AIM: To determine the prevalence of unsuspected thyroid nodules on contrast enhanced 16and 64-modified discrete cosine transform (MDCT) of the chest, in a population of adult outpatients imaged for indications other t...AIM: To determine the prevalence of unsuspected thyroid nodules on contrast enhanced 16and 64-modified discrete cosine transform (MDCT) of the chest, in a population of adult outpatients imaged for indications other than thyroid disease. METHODS: This retrospective study involved review of intravascular contrast-enhanced MDCT scans of the chest from 3077 consecutive adult outpatients, to identify unsuspected thyroid nodules. Exclusion criteria included history of thyroid cancer, known thyroid nodules or thyroid disease and risk factors for thyroid cancer, as evidenced by their medical records. One of 9 radiologists recorded number of nodules, location and bidirectional measurement of largest nodule, as well as amount of thyroid visualized on the chest computed tomography (CT). Presence of nodule was correlated with age, gender, race and percentage of thyroid imaged. RESULTS: A total of 2510 (2510/3077 or 81.6%) study subjects were included in the data analysis; among them,one or more nodules were identified in 629 subjects (629/2510 or 25.1%), with 242 (242/629 or 38.5%) having multiple nodules. Patients with nodule(s) were significantly older than those without (64 ± 13 years vs 58 ± 14 years, P < 0.0001), and female gender was associated with presence of nodule(s) (373/1222 or 30.5% vs 256/1288 or 19.9%, P < 0.0001). Women were also more likely having multiple nodules (167/373 or 44.8%) compared to men (75/256 or 29.3%, P < 0.0001). The majority of nodules (427/629 or 67.9%) were less than 1 cm. CONCLUSION: This retrospective review revealed a prevalence of 25.1% for unsuspected thyroid nodules on contrast-enhanced chest CT.展开更多
Near-infrared spectroscopy(NIRS)can provide the hemodynamics information based on the hemoglobin concentration representing the blood oxygen metabolism of the cerebral cortical,which can be deployed for the cerebral f...Near-infrared spectroscopy(NIRS)can provide the hemodynamics information based on the hemoglobin concentration representing the blood oxygen metabolism of the cerebral cortical,which can be deployed for the cerebral function study.However,NIRS-based cerebral function detection accuracy can be signi¯cantly in°uenced by the physiological activities such as cardic cycle,respiration,spontaneous low-frequency oscillation and ultra-low frequency oscillation.The distribution difference of the capillary,artery and vein leads to the heterogeneity feature of the cerebral tissues.In the case that the heterogeneity is not serious,good detection accuracy and stable performance can be achieved through the regression analysis as the reference signal can well represent the interference in the measurement signal when conducting the multi-distance measurement approach.The direct use of the reference signal to estimate the interference is not able to achieve good performance in the case that the heterogeneity is serious.In this study,the cerebral function activity signal is extracted using recursive least square(RLS)method based on the multi-distance measurement method in which the reference signal is processed by ensemble empirical mode decomposition(EEMD)algorithm.The temporal and dimensional correlation of the neighboring sampling values are applied to estimate the interference in the measurement signal.Monte Carlo simulation based on a heterogeneous model is adopted here to investigate the effectiveness of this methodology.The results show that this methodology can effectively suppress the physiological interference and improve the detection accuracy of cerebral activity signal.展开更多
Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53; hence, this relationship is the focus of many cancerrelated studies. A multitude of experiments across various developmental stages have been conduct...Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53; hence, this relationship is the focus of many cancerrelated studies. A multitude of experiments across various developmental stages have been conducted to explore the tissuespecific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germiine or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethaLity. Mdm2 loss is often more deleterious than toss of its homotogue Mdm4. ALL tissues experience activation of p53 target genes upon toss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological pheno- types. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evoLving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the celt-specific level.展开更多
随着医学的发展,精准医疗逐渐成为现代医疗的发展方向.为了给患者制定有效的个体化治疗方案,临床医师对病理诊断的精准性提出了更高的要求.规范化的取材是精准病理诊断的基础,也是精准治疗的前提[1].近几年来,随着乳腺B超引导下粗针穿...随着医学的发展,精准医疗逐渐成为现代医疗的发展方向.为了给患者制定有效的个体化治疗方案,临床医师对病理诊断的精准性提出了更高的要求.规范化的取材是精准病理诊断的基础,也是精准治疗的前提[1].近几年来,随着乳腺B超引导下粗针穿刺活检已经逐渐取代手术活检,多数患者在手术切除时已经有了明确诊断.为了更精准测量肿瘤的位置,客观地评判手术范围,准确地评估肿瘤分期和治疗反应,乳腺标本的大体取材受到临床与病理的共同重视,取材方法也在逐渐改进[1-5].准确的大体检查往往依赖于病理医师、放射医师及外科医师的合作.我们旨在介绍乳腺癌手术切除标本和前哨淋巴结的大体取材方法,其主要内容来自于美国MD安德森癌症中心(MD Anderson Cancer Center,MDACC) 行之有效的多年实践.展开更多
We investigate and compare the performance of four optical transport schemes for distributing Local Multipoint Distribution Service (LMDS) signals using an optical fiber backbone.
Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer treatment....Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer treatment.Using phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration range.Here we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular design.Functional assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration calorimetry.Co-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,respectively.Similar to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu 10.Notable differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both proteins.By adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent manner.This super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.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
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
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
Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and i...Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.展开更多
Dear Editor,Pancreatic cancer is one of the most aggressive human cancers and is predicted to become the second leading cause of cancer-related death by the year 2030[1,2].In the United States,approximately 60,000 new...Dear Editor,Pancreatic cancer is one of the most aggressive human cancers and is predicted to become the second leading cause of cancer-related death by the year 2030[1,2].In the United States,approximately 60,000 newly diagnosed cases and 48,000 deaths were estimated to occur in 2021[3].Because early screening is very difficult and most patients are diagnosed with advanced disease,curing pancreatic cancer patients still faces huge challenges.Accordingly,a comprehensive understanding of the pathogenesis of pan-creatic cancer is required to promote the development of efficient treatment modalities.展开更多
Aim:Hepatocellular carcinoma(HCC)has emerged as one of the most commonly diagnosed forms of human cancer;yet,the current treatment for HCC is less effective than those used against other cancers.Transcription factor p...Aim:Hepatocellular carcinoma(HCC)has emerged as one of the most commonly diagnosed forms of human cancer;yet,the current treatment for HCC is less effective than those used against other cancers.Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress,thereby playing a critical role in protecting cells from malignant transformation.The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53,conferring tumor development and survival.Methods:In this work,we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas.Moreover,we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at(i,i+4)positions,and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX,termed p53-MDM2/MDMX inhibitor(PMI).Results:Notably,all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinity ;as PMI.More importantly,this stapling functionally rescued PMI that,on its own,failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation.Conclusion:Taken together,this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy,but promises an important new tool for peptide drug discovery and development for a variety of human diseases.展开更多
文摘AIM: To determine the prevalence of unsuspected thyroid nodules on contrast enhanced 16and 64-modified discrete cosine transform (MDCT) of the chest, in a population of adult outpatients imaged for indications other than thyroid disease. METHODS: This retrospective study involved review of intravascular contrast-enhanced MDCT scans of the chest from 3077 consecutive adult outpatients, to identify unsuspected thyroid nodules. Exclusion criteria included history of thyroid cancer, known thyroid nodules or thyroid disease and risk factors for thyroid cancer, as evidenced by their medical records. One of 9 radiologists recorded number of nodules, location and bidirectional measurement of largest nodule, as well as amount of thyroid visualized on the chest computed tomography (CT). Presence of nodule was correlated with age, gender, race and percentage of thyroid imaged. RESULTS: A total of 2510 (2510/3077 or 81.6%) study subjects were included in the data analysis; among them,one or more nodules were identified in 629 subjects (629/2510 or 25.1%), with 242 (242/629 or 38.5%) having multiple nodules. Patients with nodule(s) were significantly older than those without (64 ± 13 years vs 58 ± 14 years, P < 0.0001), and female gender was associated with presence of nodule(s) (373/1222 or 30.5% vs 256/1288 or 19.9%, P < 0.0001). Women were also more likely having multiple nodules (167/373 or 44.8%) compared to men (75/256 or 29.3%, P < 0.0001). The majority of nodules (427/629 or 67.9%) were less than 1 cm. CONCLUSION: This retrospective review revealed a prevalence of 25.1% for unsuspected thyroid nodules on contrast-enhanced chest CT.
基金the support from the National Science Foundation of China(Grants Nos.61401117 and 61201017)the Fundamental Research Funds for the Central Universities(Grants Nos.HIT.IBRSEM.201303 and HIT.IBRSEM.B.201401).
文摘Near-infrared spectroscopy(NIRS)can provide the hemodynamics information based on the hemoglobin concentration representing the blood oxygen metabolism of the cerebral cortical,which can be deployed for the cerebral function study.However,NIRS-based cerebral function detection accuracy can be signi¯cantly in°uenced by the physiological activities such as cardic cycle,respiration,spontaneous low-frequency oscillation and ultra-low frequency oscillation.The distribution difference of the capillary,artery and vein leads to the heterogeneity feature of the cerebral tissues.In the case that the heterogeneity is not serious,good detection accuracy and stable performance can be achieved through the regression analysis as the reference signal can well represent the interference in the measurement signal when conducting the multi-distance measurement approach.The direct use of the reference signal to estimate the interference is not able to achieve good performance in the case that the heterogeneity is serious.In this study,the cerebral function activity signal is extracted using recursive least square(RLS)method based on the multi-distance measurement method in which the reference signal is processed by ensemble empirical mode decomposition(EEMD)algorithm.The temporal and dimensional correlation of the neighboring sampling values are applied to estimate the interference in the measurement signal.Monte Carlo simulation based on a heterogeneous model is adopted here to investigate the effectiveness of this methodology.The results show that this methodology can effectively suppress the physiological interference and improve the detection accuracy of cerebral activity signal.
文摘Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53; hence, this relationship is the focus of many cancerrelated studies. A multitude of experiments across various developmental stages have been conducted to explore the tissuespecific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germiine or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethaLity. Mdm2 loss is often more deleterious than toss of its homotogue Mdm4. ALL tissues experience activation of p53 target genes upon toss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological pheno- types. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evoLving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the celt-specific level.
文摘随着医学的发展,精准医疗逐渐成为现代医疗的发展方向.为了给患者制定有效的个体化治疗方案,临床医师对病理诊断的精准性提出了更高的要求.规范化的取材是精准病理诊断的基础,也是精准治疗的前提[1].近几年来,随着乳腺B超引导下粗针穿刺活检已经逐渐取代手术活检,多数患者在手术切除时已经有了明确诊断.为了更精准测量肿瘤的位置,客观地评判手术范围,准确地评估肿瘤分期和治疗反应,乳腺标本的大体取材受到临床与病理的共同重视,取材方法也在逐渐改进[1-5].准确的大体检查往往依赖于病理医师、放射医师及外科医师的合作.我们旨在介绍乳腺癌手术切除标本和前哨淋巴结的大体取材方法,其主要内容来自于美国MD安德森癌症中心(MD Anderson Cancer Center,MDACC) 行之有效的多年实践.
文摘We investigate and compare the performance of four optical transport schemes for distributing Local Multipoint Distribution Service (LMDS) signals using an optical fiber backbone.
基金supported by grants from the National Natural Science Foundation of China,No.21807112(to Xiang Li),No.82030062(to Wuyuan Lu),Nos.91849129 and 22077078(to Honggang Hu)Shanghai Rising-Star Program(to Xiang Li,China)+1 种基金supported by the U.S.Department of Energy,Office of Science,Office of Basic Energy Sciences under Contract No.DE-AC02-76SF00515supported by the DOE Office of Biological and Environmental Research,and by the National Institutes of Health,National Institute of General Medical Sciences
文摘Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer treatment.Using phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration range.Here we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular design.Functional assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration calorimetry.Co-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,respectively.Similar to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu 10.Notable differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both proteins.By adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent manner.This super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.
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 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.
基金This work was supported,in part,by grants from the National Health Research Institutes,Taiwan(EOPP10-014 and EOSP07-014 to S.-K.H.)Kaohsiung Medical University“The Talent Plan”(105KMUOR04 to S.-K.H.)+6 种基金the Ministry of Science and Technology,Taiwan(MOST 105-2320-B-039-004 and MOST 106-2320-B-039-037,to H.-C.W.)China Medical University Hospital,Taiwan(DMR-106-154 and DMR-107-117,to H.-C.W.)the Community Medicine Research Center,Chang Gung Memorial Hospital at Keelung(CMRPG3E1183 to L.-C.C.)the 1000 Young Talents Plan Program,China(to Y.Z.)the Initial Funding for New PI,Fudan Children’s Hospital and Fudan University(to Y.Z.)the National Natural Science Foundation of China(81671561,to Y.Z.)the National Key Research and Development Program of China(2016YFC1305102,to Y.Z.)。
文摘Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.
基金supported by the Intramural Research Pro-gram of the NIH,National Cancer Institute,Center for Cancer Research(Project No.ZIA BC 011652).
文摘Dear Editor,Pancreatic cancer is one of the most aggressive human cancers and is predicted to become the second leading cause of cancer-related death by the year 2030[1,2].In the United States,approximately 60,000 newly diagnosed cases and 48,000 deaths were estimated to occur in 2021[3].Because early screening is very difficult and most patients are diagnosed with advanced disease,curing pancreatic cancer patients still faces huge challenges.Accordingly,a comprehensive understanding of the pathogenesis of pan-creatic cancer is required to promote the development of efficient treatment modalities.
基金This work was supported by the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University(XJTU1AF-CRF-2017-003)to Hou P and He WX.
文摘Aim:Hepatocellular carcinoma(HCC)has emerged as one of the most commonly diagnosed forms of human cancer;yet,the current treatment for HCC is less effective than those used against other cancers.Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress,thereby playing a critical role in protecting cells from malignant transformation.The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53,conferring tumor development and survival.Methods:In this work,we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas.Moreover,we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at(i,i+4)positions,and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX,termed p53-MDM2/MDMX inhibitor(PMI).Results:Notably,all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinity ;as PMI.More importantly,this stapling functionally rescued PMI that,on its own,failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation.Conclusion:Taken together,this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy,but promises an important new tool for peptide drug discovery and development for a variety of human diseases.
