Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introducti...Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.展开更多
Objective To investigate whether exposure to particulate matter of diameter equal to or less than 2.5μm(PM2.5)alters the response of lung epithelial cells to extrinsic regulation by globally profiling cell surface li...Objective To investigate whether exposure to particulate matter of diameter equal to or less than 2.5μm(PM2.5)alters the response of lung epithelial cells to extrinsic regulation by globally profiling cell surface ligands and quantifying their binding activity.Methods Human A549 lung epithelial cells(LECs)were treated with or without PM2.5.Ligandomic profiling was applied to these cells for the global identification of LEC-binding ligands with simultaneous quantification of binding activity.Quantitative comparisons of the entire ligandome profiles systematically identified ligands with increased or decreased binding to PM2.5-treated LECs.Results We found 143 ligands with increased binding to PM2.5-treated LECs and 404 ligands with decreased binding.Many other ligands showed no change in binding activity.For example,apolipoprotein E(ApoE),Notch2,and growth arrest-specific 6(Gas6)represent ligands with increased,decreased,or unchanged binding activity,respectively.Both ApoE and Gas6 are phagocytosis ligands,suggesting that phagocytic receptors on LECs after stimulation with PM2.5 were differentially upregulated by PM2.5.Conclusion These results suggest that the newly-developed ligandomics is a valuable approach to globally profile the response of LECs to PM2.5 in terms of regulating the expression of cell surface receptors,as quantified by ligand binding activity.This quantitative ligandome profiling will provide indepth understanding of the LEC molecular response on the cell surface to particulate matter air pollution.展开更多
Type 2 diabetes mellitus(T2DM)is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030.Long-term vascular complications,such as corona...Type 2 diabetes mellitus(T2DM)is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030.Long-term vascular complications,such as coronary artery disease,myocardial infarction,stroke,are the leading causes of morbidity and mortality among diabetic patients.The recent advances in genome-wide technologies have given a powerful impetus to the study of risk markers for multifactorial diseases.To date,the role of genetic and epigenetic factors in modulating susceptibility to T2DM and its vascular complications is being successfully studied that provides the accumulation of genomic knowledge.In the future,this will provide an opportunity to reveal the pathogenetic pathways in the development of the disease and allow to predict the macrovascular complications in T2DM patients.This review is focused on the evidence of the role of genetic variants and epigenetic changes in the development of macrovascular pathology in diabetic patients.展开更多
Type 2 diabetes(T2D)mellitus is a common complex disease that currently affects more than 400 million people worldwide and has become a global health problem.High-throughput sequencing technologies such as whole-genom...Type 2 diabetes(T2D)mellitus is a common complex disease that currently affects more than 400 million people worldwide and has become a global health problem.High-throughput sequencing technologies such as whole-genome and whole-exome sequencing approaches have provided numerous new insights into the molecular bases of T2D.Recent advances in the application of sequencing technologies to T2D research include,but are not limited to:(1)Fine mapping of causal rare and common genetic variants;(2)Identification of confident genelevel associations;(3)Identification of novel candidate genes by specific scoring approaches;(4)Interrogation of disease-relevant genes and pathways by transcriptional profiling and epigenome mapping techniques;and(5)Investigation of microbial community alterations in patients with T2D.In this work we review these advances in application of next-generation sequencing methods for elucidation of T2D pathogenesis,as well as progress and challenges in implementation of this new knowledge about T2D genetics in diagnosis,prevention,and treatment of the disease.展开更多
BACKGROUND Dyslipidemias are metabolic abnormalities associated with chronic diseases caused by genetic and environmental factors.The Mexican population displays regional differences according to ethnicity with an imp...BACKGROUND Dyslipidemias are metabolic abnormalities associated with chronic diseases caused by genetic and environmental factors.The Mexican population displays regional differences according to ethnicity with an impact on the type of dyslipidemia.AIM To define the main dyslipidemias,the frequency of lipid-related risk alleles,and their association with hyperlipidemic states among different ethnic groups in West Mexico.METHODS In a retrospective study,1324 adults were selected to compare dyslipidemias and lipid-related gene polymorphisms.Demographic,clinical,and laboratory data were collected.A subgroup of 196 normal weight subjects without impaired glucose was selected for the association analyses.Genotyping was determined by allelic discrimination assay.RESULTS Hypercholesterolemia was the most prevalent dyslipidemia(42.3%).The frequency of the risk alleles associated with hypoalphalipoproteinemia(ABCA1)and hypercholesterolemia(APOE,LDLR)was higher in the Native Americans(P=0.047).In contrast,the Mestizos with European ancestry showed a higher frequency of the risk alleles for hypertriglyceridemia(APOE2,MTTP)(P=0.045).In normal weight Mestizo subjects,the APOB TT and LDLR GG genotypes were associated risk factors for hypercholesterolemia(OR=5.33,95%CI:1.537-18.502,P=0.008 and OR=3.90,95%CI:1.042-14.583,P=0.043,respectively),and displayed an increase in low-density lipoprotein cholesterol levels(APOB:β=40.39,95%CI:14.415-66.366,P=0.004;LDLR:β=20.77,95%CI:5.763-35.784,P=0.007).CONCLUSION Gene polymorphisms and dyslipidemias showed a differential distribution.Regional primary health care strategies are required to mitigate their prevalence considering the genetic and environmental features which could have important implications for personalized medicine within the new era of precision medicine.展开更多
Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like components.The molecular and immune lan...Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like components.The molecular and immune landscape of PSC has not been well defined.Methods:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and RNA sequencing.We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.Results:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by KRAS.Interestingly,most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC tumors.We identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and signaling.The Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.Conclusions:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis.IM-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.展开更多
BACKGROUND Adenocarcinoma originating from heterotopic pancreas tissue is a rare disease.Furthermore,to our knowledge,no HER2-positive cases in the duodenum have been reported in the scientific literature nor has the ...BACKGROUND Adenocarcinoma originating from heterotopic pancreas tissue is a rare disease.Furthermore,to our knowledge,no HER2-positive cases in the duodenum have been reported in the scientific literature nor has the efficacy of trastuzumab treatment for the disease been reported.CASE SUMMARY A 65-year-old woman whose clinical diagnosis was unresectable advanced duodenal cancer with HER2 overexpression responded well to trastuzumab chemotherapy.The main tumor in the duodenum reduced drastically.The patient underwent pancreaticoduodenectomy and lymph node dissection.A small number of cancer cells remained in the submucosal layer of the duodenum and pancreas head.After histological and immunohistochemical examination,the patient was diagnosed with duodenal adenocarcinoma originating from heterotopic pancreas tissue.CONCLUSION Trastuzumab treatment is effective in HER2-positive adenocarcinoma originating from heterotopic pancreas tissue in the duodenum.展开更多
Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
Congenital heart disease(CHD)is the most common congenital anomaly and is an important cause of infant morbidity and mortality.Besides the epigenetic and environmental basis of CHD,genetics plays a central role in CHD...Congenital heart disease(CHD)is the most common congenital anomaly and is an important cause of infant morbidity and mortality.Besides the epigenetic and environmental basis of CHD,genetics plays a central role in CHD pathogenesis.Traditional genetic testing strategies including conventional chromosome analysis,fluorescence in situ hybridization,and Sanger sequencing have largely focused on syndromic CHD or selected CHD phenotypes that are strongly associated with a particular genotype.The landscape of clinical genetic testing in CHD is rapidly evolving due to technical advances in genetic testing,including the identification of copy number variants by chromosomal microarray and nucleotide level alterations/variants by next-generation sequencing(NGS),which are essential to detect genetic causes of CHD and identify associations between genotypes and longitudinal clinical phenotypes.Whole-exome and whole-genome NGS not only reveal pathogenic variants in CHD genes,but also identify non-coding variants that influence the expression of CHD genes.Given the increasing availability and cost-effectiveness of clinical NGS to provide information on the causes of CHD and to detect incidental findings that are clinically actionable,the guidance of genetic counselors or experienced clinicians is essential.The identification of definitive causal CHD variants influences patient care and helps to inform the risk of recurrence,prenatal genetic counseling,and pre-implantation testing for the family of a CHD infant and adults with repaired/palliated CHD.Prenatally,circulating cell-free DNA screening as a non-invasive approach is available as early as 9 weeks of gestation and can screen for the common aneuploidies,which may underlie CHD.In this review,we present past and recent genetic testing in CHD based on our increased understanding of the pathogenesis of CHD along with current challenges with the interpretation of de novo genetic variants.Identification of a genetic diagnosis can help to predict and potentially improve clinical outcomes in CHD patients.展开更多
Background and Aims:Lamivudine(3TC),telbivudine(LdT),entecavir(ETV),adefovir(ADF),and tenofovir(TFV)are drugs used to treat hepatitis B virus(HBV)infection,but specific mutations allow some viruses to become resistant...Background and Aims:Lamivudine(3TC),telbivudine(LdT),entecavir(ETV),adefovir(ADF),and tenofovir(TFV)are drugs used to treat hepatitis B virus(HBV)infection,but specific mutations allow some viruses to become resistant to antiviral drugs or to acquire immune escape capacities.These mutations have not been thoroughly investigated in Mexico.This study aimed to estimate the prevalence of HBV antiviral resistance and escape mutations.Methods:This cross-sectional study analyzed 158 samples.HBV DNA was extracted,amplified,and sequenced in serum samples using the spin column method,PCR assay,and Sanger’s sequencing,respectively.HBV genotypes were determined,and HBV mutations were tested using the Geno2pheno tool.Results:Overall,68.4%(108/158)of HBV patients were infected with genotype H,followed by G(11.4%,18/158),A2(10.8%,17/158),F1b(6.9.0%,11/158),D(1.9%,3/158),and E(0.6%,1/158),and 5.1%(8/158)had evidence of recombination.The prevalence of resistance mutations was 8.2%(13/158)and the most common combined mutation was rt180M+rt204V.Notably,we found the combinations rt180M+rt204V+rt173L(n=2)and rt180M+rt204V+rt202G(n=1)that confer multidrug resistance to 3TC,LdT,and ETV.Resistance mutations were found in genotypes A2(11.8%,2/17),and H(10.2%,11/108),and escape mutations were detected in HBV genotypes A2(11.8%,2/17),H(10.2%,11/108),F1b(9.1%,1/11)and G(5.6%,1/18).Conclusions:The highest prevalence of antiviral resistance mutations or escape mutations was detected in HBV genotypes A2 and H.The earliest cases of HBV multidrug resistance were detected in Mexico.展开更多
Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-lin...Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.展开更多
Autosomal reciprocal translocations represent exchanges of chromatin fragments between non-homologous chromosomes.Translocations are facilitated by the creation of quadrivalent structures during the first meiotic divi...Autosomal reciprocal translocations represent exchanges of chromatin fragments between non-homologous chromosomes.Translocations are facilitated by the creation of quadrivalent structures during the first meiotic division,which are characterized by the length of the translocated and centric segments,asymmetry,and the presence of terminal breakpoints,all of which may impact segregation mode.Here,we report a rare case of multiple reciprocal translocations within a single family.This includes the evaluation of the translocations in each of the spouses and an analysis of their chromosome segregation patterns as determined by the constellation of universal characteristics in each of their quadrivalents.The obtained results will be of interest to fundamental biology,as they will expand the understanding of the factors affecting chromosome segregation during meiosis.展开更多
基金NIH grants 1K08CA160692-01A1,U54CA163125-01 and the generous philanthropic support of several families whose lives have been affected by melanoma
文摘Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.
基金supported by the National Institute of Health under Grant#R01EY027749-01A1,#R24EY028764-01A1,#R21EY027065-02,#R41EY027665-01A1 to LW,and#P30-EY014801The American Diabetes Association under Grant#1-18-IBS-172 to LW+1 种基金An institutional grant from Research to Prevent BlindnessThe National Natural Science Foundation of China under Grant#81573112 and#81373030 to WWD.
文摘Objective To investigate whether exposure to particulate matter of diameter equal to or less than 2.5μm(PM2.5)alters the response of lung epithelial cells to extrinsic regulation by globally profiling cell surface ligands and quantifying their binding activity.Methods Human A549 lung epithelial cells(LECs)were treated with or without PM2.5.Ligandomic profiling was applied to these cells for the global identification of LEC-binding ligands with simultaneous quantification of binding activity.Quantitative comparisons of the entire ligandome profiles systematically identified ligands with increased or decreased binding to PM2.5-treated LECs.Results We found 143 ligands with increased binding to PM2.5-treated LECs and 404 ligands with decreased binding.Many other ligands showed no change in binding activity.For example,apolipoprotein E(ApoE),Notch2,and growth arrest-specific 6(Gas6)represent ligands with increased,decreased,or unchanged binding activity,respectively.Both ApoE and Gas6 are phagocytosis ligands,suggesting that phagocytic receptors on LECs after stimulation with PM2.5 were differentially upregulated by PM2.5.Conclusion These results suggest that the newly-developed ligandomics is a valuable approach to globally profile the response of LECs to PM2.5 in terms of regulating the expression of cell surface receptors,as quantified by ligand binding activity.This quantitative ligandome profiling will provide indepth understanding of the LEC molecular response on the cell surface to particulate matter air pollution.
基金Supported by Ministry of Science and Higher Education of the Russian Federation within the Applied Science Research Program,No.AAAA-A20-120041390028-0Estonia-Russia Cross Border Cooperation Programme 2014-2020,No.ER24.
文摘Type 2 diabetes mellitus(T2DM)is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030.Long-term vascular complications,such as coronary artery disease,myocardial infarction,stroke,are the leading causes of morbidity and mortality among diabetic patients.The recent advances in genome-wide technologies have given a powerful impetus to the study of risk markers for multifactorial diseases.To date,the role of genetic and epigenetic factors in modulating susceptibility to T2DM and its vascular complications is being successfully studied that provides the accumulation of genomic knowledge.In the future,this will provide an opportunity to reveal the pathogenetic pathways in the development of the disease and allow to predict the macrovascular complications in T2DM patients.This review is focused on the evidence of the role of genetic variants and epigenetic changes in the development of macrovascular pathology in diabetic patients.
基金Supported by D.O.Ott Research Institute of Obstetrics,Gynaecology and Reproductology,project 558-2019-0012(АААА-А19-119021290033-1)of FSBSI
文摘Type 2 diabetes(T2D)mellitus is a common complex disease that currently affects more than 400 million people worldwide and has become a global health problem.High-throughput sequencing technologies such as whole-genome and whole-exome sequencing approaches have provided numerous new insights into the molecular bases of T2D.Recent advances in the application of sequencing technologies to T2D research include,but are not limited to:(1)Fine mapping of causal rare and common genetic variants;(2)Identification of confident genelevel associations;(3)Identification of novel candidate genes by specific scoring approaches;(4)Interrogation of disease-relevant genes and pathways by transcriptional profiling and epigenome mapping techniques;and(5)Investigation of microbial community alterations in patients with T2D.In this work we review these advances in application of next-generation sequencing methods for elucidation of T2D pathogenesis,as well as progress and challenges in implementation of this new knowledge about T2D genetics in diagnosis,prevention,and treatment of the disease.
文摘BACKGROUND Dyslipidemias are metabolic abnormalities associated with chronic diseases caused by genetic and environmental factors.The Mexican population displays regional differences according to ethnicity with an impact on the type of dyslipidemia.AIM To define the main dyslipidemias,the frequency of lipid-related risk alleles,and their association with hyperlipidemic states among different ethnic groups in West Mexico.METHODS In a retrospective study,1324 adults were selected to compare dyslipidemias and lipid-related gene polymorphisms.Demographic,clinical,and laboratory data were collected.A subgroup of 196 normal weight subjects without impaired glucose was selected for the association analyses.Genotyping was determined by allelic discrimination assay.RESULTS Hypercholesterolemia was the most prevalent dyslipidemia(42.3%).The frequency of the risk alleles associated with hypoalphalipoproteinemia(ABCA1)and hypercholesterolemia(APOE,LDLR)was higher in the Native Americans(P=0.047).In contrast,the Mestizos with European ancestry showed a higher frequency of the risk alleles for hypertriglyceridemia(APOE2,MTTP)(P=0.045).In normal weight Mestizo subjects,the APOB TT and LDLR GG genotypes were associated risk factors for hypercholesterolemia(OR=5.33,95%CI:1.537-18.502,P=0.008 and OR=3.90,95%CI:1.042-14.583,P=0.043,respectively),and displayed an increase in low-density lipoprotein cholesterol levels(APOB:β=40.39,95%CI:14.415-66.366,P=0.004;LDLR:β=20.77,95%CI:5.763-35.784,P=0.007).CONCLUSION Gene polymorphisms and dyslipidemias showed a differential distribution.Regional primary health care strategies are required to mitigate their prevalence considering the genetic and environmental features which could have important implications for personalized medicine within the new era of precision medicine.
基金ASCO,Cancer Prevention&Research Institute of Texas(CPRIT),University Cancer Foundation,CPRIT Research Training Program,Grant/Award Number:RP170067TJ Martell Foundation,NIH/NCI,Grant/Award Number:R01-CA207295+6 种基金University of Texas MD Anderson Cancer Center,the Happy Lungs ProjectCancer Prevention&Research Institute of TexasRexanna's Foundation for Fighting Lung CancerConquer Cancer FoundationNIH/NCI,Grant/Award Number:U01-CA213273Department of Defense,Grant/Award Number:LC170171Damon Runyon Mark Foundation Physician Scientist Award,Rexanna Foundation,Grant/Award Number:R01 CA276178-01A1。
文摘Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like components.The molecular and immune landscape of PSC has not been well defined.Methods:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and RNA sequencing.We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.Results:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by KRAS.Interestingly,most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC tumors.We identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and signaling.The Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.Conclusions:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis.IM-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.
文摘BACKGROUND Adenocarcinoma originating from heterotopic pancreas tissue is a rare disease.Furthermore,to our knowledge,no HER2-positive cases in the duodenum have been reported in the scientific literature nor has the efficacy of trastuzumab treatment for the disease been reported.CASE SUMMARY A 65-year-old woman whose clinical diagnosis was unresectable advanced duodenal cancer with HER2 overexpression responded well to trastuzumab chemotherapy.The main tumor in the duodenum reduced drastically.The patient underwent pancreaticoduodenectomy and lymph node dissection.A small number of cancer cells remained in the submucosal layer of the duodenum and pancreas head.After histological and immunohistochemical examination,the patient was diagnosed with duodenal adenocarcinoma originating from heterotopic pancreas tissue.CONCLUSION Trastuzumab treatment is effective in HER2-positive adenocarcinoma originating from heterotopic pancreas tissue in the duodenum.
基金This research was supported in part by the Japan Agency for Medical Research and Development(AMED)(JP15ck0106096 to TK)Japan Science and Tech-nology Agency(JST)Core Research for Evolutionary Science and Technology(JPMJCR1689 to RH)+5 种基金Artifi-cial Intelligence,Big Data,IoT,Cyber Security Integration Project of the Public/Private R&D Investment Strategic Expansion Program(JPMJCR18Y4 to RH)the Japan Soci-ety for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research(S)(17H06162 to HN),Grant-in-Aid for Scientific Research(B)(20H03695 to KS),Grants-in-Aid for the Tailor-Made Medical Treatment Program(BioBank Japan Project)from the Japanese Ministry of Education,Culture,Sports,ScienceandTechnology(MEXT),Princess Takamatsu Cancer Research Fund,and National Cancer Center Research and Development Fund(NCC Biobank and NCC Core Facility).The J-MICC study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer(No.17015018 to KW)Innovative Areas(No.221S0001 to KW)from MEXTby JSPS Grant-in-Aid for Scientific Research Grant(No.16H06277[CoBiA])The JPHC Study was supported by National Cancer Center Research and Development Fund since 2011(latest grant number:2020-J4)and a Grant-in-Aid for Cancer Research from the Ministry of Health,Labor and Welfare of Japan(1989-2010).ToMMoissupportedinpartbyMEXT-JSTand AMED(most recent grant numbers:JP20km0105001 and JP20km0105002)Iwate Tohoku Medical Megabank Orga-nization(Iwate Medical University)is supported in part by MEXT-JST and AMED(most recent grant numbers:JP20km0105003 and JP20km0105004).
文摘Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
文摘Congenital heart disease(CHD)is the most common congenital anomaly and is an important cause of infant morbidity and mortality.Besides the epigenetic and environmental basis of CHD,genetics plays a central role in CHD pathogenesis.Traditional genetic testing strategies including conventional chromosome analysis,fluorescence in situ hybridization,and Sanger sequencing have largely focused on syndromic CHD or selected CHD phenotypes that are strongly associated with a particular genotype.The landscape of clinical genetic testing in CHD is rapidly evolving due to technical advances in genetic testing,including the identification of copy number variants by chromosomal microarray and nucleotide level alterations/variants by next-generation sequencing(NGS),which are essential to detect genetic causes of CHD and identify associations between genotypes and longitudinal clinical phenotypes.Whole-exome and whole-genome NGS not only reveal pathogenic variants in CHD genes,but also identify non-coding variants that influence the expression of CHD genes.Given the increasing availability and cost-effectiveness of clinical NGS to provide information on the causes of CHD and to detect incidental findings that are clinically actionable,the guidance of genetic counselors or experienced clinicians is essential.The identification of definitive causal CHD variants influences patient care and helps to inform the risk of recurrence,prenatal genetic counseling,and pre-implantation testing for the family of a CHD infant and adults with repaired/palliated CHD.Prenatally,circulating cell-free DNA screening as a non-invasive approach is available as early as 9 weeks of gestation and can screen for the common aneuploidies,which may underlie CHD.In this review,we present past and recent genetic testing in CHD based on our increased understanding of the pathogenesis of CHD along with current challenges with the interpretation of de novo genetic variants.Identification of a genetic diagnosis can help to predict and potentially improve clinical outcomes in CHD patients.
基金funded in part by Consejo Nacional de Ciencia y Tecnologia(CONACYT)grant number PN-2017-5254 to AP,FOSSIS-S0008-2010-1-08-139085 to SRthe Programa de Apoyo a la Incorporación de NPTC.No.UDG-PTC-1439 to AJ-A.
文摘Background and Aims:Lamivudine(3TC),telbivudine(LdT),entecavir(ETV),adefovir(ADF),and tenofovir(TFV)are drugs used to treat hepatitis B virus(HBV)infection,but specific mutations allow some viruses to become resistant to antiviral drugs or to acquire immune escape capacities.These mutations have not been thoroughly investigated in Mexico.This study aimed to estimate the prevalence of HBV antiviral resistance and escape mutations.Methods:This cross-sectional study analyzed 158 samples.HBV DNA was extracted,amplified,and sequenced in serum samples using the spin column method,PCR assay,and Sanger’s sequencing,respectively.HBV genotypes were determined,and HBV mutations were tested using the Geno2pheno tool.Results:Overall,68.4%(108/158)of HBV patients were infected with genotype H,followed by G(11.4%,18/158),A2(10.8%,17/158),F1b(6.9.0%,11/158),D(1.9%,3/158),and E(0.6%,1/158),and 5.1%(8/158)had evidence of recombination.The prevalence of resistance mutations was 8.2%(13/158)and the most common combined mutation was rt180M+rt204V.Notably,we found the combinations rt180M+rt204V+rt173L(n=2)and rt180M+rt204V+rt202G(n=1)that confer multidrug resistance to 3TC,LdT,and ETV.Resistance mutations were found in genotypes A2(11.8%,2/17),and H(10.2%,11/108),and escape mutations were detected in HBV genotypes A2(11.8%,2/17),H(10.2%,11/108),F1b(9.1%,1/11)and G(5.6%,1/18).Conclusions:The highest prevalence of antiviral resistance mutations or escape mutations was detected in HBV genotypes A2 and H.The earliest cases of HBV multidrug resistance were detected in Mexico.
基金supported by National Key Research and Development Project(Nos.2022YFC2505004,2022YFC2505000 to Z.W.and J.W.)NSFC special program(No.82241229 to J.W.)+2 种基金the National Youth Talent(to Z.W)CAMS Innovation Fund for Medical Sciences(No.2021-1-I2M-012 to Z.W.)National Natural Sciences Foundation of China(Nos.81871889 and 82072586 to Z.W.)。
文摘Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.
基金supported by the Ministry of Science and Higher Education of Russian Federation(project“Multicenter research bioresource collection Human Reproductive Health”contract No 075-15-2021-1058 from September 28,2021).
文摘Autosomal reciprocal translocations represent exchanges of chromatin fragments between non-homologous chromosomes.Translocations are facilitated by the creation of quadrivalent structures during the first meiotic division,which are characterized by the length of the translocated and centric segments,asymmetry,and the presence of terminal breakpoints,all of which may impact segregation mode.Here,we report a rare case of multiple reciprocal translocations within a single family.This includes the evaluation of the translocations in each of the spouses and an analysis of their chromosome segregation patterns as determined by the constellation of universal characteristics in each of their quadrivalents.The obtained results will be of interest to fundamental biology,as they will expand the understanding of the factors affecting chromosome segregation during meiosis.
