Epidemiology of human leukocyte antigens among omani population.

Saudi J Kidney Dis Transpl. 2017 Sep-Oct;28(5):1021-1026

Authors: Al Salmi I, Metry AM, Al Ismaili F, Hola A, Shaheen F, Fakhoury H, Hannawi S

Abstract
Oman is located on the Southeastern coast of the Arabian Peninsula, and its population has high levels of consanguinity. Human leukocytic antigen (HLA) typing analysis in human population holds unexploited potential for elucidating the genetic causes of human disease and possibly leads to personalized medicine. This is a retrospective, descriptive study evaluating HLA frequencies of Omani individuals who underwent workup for kidney transplantation at the Royal Hospital (RH) from 2005 to 2016. Data on 870 subjects were collected from the Oman kidney transplant registry at RH as well from electronic medical record system. The mean age (standard deviation) years for the cohort were 33.2 (13.0). Males constituted 56.3% (490) while females constituted 43.7% (380). Seven HLA-A alleles accounted for more than 70% of the total alleles. Of which, HLA-A2 contributed the highest frequency (24%), followed by HLA A11 (9.4%), and A32 (8.1%). Ten alleles accounted for 70% of HLA-B alleles. Of which, HLA-B51 was the most common (18.9%), followed by HLA-B-35 (13.6%), and HLA-B8 (7.9%). Seven HLA-DRB1 alleles accounted for more than 70% of the total HLA DRB1 alleles, of which HLA- DRB1*16 contributed the highest frequency (29.56%). This was followed by HLA-DRB1*03 (14.57%) and HLA-DRB1*11 (9.48%). While three alleles accounted for more than 75% of the total HLA DQB1alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%). This was followed by allele HLA-DQB1*02 (26.48%) and HLA-DQB1*03 (17.18%). This study showed considerable heterogeneity in both HLA Class I and Class II antigens, which reflects admixture of our population with rest of old world countries. Despite the high levels of consanguinity, this population is genetically highly heterogeneous. These findings may be useful for transplantation programs, noncommunicable diseases, epidemiology of HLA linked diseases, pharmacogenomics, and anthropology.

PMID: 28937058 [PubMed - in process]

The drug transporter ABCB1 c.3435C>T SNP influences artemether-lumefantrine treatment outcome.

Malar J. 2017 Sep 21;16(1):383

Authors: Kiaco K, Rodrigues AS, do Rosário V, Gil JP, Lopes D

Abstract
Malaria treatment performance is potentially influenced by pharmacogenetic factors. This study reports an association study between the ABCB1 c.3435C>T, CYP3A4*1B (g.-392A>G), CYP3A5*3 (g.6986A>G) SNPs and artemether + lumefantrine treatment outcome in 103 uncomplicated malaria patients from Angola. No significant associations with the CYP3A4*1B and CYP3A5*3 were observed, while a significant predominance of the ABCB1 c.3435CC genotype was found among the recurrent infection-free patients (p < 0.01), suggesting a role for this transporter in AL inter-individual performance.

PMID: 28934955 [PubMed - in process]

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer.

Acta Pharmacol Sin. 2017 Apr;38(4):581-590

Authors: Gong WJ, Peng JB, Yin JY, Li XP, Zheng W, Xiao L, Tan LM, Xiao D, Chen YX, Li X, Zhou HH, Liu ZQ

Abstract
Platinum-based chemotherapy is the standard first-line treatment for most lung cancer patients. However, the toxicity induced by platinum-based chemotherapy greatly impedes its clinical use. Previous studies showed that long non-coding RNAs (lncRNAs) with over 200 nucleotides in length affect drug response and toxicity. In the present study, we investigated the association of well-characterized lung cancer lncRNA polymorphisms with platinum-based chemotherapy toxicity in Chinese patients with lung cancer. A total of 467 lung cancer patients treated with platinum-based chemotherapy for at least two cycles were recruited. We primarily focused on gastrointestinal and hematological toxicities. A total of 14 potentially functional polymorphisms within 8 lncRNAs (HOTTIP, HOTAIT, H19, ANRIL, CCAT2, MALAT1, MEG3, and POLR2E) were genotyped. Unconditional logistical regression analysis was conducted to assess the associations. Gene-gene and gene-environment interactions were identified using the software generalized multifactor dimensionality reduction (GMDR). ANRIL rs1333049 was associated with severe overall toxicity in an additive model (adjusted OR=0.723, 95% CI=0.541-0.965, P=0.028). ANRIL rs1333049 was also associated with severe gastrointestinal toxicity in both the additive (adjusted OR=0.690, 95% CI=0.489-0.974, P=0.035) and dominant (adjusted OR=0.558, 95% CI=0.335-0.931, P=0.025) models. MEG3 rs116907618 was associated with severe gastrointestinal toxicity in an additive model (adjusted OR=1.717, 95% CI=1.007-2.927, P=0.047). GMDR identified the three-factor interaction model of POLR2E rs3787016-HOTTIP rs3807598-chemotherapy regimen as the best predictive model for hematological toxicity. In conclusion, ANRIL and MEG3 genetic polymorphisms are associated with severe platinum toxicity and could be considered as biomarkers for pretreatment evaluation in Chinese patients with lung cancer.

PMID: 28260796 [PubMed - indexed for MEDLINE]

Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose.

Oncotarget. 2017 Feb 21;8(8):13575-13585

Authors: Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y

Abstract
Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13-10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.

PMID: 28088792 [PubMed - indexed for MEDLINE]

The role of long non-coding RNAs in nasopharyngeal carcinoma: As systemic review.

Oncotarget. 2017 Feb 28;8(9):16075-16083

Authors: He R, Hu Z, Wang Q, Luo W, Li J, Duan L, Zhu YS, Luo DX

Abstract
Recent development of cutting edge research found that long noncoding RNAs (lncRNAs) plays important roles in carcinogenesis and progression. In Southeast Asia and North Africa, nasopharyngeal carcinoma (NPC) is the most common aggressive squamous cell carcinoma. Nasopharyngeal carcinoma is most frequently occurring in males. However, nasopharyngeal carcinoma is caused by a combination of several factors as viral, environmental factors, and heredity. Till now, the potential pathway or mechanism of NPC is not well known. In our present review, we strongly emphasized on long noncoding RNAs (lncRNAs) and its significant role in nasopharyngeal carcinoma. It has been showed that lncRNAs regulate the development and progression of different types of cancers, including NPC. In addition, it has been found that chromatin organization, transcriptional and post-transcriptional events are regulated by lncRNAs. Our present review summarizes the roles of lncRNAs in nasopharyngeal carcinoma and provides an overview of the feasibility of lncRNAs as diagnosis, prognosis and potential treatment for NPC patients.

PMID: 28039476 [PubMed - indexed for MEDLINE]

New Laboratory Tests in Psychiatry: What Should Mental Health Practitioners Know?

J Psychiatr Pract. 2016 Jul;22(4):308-12

Authors: Preskorn SH

Abstract
In recent years, a significant upsurge in the development of new laboratory tests for use in psychiatric practice has occurred. This column discusses salient questions about those tests to help mental health practitioners better understand the potential role of such tests in their clinical practices. These issues are particularly relevant for mental health professionals who prescribe psychotropic medications. The column does not provide an exhaustive list of tests nor does it review the pros and cons of any specific company's tests.

PMID: 27427842 [PubMed - indexed for MEDLINE]

Importance of Publishing Adverse Drug Reaction Case Reports: Promoting Public Health and Advancing Pharmacology and Therapeutics.

Drug Saf Case Rep. 2017 Sep 20;4(1):11

Authors: Shah RR

Abstract
This article, which encourages physicians to publish case reports of adverse drug reactions (ADRs), is a review of how well-documented published case reports have contributed to promoting public safety and health and thus served to advance basic pharmacology. The origin of a number of regulatory guidelines can ultimately be traced to safety concerns triggered by such reports. It illustrates how case reports of ADRs, when coupled with simultaneous monitoring of drug pharmacokinetics, have also led to further investigations resulting in major advances in pharmacology, especially pharmacogenetics, mechanisms of drug-drug interactions and modulation of drug metabolism during inflammatory co-morbidities. Published case reports differ significantly from spontaneous case reports since they enjoy quality-compliant peer review and an immediate wider visibility among the readership, triggering others to report similar cases, and ultimately leading to prescribing restrictions on or withdrawals of the drug from the market depending on the risk. Therefore, the reporter should not be discouraged by (a) the unusual or bizarre nature of the reaction; (b) the interval, however long, from commencing drug administration to the onset of the suspected reaction; (c) however well-known the drug or the period for which it has been on the market; and (d) any pressure not to publish. Case reports should be published in reputable journals that are searchable through databases such as PubMed.

PMID: 28933008 [PubMed]

Derivatives of Bst-like Gss-polymerase with improved processivity and inhibitor tolerance.

Nucleic Acids Res. 2017 Sep 19;45(16):9595-9610

Authors: Oscorbin IP, Belousova EA, Boyarskikh UA, Zakabunin AI, Khrapov EA, Filipenko ML

Abstract
At the moment, one of the actual trends in medical diagnostics is a development of methods for practical applications such as point-of-care testing, POCT or research tools, for example, whole genome amplification, WGA. All the techniques are based on using of specific DNA polymerases having strand displacement activity, high synthetic processivity, fidelity and, most significantly, tolerance to contaminants, appearing from analysed biological samples or collected under purification procedures. Here, we have designed a set of fusion enzymes based on catalytic domain of DNA polymerase I from Geobacillus sp. 777 with DNA-binding domain of DNA ligase Pyrococcus abyssi and Sto7d protein from Sulfolobus tokodaii, analogue of Sso7d. Designed chimeric DNA polymerases DBD-Gss, Sto-Gss and Gss-Sto exhibited the same level of thermal stability, thermal transferase activity and fidelity as native Gss; however, the processivity was increased up to 3-fold, leading to about 4-fold of DNA product in WGA which is much more exiting. The attachment of DNA-binding proteins enhanced the inhibitor tolerance of chimeric polymerases in loop-mediated isothermal amplification to several of the most common DNA sample contaminants-urea and whole blood, heparin, ethylenediaminetetraacetic acid, NaCl, ethanol. Therefore, chimeric Bst-like Gss-polymerase will be promising tool for both WGA and POCT due to increased processivity and inhibitor tolerance.

PMID: 28934494 [PubMed - in process]

Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.

J Infect Dis. 2017 Sep 01;216(5):554-564

Authors: Mollan KR, Tierney C, Hellwege JN, Eron JJ, Hudgens MG, Gulick RM, Haubrich R, Sax PE, Campbell TB, Daar ES, Robertson KR, Ventura D, Ma Q, Edwards DRV, Haas DW, AIDS Clinical Trials Group

Abstract
Background: We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States.
Methods: Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates.
Results: Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication.
Conclusions: Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.

PMID: 28931220 [PubMed - in process]

Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.

Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):235-250

Authors: Malki K, Tosto MG, Mouriño-Talín H, Rodríguez-Lorenzo S, Pain O, Jumhaboy I, Liu T, Parpas P, Newman S, Malykh A, Carboni L, Uher R, McGuffin P, Schalkwyk LC, Bryson K, Herbster M

Abstract
Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi-class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene-network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

PMID: 27696737 [PubMed - indexed for MEDLINE]

Preliminary examination of microRNA expression profiling in bipolar disorder I patients during antipsychotic treatment.

Am J Med Genet B Neuropsychiatr Genet. 2016 Sep;171(6):867-74

Authors: Lim CH, Zainal NZ, Kanagasundram S, Zain SM, Mohamed Z

Abstract
Although major progress has been achieved in research and development of antipsychotic medications for bipolar disorder (BPD), knowledge of the molecular mechanisms underlying this disorder and the action of atypical antipsychotics remains incomplete. The levels of microRNAs (miRNAs)-small non-coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity-are frequently altered in psychiatric disorders. This study aimed to examine changes in miRNA expression in bipolar mania patients after treatment with asenapine and risperidone. Using a miRNA microarray, we analyzed miRNA expression in the blood of 10 bipolar mania patients following 12 weeks of treatment with asenapine or risperidone. Selected miRNAs were validated by using real-time PCR. A total of 16 miRNAs were differentially expressed after treatment in the asenapine group, 14 of which were significantly upregulated and the other two significantly downregulated. However, all three differentially expressed miRNAs in the risperidone group were downregulated. MiRNA target gene prediction and gene ontology analysis revealed significant enrichment for pathways associated with immune system response and regulation of programmed cell death and transcription. Our results suggest that candidate miRNAs may be involved in the mechanism of action of both antipsychotics in bipolar mania. © 2016 Wiley Periodicals, Inc.

PMID: 27177356 [PubMed - indexed for MEDLINE]

Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study.

Clin Pharmacokinet. 2016 Jul;55(7):861-73

Authors: Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, Khoo S, Back D, Orrell C, Clarke A, Losso M, Phanuphak P, Carey D, Cooper DA, Emery S, Puls R

Abstract
BACKGROUND: ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated.
METHODS: Relationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6, CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C12) cutoffs and 96-week pVL.
RESULTS: A total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C12, were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41-67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15-0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02-2.09, p = 0.040; OR 2.31, 95 % CI 1.33-4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19-5.43, p = 0.016). C12 between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks.
CONCLUSIONS: A higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy.

PMID: 26715213 [PubMed - indexed for MEDLINE]

Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency.

Int J Cancer. 2017 Sep 20;:

Authors: Henricks LM, Siemerink EJ, Rosing H, Meijer J, Goorden SM, Polstra AM, Zoetekouw L, Cats A, Schellens JH, van Kuilenburg AB

Abstract
Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exon 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every five days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively ten-fold and four-fold higher compared to control values of patients receiving capecitabine 850 mg/m(2) . When extrapolating from the dosing schedule of once every five days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients. This article is protected by copyright. All rights reserved.

PMID: 28929491 [PubMed - as supplied by publisher]

Revisiting inconsistency in large pharmacogenomic studies.

F1000Res. 2016;5:2333

Authors: Safikhani Z, Smirnov P, Freeman M, El-Hachem N, She A, Rene Q, Goldenberg A, Birkbak NJ, Hatzis C, Shi L, Beck AH, Aerts HJWL, Quackenbush J, Haibe-Kains B

Abstract
In 2013, we published a comparative analysis mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized in the 471 cancer cell lines screened in the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE). While we found good concordance in gene expression profiles, there was substantial inconsistency in the drug responses reported by the GDSC and CCLE projects. We received extensive feedback on the comparisons that we performed. This feedback, along with the release of new data, prompted us to revisit our initial analysis. Here we present a new analysis using these expanded data in which we address the most significant suggestions for improvements on our published analysis - that targeted therapies and broad cytotoxic drugs should have been treated differently in assessing consistency, that consistency of both molecular profiles and drug sensitivity measurements should both be compared across cell lines, and that the software analysis tools we provided should have been easier to run, particularly as the GDSC and CCLE released additional data.             Our re-analysis supports our previous finding that gene expression data are significantly more consistent than drug sensitivity measurements. The use of new statistics to assess data consistency allowed us to identify two broad effect drugs and three targeted drugs with moderate to good consistency in drug sensitivity data between GDSC and CCLE. For three other targeted drugs, there were not enough sensitive cell lines to assess the consistency of the pharmacological profiles. We found evidence of inconsistencies in pharmacological phenotypes for the remaining eight drugs.             Overall, our findings suggest that the drug sensitivity data in GDSC and CCLE continue to present challenges for robust biomarker discovery. This re-analysis provides additional support for the argument that experimental standardization and validation of pharmacogenomic response will be necessary to advance the broad use of large pharmacogenomic screens.

PMID: 28928933 [PubMed]

Downregulation of Rab27A contributes to metformin-induced suppression of breast cancer stem cells.

Oncol Lett. 2017 Sep;14(3):2947-2953

Authors: Feng F, Zhang J, Fan X, Yuan F, Jiang Y, Lv R, Ma Y

Abstract
Cancer stem cells (CSCs) are associated with tumor initiation, therapeutic resistance, relapse and metastasis. However, the underlying mechanisms CSCs use to preserve stemness are not yet fully understood. The present study demonstrated that the expression of RAB27A, member RAS oncogene family (Rab27a), which was reported to promote tumor progression by upregulating exocytosis of extracellular vesicles, was higher in mammosphere cells than in adherent MDA-MB-231 breast cancer cells. Downregulation of Rab27A inhibited mammosphere formation by decreasing the proportion of CD44+CD24-/low cells of the MDA-MB-231 cell line. Furthermore, Rab27A overexpression redistributed the cell cycle of breast (b) CSCs. The present study revealed that downregulation of Rab27A enhanced the capacity of metformin, the most widely used oral hypoglycemic drug for the treatment of type II diabetes, to inhibit mammosphere growth. Metformin reduced the expression of Rab27A dose-dependently. These data suggested that Rab27A acts as a mediator of human bCSCs by promoting the growth of mammospheres and that synergistic suppression of Rab27A, alone or in combination with metformin, holds promise for therapeutically targeting bCSCs.

PMID: 28928832 [PubMed]

Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening and in vitro biological activities study.

Oncotarget. 2017 Mar 14;8(11):18118-18128

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

Abstract
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer's disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against Aβ25-35- induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer's disease treatment.

PMID: 28179579 [PubMed - indexed for MEDLINE]

Cancer Precision Medicine: From Cancer Screening to Drug Selection and Personalized Immunotherapy.

Trends Pharmacol Sci. 2017 Jan;38(1):15-24

Authors: Deng X, Nakamura Y

Abstract
With the accelerating progress in basic and clinical cancer research, a huge body of new discoveries and powerful technologies has allowed us to implement a 'Cancer Precision Medicine (CPM)' system for cancer patients. The CPM system covers a wide range of cancer management including cancer screening, monitoring of relapse/recurrence, selection/prediction of effective drugs/treatments, and personalized immunotherapy. In this system individual cancer patients expect to receive personalized care: an appropriate dose of the right drug at the right time. We here aim to summarize and discuss a possible workflow for precision medicine for cancer patients by reviewing recent booming technologies and treatments that have been used or will potentially be used in the CPM system.

PMID: 27842888 [PubMed - indexed for MEDLINE]

Precision Obesity Treatments Including Pharmacogenetic and Nutrigenetic Approaches.

Trends Pharmacol Sci. 2016 Jul;37(7):575-93

Authors: Solas M, Milagro FI, Martínez-Urbistondo D, Ramirez MJ, Martínez JA

Abstract
Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management.

PMID: 27236593 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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

pharmacogenomics

These pubmed results were generated on 2017/09/19

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.