Pub Date : 2020-10-28DOI: 10.2174/1875692118666200309130307
I. Gulati, Harsh Patel, B. Prabhakar, S. Nair
Temozolomide is used as frontline chemotherapy in the management of glioblastoma multiforme (GBM); however, its clinical utility is limited by the occurrence of significant resistance, majorly caused due to direct DNA repair. O6- methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein, mediates this direct repair pathway and reverses the activity of temozolomide. We characterize and underscore the functional relevance and molecular aspects of MGMT in the development of sensitivity/resistance to temozolomide treatment. We review early translational, as well as clinical, evidence for the role of MGMT in mediating temozolomide resistance in vitro in cell lines, in vivo in small animals as well as in GBM patients. Various approaches have been delineated to mitigate MGMT-induced temozolomide resistance. The most promising means in discovery biology appears to be the co-administration of MGMT inhibitors such as O6 benzyl guanine or lomeguatrib. Surprisingly, the validation of these pharmacologic inhibitors to assess the reversal of chemoresistance by appropriately designed safety and efficacy trials in combination with temozolomide is yet to be demonstrated. Taken together, given the regulation of temozolomide resistance by MGMT, intermediate and late discovery groups may focus their efforts on pharmacologic inhibition of MGMT, singly or in combination with radiotherapy or immunotherapy, to combat temozolomide resistance in GBM patients. In addition, one may speculate that the combined clinical use of temozolomide with a drug regulator-approved MGMT inhibitor as well as an immune checkpoint inhibitor such as nivolumab may prove beneficial. Future studies may also investigate any inter-ethnic variability in population pharmacogenetics of MGMT and pharmacometric approaches to optimize cancer precision medicine.
{"title":"Current Translational Insights into MGMT Methylation Regulating Temozolomide Sensitivity and Resistance in Glioblastoma Multiforme","authors":"I. Gulati, Harsh Patel, B. Prabhakar, S. Nair","doi":"10.2174/1875692118666200309130307","DOIUrl":"https://doi.org/10.2174/1875692118666200309130307","url":null,"abstract":"\u0000\u0000Temozolomide is used as frontline chemotherapy in the management\u0000of glioblastoma multiforme (GBM); however, its clinical utility is limited by the\u0000occurrence of significant resistance, majorly caused due to direct DNA repair. O6-\u0000methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein, mediates this direct\u0000repair pathway and reverses the activity of temozolomide.\u0000\u0000\u0000\u0000We characterize and underscore the functional relevance and molecular aspects\u0000of MGMT in the development of sensitivity/resistance to temozolomide treatment. We review\u0000early translational, as well as clinical, evidence for the role of MGMT in mediating\u0000temozolomide resistance in vitro in cell lines, in vivo in small animals as well as in GBM\u0000patients.\u0000\u0000\u0000\u0000Various approaches have been delineated to mitigate MGMT-induced temozolomide\u0000resistance. The most promising means in discovery biology appears to be the\u0000co-administration of MGMT inhibitors such as O6 benzyl guanine or lomeguatrib. Surprisingly,\u0000the validation of these pharmacologic inhibitors to assess the reversal of chemoresistance\u0000by appropriately designed safety and efficacy trials in combination with temozolomide\u0000is yet to be demonstrated.\u0000\u0000\u0000\u0000 Taken together, given the regulation of temozolomide resistance by MGMT,\u0000intermediate and late discovery groups may focus their efforts on pharmacologic inhibition\u0000of MGMT, singly or in combination with radiotherapy or immunotherapy, to combat\u0000temozolomide resistance in GBM patients. In addition, one may speculate that the combined\u0000clinical use of temozolomide with a drug regulator-approved MGMT inhibitor as\u0000well as an immune checkpoint inhibitor such as nivolumab may prove beneficial. Future\u0000studies may also investigate any inter-ethnic variability in population pharmacogenetics of\u0000MGMT and pharmacometric approaches to optimize cancer precision medicine.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"6 1","pages":"76-93"},"PeriodicalIF":0.0,"publicationDate":"2020-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88586714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-28DOI: 10.2174/187569211702200921093217
R. Cacabelos
Epigenetics is a discipline that studies heritable changes in gene expression without structural changes in the DNA sequence. Epigenetics is one of the most rapidly developing fields in the history of biology. The concept of epigenetics has evolved since Waddington defined it in the late 1930s, becoming a multifaceted contextual discipline with influence in evolution, speciation, functional genomics, transcriptomics, proteomics, metabolomics, and obviously in species-specific health and disease [1]. Epigenetics plays an important role in phenotypic variation in different species of animal and vegetal kingdom [2]. Epigenetic memory can persist across generations. A stressinduced signal can be transmitted across multiple unexposed generations leading to persistent changes in epigenetic gene regulation [3]. Epigenetic mechanisms contribute to phenotypic variation and disparities in morbidity and mortality [4]. Epigenetics acts as an interface between the genome and the environment, and the mechanistic changes associated with the epigenetic phenomena can also be considered a sophisticated form of intracellular and intercellular communication [5]. Epigenetics is an adaptive mechanism of developmental plasticity, a phenomenon of relevance in evolutionary biology and human health and disease, which enables organisms to respond to their environment based on previous experience without changes to the underlying nucleotide sequence [6]. Genetic variation correlates with phenotypes depending upon allele-specific genetic changes linked to gene expression, DNA methylation, histone marks, and miRNA regulation of proteomic and metabolomic processes [7].
{"title":"The PharmacoEpiGenetic Connection","authors":"R. Cacabelos","doi":"10.2174/187569211702200921093217","DOIUrl":"https://doi.org/10.2174/187569211702200921093217","url":null,"abstract":"Epigenetics is a discipline that studies heritable changes in gene expression without structural changes in the DNA sequence. Epigenetics is one of the most rapidly developing fields in the history of biology. The concept of epigenetics has evolved since Waddington defined it in the late 1930s, becoming a multifaceted contextual discipline with influence in evolution, speciation, functional genomics, transcriptomics, proteomics, metabolomics, and obviously in species-specific health and disease [1]. Epigenetics plays an important role in phenotypic variation in different species of animal and vegetal kingdom [2]. Epigenetic memory can persist across generations. A stressinduced signal can be transmitted across multiple unexposed generations leading to persistent changes in epigenetic gene regulation [3]. Epigenetic mechanisms contribute to phenotypic variation and disparities in morbidity and mortality [4]. Epigenetics acts as an interface between the genome and the environment, and the mechanistic changes associated with the epigenetic phenomena can also be considered a sophisticated form of intracellular and intercellular communication [5]. Epigenetics is an adaptive mechanism of developmental plasticity, a phenomenon of relevance in evolutionary biology and human health and disease, which enables organisms to respond to their environment based on previous experience without changes to the underlying nucleotide sequence [6]. Genetic variation correlates with phenotypes depending upon allele-specific genetic changes linked to gene expression, DNA methylation, histone marks, and miRNA regulation of proteomic and metabolomic processes [7].","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"18 1","pages":"72-75"},"PeriodicalIF":0.0,"publicationDate":"2020-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85280560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-28DOI: 10.2174/1875692118666200122163559
Nazanin Mousavi, Seyyed Amir Yasin Ahmadi, Z. Mahmoudi, Reza Nekouian, Bijan Ansari-moghaddam, F. Shahsavar
OXP3 is a gene related to regulatory T cells existing on chromosome X. This meta-analysis, based on genetic association studies, was conducted to investigate the association of FOXP3 polymorphisms with susceptibility to multiple sclerosis (MS). All genetic association studies covering both FOXP3 and multiple sclerosis terms were searched in PubMed, Web of Science and Google Scholar. The information of genotype frequencies was summarized and results were synthesized through odds ratio (OR). Heterogeneity and publication bias were investigated using I2 scale and Begg's funnel plot, respectively. For rs3761548 -3279 C/A polymorphism, AA/AY genotypes were a risk factor in comparison to CC/CY genotypes (P =0.022; OR =1.752; 95% confidence interval [CI] =1.084-2.830; random). AC genotype was a risk factor in comparison to CC/CY genotypes (P =0.004; OR =1.537; 95% CI =1.145-2.062; random) and homozygote genotypes (P =0.016; OR =1.216; 95% CI =1.038-1.426; fixed). For rs2232365 -924 G/A polymorphism, 2 significant associations were found according to a fixed effect model; of course, they did not remain significant in the random effect model. According to the collected populations, susceptibility to and protection from MS are associated with rs3761548 -3279 C/A upstream polymorphism. However, it should be regarded that this association is ethnicity dependent with low effect size.
OXP3是一个存在于染色体上的与调节性T细胞相关的基因。本荟萃分析基于遗传关联研究，旨在研究FOXP3多态性与多发性硬化症(MS)易感性的关系。在PubMed, Web of Science和Google Scholar中检索了所有涉及FOXP3和多发性硬化的遗传关联研究。总结基因型频率信息，并通过比值比(OR)综合结果。异质性和发表偏倚分别采用I2量表和Begg漏斗图进行调查。与CC/CY基因型相比，AA/AY基因型是rs3761548 -3279 C/A多态性的危险因素(P =0.022;或= 1.752;95%置信区间[CI]=1.084-2.830;随机)。与CC/CY基因型相比，AC基因型是危险因素(P =0.004;或= 1.537;95% ci =1.145-2.062;随机)和纯合子基因型(P =0.016;或= 1.216;95% ci =1.038 ~ 1.426;固定)。rs2232365 -924 G/A多态性根据固定效应模型发现2个显著相关;当然，它们在随机效应模型中并不显著。根据收集到的群体，ms的易感性和保护作用与rs3761548 -3279 C/A上游多态性相关。然而，应该考虑到这种关联是种族依赖的，效应量低。
{"title":"Association of FOXP3 Polymorphisms with Susceptibility to Multiple Sclerosis: A Meta-Analysis on Genetic Association Studies","authors":"Nazanin Mousavi, Seyyed Amir Yasin Ahmadi, Z. Mahmoudi, Reza Nekouian, Bijan Ansari-moghaddam, F. Shahsavar","doi":"10.2174/1875692118666200122163559","DOIUrl":"https://doi.org/10.2174/1875692118666200122163559","url":null,"abstract":"\u0000\u0000OXP3 is a gene related to regulatory T cells existing on chromosome\u0000X. This meta-analysis, based on genetic association studies, was conducted to investigate\u0000the association of FOXP3 polymorphisms with susceptibility to multiple sclerosis\u0000(MS).\u0000\u0000\u0000\u0000All genetic association studies covering both FOXP3 and multiple sclerosis\u0000terms were searched in PubMed, Web of Science and Google Scholar. The information of\u0000genotype frequencies was summarized and results were synthesized through odds ratio\u0000(OR). Heterogeneity and publication bias were investigated using I2 scale and Begg's funnel\u0000plot, respectively.\u0000\u0000\u0000\u0000For rs3761548 -3279 C/A polymorphism, AA/AY genotypes were a risk factor in\u0000comparison to CC/CY genotypes (P =0.022; OR =1.752; 95% confidence interval [CI]\u0000=1.084-2.830; random). AC genotype was a risk factor in comparison to CC/CY genotypes\u0000(P =0.004; OR =1.537; 95% CI =1.145-2.062; random) and homozygote genotypes\u0000(P =0.016; OR =1.216; 95% CI =1.038-1.426; fixed). For rs2232365 -924 G/A polymorphism,\u00002 significant associations were found according to a fixed effect model; of course,\u0000they did not remain significant in the random effect model.\u0000\u0000\u0000\u0000According to the collected populations, susceptibility to and protection from\u0000MS are associated with rs3761548 -3279 C/A upstream polymorphism. However, it\u0000should be regarded that this association is ethnicity dependent with low effect size.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"3 1","pages":"94-103"},"PeriodicalIF":0.0,"publicationDate":"2020-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81353654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-08-31DOI: 10.2174/1875692118666200316130727
Mina Zafarpiran, R. Sharifi, Zeinab Shirvani-Farsani
Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system, and genetic factors play an important role in its susceptibility. The expressions of many inflammatory genes implicated in MS are regulated by microRNA (miRNAs), whose function is to suppress the translation by pairing with miRNA Recognition Elements (MREs) present in the 3' untranslated region (3'UTR) of target mRNA. Recently, it has been shown that the Single Nucleotide Polymorphism (SNPs) present within the 3'UTR of mRNAs can affect the miRNA-mediated gene regulation and susceptibility to a variety of human diseases. The aim of this study was to analyze the SNPs within the 3'UTR of miRNA inflammatory target genes related to multiple sclerosis. By DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases, 3'UTR genetic variants were identified in all inflammatory genes associated with MS. Also, miRNA's target prediction databases were used for predicting the miRNA binding sites. We identified 125 SNPs with MAF>0.05 located in the binding site of the miRNA of 35 genes among 59 inflammatory genes related to MS. Bioinformatics analysis predicted 62 MRE-modulating SNPs and 59 MRE-creating SNPs in the 3'UTR of MSimplicated inflammatory genes. These candidate SNPs within miRNA binding sites of inflammatory genes can alter the miRNAs binding, and consequently lead to the mRNA gene regulation. Therefore, these miRNA and MRE-SNPs may play important roles in personalized medicine of MS, and hence, they would be valuable for further functional verification investigations.
多发性硬化症(MS)是一种中枢神经系统炎症性脱髓鞘疾病，遗传因素在其易感性中起重要作用。许多与MS相关的炎症基因的表达是由microRNA (miRNAs)调控的，其功能是通过与靶mRNA的3'非翻译区(3' utr)中的mirna识别元件(MREs)配对来抑制翻译。最近，研究表明mrna 3'UTR内的单核苷酸多态性(snp)可以影响mirna介导的基因调控和对多种人类疾病的易感性。本研究的目的是分析与多发性硬化症相关的miRNA炎症靶基因3'UTR内的snp。通过DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge和snp数据库，在所有与ms相关的炎症基因中鉴定出3'UTR遗传变异。同时，miRNA的靶标预测数据库用于预测miRNA结合位点。在59个与ms相关的炎症基因中，我们发现了125个MAF>0.05的snp位于35个基因的mirna结合位点，生物信息学分析预测了62个mre调节snp和59个mre产生snp在mre简化炎症基因的3'UTR中。这些炎性基因miRNA结合位点内的候选snp可以改变miRNA的结合，从而导致mRNAgene的调控。因此，这些miRNA和MRE-SNPs可能在MS的个性化治疗中发挥重要作用，因此，它们将对进一步的功能验证研究有价值。
{"title":"The SNPs within 3'UTR of miRNA Target Genes Related to Multiple Sclerosis: A Computational Prediction","authors":"Mina Zafarpiran, R. Sharifi, Zeinab Shirvani-Farsani","doi":"10.2174/1875692118666200316130727","DOIUrl":"https://doi.org/10.2174/1875692118666200316130727","url":null,"abstract":"\u0000\u0000Multiple Sclerosis (MS) is an inflammatory and demyelinating\u0000disease of the central nervous system, and genetic factors play an important role in its susceptibility.\u0000The expressions of many inflammatory genes implicated in MS are regulated\u0000by microRNA (miRNAs), whose function is to suppress the translation by pairing with\u0000miRNA Recognition Elements (MREs) present in the 3' untranslated region (3'UTR) of\u0000target mRNA. Recently, it has been shown that the Single Nucleotide Polymorphism\u0000(SNPs) present within the 3'UTR of mRNAs can affect the miRNA-mediated gene regulation\u0000and susceptibility to a variety of human diseases.\u0000\u0000\u0000\u0000The aim of this study was to analyze the SNPs within the 3'UTR of miRNA inflammatory\u0000target genes related to multiple sclerosis.\u0000\u0000\u0000\u0000By DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases,\u00003'UTR genetic variants were identified in all inflammatory genes associated with MS. Also,\u0000miRNA's target prediction databases were used for predicting the miRNA binding sites.\u0000\u0000\u0000\u0000We identified 125 SNPs with MAF>0.05 located in the binding site of the miRNA\u0000of 35 genes among 59 inflammatory genes related to MS. Bioinformatics analysis\u0000predicted 62 MRE-modulating SNPs and 59 MRE-creating SNPs in the 3'UTR of MSimplicated\u0000inflammatory genes. These candidate SNPs within miRNA binding sites of inflammatory\u0000genes can alter the miRNAs binding, and consequently lead to the mRNA\u0000gene regulation.\u0000\u0000\u0000\u0000Therefore, these miRNA and MRE-SNPs may play important roles in personalized\u0000medicine of MS, and hence, they would be valuable for further functional verification\u0000investigations.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"17 1","pages":"133-147"},"PeriodicalIF":0.0,"publicationDate":"2020-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81751228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-04-28DOI: 10.2174/187569211701200318091701
R. Cacabelos
{"title":"Towards a Mature Discipline of Pharmacogenomics: Epistemological Reflections","authors":"R. Cacabelos","doi":"10.2174/187569211701200318091701","DOIUrl":"https://doi.org/10.2174/187569211701200318091701","url":null,"abstract":"","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"22 1","pages":"3-6"},"PeriodicalIF":0.0,"publicationDate":"2020-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85069960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-31DOI: 10.2174/1875692117666190416145331
M. Ibrahim, Zalina Zahari, Nurfadhlina Musa, K. Yin
Identifying the genetic polymorphisms of drug metabolizing enzyme CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence of the CYP2D6 polymorphisms among Kurds is scarce. In this study, we explored the CYP2D6 polymorphisms among Kurds. Four hundred and fifty-nine unrelated healthy Kurds were recruited for the study. DNA was extracted from whole blood and was then used for genotyping CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific multiplex Polymerase Chain Reaction (PCR). The data add to our knowledge of CYP2D6 alleles, the genotypes and the distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles confer no function and gene duplication. CYP2D6 polymorphisms were found to be very heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation of drug therapy adjustment based on CYP2D6 genotype may help to understand the clinical consequences of CYP2D6 polymorphisms.
{"title":"Genetic Polymorphisms of CYP2D6: Prevalence in Healthy Kurds","authors":"M. Ibrahim, Zalina Zahari, Nurfadhlina Musa, K. Yin","doi":"10.2174/1875692117666190416145331","DOIUrl":"https://doi.org/10.2174/1875692117666190416145331","url":null,"abstract":"\u0000\u0000Identifying the genetic polymorphisms of drug metabolizing enzyme\u0000CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence\u0000of the CYP2D6 polymorphisms among Kurds is scarce.\u0000\u0000\u0000\u0000In this study, we explored the CYP2D6 polymorphisms among Kurds.\u0000\u0000\u0000\u0000Four hundred and fifty-nine unrelated healthy Kurds were recruited for the\u0000study. DNA was extracted from whole blood and was then used for genotyping\u0000CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific\u0000multiplex Polymerase Chain Reaction (PCR).\u0000\u0000\u0000\u0000The data add to our knowledge of CYP2D6 alleles, the genotypes and the\u0000distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles\u0000confer no function and gene duplication. CYP2D6 polymorphisms were found to be very\u0000heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation\u0000of drug therapy adjustment based on CYP2D6 genotype may help to understand the\u0000clinical consequences of CYP2D6 polymorphisms.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"38 1","pages":"40-47"},"PeriodicalIF":0.0,"publicationDate":"2020-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82758746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-31DOI: 10.2174/1875692117666191106105918
J. Kang
Prenatal genetic diagnosis provides information for pregnancy and perinatal decision- making and management. Cytogenetic testing methods, including chromosomal microarray analysis and gene panels, have evolved to become a part of routine laboratory testing, providing valuable diagnostic and prognostic information for prenatal diagnoses. Despite this progress, however, cytogenetic analyses are limited by their resolution and diagnosis is only possible in around 40% of the dysmorphic fetuses. The advent of nextgeneration sequencing (NGS), whole-genome sequencing or whole-exome sequencing has revolutionized prenatal diagnosis and fetal medicine. These technologies have improved the identification of genetic disorders in fetuses with structural abnormalities and provide valuable diagnostic and prognostic information for the detection of genomic defects. Here, the potential future of prenatal genetic diagnosis, including a move toward NGS technologies, is discussed.
{"title":"The Promise of Whole-exome Sequencing for Prenatal Genetic Diagnosis","authors":"J. Kang","doi":"10.2174/1875692117666191106105918","DOIUrl":"https://doi.org/10.2174/1875692117666191106105918","url":null,"abstract":"\u0000\u0000Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-\u0000making and management. Cytogenetic testing methods, including chromosomal\u0000microarray analysis and gene panels, have evolved to become a part of routine laboratory\u0000testing, providing valuable diagnostic and prognostic information for prenatal diagnoses.\u0000Despite this progress, however, cytogenetic analyses are limited by their resolution and\u0000diagnosis is only possible in around 40% of the dysmorphic fetuses. The advent of nextgeneration\u0000sequencing (NGS), whole-genome sequencing or whole-exome sequencing has\u0000revolutionized prenatal diagnosis and fetal medicine. These technologies have improved\u0000the identification of genetic disorders in fetuses with structural abnormalities and provide\u0000valuable diagnostic and prognostic information for the detection of genomic defects. Here,\u0000the potential future of prenatal genetic diagnosis, including a move toward NGS technologies,\u0000is discussed.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"8 1","pages":"25-31"},"PeriodicalIF":0.0,"publicationDate":"2020-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86097821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-31DOI: 10.2174/1875692117666190820105134
A. Mishra, Ishant Kataria, S. Nair
Hu5F9-G4, a human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) has recently been granted fast-track designation by the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Hu5F9-G4 has the ability to block CD47-SIRPα signaling along with anti- EGFR and anti-PD-L1 immune checkpoint activity that is involved in a variety of cancers like solid tumors, Non-Hodgkin’s Lymphoma (NHL), colorectal cancer (CRC), breast, ovarian and bladder cancers, and hematological malignancies. Thus, Hu5F9-G4 is an important biologic that has increasing clinical relevance in cancer care. We queried PubMed, Web of Science, Google Scholar, Science Direct and Scopus databases with keywords pertaining to Hu5F9-G4. In addition, we have included the Hu5F9-G4 data presented at the 60th American Society of Hematology (ASH) Annual Meeting, the American Society of Clinical Oncology (ASCO) Annual Meeting and 23rd Congress of the European Hematology Association (EHA). We discuss the mechanistic basis and preclinical evidence for the anticancer activity of Hu5F9-G4. Further, we delineate clinical studies, alone and in combination with anti-CD20 mAb rituximab, anti-EGFR mAb cetuximab, PD-L1 checkpoint inhibitors avelumab and atezolizumab, and anti-HER2 mAb trastuzumab. Moreover, the potential adverse effects, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 with emphasis on the role of CD47-SIRPα signaling in phagocytosis are presented. Taken together, we review the pharmacokinetics and systems pharmacology of Hu5F9-G4 which appears to hold great promise for the future of cancer care.
Hu5F9-G4是一种人免疫球蛋白G4 (IgG4)单克隆抗体(mAb)，最近被FDA授予快速通道指定用于治疗复发或难治性弥漫性大b细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤。Hu5F9-G4具有阻断CD47-SIRPα信号通路以及抗egfr和抗pd - l1免疫检查点活性的能力，这种能力涉及多种癌症，如实体瘤、非霍奇金淋巴瘤(NHL)、结直肠癌(CRC)、乳腺癌、卵巢癌和膀胱癌以及血液系统恶性肿瘤。因此，Hu5F9-G4是一种重要的生物制剂，在癌症治疗中具有越来越重要的临床意义。我们在PubMed, Web of Science, Google Scholar, Science Direct和scopusdatabase中查询了与Hu5F9-G4相关的关键词。此外，我们还纳入了在第60届美国血液学学会(ASH)年会、美国临床肿瘤学会(ASCO)年会和欧洲血液学协会(EHA)第23届大会上提交的hu5f9 - g4数据。我们讨论了Hu5F9-G4抗癌活性的机制基础和临床前证据。此外，我们描述了临床研究，单独和联合抗cd20单抗利妥昔单抗，抗egfr单抗西妥昔单抗，PD-L1检查点抑制剂阿维鲁巴和阿特唑单抗，抗her2单抗曲妥珠单抗。此外，还介绍了Hu5F9-G4的潜在副作用、药代动力学和药效学，重点介绍了CD47-SIRPα信号通路在吞噬作用中的作用。综上所述，我们回顾了Hu5F9-G4的药代动力学和系统药理学，它似乎对未来的癌症治疗有很大的希望。
{"title":"Pharmacokinetics and Systems Pharmacology of Anti-CD47 Macrophage Immune Checkpoint Inhibitor Hu5F9-G4","authors":"A. Mishra, Ishant Kataria, S. Nair","doi":"10.2174/1875692117666190820105134","DOIUrl":"https://doi.org/10.2174/1875692117666190820105134","url":null,"abstract":"\u0000\u0000Hu5F9-G4, a human immunoglobulin G4 (IgG4) monoclonal antibody\u0000(mAb) has recently been granted fast-track designation by the FDA for the treatment\u0000of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular\u0000lymphoma. Hu5F9-G4 has the ability to block CD47-SIRPα signaling along with anti-\u0000EGFR and anti-PD-L1 immune checkpoint activity that is involved in a variety of cancers\u0000like solid tumors, Non-Hodgkin’s Lymphoma (NHL), colorectal cancer (CRC), breast,\u0000ovarian and bladder cancers, and hematological malignancies. Thus, Hu5F9-G4 is an important\u0000biologic that has increasing clinical relevance in cancer care.\u0000\u0000\u0000\u0000We queried PubMed, Web of Science, Google Scholar, Science Direct and Scopus\u0000databases with keywords pertaining to Hu5F9-G4. In addition, we have included the\u0000Hu5F9-G4 data presented at the 60th American Society of Hematology (ASH) Annual\u0000Meeting, the American Society of Clinical Oncology (ASCO) Annual Meeting and 23rd\u0000Congress of the European Hematology Association (EHA).\u0000\u0000\u0000\u0000We discuss the mechanistic basis and preclinical evidence for the anticancer activity\u0000of Hu5F9-G4. Further, we delineate clinical studies, alone and in combination with\u0000anti-CD20 mAb rituximab, anti-EGFR mAb cetuximab, PD-L1 checkpoint inhibitors avelumab\u0000and atezolizumab, and anti-HER2 mAb trastuzumab. Moreover, the potential adverse\u0000effects, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 with emphasis on\u0000the role of CD47-SIRPα signaling in phagocytosis are presented.\u0000\u0000\u0000\u0000Taken together, we review the pharmacokinetics and systems pharmacology\u0000of Hu5F9-G4 which appears to hold great promise for the future of cancer care.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"38 1","pages":"14-24"},"PeriodicalIF":0.0,"publicationDate":"2020-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86987425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-31DOI: 10.2174/1875692117666191211154755
Alvina Arum Puspitasari, Z. Ikawati, S. Swasthikawati, Anindya Rahmawati
The opioid receptor μ-1 (OPRM1) has become one of the most studied genes in pharmacogenetics, as this gene encodes the μ-opioid receptor (MOR), which plays a role in opioid drugs response, as well as in various disorders. One of its variants, A118G, which is found at a high frequency in the Asian population, has been associated with loss of sensitivity to and an increased requirement for analgesics in the treatment of pain, increased pain sensitivity, various types of substance dependencies, and the development of breast cancer. However, there are still limited reports about this gene polymorphism in the Indonesian population. The study aimed to determine the allele frequencies of the OPRM1 A118G polymorphism among the Indonesian population. A cross-sectional study of 158 subjects, comprising 79 males and 79 females, was conducted among Indonesians, and genotype analysis was carried out by a modified allele-specific Polymerase Chain Reaction (PCR) method. A frequency of 60.4% was found for the G allele among Indonesian samples, with a higher frequency being present in males (66.5%). The A allele was found at frequencies of 33.5% and 45.6% in males and females, respectively. A significant difference in allele frequency was found between males and females (p = 0.029, OR = 1.659, 95% CI [1.052–2.614]), while there was no significant difference in genotype frequencies between groups. A high prevalence of the OPRM1 A118G polymorphism was found in the Indonesian population, with the G allele frequency tending to be higher in males.
{"title":"High Frequency of the Opioid Receptor µ-1 (OPRM1) A118G Polymorphism, an Opioid Drug Therapy Related Gene, in the Indonesian Population","authors":"Alvina Arum Puspitasari, Z. Ikawati, S. Swasthikawati, Anindya Rahmawati","doi":"10.2174/1875692117666191211154755","DOIUrl":"https://doi.org/10.2174/1875692117666191211154755","url":null,"abstract":"\u0000\u0000The opioid receptor μ-1 (OPRM1) has become one of the most\u0000studied genes in pharmacogenetics, as this gene encodes the μ-opioid receptor (MOR),\u0000which plays a role in opioid drugs response, as well as in various disorders. One of its\u0000variants, A118G, which is found at a high frequency in the Asian population, has been associated\u0000with loss of sensitivity to and an increased requirement for analgesics in the\u0000treatment of pain, increased pain sensitivity, various types of substance dependencies, and\u0000the development of breast cancer. However, there are still limited reports about this gene\u0000polymorphism in the Indonesian population.\u0000\u0000\u0000\u0000The study aimed to determine the allele frequencies of the OPRM1 A118G\u0000polymorphism among the Indonesian population.\u0000\u0000\u0000\u0000A cross-sectional study of 158 subjects, comprising 79 males and 79 females,\u0000was conducted among Indonesians, and genotype analysis was carried out by a modified\u0000allele-specific Polymerase Chain Reaction (PCR) method.\u0000\u0000\u0000\u0000A frequency of 60.4% was found for the G allele among Indonesian samples,\u0000with a higher frequency being present in males (66.5%). The A allele was found at frequencies\u0000of 33.5% and 45.6% in males and females, respectively. A significant difference\u0000in allele frequency was found between males and females (p = 0.029, OR = 1.659, 95% CI\u0000[1.052–2.614]), while there was no significant difference in genotype frequencies between\u0000groups.\u0000\u0000\u0000\u0000A high prevalence of the OPRM1 A118G polymorphism was found in the\u0000Indonesian population, with the G allele frequency tending to be higher in males.\u0000","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"295 ","pages":"64-69"},"PeriodicalIF":0.0,"publicationDate":"2020-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1875692117666191211154755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72423827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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