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RePhine: An Integrative Method for Identification of Drug Response-related Transcriptional Regulators

Genomics, Proteomics & Bioinformatics 2021年第4期19卷 534-548页

作者： Xujun Wang Zhengtao Zhang Wenyi Qin Shiyi Liu Cong Liu Georgi ZGenchev Lijian Hui Hongyu Zhao Hui Lu SJTU-Yale Joint Center for Biostatistics and Data Science Department of Bioinformatics and BiostatisticsSchool of Life Science and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyShanghai 200031China Department of Bioengineering University of Illinois at ChicagoIL 60607USA Department of Genetics School of MedicineYale UniversityNew HavenCT 06511USA Department of Medical Informatics Columbia UniversityNew YorkNY 10032USA Bulgarian Institute for Genomics and Precision Medicine Sofia 1000Bulgaria Department of Biostatistics Yale School of Public Health.New HavenCT 06511USA Institute of Science and Technology for Brain-Inspired Intelligence Fudan UniversityShanghai 200433China Center for Biomedical informatics Shanghai Children’s HospitalShanghai 200040China

Transcriptional regulators(TRs)participate in essential processes in cancer pathogenesis and are critical therapeutic targets.Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low m RNA abundance of TRs,protein modifications,and other confounders(CFs).In this study,we developed a regression-based pharmacogenomic and Ch IP-seq data integration method(Re Phine)to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and Ch IP-seq data.Re Phine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery.In simulation data with added noises or CFs and in pharmacogenomic data,Re Phine demonstrated an improved performance in comparison with three commonly used methods(including Pearson correlation analysis,logistic regression model,and gene set enrichment analysis).Utilizing Re Phine and Cancer Cell Line Encyclopedia data,we observed that Re Phinederived TR signatures could effectively cluster drugs with different mechanisms of action.Re Phine predicted that loss-offunction of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720.Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment.Our results support that Re Phine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications.The source code for Re Phine is freely available at https://***/coexps/Re Phine.

关键词： pharmacogenomics ChIP-seq Transcriptional regulator BRAF inhibitor resistance Drug resistance

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Association of farnesyl diphosphate synthase polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis

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Chinese Medical Journal 2014年第4期127卷 662-668页

作者： Liu Y Li M Zhou PR Xing XP Xia WB Xu L Liu H J Zhang ZL LiaoEY Chen DC Liu J Tao TZ Wu W Department of Endocrinology Key Laboratory of EndocrinologyMinistry of HealthPeking Union Medical College Hospital Peking Union Medical College Chinese Academy of Medical Sciences Beijing 100730 China Department of Endocrinology People&#39 s Hospital of Liaocheng Liaocheng Shandong 252002 China Metabolic Bone Disease and Genetics Research Unit Department of Osteoporosis and Bone Diseases Shanghai Sixth People&#39 s Hospital Affiliated with Shanghai Jiao Tong University Shanghai 200233 China Osteoporosis and Bone Diseases Shanghai Sixth People's HospitalAffiliated with Shanghai Jiao Tong University Shanghai 200233China Institute of Endocrinology and Metabolism Second Xiangya Hospitalof Central South University Changsha Hunan 410011 China Department of Endocrinology Osteoporosis Education Center WestChina Hospital Sichuan University Chengdu Sichuan 610041China Department of Orthopedics Xijing Hospital Fourth Liberation ArmyUniversity Xi'an Shannxi 710032 China Department of Orthopedics Harbin Medical University AffiliatedSecond Hospital Harbin Heilongjiang 150081 China Department of Endocrinology Guangdong General HospitalGuangzhou Guangdong 510080 China

Background Genetic factors are important in the pathogenesis of osteoporosis,but less is known about the genetic determinants of osteoporosis treatment.We aimed to explore the association between the gene polymorphisms of key enzyme farnesyl diphosphate synthase （FDPS） in mevalonate signaling pathway of osteoclast and response to alendronate therapy in osteoporotic postmenopausal women in China.Methods The study group comprised 639 postmenopausal women aged （62.2＆#177;7.0） years with osteoporosis or osteopenia who had been randomly assigned to low dose group （70 mg/2w） or standard dose group （70 mg/w） of alendronate in this 1-year study.We identified allelic variant of the FDPS gene using the polymerase chain reaction and restriction enzyme Faul.Before and after treatment,serum levels of calcium,phosphate,alkaline phosphatase （ALP）,cross linked C-telopeptide of type Ⅰ collagen （β-CTX） were detected.Bone mineral density （BMD） at lumbar spine and proximal femur was measured.The association was analyzed between the polymorphisms of FDPS gene and the changes of BMD,bone turnover biomarkers after the treatment.Results The FDPS rs2297480 polymorphisms were associated with baseline BMD at femoral neck,and patients with CC genotype had significantly higher baseline femoral neck BMD （（733.6＆#177;84.1） mg/cm2） than those with AC genotypes （（703.0＆#177;86.9） mg/cm2） and AA genotypes （（649.8＆#177;62.4） mg/cm2）（P 〈0.01）.No significant difference in BMD at lumbar spine was observed among different genotypes of FDPS.The percentage change of serum ALP level was significantly lower in patients with CC genotype （-22.9%） than that in those with AC genotype （-24.1%） and AA genotype （-29.8%） of FDPS after 12 months of alendronate treatment （P 〈0.05）.Neither percentage change of BMD nor β-CTX level after alendronate treatment had association with FDPS genotype.Conclusions FDPS gene was probably a candidate gene to predict femoral neck BMD at baseline.FDPS gene alleles could predict change percentage of ALP after treatment of alendron

关键词： farnesyl diphosphate synthase polymorphism alendronate osteoporosis pharmacogenomics

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pharmacogenomics-based tailored strategy for Helicobacter pylori infection

Pharmacogenomics-based tailored strategy for Helicobacter py...

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第三届中日双边药理学和临床药理学学术会议

作者： FURUTA Takahisa SUGIMOTO Mitsushige SHIRAI Naohito KODAIRA Chise NISHINO Masafumi YAMADE Mihoko IKUMA Mutsuhiro WATANABE Hiroshi UMEMURA Kazuo OHASHI Kyoichi ISHIZAKI Takashi HISHIDA Akira Center for Clinical Research First Department of Medicine Department of Laboratory Medicine First Department of Medicine First Department of Medicine First Department of Medicine First Department of Medicine Department of Clinical Pharmacology and Therapeutics Department of Pharmacology Hamamatsu University School of MedicineHamamatsuJapan Department of Clinical Pharmacology and Therapeutics Clinical Pharmacology CenterFaculty of MedicineOita UniversityOitaJapan Department of Clinical Pharmacology and Therapeutics First Department of Medicine

＜正＞AIM Helicobacter pylori eradication rates by triple therapy with a proton pump inhibitor,amoxicillin and clarithromycin at standard doses depend on bacterial susceptibility to clarithromycin and patient CYP2C19 gen- otypes.We examined the usefulness of a personalized therapy for H.pylori infection based on these factors as determined by genetic testing.METHODS First,opti- mal lansoprazole dosing schedules that would achieve suffi- cient acid inhibition to allow H.pylori eradication therapy in each of different CYP2C19 genotype groups were deter- mined by a 24-h intragastric pH monitoring.Next,300 H. pylori-positive patients were randomly assigned to the standard regimen group （lansoprazole 30 mg bid,clar- ithromycin 400 mg bid,and amoxicillin 750 mg bid for one week）or the tailored regimen group based on CYP2C19 status and bacterial susceptibility to clarithromy- cin assessed by genetic testing.Patients with failure of e- radication underwent the second-line regimen.RESULTS In the first-line therapy,the intention-to-treat eradication rate in the tailored regimen group was 96.0%,significant- ly higher than that in the standard regimen group （70.0%）.CONCLUSION The phannacogenomics- based tailored treatment for H.pylori infection allowed a higher eradication rate by the initial treatment.

关键词： CYP2C19 Helicobacter pylori lansoprazole clarithromycin pharmacogenomics

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Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia

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Frontiers of Medicine 2015年第1期9卷 1-9页

作者： Ching-Hon Pui Departments of Oncology and Pathology St. Jude Children's Research Hospital Memphis TN 38105 USA the University of Tennessee Health Science Center Memphis 7N 38105 USA

With the cure rate of childhood acute lymphoblastic leukemia （ALL） approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future.

关键词： acute lymphoblastic leukemia genomics pharmacogenetics pharmacogenomics

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Large-scale pharmacogenomic studies and drug response prediction for personalized cancer medicine

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Journal of Genetics and Genomics 2021年第7期48卷 540-551页

作者： Fangyoumin Feng Bihan Shen Xiaoqin Mou Yixue Lia Hong Li CAS Key Laboratory of Computational Biology Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China Hangzhou Institute for Advanced Study University of Chinese Academy of SciencesHangzhou 330106China

The response rate of most anti-cancer drugs is limited because of the high heterogeneity of cancer and the complex mechanism of drug action.Personalized treatment that stratifies patients into subgroups using molecular biomarkers is promising to improve clinical benefit.With the accumulation of preclinical models and advances in computational approaches of drug response prediction,pharmacogenomics has made great success over the last 20 years and is increasingly used in the clinical practice of personalized cancer medicine.In this article,we first summarize FDA-approved pharmacogenomic biomarkers and large-scale pharmacogenomic studies of preclinical cancer models such as patient-derived cell lines,organoids,and xenografts.Furthermore,we comprehensively review the recent developments of computational methods in drug response prediction,covering network,machine learning,and deep learning technologies and strategies to evaluate immunotherapy response.In the end,we discuss challenges and propose possible solutions for further improvement.

关键词： pharmacogenomics Personalized medicine Drug response Biomarkers Deep learning

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Personalized medicine in functional gastrointestinal disorders:Understanding pathogenesis to increase diagnostic and treatment efficacy

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World Journal of Gastroenterology 2019年第10期25卷 1185-1196页

作者： Xiao Jing Wang Michael Camilleri Division of Gastroenterology and Hepatology Clinical Enteric Neuroscience Translational and Epidemiological ResearchMayo Clinic

There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of gen

关键词： Gastrointestinal symptoms Gastric emptying Gastric accommodation Diarrhea Constipation Irritable bowel syndrome Bile acid diarrhea Phenotypes pharmacogenomics Prokinetics Neuromodulators

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Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

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Cancer Drug Resistance 2019年第2期2卷 242-255页

作者： Rachid Abaji Maja Krajinovic Charles Bruneau Cancer Centre Research CenterCHU Sainte-JustineUniversity of MontrealMontrealQC H3T 1C5Canada Department of Pharmacology&Physiology University of MontrealMontrealQC H3C 3J7Canada Department of Pediatrics University of MontrealMontrealQC H3T 1C5Canada.

Asparaginase is a key component in leukemias and lymphomas treatment protocols and is suggested as a treatment for other malignancies in which an amino acid depletion strategy is indicated.Asparaginase intolerance is subject to inter-individual variability and can manifest as hypersensitivity reactions,pancreatitis,thrombosis,as well as metabolic abnormalities,and may affect treatment outcome.Pharmacogenetics aims at enhancing treatment efficacy and safety by better understanding the genetic basis of variability and its effect on the pharmacological responses.Many groups tried to tackle the pharmacogenetics of asparaginase but the potential implementation of such findings remains debatable.In this review,we highlight the most important findings reported in studies of the pharmacogenetics of asparaginase related complications and treatment outcome in acute lymphoblastic leukemia.

关键词： Asparaginase pharmacogenomics hypersensitivity reactions pancreatitis relapse acute lymphoblastic leukemia adverse drug reactions

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Pharmacogenetic and pharmacogenomic discovery strategies

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Cancer Drug Resistance 2019年第2期2卷 225-241页

作者： Concetta Crisafulli Petronilla Daniela Romeo Marco Calabrò Ludovica Martina Epasto Saverio Alberti Department of Biomedical Sciences-BIOMORF University of Messinavia Consolare Valeria98125 MessinaItaly Unit of Medical Genetics University of Messinavia Consolare Valeria98125 MessinaItaly.

Genetic/genomic profiling at a single-patient level is expected to provide critical information for determining inter-individual drug toxicity and potential efficacy in cancer therapy.A better definition of cancer subtypes at a molecular level,may correspondingly complement such pharmacogenetic and pharmacogenomic approaches,for more effective personalized treatments.Current pharmacogenetic/pharmacogenomic strategies are largely based on the identification of known polymorphisms,thus limiting the discovery of novel or rarer genetic variants.Recent improvements in cost and throughput of next generation sequencing(NGS)are now making whole-genome profiling a plausible alternative for clinical procedures.Beyond classical pharmacogenetic/pharmacogenomic traits for drug metabolism,NGS screening programs of cancer genomes may lead to the identification of novel cancer-driving mutations.These may not only constitute novel therapeutic targets,but also effector determinants for metabolic pathways linked to drug metabolism.An additional advantage is that cancer NGS profiling is now leading to discovering targetable mutations,e.g.,in glioblastomas and pancreatic cancers,which were originally discovered in other tumor types,thus allowing for effective repurposing of active drugs already on the market.

关键词： Pharmacogenetics pharmacogenomics cancer next-generation sequencing genomic variants

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Pharmacogenetics of anticancer monoclonal antibodies

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Cancer Drug Resistance 2019年第1期2卷 69-81页

作者： Dmitrii Shek Scott ARead Golo Ahlenstiel Irina Piatkov Blacktown Clinical School Western Sydney UniversityBlacktownNSW 2148Australia Storr Liver Centre The Westmead Institute for Medical ResearchThe University of SydneyWestmeadNSW 2145Australia Blacktown Hospital BlacktownNSW 2148Australia

Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background.Monoclonal antibodies(mAbs)are a rapidly evolving field in cancer therapy,however a number of newly developed and highly effective mAbs(e.g.,anti-CTLA-4 and anti-PD-1)possess pharmacogenomic profiles that remain largely undefined.Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment,a broad number of other mAbs have been successfully developed and implemented into oncological practice.Nowadays,mAbs are considered as one of the most promising new approaches for cancer treatment.The efficacy of mAb treatment can however be significantly affected by genetic background,where genes responsible for antibody presentation and metabolism,for example,can seriously affect patient outcome.This review will focus on current anticancer mAb treatments,patient genetics that shape their efficacy,and the molecular pathways that bridge the two.

关键词： Pharmacogenetics pharmacogenomics immune-checkpoint proteins monoclonal antibodies cancer immunotherapy personalized medicine

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Research and applications of biochip technologies

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Chinese Science Bulletin 2000年第2期45卷 101-108页

作者： XU Junquan HE Xuezhong ZHOU Yuxiang LIU Litian CHENG Jing Biochip Research and Development Center Tsinghua UniversityBeijing 100084China State Key Laboratory of Biomembrane and Membrane Biotechnology SchooI of Biological Sciences and Engineering Tsinghua UniversityBeijing 100084China 不详

Biochip as a new research field has enjoyed its rapid development in the past 10 years. Using microfabrication technology, thousands or hundred thousands of biological molecules can be assembled on a centimeter square microchip. Those chip-based devices can be used to analyze mutations, antigens, cells, etc. Compared with the traditional analytical instruments, chip-based micro total analytical systems have many advantages, such as reduced size, lower consumption of both reagents and energy contamination-free, etc. Biochip technology is believed to revolutionize the future research in life sciences, disease diagnosis, drug discovery forensic sciences and outer space exploitation in the coming

关键词： biocbip disease diagnosis pharmacogenomics lahoratory-on-a-chip.

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