Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear...Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear divisions and one cytokinesis）. In the majority of known cases the proper segregation of the parental genome into gametes is accom- panied and facilitated by meiotic crossover formation, which contributes to physical association between homologous chromosomes and results in the generation of new combina- tions of alleles in the progeny. This is necessarily a complex and highly regulated process with multiple steps in a tight sequence, including exit from mitosis, DNA double strand break （DSB） formation, homology search, recombinational repair of DSBs and regulation of cohesion between homolo- gous chromosomes. The process of meiosis is astonishingly effective, even in mammals and flowering plants with extremely large genomes, in which this entails the manipula- tion of approximately twelve metres or even more of the replicated diploid DNA, on the order of 10^10 base pairs, with close to base pair accuracy. In plants, meiosis does not pro- duce gametes directly, but progenitors of haploid multicellular structures called gametophytes, which contain haploid cells that differentiate into gametes.展开更多
Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper...Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.展开更多
Gallbladder cancer(GBC)is a lethal biliary tract malignancy,which is infrequent in most developed countries,but common in many developing countries in specific geographical regions of the world.Non-specific symptoms l...Gallbladder cancer(GBC)is a lethal biliary tract malignancy,which is infrequent in most developed countries,but common in many developing countries in specific geographical regions of the world.Non-specific symptoms leading to late diagnosis is one of the primary factors contributing to poor prognosis in GBC.An understanding of the complex relationship between molecular genetics and epidemiological variances in the incidence rates of GBC is thus of utmost importance.Present review summarizes recent updates on population-specific dysregulated genetic expressions in the genesis of GBC,highlighting the pattern of ethno-geographic variations and on advances in targeted therapies conducted till date;points out the lacunae that deserve further attention and suggest possible new directions for future clinical trials in GBC.The review calls for the need of genetic screening of each GBC patients and for more extensive clinical trials on targeted therapies to move towards the goal of personalized medicine,bringing about more favourable survival outcomes.展开更多
AIM： To identify the variants in U rase 1 （UGT1A1） gene in Gilbert＇s syndrome （GS） and to estimate the association between homozygosity for TA insertion and GS in India, as well as the frequency of TA insertion ...AIM： To identify the variants in U rase 1 （UGT1A1） gene in Gilbert＇s syndrome （GS） and to estimate the association between homozygosity for TA insertion and GS in India, as well as the frequency of TA insertion and its impact among normal controls in India. METHODS： Ninety-five GS cases and 95 normal controls were selected. Liver function and other tests were done. The promoter and all 5 exons of UGT1A1 gene were resequenced. Functional assessment of a novel trinucleotide insertion was done by in silico analysis and by estimating UGT1A1 promoter activity carried out by ludferase reporter assay of appropriate constructs in Hep G2 cell line. RESULTS： Among the GS patients, 80% were homozygous for the TA insertion, which was several-fold higher than reports from other ethnic groups. The mean UCB level was elevated among individuals with only one copy of this insertion, which was not significantly different from those with two copies. Many new DNA variants in UGT1A1 gene were discovered, including a trinucleotide （CAT） insertion in the promoter found in a subset （10%） of GS patients, but not among normal controls. In-silico analysis showed marked changes in the DNA-folding of the promoter and functional analysis showed a 20-fold reduction in transcription efficiency of UGT1A1 gene resulting from this insertion, thereby significantly elevating the UCB level. CONCLUSION： The genetic epidemiology of GS is variable across ethnic interactions among UGT1A1 groups and the epistatic promoter variants modulate bilirubin glucuronidation.展开更多
The blood-testis barrier （BTB） is found between adjacent Sertoli cells in the testis where it creates a unique microenvironment for the development and maturation of meiotic and postmeiotic germ cells in seminiferou...The blood-testis barrier （BTB） is found between adjacent Sertoli cells in the testis where it creates a unique microenvironment for the development and maturation of meiotic and postmeiotic germ cells in seminiferous tubes. It is a compound proteinous structure, composed of several types of cell junctions including tight junctions （TJs）, adhesion junctions and gap junctions （GJs）. Some of the junctional proteins function as structural proteins of BTB and some have regulatory roles. The deletion or functional silencing of genes encoding these proteins may disrupt the BTB, which may cause immunological or other damages to meiotic and postmeiotic cells and ultimately lead to spermatogenic arrest and infertility. In this review, we will summarize the findings on the BTB structure and function from genetically-modified mouse models and discuss the future perspectives.展开更多
Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised eve...Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised events during prophase to allow meiotic recombination, homologous chromosome synapsis and reductional chromosome segregation to occur. In mammalian cells, DNA phys- ically associates with histones to form chromatin, which can be modified by methylation, phosphorylation, ubiquitination and acetylation to help regulate higher order chromatin structure, gene expression, and chromosome organisation. Recent studies have identified some of the enzymes responsible for generating chromatin modifications in meiotic mammalian cells, and shown that these chromatin modifying enzymes are required for key meiosis-specific events that occur during meiotic prophase. This review will discuss the role of chromatin modifications in meiotic recombination, homologous chromosome synapsis and regulation of meiotic gene expression in mammals.展开更多
A global increase in the incidence of pancreatic cancer(PanCa)presents a major concern and health burden.The traditional tissue-based diagnostic techniques provided a major way forward for molecular diagnostics;howeve...A global increase in the incidence of pancreatic cancer(PanCa)presents a major concern and health burden.The traditional tissue-based diagnostic techniques provided a major way forward for molecular diagnostics;however,they face limitations based on diagnosis-associated difficulties and concerns surrounding tissue availability in the clinical setting.Late disease development with asymptomatic behavior is a drawback in the case of existing diagnostic procedures.The capability of cell free markers in discriminating PanCa from autoimmune pancreatitis and chronic pancreatitis along with other precancerous lesions can be a boon to clinicians.Early-stage diagnosis of PanCa can be achieved only if these biomarkers specifically discriminate the non-carcinogenic disease stage from malignancy with respect to tumor stages.In this review,we comprehensively described the non-invasive disease detection approaches and why these approaches are gaining popularity for their early-stage diagnostic capability and associated clinical feasibility.展开更多
Background:Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality.In addition to having genetic causes,cancer can also be considered an epigenetic disease.DNA methylation ...Background:Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality.In addition to having genetic causes,cancer can also be considered an epigenetic disease.DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor.In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma(PDAC),the epigenetic changes play a significant role.Data sources:Relevant studies for this review were derived via an extensive literature search in Pub Med via using various keywords such as pancreatic ductal adenocarcinoma,precancerous lesions,methylation profile,epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest.The literature search was intensively done considering a time frame of 20 years(1998–2018).Result:In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions(pancreatic intra-epithelial neoplasia,intraductal papillary mucinous neoplasm,mucinous cystic neoplasm and chronic pancreatitis)and PDAC along with the potential biomarkers.We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC.A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC(pp ENK,APC,p14/5/16/17,h MLH1 and MGMT)are also documented.We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy.Epigenetic inactivation occurs by hypermethylation of Cp G islands in the promoter regions of tumor suppressor genes.We listed all hyper-and hypomethylation of Cp G islands of several genes in PDAC including its precancerous lesions.Conclusions:The concept of the review would help to understand their biological effects,and to determine whether they may be successfully combined with other epigenetic drugs.However,we need to continue our research to develop more specific DNA-demethylating agents,which are the targets for hypermethylated Cp G methylation sites.展开更多
Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulatio...Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.展开更多
BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless...BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless of family history,we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer.We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1,MSH2,and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes.Stage 1 of the model incorporated only clinical variables;stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability.The model was validated in an independent population of patients.We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.RESULTS:There were 38 mutations among the 870 participants(4 percent) :15 mutations in MLH1,16 in SH2,and 7 in MSH6.Carrier frequencies in men(6 percent) and women(3 percent) differed significantly(P < 0.04) .The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent.There were 35 mutations in the validation series of 155 patients(23 percent) :19 mutations in MLH1,13 in MSH2,and 3 in MSH6.The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer.Survival among carriers was not significantly different from that among noncarriers.CONCLUSIONS:We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes.Survival was similar among carriers and noncarriers.展开更多
AIM To estimate prevalence and phenotypic associations of selected inflammatory bowel disease(IBD)-associated genetic variants among Sri Lankan patients.METHODS A case study of histologically confirmed ulcerative coli...AIM To estimate prevalence and phenotypic associations of selected inflammatory bowel disease(IBD)-associated genetic variants among Sri Lankan patients.METHODS A case study of histologically confirmed ulcerative colitis(UC)or Crohn's disease(CD)patients with≥1 year disease duration,who were compared to unrelated,gender-matched,healthy individuals as controls,was conducted at four major centers in Sri Lanka.Phenotypic data of the cases were obtained and all participants were genotyped for 16 selected genetic variants:IL12 B:rs1045431,IL23 R:rs11805303,ARPC2:rs12612347,IRGM:rs13361189,IL26/IL22:rs1558744,CDH1:rs1728785,IL10:rs3024505,FCGR2 A:rs3737240,PTGER4:rs4613763,IL17 REL/PIM3:rs5771069,HNF4 a:rs6017342,STAT3:rs744166,SMURF1:rs7809799,LAMB1:rs886774,HLA-DRB5,DQA1,DRB1,DRA:rs9268853,MST1,UBA7,and APEH:rs9822268.The genotypes of all variants were in Hardy-Weinberg Equilibrium(P>10^(-3)).To account for multiple hypothesis testing,P-values<0.003 were considered significant.RESULTS A total of 415 patients and 465 controls were recruited.Out of the single nucleotide polymorphisms(SNPs)tested,the majority were not associated with IBD in Sri Lankans.Significant positive associations were noted between rs886774(LAMB1-gene)and UC(odds ratio(OR)=1.42,P=0.001).UC patients with rs886774 had mild disease(OR=1.66,P<0.001)and remained in remission(OR=1.48,P<0.001).A positive association was noted between rs10045431(IL 12 B gene)and upper gastrointestinal involvement in CD(OR=4.76,P=0.002).CONCLUSION This confirms the heterogeneity of allelic mutations in South Asians compared to Caucasians.Most SNPs and disease associations reported here have not been described in South Asians.展开更多
The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial dispar...The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial disparities and risk factors.Overweight black men aged 40-59 years and white men over 40 years with higher incomes showed an elevated risk of PDAC among CP patients.The study,which included 14.2 million admissions from 2016-2017,found that 2.6%of adult patients were diagnosed with CP,with white males being the majority.Multivariate regression analysis identified men,black individuals,those aged 40-59 years,and individuals with a body mass index(BMI)between 25 and 29.9 as having an increased risk for CP.Moreover,0.78%of CP patients also had PDAC,with older age and BMI being significant risk factors for developing PDAC in CP patients.The study also highlighted disparities in healthcare access and utilization among different socioeconomic and ethno-racial groups,which may impact the risk and outcomes of CP and PDAC.展开更多
β-defensin peptides are a large family of antimicrobial peptides. Although they kill microbes in vitroand interact with immune cells, the precise role of these genes in vivo remains uncertain. Despite their inducible...β-defensin peptides are a large family of antimicrobial peptides. Although they kill microbes in vitroand interact with immune cells, the precise role of these genes in vivo remains uncertain. Despite their inducible presence at mucosal surfaces, their main site of expression is the epididymis. Recent evidence suggests that a major function of these peptides is in sperm maturation. In addition to previous work suggesting this, work at the MRC Human Genetics Unit, Edinburgh, has shown that homozygous deletion of a cluster of nine β-defensin genes in the mouse results in profound male sterility. The spermatozoa derived from the mutants had reduced motility and increased fragility. Epididymal spermatozoa isolated from the cauda region of the homozygous mutants demonstrated precocious capacitation and increased spontaneous acrosome reactions compared with those from wild-types. Despite this, these mutant spermatozoa had reduced ability to bind to the zona pellucida of oocytes. Ultrastructural examination revealed a disintegration of the microtubule structure of mutant-derived spermatozoa isolated from the epididymal cauda region, but not from the caput. Consistent with premature acrosome reaction and hyperactivation, spermatozoa from mutant animals had significantly increased intracellular calcium content. This work demonstrates that in vivo β-defensins are essential for successful sperm maturation, and that their disruption alters intracellular calcium levels, which most likely leads to premature activation and spontaneous acrosome reactions that result in hyperactivation and loss of microtubule structure of the axoneme. Determining which of the nine genes are responsible for the phenotype and the relevance to human sperm function is important for future work on male infertility.展开更多
Background: Animal research is conducted in many countries across the world.However, concepts of recording and reporting the numbers of animals used vary. In the context of animal studies, inadequate reporting raises ...Background: Animal research is conducted in many countries across the world.However, concepts of recording and reporting the numbers of animals used vary. In the context of animal studies, inadequate reporting raises both ethical and scientific concerns. Sri Lanka has yet to publish data on animal research statistics.Methods: The objective of this survey was to present the number and types of vertebrate animals used for research and establish the species used for different types of research studies. All facilities/personnel engaged in animal research were invited to participate and a web-based survey was performed.Results: Based on the data collected, rats and mice were the most widely used animals in Sri Lankan laboratories. Of these, the most reported model were rats of the Wistar strain(42%) and mice of the BALB/c strain(15%). The highest number of animals used in laboratory research occurred in 2011, with a 12% decrease observed in 2012.展开更多
Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirm...Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics.This inimitable tumor microenvironment(TME)or desmoplasia with excessive extracellular matrix accumulation,create an extremely hypovascular,hypoxic and nutrient-deficient zone inside the tumor.To survive,grow and proliferate in such tough TME,pancreatic tumor and stromal cells transform their metabolism.Transformed glucose,glu-tamine,fat,nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism,impart therapy resistance,and immunosuppression in PanCa.Thus,a finer knowledge of altered metabolism would uncover its metabolic susceptibilities.These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa.In this review,we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.展开更多
High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological ...High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.展开更多
Arecent study published in Nature Immunology by Sheedy et al.1 indicates that uptake of modified low-den- sity lipoprotein （LDL） by the scavenger receptor CD36 primes and activates the NLRP3 inflammasome, providing ...Arecent study published in Nature Immunology by Sheedy et al.1 indicates that uptake of modified low-den- sity lipoprotein （LDL） by the scavenger receptor CD36 primes and activates the NLRP3 inflammasome, providing an early pathogenic pathway that links cho- lesterol accumulation to the chronic inflammatory process of atherosclero- sis.1 Atherosclerosis arises from chronic vascular inflammation elicited by lipids.展开更多
Background: Cytogenetic analysis is a valuable investigation in the diagnostic work up of children with suspected chromosomal disorders. The objective of this study was to describe the prevalence of various types of c...Background: Cytogenetic analysis is a valuable investigation in the diagnostic work up of children with suspected chromosomal disorders. The objective of this study was to describe the prevalence of various types of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis. Methods: Cytogenetic reports of 1554 consecutive children with suspected chromosomal disorders who underwent karyotyping in two genetic centers in Sri Lanka from January 2006 to December 2011 were reviewed retrospectively. Results: A total of 1548 children were successfully karyotyped. Abnormal karyotypes were found in 783 (50.6%) children. Numerical and structural abnormalities accounted for 90.8% and 9.2%, respectively. Down syndrome was the commonest aneuploidy identifi ed. Other various autosomal and sex chromosomal aneuploidies as well as micro-deletion syndromes were also detected. Conclusions: The prevalence of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis for suspected chromosomal disorders was relatively higher than that in Caucasian and other Asian populations.展开更多
We agree with the reader's comments that the availability of clinical features would benefit the clinical diagnosis greatly,and help the medical professionals to decide whether cytogenetic analysis is,or is not ne...We agree with the reader's comments that the availability of clinical features would benefit the clinical diagnosis greatly,and help the medical professionals to decide whether cytogenetic analysis is,or is not necessary for certain clinical features.However,the main aim of our study was to describe the frequency of various types of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis since there was paucity of data in this field.展开更多
文摘Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear divisions and one cytokinesis）. In the majority of known cases the proper segregation of the parental genome into gametes is accom- panied and facilitated by meiotic crossover formation, which contributes to physical association between homologous chromosomes and results in the generation of new combina- tions of alleles in the progeny. This is necessarily a complex and highly regulated process with multiple steps in a tight sequence, including exit from mitosis, DNA double strand break （DSB） formation, homology search, recombinational repair of DSBs and regulation of cohesion between homolo- gous chromosomes. The process of meiosis is astonishingly effective, even in mammals and flowering plants with extremely large genomes, in which this entails the manipula- tion of approximately twelve metres or even more of the replicated diploid DNA, on the order of 10^10 base pairs, with close to base pair accuracy. In plants, meiosis does not pro- duce gametes directly, but progenitors of haploid multicellular structures called gametophytes, which contain haploid cells that differentiate into gametes.
基金Supported by Department of Biotechnology,Government of India,No.RLS/BT/Re-entry/05/2012.
文摘Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.
文摘Gallbladder cancer(GBC)is a lethal biliary tract malignancy,which is infrequent in most developed countries,but common in many developing countries in specific geographical regions of the world.Non-specific symptoms leading to late diagnosis is one of the primary factors contributing to poor prognosis in GBC.An understanding of the complex relationship between molecular genetics and epidemiological variances in the incidence rates of GBC is thus of utmost importance.Present review summarizes recent updates on population-specific dysregulated genetic expressions in the genesis of GBC,highlighting the pattern of ethno-geographic variations and on advances in targeted therapies conducted till date;points out the lacunae that deserve further attention and suggest possible new directions for future clinical trials in GBC.The review calls for the need of genetic screening of each GBC patients and for more extensive clinical trials on targeted therapies to move towards the goal of personalized medicine,bringing about more favourable survival outcomes.
基金Supported by grants from the Department of Biotechnology, Government of India (to PPM) and the Department of Science & Technology, Government of West Bengal (to AC)
文摘AIM： To identify the variants in U rase 1 （UGT1A1） gene in Gilbert＇s syndrome （GS） and to estimate the association between homozygosity for TA insertion and GS in India, as well as the frequency of TA insertion and its impact among normal controls in India. METHODS： Ninety-five GS cases and 95 normal controls were selected. Liver function and other tests were done. The promoter and all 5 exons of UGT1A1 gene were resequenced. Functional assessment of a novel trinucleotide insertion was done by in silico analysis and by estimating UGT1A1 promoter activity carried out by ludferase reporter assay of appropriate constructs in Hep G2 cell line. RESULTS： Among the GS patients, 80% were homozygous for the TA insertion, which was several-fold higher than reports from other ethnic groups. The mean UCB level was elevated among individuals with only one copy of this insertion, which was not significantly different from those with two copies. Many new DNA variants in UGT1A1 gene were discovered, including a trinucleotide （CAT） insertion in the promoter found in a subset （10%） of GS patients, but not among normal controls. In-silico analysis showed marked changes in the DNA-folding of the promoter and functional analysis showed a 20-fold reduction in transcription efficiency of UGT1A1 gene resulting from this insertion, thereby significantly elevating the UCB level. CONCLUSION： The genetic epidemiology of GS is variable across ethnic interactions among UGT1A1 groups and the epistatic promoter variants modulate bilirubin glucuronidation.
基金This work was supported by the National Basic Research Program （Nos. 2013CB947900, 2013CB945502 and 2014CB943101） of China （973）, by grants from National Natural Science Foundation of China （No. 31371519） and the Knowledge Innovation Program of the Chinese Academy of Sciences （No. KSCX2-EW-R-07）.
文摘The blood-testis barrier （BTB） is found between adjacent Sertoli cells in the testis where it creates a unique microenvironment for the development and maturation of meiotic and postmeiotic germ cells in seminiferous tubes. It is a compound proteinous structure, composed of several types of cell junctions including tight junctions （TJs）, adhesion junctions and gap junctions （GJs）. Some of the junctional proteins function as structural proteins of BTB and some have regulatory roles. The deletion or functional silencing of genes encoding these proteins may disrupt the BTB, which may cause immunological or other damages to meiotic and postmeiotic cells and ultimately lead to spermatogenic arrest and infertility. In this review, we will summarize the findings on the BTB structure and function from genetically-modified mouse models and discuss the future perspectives.
基金supported by a Medical Research Council (MRC)intramural program grant to I.R.A.at the MRC Human Genetics Unit in UK
文摘Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised events during prophase to allow meiotic recombination, homologous chromosome synapsis and reductional chromosome segregation to occur. In mammalian cells, DNA phys- ically associates with histones to form chromatin, which can be modified by methylation, phosphorylation, ubiquitination and acetylation to help regulate higher order chromatin structure, gene expression, and chromosome organisation. Recent studies have identified some of the enzymes responsible for generating chromatin modifications in meiotic mammalian cells, and shown that these chromatin modifying enzymes are required for key meiosis-specific events that occur during meiotic prophase. This review will discuss the role of chromatin modifications in meiotic recombination, homologous chromosome synapsis and regulation of meiotic gene expression in mammals.
基金Supported by the Department of Biotechnology,Government of India Grant Sanction,Ramalingaswami Re-entry Fellowship,No.RLS/BT/Re-entry/05/2012.
文摘A global increase in the incidence of pancreatic cancer(PanCa)presents a major concern and health burden.The traditional tissue-based diagnostic techniques provided a major way forward for molecular diagnostics;however,they face limitations based on diagnosis-associated difficulties and concerns surrounding tissue availability in the clinical setting.Late disease development with asymptomatic behavior is a drawback in the case of existing diagnostic procedures.The capability of cell free markers in discriminating PanCa from autoimmune pancreatitis and chronic pancreatitis along with other precancerous lesions can be a boon to clinicians.Early-stage diagnosis of PanCa can be achieved only if these biomarkers specifically discriminate the non-carcinogenic disease stage from malignancy with respect to tumor stages.In this review,we comprehensively described the non-invasive disease detection approaches and why these approaches are gaining popularity for their early-stage diagnostic capability and associated clinical feasibility.
基金supported by grants from Department of Biotechnology,Government ofIndia(RLS/BT/Re-entry/05/2012)Department of Higher,Education,Science&Technology and Biotechnology,Government of West Bengal,India(BT/P/Budget/RD-37/2016)。
文摘Background:Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality.In addition to having genetic causes,cancer can also be considered an epigenetic disease.DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor.In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma(PDAC),the epigenetic changes play a significant role.Data sources:Relevant studies for this review were derived via an extensive literature search in Pub Med via using various keywords such as pancreatic ductal adenocarcinoma,precancerous lesions,methylation profile,epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest.The literature search was intensively done considering a time frame of 20 years(1998–2018).Result:In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions(pancreatic intra-epithelial neoplasia,intraductal papillary mucinous neoplasm,mucinous cystic neoplasm and chronic pancreatitis)and PDAC along with the potential biomarkers.We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC.A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC(pp ENK,APC,p14/5/16/17,h MLH1 and MGMT)are also documented.We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy.Epigenetic inactivation occurs by hypermethylation of Cp G islands in the promoter regions of tumor suppressor genes.We listed all hyper-and hypomethylation of Cp G islands of several genes in PDAC including its precancerous lesions.Conclusions:The concept of the review would help to understand their biological effects,and to determine whether they may be successfully combined with other epigenetic drugs.However,we need to continue our research to develop more specific DNA-demethylating agents,which are the targets for hypermethylated Cp G methylation sites.
文摘Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.
文摘BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless of family history,we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer.We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1,MSH2,and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes.Stage 1 of the model incorporated only clinical variables;stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability.The model was validated in an independent population of patients.We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.RESULTS:There were 38 mutations among the 870 participants(4 percent) :15 mutations in MLH1,16 in SH2,and 7 in MSH6.Carrier frequencies in men(6 percent) and women(3 percent) differed significantly(P < 0.04) .The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent.There were 35 mutations in the validation series of 155 patients(23 percent) :19 mutations in MLH1,13 in MSH2,and 3 in MSH6.The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer.Survival among carriers was not significantly different from that among noncarriers.CONCLUSIONS:We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes.Survival was similar among carriers and noncarriers.
基金Supported by National Research Council,Sri Lanka,Grant No.NRC 13-108
文摘AIM To estimate prevalence and phenotypic associations of selected inflammatory bowel disease(IBD)-associated genetic variants among Sri Lankan patients.METHODS A case study of histologically confirmed ulcerative colitis(UC)or Crohn's disease(CD)patients with≥1 year disease duration,who were compared to unrelated,gender-matched,healthy individuals as controls,was conducted at four major centers in Sri Lanka.Phenotypic data of the cases were obtained and all participants were genotyped for 16 selected genetic variants:IL12 B:rs1045431,IL23 R:rs11805303,ARPC2:rs12612347,IRGM:rs13361189,IL26/IL22:rs1558744,CDH1:rs1728785,IL10:rs3024505,FCGR2 A:rs3737240,PTGER4:rs4613763,IL17 REL/PIM3:rs5771069,HNF4 a:rs6017342,STAT3:rs744166,SMURF1:rs7809799,LAMB1:rs886774,HLA-DRB5,DQA1,DRB1,DRA:rs9268853,MST1,UBA7,and APEH:rs9822268.The genotypes of all variants were in Hardy-Weinberg Equilibrium(P>10^(-3)).To account for multiple hypothesis testing,P-values<0.003 were considered significant.RESULTS A total of 415 patients and 465 controls were recruited.Out of the single nucleotide polymorphisms(SNPs)tested,the majority were not associated with IBD in Sri Lankans.Significant positive associations were noted between rs886774(LAMB1-gene)and UC(odds ratio(OR)=1.42,P=0.001).UC patients with rs886774 had mild disease(OR=1.66,P<0.001)and remained in remission(OR=1.48,P<0.001).A positive association was noted between rs10045431(IL 12 B gene)and upper gastrointestinal involvement in CD(OR=4.76,P=0.002).CONCLUSION This confirms the heterogeneity of allelic mutations in South Asians compared to Caucasians.Most SNPs and disease associations reported here have not been described in South Asians.
文摘The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial disparities and risk factors.Overweight black men aged 40-59 years and white men over 40 years with higher incomes showed an elevated risk of PDAC among CP patients.The study,which included 14.2 million admissions from 2016-2017,found that 2.6%of adult patients were diagnosed with CP,with white males being the majority.Multivariate regression analysis identified men,black individuals,those aged 40-59 years,and individuals with a body mass index(BMI)between 25 and 29.9 as having an increased risk for CP.Moreover,0.78%of CP patients also had PDAC,with older age and BMI being significant risk factors for developing PDAC in CP patients.The study also highlighted disparities in healthcare access and utilization among different socioeconomic and ethno-racial groups,which may impact the risk and outcomes of CP and PDAC.
文摘β-defensin peptides are a large family of antimicrobial peptides. Although they kill microbes in vitroand interact with immune cells, the precise role of these genes in vivo remains uncertain. Despite their inducible presence at mucosal surfaces, their main site of expression is the epididymis. Recent evidence suggests that a major function of these peptides is in sperm maturation. In addition to previous work suggesting this, work at the MRC Human Genetics Unit, Edinburgh, has shown that homozygous deletion of a cluster of nine β-defensin genes in the mouse results in profound male sterility. The spermatozoa derived from the mutants had reduced motility and increased fragility. Epididymal spermatozoa isolated from the cauda region of the homozygous mutants demonstrated precocious capacitation and increased spontaneous acrosome reactions compared with those from wild-types. Despite this, these mutant spermatozoa had reduced ability to bind to the zona pellucida of oocytes. Ultrastructural examination revealed a disintegration of the microtubule structure of mutant-derived spermatozoa isolated from the epididymal cauda region, but not from the caput. Consistent with premature acrosome reaction and hyperactivation, spermatozoa from mutant animals had significantly increased intracellular calcium content. This work demonstrates that in vivo β-defensins are essential for successful sperm maturation, and that their disruption alters intracellular calcium levels, which most likely leads to premature activation and spontaneous acrosome reactions that result in hyperactivation and loss of microtubule structure of the axoneme. Determining which of the nine genes are responsible for the phenotype and the relevance to human sperm function is important for future work on male infertility.
文摘Background: Animal research is conducted in many countries across the world.However, concepts of recording and reporting the numbers of animals used vary. In the context of animal studies, inadequate reporting raises both ethical and scientific concerns. Sri Lanka has yet to publish data on animal research statistics.Methods: The objective of this survey was to present the number and types of vertebrate animals used for research and establish the species used for different types of research studies. All facilities/personnel engaged in animal research were invited to participate and a web-based survey was performed.Results: Based on the data collected, rats and mice were the most widely used animals in Sri Lankan laboratories. Of these, the most reported model were rats of the Wistar strain(42%) and mice of the BALB/c strain(15%). The highest number of animals used in laboratory research occurred in 2011, with a 12% decrease observed in 2012.
基金Supported by the Department of Biotechnology,Government of India,Ramalingaswami Reentry Fellowship,No.RLS/BT/Reentry/05/2012Department of Higher,Education,Science&Technology and Biotechnology,Government of West Bengal,India,No.BT/P/Budget/RD-37/2016.
文摘Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics.This inimitable tumor microenvironment(TME)or desmoplasia with excessive extracellular matrix accumulation,create an extremely hypovascular,hypoxic and nutrient-deficient zone inside the tumor.To survive,grow and proliferate in such tough TME,pancreatic tumor and stromal cells transform their metabolism.Transformed glucose,glu-tamine,fat,nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism,impart therapy resistance,and immunosuppression in PanCa.Thus,a finer knowledge of altered metabolism would uncover its metabolic susceptibilities.These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa.In this review,we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
文摘High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.
文摘Arecent study published in Nature Immunology by Sheedy et al.1 indicates that uptake of modified low-den- sity lipoprotein （LDL） by the scavenger receptor CD36 primes and activates the NLRP3 inflammasome, providing an early pathogenic pathway that links cho- lesterol accumulation to the chronic inflammatory process of atherosclero- sis.1 Atherosclerosis arises from chronic vascular inflammation elicited by lipids.
文摘Background: Cytogenetic analysis is a valuable investigation in the diagnostic work up of children with suspected chromosomal disorders. The objective of this study was to describe the prevalence of various types of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis. Methods: Cytogenetic reports of 1554 consecutive children with suspected chromosomal disorders who underwent karyotyping in two genetic centers in Sri Lanka from January 2006 to December 2011 were reviewed retrospectively. Results: A total of 1548 children were successfully karyotyped. Abnormal karyotypes were found in 783 (50.6%) children. Numerical and structural abnormalities accounted for 90.8% and 9.2%, respectively. Down syndrome was the commonest aneuploidy identifi ed. Other various autosomal and sex chromosomal aneuploidies as well as micro-deletion syndromes were also detected. Conclusions: The prevalence of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis for suspected chromosomal disorders was relatively higher than that in Caucasian and other Asian populations.
文摘We agree with the reader's comments that the availability of clinical features would benefit the clinical diagnosis greatly,and help the medical professionals to decide whether cytogenetic analysis is,or is not necessary for certain clinical features.However,the main aim of our study was to describe the frequency of various types of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis since there was paucity of data in this field.
