Current Pharmacogenomics and Personalized Medicine最新文献

{"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}

{"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}

{"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}

{"title":"Meet Our Editor-in-Chief","authors":"R. Cacabelos","doi":"10.2174/187569211702200921090746","DOIUrl":"https://doi.org/10.2174/187569211702200921090746","url":null,"abstract":"","PeriodicalId":11056,"journal":{"name":"Current Pharmacogenomics and Personalized Medicine","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87173081","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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}