Human bocavirus(HBoV) is a parvovirus isolated about a decade ago and found worldwide in both respiratory samples, mainly from early life and children of 6-24 mo of age with acute respiratory infection, and in stool s...Human bocavirus(HBoV) is a parvovirus isolated about a decade ago and found worldwide in both respiratory samples, mainly from early life and children of 6-24 mo of age with acute respiratory infection, and in stool samples, from patients with gastroenteritis. Since then, other viruses related to the first HBoV isolate(HBoV 1), namely HBoV 2, HBoV 3 and HBoV 4, have been detected principally in human faeces. HBo Vs are small nonenveloped single-stranded DNA viruses of about 5300 nucleotides, consisting of three open reading frames encoding the first two the non-structural protein 1(NS1) and nuclear phosphoprotein(NP1) and the third the viral capsid proteins 1 and 2(VP1 and VP2). HBoV pathogenicity remains to be fully clarified mainly due to the lack of animal models for the difficulties in replicating the virus in in vitro cell cultures, and the fact that HBo V infection is frequently accompanied by at least another viral and/or bacterial respiratory and/or gastroenteric pathogen infection. Current diagnostic methods to support HBoV detection include polymerase chain reaction, real-time PCR, enzymelinked immunosorbent assay and enzyme immunoassay using recombinant VP2 or virus-like particle capsid proteins, although sequence-independent amplification techniques combined with next-generation sequencing platforms promise rapid and simultaneous detection of the pathogens in the future. This review presents the current knowledge on HBoV genotypes with emphasis on taxonomy, phylogenetic relationship and genomic analysis, biology, epidemiology, pathogenesis and diagnostic methods. The emerging discussion on HBoV s as true pathogen or innocent bystander is also emphasized.展开更多
Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulati...Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulation of abnormalα-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of eitherα-synuclein,as in the case of Multiple System Atrophy(MSA)or tau,as in the case of Corticobasal Degeneration(CBD)and Progressive Supranuclear Palsy(PSP),in other disease-specific brain regions.Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization ofα-synuclein or tau aggregates in the brain.Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues,including receptor neurons of the olfactory mucosa(OM).Methods:We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion(RT-QuIC)assay for OM analysis.In particular,by using human recombinantα-synuclein as substrate of reaction,we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induceα-synuclein aggregation,and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.Results:Our results showed that a significant percentage of MSA and PD samples inducedα-synuclein aggregation with high efficiency,but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect.Notably,the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.Conclusions:Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities forα-synuclein.Additional studies are required for(i)estimating sensitivity and specificity of the technique and for(ii)evaluating its application for t展开更多
Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an...Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism.Here,we investigated whether GPR37 is upregulated in sporadic PD,and thus a suitable potential biomarker for PD.Methods:GPR37 protein density and mRNA expression in postmortem substantia nigra(SN)from PD patients were analysed by immunoblot and RT-qPCR,respectively.The presence of peptides from the N-terminus-cleaved domain of GPR37(i.e.ecto-GPR37)in human cerebrospinal fluid(CSF)was determined by liquid chromatography-mass spectrometric analysis.An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control(NC)subjects,PD patients and Alzheimer's disease(AD)patients.Results:GPR37 protein density and mRNA expression were significantly augmented in sporadic PD.Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method.However,the CSF total a-synuclein level in PD patients did not differ from that in NC subjects.Similarly,the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered.Conclusion:GPR37 expression is increased in SN of sporadic PD patients.The ecto-GPR37 peptides are significantly increased in the CSF of PD patients,but not in AD patients.These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.展开更多
The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct mol...The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.展开更多
Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal mode...Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance mechanisms.Furthermore,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less understood.However,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance.In this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented processes.This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen masking.Such type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell type.However,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol metabolism.Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities.Together,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.展开更多
Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and ...Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far.Unfortunately,diagnostic and prognostic biomarkers are lacking in clinical practice.Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum.Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis,reflecting the extensive damage of motor neurons and axons.Hence,neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis.The potential usefulness of neurofilaments regards various aspects,including diagnosis,prognosis,patient stratification in clinical trials and evaluation of treatment response.In this review paper,we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis.We also discuss the open issues concerning the use of neurofilaments clinical practice,as no overall guideline exists to date;finally,we address the most recent evidence and future perspectives.展开更多
The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenu...The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.展开更多
In this study, the effects of Radio Electric Asymmetric Conveyer(REAC), a non-invasive physical treatment, on neuroinflammatory responses in a mouse model of parkinsonism induced by intoxication with1-methyl-4-phenyl-...In this study, the effects of Radio Electric Asymmetric Conveyer(REAC), a non-invasive physical treatment, on neuroinflammatory responses in a mouse model of parkinsonism induced by intoxication with1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),were investigated in vivo. We found that the REAC tissue optimization treatment specific for neuro-regenerative purposes(REAC TO-RGN-N) attenuated the inflammatory picture evoked by MPTP-induced nigro-striatal damage inmice, decreasing the levels of pro-inflammatory molecules and increasing anti-inflammatory mediators. Besides, there was a significant reduction of both astrocyte and microglial activation in MPTP-treated mice exposed to REAC TORGN-N. These results indicated that REAC TO-RGN-N treatment modulates the pro-inflammatory responses and reduces neuronal damage in MPTP-induced parkinsonism.展开更多
Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for ...Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms.Epidermal growth factor receptor(EGFR)amplification and EGFR-vIII mutation are often detected in GBM cells,contributing to the malignant behavior.This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Methods Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis.A metabolism-associated RTK-fatty acid-gene signature was constructed and verified.MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism.Energy metabolism in GBM with activated EGFR pathway was monitored.The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide(TMZ)was analyzed by an intracranial tumor model in vivo.Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels,supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples.Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production.Mechanistically,the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3(ACSS3),acyl-CoA synthetase long-chain family member 3(ACSL3),and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2(ELOVL2)in an NF-κB-dependent manner.Moreover,inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes,thereby affecting the signal transduction of the EGFR/AKT pathway.Therefore,targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Conclusions Our findings not only uncovered the mechanism of metabolic rep展开更多
The prognosis for diffusely infiltrating gliomas at World Health Organization(WHO)grade 2-4 remains dismal due to their heterogeneity.The rapid development of genome-wide molecular-profiling-associated studies has gre...The prognosis for diffusely infiltrating gliomas at World Health Organization(WHO)grade 2-4 remains dismal due to their heterogeneity.The rapid development of genome-wide molecular-profiling-associated studies has greatly promoted the accuracy of glioma classification.Thus,the latest version of the WHO classification of the central nervous system tumors published in 2021 has incorporated more molecular biomarkers together with histological features for the diagnosis of gliomas.Advanced usage of molecular pathology in clinical diagnostic practice provides also new opportunities for the therapy of patients with glioma,including surgery,radiotherapy and chemotherapy,targeted therapy,immunotherapy,and more precision clinical trials.Herein,we highlight the updates in the classification of gliomas according to the latest WHO guidelines and summarize the clinically relevant molecular markers by focusing on their applications in clinical practice.We also review the advances in molecular features of gliomas,which can facilitate the development of glioma therapies,thereby discussing the challenges and future directions of molecular pathology toward precision medicine for patients with glioma.展开更多
文摘Human bocavirus(HBoV) is a parvovirus isolated about a decade ago and found worldwide in both respiratory samples, mainly from early life and children of 6-24 mo of age with acute respiratory infection, and in stool samples, from patients with gastroenteritis. Since then, other viruses related to the first HBoV isolate(HBoV 1), namely HBoV 2, HBoV 3 and HBoV 4, have been detected principally in human faeces. HBo Vs are small nonenveloped single-stranded DNA viruses of about 5300 nucleotides, consisting of three open reading frames encoding the first two the non-structural protein 1(NS1) and nuclear phosphoprotein(NP1) and the third the viral capsid proteins 1 and 2(VP1 and VP2). HBoV pathogenicity remains to be fully clarified mainly due to the lack of animal models for the difficulties in replicating the virus in in vitro cell cultures, and the fact that HBo V infection is frequently accompanied by at least another viral and/or bacterial respiratory and/or gastroenteric pathogen infection. Current diagnostic methods to support HBoV detection include polymerase chain reaction, real-time PCR, enzymelinked immunosorbent assay and enzyme immunoassay using recombinant VP2 or virus-like particle capsid proteins, although sequence-independent amplification techniques combined with next-generation sequencing platforms promise rapid and simultaneous detection of the pathogens in the future. This review presents the current knowledge on HBoV genotypes with emphasis on taxonomy, phylogenetic relationship and genomic analysis, biology, epidemiology, pathogenesis and diagnostic methods. The emerging discussion on HBoV s as true pathogen or innocent bystander is also emphasized.
基金This study was supported in part by the Italian Ministry of Health(GR-2013-02355724)the Michael J.Fox Foundation,Alzheimer’s Association,Alzheimer’s Research UK and the Weston Brain Institute(BAND 11035)+1 种基金Associazione Italiana Encefalopatie da Prioni(AIEnP)to FMItalian Ministry of Health(GR-2009-1607326)to AEE,Italian Ministry of Health(NET-2011-02346784)to FT and NIH/NIA(P30 AG10133)to Bernardino Ghetti.
文摘Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulation of abnormalα-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of eitherα-synuclein,as in the case of Multiple System Atrophy(MSA)or tau,as in the case of Corticobasal Degeneration(CBD)and Progressive Supranuclear Palsy(PSP),in other disease-specific brain regions.Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization ofα-synuclein or tau aggregates in the brain.Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues,including receptor neurons of the olfactory mucosa(OM).Methods:We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion(RT-QuIC)assay for OM analysis.In particular,by using human recombinantα-synuclein as substrate of reaction,we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induceα-synuclein aggregation,and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.Results:Our results showed that a significant percentage of MSA and PD samples inducedα-synuclein aggregation with high efficiency,but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect.Notably,the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.Conclusions:Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities forα-synuclein.Additional studies are required for(i)estimating sensitivity and specificity of the technique and for(ii)evaluating its application for t
基金supported by Ministerio de Ciencia,Innovacion y Universidades-Agencia Estatal de Investigacion/FEDER(SAF2017-87349-R and MDM-2017-0729)ISCIII/FEDER(PIE14/00034 and PI19/00144)+5 种基金Generalitat de Catalunya(2017SGR1604,2017SGR595)Fundacio la Marato de TV3(Grant 20152031)FWO(SBO-140028)ERC consolidator grant(Progsy 649116)Stiftelsen for Strategisk Forskning and a Wallenberg Clinical Scholarship to PS.The CRG/UPF Proteomics Unit is part of the Spanish Infrastruaure for Omics Technologies(ICTS OmicsTech)is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PEI+D+i 2013-2016 from the Instituto de Salud Carlos Ⅲ(ISCⅢ)and ERDF.
文摘Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism.Here,we investigated whether GPR37 is upregulated in sporadic PD,and thus a suitable potential biomarker for PD.Methods:GPR37 protein density and mRNA expression in postmortem substantia nigra(SN)from PD patients were analysed by immunoblot and RT-qPCR,respectively.The presence of peptides from the N-terminus-cleaved domain of GPR37(i.e.ecto-GPR37)in human cerebrospinal fluid(CSF)was determined by liquid chromatography-mass spectrometric analysis.An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control(NC)subjects,PD patients and Alzheimer's disease(AD)patients.Results:GPR37 protein density and mRNA expression were significantly augmented in sporadic PD.Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method.However,the CSF total a-synuclein level in PD patients did not differ from that in NC subjects.Similarly,the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered.Conclusion:GPR37 expression is increased in SN of sporadic PD patients.The ecto-GPR37 peptides are significantly increased in the CSF of PD patients,but not in AD patients.These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.
文摘The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.
基金supported by grants from National Natural Science Foundation of China(No.82192894,T.J.,No.82072768,W.Z.,No.82202896,GZ.L)Mainland(MOST)-Hong Kong(ITC)Joint Funding Scheme(No.2019YFE0109400 to Tao Jiang lab,No.MHP/004/19 to Jiguang Wang lab)+2 种基金Beijing Hospitals Authority Clinical Medicine Development of special funding support(ZLRK202314,W.Z)the public welfare development and reform pilot project of Beijing Medical Research Institute(JYY 2021-4,W.Z.)Sino-German Center Cooperation and Exchanges Program(M-0020,W.Z).
文摘Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance mechanisms.Furthermore,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less understood.However,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance.In this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented processes.This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen masking.Such type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell type.However,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol metabolism.Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities.Together,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.
文摘Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far.Unfortunately,diagnostic and prognostic biomarkers are lacking in clinical practice.Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum.Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis,reflecting the extensive damage of motor neurons and axons.Hence,neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis.The potential usefulness of neurofilaments regards various aspects,including diagnosis,prognosis,patient stratification in clinical trials and evaluation of treatment response.In this review paper,we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis.We also discuss the open issues concerning the use of neurofilaments clinical practice,as no overall guideline exists to date;finally,we address the most recent evidence and future perspectives.
文摘The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.
基金supported by a Fondazione Umberto Veronesi 2011 grant to RRa grant from the University of Bari(Fondi di Ateneo 2014)a grant from the University of Salento(Fondi di Ateneo 2014)
文摘In this study, the effects of Radio Electric Asymmetric Conveyer(REAC), a non-invasive physical treatment, on neuroinflammatory responses in a mouse model of parkinsonism induced by intoxication with1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),were investigated in vivo. We found that the REAC tissue optimization treatment specific for neuro-regenerative purposes(REAC TO-RGN-N) attenuated the inflammatory picture evoked by MPTP-induced nigro-striatal damage inmice, decreasing the levels of pro-inflammatory molecules and increasing anti-inflammatory mediators. Besides, there was a significant reduction of both astrocyte and microglial activation in MPTP-treated mice exposed to REAC TORGN-N. These results indicated that REAC TO-RGN-N treatment modulates the pro-inflammatory responses and reduces neuronal damage in MPTP-induced parkinsonism.
基金supported by grants from the National Natural Science Foundation of China(82002657,82073322,81761168038)the Hebei Natural Science Foundation Precision Medicine Joint Project(H2020201206)+4 种基金the Tianjin Key R&D Plan of Tianjin Science and Technology Plan Project(20YFZCSY00360)Brain Tumor Precision Diagnosis and Treatment and Translational Medicine Innovation Unit,Chinese Academy of Medical Sciences(2019-I2M-5-021)the Science and Technology Project of Tianjin Municipal Health Commission(TJWJ2021QN003)Key-Area Research and Development Program of Guangdong Province(2023B1111020008)Multi-input Project by Natural Science Foundation of Tianjin Municipal Science and Technology Commission(21JCQNJC01250)。
文摘Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms.Epidermal growth factor receptor(EGFR)amplification and EGFR-vIII mutation are often detected in GBM cells,contributing to the malignant behavior.This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Methods Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis.A metabolism-associated RTK-fatty acid-gene signature was constructed and verified.MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism.Energy metabolism in GBM with activated EGFR pathway was monitored.The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide(TMZ)was analyzed by an intracranial tumor model in vivo.Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels,supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples.Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production.Mechanistically,the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3(ACSS3),acyl-CoA synthetase long-chain family member 3(ACSL3),and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2(ELOVL2)in an NF-κB-dependent manner.Moreover,inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes,thereby affecting the signal transduction of the EGFR/AKT pathway.Therefore,targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Conclusions Our findings not only uncovered the mechanism of metabolic rep
基金Beijing Nova Program(No.Z201100006820118)National Natural Science Foundation of China(Nos.82192894 and 81903078)Research Unit of Accurate Diagnosis,Treatment,and Translational Medicine of Brain Tumors Chinese(No.2019-I2M-5-021)
文摘The prognosis for diffusely infiltrating gliomas at World Health Organization(WHO)grade 2-4 remains dismal due to their heterogeneity.The rapid development of genome-wide molecular-profiling-associated studies has greatly promoted the accuracy of glioma classification.Thus,the latest version of the WHO classification of the central nervous system tumors published in 2021 has incorporated more molecular biomarkers together with histological features for the diagnosis of gliomas.Advanced usage of molecular pathology in clinical diagnostic practice provides also new opportunities for the therapy of patients with glioma,including surgery,radiotherapy and chemotherapy,targeted therapy,immunotherapy,and more precision clinical trials.Herein,we highlight the updates in the classification of gliomas according to the latest WHO guidelines and summarize the clinically relevant molecular markers by focusing on their applications in clinical practice.We also review the advances in molecular features of gliomas,which can facilitate the development of glioma therapies,thereby discussing the challenges and future directions of molecular pathology toward precision medicine for patients with glioma.
