BACKGROUND Neonatal hypertension is a rare but potentially serious condition that requires careful monitoring and treatment.Pharmacogenomics can help guide individualized drug therapy and improve outcomes.CASE SUMMARY...BACKGROUND Neonatal hypertension is a rare but potentially serious condition that requires careful monitoring and treatment.Pharmacogenomics can help guide individualized drug therapy and improve outcomes.CASE SUMMARY We report a case of a preterm infant with multiple complications,including bronchopulmonary dysplasia(BPD),sepsis,intracranial hemorrhage,and hypertension.The infant was treated with various drugs,including dexamethasone and amlodipine.The infant was diagnosed with neonatal hypertension based on blood pressure measurements exceeding the 95th percentile for his age and sex.The possible causes of hypertension included dexamethasone,hydrochlorothiazide,spironolactone,and BPD.The infant was treated with oral amlodipine to lower his blood pressure.A pharmacogenomic test was performed to evaluate the genetic polymorphisms of ABCB1 and CYP3A5,which are involved in the metabolism and transport of dexamethasone and amlodipine.The infant’s blood pressure was well controlled after the dose of amlodipine was reduced according to the pharmacogenomic results.The infant had a stable general condition and was discharged on the 100th d after birth.CONCLUSION This case illustrates the importance of regular blood pressure monitoring and etiological investigation in preterm infants with hypertension.Pharmacogenomics can provide useful information for individualized drug therapy and safety in this population.展开更多
BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their...BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care,with the aim to inform wider adoption of PG into routine clinical practice.AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians.METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021.Via electronic surveys we compared and contrasted the experience,understanding and usage of results between these patients and their clinicians.RESULTS Of 100 patients who had PG,84% were taking prescription medications,of which 67% were taking medications with actionable drug-gene interactions.Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys.Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing.Paired patient-clinician surveys showed patient-perceived utility and experience was positive,contrasting their clinicians’hesitancy on PG adoption who identified insufficient education/training,lack of clinical support,test turnaround time and cost as barriers to adoption.CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.展开更多
Osteoporosis has emerged as a significant health issue among postmenopausal women.Addressing this concern necessitates a multifaceted approach encompassing genetics,pharmacogenomics,bone turnover markers,lifestyle fac...Osteoporosis has emerged as a significant health issue among postmenopausal women.Addressing this concern necessitates a multifaceted approach encompassing genetics,pharmacogenomics,bone turnover markers,lifestyle factors,concurrent medical conditions,biomarkers,and advanced imaging techniques.Nonetheless,challenges in terms of cost-effectiveness and ethical considerations do exist.Fortunately,the convergence of technological progress and research endeavors offers a promising trajectory.The integration of genetic testing and pharmacogenomics into clinical practice holds substantial potential.This integration empowers healthcare professionals to forecast treatment responses and pinpoint individuals with elevated susceptibility,thereby enabling the implementation of tailored and efficacious interventions that optimize outcomes–personalized medicine.Given the intricate nature of osteoporosis,personalized strategies stand to greatly benefit women grappling with this condition.Further research and collaborative efforts are imperative to propel advancements within this domain,paving the way for further breakthroughs.展开更多
The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transpla...The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient’s immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES:The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS:Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly-used im- munosuppressants. Recent progress in study of pharmaco-kinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS:Individualizing organ recipient’s immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.展开更多
Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Gen...Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have been identified with children in recent years, suggesting genetic associations between certain populations carrying specific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of compounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for natural products capable of inhibiting targets which can lead to the development of rational treatment of various diseases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more opportunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacodynamic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mechanisms underlying these interactions and their modification by genetic variation is expected to result in the development of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to improved results for patients.展开更多
Pharmacogenetics refers to the effect of single nucleotide polymorphisms(SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving ...Pharmacogenetics refers to the effect of single nucleotide polymorphisms(SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction(HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus(HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1(MDR1) 3435 C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.展开更多
The availability of newer technologies for identification and characterization of the human genome has enabled our understanding of the genetic variations in a majority of human diseases.Human genomic sequence varies ...The availability of newer technologies for identification and characterization of the human genome has enabled our understanding of the genetic variations in a majority of human diseases.Human genomic sequence varies in less than 1%among the different population group and these differences known as gene polymorphisms are the primary reasons for differences in individuals’response to various drug therapy.Also understanding the genetic changes may enable implementation of targeted therapy,thus providing for effective treatment strategies and minimizing the adverse side effects.Pharmacogenomics is a recent development in the field of personalized medicine which focuses on the genetic determinants of drug response at the levels of entire human genome.It primarily deals with tailoring of drug therapy for every individual based on their genetic make-up and identifying new target in various diseases for drug therapy.While the application of pharmacogenomics in systemic illness is well researched,its role in oral diseases needs documentation.Identifying specific targets in periodontitis,head and neck cancer,infections and genetic disorders can be beneficial in discovery of new drugs.This editorial provides an overview of basics of pharmacoge-nomics,its current role in disease management and its potential role in various head and neck diseases.展开更多
Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, t...Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase(TKI), anaplastic lymphoma kinase(ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s).Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.展开更多
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study o...The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.展开更多
Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenan...Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.展开更多
Gastrointestinal stromal tumors(GISTs)are rare entities,which,however,represent the most common mesenchymal tumor of the gastrointestinal tract.The discovery of gain of function mutations on KIT and PDGFRA receptor ge...Gastrointestinal stromal tumors(GISTs)are rare entities,which,however,represent the most common mesenchymal tumor of the gastrointestinal tract.The discovery of gain of function mutations on KIT and PDGFRA receptor genes led to a deep revolution in the knowledge of this tumor.This paved the way to the introduction of imatinib and other tyrosine-kinase inhibitors(TKIs),which terrifically revolutionized the prognosis of GIST patients.Currently,it is well established that tumor mutational status is the main player in clinical outcome;however,with the research advances,it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes.For this reason,in the era of tailored/personalized medicine,each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.展开更多
Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic effort...Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic efforts.Part of the discarded drugs might be beneficial only in a subgroup of the study patients,and some adverse events might be prevented by identifying those patients more vulnerable to toxicities.The implementation of pharmacogenomic biomarkers allows the categorization of patients,to predict efficacy and toxicity and to optimize the drug development process.Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration,and with the progress of Precision Medicine tailoring therapies on individuals’genomic landscape promises to become a new standard of cancer care.In the current article we review the role of pharmacogenomics in cancer drug development,underlying the advantages and challenges of their implementation.展开更多
Schizophrenia is a widespread mental disease with a prevalence of about 1%in the world population,and heritability of up to 80%.Drug therapy is an important approach to treating the disease.However,the curative effect...Schizophrenia is a widespread mental disease with a prevalence of about 1%in the world population,and heritability of up to 80%.Drug therapy is an important approach to treating the disease.However,the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects.Many studies have indicated that about 30%of the patients exhibit little or no improvements associated with antipsychotics.The response of individual patients who are given the same dose of the same drug varies considerably.In addition,antipsychotic drugs are often accompanied by adverse drug reactions(ADRs),which can cause considerable financial loss in addition to the obvious societal harm.So,it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity.There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians.Individual differences in drug response is due to a combination of many complex factors including ADEM(absorption,distribution,metabolism,excretion)process,transporting,binding with receptor and intracellular signal transduction.Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response.In addition,epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients.In this review,we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes(CYP2D6,CYP1A2,CYP3A4,etc.),drug transporters(mainly ABCB1)and neurotransmitter receptors(dopamine receptors and serotonin receptors,etc.).We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.展开更多
Dear Editor,I would like to offer some comments on the excellent article by Hai-Yan He and colleagues published in Genomics,Proteomics&Bioinformatics on 1st April 2017[1].The authors include,in the list of genetic...Dear Editor,I would like to offer some comments on the excellent article by Hai-Yan He and colleagues published in Genomics,Proteomics&Bioinformatics on 1st April 2017[1].The authors include,in the list of genetic polymorphisms that have an effect on vitamins,the low concentrations of cellular and plasma vitamin B12in GG carriers of SNP rs602662(772 G>A)in the gene encoding fucosyltransferase 2(FUT2).展开更多
The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been d...The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices.Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers,while supporting the rationale for the development of new drugs and treatment combinations.Clinical validation of promising biomarkers,however,is often an issue.More recently,a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field.This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC,in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach,comprising genomics and epigenetics.展开更多
Dear Editor,We thank the author for making meaningful comments on our recent article[1].The SNP 772G>A(rs602662)in exon 2 of the gene encoding fucosyl transferase(FUT2)has been found to be related with the alterati...Dear Editor,We thank the author for making meaningful comments on our recent article[1].The SNP 772G>A(rs602662)in exon 2 of the gene encoding fucosyl transferase(FUT2)has been found to be related with the alterations in plasma vitamin B_(12) levels.展开更多
Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excre...Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excretion has been performed in addition to the analyses of blood concentrations of drugs. Such pharmacogenetic factors play an important role in predicting therapeutic effects and adverse events and in the proper use of drugs. With the recent launch of immune checkpoint inhibitors (ICIs) and the rapid development of antibody-drug conjugates (ADCs) currently underway, there is no doubt that antibody drugs, which are large molecule compounds, will become key drugs in anticancer drug treatment. However, the pharmacokinetic and pharmacodynamic analysis of antibody drugs is still not sufficient, and further elucidation of factors and mechanisms affecting their dynamics in the human body is necessary. Moreover, the pharmacogenomic factors of antibody drugs have not yet been fully studied. There are many factors that should be clarified, such as factors that regulate the host immune response in ICI therapy and the effects of ATP-binding cassette transporter and cytochrome P450 on the payload of ADCs. This review provides an outline of antibody drugs in cancer treatment and summarizes the pharmacogenomic factors of antibody drugs known to date.展开更多
Objective:Second-generation antipsychotics are widely used in mental illness,but the treatment effects and side effects are affected by single nucleotide polymorphisms(SNPs)of related genes.Quetiapine and aripiprazole...Objective:Second-generation antipsychotics are widely used in mental illness,but the treatment effects and side effects are affected by single nucleotide polymorphisms(SNPs)of related genes.Quetiapine and aripiprazole are two frequently used secondgeneration antipsychotic drugs.The aim of this study was to develop two different SNP detection methods for four SNP alleles associated with the pharmacokinetics of quetiapine and aripiprazole,based on high-resolution melting(HRM)and multicolor melting curve assay(MMCA)respectively.Methods:Whole genome DNA samples were obtained from 240 healthy people(107 females and 133 males)without genetic diseases.HRM methods were established using four kinds of specific primers and a saturated fluorescent dye.Each SNP allele with their own primers was detected in a single reaction.In the MMCA method,a multiplex polymerase chain reaction with 4 different-colored fluorescent probes was established to detect four SNP alleles in a single reaction.All experimental protocols were approved by the Ethics Committee of the Shanghai Children’s Medical Center,China(SCMC-201015)on November 22,2010.Results:Two detection methods for the pharmacogenomics of quetiapine and aripiprazole,based on HRM and MMCA respectively,were established in this study.The single-target HRM method can be completed in 96 minutes,whereas the quadruplex MMCA method takes 133 minutes.It was found that the results of HRM and MMCA for the four SNP alleles had 100%coincidence with Sanger sequencing in the 240 samples.Conclusion:This study developed two methods for the detection of four pharmacogenomic SNP alleles that correlated with quetiapine and aripiprazole.Both methods are rapid,cost-saving,highly accurate and potentially facilitate rational use of second-generation antipsychotics for clinical medication.展开更多
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,...During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.展开更多
Lung cancer is currently the leading cause of cancer death in Western nations.Non-small cell lung cancer(NSCLC)represents 80%of all lung cancers,and adenocarcinoma is the predominant histological type.Despite the inte...Lung cancer is currently the leading cause of cancer death in Western nations.Non-small cell lung cancer(NSCLC)represents 80%of all lung cancers,and adenocarcinoma is the predominant histological type.Despite the intensive research carried out on this field and therapeutic advances,the overall prognosis of these patients remains unsatisfactory,with a 5-year overall survival rate of less than 15%.Nowadays,pharmacogenetics and pharmacogenomics represent the key to successful treatment.Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma:one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor(EGFR).The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR(erlotinib and gefitinib)and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs.This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR,K-Ras and EGFR targeted therapies in NSCLC tumor behavior.展开更多
文摘BACKGROUND Neonatal hypertension is a rare but potentially serious condition that requires careful monitoring and treatment.Pharmacogenomics can help guide individualized drug therapy and improve outcomes.CASE SUMMARY We report a case of a preterm infant with multiple complications,including bronchopulmonary dysplasia(BPD),sepsis,intracranial hemorrhage,and hypertension.The infant was treated with various drugs,including dexamethasone and amlodipine.The infant was diagnosed with neonatal hypertension based on blood pressure measurements exceeding the 95th percentile for his age and sex.The possible causes of hypertension included dexamethasone,hydrochlorothiazide,spironolactone,and BPD.The infant was treated with oral amlodipine to lower his blood pressure.A pharmacogenomic test was performed to evaluate the genetic polymorphisms of ABCB1 and CYP3A5,which are involved in the metabolism and transport of dexamethasone and amlodipine.The infant’s blood pressure was well controlled after the dose of amlodipine was reduced according to the pharmacogenomic results.The infant had a stable general condition and was discharged on the 100th d after birth.CONCLUSION This case illustrates the importance of regular blood pressure monitoring and etiological investigation in preterm infants with hypertension.Pharmacogenomics can provide useful information for individualized drug therapy and safety in this population.
基金Supported by Partially funded by St Vincent’s Health Australia Inclusive Health ProgramEarly Career Research Grant from Avant.
文摘BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care,with the aim to inform wider adoption of PG into routine clinical practice.AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians.METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021.Via electronic surveys we compared and contrasted the experience,understanding and usage of results between these patients and their clinicians.RESULTS Of 100 patients who had PG,84% were taking prescription medications,of which 67% were taking medications with actionable drug-gene interactions.Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys.Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing.Paired patient-clinician surveys showed patient-perceived utility and experience was positive,contrasting their clinicians’hesitancy on PG adoption who identified insufficient education/training,lack of clinical support,test turnaround time and cost as barriers to adoption.CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.
文摘Osteoporosis has emerged as a significant health issue among postmenopausal women.Addressing this concern necessitates a multifaceted approach encompassing genetics,pharmacogenomics,bone turnover markers,lifestyle factors,concurrent medical conditions,biomarkers,and advanced imaging techniques.Nonetheless,challenges in terms of cost-effectiveness and ethical considerations do exist.Fortunately,the convergence of technological progress and research endeavors offers a promising trajectory.The integration of genetic testing and pharmacogenomics into clinical practice holds substantial potential.This integration empowers healthcare professionals to forecast treatment responses and pinpoint individuals with elevated susceptibility,thereby enabling the implementation of tailored and efficacious interventions that optimize outcomes–personalized medicine.Given the intricate nature of osteoporosis,personalized strategies stand to greatly benefit women grappling with this condition.Further research and collaborative efforts are imperative to propel advancements within this domain,paving the way for further breakthroughs.
文摘The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient’s immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES:The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS:Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly-used im- munosuppressants. Recent progress in study of pharmaco-kinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS:Individualizing organ recipient’s immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.
文摘Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have been identified with children in recent years, suggesting genetic associations between certain populations carrying specific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of compounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for natural products capable of inhibiting targets which can lead to the development of rational treatment of various diseases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more opportunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacodynamic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mechanisms underlying these interactions and their modification by genetic variation is expected to result in the development of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to improved results for patients.
文摘Pharmacogenetics refers to the effect of single nucleotide polymorphisms(SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction(HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus(HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1(MDR1) 3435 C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.
文摘The availability of newer technologies for identification and characterization of the human genome has enabled our understanding of the genetic variations in a majority of human diseases.Human genomic sequence varies in less than 1%among the different population group and these differences known as gene polymorphisms are the primary reasons for differences in individuals’response to various drug therapy.Also understanding the genetic changes may enable implementation of targeted therapy,thus providing for effective treatment strategies and minimizing the adverse side effects.Pharmacogenomics is a recent development in the field of personalized medicine which focuses on the genetic determinants of drug response at the levels of entire human genome.It primarily deals with tailoring of drug therapy for every individual based on their genetic make-up and identifying new target in various diseases for drug therapy.While the application of pharmacogenomics in systemic illness is well researched,its role in oral diseases needs documentation.Identifying specific targets in periodontitis,head and neck cancer,infections and genetic disorders can be beneficial in discovery of new drugs.This editorial provides an overview of basics of pharmacoge-nomics,its current role in disease management and its potential role in various head and neck diseases.
文摘Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase(TKI), anaplastic lymphoma kinase(ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s).Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.
基金supported by the Major National R&D Projects (Grant No.2012ZX09506001-004)National Natural Science Foundation of China (Grant No.81273578)
文摘The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
基金supports from the NIH/NIGMS (Grant Nos. U01GM61393 and K08GM089941)NIH/NCI (Grant No. R21 CA139278)+2 种基金Avon Foundation Research Grant, University of Chicago Cancer Center Support Grant (Grant No. P30 CA14599)Breast Cancer SPORE Career Development Award (Grant No. CA125183)the National Center for Advancing Translational Sciences of the NIH (Grant No. UL1RR024999) of the United States
文摘Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.
文摘Gastrointestinal stromal tumors(GISTs)are rare entities,which,however,represent the most common mesenchymal tumor of the gastrointestinal tract.The discovery of gain of function mutations on KIT and PDGFRA receptor genes led to a deep revolution in the knowledge of this tumor.This paved the way to the introduction of imatinib and other tyrosine-kinase inhibitors(TKIs),which terrifically revolutionized the prognosis of GIST patients.Currently,it is well established that tumor mutational status is the main player in clinical outcome;however,with the research advances,it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes.For this reason,in the era of tailored/personalized medicine,each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.
文摘Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic efforts.Part of the discarded drugs might be beneficial only in a subgroup of the study patients,and some adverse events might be prevented by identifying those patients more vulnerable to toxicities.The implementation of pharmacogenomic biomarkers allows the categorization of patients,to predict efficacy and toxicity and to optimize the drug development process.Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration,and with the progress of Precision Medicine tailoring therapies on individuals’genomic landscape promises to become a new standard of cancer care.In the current article we review the role of pharmacogenomics in cancer drug development,underlying the advantages and challenges of their implementation.
基金supported by the National High Technology Research and Development Program of China(863 Program,2012AA 02A515)the National Basic Research Program of China(973 Program,2010CB529600)+6 种基金the National Key Technology R&D Program(2012BAI01B09)the National Natural Science Foundation of China(Grant Nos.30900799,30972823,81121001)the Shanghai Jiao Tong University Med-X Fund(YG2010MS61)Public Science and Technology Research Funds(201210056)the Shanghai Jiao Tong University Interdisciplinary Research Fund,the Major Program of Shanghai Committee of Science and Technology(11dz1950300)the Shanghai Municipal Commission of Science and Technology Program(09DJ1400601)the Shanghai Leading Academic Discipline Project(B205).
文摘Schizophrenia is a widespread mental disease with a prevalence of about 1%in the world population,and heritability of up to 80%.Drug therapy is an important approach to treating the disease.However,the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects.Many studies have indicated that about 30%of the patients exhibit little or no improvements associated with antipsychotics.The response of individual patients who are given the same dose of the same drug varies considerably.In addition,antipsychotic drugs are often accompanied by adverse drug reactions(ADRs),which can cause considerable financial loss in addition to the obvious societal harm.So,it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity.There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians.Individual differences in drug response is due to a combination of many complex factors including ADEM(absorption,distribution,metabolism,excretion)process,transporting,binding with receptor and intracellular signal transduction.Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response.In addition,epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients.In this review,we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes(CYP2D6,CYP1A2,CYP3A4,etc.),drug transporters(mainly ABCB1)and neurotransmitter receptors(dopamine receptors and serotonin receptors,etc.).We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.
文摘Dear Editor,I would like to offer some comments on the excellent article by Hai-Yan He and colleagues published in Genomics,Proteomics&Bioinformatics on 1st April 2017[1].The authors include,in the list of genetic polymorphisms that have an effect on vitamins,the low concentrations of cellular and plasma vitamin B12in GG carriers of SNP rs602662(772 G>A)in the gene encoding fucosyltransferase 2(FUT2).
文摘The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices.Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers,while supporting the rationale for the development of new drugs and treatment combinations.Clinical validation of promising biomarkers,however,is often an issue.More recently,a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field.This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC,in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach,comprising genomics and epigenetics.
基金supported by grants from the National Key Research and Development Program(Grant No.2016YFC0905000)National High-tech R&D Program of China(863 Program+2 种基金Grant No.2012AA02A518)National Natural Scientific Foundation of China(Grant Nos.81522048,81573511,81273595)the Innovation-driven Project of Central South University,China(Grant No.2016CX024)
文摘Dear Editor,We thank the author for making meaningful comments on our recent article[1].The SNP 772G>A(rs602662)in exon 2 of the gene encoding fucosyl transferase(FUT2)has been found to be related with the alterations in plasma vitamin B_(12) levels.
文摘Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excretion has been performed in addition to the analyses of blood concentrations of drugs. Such pharmacogenetic factors play an important role in predicting therapeutic effects and adverse events and in the proper use of drugs. With the recent launch of immune checkpoint inhibitors (ICIs) and the rapid development of antibody-drug conjugates (ADCs) currently underway, there is no doubt that antibody drugs, which are large molecule compounds, will become key drugs in anticancer drug treatment. However, the pharmacokinetic and pharmacodynamic analysis of antibody drugs is still not sufficient, and further elucidation of factors and mechanisms affecting their dynamics in the human body is necessary. Moreover, the pharmacogenomic factors of antibody drugs have not yet been fully studied. There are many factors that should be clarified, such as factors that regulate the host immune response in ICI therapy and the effects of ATP-binding cassette transporter and cytochrome P450 on the payload of ADCs. This review provides an outline of antibody drugs in cancer treatment and summarizes the pharmacogenomic factors of antibody drugs known to date.
文摘Objective:Second-generation antipsychotics are widely used in mental illness,but the treatment effects and side effects are affected by single nucleotide polymorphisms(SNPs)of related genes.Quetiapine and aripiprazole are two frequently used secondgeneration antipsychotic drugs.The aim of this study was to develop two different SNP detection methods for four SNP alleles associated with the pharmacokinetics of quetiapine and aripiprazole,based on high-resolution melting(HRM)and multicolor melting curve assay(MMCA)respectively.Methods:Whole genome DNA samples were obtained from 240 healthy people(107 females and 133 males)without genetic diseases.HRM methods were established using four kinds of specific primers and a saturated fluorescent dye.Each SNP allele with their own primers was detected in a single reaction.In the MMCA method,a multiplex polymerase chain reaction with 4 different-colored fluorescent probes was established to detect four SNP alleles in a single reaction.All experimental protocols were approved by the Ethics Committee of the Shanghai Children’s Medical Center,China(SCMC-201015)on November 22,2010.Results:Two detection methods for the pharmacogenomics of quetiapine and aripiprazole,based on HRM and MMCA respectively,were established in this study.The single-target HRM method can be completed in 96 minutes,whereas the quadruplex MMCA method takes 133 minutes.It was found that the results of HRM and MMCA for the four SNP alleles had 100%coincidence with Sanger sequencing in the 240 samples.Conclusion:This study developed two methods for the detection of four pharmacogenomic SNP alleles that correlated with quetiapine and aripiprazole.Both methods are rapid,cost-saving,highly accurate and potentially facilitate rational use of second-generation antipsychotics for clinical medication.
文摘During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
文摘Lung cancer is currently the leading cause of cancer death in Western nations.Non-small cell lung cancer(NSCLC)represents 80%of all lung cancers,and adenocarcinoma is the predominant histological type.Despite the intensive research carried out on this field and therapeutic advances,the overall prognosis of these patients remains unsatisfactory,with a 5-year overall survival rate of less than 15%.Nowadays,pharmacogenetics and pharmacogenomics represent the key to successful treatment.Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma:one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor(EGFR).The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR(erlotinib and gefitinib)and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs.This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR,K-Ras and EGFR targeted therapies in NSCLC tumor behavior.
