead to new therapeutic strategies in oncology.

Protective effects of pharmacological therapies in animal models of multiple sclerosis: a review of studies 2014–2019

Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible.Once there is considerable loss of axons,MS patients enter a secondary progressive stage.Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage.Various animal models of MS(mostly mouse and rat)have been established and proved useful in studying the disease process and response to therapy.The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund's adjuvant.The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to,at,or after peak disease,and the agents had protective effects as shown by inhibiting demyelination and damage to neurons,axons and oligodendrocytes.In the cuprizone-induced toxicity animal studies,the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically.A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler's murine encephalomyelitis virus.In all these studies the pharmacological agents were administered singly.A combination therapy may be more effective,especially using agents that target neuroinflammation and neurodegeneration,as they may exert synergistic actions.

Clinical Advances in Fibrosis Progression of Chronic Hepatitis B and C

Chronic liver diseases, such as chronic hepatitis B (CHB) and chronic hepatitis C (CHC), are characterized by the presence of liver fibrosis, which may ultimately lead to cirrhosis. The progression of fibrosis is associated with various factors. Here, we review recent advances in the study of factors related to the progression rate of CHB- and CHC-induced fibrosis. Identification of these factors and establishment of a scoring system for cirrhosis risk are particularly important for predict-ing cirrhosis development, planning individualized treatment, and preventing fibrosis progression.