Benefits of and Barriers to Pharmacogenomics-Guided Treatment for Major Depressive Disorder.

Clin Pharmacol Ther. 2018 Feb 01;:

Authors: Ahmed AT, Weinshilboum R, Frye MA

Abstract
Antidepressants have reduced the symptom burden for many Major Depressive Disorder (MDD) patients, but drug-related side effects and treatment resistance continue to present major challenges. Pharmacogenomics represents one approach to enhance antidepressant efficacy and avoid adverse reactions, but concerns remain with regard to the overall "value equation," and several barriers must be overcome to achieve the full potential of MDD pharmacogenomics.

PMID: 29388201 [PubMed - as supplied by publisher]

Pharmacogenomics: Know your GPCR mutations (and target them right).

Nat Rev Drug Discov. 2018 Feb 01;17(2):94

Authors: Villanueva MT

PMID: 29386607 [PubMed - in process]

Pharmacogenetic Tests in Psychiatry.

Am J Psychiatry. 2018 Feb 01;175(2):189

Authors: Bousman C, Allen J, Eyre HA

PMID: 29385827 [PubMed - in process]

The Impact of Disease and Drugs on Hip Fracture Risk.

Calcif Tissue Int. 2017 Jan;100(1):1-12

Authors: Leavy B, Michaëlsson K, Åberg AC, Melhus H, Byberg L

Abstract
We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ≥50 years (n = 117,494) including all incident hip fractures during 1 year (n = 477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0-S72.2) during 1 year (2009-2010). Exposures included: prevalence of (1) inpatient diseases [International Classification of Diseases (ICD) codes A00-T98 in the National Patient Register 1987-2010] and (2) prescribed drugs dispensed in 2010 or the year prior to fracture. We present age- and sex-standardized risk ratios (RRs), risk differences (RDs) and population attributable risks (PARs) of disease and drug categories in relation to hip fracture risk. All disease categories were associated with increased risk of hip fracture. Largest risk ratios and differences were for mental and behavioral disorders, diseases of the blood and previous fracture (RRs between 2.44 and 3.00; RDs (per 1000 person-years) between 5.0 and 6.9). For specific drugs, strongest associations were seen for antiparkinson (RR 2.32 [95 % CI 1.48-1.65]; RD 5.2 [1.1-9.4]) and antidepressive drugs (RR 1.90 [1.55-2.32]; RD 3.1 [2.0-4.3]). Being prescribed ≥10 drugs during 1 year incurred an increased risk of hip fracture, whereas prescription of cardiovascular drugs or ≤5 drugs did not appear to increase risk. Diseases inferring the greatest PARs included: cardiovascular diseases PAR 22 % (95 % CI 14-29) and previous injuries (PAR 21 % [95 % CI 16-25]; for specific drugs, antidepressants posed the greatest risk (PAR 16 % [95 % CI 12.0-19.3]).

PMID: 27671989 [PubMed - indexed for MEDLINE]

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 2018/02/01

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.

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 2018/01/31

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.

Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug.

Br J Clin Pharmacol. 2018 Jan 28;:

Authors: Zhao W, Leroux S, Biran V, Jacqz-Aigrain E

Abstract
BACKGROUND: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug.
METHODS: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM.
RESULTS: Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CLOMZ-M1 ) increases with postnatal age. In CYP2C19 poor and intermediate metabolizer, model-predicted CLOMZ-M1 are 12.5% (5%-95% percentile: 3%-14.9%) and 44.9% (5%-95% percentile: 29.9%-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant (Ka) of omeprazole is 6.93 (5%-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5%-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients.
CONCLUSIONS: Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semi-physiological developmental pharmacokinetic modeling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation.

PMID: 29377228 [PubMed - as supplied by publisher]

A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S-1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG-M01 study).

Cancer Med. 2017 Dec;6(12):2909-2917

Authors: Ishiguro H, Saji S, Nomura S, Tanaka S, Ueno T, Onoue M, Iwata H, Yamanaka T, Sasaki Y, Toi M

Abstract
S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose-escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m2  days 1-8 and S-1 80 mg/m2  days 1-14 every 3 weeks; level 2: irinotecan 100 mg/m2 and S-1 80 mg/m2 ). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34+ circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34+ CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation.

PMID: 29131533 [PubMed - indexed for MEDLINE]

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier.

Acta Pharmacol Sin. 2017 Jun;38(6):823-834

Authors: Sun JJ, Chen YC, Huang YX, Zhao WC, Liu YH, Venkataramanan R, Lu BF, Li S

Abstract
To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10 micelles displayed spherical morphology with a size of ∼170 nm. DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells. In 4T1.2 tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs. The PSSN10 carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments, and significantly inhibited tumor growth in vivo. DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice. In addition, a more immunoactive tumor microenvironment was observed in the mice treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in synergistic anti-tumor activity.

PMID: 28504251 [PubMed - indexed for MEDLINE]

Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience.

Oncologist. 2017 Feb;22(2):144-151

Authors: Knepper TC, Bell GC, Hicks JK, Padron E, Teer JK, Vo TT, Gillis NK, Mason NT, McLeod HL, Walko CM

Abstract
BACKGROUND: The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice.
MATERIALS AND METHODS: In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine.
RESULTS: Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting-edge practice merged with individualized preferences in treatment and care.
CONCLUSIONS: Genomic-driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence-based translation of observed molecular alterations into patient-centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards. The Oncologist 2017;22:144-151Implications for Practice: It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards.

PMID: 28179575 [PubMed - indexed for MEDLINE]

Circulating tumor stem like cells in oral squamous cell carcinoma: An unresolved paradox.

Oral Oncol. 2016 Nov;62:139-146

Authors: Patel S, Shah K, Mirza S, Shah K, Rawal R

Abstract
OBJECTIVE: Circulating tumor cells (CTCs) are increasingly gaining importance due to their immense potential in enhancing diagnosis, prognosis and response to therapy in solid malignancies. Therefore, we aimed to comprehend the molecular diversity and critical role of this disseminated tumor population in OSCC.
METHODOLOGY: CD44+ subpopulation was isolated using immuno-magnetic cell separation and their purity was validated using flow cytometry. Characterisation of self renewal potential and resistance to chemotherapy was assessed using tumor sphere forming and cytotoxicity assay. Gene expression profile of pertinent CSC (CD44s, CD44v3, CD44v6) and stemness markers (Bmi1 and Nanog) was carried out in CD44+ cells using Real Time PCR. Predominantly expressed markers and their association with clinico-pathological conditions were substantiated in 30 OSCC patients.
RESULT: Flow cytometry analysis depicted a predominant population of CD44+CD24-CD45- cells suggesting that circulating tumor cells had a subpopulation of CSC like cells in the circulation. These cells demonstrated increased sphere forming capability and intrinsic chemo-resistance compared to non-CSC, thus indicating the CSC features of self-renewal and chemo-resistance. Additionally, CD44+ cells showed significantly increased expression levels of CD44v6 and Nanog compared to CD44- cells. Clinically, expression pattern of CD44v6 and Nanog correlated with different anatomical subsites, loco-regional aggressiveness of the disease and recurrence, thus opening newer avenues that can be explored for better prognostic and therapeutic implications.
CONCLUSION: This study explored the inevitable role of CD44v6 and Nanog as circulating stem like cell markers in assessment of loco-regional aggressiveness, detection of relapse and therapeutic response and resistance.

PMID: 27865367 [PubMed - indexed for MEDLINE]

Payer view of personalized medicine.

Am J Health Syst Pharm. 2016 Dec 01;73(23):2007-2012

Authors: Pezalla EJ

Abstract
PURPOSE: The process and methods used by payers when evaluating coverage of personalized medicine testing are described.
SUMMARY: Personalized medicine encompasses a number of diagnostic tools that measure drug metabolism, genetic risk for disease development, and tumor type or markers that can guide oncology treatments. However, whole genome testing, tumor marker testing, and testing for drug metabolism are additional costs to the healthcare system. In order to justify these costs, payers and health technology assessment bodies must evaluate the individual tests or groups of tests on their own merits. In order for a test to be covered by payers, test developers must demonstrate clinical utility as measured by improved outcomes or well-informed decision-making. In the United States, payers generally focus on clinical benefit to individual patients and benefits to the healthcare system. Clinical benefits include improved outcomes. Benefits to the healthcare system are generally considered to be cost offsets, which may be due to reductions in the use of unnecessary interventions or to more efficient use of resources. Provider organizations have been assuming more responsibility and liability for healthcare costs through various risk arrangements, including accountable care organizations and patient-centered medical homes. Diagnostic tests that increase efficiency, reduce unnecessary interventions, and improve outcomes will be chosen by specialists in provider organizations.
CONCLUSION: For personalized medicine approaches to be adopted and covered by health plans, the methods must be shown to be analytically and clinically valid and provide clinical utility at a reasonable level of cost-effectiveness to payers.

PMID: 27864208 [PubMed - indexed for MEDLINE]

PharmGKB summary: very important pharmacogene information for MT-RNR1.

Pharmacogenet Genomics. 2016 12;26(12):558-567

Authors: Barbarino JM, McGregor TL, Altman RB, Klein TE

PMID: 27654872 [PubMed - indexed for MEDLINE]

Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: 1H-MRS Study.

Int J Neuropsychopharmacol. 2016 Aug;19(8):

Authors: Soeiro-de-Souza MG, Pastorello BF, Leite Cda C, Henning A, Moreno RA, Garcia Otaduy MC

Abstract
OBJECTIVE: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls.
METHODS: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program.
RESULTS: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed.
CONCLUSION: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.

PMID: 27207914 [PubMed - indexed for MEDLINE]

Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients.

Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jan 24;:

Authors: Angyal N, Horvath EZ, Tarnok Z, Richman MJ, Bognar E, Lakatos K, Sasvari-Szekely M, Nemoda Z

Abstract
AIMS: Methylphenidate (MPH) is the most frequently prescribed drug in Attention Deficit Hyperactivity Disorder (ADHD). Hitherto mostly the dopamine transporter gene has been studied in MPH-response and only a few studies analyzed the norepinephrine transporter (NET, SLC6A2) gene, although MPH is a potent inhibitor of both dopamine and norepinephrine transporters. We aimed to analyze this monoamine transporter gene in relation to ADHD per se and MPH-response in particular to gain further knowledge in ADHD pharmacogenetics using a Caucasian sample.
METHODS: Six single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143, rs3785157, rs5569, rs7194256 SNP) were studied across the NET gene in 163 ADHD children (age: 9.3±2.6; 86.5% male) using ADHD-RS hyperactivity-impulsivity and inattention scales. For case-control analysis 486 control subjects were also genotyped. At the MPH-response analysis responders had minimum 25% decrease of ADHD-RS total score after 2months of treatment, and chi-square test compared 90 responders and 32 non-responders, whereas ANOVA was used to assess symptom improvement after the first month among the 122 ADHD patients.
RESULTS: The classical case-control analysis did not yield any association with ADHD diagnosis, which was supported by meta-analysis conducted on the available genetic data (combining previously published and the present studies). On the other hand, the intronic rs3785143 showed nominal association with inattention symptoms (p=0.01). The haplotype analysis supported this association, and indicated the importance of the first haploblock encompassing the intronic and 2 promoter SNPs. With MPH-response only the promoter rs28386840 showed nominal association: Those with at least one T-allele were overrepresented in the responder group (42% vs 19%, p=0.08), and they had better improvement on the hyperactivity-impulsivity scale compared to the AA genotype (p=0.04).
CONCLUSION: Although none of our single SNP findings remained significant after correcting for multiple testing, our results from the MPH-response analysis indicate the potential importance of promoter variants in the NET gene.

PMID: 29374517 [PubMed - as supplied by publisher]

How Primary Care Providers Talk to Patients about Genome Sequencing Results: Risk, Rationale, and Recommendation.

J Gen Intern Med. 2018 Jan 26;:

Authors: Vassy JL, Davis JK, Kirby C, Richardson IJ, Green RC, McGuire AL, Ubel PA

Abstract
BACKGROUND: Genomics will play an increasingly prominent role in clinical medicine.
OBJECTIVE: To describe how primary care physicians (PCPs) discuss and make clinical recommendations about genome sequencing results.
DESIGN: Qualitative analysis.
PARTICIPANTS: PCPs and their generally healthy patients undergoing genome sequencing.
APPROACH: Patients received clinical genome reports that included four categories of results: monogenic disease risk variants (if present), carrier status, five pharmacogenetics results, and polygenic risk estimates for eight cardiometabolic traits. Patients' office visits with their PCPs were audio-recorded, and summative content analysis was used to describe how PCPs discussed genomic results.
KEY RESULTS: For each genomic result discussed in 48 PCP-patient visits, we identified a "take-home" message (recommendation), categorized as continuing current management, further treatment, further evaluation, behavior change, remembering for future care, or sharing with family members. We analyzed how PCPs came to each recommendation by identifying 1) how they described the risk or importance of the given result and 2) the rationale they gave for translating that risk into a specific recommendation. Quantitative analysis showed that continuing current management was the most commonly coded recommendation across results overall (492/749, 66%) and for each individual result type except monogenic disease risk results. Pharmacogenetics was the most common result type to prompt a recommendation to remember for future care (94/119, 79%); carrier status was the most common type prompting a recommendation to share with family members (45/54, 83%); and polygenic results were the most common type prompting a behavior change recommendation (55/58, 95%). One-fifth of recommendation codes associated with monogenic results were for further evaluation (6/24, 25%). Rationales for these recommendations included patient context, family context, and scientific/clinical limitations of sequencing.
CONCLUSIONS: PCPs distinguish substantive differences among categories of genome sequencing results and use clinical judgment to justify continuing current management in generally healthy patients with genomic results.

PMID: 29374360 [PubMed - as supplied by publisher]

Beyond genomics: understanding exposotypes through metabolomics.

Hum Genomics. 2018 Jan 26;12(1):4

Authors: Rattray NJW, Deziel NC, Wallach JD, Khan SA, Vasiliou V, Ioannidis JPA, Johnson CH

Abstract
BACKGROUND: Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact.
MAIN TEXT: Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics.
CONCLUSIONS: Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation.

PMID: 29373992 [PubMed - in process]

Genetic Polymorphism of Thiopurine S-methyltransferase in Children with Acute Lymphoblastic Leukemia in Jordan

Asian Pac J Cancer Prev. 2018 01 27;19(1):199-205

Authors: Alsous M, Yousef AM, Abdel Jalil M, Zawiah M, Yacoub S, Momani D, Gharabli A, Omar S, Rihani R

Abstract
Background and Aims: It has been demonstrated that homozygote and heterozygote mutant allele carriers for thiopurine S-methyltransferase (TPMT) are at high risk of developing myelosuppression after receiving standard doses of 6-mercaptopurine (6-MP). The aim of this study was to determine the frequency of TPMT deficient alleles in children with acute lymphoblastic leukemia (ALL) in Jordan and to compare it with other ethnic groups. Methods: We included 52 ALL childhood cases from King Hussein Cancer Research Center in Jordan. Genotyping of the rs1800460, rs1800462, and rs1142345 SNPs was performed by polymerase chain reaction (PCR) followed by sequencing. Comparisons were made with historical data for controls and for both volunteers and cases from other middle-eastern countries. Results: Mutant TPMT alleles were present in 3.8% (2/52) of patients. Allelic frequencies were 1.0% for both TPMT*B and TPMT*C. None of the patients were heterozygous or homozygous for TPMT*3A or TPMT *2. We did not find statistically significant differences in the distribution of mutant alleles between Jordan and other middle-eastern countries for both healthy volunteers or ALL patients. Conclusions: The overall frequency of TPMT mutant alleles was low and did not exhibit differences compared to other middle-eastern countries, including Jordanian studies assessing TPMT mutant alleles in healthy volunteers. The current results question the value of TPMT genotyping in the Jordanian population.

PMID: 29373914 [PubMed - as supplied by publisher]

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 2018/01/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

Biol Psychiatry. 2017 Dec 07;:

Authors: Ferguson BR, Gao WJ

Abstract
BACKGROUND: The mediodorsal thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. Maintaining the proper balance between excitation and inhibition (E/I balance) is of principal importance for organizing cortical activity. Furthermore, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders.
METHODS: Here, we used a pharmacogenetic strategy to decrease mediodorsal thalamic activity in adult male rats and evaluated the consequences for E/I balance in PFC pyramidal neurons as well as cognition, social interaction, and anxiety.
RESULTS: We found that dampening mediodorsal thalamic activity caused significant reductions in gamma-aminobutyric acidergic signaling and increased E/I balance in the mPFC and was concomitant with abnormalities in these behaviors. Furthermore, by selectively activating parvalbumin interneurons in the mPFC with a novel pharmacogenetic approach, we restored gamma-aminobutyric acidergic signaling and E/I balance as well as ameliorated all behavioral impairments.
CONCLUSIONS: These findings underscore the importance of thalamocortical activation of mPFC gamma-aminobutyric acidergic interneurons in a broad range of mPFC-dependent behaviors. Furthermore, they highlight this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.

PMID: 29373121 [PubMed - as supplied by publisher]