A comprehensive screening of copy number variability in dementia with Lewy bodies.

Neurobiol Aging. 2018 Oct 24;:

Authors: Kun-Rodrigues C, Orme T, Carmona S, Hernandez DG, Ross OA, Eicher JD, Shepherd C, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Dawson T, Rosenthal L, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Guerreiro R, Bras J

Abstract
The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

PMID: 30448004 [PubMed - as supplied by publisher]

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pharmacogenomics

These pubmed results were generated on 2018/11/18

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.

Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update.

Clin Pharmacol Ther. 2018 Nov 17;:

Authors: Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, Moyer AM, Evans WE, Klein TE, Antillon-Klussmann FG, Caudle KE, Kato M, Yeoh AEJ, Schmiegelow K, Yang JJ

Abstract
TPMT activity exhibits a monogenic co-dominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmalogic effecs of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduces the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting dosesof azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes. This article is protected by copyright. All rights reserved.

PMID: 30447069 [PubMed - as supplied by publisher]

Integrating anatomo-physiological changes and pharmacogenomics in anti-infective therapy management: is it a major concern?

Br J Clin Pharmacol. 2018 Nov 16;:

Authors: Beaumier L, Chanoine S, Gautier-Veyret E, Pluchart H, Cornet M, Brenier-Pinchart MP, Fonrose X, Camara B, Bedouch P

Abstract
Success of anti-infective therapy is a major challenge in some patients given anatomo-physiological changes and genetic variations. In this case anecdote, we report the management strategy of a patient suffering from chronic pulmonary aspergillosis in a context of anorexia nervosa and genetic polymorphism.

PMID: 30447013 [PubMed - as supplied by publisher]

Clinical and Experimental Human Sleep-Wake Pharmacogenetics.

Handb Exp Pharmacol. 2018 Nov 16;:

Authors: Landolt HP, Holst SC, Valomon A

Abstract
Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, γ-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics.

PMID: 30443785 [PubMed - as supplied by publisher]

Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway.

Int J Biol Sci. 2018;14(13):1859-1872

Authors: Mei Y, Liu YB, Hu DL, Zhou HH

Abstract
Platinum-based chemotherapy is used as first-line therapy for advanced non-small-cell lung cancer (NSCLC). However, there is no effective indicator to predict whether the patient would be chemo-resistant or sensitive to the therapy. In addition, it is urgent to elucidate the mechanisms of cisplatin resistance. RIF1 plays important roles in DNA replication regulation and DNA repair pathway. However, the role of RIF1 in NSCLC progression and chemotherapy response is still unknown. In this study, we found that RIF1 expression was correlated with the response of NSCLC patients to platinum-based chemotherapy (n=89, P=0.002). Among patients who have been treated with platinum chemo-therapy, those with high levels of RIF1 expression had significantly shorter survival than those with low RIF1 expression (P<0.05). RIF1 knockdown increased sensitivity to cisplatin in NSCLC patients both in vitro and in vivo. Moreover, RIF1 knockdown induced G0/G1 phase arrest and increased cisplatin-induced apoptosis and DNA damage. Further investigation showed that RIF1 regulated the expression of MYC and MYC downstream targets, including the cell cycle and double-stranded break (DSB) repair genes which might mediate the effect of RIF1 on cellular response to cisplatin. Overexpression of MYC could reverse the inhibition of MYC targets by RIF1 knockdown. Taken together, these data revealed that RIF1 played an important role in regulating MYC and MYC-activated genes, which in turn contributes to cellular response to cisplatin and NSCLC patients' response to platinum-based chemotherapy. RIF1 might serve as a novel biomarker for predicting platinum-based chemo-sensitivity and the prognosis of NSCLC patients, so as to guide the chemotherapy regimen adjustment for individual patient with NSCLC and improve their clinical outcomes.

PMID: 30443189 [PubMed - in process]

Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing.

Pharmacogenomics J. 2018 Nov 16;:

Authors: Dorr CR, Wu B, Remmel RP, Muthusamy A, Schladt DP, Abrahante JE, Guan W, Mannon RB, Matas AJ, Oetting WS, Jacobson PA, Israni AK, for DeKAF Genomics

Abstract
An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned > 3 Mb of 28 genes and identified 18,661 genetic variants (3961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p = 0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p = 0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation.

PMID: 30442921 [PubMed - as supplied by publisher]

Mechanisms and Clinical Significance of Pharmacokinetic-based Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017.

Drug Metab Dispos. 2018 Nov 15;:

Authors: Yu J, Petrie ID, Levy RH, Ragueneau-Majlessi I

Abstract
Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained a majority of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. OATP1B1/1B3 played a significant role, mediating more than half of the drug interactions with AUC changes ≥ 5-fold. As victims, five new drugs were identified as sensitive substrates, namely abemeciclib, midostaurin, and neratinib for CYP3A, and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and BCRP. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ≥ 5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes < 2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy.

PMID: 30442649 [PubMed - as supplied by publisher]

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

J Am Coll Cardiol. 2018 Nov 13;72(20):2457-2467

Authors: Ochoa JP, Sabater-Molina M, García-Pinilla JM, Mogensen J, Restrepo-Córdoba A, Palomino-Doza J, Villacorta E, Martinez-Moreno M, Ramos-Maqueda J, Zorio E, Peña-Peña ML, García-Granja PE, Rodríguez-Palomares JF, Cárdenas-Reyes IJ, de la Torre-Carpente MM, Bautista-Pavés A, Akhtar MM, Cicerchia MN, Bilbao-Quesada R, Mogollón-Jimenez MV, Salazar-Mendiguchía J, Mesa Latorre JM, Arnaez B, Olavarri-Miguel I, Fuentes-Cañamero ME, Lamounier A, Pérez Ruiz JM, Climent-Payá V, Pérez-Sanchez I, Trujillo-Quintero JP, Lopes LR, Repáraz-Andrade A, Marín-Iglesias R, Rodriguez-Vilela A, Sandín-Fuentes M, Garrote JA, Cortel-Fuster A, Lopez-Garrido M, Fontalba-Romero A, Ripoll-Vera T, Llano-Rivas I, Fernandez-Fernandez X, Isidoro-García M, Garcia-Giustiniani D, Barriales-Villa R, Ortiz-Genga M, García-Pavía P, Elliott PM, Gimeno JR, Monserrat L

Abstract
BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy.
OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy.
METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes.
RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up.
CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.

PMID: 30442288 [PubMed - in process]

Use of polygenic risk scores of nicotine metabolism in predicting smoking behaviors.

Pharmacogenomics. 2018 Nov 16;:

Authors: Chen LS, Hartz SM, Baker TB, Ma Y, L Saccone N, Bierut LJ

Abstract
AIM: This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data.
MATERIALS & METHODS: Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation.
RESULTS: Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R2 range: 9.2-16%; minimum p = 7.6 × 10-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R2 range: 14-17%; minimum p = 4.4 × 10-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation.
CONCLUSION: Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual's nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors.

PMID: 30442082 [PubMed - as supplied by publisher]

Dimensionality Reduction based Transfer Learning applied to Pharmacogenomics Databases.

Conf Proc IEEE Eng Med Biol Soc. 2018 Jul;2018:1246-1249

Authors: Dhruba SR, Rahmanl R, Matlockl K, Ghosh S, Pal R

Abstract
Recent years have observed a number of Pharmacogenomics databases being published that enable testing of various predictive modeling techniques for personalized therapy applications. However, the consistencies between the databases are usually limited in spite of having significant number of common cell lines and drugs. In this article, we consider the problem of whether we can use the model learned from one secondary database to improve the prediction for the other target database. We illustrate using two pharmacogenomics databases that representing the databases using common basis vectors can improve prediction performance as compared to the naive application of a model trained on one database to another. We also elucidate the robustness of using PCA based basis vectors for scenarios with low correlated input features.

PMID: 30440616 [PubMed - in process]

Adaptive Multi-task Elastic Net based feature selection from Pharmacogenomics Databases.

Conf Proc IEEE Eng Med Biol Soc. 2018 Jul;2018:279-282

Authors: Rahmanl R, Perera C, Ghosh S, Pall R

Abstract
Integrating multiple databases of similar tasks is a significant problem in biological data analysis. In this paper, we consider whether feature selection in a single database can benefit from incorporating similar databases. We report that by using adaptive multi-task elastic net for feature selection and Random Forest for prediction, the prediction performance can be improved for pharmacogenomics databases. We also present a simulation study to explain the robust feature selection benefit of adaptive multi task elastic net while dealing with noisy features.

PMID: 30440392 [PubMed - in process]

[Clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy and the corresponding pharmacogenomics analysis].

Zhonghua Yi Xue Za Zhi. 2018 Nov 13;98(42):3420-3425

Authors: Chen WC, Wu G, Zhang W, Zhu YZ, Zhou Y, Zhang H, Xia XB, Sun PC

Abstract
Objective: To investigate the association between Thymidine phosphorylase(TYMP)genetic variation and clinical outcomes of postoperative gastric cancer (GC) patients received capecitabine based regimens. Methods: A total of 198 GC patients underwent surgical treatment and received capecitabine based adjuvant chemotherapy were included in this retrospective study. Peripheral blood and the postoperative tissue specimen of the GC patients were collected for the genotyping of polymorphism and TYMP mRNA expression, respectively. The correlation between polymorphism and clinical outcomes and safety of postoperative GC patients were analysed. Results: Located in the upstream, rs11479 was of clinical significance. The prevalence of rs11479 in TYMP among the GC patients were as follows: CC genotype 125 cases (63.13%), CT genotype 65 cases (32.83%), TT genotype 8 cases (4.04%), minor allele frequency of rs11479 is 0.20. The distribution of three genotypes were in accordance with Hardy-Weinberg Equilibrium (P=0.901). The analysis results of patients with different genotypes found that the 3-year disease free survival rate of the patients with CT/TT genotype and CC genotype were 73.97% and 65.60%, respectively, which was statistically significant (P=0.003). In terms of overall survival, the 3-year overall survival rate of the two genotypes were 83.56% and 72.80% (P=0.012), respectively. Adjusted in multivariate Cox regression analysis, CT/TT genotype was an independent favorable factor for disease free survival (OR=0.55, P=0.011). Safety analysis indicated that there was no significant association between genotypes and grade 2 adverse reaction. Additionally, of the 79 postoperative tissue specimens, the results showed that the expression of TYMP in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the wild type CC genotype patients (P<0.001). Conclusion: The polymorphism rs11479 of TYMP have favorable influence on the clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy treatment through changing the mRNA expression of TYMP.

PMID: 30440137 [PubMed - in process]

The right blood collection tube for therapeutic drug monitoring and toxicology screening procedures: Standard tubes, gel or mechanical separator?

Clin Chim Acta. 2018 Nov 12;:

Authors: Schrapp A, Mory C, Duflot T, Pereira T, Imbert L, Lamoureux F

Abstract
Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PST™ II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical Barricor™ tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logP > 3.3 was determined as a cut-off value to predict a potential lack of stability in PST™ II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logP > 3.3 should be carried out with caution in plasma samples withdrawn on PST™ II. The study showed the Barricor™ and non-gel tubes cause less drug interference and are recommended for the drugs studied.

PMID: 30439354 [PubMed - as supplied by publisher]

Genetic polymorphism contributes to 131I radiotherapy-induced toxicities in patients with differentiated thyroid cancer.

Pharmacogenomics. 2018 Nov;19(17):1335-1344

Authors: Liu J, Tang X, Shi F, Li C, Zhang K, Liu J, Wang G, Yin J, Li Z

Abstract
AIM: To investigate the association between SNPs in DNA damage response pathways and toxicities following 131I radiotherapy of differentiated thyroid cancer (DTC). Materials & methods: We identified 22 functional SNPs of genes in DNA damage response pathways. MassArray was used to sequence SNP genotypes in 203 DTC patients. Hardy-Weinberg equilibrium and the associations between the two alleles of each SNP and toxicity reactions were evaluated using χ2 analysis.
RESULTS: Ataxia-telangiectasia mutated (ATM) rs620815 T-allele carriers were at increased risk of 131I radiation-induced gastrointestinal reaction compared with C allele carriers. TNFα rs1800629 GA genotype may increase the incidence of neck pain compared with GG genotype. Furthermore, TNFα rs1800629, ATM rs11212570, NF-κβ rs230493, and TGF-β rs1800469, rs2241716 were associated with throat pain following 131I radiotherapy.
CONCLUSION: The identified SNPs might serve as novel biomarkers for DTC treated with 131I radiotherapy.

PMID: 30430914 [PubMed - in process]

Radiomics and liquid biopsy in oncology: the holons of systems medicine.

Insights Imaging. 2018 Nov 14;:

Authors: Neri E, Del Re M, Paiar F, Erba P, Cocuzza P, Regge D, Danesi R

Abstract
Radiomics is a process of extraction and analysis of quantitative features from diagnostic images. Liquid biopsy is a test done on a sample of blood to look for cancer cells or for pieces of tumourigenic DNA circulating in the blood. Radiomics and liquid biopsy have great potential in oncology, since both are minimally invasive, easy to perform, and can be repeated in patient follow-up visits, enabling the extraction of valuable information regarding tumour type, aggressiveness, progression, and response to treatment. Both methods are in their infancy, with major evidence of application in lung and gastrointestinal cancer, while still undergoing evaluation in other cancer types. In this paper, the main oncologic applications of radiomics and liquid biopsy are reviewed, and a synergistic approach incorporating both tests for cancer diagnosis and follow-up is discussed within the context of systems medicine. TEACHING POINTS: • Radiomics is a process of extraction and analysis of quantitative features from diagnostic images. • Most clinical applications of radiomics are in the field of oncologic imaging. • Radiomics applies to all imaging modalities. • A cluster of radiomic features is a "radiomic signature". • Machine learning may improve the efficacy of radiomics analysis.

PMID: 30430428 [PubMed - as supplied by publisher]

Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma.

Cell Mol Life Sci. 2018 Nov 14;:

Authors: Buondonno I, Gazzano E, Tavanti E, Chegaev K, Kopecka J, Fanelli M, Rolando B, Fruttero R, Gasco A, Hattinger C, Serra M, Riganti C

Abstract
Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H2S-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down-regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up-regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-β LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions.

PMID: 30430199 [PubMed - as supplied by publisher]

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 2018/11/15

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.

iTOP: inferring the topology of omics data.

Bioinformatics. 2018 Sep 01;34(17):i988-i996

Authors: Aben N, Westerhuis JA, Song Y, Kiers HAL, Michaut M, Smilde AK, Wessels LFA

Abstract
Motivation: In biology, we are often faced with multiple datasets recorded on the same set of objects, such as multi-omics and phenotypic data of the same tumors. These datasets are typically not independent from each other. For example, methylation may influence gene expression, which may, in turn, influence drug response. Such relationships can strongly affect analyses performed on the data, as we have previously shown for the identification of biomarkers of drug response. Therefore, it is important to be able to chart the relationships between datasets.
Results: We present iTOP, a methodology to infer a topology of relationships between datasets. We base this methodology on the RV coefficient, a measure of matrix correlation, which can be used to determine how much information is shared between two datasets. We extended the RV coefficient for partial matrix correlations, which allows the use of graph reconstruction algorithms, such as the PC algorithm, to infer the topologies. In addition, since multi-omics data often contain binary data (e.g. mutations), we also extended the RV coefficient for binary data. Applying iTOP to pharmacogenomics data, we found that gene expression acts as a mediator between most other datasets and drug response: only proteomics clearly shares information with drug response that is not present in gene expression. Based on this result, we used TANDEM, a method for drug response prediction, to identify which variables predictive of drug response were distinct to either gene expression or proteomics.
Availability and implementation: An implementation of our methodology is available in the R package iTOP on CRAN. Additionally, an R Markdown document with code to reproduce all figures is provided as Supplementary Material.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 30423084 [PubMed - in process]

Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia: A Randomized Clinical Trial.

JAMA Psychiatry. 2018 Nov 07;:

Authors: Wang Q, Man Wu H, Yue W, Yan H, Zhang Y, Tan L, Deng W, Chen Q, Yang G, Lu T, Wang L, Zhang F, Yang J, Li K, Lv L, Tan Q, Zhang H, Ma X, Yang F, Li L, Wang C, Ma X, Zhao L, Ren H, Yu H, Wang Y, Hu X, Zhang D, Sham P, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

Abstract
Importance: The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown.
Objective: To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy.
Design, Setting, and Participants: In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017.
Main Outcomes and Measures: Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach.
Results: Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs.
Conclusions and Relevance: Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics.
Trial Registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934.

PMID: 30422257 [PubMed - as supplied by publisher]