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

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Neural Regeneration Research 2024年第4期19卷 747-753页

作者： Peter H.King Department of Neurology and Center for Neurodegeneration and Experimental Therapeutics The University of Alabama at BirminghamBirminghamALUSA Birmingham Veterans Affairs Medical Center BirminghamALUSA

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 SO

关键词： amyotrophic lateral sclerosis biomarkers clinicopathological correlation disease progression muscle biomarkers neurogenic atrophy neuromuscular junction non-coding RNAs presymptomatic stages skeletal muscle SOD1G93A mouse model

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

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World Journal of Gastroenterology 2024年第10期30卷 1295-1312页

作者： Hui Ma Qing-Zhu Yan Jing-Ru Ma Dong-Fu Li Jun-Ling Yang Department of Clinical Laboratory The Second Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina Department of Ultrasound Medicine The Second Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina Digestive diseases Center Department of Hepatopancreatobiliary MedicineThe Second Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina Department of Respiratory and Critical Care Medicine The Second Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina

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.

关键词： Hepatitis B virus reactivation Immunological mechanisms disease progression Management strategies Immune response

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Promotion effect of FOXCUT as a microRNA sponge for miR-24-3p on progression in triple-negative breast cancer through the p38 MAPK signaling pathway

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Chinese Medical Journal 2024年第1期137卷 105-114页

作者： Xiafei Yu Fangze Qian Xiaoqiang Zhang Yanhui Zhu Gao He Junzhe Yang Xian Wu Yi Zhou Li Shen Xiaoyue Shi Hongfei Zhang Xiao’an Liu Department of Breast Surgery The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China

Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor prognosis.According to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of cancer.Although the role of lncRNAs in breast cancer has been well reported,few studies have focused on TNBC.This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript(FOXCUT)in triple-negative breast cancer.Methods:Based on a bioinformatic analysis of the cancer genome atlas(TCGA)database,we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues,which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University.The functions of FOXCUT in proliferation,migration,and invasion were detected in vitro or in vivo.Luciferase assays and RNA immunoprecipitation(RIP)were performed to reveal that FOXCUT acted as a competitive endogenous RNA(ceRNA)for the microRNA miR-24-3p and consequently inhibited the degradation of p38.Results:lncRNA FOXCUT was markedly highly expressed in breast cancer,which was associated with poor prognosis in some cases.Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo.Mechanistically,FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38,which might act as an oncogene in breast cancer.Conclusion:Collectively,this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.

关键词： Triple negative breast neoplasms RNA,long noncoding FOXCUT miR-24-3p p38 MAPK signaling pathway disease progression

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

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World Journal of Clinical Cases 2023年第19期11卷 4664-4669页

作者： Kai-Fuan Yeo Amy Ker Pei-En Kao Chi-Chih Wang Division of Gastroenterology and Hepatology Department of Internal MedicineChung Shan Medical University HospitalTaichung 402306Taiwan China School of Medicine Chung Shan Medical UniversityTaichung 402306TaiwanChina

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.

关键词： Carcinoma hepatocellular Transarterial chemoembolization Tumor hypoxia disease progression Tumor burden Case report

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

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Translational Neurodegeneration 2014年第1期3卷 109-118页

作者： Eng A Toh Michael R MacAskill John C Dalrymple-Alford Daniel J Myall Leslie Livingston Sandy AD Macleod Tim J Anderson Department of Medicine Christchurch School of Medicine&Health SciencesUniversity of OtagoChristchurchNew Zealand New Zealand Brain Research Institute ChristchurchNew Zealand Department of Psychology University of CanterburyChristchurchNew Zealand Brain Injury Rehabilitation Service Canterbury District Health BoardChristchurchNew Zealand Department of Neurology Canterbury District Health BoardChristchurchNew Zealand

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.

关键词： Huntington’s disease disease progression Cognition UHDRS Longitudinal

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

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Medical Data Mining 2023年第2期6卷 41-49页

作者： Jia-Shu Shen Qing-Qing Yang Qiao-Xin Shi Hou-Yu Zhao Lin Zhuo Hai-Bo Song Yun Lu Si-Yan Zhan Hong Cheng Feng Sun Department of School of Public Health Peking University Health Science CenterBeijing 100191China Department of Research Center of Clinical Epidemiology Peking University Third HospitalBeijing 100191China Department of Pharmacovigilance National Center for ADR MonitoringBeijing 100191China Department of Pharmacy Zhongnan Hospital of Wuhan UniversityWuhan 430000China

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.

关键词： coronavirus disease 2019(COVID-19) predictive model disease progression

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Association of serum uric acid levels with the progression of Parkinson＇s disease in Chinese patients

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Chinese Medical Journal 2012年第4期125卷 583-587页

作者： Sun Cong-cong Luo Fei-fei Wei Lei Lei Mi Li Guo-fei Liu Zhuo-lin Le Wei-dong Xu Ping-yi Sun Yat Sen Univ Affiliated Hosp 1 Dept Neurol Guangzhou 510080 Guangdong Peoples R China Henan Univ Huaihe Hosp Dept Neurol Kaifeng 47500 Henan Peoples R China Baylor Coll Med Dept Neurol Houston TX 77030 USA Shanghai Jiao Tong Univ Sch Med Shanghai 200025 Peoples R China Chinese Acad Sci Inst Biol Sci Inst Hlth Sci Key Lab Stem Cell Biol Shanghai 200025 Peoples R China

Background Uric acid （UA） is suspected to play a neuro-protective role in Parkinson＇s disease （PD）.This study aimed to evaluate whether the serum UA level was associated with the disease progression of PD in a relatively large population of Chinese patients.Methods Serum UA levels were measured from 411 Chinese PD patients and 396 age-matched controls; following the uric acid colorimetric method,the serum creatinine （Scr） levels were also measured to reduce the bias caused by possible differences in renal excretion function.The disease progression was scored by Hoehn and Yahr （H＆Y） scales and disease durations; PD group was divided into 3 subgroups according to H＆Y scales.Independent-samples ttest was performed to analyze the differences between PD group and control group.Multiple analysis of covariance was performed to analyze the differences between PD subgroups.Spearman rank-correlation was performed to evaluate the associations between serum UA or Scr level and disease progression.Results PD patients were found to have significantly lower levels of serum UA than controls （（243.38±78.91） vs.（282.97±90.80） pmol/L,P〈0.01）.As the disease progression,the serum UA levels were gradually reduced.There was a significantly inverse correlation of UA levels with H＆Y scales （Rs=-0.429,P 〈0.01） and disease duration （Rs=-0.284,P 〈0.01） in PD patients of both females and males.No significant difference of the Scr level between PD patients and controls was found （（70.01±14.70） vs.（69.84±16.46） μmol/L）,and the Scr level was not involved in disease progression.Conclusion Lower serum UA levels may possess a higher risk of PD,which may be a potential useful biomarker to indicate the progression of PD.

关键词： uric acid Parkinson＇s disease disease progression

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Risk factors associated with the progression from mild keloids to severe keloids

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Chinese Medical Journal 2022年第7期135卷 828-836页

作者： Ruolin Liu Haitao Xiao Ru Wang Wei Li Ke Deng Ying Cen Xuewen Xu Department of Burn and Plastic Surgery West China Hospital of Sichuan UniversityChengduSichuan 610041China Laboratory of Mitochondrial and Metabolism West China Hospital of Sichuan UniversityChengduSichuan 610041China

Background:Keloids are benign fibrous growths that are caused by excessive tissue build-up.Severe keloids exert more significant effects on patients’quality of life than do mild keloids.We aimed to identify factors associated with the progression from mild keloids to severe keloids,as distinct from those associated with the formation of keloids.Methods:In this retrospective case-control study,251 patients diagnosed with keloids at West China Hospital between November 2018 and April 2021 were grouped according to the severity of lesions(mild[n=162]or severe[n=89]).We collected their basic characteristics,living habits,incomes,comorbidities,and keloid characteristics from Electronic Medical Records in the hospital and the patients’interviews.Conditional multivariable regression was performed to identify the independent risk factors for the progression of keloids.Results:Eighty-nine patients(35.5%)were classified as having severe keloids.We found the distribution of severe keloids varied with sex,age,excessive scrubbing of keloids,family income,the comorbidity of rheumatism,disease duration,characteristics of the location,location in sites of high-stretch tension,the severity and frequency of pain,the severity of pruritus,and infection.Multivariable analysis revealed significant associations between severe keloids and infection(odds ratio[OR],3.55;P=0.005),excessive scrubbing of keloids(OR,8.65;P=0.001),low or middle family income(OR,13.44;P=0.021),comorbidity of rheumatism(OR,18.97;P=0.021),multiple keloids located at multiple sites(OR,3.18;P=0.033),and disease duration>15 years(OR,2.98;P=0.046).Conclusion:Doctors should implement more active and thorough measures to minimize the progression of mild keloids in patients who have any of the following risk factors:infection,excessive scrubbing of keloids,low or middle family income,comorbidity of rheumatism,multiple keloids located at multiple sites,and disease duration>15 years.

关键词： Keloid disease progression Risk factors Multivariate analysis

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

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Neural Regeneration Research 2022年第4期17卷 867-874页

作者： Huifangjie Li William C.Knight Jinbin Xu Department of Radiology Washington University School of MedicineSt.LouisMOUSA

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 Heal

关键词： Alzheimer disease disease progression Lewy body diseases microglia neurodegeneration oxidative damage striatum survival

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

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Translational Neurodegeneration 2021年第3期10卷 400-411页

作者： Simon Witzel Felix Frauhammer† Petra Steinacker David Devos Pierre‑François Pradat Vincent Meininger Stefen Halbgebauer Patrick Oeckl Joachim Schuster Simon Anders Johannes Dorst Markus Otto Albert C.Ludolph Department of Neurology University of UlmUlmGermany Center for Molecular Biology Heidelberg UniversityHeidelbergGermany Depart‑ment of Medical Pharmacology Expert center for ParkinsonCHU‑LilleLille Neuroscience and CognitionInsermUMR‑S1172LICENDNS‑Park NetworkUniversity of LilleLilleFrance Laboratoire D’Imagerie Biomédicale Sorbonne UniversitéCNRSINSERMParisFrance APHP Département de NeurologieHôpital Pitié-SalpêtrièreParisFrance German Centre for Neurodegenerative diseases(DZNE)Site Ulm UlmGermany

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.

关键词： Neuroflament light Prediction model disease progression Amyotrophic lateral sclerosis Interventional trials Statistical power

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