AIM: To identify signaling pathways and genes that initiate and commit hepatic stellate cells (HSCs) to transdifferentiation. METHODS: Primary HSCs were isolated from male Sprague-Dawley rats and cultured on plastic f...AIM: To identify signaling pathways and genes that initiate and commit hepatic stellate cells (HSCs) to transdifferentiation. METHODS: Primary HSCs were isolated from male Sprague-Dawley rats and cultured on plastic for 0-10 d. Gene expression was assessed daily (quiescent to day 10 culture-activation) by real time polymerase chain reaction and data clustered using AMADA software. The significance of JAK/STAT signaling to HSC transdifferentiation was determined by treating cells with a JAK2 inhibitor. RESULTS: Genetic cluster analyses, based on expression of these 21 genes, showed similar expression profiles on days 1-3, days 5 and 6, and days 7-10, while freshly isolated cells (day Q) and day 4 cells were genotypically distinct from any of the other days. Additionally, gene expression clustering revealed strong upregulation of interleukin-6, JAK2 and STAT3 mRNA in the early stages of activation. Inhibition of the JAK/STAT signaling pathway impeded the morphological transdifferentiation of HSCs which correlated with decreased mRNA expression of several profibrotic genes including collagens, α-SMA, PDGFR and TGFβR. CONCLUSION: These data demonstrate unique clustered genetic profiles during the daily progression of HSC transdifferentiation and that JAK/STAT signaling may be critical in the early stages of transdifferentiation.展开更多
Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in case...Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant CRCs.Methods:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is imperative.Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)expression.Results:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation sites.In comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt vs.ERBB2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed MSI-H.Mutant genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China.These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.展开更多
Circulating cell-free tumor DNA(ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a ...Circulating cell-free tumor DNA(ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing(MPS), ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy. This review provides an overview of the latest development in our understanding of the biologic characteristics, detection methodologies, and potential clinical implications of ctDNA, as well as the challenges in translating ctDNA analysis from the research arena to patient care.展开更多
Objective: To analyze the main etiological diagnoses of patients attended at a genetics outpatient clinic of the Association of Parents and Friends of Exceptional Children/APAE in the state of Amazonas, Brazil. Meth...Objective: To analyze the main etiological diagnoses of patients attended at a genetics outpatient clinic of the Association of Parents and Friends of Exceptional Children/APAE in the state of Amazonas, Brazil. Methods: retrospective study of patients seen in the period 2005-2016, with review of medical records. The following data were recorded: sex, origin of referral and etiological diagnosis. Results: 362 patients were attended, 94.7% of them from Manaus, and 5.3% from the interior of the state. The etiological diagnosis was defined in 262 (72.3%) of the sample, of which 254 (70.2%) were of genetic etiology and 8 (2.2%) non-genetic. Of the genetic etiologies, 46 (12.7%) cases were monogenic syndromes, 136 (37.6%) were chromosomal aberrations and 72 (19.9%) had multifactorial causes, however, 100 (27.6%) cases remained unclear. There were several syndromes found, with Down syndrome being the most frequent and correlating significantly with the sex of the patient (male predominance, p 〈 0.05). Conclusions: The study carried out in the APAE/Manaus genetics outpatient clinic allowed the profile of the patients being attended to be traced. It was verified that the majority of the patients were male and that the diagnosis of chromosomal alterations was the most frequent.展开更多
Tibeto-Burman(TB)people have endeavored to adapt to the hypoxic,cold,and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period...Tibeto-Burman(TB)people have endeavored to adapt to the hypoxic,cold,and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period.However,the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people,as well as their interaction mechanism,remain unknown.Here,we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity,admixture history,and differentiated adaptative features of geographically different TB-speaking people.We identify genetic differentiation related to geography and language among TB-speaking people,consistent with their differentiated admixture process with incoming or indigenous ancestral source populations.A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis.We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers.Adaptative signatures associated with the physical pigmentation(EDAR and SLC24A5)and metabolism(ALDH9A1)are identified in Loloish people,which differed from the high-altitude adaptative genetic architecture in Tibetan.TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.展开更多
Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of t...Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of tumor/host interactions in the tumor microenvironment through a high-throughput discovery-driven approach.This conclusion is derived from our recognition that too many hypotheses or,in other words,no solid single hypothesis exist,based on experimental results,to further drive experimentation in human subjects.Functional genomic studies entertained during the last few years consolidated the belief that in humans the interactions between tumor and immune cells are too complex to be approached exclusively with a hypothesis driven method.We believe that immune cells suit cancer cells in a Yin and Yang balance by opposing and yet mutually depending on each other.Indeed,immune infiltration in tumors may play a dual role modulating in different circumstances cancer cell growth or destruction through a physiological modulation of inflammation.It is reasonable to question what induces inflammation at the tumor site.We hypothesize that inflammation is primarily driven by the phenotype of tumor cells that can modulate their microenvironment through cell-to-cell interactions or the secretion of soluble factors.Thus,in analogy the observation of immune cells within tumors parallels the presence of paramedics,police and firemen at the scene of an accident,which is reactive to and not causative of the occurrence.In this review we will explore this hypothesis by reporting and summarizing most of our recent work in the frame of available literature on the subject.Cellular & Molecular Immunology.2004;1(4):256-265.展开更多
基金Supported by National Institutes of Health Grant RO1 AA014891
文摘AIM: To identify signaling pathways and genes that initiate and commit hepatic stellate cells (HSCs) to transdifferentiation. METHODS: Primary HSCs were isolated from male Sprague-Dawley rats and cultured on plastic for 0-10 d. Gene expression was assessed daily (quiescent to day 10 culture-activation) by real time polymerase chain reaction and data clustered using AMADA software. The significance of JAK/STAT signaling to HSC transdifferentiation was determined by treating cells with a JAK2 inhibitor. RESULTS: Genetic cluster analyses, based on expression of these 21 genes, showed similar expression profiles on days 1-3, days 5 and 6, and days 7-10, while freshly isolated cells (day Q) and day 4 cells were genotypically distinct from any of the other days. Additionally, gene expression clustering revealed strong upregulation of interleukin-6, JAK2 and STAT3 mRNA in the early stages of activation. Inhibition of the JAK/STAT signaling pathway impeded the morphological transdifferentiation of HSCs which correlated with decreased mRNA expression of several profibrotic genes including collagens, α-SMA, PDGFR and TGFβR. CONCLUSION: These data demonstrate unique clustered genetic profiles during the daily progression of HSC transdifferentiation and that JAK/STAT signaling may be critical in the early stages of transdifferentiation.
基金sponsored by National Natural Science Foundation of China(Grant Numbers 81972280,81972290)Natural Science Foundation of Shanghai(Grant Number 23ZR1452300)+2 种基金Research Grant for Health Science and Technology of Pudong Health Bureau of Shanghai(Grant Number PW2022E-02)Academic Leaders Training Program of Pudong Health Bureau of Shanghai(Grant Number PWRd2022-02)Foundation of Beijing CSCO Clinical Oncology Research(Grant Number Y-HR2019-0384).
文摘Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant CRCs.Methods:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is imperative.Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)expression.Results:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation sites.In comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt vs.ERBB2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed MSI-H.Mutant genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China.These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.
文摘Circulating cell-free tumor DNA(ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing(MPS), ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy. This review provides an overview of the latest development in our understanding of the biologic characteristics, detection methodologies, and potential clinical implications of ctDNA, as well as the challenges in translating ctDNA analysis from the research arena to patient care.
文摘Objective: To analyze the main etiological diagnoses of patients attended at a genetics outpatient clinic of the Association of Parents and Friends of Exceptional Children/APAE in the state of Amazonas, Brazil. Methods: retrospective study of patients seen in the period 2005-2016, with review of medical records. The following data were recorded: sex, origin of referral and etiological diagnosis. Results: 362 patients were attended, 94.7% of them from Manaus, and 5.3% from the interior of the state. The etiological diagnosis was defined in 262 (72.3%) of the sample, of which 254 (70.2%) were of genetic etiology and 8 (2.2%) non-genetic. Of the genetic etiologies, 46 (12.7%) cases were monogenic syndromes, 136 (37.6%) were chromosomal aberrations and 72 (19.9%) had multifactorial causes, however, 100 (27.6%) cases remained unclear. There were several syndromes found, with Down syndrome being the most frequent and correlating significantly with the sex of the patient (male predominance, p 〈 0.05). Conclusions: The study carried out in the APAE/Manaus genetics outpatient clinic allowed the profile of the patients being attended to be traced. It was verified that the majority of the patients were male and that the diagnosis of chromosomal alterations was the most frequent.
基金the National Natural Science Foundation of China(82202078)the Center for Archaeological Science of Sichuan University(23SASA01).
文摘Tibeto-Burman(TB)people have endeavored to adapt to the hypoxic,cold,and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period.However,the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people,as well as their interaction mechanism,remain unknown.Here,we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity,admixture history,and differentiated adaptative features of geographically different TB-speaking people.We identify genetic differentiation related to geography and language among TB-speaking people,consistent with their differentiated admixture process with incoming or indigenous ancestral source populations.A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis.We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers.Adaptative signatures associated with the physical pigmentation(EDAR and SLC24A5)and metabolism(ALDH9A1)are identified in Loloish people,which differed from the high-altitude adaptative genetic architecture in Tibetan.TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.
文摘Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of tumor/host interactions in the tumor microenvironment through a high-throughput discovery-driven approach.This conclusion is derived from our recognition that too many hypotheses or,in other words,no solid single hypothesis exist,based on experimental results,to further drive experimentation in human subjects.Functional genomic studies entertained during the last few years consolidated the belief that in humans the interactions between tumor and immune cells are too complex to be approached exclusively with a hypothesis driven method.We believe that immune cells suit cancer cells in a Yin and Yang balance by opposing and yet mutually depending on each other.Indeed,immune infiltration in tumors may play a dual role modulating in different circumstances cancer cell growth or destruction through a physiological modulation of inflammation.It is reasonable to question what induces inflammation at the tumor site.We hypothesize that inflammation is primarily driven by the phenotype of tumor cells that can modulate their microenvironment through cell-to-cell interactions or the secretion of soluble factors.Thus,in analogy the observation of immune cells within tumors parallels the presence of paramedics,police and firemen at the scene of an accident,which is reactive to and not causative of the occurrence.In this review we will explore this hypothesis by reporting and summarizing most of our recent work in the frame of available literature on the subject.Cellular & Molecular Immunology.2004;1(4):256-265.