IL17RA gene variants and anti-TNF response among psoriasis patients.

Pharmacogenomics J. 2016 Sep 27;

Authors: Batalla A, Coto E, Gómez J, Eirís N, González-Fernández D, Gómez-De Castro C, Daudén E, Llamas-Velasco M, Prieto-Perez R, Abad-Santos F, Carretero G, García FS, Godoy YB, Cardo LF, Alonso B, Iglesias S, Coto-Segura P

Abstract
Polymorphisms at genes encoding proteins involved in the pathogenesis of psoriasis (Psor) or in the mechanism of action of biological drugs could influence the treatment response. Because the interleukin (IL)-17 family has a central role in the pathogenesis of Psor, we hypothesized that IL17RA variants could influence the response to anti-TNF drugs among Psor patients. To address this issue we performed a cross-sectional study of Psor patients who received the biological treatments for the first time, with a follow-up of at least 6 months. All of the patients were Caucasian, older than 18 years old, with chronic plaque Psor, and had completed at least 24 weeks of anti-TNF therapy (adalimumab, etanercept or infliximab). The treatment response to anti-TNF agents was evaluated according to the achievement of PASI50 and PASI75 at weeks 12 and 24. Those who achieved PASI75 at week 24 were considered good responders. All patients were genotyped for the selected single-nucleotide polymorphisms (SNPs) at IL17RA gene. A total of 238 patients were included (57% male, mean age 46 years). One hundred and five patients received adalimumab, 91 patients etanercept and 42 infliximab. The rs4819554 promoter SNP allele A was significantly more common among responders at weeks 12 (P=0.01) and 24 (P=0.04). We found a higher frequency of AA versus AG+GG among responders, but the difference was only significant at week 12 (P=0.03, odd ratio=1.86, 95% confidence of interval=1.05-3.27). Thus, in the study population, the SNP rs4819554 in the promoter region of IL17RA significantly influences the response to anti-TNF drugs at week 12.The Pharmacogenomics Journal advance online publication, 27 September 2016; doi:10.1038/tpj.2016.70.

PMID: 27670766 [PubMed - as supplied by publisher]

New polymorphisms associated with response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis.

Pharmacogenomics J. 2016 Sep 27;

Authors: Prieto-Pérez R, Solano-López G, Cabaleiro T, Román M, Ochoa D, Talegón M, Baniandrés O, López-Estebaranz JL, de la Cueva P, Daudén E, Abad-Santos F

Abstract
Anti-tumor necrosis factor (anti-TNF) drugs are effective against psoriasis, although 20-30% of patients are nonresponders. Few pharmacogenomic studies have been performed to predict the response to anti-TNF drugs in psoriasis. We studied 173 polymorphisms to establish an association with the response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis (N=144). We evaluated the response using PASI75 at 3, 6 and 12 months. The results of the multivariate analysis showed an association between polymorphisms in PGLYR4, ZNF816A, CTNNA2, IL12B, MAP3K1 and HLA-C genes and the response at 3 months. Besides, the results for polymorphisms in IL12B and MAP3K1 were replicated at 6 months. We also obtained significant results for IL12B polymorphism at 1 year. Moreover, polymorphisms in FCGR2A, HTR2A and CDKAL1 were significant at 6 months. This is the first study to show an association with these polymorphisms. However, these biomarkers should be validated in large-scale studies before implementation in clinical practice.The Pharmacogenomics Journal advance online publication, 27 September 2016; doi:10.1038/tpj.2016.64.

PMID: 27670765 [PubMed - as supplied by publisher]

OSAnalyzer: A Bioinformatics Tool for the Analysis of Gene Polymorphisms Enriched with Clinical Outcomes.

Microarrays (Basel). 2016;5(4)

Authors: Agapito G, Botta C, Guzzi PH, Arbitrio M, Di Martino MT, Tassone P, Tagliaferri P, Cannataro M

Abstract
BACKGROUND: The identification of biomarkers for the estimation of cancer patients' survival is a crucial problem in modern oncology. Recently, the Affymetrix DMET (Drug Metabolizing Enzymes and Transporters) microarray platform has offered the possibility to determine the ADME (absorption, distribution, metabolism, and excretion) gene variants of a patient and to correlate them with drug-dependent adverse events. Therefore, the analysis of survival distribution of patients starting from their profile obtained using DMET data may reveal important information to clinicians about possible correlations among drug response, survival rate, and gene variants.
METHODS: In order to provide support to this analysis we developed OSAnalyzer, a software tool able to compute the overall survival (OS) and progression-free survival (PFS) of cancer patients and evaluate their association with ADME gene variants.
RESULTS: The tool is able to perform an automatic analysis of DMET data enriched with survival events. Moreover, results are ranked according to statistical significance obtained by comparing the area under the curves that is computed by using the log-rank test, allowing a quick and easy analysis and visualization of high-throughput data.
CONCLUSIONS: Finally, we present a case study to highlight the usefulness of OSAnalyzer when analyzing a large cohort of patients.

PMID: 27669316 [PubMed - as supplied by publisher]

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine.

Prog Retin Eye Res. 2016 Sep 22;

Authors: Elizabeth Fini M, Schwartz SG, Gao X, Jeong S, Patel N, Itakura T, Price MO, Price FW, Varma R, Daniel Stamer W

Abstract
Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative(®), announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

PMID: 27666015 [PubMed - as supplied by publisher]

Cardiovascular Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics for the Clinical Practitioner.

J Cardiovasc Pharmacol Ther. 2016 Jan;21(1):20-6

Authors: Sleder AT, Kalus J, Lanfear DE

Abstract
Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner.

PMID: 26054891 [PubMed - indexed for MEDLINE]

Pediatric chemotherapy induced peripheral neuropathy: A systematic review of current knowledge.

Cancer Treat Rev. 2016 Sep 10;50:118-128

Authors: Kandula T, Park SB, Cohn RJ, Krishnan AV, Farrar MA

Abstract
BACKGROUND: The dramatic increase in the number of childhood cancer survivors over the last 60years has made monitoring and minimising long term side effects of cancer treatment increasingly important. Chemotherapy induced peripheral neuropathy (CIPN) has been described with many commonly used chemotherapy agents. This article provides a critical overview of pediatric CIPN, its incidence, clinical manifestations, late effects, and recent advances in understanding of risk factors and pharmacogenomics as well as evaluating current assessment strategies and treatment approaches.
METHODS: Neurotoxicity data was systematically collated from Medline, Embase and Pubmed and analysed for quality, relevance and originality in three stages prior to inclusion. Quality scoring was done using the QUALSYST assessment tool.
RESULTS: A total of 61 studies met inclusion criteria. Peripheral neuropathy is common and may be long lasting with characteristics specific to each chemotherapy agent. There is significant variability in reported incidence and natural history, related to challenges in clinical assessment and diagnosis. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication and patient factors such as age and inherited susceptibilities. Recent identification of individual genetic variations has advanced understanding of pathomechanisms and may direct future treatment approaches.
CONCLUSION: While these studies guide suggestions for current clinical practice, further systematic research with development of strategies for amelioration and prevention of CIPN is necessary. Standardised assessment protocols and objective outcomes measures of CIPN applicable to patients of different ages are critical to enabling the development of novel treatments and facilitation of future clinical trials and treatment individualisation.

PMID: 27664395 [PubMed - as supplied by publisher]

Psychiatric Pharmacogenomics: How Close Are We?

Biol Psychiatry. 2016 Oct 15;80(8):e63-5

Authors: Hirschtritt ME, Besterman AD, Ross DA

PMID: 27663067 [PubMed - in process]

Pharmacogenomics in pain treatment.

Drug Metab Pers Ther. 2016 Sep 1;31(3):131-142

Authors: Peiró AM, Planelles B, Juhasz G, Bagdy G, Libert F, Eschalier A, Busserolles J, Sperlagh B, Llerena A

Abstract
The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics. However, uptake of this information has been slow due in large part to the lack of robust evidences demonstrating clinical utility. Furthermore, novel therapies, including targeting of epigenetic changes and gene therapy-based approaches are further broadening future options for the treatment of chronic pain. The aim of this article is to review the evidences behind pharmacogenetics (PGx) to individualize therapy (boosting the efficacy and minimizing potential toxicity) and genes implicated in pain medicine, in two parts: (i) genetic variability with pain sensitivity and analgesic response; and (ii) pharmacological concepts applied on PGx.

PMID: 27662648 [PubMed - as supplied by publisher]

From Metabonomics to Pharmacometabonomics: The Role of Metabolic Profiling in Personalized Medicine.

Front Pharmacol. 2016;7:297

Authors: Everett JR

Abstract
Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalized medicine, that is the selection of medicines for subgroups of patients so as to maximize drug efficacy and minimize toxicity, is a key goal of twenty-first century healthcare. Currently, most personalized medicine paradigms rely on clinical judgment based on the patient's history, and on the analysis of the patients' genome to predict drug effects i.e., pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as "the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures." The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments.

PMID: 27660611 [PubMed]

Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors.

Trends Pharmacol Sci. 2016 Sep 19;

Authors: Neul C, Schaeffeler E, Sparreboom A, Laufer S, Schwab M, Nies AT

Abstract
Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.

PMID: 27659854 [PubMed - as supplied by publisher]

Response to "personalized medicine, genomics, and pharmacogenomics".

Clin J Oncol Nurs. 2014 Dec;18(6):618

Authors: Mayer DK

PMID: 25427694 [PubMed - indexed for MEDLINE]

Multidisciplinary model to implement pharmacogenomics at the point of care.

Genet Med. 2016 Sep 22;

Authors: Caraballo PJ, Hodge LS, Bielinski SJ, Stewart AK, Farrugia G, Schultz CG, Rohrer-Vitek CR, Olson JE, St Sauver JL, Roger VL, Parkulo MA, Kullo IJ, Nicholson WT, Elliott MA, Black JL, Weinshilboum RM

Abstract
PURPOSE: Despite potential clinical benefits, implementation of pharmacogenomics (PGx) faces many technical and clinical challenges. These challenges can be overcome with a comprehensive and systematic implementation model.
METHODS: The development and implementation of PGx were organized into eight interdependent components addressing resources, governance, clinical practice, education, testing, knowledge translation, clinical decision support (CDS), and maintenance. Several aspects of implementation were assessed, including adherence to the model, production of PGx-CDS interventions, and access to educational resources.
RESULTS: Between August 2012 and June 2015, 21 specific drug-gene interactions were reviewed and 18 of them were implemented in the electronic medical record as PGx-CDS interventions. There was complete adherence to the model with variable production time (98-392 days) and delay time (0-148 days). The implementation impacted approximately 1,247 unique providers and 3,788 unique patients. A total of 11 educational resources complementary to the drug-gene interactions and 5 modules specific for pharmacists were developed and implemented.
CONCLUSION: A comprehensive operational model can support PGx implementation in routine prescribing. Institutions can use this model as a roadmap to support similar efforts. However, we also identified challenges that will require major multidisciplinary and multi-institutional efforts to make PGx a universal reality.Genet Med advance online publication 22 September 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.120.

PMID: 27657685 [PubMed - as supplied by publisher]

Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients.

J Antimicrob Chemother. 2016 Sep 21;

Authors: Sandkovsky U, Podany AT, Fletcher CV, Owen A, Felton-Coleman A, Winchester LC, Robertson K, Swindells S

Abstract
BACKGROUND: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OH-efavirenz) have not been robustly evaluated in older HIV-infected persons.
OBJECTIVES: We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals >50 years of age.
METHODS: A cross-sectional study of HIV-infected adults on an efavirenz-containing regimen. The 12 and 18 h post-dose plasma efavirenz and 8-OH-efavirenz were quantified. CYP2B6 polymorphisms were investigated. Participants underwent neuropsychological tests; surveys were used for depression, sleep quality and anxiety. We investigated potential correlations of efavirenz and 8-OH-efavirenz plasma concentrations with NP performance, sleep, depression, anxiety and CYP2B6 polymorphisms.
RESULTS: Thirty participants (24 men and 6 women) with mean age 57 years (range 50-68). Plasma efavirenz concentrations did not correlate with NP performance; however, higher plasma 8-OH-efavirenz correlated with better learning (P = 0.002), language (P = 0.002) and total NP z-scores (P = 0.003). No correlation was seen for efavirenz or 8-OH-efavirenz with sleep, anxiety or depression. Median 12 and 18 h efavirenz plasma concentrations were 1967 ng/mL (IQR 1476-2394) and 1676 ng/mL (IQR 1120-2062), respectively. Median 12 and 18 h 8-OH-efavirenz plasma concentrations were 378 ng/mL (IQR 223-589) and 384 ng/mL (IQR 216-621), respectively. CYP2B6 G516T was associated with significantly higher plasma efavirenz at 12 and 18 h (P = 0.02) but not worse NP function.
CONCLUSIONS: Better neurocognitive functioning was associated with higher 8-OH-efavirenz but not efavirenz plasma concentrations. No correlation was observed with sleep or depression. These findings point to a need for greater understanding of the metabolic profile of efavirenz and 8-OH-efavirenz in plasma and the CNS and relationships with antiviral effect and neurotoxicity.

PMID: 27655857 [PubMed - as supplied by publisher]

Getting Pharmacogenomics Into the Clinic.

JAMA. 2016 Sep 21;

Authors: Abbasi J

PMID: 27653422 [PubMed - as supplied by publisher]

The role of pharmacogenetics and advances in gene therapy in the treatment of diabetic retinopathy.

Pharmacogenomics. 2016 Feb;17(3):309-20

Authors: Agarwal A, Ingham SA, Harkins KA, Do DV, Nguyen QD

Abstract
Diabetic retinopathy (DR) and its complications such as diabetic macular edema continue to remain a major cause for legal blindness in the developed world. While the introduction of anti-tVEGF agents has significantly improved visual outcomes of patients with DR, unpredictable response, largely due to genetic polymorphisms, appears to be a challenge with this therapy. With advances in identification of various genetic biomarkers, novel therapeutic strategies consisting of gene transfer are being developed and tested for patients with DR. Application of pharmacogenetic principles appears to be a promising futuristic strategy to attenuate diabetes-mediated retinal vasculopathy. In this comprehensive review, data from recent studies in the field of pharmacogenomics for the treatment of DR have been provided.

PMID: 26807609 [PubMed - indexed for MEDLINE]

Predictive or not predictive: understanding the mixed messages from the patient's DNA sequence.

J Clin Nurs. 2015 Dec;24(23-24):3730-5

Authors: Janssens AC, Patch C, Skirton H

Abstract
AIMS AND OBJECTIVES: The aim of this discussion paper is to enable nurses to understand how deoxyribonucleic acid analysis can be predictive for some diseases and not predictive for others. This will facilitate nurses to interpret genomic test results and explain them to patients.
BACKGROUND: Advances in technology mean that genetic testing is now commonly performed by sequencing the majority of an individual's genome or exome. This results in a huge amount of data, some of which can be used to predict or diagnose disease.
DESIGN: This is a discussion paper.
METHODS: This paper emerged from multiple discussions between the three authors over many months, culminating in a writing workshop to prepare this text.
RESULTS: The results of DNA analysis can be used to diagnose or predict rare diseases that are caused by a mutation in a single gene. However, while there are a number of genetic factors that contribute to common diseases, the ability to predict whether an individual will develop that condition is limited by the overall heritability of the condition. Environmental factors (such as lifestyle) are likely to be more useful in predicting common disease than genomic testing. Genomic tests may be of use to inform management of diseases in specific situations.
CONCLUSIONS: Genomic testing will be of use in diagnosing disorders due to single gene mutations, but the use of genomic testing to predict the chance of a patient being affected in the future by a common disease is unlikely to be a realistic option within a health service setting.
RELEVANCE TO CLINICAL PRACTICE: Nurses will increasingly be involved in the use of genomic tests in mainstream patient care. However, they need to understand and be able to explain to patients the practical applications of and limitations of such tests.

PMID: 26542756 [PubMed - indexed for MEDLINE]

Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells.

J Ethnopharmacol. 2015 Dec 24;176:55-68

Authors: Wu CF, Hong C, Klauck SM, Lin YL, Efferth T

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated.
AIM OF THE STUDY: Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells.
MATERIALS AND METHODS: Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM, multidrug-resistant CEM/ADR5000 cells and normal lymphocytes), flow cytometry (cell cycle arrest, apoptosis, necroptosis, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP)), single cell gel electrophoresis (DNA damage), molecular docking and gene promoter binding motif analysis (NFκB), Western blotting (nuclear NFκB translocation, PARP cleavage, caspase 3/7/9 expression), and fibronectin-based cell adhesion assay.
RESULTS: RA dose-dependently inhibited CCRF-CEM and CEM/ADR5000 cells, but caused less cytotoxicity towards normal lymphocytes. RA simultaneously induced apoptosis and necrosis, as shown by cell morphology and annexin V-PI assay. DNA damage was dose-dependently induced without ROS generation, which subsequently led to cell cycle arrest. RA-stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis. In accordance with molecular docking and gene promoter binding motif analyses, p65 translocation from the cytosol to the nucleus was blocked by RA, indicating a mechanistic role of the NFκB pathway to explain RA's action. RA affected cellular movement as evaluated by ameliorating cell adhesion to fibronectin.
CONCLUSIONS: RA induced apoptosis and necrosis in a ROS-independent DNA damage and caspase-independent manner. These results may contribute to the rationale use of S. miltiorrhiza and RA in traditional medicine of leukemia.

PMID: 26476154 [PubMed - indexed for MEDLINE]

Identification of cromolyn sodium as an anti-fibrotic agent targeting both hepatocytes and hepatic stellate cells.

Pharmacol Res. 2015 Dec;102:176-83

Authors: Choi JS, Kim JK, Yang YJ, Kim Y, Kim P, Park SG, Cho EY, Lee DH, Choi JW

Abstract
Liver fibrosis and cirrhosis, the late stage of fibrosis, are threatening diseases that lead to liver failure and patient death. Although aberrantly activated hepatic stellate cells (HSCs) are the main cause of disease initiation, the symptoms are primarily related to damaged hepatocytes. Thus, damaged hepatocytes, as well as HSCs, need to be simultaneously considered as therapeutic targets to develop more efficient treatments. Here, we suggest cromolyn sodium as an anti-fibrotic agent to commonly modulate hepatocytes and hepatic stellate cells. The differentially expressed genes from 6 normal and 40 cirrhotic liver tissues which were collected from GEO data were assessed by pharmacokinetic analysis using a connectivity map to identify agents that commonly revert abnormal hepatocytes and HSCs to normal conditions. Based on a series of analyses, a few candidates were selected. Candidates were tested in vitro to determine their anti-fibrotic efficacy on HSCs and hepatocytes. Cromolyn, which was originally developed as a mast cell stabilizer, showed the potential to ameliorate activated HSCs in vitro. The activation and collagen accumulation for HSC cell lines LX2 and HSC-T6 were reduced by 50% after cromolyn treatment at a low concentration without apoptosis. Furthermore, cromolyn treatment compromised the TGF-β-induced epithelial mesenchyme transition and replicative senescence rate of hepatocytes, which are generally associated with fibrogenesis. Taken together, cromolyn may be the basis for an effective cure for fibrosis and cirrhosis because it targets both HSCs and hepatocytes.

PMID: 26453959 [PubMed - indexed for MEDLINE]

[Recent progress in research of pathogeneses of Stevens-Johnson syndrome and toxic epidermal necrolysis].

Zhonghua Yan Ke Za Zhi. 2016 Sep 11;52(9):708-713

Authors: Gao TT, Long Q

Abstract
Stevens-Johnson syndrome(SJS)and toxic epidermal necrolysis(TEN)are life-threatening cutaneous adverse drug reactions that induce widespread epidermal necrosis. Ocular and cutaneous diseases are common chronic sequelae of SJS and TEN. Several concepts have been proposed to explain the pathogenesis of severe cutaneous adverse drug reactions. Recent advances in genetic, pharmacogenomics and immunologic studies have provided evidences of genetic predispositions, drug metabolism and cytokines related to SJS and TEN. With regard to keratinocyte death, several cell death mediators, such as Fas/FasL, granulysin and TNF, have been proposed to play an important role in the pathogeneses of SJS and TEN. A subset of T lymphocytes, including regulatory T cells, may also play a role. This review summarizes the pathogeneses of SJS and TEN mainly from the aspects of genetic susceptibilities, drug metabolism, and immune cells and cytokines. (Chin J Ophthalmol, 2016, 52: 708-713).

PMID: 27647252 [PubMed - as supplied by publisher]

Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties.

Sci Rep. 2016;6:32679

Authors: Wang Y, Fang J, Chen S

Abstract
Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell 'A549_LUNG' and compound 'Topotecan'. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

PMID: 27645580 [PubMed - as supplied by publisher]