During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatme...During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration(aged,SM/J,and young lumbar spine instability mice).Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5^(+)and CGRP^(+)nerve fibers,as well as CGRP expression in dorsal root ganglia.The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2.PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests.Altogether,PTH stimulated osteoblast production of Slit3,decreased aberrant sensory nerve innervation,and provided symptomatic relief of LBP associated with mouse spinal degeneration.展开更多
Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patien...Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.展开更多
Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this com...Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this complex problem.One such model,the Oncopig,has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation.However,the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.Methods:Herein,we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and re-placed in the tissue.The study consisted of 3 animals in 3 cohorts(total of 9 animals)that were evaluated at 14,21,and 28 days.CT imaging,immunohistochemistry,multiplex immunofluorescence,and comprehensive blood analyses were used to quantify composition of the hepatic masses that developed following AdCre inoculation.Results:The tumors were hypovascular on CT and predominantly composed of CD45+cells with a strong lymphohistiocytic component,with no carcinomas identified.Ki-67 staining showed proliferation of CD45+immune cells but no neoplastic component.To provide further insight,the results are evaluated in the context of tumor growth kinetics.Conclusion:While progress has been made in generating targetable lesions,achieving a robust large animal model of liver cancer that faithfully recapitulates the human disease remains a challenging goal.展开更多
In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affectin...In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affecting the brain,making the eye a unique and accessible model for studying these disorders.The transparency of eyes allows researchers to monitor disease progression non-invasively,offering a window into neural health.展开更多
Structural variations(SVs≥50 bp)are a critical but underexplored source of genetic diversity in cattle,shaping traits vital for productivity,adaptability,and health.Advances in long-read sequencing,pangenome graph co...Structural variations(SVs≥50 bp)are a critical but underexplored source of genetic diversity in cattle,shaping traits vital for productivity,adaptability,and health.Advances in long-read sequencing,pangenome graph construction,and near-complete genome assemblies now allow accurate SV detection and genotyping.These innovations overcome the limitations of single-reference genomes,enabling the discovery of complex SVs,including nested and overlapping variants,and providing access to previously inaccessible genomic regions such as centromeres and telomeres.This review highlights the current landscape of cattle SV research,with emphasis on integrating longread sequencing and pangenome frameworks to uncover breed-specific and population-level variation.While many SVs are linked to economically important traits such as feed efficiency and disease resistance,their broader regulatory impacts remain an active area of investigation.Emerging functional genomics approaches,including transcriptomics,epigenomics,and genome editing,will clarify how SVs influence gene regulation and phenotype.Looking forward,the integration of SV catalogs with multi-omics data,imputation resources,and artificial intelligence-driven models will be essential for translating discoveries into breeding and conservation applications.Integrating structural variants into breeding pipelines promises to revolutionize livestock genomics,enabling precision selection and sustainable agriculture despite challenges in cost,data sharing,and functional validation.展开更多
The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral bloo...The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.展开更多
N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)...Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)introduced the Single Tremelimumab Regular Interval Durvalumab(STRIDE)regimen,an immunotherapy-based approach that achieved a median overall survival(OS)of 16.43 months compared to 13.77 months with sorafenib.While statistically significant,this~2.7 months OS gain warrants scrutiny in light of STRIDE’s increased immune-related toxicity and cost.This commentary evaluates STRIDE’s impact within the broader landscape of first-line systemic therapy for unresectable HCC,alongside other regimens such as atezolizumab plus bevacizumab and nivolumab plus ipilimumab.We explore STRIDE’s mechanism of action,safety profile,modest progression-free survival(PFS)improvement,and implementation challenges,incorporating insights from 2023-2025 research.In addition,we discussed its limitations in non-viral HCC and Child-Pugh B patients,the role of emerging biomarkers,and the potential of radiation to enhance immunotherapy efficacy.As a dual immune checkpoint inhibitor(ICI)strategy,STRIDE offers an important advance that may not only extend survival but also open the door to future curative approaches.However,optimizing its use will require refined patient selection and further investigation of synergistic combination therapies.展开更多
Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of mul...Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.展开更多
Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated...Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neu...Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neurons.It affects nearly one million people in the United States and 8.5 million worldwide.While there are some pharmacological and surgical options available,they only provide symptomatic relief,as there is currently no cure for PD.In contrast,exercise training,a non-pharmacological intervention,has emerged as a powerful strategy to enhance the psychological,cognitive,and physiological(motor)impairments associated with PD.Given that the beneficial effects of exercise differ based on the intensity and type of training,gaining a thorough understanding of the molecular mechanisms underlying exercise-induced protection is crucial for developing innovative therapies that improve the quality of life for PD patients around the globe.This review discusses PD pathogenesis and pathophysiology and provides recent clinical evidence of neuroprotective benefits from various exercise modalities and intensity.Furthermore,the molecular mechanisms of exercise in PD pathogenesis(e.g.,modulations on neurotrophic factors,oxidative stress,mitochondria dysfunction,endoplasmic reticulum stress,and autophagy)will be emphasized.展开更多
Background This study compared knee osteoarthritis(OA)outcomes specific to pain,physical function,and quality of life in later life based on strength training(ST)participation over a lifetime.Methods Participants from...Background This study compared knee osteoarthritis(OA)outcomes specific to pain,physical function,and quality of life in later life based on strength training(ST)participation over a lifetime.Methods Participants from the Osteoarthritis Initiative(n=3192)were grouped by ST engagement during ages 12–18 years,19–34 years,35–49 years,and 50+years.Participants were categorized as:No ST(no ST at any point;61.7±9.0 years(mean±SD)),Some ST(engaged in ST during 1–3 life stages;58.9±8.7 years),and Lifelong ST(consistently engaged in ST across all life stages;55.6±8.1 years).Measures were collected at baseline and Year 4:Western Ontario and McMaster Universities Osteoarthritis Index Scores(WOMAC;pain,daily activities),Knee Injury and Osteoarthritis Outcome Score(KOOS;sports,recreation),Physical Activity Score for the Elderly(PASE),Short Form-12 Physical Component Score(SF-12 PCS),mobility disability,chair rise time,and walking speed(20 m and 400 m).Results At Year 4,the Lifelong ST group reported better WOMAC activity scores in the right knee along with better WOMAC pain,KOOS sports/recreation,and PASE scores compared to other groups(p<0.05).The Lifelong ST group had the lowest incidence of mobility disability of all groups(0.8%vs.2.3%–4.1%;p=0.015)and maintained the fastest walking speeds in Year 4.Conclusion For those with knee OA,ST throughout life may help preserve function and mobility,allowing for greater physical activity engagement while keeping pain levels relatively lower.展开更多
This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships an...This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships and taxonomy within Batrachospermaceae,we integrated molecular and morphological data,and explored the phylogeny,character evolution,and ancestral geographical origin and provided a theoretical support for the classification and geographic origination of Batrachospermaceae.Our findings reveal distinct relationships within the phylogenetic tree.Notably,10 genera(Sirodotia,Batrachospermum,Tuomeya,Volatus,Lympha,Nothocladus,Torularia,Sheathia,Nocturama,and Petrohua)are closely associated in the rbcL phylogenetic tree.Additionally,four genera(Kumanoa,Hoefkenia,Notohesperus,and Virescentia)exhibit high support ratios,indicating their close interrelations.Other genera,including Paludicola,Visia,Acarposporophycos,Macrosporophycos,Visioidea,Balliopsis,and Psilosiphon,exhibit clustering traits.Furthermore,the multigene sequences provide a robust support for Montagnia that forms a monophyletic group.Ancestral reconstruction of morphological characters identifies nine primitive character states,including whorl,fascicle length,cortical cells,secondary fascicles,the shape of carpogonical branch,spermatangia,carposporophyte,carpogonium and trichogyne,with Visia likely representing ancestral traits in Batrachospermaceae.Furthermore,geographical origin maps suggest a potential common ancestral of Batrachospermaceae origin in the American continent.Additional to conventional analyses,including evolutionary and ancestral reconstruction investigations into key morphological characters,we attempt to reconstruct the biogeography within the Batrachospermaceae,thus contributing to a nuanced understanding of its origin.展开更多
Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In th...Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.展开更多
The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates ...The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.展开更多
基金supported by the U.S.Department of Health&Human Services NIH National Institute on Aging under Award Number P01AG066603(to J.C.)。
文摘During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration(aged,SM/J,and young lumbar spine instability mice).Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5^(+)and CGRP^(+)nerve fibers,as well as CGRP expression in dorsal root ganglia.The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2.PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests.Altogether,PTH stimulated osteoblast production of Slit3,decreased aberrant sensory nerve innervation,and provided symptomatic relief of LBP associated with mouse spinal degeneration.
基金supported by the Canadian Institutes of Health Research(DFD-181599)the National Institutes of Health(T32AG058527)to RJB and R0190106435 to VM.
文摘Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.
基金Institutional Research Grant,MD Anderson Cancer CenterUPWARDS Training Program(Undergraduate Students Working Towards Research in Science),Grant/Award Number:1R25CA240137-01A1the CPRIT Research Training Award CPRIT Training Program,Grant/Award Number:RP210028。
文摘Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this complex problem.One such model,the Oncopig,has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation.However,the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.Methods:Herein,we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and re-placed in the tissue.The study consisted of 3 animals in 3 cohorts(total of 9 animals)that were evaluated at 14,21,and 28 days.CT imaging,immunohistochemistry,multiplex immunofluorescence,and comprehensive blood analyses were used to quantify composition of the hepatic masses that developed following AdCre inoculation.Results:The tumors were hypovascular on CT and predominantly composed of CD45+cells with a strong lymphohistiocytic component,with no carcinomas identified.Ki-67 staining showed proliferation of CD45+immune cells but no neoplastic component.To provide further insight,the results are evaluated in the context of tumor growth kinetics.Conclusion:While progress has been made in generating targetable lesions,achieving a robust large animal model of liver cancer that faithfully recapitulates the human disease remains a challenging goal.
基金supported[in part]by the IntramuralResearch Program of the National Institutes ofHealth(NIH)(to KJM),and also supported by theOffice by the Office of the Assistant Secretary ofDefense for Health Affairs and the Defense HealthAgency J9,Research and Development Directorate,through the Vision Research Program under AwardNo.(CDMRPL-18-0-VR180205 to KJM and FMN-N).
文摘In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affecting the brain,making the eye a unique and accessible model for studying these disorders.The transparency of eyes allows researchers to monitor disease progression non-invasively,offering a window into neural health.
基金supported in part by AFRI grant numbers 2019-7015-29321 and 2021-67015-33409 from the USDA National Institute of Food and Agriculture(NIFA)the SCINet project of the USDA ARS project number 0500-00093-001-00-D。
文摘Structural variations(SVs≥50 bp)are a critical but underexplored source of genetic diversity in cattle,shaping traits vital for productivity,adaptability,and health.Advances in long-read sequencing,pangenome graph construction,and near-complete genome assemblies now allow accurate SV detection and genotyping.These innovations overcome the limitations of single-reference genomes,enabling the discovery of complex SVs,including nested and overlapping variants,and providing access to previously inaccessible genomic regions such as centromeres and telomeres.This review highlights the current landscape of cattle SV research,with emphasis on integrating longread sequencing and pangenome frameworks to uncover breed-specific and population-level variation.While many SVs are linked to economically important traits such as feed efficiency and disease resistance,their broader regulatory impacts remain an active area of investigation.Emerging functional genomics approaches,including transcriptomics,epigenomics,and genome editing,will clarify how SVs influence gene regulation and phenotype.Looking forward,the integration of SV catalogs with multi-omics data,imputation resources,and artificial intelligence-driven models will be essential for translating discoveries into breeding and conservation applications.Integrating structural variants into breeding pipelines promises to revolutionize livestock genomics,enabling precision selection and sustainable agriculture despite challenges in cost,data sharing,and functional validation.
基金supported by Department of Defense grant HT9425-24-1-0030 a grant from the Stanley Medical Research Institute(to SS).
文摘The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
文摘Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)introduced the Single Tremelimumab Regular Interval Durvalumab(STRIDE)regimen,an immunotherapy-based approach that achieved a median overall survival(OS)of 16.43 months compared to 13.77 months with sorafenib.While statistically significant,this~2.7 months OS gain warrants scrutiny in light of STRIDE’s increased immune-related toxicity and cost.This commentary evaluates STRIDE’s impact within the broader landscape of first-line systemic therapy for unresectable HCC,alongside other regimens such as atezolizumab plus bevacizumab and nivolumab plus ipilimumab.We explore STRIDE’s mechanism of action,safety profile,modest progression-free survival(PFS)improvement,and implementation challenges,incorporating insights from 2023-2025 research.In addition,we discussed its limitations in non-viral HCC and Child-Pugh B patients,the role of emerging biomarkers,and the potential of radiation to enhance immunotherapy efficacy.As a dual immune checkpoint inhibitor(ICI)strategy,STRIDE offers an important advance that may not only extend survival but also open the door to future curative approaches.However,optimizing its use will require refined patient selection and further investigation of synergistic combination therapies.
基金funded by the Research,Development,and Innovation Authority(RDIA)—Kingdom of Saudi Arabia(Grant No.13292-psu-2023-PSNU-R-3-1-EF-).
文摘Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.
文摘Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).
基金supported by an AIMS fellowship grant from the University of West Florida(04523:YL)partially by the National Institutes of Health grant under Award Number R16-GM149358the National Science Foundation grant DUE 2344997.
文摘Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neurons.It affects nearly one million people in the United States and 8.5 million worldwide.While there are some pharmacological and surgical options available,they only provide symptomatic relief,as there is currently no cure for PD.In contrast,exercise training,a non-pharmacological intervention,has emerged as a powerful strategy to enhance the psychological,cognitive,and physiological(motor)impairments associated with PD.Given that the beneficial effects of exercise differ based on the intensity and type of training,gaining a thorough understanding of the molecular mechanisms underlying exercise-induced protection is crucial for developing innovative therapies that improve the quality of life for PD patients around the globe.This review discusses PD pathogenesis and pathophysiology and provides recent clinical evidence of neuroprotective benefits from various exercise modalities and intensity.Furthermore,the molecular mechanisms of exercise in PD pathogenesis(e.g.,modulations on neurotrophic factors,oxidative stress,mitochondria dysfunction,endoplasmic reticulum stress,and autophagy)will be emphasized.
文摘Background This study compared knee osteoarthritis(OA)outcomes specific to pain,physical function,and quality of life in later life based on strength training(ST)participation over a lifetime.Methods Participants from the Osteoarthritis Initiative(n=3192)were grouped by ST engagement during ages 12–18 years,19–34 years,35–49 years,and 50+years.Participants were categorized as:No ST(no ST at any point;61.7±9.0 years(mean±SD)),Some ST(engaged in ST during 1–3 life stages;58.9±8.7 years),and Lifelong ST(consistently engaged in ST across all life stages;55.6±8.1 years).Measures were collected at baseline and Year 4:Western Ontario and McMaster Universities Osteoarthritis Index Scores(WOMAC;pain,daily activities),Knee Injury and Osteoarthritis Outcome Score(KOOS;sports,recreation),Physical Activity Score for the Elderly(PASE),Short Form-12 Physical Component Score(SF-12 PCS),mobility disability,chair rise time,and walking speed(20 m and 400 m).Results At Year 4,the Lifelong ST group reported better WOMAC activity scores in the right knee along with better WOMAC pain,KOOS sports/recreation,and PASE scores compared to other groups(p<0.05).The Lifelong ST group had the lowest incidence of mobility disability of all groups(0.8%vs.2.3%–4.1%;p=0.015)and maintained the fastest walking speeds in Year 4.Conclusion For those with knee OA,ST throughout life may help preserve function and mobility,allowing for greater physical activity engagement while keeping pain levels relatively lower.
基金Supported by the National Natural Science Foundation of China(No.32170204)。
文摘This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships and taxonomy within Batrachospermaceae,we integrated molecular and morphological data,and explored the phylogeny,character evolution,and ancestral geographical origin and provided a theoretical support for the classification and geographic origination of Batrachospermaceae.Our findings reveal distinct relationships within the phylogenetic tree.Notably,10 genera(Sirodotia,Batrachospermum,Tuomeya,Volatus,Lympha,Nothocladus,Torularia,Sheathia,Nocturama,and Petrohua)are closely associated in the rbcL phylogenetic tree.Additionally,four genera(Kumanoa,Hoefkenia,Notohesperus,and Virescentia)exhibit high support ratios,indicating their close interrelations.Other genera,including Paludicola,Visia,Acarposporophycos,Macrosporophycos,Visioidea,Balliopsis,and Psilosiphon,exhibit clustering traits.Furthermore,the multigene sequences provide a robust support for Montagnia that forms a monophyletic group.Ancestral reconstruction of morphological characters identifies nine primitive character states,including whorl,fascicle length,cortical cells,secondary fascicles,the shape of carpogonical branch,spermatangia,carposporophyte,carpogonium and trichogyne,with Visia likely representing ancestral traits in Batrachospermaceae.Furthermore,geographical origin maps suggest a potential common ancestral of Batrachospermaceae origin in the American continent.Additional to conventional analyses,including evolutionary and ancestral reconstruction investigations into key morphological characters,we attempt to reconstruct the biogeography within the Batrachospermaceae,thus contributing to a nuanced understanding of its origin.
基金supported by the National Natural Science Foundation of China,No.82201626(to CC)the Natural Science Foundation of LiaoningProvince,No.2022-MS-442(to CC)the Dalian Municipal Medical Key Specialty Climbing Project,No.2024ZZ040(to MZ).
文摘Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.
基金supported by grants PID2020-120308RB-I00 and PID2023-147802OB-I00 funded by MICIU/AEI/10.13039/501100011033FEDER,UE,by Aligning Science Across Parkinson’s(ref.ASAP-020505)through the Michael J.Fox Foundation for Parkinson’s Research+1 种基金by CiberNed Intramural Collaborative Projects(ref.PI2020/09)by the Spanish Fundación Mutua Madrile?a de Investigación Médica(to JLL)。
文摘The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.
