Managing Bardet-Biedl Syndrome-Now and in the Future.

Front Pediatr. 2018;6:23

Authors: Forsythe E, Kenny J, Bacchelli C, Beales PL

Abstract
Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet-Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet-Biedl syndrome and increasing the number of cases with diagnostic uncertainty. As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet-Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing. Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed.

PMID: 29487844 [PubMed]

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer.

Oncotarget. 2018 Jan 30;9(8):7859-7866

Authors: Cremolini C, Del Re M, Antoniotti C, Lonardi S, Bergamo F, Loupakis F, Borelli B, Marmorino F, Citi V, Cortesi E, Moretto R, Ronzoni M, Tomasello G, Zaniboni A, Racca P, Buonadonna A, Allegrini G, Ricci V, Di Donato S, Zagonel V, Boni L, Falcone A, Danesi R

Abstract
Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing DPYD c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the DPYD c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned DPYD and UGT1A1 variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments' safety through a "genotype-guided" approach.

PMID: 29487697 [PubMed]

Genetic Parameter Estimates for Metabolizing Two Common Pharmaceuticals in Swine.

Front Genet. 2018;9:40

Authors: Howard JT, Ashwell MS, Baynes RE, Brooks JD, Yeatts JL, Maltecca C

Abstract
In livestock, the regulation of drugs used to treat livestock has received increased attention and it is currently unknown how much of the phenotypic variation in drug metabolism is due to the genetics of an animal. Therefore, the objective of the study was to determine the amount of phenotypic variation in fenbendazole and flunixin meglumine drug metabolism due to genetics. The population consisted of crossbred female and castrated male nursery pigs (n = 198) that were sired by boars represented by four breeds. The animals were spread across nine batches. Drugs were administered intravenously and blood collected a minimum of 10 times over a 48 h period. Genetic parameters for the parent drug and metabolite concentration within each drug were estimated based on pharmacokinetics (PK) parameters or concentrations across time utilizing a random regression model. The PK parameters were estimated using a non-compartmental analysis. The PK model included fixed effects of sex and breed of sire along with random sire and batch effects. The random regression model utilized Legendre polynomials and included a fixed population concentration curve, sex, and breed of sire effects along with a random sire deviation from the population curve and batch effect. The sire effect included the intercept for all models except for the fenbendazole metabolite (i.e., intercept and slope). The mean heritability across PK parameters for the fenbendazole and flunixin meglumine parent drug (metabolite) was 0.15 (0.18) and 0.31 (0.40), respectively. For the parent drug (metabolite), the mean heritability across time was 0.27 (0.60) and 0.14 (0.44) for fenbendazole and flunixin meglumine, respectively. The errors surrounding the heritability estimates for the random regression model were smaller compared to estimates obtained from PK parameters. Across both the PK and plasma drug concentration across model, a moderate heritability was estimated. The model that utilized the plasma drug concentration across time resulted in estimates with a smaller standard error compared to models that utilized PK parameters. The current study found a low to moderate proportion of the phenotypic variation in metabolizing fenbendazole and flunixin meglumine that was explained by genetics in the current study.

PMID: 29487615 [PubMed]

[Dihydropyrimidine dehydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks].

Bull Cancer. 2018 Feb 24;:

Authors: Loriot MA, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G, Picard N, Becquemont L, Verstuyft C, Narjoz C, Schmitt A, Bobin-Dubigeon C, Harle A, Paci A, Poinsignon V, Quaranta S, Evrard A, Hennart B, Broly F, Fonrose X, Lafay-Chebassier C, Wozny AS, Masskouri F, Boyer JC, Etienne-Grimaldi MC

Abstract
Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency.

PMID: 29486921 [PubMed - as supplied by publisher]

The Alpha-2A Adrenergic Receptor Gene -1291C/G Single Nucleotide Polymorphism is Associated with the Efficacy of Methylphenidate in Treating Taiwanese Children and Adolescents with Attention-Deficit Hyperactivity Disorder.

Psychiatry Investig. 2018 Feb 28;:

Authors: Huang HC, Wu LS, Yu SC, Wu BJ, Lua AC, Lee SM, Liu CZ

Abstract
Objective: The therapeutic effect of methylphenidate (MPH) in treating attention-deficit/hyperactivity disorder (ADHD) has been related to the alpha-2A adrenergic receptor (ADRA2A) gene -1291C/G single nucleotide polymorphism (SNP). We investigated the effect of MPH in treating Taiwanese children and adolescent with ADHD and its relation to the ADRA2A gene -1291C/G SNP.
Methods: The subjects with DSM-IV ADHD diagnosis underwent a titration period to find out the dose of MPH for maintenance treatment. After 4 weeks maintenance treatment, the effect of MPH was evaluated by the Swanson, Nolan and Pelham version IV total scores. The subjects with more than 25% score reduction were referred to responders and those with ≥50% improvement were considered as better responders. The -1291C/G variant of the ADRA2A gene was identified by DNA sequencing and what relevance it has to the MPH response was examined by binary logistic regression analysis.
Results: Of the 59 subjects, 44 (74.6%) were responsive to MPH treatment and the responsiveness was not shown to be associated with the ADRA2A gene -1291C/G SNP. As the responsive subjects were categorized as moderate responders and better responders and subjected to statistical analysis, the GG homozygotes showed a greater chance to have a better response to MPH treatment than CC homozygotes (p=0.02), with an odds ratio of 32.14 (95% CI=1.64-627.80).
Conclusion: The ADRA2A gene -1291C/G SNP is associated with the efficacy of MPH for the treatment of ADHD in Taiwanese children and adolescents. The responsive subjects bearing homozygous -1291G allele are more likely to have a better response to MPH treatment.

PMID: 29486545 [PubMed - as supplied by publisher]

Pharmacogenetics and target identification in diabetes.

Curr Opin Genet Dev. 2018 Feb 24;50:68-73

Authors: Pearson ER

Abstract
In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes.

PMID: 29486427 [PubMed - as supplied by publisher]

Genome-wide association studies in Crohn's disease: Past, present and future.

Clin Transl Immunology. 2018;7(1):e1001

Authors: Verstockt B, Smith KG, Lee JC

Abstract
Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven 'within-cases' analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.

PMID: 29484179 [PubMed]

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

Oncotarget. 2018 Jan 26;9(7):7631-7643

Authors: Feng PH, Yu CT, Chen KY, Luo CS, Wu SM, Liu CY, Kuo LW, Chan YF, Chen TT, Chang CC, Lee CN, Chuang HC, Lin CF, Han CL, Lee WH, Lee KY

Abstract
Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated.
Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown.
Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway.
Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

PMID: 29484139 [PubMed]

Pharmacogenetics as Personalized Medicine: Association Investigation of SOD2 rs4880, CYP2C19 rs4244285, and FCGR2A rs1801274 Polymorphisms in a Breast Cancer Population in Iraqi Women.

Clin Breast Cancer. 2018 Jan 31;:

Authors: Jabir FA, Hoidy WH

Abstract
BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with targeted therapies.
PATIENTS AND METHODS: In this study, we performed a population-based approach intersecting high-throughput genotype data from Iraqi populations with publicly available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. A total of 50 patients and 25 healthy controls were enrolled in our study. Genotyping of rs4880, rs4244285, and rs1801274 were examined in association with breast cancer in Iraqi women.
RESULTS: We found that individuals carrying the CT genotype of rs4880 manifested an increased risk of breast cancer compared with those carrying the TT genotype (odds ratio [OR], 0.171; 95% confidence interval [CI], 0.053-0.551; P = .002). In the dominant model, we observed that the CT and CC genotype of rs4880 showed an increased risk of breast cancer compared with the TT genotype (OR, 0.248; 95% CI, 0.089-0.690; P = .006). Moreover, subjects with the GA genotype of rs4244285 presented a higher risk of breast cancer than the GG genotype (OR, 0.256; 95% CI, 0.066-0.987; P = .038) and dominant models (OR, 0.025; 95% CI, 0.054-0.775; P = .013).
CONCLUSION: The analysis revealed that rs1801274 showed linkage disequilibrium and decreased risk of breast cancer. In conclusion, our study suggests that rs4880 and rs4244285 polymorphisms play an important role in development of breast cancer in an Iraqi population, and no significant association was found between rs1801274 and the risk of breast cancer.

PMID: 29482947 [PubMed - as supplied by publisher]

COL3A1 and SNAP91: novel glioblastoma markers with diagnostic and prognostic value.

Oncotarget. 2016 Oct 25;7(43):70494-70503

Authors: Gao YF, Mao XY, Zhu T, Mao CX, Liu ZX, Wang ZB, Li L, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Although patients with glioblastoma (GBM) have grave prognosis, significant variability in patient outcome is observed. This study aims to identify novel targets for GBM diagnosis and therapy. Microarray data (GSE4290, GSE7696, and GSE4412) obtained from the Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) by significant analysis of microarray (SAM). Intersection of the identified DEGs for each profile revealed 46 DEGs in GBM. A subset of common DEGs were validated by real-time reverse transcription quantitative PCR (qPCR). The prognostic value of some of the markers was also studied. We determined that RRM2 and COL3A1 were increased and directly correlated with glioma grade, while SH3GL2 and SNAP91 were decreased in GBM and inversely correlated with glioma grade. Kaplan-Meir analysis of GSE7696 revealed that COL3A1 and SNAP91 correlated with survival, suggesting that COL3A1 and SNAP91 may be suitable biomarkers for diagnostic or therapeutic strategies for GBM.

PMID: 27655637 [PubMed - indexed for MEDLINE]

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.

Neurobiol Dis. 2016 Oct;94:55-62

Authors: Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, Rosenthal LS, Pantelyat A, Gibbs JR, Albert MS, Hernandez DG, Hillis AE, Stone DJ, Singleton AB, North American Brain Expression Consortium, Hardy JA, Troncoso JC, Scholz SW

Abstract
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

PMID: 27312774 [PubMed - indexed for MEDLINE]

14 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 2018/02/27

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.

Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response - A theoretical insight.

J Mol Graph Model. 2018 Feb 12;81:14-24

Authors: Muthusamy K, Nagamani S

Abstract
Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 Å3 in wild type Vs. 738.8 in Leu230Val, 820.7 Å3 in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.

PMID: 29476931 [PubMed - as supplied by publisher]

Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell sensitivity to everolimus in vitro.

Cancer Chemother Pharmacol. 2018 Feb 23;:

Authors: Citi V, Del Re M, Martelli A, Calderone V, Breschi MC, Danesi R

Abstract
BACKGROUND: Everolimus is the hydroxyethyl derivative of sirolimus and a strong inhibitor of mammalian target of rapamycin (mTOR). This drug has immunosuppressive and anticancer activities and the present in vitro study was aimed at identifying the cellular and molecular profiles of breast cancer cells predictive of sensitivity to everolimus.
MATERIALS AND METHODS: MCF-7, T-47D, ZR-75-1, CAMA-1, HCC-1500 and MCF-10A cells were used and viability was assessed using WST-1 dye. Sensitivity to everolimus was correlated with phosphorylation of AKT (Ser473/Thr308), mTOR (Ser2448), and ERK1/2 (Thr202/Tyr204) and mutational profile of KRAS, NRAS, BRAF, PIK3CA, PTEN, TSC1, TSC2 and FRAP genes. Protein phosphorylation was evaluated by AlphaScreen SureFire, while the mutational status was examined by digital droplet PCR and Sanger sequencing.
RESULTS: Everolimus showed a transient growth inhibition in non-tumorigenic cells, while in tumorigenic lines the drug suppressed the proliferation in a concentration-dependent manner but with different potency (IC50) and efficacy (Emax), being ZR-75-1 the most sensitive and T47D the least sensitive. MCF-7, T47D and HCC1500 had activating mutations in PIK3CA gene, while loss-of-activity PTEN mutations were detected in sensitive cell lines, including ZR-75-1, which showed no changes or minimal increase in the amount of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204) induced by everolimus compared to the resistant cell line T47D in which phosphorylation of AKT and ERK was increased.
CONCLUSIONS: Cellular levels of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204), activating mutations of PIK3CA and inactivating mutations of PTEN may predict response to everolimus in breast cancer cells; these findings have potential applications for treatment personalization of everolimus in breast cancer patients.

PMID: 29476223 [PubMed - as supplied by publisher]

14 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 2018/02/24

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.

15 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 2018/02/23

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.

[MODERN VIEWS ON THE PHARMACOGENETICS OF PAIN.]

Anesteziol Reanimatol. 2017 Sep;61:219-223

Authors: Makharin OA, Zhenilo VM, Patyuchenko OY

Abstract
Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics.Describe the effect ofgene polymorphisms of OPRM, 5HTRIA, 5HTR2A, COMT GCHI, SCN9A, KCNSI, CACNA2D3, CACNG2, PTGSI, PTGS2, MDRJ/ABCB] on the perception of pain, and CYP2D6, CYP2C9, CYP3A4 on the pharmacokinetics and pharmacodynamics of medi- cations used in the treatment of pain.

PMID: 29465208 [PubMed - in process]

Pharmacogenetic Testing May Improve Drug Treatments and Shorten Disability Leaves.

Benefits Q. 2017;33(1):43-49

Authors: Lefaivre A, Litinski V, Vandenhurk M

Abstract
This article describes how methods of personalized medicine-specifically, pharmacogenetic (PGx) testing-can benefit private health plans, benefits managers, care providers and consumers alike. The authors cover pharmacogenomics as a science and also introduce an innovative way to optimize drug treatments. The article touches on some important clinical outcomes drawn from a recent study in community pharmacy and reviews the application and return on investment of PGx testing in disability and medication management.

PMID: 29465186 [PubMed - in process]

Genetic variations in genes of the stress response pathway are associated with prolonged abstinence from heroin.

Pharmacogenomics. 2018 Feb 21;:

Authors: Levran O, Peles E, Randesi M, Correa da Rosa J, Shen PH, Rotrosen J, Adelson M, Kreek MJ

Abstract
AIM: This study assesses whether genetic variants in stress-related genes are associated with prolonged abstinence from heroin in subjects that are not in long-term methadone treatment.
METHODS: Frequencies of 117 polymorphisms in 30 genes were compared between subjects with history of heroin addiction, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 923).
RESULTS: SNP rs1500 downstream of CRHBP and an interaction of SNPs rs10482672 (NR3C1) and rs4234955 (NPY1R/NPY5R) were significantly associated with prolonged abstinence without agonist treatment.
CONCLUSION: This study suggests that variability in stress-related genes may contribute to the ability of certain subjects to remain in prolonged abstinence from heroin, possibly due to higher resilience to stress.

PMID: 29465008 [PubMed - as supplied by publisher]

Implications of KRAS mutations in acquired resistance to treatment in NSCLC.

Oncotarget. 2018 Jan 19;9(5):6630-6643

Authors: Re MD, Rofi E, Restante G, Crucitta S, Arrigoni E, Fogli S, Maio MD, Petrini I, Danesi R

Abstract
Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.
Materials and Methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

PMID: 29464099 [PubMed]