Clinical sequencing: from raw data to diagnosis with lifetime value.

Clin Genet. 2017 Dec 05;:

Authors: Caspar SM, Dubacher N, Kopps AM, Meienberg J, Henggeler C, Matyas G

Abstract
High-throughput sequencing (HTS) has revolutionized genetics by enabling the detection of sequence variants at hitherto unprecedented large scale. Despite these advances, however, there are still remaining challenges in the complete coverage of targeted regions (genes, exome or genome) as well as in HTS data analysis and interpretation. Moreover, it is easy to get overwhelmed by the plethora of available methods and tools for HTS. Here, we review the step-by-step process from the generation of sequence data to molecular diagnosis of Mendelian diseases. Highlighting advantages and limitations, this review addresses the current state of (i) HTS technologies, considering targeted, whole-exome, and whole-genome sequencing on short- and long-read platforms; (ii) read alignment, variant calling and interpretation; as well as (iii) regulatory issues related to genetic counseling, reimbursement, and data storage.

PMID: 29206278 [PubMed - as supplied by publisher]

Pharmacogenetic Analysis of the Model-Based Pharmacokinetics of Five Anti-HIV Drugs: How Does This Influence the Effect of Aging?

Clin Transl Sci. 2017 Dec 03;:

Authors: Chen J, Akhtari FS, Wagner MJ, Suzuki O, Wiltshire T, Motsinger-Reif AA, Dumond JB

Abstract
Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants. The clearance and cellular distribution of TFV were associated with P-gp, MRP2, and concentrative nucleoside transporters (CNTs), and FTC parameters were associated with organic cation transporters (OCTs) and MRP2 genetic variants. Notably, p16INK4a expression, a cellular aging marker, predicted EFV and FTC PK when genetic factors were adjusted. Both age and p16INK4a expression interacted with PGx on ATV and TFV disposition, implying potential dose adjustment based on aging may depend on genetic background.

PMID: 29205871 [PubMed - as supplied by publisher]

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates.

Pharmacogenomics J. 2017 Dec 05;:

Authors: Staquicini DI, D'Angelo S, Ferrara F, Karjalainen K, Sharma G, Smith TL, Tarleton CA, Jaalouk DE, Kuniyasu A, Baze WB, Chaffee BK, Hanley PW, Barnhart KF, Koivunen E, Marchiò S, Sidman RL, Cortes JE, Kantarjian HM, Arap W, Pasqualini R

Abstract
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.The Pharmacogenomics Journal advance online publication, 5 December 2017; doi:10.1038/tpj.2017.46.

PMID: 29205207 [PubMed - as supplied by publisher]

Applications of pharmacogenomics in regulatory science: a product life cycle review.

Pharmacogenomics J. 2017 Dec 05;:

Authors: Tan-Koi WC, Leow PC, Teo YY

Abstract
With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents. Approximately one-third of Food and Drug Administration (FDA)-approved drugs with PGx information in drug labels and half of the European labels posted on PharmGKB website contain recommendations on genetic testing. The drugs affected 19 and 15 World Health Organization Anatomical Therapeutic Chemical drug classes (fourth level) in the United States and Europe, respectively, with protein kinase inhibitors (13 drugs in the United States and 16 drugs in Europe) being most prevalent. Topics of emerging interest were novel technologies, adaptive design in clinical trial and sample collection.The Pharmacogenomics Journal advance online publication, 5 December 2017; doi:10.1038/tpj.2017.47.

PMID: 29205206 [PubMed - as supplied by publisher]

Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance.

Pharmacogenomics J. 2017 Dec 05;:

Authors: Jack J, Small GW, Brown CC, Havener TM, McLeod HL, Motsinger-Reif AA, Richards KL

Abstract
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.The Pharmacogenomics Journal advance online publication, 5 December 2017; doi:10.1038/tpj.2017.41.

PMID: 29205205 [PubMed - as supplied by publisher]

MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

Pharmacogenomics J. 2017 Dec 05;:

Authors: Visani G, Loscocco F, Ruzzo A, Galimberti S, Graziano F, Voso MT, Giacomini E, Finelli C, Ciabatti E, Fabiani E, Barulli S, Volpe A, Magro D, Piccaluga P, Fuligni F, Vignetti M, Fazi P, Piciocchi A, Gabucci E, Rocchi M, Magnani M, Isidori A

Abstract
We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.The Pharmacogenomics Journal advance online publication, 5 December 2017; doi:10.1038/tpj.2017.48.

PMID: 29205204 [PubMed - as supplied by publisher]

HLA-DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.

J Invest Dermatol. 2017 Dec 01;:

Authors: Ujiie H, Muramatsu K, Mushiroda T, Ozeki T, Miyoshi H, Iwata H, Nakamura A, Nomoto H, Cho KY, Sato N, Nishimura M, Ito T, Izumi K, Nishie W, Shimizu H

PMID: 29203362 [PubMed - as supplied by publisher]

Precision medicine for HIV: where are we?

Pharmacogenomics. 2017 Dec 05;:

Authors: Cusato J, Allegra S, Nicolò A, Calcagno A, D'Avolio A

Abstract
To date, antiretroviral therapy is highly effective in HIV-affected patients, but the individualization of such a life-long therapy may be advised. This review briefly summarizes the main factors involved in the potential personalization of antiretroviral treatment. Relevant articles in English were identified by PubMed and recent congresses' abstracts. Foremost influences concerning pharmacodynamics, therapeutic drug monitoring, pharmacogenetics, comorbidities, immune recovery and viral characteristics affecting the healthcare of HIV-positive patients are listed here. Furthermore, pharmacoeconomic aspects are mentioned. Applying pharmacokinetic and pharmacogenetic knowledge may be informative and guide the better choice of treatment in order to achieve long-term efficacy and avoid adverse events. Randomized investigations of the clinical relevance of tailored antiretroviral regimens are needed in order to obtain a better management of HIV/AIDS-affected patients.

PMID: 29202676 [PubMed - as supplied by publisher]

eIF3a: A new anticancer drug target in the eIF family.

Cancer Lett. 2018 Jan 01;412:81-87

Authors: Yin JY, Zhang JT, Zhang W, Zhou HH, Liu ZQ

Abstract
eIF3a is the largest subunit of eIF3, which is a key player in all steps of translation initiation. During the past years, eIF3a is recognized as a proto-oncogene, which is an important discovery in this field. It is widely reported to be correlated with cancer occurrence, metastasis, prognosis, and therapeutic response. Recently, the mechanisms of eIF3a action in the carcinogenesis are unveiled gradually. A number of cellular, physiological, and pathological processes involving eIF3a are identified. Most importantly, it is emerging as a new potential drug target in the eIF family, and some small molecule inhibitors are being developed. Thus, we perform a critical review of recent advances in understanding eIF3a physiological and pathological functions, with specific focus on its role in cancer and anticancer drug targets.

PMID: 29031564 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/05

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LncRNAs and CircRNAs from the same gene: Masterpieces of RNA splicing.

Cancer Lett. 2017 Nov 28;:

Authors: Huang MS, Zhu T, Li L, Xie P, Li X, Zhou HH, Liu ZQ

Abstract
Accumulating evidence has shown that lncRNAs and circRNAs are novel regulators of gene expression. The discovery of numerous lncRNAs and circRNAs, and investigation into their structures and functions will contribute to our understanding of the pathogenesis of diseases as well as better prevention, diagnosis, and treatment of diseases. There is a close relationship between circRNAs and lncRNAs regarding to their origins and functions. Recent studies have shown that non-coding linear and circular transcripts can be transcribed from the same gene and are potential super-enhancers modulating gene transcription. In this review, we summarize the categories, characteristics, biological functions and databases of both lncRNAs and circRNAs, focusing on their transcriptions derived from the same gene, which might give us a deeper understanding of and enable us to better recognize and distinguish their physiological roles.

PMID: 29196127 [PubMed - as supplied by publisher]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

37 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/11/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

37 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/11/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/11/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/11/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Human leukocyte antigens: key regulators of T-cell mediated drug hypersensitivity.

HLA. 2017 Nov 24;:

Authors: Redwood AJ, Pavlos RK, White KD, Phillips EJ

Abstract
Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose dependant. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast off-target ADRs, including immune mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B cell-mediated (Gell-Coombs type I-III reactions) and T cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced liver disease (DILI). T-cell mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.

PMID: 29171940 [PubMed - as supplied by publisher]

[Genetic and clinical predictors of treatment efficacy in depressive disorders].

Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(10):55-64

Authors: Ivanets NN, Kinkulkina MA, Tikhonova YG, Izumina TA, Avdeeva TI, Morozov DI

Abstract
AIM: To study clinical and genetic characteristics that impact on the efficacy of pharmacotherapy of depressive disorders.
MATERIAL AND METHODS: The study included 188 patients with unipolar depressive disorders of different genesis (psychogenic, endogenous and organic). A clinical-psychopathological method and depression psychometric scales were used. Serotonin transporter 5-HTTLPR and STin2 and dopamine transporter 3',-VNTR polymorphisms were determined.
RESULTS AND CONCLUSION: The S-allele of the 5-HTTLPR polymorphism is associated with the low efficacy of treatment with selective serotonin reuptake inhibitors. Tricyclic antidepressants are more effective in treatment of psychogenic depression. The authors determined clinical factors that can predict response to treatment of psychogenic and endogenous depression. No predictors were found for organic depression.

PMID: 29171490 [PubMed - in process]