Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver.

Eur J Pharm Sci. 2017 Dec 06;:

Authors: Murray M, Gillani TB, Ghassabian S, Edwards RJ, Rawling T

Abstract
The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40-44% of control (P<0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction.

PMID: 29223619 [PubMed - as supplied by publisher]

Leveraging precision medicine to mitigate medication-safety challenges.

Am J Health Syst Pharm. 2017 Dec 15;74(24):2031-2032

Authors: Gammal RS, Hoffman JM

PMID: 29222358 [PubMed - in process]

Progress in adult ALL: incorporation of new agents to frontline treatment.

Hematology Am Soc Hematol Educ Program. 2017 Dec 08;2017(1):28-36

Authors: Leonard J, Stock W

Abstract
Treatment of acute lymphoblastic leukemia (ALL) in adults remains a challenge, as the delivery of intensive chemotherapeutic regimens in this population is less feasible than it is in the pediatric population. This has led to higher rates of treatment-related toxicity as well as lower overall survival in the adult population. Over the past several years, a host of novel therapies (eg, immunotherapy and targeted therapies) with better tolerability than traditional chemotherapy are now being introduced into the relapsed/refractory population with very encouraging results. Additionally, insights into how to choose effective therapies for patients while minimizing drug toxicity through pharmacogenomics and the use of minimal residual disease (MRD) monitoring to escalate/de-escalate therapy have enhanced our ability to reduce treatment-related toxicity. This has led to the design of a number of clinical trials which incorporate both novel therapeutics as well as MRD-directed treatment pathways into the frontline setting. The use of increasingly personalized treatment strategies for specific disease subsets combined with standardized and rapid molecular diagnostic testing in the initial diagnosis and frontline treatment of ALL will hopefully lead to further improvements in survival for our adult patients.

PMID: 29222234 [PubMed - in process]

The molecular classification of astrocytic tumors.

Oncotarget. 2017 Nov 10;8(56):96340-96350

Authors: Mao CX, Yin JY, Zhang Y, Wang ZB, Yang ZQ, He ZW, Li XM, Mao XY, Cui RT, Li XJ, Li X, Zhang W, Zhou HH, Liu ZQ

Abstract
Aim: This study will explore the genetic and epigenetic alterations in astrocytomas, and identify the critical molecular signatures and signaling pathways for prognosis assessment by multiplatform comprehensive analysis.
Method: We performed integration analyses of incorporating DNA methylation, mRNA expression, microRNA expression, and long non-coding RNA (lncRNA) expression in 33 astrocytic tumor tissues and 9 non-tumor brain tissues.
Result: We observed that 11,795 DNA methylation sites, 3,627 genes, 136 microRNAs, and 3,334 lncRNAs were significantly differential between tumors and non-tumor brain tissues, and the filtered signatures through comprehensive analysis were significantly enriched in calcium signaling pathway. Furthermore, four signatures involved in calcium signaling pathway and age could contribute to predicting the patients' overall survival. Additionally, we identified differentially expressed signatures between IDH-mutated and IDH wild-type astrocytic tumors, and complement and coagulation cascades pathway was the most significant pathway in functional enrichment analysis using multiplatform data. The IDH wild-type astrocytomas were divided into two subtypes by Cluster of Cluster (CoC) analysis, one of which was enriched for astrocytomas overexpressed in chemokine signaling pathway.
Conclusion: The calcium signaling pathway played a key role in astrocytoma tumorigenesis and prognosis. IDH mutation was a vital biomarker, and resulted in the change of expression level in complement and coagulation cascades pathway. The chemokine signaling pathway could characterize subtypes of IDH wild-type astrocytomas.

PMID: 29221210 [PubMed]

Prediction on the risk population of idiosyncratic adverse reactions based on molecular docking with mutant proteins.

Oncotarget. 2017 Nov 10;8(56):95568-95576

Authors: Xie H, Zeng D, Chen X, Huo D, Liu L, Zhang D, Jin Q, Ke K, Hu M

Abstract
Idiosyncratic adverse drug reactions are drug reactions that occur rarely and unpredictably among the population. These reactions often occur after a drug is marketed, which means that they are strongly related to the genotype of the population. The prediction of such adverse reactions is a major challenge because of the lack of appropriate test models during the drug development process. In this study, we chose withdrawn drugs because the reasons why they were withdrawn and from which countries or regions is easily obtained. We selected Dilevalol and its chiral drug (Labetalol) as the investigatory drugs, as they have been withdrawn from a European market (Britain) because of serious hepatotoxicity. First, we searched for and obtained the Dilevalol-induced- liver-injury related protein, multidrug resistance protein 1 (MDR1), from the Comparative Toxicogenomics Database (CTD). Then, we searched and extracted 477 non-synonymous single nucleotide polymorphisms (nsSNP) on MDR1 in the dbSNP database. Second, we used the VarMod tool to predict the functional changes of MDR1 induced by these nsSNPs, from which we extracted the nsSNPs that significantly change the functions of this protein. Third, we built the three-dimensional structures of those variant proteins and used AutoDock to perform a docking study, choosing the best model to determine the sites of nsSNPs. Finally, we used the data from the 1000 Genomes Project to verify the dominant population distribution of the risk SNP. We applied the same strategy to the post-marketing drug-induced liver injury drugs to further test the feasibility of our method.

PMID: 29221149 [PubMed]

A boosting approach for prediction of protein-RNA binding residues.

BMC Bioinformatics. 2017 Dec 01;18(Suppl 13):465

Authors: Tang Y, Liu D, Wang Z, Wen T, Deng L

Abstract
BACKGROUND: RNA binding proteins play important roles in post-transcriptional RNA processing and transcriptional regulation. Distinguishing the RNA-binding residues in proteins is crucial for understanding how protein and RNA recognize each other and function together as a complex.
RESULTS: We propose PredRBR, an effectively computational approach to predict RNA-binding residues. PredRBR is built with gradient tree boosting and an optimal feature set selected from a large number of sequence and structure characteristics and two categories of structural neighborhood properties. In cross-validation experiments on the RBP170 data set show that PredRBR achieves an overall accuracy of 0.84, a sensitivity of 0.85, MCC of 0.55 and AUC of 0.92, which are significantly better than that of other widely used machine learning algorithms such as Support Vector Machine, Random Forest, and Adaboost. We further calculate the feature importance of different feature categories and find that structural neighborhood characteristics are critical in the recognization of RNA binding residues. Also, PredRBR yields significantly better prediction accuracy on an independent test set (RBP101) in comparison with other state-of-the-art methods.
CONCLUSIONS: The superior performance over existing RNA-binding residue prediction methods indicates the importance of the gradient tree boosting algorithm combined with the optimal selected features.

PMID: 29219069 [PubMed - in process]

The effects of genetic polymorphism on treatment response of recombinant human growth hormone.

Curr Drug Metab. 2017 Dec 06;:

Authors: Chen S, You H, Pan H, Zhu H, Yang H, Gong F, Wang L, Jiang Y, Yan C

Abstract
Recombinant human growth hormone (rhGH) has been widely used in clinical treatment of growth hormone deficiency (GHD) or non GHD since 1985 and technology have achieved a great development in different long-acting formulations. Although the mathematical models for predicting the growth hormone response could help clinicians get to an individual personalized growth dose, many patients just can't reach the target height and the growth hormone responses differed.Genetic polymorphisms may play a role in the varies of individual responses in this treatment process.This article gives an overview of the genetic polymorphisms research of growth hormone in recent years, in order to give some potential suggestion and guide for the dose titration during treatment.

PMID: 29219047 [PubMed - as supplied by publisher]

VKORC1-1639A allele influences warfarin maintenance dosage among Blacks receiving warfarin anticoagulation: a retrospective cohort study.

Future Cardiol. 2017 Dec 08;:

Authors: Mili FD, Allen T, Wadell PW, Hooper WC, Staercke C, Bean CJ, Lally C, Austin H, Wenger NK

Abstract
AIM: The study objectives were to investigate the association between selected CYP2C9 and VKORC1 single nucleotide polymorphisms with serious bleeding or thrombotic risk, and to estimate mean daily maintenance dose of warfarin and international normalized ratio measurements among Blacks receiving warfarin anticoagulation.
METHODS: We conducted a retrospective cohort study among 230 Black adults receiving warfarin for a minimum of three consecutive months with a confirmed date of first dosage.
RESULTS: A lower mean daily maintenance dosage of warfarin was required to maintain an international normalized ratio measurement within the therapeutic range among Blacks with the VKORC1-1639G>A variant alleles ([G/A vs G/G, p = 0.02], [A/A vs G/A, p = 0.008] and [A/A vs G/G, p = 0.001]).
CONCLUSION: Data indicated that VKORC1-1639A variant allele influenced warfarin daily maintenance dosage among our small, likely admixed Black patient population.

PMID: 29218998 [PubMed - as supplied by publisher]

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol.

Front Pharmacol. 2017;8:863

Authors: Gonzalez-Covarrubias V, Urena-Carrion J, Villegas-Torres B, Cossío-Aranda JE, Trevethan-Cravioto S, Izaguirre-Avila R, Fiscal-López OJ, Soberon X

Abstract
Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40-55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos.

PMID: 29218011 [PubMed]

Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression.

Transl Psychiatry. 2017 Dec 08;7(12):1269

Authors: Rossetti C, Sciarra D, Petit JM, Eap CB, Halfon O, Magistretti PJ, Boutrel B, Cardinaux JR

Abstract
Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1 -/- mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1 -/- mice was further characterized by investigating CRTC1's role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1 -/- mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1 -/- females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1 -/- mice, suggesting that mutant males' hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.

PMID: 29217834 [PubMed - in process]

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway.

Cell Physiol Biochem. 2017 Dec 06;44(5):1696-1714

Authors: Wang N, Gao J, Jia M, Ma X, Lei Z, Da F, Yan F, Zhang H, Zhou Y, Li M, He G, Meng J, Luo X

Abstract
BACKGROUND/AIMS: The synthesis and degradation processes involved in bone remodeling are critically regulated by osteoblasts and osteoclasts. The GLP-1 receptor agonist Exendin-4 is beneficial for osteoblast differentiation and increases the number of osteoblasts.
METHODS: We constructed an ovariectomized model to evaluate the impact of Exendin-4 on bone formation in osteoporosis. A macrophage-depleted model was also created to investigate the effect of macrophages on bone formation. Thirty-two female WT C57BL/6 mice (aged 3 months) were randomly assigned to a normal control group and four ovariectomized (OVX) subgroups: OVX + vehicle group, OVX + Exendin-4 (4.2 µg/kg/day) group, OVX + chloride phosphate liposome group and OVX + chloride phosphate liposome + Exendin-4 group.
RESULTS: In this study, we found that Exendin-4 not only increased the number of osteoblasts and decreased the number of osteoclasts, but also increased the number of bone marrow stromal cells (BMSCs) at the bone surface. Moreover, we found that OVX mice treated with Exendin-4 increased TGF-β1 levels at the bone surface compared with that in OVX mice. Besides, Exendin-4 promoted the polarization of bone marrow-derived macrophages into M2 subtype and increased TGF-β1 secretion by the M2 subtype. Finally, we found that Exendin-4 induced macrophage polarization via the cAMP-PKA-STAT3 signaling pathway.
CONCLUSION: Exendin-4 promotes bone marrow-derived macrophage polarization to the M2 subtype and induces BMSC migration to the bone surface via PKA-STAT3 signaling.

PMID: 29216639 [PubMed - as supplied by publisher]

Attempted replication of SNPs in RANKL and OPG with musculoskeletal adverse events during aromatase inhibitor treatment for breast cancer.

Physiol Genomics. 2017 Dec 06;:physiolgenomics.00085.2017

Authors: Dempsey JM, Xi J, Henry NL, Rae JM, Hertz DL

Abstract
Aromatase inhibitor (AI) therapy is highly efficacious in the treatment of estrogen receptor-positive breast cancer, however in a subset of patients AI use is discontinued due to drug-induced musculoskeletal adverse events (MS-AE). Several studies have investigated the role of germline single nucleotide polymorphisms on patients' risk of MS-AE's, however no associations have yet to be validated for translation into clinical practice. This study attempted to replicate SNPs in RANKL (rs7984870) and OPG (rs2073618) on the risk of AI-induced MS-AEs, and screen for secondary associations with MS-AE related treatment discontinuation and serum and urine markers of bone health. Previously reported associations were not replicated with our primary hypothesis, change in MS-AE from baseline to three months, however, patients homozygous for the G allele of rs7984870 in RANKL had lower risk of MS-AE-associated treatment discontinuation in analyses of secondary phenotypes without statistical correction.

PMID: 29212847 [PubMed - as supplied by publisher]

Association of ARMS2 genotype with response to anti-vascular endothelial growth factor treatment in polypoidal choroidal vasculopathy.

BMC Ophthalmol. 2017 Dec 07;17(1):241

Authors: Park UC, Shin JY, Chung H, Yu HG

Abstract
BACKGROUND: To investigate whether genetic risk variants for age-related macular degeneration (AMD) are associated with response to intravitreal anti-vascular endothelial growth factor (VEGF) in polypoidal choroidal vasculopathy (PCV) patients.
METHODS: This prospective cohort study included 95 treatment-naïve patients that underwent anti-VEGF treatment for PCV for 12 months. Patients were genotyped for 10 single nucleotide polymorphisms in eight AMD-relevant genes. Genotypic association with visual and anatomic outcome measures at 12 months after initial treatment, including mean change in best-corrected visual acuity (BCVA) and total foveal thickness, visual gain of ≥ 15 letters, dry status on optical coherence tomography (OCT), pigment epithelial detachment (PED) regression on OCT, polyp regression on indocyanine green angiography, and injection numbers, were investigated using regression models with adjustment for non-genetic covariates under additive genetic model.
RESULTS: In 81 patients who completed 12-month anti-VEGF monotherapy without photodynamic therapy, significant pharmacogenetic association was found between ARMS2 rs10490924 and PED regression on OCT. Proportions of PED regression were 26.4% for TT, 45.7% for TG, and 63.6% for GG genotype, showing additive effect of G allele for higher chance of PED regression (OR, 2.96; 95% CI, 1.38-6.36; corrected P = 0.043). For entire 95 patients, no significant association was found between candidate polymorphisms and receiving photodynamic therapy within 12 months.
CONCLUSIONS: In PCV patients, ARMS2 rs10490924 showed association with anatomic therapeutic response to anti-VEGF, suggesting pharmacogenetic relationship.

PMID: 29212537 [PubMed - in process]

Establishing and characterizing patient-derived xenografts using pre-chemotherapy percutaneous biopsy and post-chemotherapy surgical samples from a prospective neoadjuvant breast cancer study.

Breast Cancer Res. 2017 Dec 06;19(1):130

Authors: Yu J, Qin B, Moyer AM, Sinnwell JP, Thompson KJ, Copland JA, Marlow LA, Miller JL, Yin P, Gao B, Minter-Dykhouse K, Tang X, McLaughlin SA, Moreno-Aspitia A, Schweitzer A, Lu Y, Hubbard J, Northfelt DW, Gray RJ, Hunt K, Conners AL, Suman VJ, Kalari KR, Ingle JN, Lou Z, Visscher DW, Weinshilboum R, Boughey JC, Goetz MP, Wang L

Abstract
BACKGROUND: Patient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response. Most available breast cancer PDXs have been generated in the metastatic setting. However, in the setting of operable breast cancer, PDX models both sensitive and resistant to chemotherapy are needed for drug development and prospective data are lacking regarding the clinical and molecular characteristics associated with PDX take rate in this setting.
METHODS: The Breast Cancer Genome Guided Therapy Study (BEAUTY) is a prospective neoadjuvant chemotherapy (NAC) trial of stage I-III breast cancer patients treated with neoadjuvant weekly taxane+/-trastuzumab followed by anthracycline-based chemotherapy. Using percutaneous tumor biopsies (PTB), we established and characterized PDXs from both primary (untreated) and residual (treated) tumors. Tumor take rate was defined as percent of patients with the development of at least one stably transplantable (passed at least for four generations) xenograft that was pathologically confirmed as breast cancer.
RESULTS: Baseline PTB samples from 113 women were implanted with an overall take rate of 27.4% (31/113). By clinical subtype, the take rate was 51.3% (20/39) in triple negative (TN) breast cancer, 26.5% (9/34) in HER2+, 5.0% (2/40) in luminal B and 0% (0/3) in luminal A. The take rate for those with pCR did not differ from those with residual disease in TN (p = 0.999) and HER2+ (p = 0.2401) tumors. The xenografts from 28 of these 31 patients were such that at least one of the xenografts generated had the same molecular subtype as the patient. Among the 35 patients with residual tumor after NAC adequate for implantation, the take rate was 17.1%. PDX response to paclitaxel mirrored the patients' clinical response in all eight PDX tested.
CONCLUSIONS: The generation of PDX models both sensitive and resistant to standard NAC is feasible and these models exhibit similar biological and drug response characteristics as the patients' primary tumors. Taken together, these models may be useful for biomarker discovery and future drug development.

PMID: 29212525 [PubMed - in process]

Sex steroid hormones in relation to Barrett's esophagus: an analysis of the FINBAR Study.

Andrology. 2017 Mar;5(2):240-247

Authors: Cook MB, Wood S, Hyland PL, Caron P, Drahos J, Falk RT, Pfeiffer RM, Dawsey SM, Abnet CC, Taylor PR, Guillemette C, Murray LJ, Anderson LA

Abstract
Previously, we observed strong positive associations between circulating concentrations of free testosterone and free dihydrotestosterone (DHT) in relation to Barrett's esophagus in a US male military population. To replicate these findings, we conducted a second study of sex steroid hormones and Barrett's esophagus in the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study based in Northern Ireland and Ireland. We used mass spectrometry to quantitate EDTA plasma concentrations of nine sex steroid hormones and ELISA to quantitate sex hormone-binding globulin in 177 male Barrett's esophagus cases and 185 male general population controls within the FINBAR Study. Free testosterone, free DHT, and free estradiol were estimated using standard formulas. Multivariable logistic regression estimated odds ratios (OR) and 95% confidence intervals (95%CI) of associations between exposures and Barrett's esophagus. While plasma hormone and sex hormone-binding globulin concentrations were not associated with all cases of Barrett's esophagus, we did observe positive associations with estrogens in younger men (e.g. estrone + estradiol ORcontinuous per ½IQR  = 2.92, 95%CI:1.08, 7.89), and free androgens in men with higher waist-to-hip ratios (e.g. free testosterone ORcontinuous per ½IQR  = 2.71, 95%CI:1.06, 6.92). Stratification by body mass index, antireflux medications, and geographic location did not materially affect the results. This study found evidence for associations between circulating sex steroid hormones and Barrett's esophagus in younger men and men with higher waist-to-hip ratios. Further studies are necessary to elucidate whether sex steroid hormones are consistently associated with esophageal adenocarcinogenesis.

PMID: 28241109 [PubMed - indexed for MEDLINE]

MicroRNA-567 dysregulation contributes to carcinogenesis of breast cancer, targeting tumor cell proliferation, and migration.

Breast Cancer Res Treat. 2017 Feb;161(3):605-616

Authors: Bertoli G, Cava C, Diceglie C, Martelli C, Rizzo G, Piccotti F, Ottobrini L, Castiglioni I

Abstract
PURPOSE: We demonstrated that Hsa-miR-567 expression is significantly downregulated in poor prognosis breast cancer, compared to better prognosis breast cancer, having a role in the control of cell proliferation and migration by regulating KPNA4 gene.
METHODS AND RESULTS: In this study, based on our previously published in silico results, we proved both in vitro (cell line studies) and ex vivo (clinical studies), that Hsa-miR-567 expression is significantly downregulated in breast cancer with poor prognosis when compared to breast cancer with better prognosis. More intriguingly, we demonstrated that the ectopic expression of Hsa-miR-567 in poor prognosis breast cancer cell line strongly inhibits in vitro cell proliferation and migration. Furthermore, we showed in vivo that breast cancer cells, stably expressing Hsa-miR-567, xenografted in mouse, reduce tumor growth ability. Consistently, we found that karyopherin 4 (KPNA4), predicted target gene of Hsa-miR-567 as identified by our in silico analysis, is upregulated in highly aggressive MDA-MB-231 breast cancer cell line and patient tissues with poor prognosis with respect to good prognosis.
CONCLUSIONS: Our results suggest a potential role of Hsa-miR-567 as a novel prognostic biomarker for BC and as regulator of KPNA4.

PMID: 28000015 [PubMed - indexed for MEDLINE]

Successful treatment with afatinib after grade 3 hepatotoxicity induced by both gefitinib and erlotinib in EGFR mutation-positive non-small cell lung cancer.

Lung Cancer. 2016 Sep;99:1-3

Authors: Zenke Y, Umemura S, Sugiyama E, Kirita K, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Goto K

Abstract
Hepatotoxicity is a major cause of the withdrawal of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) when treating EGFR mutation-positive non-small cell lung cancer (NSCLC). We report a case in which gefitinib- and elrotinib-induced severe hepatotoxicity arose in a patient with the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) and cytochrome p450 3A5 (CYP3A5) poor metabolizer phenotypes. Afatinib is not significantly metabolized by cytochrome p450-mediated pathways. We describe successful management of the patient's tumor by switching to afatinib. Evaluation of single nucleotide polymorphisms (SNPs) in metabolic enzymes might be useful to predict severe hepatotoxicity induced by EGFR-TKIs.

PMID: 27565905 [PubMed - indexed for MEDLINE]

Development of a bile acid-based newborn screen for Niemann-Pick disease type C.

Sci Transl Med. 2016 May 04;8(337):337ra63

Authors: Jiang X, Sidhu R, Mydock-McGrane L, Hsu FF, Covey DF, Scherrer DE, Earley B, Gale SE, Farhat NY, Porter FD, Dietzen DJ, Orsini JJ, Berry-Kravis E, Zhang X, Reunert J, Marquardt T, Runz H, Giugliani R, Schaffer JE, Ory DS

Abstract
Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3β,5α,6β-trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β,5α,6β-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry-based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs.

PMID: 27147587 [PubMed - indexed for MEDLINE]

Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response.

Genet Med. 2017 Jan;19(1):20-29

Authors: Kozyra M, Ingelman-Sundberg M, Lauschke VM

Abstract
PURPOSE: In this study we characterized the genetic variability of 146 clinically relevant genes influencing drug pharmacokinetics in African and European subpopulations, which are key determinants for interindividual variations in drug efficacy and adverse drug reactions.
METHODS: By integrating data from the 1000 Genomes Project (n = 1,092 individuals) and the Exome Sequencing Project (ESP; n = 6,503 individuals), single-nucleotide variants (SNVs) were identified and analyzed regarding frequency, functional consequences, and ethnic diversity.
RESULTS: In total, we found 12,152 SNVs in exons, 312 of which were novel. The majority of variants were rare (minor allele frequency (MAF) <1%; 92.9%) and nonsynonymous (56.2%). We calculated that individuals of European and African descent harbor, on average, 100.8 and 121.4 variants across the 146 pharmacogenes studied, respectively. Additionally, by analyzing variation patterns across these populations, we pinpointed potential priority genes for population-adjusted genetic profiling strategies. Furthermore, we estimated, based on our variant frequency analyses, that approximately 30-40% of functional variability in pharmacogenes can be attributed to rare variants.
CONCLUSIONS: Our results indicate that these clinically important genes are genetically highly variable and differ considerably between populations. Furthermore, the large extent of rare variants emphasizes the need for sequencing-based approaches and effective functionality predictions to allow for true personalized medicine.Genet Med 19 1, 20-29.

PMID: 27101133 [PubMed - indexed for MEDLINE]

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