37PGenomics and pharmacogenomics analyses of cancer cell lines using the CellMinerCDB and CellMiner web-applications.

Ann Oncol. 2019 Feb 01;30(Supplement_1):

Authors: Reinhold W, Pommier Y

PMID: 30810190 [PubMed - in process]

Pharmacogenetic variants in Bipolar Disorder with elevated treatment resistance and intolerance: towards a personalised pattern of care.

Bipolar Disord. 2019 Feb 27;:

Authors: Casetta C, Montrasio C, Cheli S, Baldelli S, Bianchi I, Clementi E, Gambini O, D'Agostino A

Abstract
BACKGROUND: Clinical psychiatry has recently begun to promote a personalised approach to care that can offer the best patient-tailored treatment in terms of efficacy and tolerability. Although still in its infancy, pharmacogenetic profiling is one of the most promising tools in a comprehensive, individualized assessment of the patient.
CASE REPORT: We present the case of a woman with treatment-resistant Bipolar Disorder, whose life has been ravaged by continuous hospitalizations for severe manic and depressive episodes. Numerous treatment attempts have been made but side effects occurred with almost all the medications administered, even the lowest doses. A retrospective pharmacogenetic analysis showed a rare pattern of expression for many of the CYP450 enzymes that are involved in the hepatic metabolism of the main compounds available for Bipolar Disorder. Several aspects of the patient's complex response to medication can be explained by a rare combination of CYP3A4/5, CYP2C19, CYP1A2 and, possibly, ABCB1 polymorphisms.
CONCLUSIONS: Although far from a widespread application, pharmacogenetics might represent an extremely useful tool to aim for an individualized therapy, especially in treatment-refractory cases. This article is protected by copyright. All rights reserved.

PMID: 30809922 [PubMed - as supplied by publisher]

Differential long noncoding RNAs expression in cancer-associated fibroblasts of non-small-cell lung cancer.

Pharmacogenomics. 2019 Feb 27;:

Authors: Teng C, Huang G, Luo Y, Pan Y, Wang H, Liao X, Li Y, Yang J

Abstract
AIM: The aim of this study was to investigate the role of long noncoding RNAs (lncRNAs) profiles in cancer-associated fibroblasts (CAFs) during non-small-cell lung cancer (NSCLC) progression.
MATERIALS & METHODS: Differentially expressed lncRNAs and mRNAs were detected by lncRNA microarray between three patient-paired CAFs and the adjacent normal fibroblasts, which were obtained from tumoral and nontumoral portions of surgically resected lung tissue from three primary NSCLCs. Bioinformatic analyses including gene ontology and pathway analysis were applied to these differentially expressed mRNAs. The qRT-PCR was conducted to identify the change of selected lncRNAs that might be involved in contribution of CAFs toward NSCLC.
RESULTS:  A total of 766 lncRNAs and 750 mRNAs abnormally expressed in CAFs (fold-change >2, p < 0.05). Bioinformatic analyses indicated that these mRNAs are associated with immune function. The qPCR results were consistent with microarray data.
CONCLUSION: The lncRNAs profiles of CAFs may provide promising targets for further research on immune regulation during NSCLC process.

PMID: 30808275 [PubMed - as supplied by publisher]

The future of pharmacogenetics in the treatment of hypertension.

Pharmacogenomics. 2019 Feb 27;:

Authors: Cunningham PN, Chapman AB

PMID: 30808251 [PubMed - as supplied by publisher]

MiR-204-5p promotes apoptosis and inhibits migration of osteosarcoma via targeting EBF2.

Biochimie. 2019 Mar;158:224-232

Authors: Li M, Shen Y, Wang Q, Zhou X

Abstract
Osteosarcoma is one of the most malignant cancer adolescents and young adults and metastatic osteosarcoma is a huge life threat with a 5-year survival lower than 20%. However, the mechanisms through which localized osteosarcoma turned metastatic are not fully understood. Here, we studied the role of miR-204-5p in osteosarcoma and found that miR-204-5p is downregulated in both osteosarcoma patients and osteosarcoma cell lines. In addition, overexpression of miR-204-5p resulted in increase of osteosarcoma cell apoptosis and decrease of osteosarcoma cell migration and invasion. Besides, our in vivo xenograft data showed strong inhibitory role of miR-204-5p in tumor growth. Importantly, our data showed that miR-204-5p regulates the mRNA stability of Early B Cell Factor 2 (EBF2), a crucial regulator in osteosarcoma apoptosis, by directly binding to 3' UTR of EBF2. Besides, our data further revealed that overexpressed EBF2 inhibited apoptosis and facilitated migration and invasion of osteosarcoma cells. Additionally, EBF2 overexpression rescued the phenotype caused by miR-204-5p.Our data indicated that miR-204-5p is an anti-oncogenic miRNA in osteosarcoma which functions through inhibiting oncogenic transcription factor EBF2. These results provided new therapeutic targets for metastatic osteosarcoma and insights into molecular regulation of EBF2.

PMID: 30529043 [PubMed - indexed for MEDLINE]

Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia.

Cancer Chemother Pharmacol. 2019 Feb 26;:

Authors: Naushad SM, Dorababu P, Rupasree Y, Pavani A, Raghunadharao D, Hussain T, Alrokayan SA, Kutala VK

Abstract
PURPOSE: The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management.
METHODS: A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning.
RESULTS: The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649.
CONCLUSIONS: TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

PMID: 30806759 [PubMed - as supplied by publisher]

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

JAMA. 2019 Feb 26;321(8):773-785

Authors: Walker GJ, Harrison JW, Heap GA, Voskuil MD, Andersen V, Anderson CA, Ananthakrishnan AN, Barrett JC, Beaugerie L, Bewshea CM, Cole AT, Cummings FR, Daly MJ, Ellul P, Fedorak RN, Festen EAM, Florin TH, Gaya DR, Halfvarson J, Hart AL, Heerasing NM, Hendy P, Irving PM, Jones SE, Koskela J, Lindsay JO, Mansfield JC, McGovern D, Parkes M, Pollok RCG, Ramakrishnan S, Rampton DS, Rivas MA, Russell RK, Schultz M, Sebastian S, Seksik P, Singh A, So K, Sokol H, Subramaniam K, Todd A, Annese V, Weersma RK, Xavier R, Ward R, Weedon MN, Goodhand JR, Kennedy NA, Ahmad T, IBD Pharmacogenetics Study Group

Abstract
Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).
Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).
Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.
Exposures: Genetic variants associated with TIM.
Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.
Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.
Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

PMID: 30806694 [PubMed - in process]

Analysis of long noncoding RNAs for acute rejection and graft outcome in kidney transplant biopsies.

Biomark Med. 2019 Feb 26;:

Authors: Zou Y, Zhang W, Zhou HH, Liu R

Abstract
AIM: To analyse long noncoding RNAs (lncRNA) in kidney transplant biopsies.
METHODS: Using a data mining approach, we constructed expression profiles in kidney transplant cohorts (n = 1105) from Gene Expression Omnibus. Integrative analysis of the lncRNAs with acute rejection (AR), T-cell-mediated acute rejection (TCMR) and graft loss were performed.
RESULTS: Six lncRNAs were identified as are associated with AR in the training and validating datasets, and with a risk score was generated with 3-lncRNAs that were predictive of graft loss (AUC = 0.73). MIR155HG is associated with AR, TCMR and graft loss. Plus it might be involved in several graft rejection and immune associated pathways.
CONCLUSION: Understanding the role of lncRNAs in AR and graft outcome in kidney transplant biopsies needs to be further investigated.

PMID: 30806516 [PubMed - as supplied by publisher]

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer.

Cancer Cell. 2018 04 09;33(4):706-720.e9

Authors: Wang Z, Yang B, Zhang M, Guo W, Wu Z, Wang Y, Jia L, Li S, Cancer Genome Atlas Research Network, Xie W, Yang D

Abstract
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

PMID: 29622465 [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 2019/02/26

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.

Real-time fMRI neurofeedback training to improve eating behavior by self-regulation of the dorsolateral prefrontal cortex: A randomized controlled trial in overweight and obese subjects.

Neuroimage. 2019 Feb 21;:

Authors: Kohl SH, Veit R, Spetter MS, Günther A, Rina A, Lührs M, Birbaumer N, Preissl H, Hallschmid M

Abstract
Obesity is associated with altered responses to food stimuli in prefrontal brain networks that mediate inhibitory control of ingestive behavior. In particular, activity of the dorsolateral prefrontal cortex (dlPFC) is reduced in obese compared to normal-weight subjects and has been linked to the success of weight-loss dietary interventions. In a randomized controlled trial in overweight/obese subjects, we investigated the effect on eating behavior of volitional up-regulation of dlPFC activity via real-time functional magnetic resonance imaging (fMRI) neurofeedback training. Thirty-eight overweight or obese subjects (BMI 25-40 kg/m2) took part in fMRI neurofeedback training with the aim of increasing activity of the left dlPFC (dlPFC group; n = 17) or of the visual cortex (VC/control group; n = 21). Participants were blinded to group assignment. The training session took place on a single day and included three training runs of six trials of up-regulation and passive viewing. Food appraisal and snack intake were assessed at screening, after training, and in a follow-up session four weeks later. Participants of both groups succeeded in up-regulating activity of the targeted brain area. However, participants of the control group also showed increased left dlPFC activity during up-regulation. Functional connectivity between dlPFC and ventromedial PFC, an area that processes food value, was generally increased during up-regulation compared to passive viewing. At follow-up compared to baseline, both groups rated pictures of high-, but not low-calorie foods as less palatable and chose them less frequently. Actual snack intake remained unchanged but palatability and choice ratings for chocolate cookies decreased after training. We demonstrate that one session of fMRI neurofeedback training enables individuals with increased body weight to up-regulate activity of the left dlPFC. Behavioral effects were observed in both groups, which might have been due to dlPFC co-activation in the control group and, in addition, unspecific training effects. Improved dlPFC-vmPFC functional connectivity furthermore suggested enhanced food intake-related control mechanisms. Neurofeedback training might support therapeutic strategies aiming at improved self-control in obesity, although the respective contribution of area-specific mechanisms and general regulation effects is in need of further investigation.

PMID: 30798010 [PubMed - as supplied by publisher]

Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats.

Neurotherapeutics. 2019 Feb 22;:

Authors: Drews HJ, Yenkoyan K, Lourhmati A, Buadze M, Kabisch D, Verleysdonk S, Petschak S, Beer-Hammer S, Davtyan T, Frey WH, Gleiter CH, Schwab M, Danielyan L

Abstract
The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (Aβ) accumulation in Alzheimer's disease (AD) and in hypertension is consistent with the remarkable neuroprotection provided by angiotensin receptor blockers (ARBs) independent of their blood pressure-lowering effect. Considering the causal relationship between hypertension and AD and that targeting cerebrovascular pathology with ARBs does not necessarily require their systemic effects, we tested intranasal losartan in the rat model of chronic hypertension (spontaneously hypertensive stroke-prone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of Aβ by enhancing key players in its metabolism and clearance, including insulin-degrading enzyme, neprilysin, and transthyretin. Furthermore, this treatment improved neurologic deficits and increased brain IL-10 concentration, hippocampal cell survival, neurogenesis, and choroid plexus cell proliferation in SHRSP. Losartan (1 μM) also reduced LDH release from cultured astroglial cells in response to toxic glutamate concentrations. This effect was completely blunted by IL-10 antibodies. These findings suggest that intranasal ARB treatment is a neuroprotective, neurogenesis-inducing, and Aβ-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway.

PMID: 30796737 [PubMed - as supplied by publisher]

Polymorphism A118G of opioid receptor mu 1 (OPRM1) is associated with emergence of suicidal ideation at antidepressant onset in a large naturalistic cohort of depressed outpatients.

Sci Rep. 2019 Feb 22;9(1):2569

Authors: Nobile B, Ramoz N, Jaussent I, Gorwood P, Olié E, Castroman JL, Guillaume S, Courtet P

Abstract
Antidepressants have been the object of an international controversy for about thirty years. Some patients are inclined to develop suicidal ideation (SI) at antidepressant onset; this phenomenon is known as Treatment Emergent Suicidal Ideation (TESI), and it has conducted regulatory bodies to prompt warnings on antidepressants. Since, few studies have explored the pharmacogenomics of TESI. Given the growing body of evidence connecting the opioidergic system with suicidal behavior (particularly mu opioid receptor (MOR)), we decided to examine the relationship between two genetic polymorphisms (SNPs) in the opioidergic system and TESI in a sample of 3566 adult depressed outpatients. General practitioners and psychiatrists throughout France followed participants for 6 weeks after an initial prescription of tianeptine, an antidepressant treatment with mu agonism. Suicidal ideation was assessed with the item 10 of the Montgomery-Asberg Depression Rating Scale (item dedicated to SI) at baseline, and after 2 weeks, 4 weeks and 6 weeks. We analysed rs1799971 from the OPRM1 gene and rs105660 from the OPRK1 gene. Within the sample, 112 patients reported TESI while 384 did not. We found a significant association between AA genotype of rs1799971 and TESI even after adjustment for potential cofounders (OR = 1.93, 95% CI = [1.07; 3.49]; p-value = 0.03). On the other hand there were no significant association between rs1799971 and rs105560 with worsening of suicidal ideation or lifetime suicide attempts. Nevertheless, our results suggest a possible involvement of opioidergic system in TESI.

PMID: 30796320 [PubMed - in process]

Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma.

Sci Rep. 2019 Feb 22;9(1):2552

Authors: Yang MH, Yen CH, Chen YF, Fang CC, Li CH, Lee KJ, Lin YH, Weng CH, Liu TT, Huang SF, Teh BT, Chen YA

Abstract
Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 - S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.

PMID: 30796242 [PubMed - in process]

12 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 2019/02/23

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.

Factors affecting tamoxifen metabolism in breast cancer patients; preliminary results of the French PHACS study (NCT01127295).

Clin Pharmacol Ther. 2019 Feb 20;:

Authors: Puszkiel A, Arellano C, Vachoux C, Evrard A, Le Morvan V, Boyer JC, Robert J, Delmas C, Dalenc F, Debled M, Venat-Bouvet L, Jacot W, Suc E, Sillet Bach I, Filleron T, Roché H, Chatelut E, White-Koning M, Thomas F

Abstract
In addition to the effect of CYP2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy, toxicity). This analysis focused on the pharmacokinetic-pharmacogenetic evaluation of tamoxifen in 730 adjuvant breast cancer patients included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single nucleotide polymorphisms and co-medications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (p < 0.0001), CYP3A4*22 genotype (p = 0.0003) and concomitant intake of potent CYP2D6 inhibitors (p < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping IM/IM and IM/PM diplotype into intermediate metaboliser (IM) phenotype for future use in tamoxifen therapy optimisation. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A4*22, CYP2C19*2 and CYP2B6*6 genetic polymorphisms. This article is protected by copyright. All rights reserved.

PMID: 30786012 [PubMed - as supplied by publisher]

Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial.

Pharmacogenomics. 2019 Feb 20;:

Authors: Fulton CR, Zang Y, Desta Z, Rosenman MB, Holmes AM, Decker BS, Zhang Y, T Callaghan J, Pratt VM, Levy KD, Gufford BT, Dexter PR, Skaar TC, Eadon MT

Abstract
BACKGROUND: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions.
METHODS: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126).
RESULT: Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94).
CONCLUSION: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.

PMID: 30784356 [PubMed - as supplied by publisher]

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology.

Mol Pharmacol. 2019 Feb 19;:

Authors: Schulte RR, Ho RH

Abstract
The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, anti-hypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite SN-38, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic and ovarian cancers suggesting potential roles for OATPs in tumor development, progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.

PMID: 30782852 [PubMed - as supplied by publisher]

A meta-analysis of genome-wide association studies identifies three loci associated with stiffness index of the calcaneus.

J Bone Miner Res. 2019 Feb 19;:

Authors: Lu HF, Hung KS, Chu HW, Wong HS, Kim J, Choi BY, Kim MK, Tai YT, Ikegawa S, Cho EC, Chang WC

Abstract
The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone-mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome-wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta-analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs as well as two novel SI-related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis. This article is protected by copyright. All rights reserved.

PMID: 30779856 [PubMed - as supplied by publisher]

A component overlapping attribute clustering (COAC) algorithm for single-cell RNA sequencing data analysis and potential pathobiological implications.

PLoS Comput Biol. 2019 Feb 19;15(2):e1006772

Authors: Peng H, Zeng X, Zhou Y, Zhang D, Nussinov R, Cheng F

Abstract
Recent advances in next-generation sequencing and computational technologies have enabled routine analysis of large-scale single-cell ribonucleic acid sequencing (scRNA-seq) data. However, scRNA-seq technologies have suffered from several technical challenges, including low mean expression levels in most genes and higher frequencies of missing data than bulk population sequencing technologies. Identifying functional gene sets and their regulatory networks that link specific cell types to human diseases and therapeutics from scRNA-seq profiles are daunting tasks. In this study, we developed a Component Overlapping Attribute Clustering (COAC) algorithm to perform the localized (subpopulation) gene co-expression network analysis from large-scale scRNA-seq profiles. Gene subnetworks that represent specific gene co-expression patterns are inferred from the components of a decomposed matrix of scRNA-seq profiles. We showed that single-cell gene subnetworks identified by COAC from multiple time points within cell phases can be used for cell type identification with high accuracy (83%). In addition, COAC-inferred subnetworks from melanoma patients' scRNA-seq profiles are highly correlated with survival rate from The Cancer Genome Atlas (TCGA). Moreover, the localized gene subnetworks identified by COAC from individual patients' scRNA-seq data can be used as pharmacogenomics biomarkers to predict drug responses (The area under the receiver operating characteristic curves ranges from 0.728 to 0.783) in cancer cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. In summary, COAC offers a powerful tool to identify potential network-based diagnostic and pharmacogenomics biomarkers from large-scale scRNA-seq profiles. COAC is freely available at https://github.com/ChengF-Lab/COAC.

PMID: 30779739 [PubMed - as supplied by publisher]