Bidirectional scaling of vocal variability by an avian cortico-basal ganglia circuit.

Physiol Rep. 2018 04;6(8):e13638

Authors: Heston JB, Simon J, Day NF, Coleman MJ, White SA

Abstract
Behavioral variability is thought to be critical for trial and error learning, but where such motor exploration is generated in the central nervous system is unclear. The zebra finch songbird species offers a highly appropriate model in which to address this question. The male song is amenable to detailed measurements of variability, while the brain contains an identified cortico-basal ganglia loop that underlies this behavior. We used pharmacogenetic interventions to separately interrogate cortical and basal ganglia nodes of zebra finch song control circuitry. We show that bidirectional manipulations of each node produce near mirror image changes in vocal control: Cortical activity promotes song variability, whereas basal ganglia activity promotes song stability. Furthermore, female conspecifics can detect these pharmacogenetically elicited changes in song quality. Our results indicate that cortex and striatopallidum can jointly and reciprocally affect behaviorally relevant levels of vocal variability, and point to endogenous mechanisms for its control.

PMID: 29687960 [PubMed - indexed for MEDLINE]

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.

Nat Genet. 2018 02;50(2):206-218

Authors: Chen M, Zhang J, Sampieri K, Clohessy JG, Mendez L, Gonzalez-Billalabeitia E, Liu XS, Lee YR, Fung J, Katon JM, Menon AV, Webster KA, Ng C, Palumbieri MD, Diolombi MS, Breitkopf SB, Teruya-Feldstein J, Signoretti S, Bronson RT, Asara JM, Castillo-Martin M, Cordon-Cardo C, Pandolfi PP

Abstract
Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

PMID: 29335545 [PubMed - indexed for MEDLINE]

Richtlinie der Gendiagnostik-Kommission (GEKO) für die Beurteilung genetischer Eigenschaften hinsichtlich ihrer Bedeutung für die Wirkung eines Arzneimittels bei einer Behandlung gemäß § 23 Abs. 2 Nr. 1b GenDG : In der Fassung vom 25. 11. 2016, veröffentlicht und in Kraft getreten am 06. 12. 2016.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2017 Apr;60(4):472-475

Authors:

PMID: 28342063 [PubMed - indexed for MEDLINE]

Correction to: TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women.

Mol Biol Rep. 2019 May 11;:

Authors: Włodarczyk M, Ciebiera M, Nowicka G

Abstract
The original publication has been updated. The names in the original publication were not in the correct order. The family name was followed by the first name. This is now corrected.

PMID: 31079317 [PubMed - as supplied by publisher]

Prospective evaluation of finger two-point discrimination and carpal tunnel syndrome among women with breast cancer receiving adjuvant aromatase inhibitor therapy.

Breast Cancer Res Treat. 2019 May 11;:

Authors: Sheng JY, Blackford AL, Bardia A, Venkat R, Rosson G, Giles J, Hayes DF, Jeter SC, Zhang Z, Hayden J, Nguyen A, Storniolo AM, Tarpinian K, Henry NL, Stearns V

Abstract
PURPOSE: Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs.
METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant.
RESULTS: Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms.
CONCLUSION: For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.

PMID: 31079282 [PubMed - as supplied by publisher]

Distribution of the cytochrome P450 2C8*2 allele in Brazzaville, Republic of Congo.

Int J Infect Dis. 2019 May 09;:

Authors: Peko SM, Ntoumi F, Vouvoungui C, Nderu D, Kobawila SC, Thirumalaisamy VP, Koukouikila Koussounda F

Abstract
BACKGROUND: Cytochrome P450 (CYP) enzymes are essential in the metabolism of most drugs used today. Single nucleotide polymorphism(s) occurring in CYP genes can adversely affect drug pharmacokinetics, efficacy and safety. Individuals carrying CYP2C8*2 c.805A > T (CYP2C8*2; rs11572103) allele have impaired amodiaquine (AQ) metabolism, increased risk of amodiaquine - related adverse events and may promote selection of drug - resistant parasite strains. This study investigated the distribution of CYP2C8*2 allele in Brazzaville, Republic of Congo, where artenusate + amodiaquine is used as second - line treatment for uncomplicated P. falciparum malaria.
METHODS: A total of 285 febrile children visiting the Marien Ngouabi pediatric hospital were genotyped for CYP2C8*2 using PCR - Restriction Fragment Length Polymorphism (PCR-RFLP). The allele frequencies and genotype distribution were determined.
RESULTS: The CYP2C8*2 allele was successfully genotyped in 75% (213/285) of the study participants. CYP2C8*2A allele had a frequency of 63% whereas CYP2C8*2T allele had 37%. Genotypes CYP2C8*2AA (rapid metaboliser), CYP2C8*2AT (intermediate metaboliser) and CYP2C8*2TT (poor metaboliser) were observed in 44%, 38% and 18% of the investigated participants, respectively.
CONCLUSION: This study gives the first description of CYP2C8*2 allele distribution in the Republic of Congo and highlights the potential risk of AQ - related adverse events. Information from this study will be beneficial during pharmacovigilance investigations.

PMID: 31078747 [PubMed - as supplied by publisher]

Should we treat bacteremic prostatitis for 7 days?

Clin Infect Dis. 2019 May 11;:

Authors: De Greef J, Doyen L, Henrard S, Elens L, Vandercam B, Belkhir L

PMID: 31077264 [PubMed - as supplied by publisher]

Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists.

J Mol Diagn. 2019 May 07;:

Authors: Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE

Abstract
The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes/allele testing across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity-associated genes/alleles.

PMID: 31075510 [PubMed - as supplied by publisher]

Unraveling the genetic underpinnings of sleep deprivation-induced impairments in human cognition.

Prog Brain Res. 2019;246:127-158

Authors: Satterfield BC, Stucky B, Landolt HP, Van Dongen HPA

Abstract
The biobehavioral phenomena of sleep and cognition involve complex phenotype-genotype associations, i.e., complex relationships between observable traits and the genetic variants that contribute to the expression of those traits. There is a general belief that investigating such relationships requires large sample sizes. However, sleep- and cognition-related phenotype-genotype associations may be strengthened through carefully controlled laboratory studies that amplify a given cognitive phenotype by perturbing the biobehavioral system through sleep deprivation and/or pharmacogenetic interventions. Utilization of performance tasks that dissociate cognitive processes allows for cognitive endophenotyping, that is, making precise measurements that capture the essence of a cognitive phenotype. This enables assessment of the genetic underpinnings of cognitive impairment due to sleep deprivation without necessarily requiring large samples. Theory-driven gene selection, selective population sampling techniques to avoid underrepresentation of rare genetic variants, and modern statistical techniques informed by prior knowledge further enhance statistical power. Here we illustrate these approaches on the basis of recent findings, supplemented with some new results, as well as a discussion of modern regression methods for statistical analysis. Ongoing research employing these methods is driving advancements in the understanding of the genetic underpinnings of cognitive impairment associated with sleep loss.

PMID: 31072559 [PubMed - in process]

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pharmacogenomics

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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 2019/05/09

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.

Relative proteome quantification of alpha, beta, gamma and delta globin chains in early eluting peaks of Bio-Rad variant II® CE-HPLC of hemoglobin from healthy and beta-thalassemia subjects in Malaysia.

Biochem Biophys Rep. 2019 Jul;18:100635

Authors: Abdullah UYH, Ibrahim HM, Jassim HM, Salleh MZ, Kek TL, Fakhruzzaman Bin Noorizhab MN, Zilfalil BA, Wilairat P, Fucharoen S

Abstract
This is the first report of QQQ-mass spectrometric identification and quantification of the Hb subunits, alpha, beta, delta and gamma globin peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the Bio-Rad cation-exchange chromatography of haemoglobin. The objectives were to assess the relationship of the quantity of the free alpha, beta, delta and gamma globin chains with the phenotypic diversity of beta-thalassaemias (β-thal). The results demonstrate that the pools of free globin chains in red blood cells were correlating with the severity of the disease in patients with different phenotypes of β-thal. The mechanism and the regulation of synthesis of free globin chains pool in a normal individual and in patients with different β-thal phenotypes could arise from several mechanisms which will require further investigation. The role of the free globin pool in patients with β-thal for development of novel therapeutic approaches based on these potential targets requires further investigation. Pertinent biomarkers improves the diagnosis of the β-thal, especially in low-income countries where they are most common and allows more effective therapeutic intervention leading to more successful therapeutic outcome.

PMID: 31061897 [PubMed]

Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial.

Pharmacotherapy. 2019 May 07;:

Authors: De Vane CL, Charles JM, Abramson RK, Williams JE, Carpenter LA, Raven S, Gwynette F, Stuck CA, Geesey ME, Bradley C, Donovan JL, Hall AG, Sherk ST, Powers NR, Spratt E, Kinsman A, Kruesi MJ, Bragg JE

Abstract
STUDY OBJECTIVE: The objective of this trial-Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART)-was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety.
DESIGN: Randomized, double-blind, parallel-group study.
SETTING: Three academic medical centers and a single private pediatric practice.
PATIENTS: Eighty children or adolescents (aged 6-17 years) with autistic disorder were enrolled, and 61 patients were randomized to study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase.
INTERVENTION: All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed United States Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks.
MEASUREMENTS AND MAIN RESULTS: Safety, physical, and psychological assessments were recorded weekly or every two weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist irritability subscale after one week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26).
CONCLUSION: Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within one week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder. This article is protected by copyright. All rights reserved.

PMID: 31063671 [PubMed - as supplied by publisher]

Pharmacogenetics in personalised drug therapy.

Tidsskr Nor Laegeforen. 2019 May 06;:

Authors: Tuv SS, Nordal K, Vethe NT, Bergan S

PMID: 31062549 [PubMed - as supplied by publisher]

[Fission Yeast as a Model System for Studying Cancer Signaling and Drug Discovery: Discovery of ACA-28 as a Novel Inducer of ERK-dependent Apoptosis Reveals a New Cancer Therapy].

Yakugaku Zasshi. 2019;139(5):753-758

Authors: Sugiura R

Abstract
Mitogen-activated protein kinase (MAPK) pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, and apoptosis. The Ras/Raf/MEK/ERK MAPK pathway is one of the most studied of the mammalian MAPK pathways and has attracted intense research interest because of its critical involvement in the regulation of cell proliferation. The mutational activation of upstream signaling components that constitutively activate ERK MAPKs as seen in various primary tumor samples has validated this pathway for drug discovery. The fission yeast Schizosaccharomyces pombe is an important tool for cancer research. This well-studied model organism has enabled groundbreaking, Nobel Prize-winning discoveries and has provided insights into how both normal and cancerous cells grow and divide. We performed chemical genetic screening using a fission yeast phenotypic assay and demonstrated that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. Importantly, the growth of normal human epidermal melanocytes was less affected by ACA-28. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells oncogenically transformed with HER2/ErbB2 but not in the parental cells. Notably, the ACA-28-induced apoptosis was abrogated when ERK activation was blocked with the specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells as compared with normal human epidermal melanocytes. ACA-28 might serve as a promising seed compound to combat ERK-dependent cancers by stimulating oncogenic signaling.

PMID: 31061345 [PubMed - in process]

[Innovative Cancer Therapeutics Propelled by Model Organisms: Paradigm Shift in Drug Discovery and Diagnosis for Cancer].

Yakugaku Zasshi. 2019;139(5):731-732

Authors: Sugiura R

PMID: 31061342 [PubMed - in process]

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Cereb Cortex. 2018 03 01;28(3):880-893

Authors: Wu GY, Liu SL, Yao J, Sun L, Wu B, Yang Y, Li X, Sun QQ, Feng H, Sui JF

Abstract
Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

PMID: 28077515 [PubMed - indexed for MEDLINE]

Polymorphisms in Dopaminergic Genes in Schizophrenia and Their Implications in Motor Deficits and Antipsychotic Treatment.

Front Neurosci. 2019;13:355

Authors: Ye J, Ji F, Jiang D, Lin X, Chen G, Zhang W, Shan P, Zhang L, Zhuo C

Abstract
Dopaminergic system dysfunction is involved in schizophrenia (SCZ) pathogenesis and can mediate SCZ-related motor disorders. Recent studies have gradually revealed that SCZ susceptibility and the associated motor symptoms can be mediated by genetic factors, including dopaminergic genes. More importantly, polymorphisms in these genes are associated with both antipsychotic drug sensitivity and adverse effects. The study of genetic polymorphisms in the dopaminergic system may help to optimize individualized drug strategies for SCZ patients. This review summarizes the current progress about the involvement of the dopamine system in SCZ-associated motor disorders and the motor-related adverse effects after antipsychotic treatment, with a special focus on polymorphisms in dopaminergic genes. We hypothesize that the genetic profile of the dopaminergic system mediates both SCZ-associated motor deficits associated and antipsychotic drug-related adverse effects. The study of dopaminergic gene polymorphisms may help to predict drug efficacy and decrease adverse effects, thereby optimizing treatment strategies.

PMID: 31057354 [PubMed]

Pharmacogenetic Testing: Why Is It So Disappointing?

J Psychosoc Nurs Ment Health Serv. 2019 Apr 01;57(4):9-12

Authors: Limandri BJ

Abstract
Pharmacogenetic testing to aid in making decisions about prescribing medications was approved by the U.S. Food and Drug Administration in 2005 and gradually became a common practice. However, an innovation that was thought to help individualize prescribing psychotropic medications with fewer trials and errors soon became a disappointment to clinicians. Current pharmacogenetic testing assesses how the liver metabolizes drugs through the cytochrome p 450 system; however, much of the variability in how a drug affects an individual also relies on the pharmacodynamics of the drug (i.e., the specific ways the drug changes the body). The current article discusses the advantages and disadvantages of pharmacogenetic testing to aid in prescribing psychotropic medications. [Journal of Psychosocial Nursing and Mental Health Services, 57(4), 9-12.].

PMID: 30933297 [PubMed - indexed for MEDLINE]

Drug-Drug Interactions With Oral Antineoplastic Agents.

JAMA Oncol. 2017 06 01;3(6):736-738

Authors: Parsad S, Ratain MJ

PMID: 27737450 [PubMed - indexed for MEDLINE]