Dose-Dependent Effects of Intranasal Insulin on Resting-State Brain Activity.

J Clin Endocrinol Metab. 2018 01 01;103(1):253-262

Authors: Kullmann S, Veit R, Peter A, Pohmann R, Scheffler K, Häring HU, Fritsche A, Preissl H, Heni M

Abstract
Context: Insulin action in the human brain influences eating behavior, cognition, and whole-body metabolism. Studies investigating brain insulin rely on intranasal application.
Objective: To investigate effects of three doses of insulin and placebo as nasal sprays on the central and autonomous nervous system and analyze absorption of insulin into the bloodstream.
Design, Participants, and Methods: Nine healthy men received placebo or 40 U, 80 U, and 160 U insulin spray in randomized order. Before and after spray, brain activity was assessed by functional magnetic resonance imaging, and heart rate variability (HRV) was assessed from electrocardiogram. Plasma insulin, C-peptide, and glucose were measured regularly.
Setting: General community.
Results: Nasal insulin administration dose-dependently modulated regional brain activity and the normalized high-frequency component of the HRV. Post hoc analyses revealed that only 160 U insulin showed a considerable difference from placebo. Dose-dependent spillover of nasal insulin into the bloodstream was detected. The brain response was not correlated with this temporary rise in circulating insulin.
Conclusions: Nasal insulin dose-dependently modulated regional brain activity with the strongest effects after 160 U. However, this dose was accompanied by a transient increase in circulating insulin concentrations due to a spillover into circulation. Our current results may serve as a basis for future studies with nasal insulin to untangle brain insulin effects in health and disease.

PMID: 29095982 [PubMed - indexed for MEDLINE]

Gαi Proteins are Indispensable for Hearing.

Cell Physiol Biochem. 2018 Jun 21;47(4):1509-1532

Authors: Beer-Hammer S, Lee SC, Mauriac SA, Leiss V, Groh IAM, Novakovic A, Piekorz RP, Bucher K, Chen C, Ni K, Singer W, Harasztosi C, Schimmang T, Zimmermann U, Pfeffer K, Birnbaumer L, Forge A, Montcouquiol M, Knipper M, Nürnberg B, Rüttiger L

Abstract
BACKGROUND/AIMS: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary ("hair") bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear.
METHODS: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gαi isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons.
RESULTS: Here we report that lack of Gαi3 but not of the ubiquitously expressed Gαi2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gαi2 or Gαi3 had no impact. In contrast, double-deficiency for Gαi2 and Gαi3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gαi3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gαi3 is selectively involved in generation of neural gain during auditory processing.
CONCLUSION: We propose a so far unrecognized complexity of isoform-specific and overlapping Gαi protein functions particular during final differentiation processes.

PMID: 29940568 [PubMed - as supplied by publisher]

Functional Pharmacogenomics and toxicity of PolyPurine Reverse Hoogsteen hairpins directed against survivin in human cells.

Biochem Pharmacol. 2018 Jun 22;:

Authors: Félix AJ, Ciudad CJ, Noé V

Abstract
PolyPurine Reverse Hoogsteen (PPRH) hairpins constitute a relatively new pharmacological agent for gene silencing that has been applied for a growing number of gene targets. Previously we reported that specific PPRHs against the antiapoptotic gene survivin were able to decrease viability of PC3 prostate cancer cells by increasing apoptosis, while not acting on HUVEC non-tumoral cells. These PPRHs were efficient both in vitro and in vivo. In the present work, we performed a functional pharmacogenomics study on the effects of specific and unspecific hairpins against survivin. Incubation of PC3 cells with the specific HpsPr-C-WT led to 244 differentially expressed genes when applying the p<0.05, FC>2, Benjamini-Hochberg filtering. Importantly, the unspecific or control Hp-WC did not originate differentially expressed genes using the same settings. Gene Set Enrichment Analysis (GSEA) revealed that the differentially expressed genes clustered very significantly within the gene sets of Regulation of cell proliferation, Cellular response to stress, Apoptosis and Prostate cancer. Network analyses using STRING identified important interacting gene-nodes within the response of PC3 cells to treatment with the PPRH against survivin, mainly POLR2G, PAK1IP1, SMC3, SF3A1, PPARGC1A, NCOA6, UGT2B7, ALG5, VAMP7 and HIST1H2BE, the former six present in the Gene Sets detected in the GSEA. Additionally, HepG2 and 786-O cell lines were used to carry out in vitro experiments of hepatotoxicity and nephrotoxicity, respectively. The unspecific hairpin did not cause toxicity in cell survival assays (MTT) and produced minor changes in gene expression for selected genes in RT-qPCR arrays specifically developed for hepatic and renal toxicity screening.

PMID: 29940174 [PubMed - as supplied by publisher]

Genetic aspects of primary hyperaldosteronism.

Adv Clin Exp Med. 2018 Jun 20;:

Authors: Korzyńska W, Jodkowska A, Gosławska K, Bogunia-Kubik K, Mazur G

Abstract
Primary hyperaldosteronism (PHA) is the most common form of secondary hypertension of hormonal origin. It affects about 10% of all hypertensive patients. It is connected with increased morbidity and mortality from cardiovascular diseases (CVD) compared to patients with essential hypertension of a similar age. Usually, it is an effect of bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), more rare causes of PHA are: unilateral adrenal hyperplasia, aldosterone-producing adrenocortical carcinoma, ectopic aldosterone-producing tumors and familial hyperaldosteronism. Recent genetic studies have thrown a new light on the pathogenesis of PHA, classifying it as a channelopathy. Several mutations within the ion channels encoding genes have been identified. A possible link between primary hyperaldosteronism and polymorphism of aldosterone synthase gene and ion channel genes is still being investigated. In this manuscript, we focus on genetic aspects of primary hyperaldosteronism, and present an up-to-date compilation of available data with the widened pathogenetic approach.

PMID: 29938936 [PubMed - as supplied by publisher]

Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array.

Eur J Clin Pharmacol. 2018 Jun 24;:

Authors: Kalra S, Kaur RP, Ludhiadch A, Shafi G, Vashista R, Kumar R, Munshi A

Abstract
PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab.
METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome.
RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group.
CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.

PMID: 29938344 [PubMed - as supplied by publisher]

The Importance of New Generation Sequencing (NGS) HLA Typing in Renal Transplantation-Preliminary Report.

Transplant Proc. 2018 Jun 21;:

Authors: Kotowski M, Bogacz A, Bartkowiak-Wieczorek J, Bukowska A, Surowiec N, Dziewanowski K, Czerny B, Grześkowiak E, Ostrowski M, Machaliński B, Sieńko J

Abstract
INTRODUCTION: Thanks to new generation sequencing (NGS) and expansion of HLA typing with additional loci, it will be possible to increase the effectiveness of graft survival and to avoid complications related to the immune system. New pharmacogenetic factors are still being researched to develop better immunosuppressive treatment.
MATERIAL AND METHODS: The incidence of polymorphic HLA loci variants was established, based on a high-resolution NGS method in kidney graft recipients. Furthermore, haplotypic analysis between examined loci was conducted to type additional loci that may influence the transplantation result. A total of 120 kidney recipients were enrolled in the study. A commercial DNA extraction kit in Tubes (QIAamp DNA Blood Mini Kit Qiagen, Germany) was used to isolate DNA from the blood. Sequencing library preparation was done with TruSight HLA set. The Conexio computer program was used to analyse the results of HLA typing.
RESULTS: The patients with alleles A*02:01:01, B*44:02:01, C*03:03:01, C*01:02:01, C*05:01:01, C*07:02:01, DQB1*03:03:02, DQB1*06:04:01, or with haplotypic variation A*25:01:01-B*18:01:01- C*15:01:01 were taking the highest doses of cyclosporine (CsA), in contrast to patients with allele B*18:01:01, DQB1*06:02:01, DQB1*02:02:01, or haplotypic variation A*02:01:01- B*44:02:01-C*01:01:01, who were taking the lowest doses. The highest dose of tacrolimus (TAC) was administered to patients with alleles A*68:01:02, A*29:01:01, B*07:02:01, B*35:02:01, B*38:01:01, DRB1*12:01:01, DQB1*05:03:01, or haplotypic variations A*02:01:01-B*57:01:01-C*07:01:01, A*03:01:01-B*07:02:01-C*13:01:01, A*29:02:01-B*44:03:01- C*07:01:01, and A*01:01:01-B*08:01:01-C*03:01:01. Additionally, it was established that HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DPA1, and HLA-DQA1 show very slight polymorphism, which suggests that there is no need for their typing for transplantation purposes. Moreover, loci HLA-C, HLA-DQB1, and HLA-DPB1, which are not routinely examined in recipient-donor matching, show genetic variability that may increase the risk of transplant rejection or shortened graft life.
CONCLUSIONS: Expanding the qualification procedure to include allele genotyping could allow clinicians to establish immunosuppressive treatment schemes that would be optimally suited for recipients' phenotype.

PMID: 29937294 [PubMed - as supplied by publisher]

A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations.

Diabetes. 2018 06;67(6):1086-1092

Authors: Agostini M, Schoenmakers E, Beig J, Fairall L, Szatmari I, Rajanayagam O, Muskett FW, Adams C, Marais AD, O'Rahilly S, Semple RK, Nagy L, Majithia AR, Schwabe JWR, Blom DJ, Murphy R, Chatterjee K, Savage DB

Abstract
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.

PMID: 29622583 [PubMed - indexed for MEDLINE]

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

Lancet Respir Med. 2017 11;5(11):869-880

Authors: Allen RJ, Porte J, Braybrooke R, Flores C, Fingerlin TE, Oldham JM, Guillen-Guio B, Ma SF, Okamoto T, John AE, Obeidat M, Yang IV, Henry A, Hubbard RB, Navaratnam V, Saini G, Thompson N, Booth HL, Hart SP, Hill MR, Hirani N, Maher TM, McAnulty RJ, Millar AB, Molyneaux PL, Parfrey H, Rassl DM, Whyte MKB, Fahy WA, Marshall RP, Oballa E, Bossé Y, Nickle DC, Sin DD, Timens W, Shrine N, Sayers I, Hall IP, Noth I, Schwartz DA, Tobin MD, Wain LV, Jenkins RG

Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses.
METHODS: We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls.
FINDINGS: 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10-9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10-66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10-28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51).
INTERPRETATION: AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF.
FUNDING: UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.

PMID: 29066090 [PubMed - indexed for MEDLINE]

Lymphoma Immunochemotherapy: Targeted Delivery of Doxorubicin via a Dual Functional Nanocarrier.

Mol Pharm. 2017 Nov 06;14(11):3888-3895

Authors: Zhai Q, Chen Y, Xu J, Huang Y, Sun J, Liu Y, Zhang X, Li S, Tang S

Abstract
Chemotherapy drug (paclitaxel, PTX) incorporated in a dual functional polymeric nanocarrier, PEG-Fmoc-NLG, has shown promise as an immunochemotherapy in a murine breast cancer model, 4T1.2. The formulation is composed of an amphiphilic polymer with a built-in immunotherapy drug NLG919 that exhibits the immunostimulatory ability through the inhibition of indoleamine 2,3-dioxygenase 1 (IDO-1) in cancer cells. This work evaluates whether the PEG-derivatized NLG polymer can also be used for delivery of doxorubicin (Dox) in treatment of leukemia. The Dox-loaded micelles were self-assembled from PEG-Fmoc-NLG conjugate, which have a spherical shape with a uniform size of ∼120 nm. In cultured murine lymphocytic leukemia cells (A20), Dox-loaded PEG-Fmoc-NLG micelles showed a cytotoxicity that was comparable to that of free Dox. For in vivo studies, significantly improved antitumor activity was observed for the Dox/PEG-Fmoc-NLG group compared to Doxil or the free Dox group in an A20 lymphoma mouse model. Flow cytometric analysis showed that treatment with Dox/PEG-Fmoc-NLG micelles led to significant increases in the numbers of both total CD4+/CD8+ T cells and the functional CD4+/CD8+ T cells with concomitant decreases in the numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg). Dox/PEG-Fmoc-NLG may represent a promising immunochemotherapy for lymphoma, which warrants more studies in the future.

PMID: 28850241 [PubMed - indexed for MEDLINE]

CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.

Br J Anaesth. 2018 Jul;121(1):58-65

Authors: Klenke S, de Vries GJ, Schiefer L, Seyffert N, Bachmann HS, Peters J, Frey UH

Abstract
BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk.
METHODS: In a prospective, controlled study, 454 subjects undergoing elective surgery were genotyped for rs2165870 and its association with PONV was investigated with log-binomial regression analysis. Subjects were randomised to receive acustimulation/dexamethasone, acustimulation/vehicle, sham acustimulation/dexamethasone, or sham acustimulation/vehicle to investigate their effects on PONV risk.
RESULTS: Early PONV occurred in 37% of subjects. The rs2165870 genotype distribution was GG in 191, GA in 207, and AA in 56 subjects. The CHRM3 polymorphism was associated with a relative risk (RR) of 1.5 for GA vs GG [95% confidence interval (CI): 1.1-1.9; P=0.003] and 1.6 for AA vs GG (95% CI: 1.1-2.2; P=0.009) genotypes to develop PONV, and this was independent from the Apfel score (RR per Apfel point: 1.3, 95% CI: 1.2-1.5; P<0.0001). While dexamethasone and acustimulation each reduced the PONV risk by 30% in AA genotype carriers with low Apfel score, combined therapy reduced the risk by 86% (P=0.015).
CONCLUSIONS: The CHRM3 polymorphism and the Apfel score independently predict PONV susceptibility. Dexamethasone/acustimulation should be considered in patients with low Apfel score but at high genetic risk.
CLINICAL TRIAL REGISTRATION: DRKS00005664.

PMID: 29935595 [PubMed - in process]

The pediatric acenocoumarol dosing algorithm: The Children Anticoagulation and Pharmacogenetics Study.

J Thromb Haemost. 2018 Jun 23;:

Authors: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, le Cessie S, Swen JJ, van der Straaten T, de Boer A, Maitland-van der Zee AH

Abstract
BACKGROUND: The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the right dose for a patient, however not for acenocoumarol.
OBJECTIVES: To develop dosing algorithms for pediatric patients on acenocoumarol with and without genetic information.
METHODS: The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as ≥3 consecutive International Normalized Ratio measurements within therapeutic range over a period of ≥3 weeks.
RESULTS: In total 175 patients were included in the study of whom 86 patients had a stable period and no missing clinical information (clinical cohort; median age 8.9 years and 49% female). Of 80 of these 86 patients genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. By adding the genotypes of VKORC1, CYP2C9, and CYP2C18 to the algorithm it increased to 61.8%.
CONCLUSIONS: These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability. This article is protected by copyright. All rights reserved.

PMID: 29935043 [PubMed - as supplied by publisher]

Liquid biopsies to optimize therapeutic efficacy in unresponsive lung cancer patients.

Expert Opin Drug Metab Toxicol. 2018 Jun 22;:

Authors: Santarpia M, Funel N, Ali A, Giovannetti E

PMID: 29933706 [PubMed - as supplied by publisher]

Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines.

Cancer Lett. 2018 Jun 19;:

Authors: Ferraiuolo M, Pulito C, Finch-Edmondson M, Korita E, Maidecchi A, Donzelli S, Muti P, Serra M, Sudol M, Strano S, Blandino G

Abstract
Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood. In the present study, we investigate the anticancer effects of Agave leaf extract in OS cells suggesting that Agave inhibits cell viability, colony formation, and cell migration, and can induce apoptosis in OS cell lines. Moreover, Agave sensitizes OS cells to cisplatin (CDDP) and radiation, to overcome chemo- and radio-resistance. We demonstrate that Agave extract induces a marked decrease of Yes Associated Protein (YAP) and Tafazzin (TAZ) mRNA and protein expression upon treatment. We propose an initial mechanism of action in which Agave induces YAP/TAZ protein degradation, followed by a secondary event whereby Agave inhibits YAP/TAZ transcription, effectively deregulating the Nuclear Factor kappa B (NF-κB) p65:p50 heterodimers responsible for transcriptional induction of YAP and TAZ.

PMID: 29933048 [PubMed - as supplied by publisher]

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

Curr Med Chem. 2018 Jun 22;:

Authors: Hahn RZ, Antunes MV, Verza SG, Perassolo MS, Suyenaga ES, Schwartsmann G, Linden R

Abstract
BACKGROUND: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment.
METHODS: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data.
CONCLUSIONS: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization.

PMID: 29932028 [PubMed - as supplied by publisher]

Identification of genetic correlates of response to Risperidone: Findings of a multicentric schizophrenia study from India.

Asian J Psychiatr. 2017 Oct;29:174-182

Authors: Kaur G, Gupta D, Chavan BS, Sinhmar V, Prasad R, Tripathi A, Garg PD, Gupta R, Khurana H, Gautam S, Margoob MA, Aneja J

Abstract
Risperidone is most commonly used as an antipsychotic in India for treatment of schizophrenia. However, the response to treatment with risperidone is affected by many factors, genetic factors being one of them. So, we attempted to evaluate the association between dopamine D2 (DRD2) receptor, serotonergic (5HT2A) receptor and CYP2D6 gene polymorphisms and response to treatment with risperidone in persons with schizophrenia from North India. It was a multicentric 12-weeks prospective study, undertaken in patients diagnosed with schizophrenia according to International Classification of Diseases 10th revision, Diagnostic Criteria for Research module (ICD-10 DCR). Patients were treated with incremental dosages of risperidone. Nine gene polymorphisms from three genes viz. DRD2, 5-HT2A and CYP2D6 along with socio-demographical and clinical variables were analyzed to ascertain the association in response to risperidone treatment. The change in the Positive and Negative Syndrome Scale (PANSS) was used to measure the outcome. Significant differences in the frequencies of single nucleotide proteins (SNPs) rs180498 (Taq1D) and rs 6305 (C516T) polymorphisms were found amongst the groups defined according to percent decline in PANSS. The CYP2D6*4 polymorphism differed significantly when drop outs were excluded from analysis. Presence of DRD2 Taq 1 D2D2 and 5-HT2A C516T CT genotypes in patients were more likely to be associated with non-response to risperidone. Ser311Cys (rs1801028) mutation was absent in the North Indian patients suffering from schizophrenia.

PMID: 28692863 [PubMed - indexed for MEDLINE]

Improvable Lifestyle Factors in Lymphoma Survivors.

Acta Haematol. 2018 Jun 21;139(4):235-237

Authors: Minoia C, Ciavarella S, Lerario G, Daniele A, De Summa S, Napolitano M, Guarini A

PMID: 29929199 [PubMed - as supplied by publisher]

Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia.

Oncotarget. 2018 Jun 01;9(42):26711-26723

Authors: Lamba JK, Cao X, Raimondi SC, Rafiee R, Downing JR, Lei S, Gruber T, Ribeiro RC, Rubnitz JE, Pounds SB

Abstract
Acute myeloid leukemia (AML) may be an epigenetically-driven malignancy because it harbors fewer genomic mutations than other cancers. In recent studies of AML in adults, DNA methylation patterns associate with clinical risk groups and prognosis. However, thorough evaluations of methylation in pediatric AML have not been done. Therefore, we performed an integrated analysis (IA) of the methylome and transcriptome with clinical outcome in 151 pediatric patients from the multi-center AML02 clinical trial discovery cohort. Intriguingly, reduced methylation and increased expression of DNMT3B was associated with worse clinical outcomes (IA p ≤ 10-5; q ≤ 0.002). In particular, greater DNMT3B expression associated with worse minimal residual disease (MRD; p < 10-5; q = 0.01), a greater rate of relapse or resistant disease (RR) (p = 0.00006; q = 0.06), and event-free survival (EFS; p = 0.00003; q = 0.04). Also, greater DNMT3B expression associated with greater genome-wide methylation burden (GWMB; R = 0.39; p = 10-6) and greater GWMB associated with worse clinical outcomes (IA p < 10-5). In an independent validation cohort of 132 similarly treated AAML0531 clinical trial patients, greater DNMT3B expression associated with greater GWMB, worse MRD, worse RR, and worse EFS (all p < 0.03); also, greater GWMB associated with worse MRD (p = 0.004) and EFS (p = 0.037). These results indicate that DNMT3B and GWMB may have a central role in the development and prognosis of pediatric AML.

PMID: 29928480 [PubMed]

Multiomics Data Triangulation for Asthma Candidate Biomarkers and Precision Medicine.

OMICS. 2018 Jun;22(6):392-409

Authors: Pecak M, Korošec P, Kunej T

Abstract
Asthma is a common complex disorder and has been subject to intensive omics research for disease susceptibility and therapeutic innovation. Candidate biomarkers of asthma and its precision treatment demand that they stand the test of multiomics data triangulation before they can be prioritized for clinical applications. We classified the biomarkers of asthma after a search of the literature and based on whether or not a given biomarker candidate is reported in multiple omics platforms and methodologies, using PubMed and Web of Science, we identified omics studies of asthma conducted on diverse platforms using keywords, such as asthma, genomics, metabolomics, and epigenomics. We extracted data about asthma candidate biomarkers from 73 articles and developed a catalog of 190 potential asthma biomarkers (167 human, 23 animal data), comprising DNA loci, transcripts, proteins, metabolites, epimutations, and noncoding RNAs. The data were sorted according to 13 omics types: genomics, epigenomics, transcriptomics, proteomics, interactomics, metabolomics, ncRNAomics, glycomics, lipidomics, environmental omics, pharmacogenomics, phenomics, and integrative omics. Importantly, we found that 10 candidate biomarkers were apparent in at least two or more omics levels, thus promising potential for further biomarker research and development and precision medicine applications. This multiomics catalog reported herein for the first time contributes to future decision-making on prioritization of biomarkers and validation efforts for precision medicine in asthma. The findings may also facilitate meta-analyses and integrative omics studies in the future.

PMID: 29927718 [PubMed - in process]

Personalized Herbal Medicine? A Roadmap for Convergence of Herbal and Precision Medicine Biomarker Innovations.

OMICS. 2018 Jun;22(6):375-391

Authors: Thomford NE, Dzobo K, Chimusa E, Andrae-Marobela K, Chirikure S, Wonkam A, Dandara C

Abstract
While drugs remain the cornerstone of medicine, herbal medicine is an important comedication worldwide. Thus, precision medicine ought to face this clinical reality and develop "companion diagnostics" for drugs as well as herbal medicines. Yet, many are in denial with respect to the extent of use of traditional/herbal medicines, overlooking that a considerable number of contemporary therapeutic drugs trace their discovery from herbal medicines. This expert review underscores that absent such appropriate attention on both classical drug therapy and herbal medicines, precision medicine biomarkers will likely not stand the full test of clinical practice while patients continue to use both drugs and herbal medicines and, yet the biomarker research and applications focus only (or mostly) on drug therapy. This asymmetry in biomarker innovation strategy needs urgent attention from a wide range of innovation actors worldwide, including governments, research funders, scientists, community leaders, civil society organizations, herbal, pharmaceutical, and insurance industries, policymakers, and social/political scientists. We discuss the various dimensions of a future convergence map between herbal and conventional medicine, and conclude with a set of concrete strategies on how best to integrate biomarker research in a realm of both herbal and drug treatment. Africa, by virtue of its vast experience and exposure in herbal medicine and a "pregnant" life sciences innovation ecosystem, could play a game-changing role for the "birth" of biomarker-informed personalized herbal medicine in the near future. At this critical juncture when precision medicine initiatives are being rolled out worldwide, precision/personalized herbal medicine is both timely and essential for modern therapeutics, not to mention biomarker innovations that stand the test of real-life practices and implementation in the clinic and society.

PMID: 29927715 [PubMed - in process]

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.

Pharmacogenomics J. 2018 Jun 21;:

Authors: Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Cremolini C, Lonardi S, Bergamo F, Ning Y, Yamamoto N, Okazaki S, Berger MD, Miyamoto Y, Gopez R, Barzi A, Yamaguchi T, Stintzing S, Heinemann V, Loupakis F, Falcone A, Lenz HJ

Abstract
PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P < 0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P = 0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45-0.91, P = 0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47-0.78, P < 0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62-1.02, P = 0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

PMID: 29925895 [PubMed - as supplied by publisher]