Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.

Cancer Discov. 2017 07;7(7):750-765

Authors: Patnaik A, Swanson KD, Csizmadia E, Solanki A, Landon-Brace N, Gehring MP, Helenius K, Olson BM, Pyzer AR, Wang LC, Elemento O, Novak J, Thornley TB, Asara JM, Montaser L, Timmons JJ, Morgan TM, Wang Y, Levantini E, Clohessy JG, Kelly K, Pandolfi PP, Rosenblatt JM, Avigan DE, Ye H, Karp JM, Signoretti S, Balk SP, Cantley LC

Abstract
Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance.Significance: This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. Cancer Discov; 7(7); 750-65. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.

PMID: 28274958 [PubMed - indexed for MEDLINE]

Treatment of familial Mediterranean fever with anakinra in patients unresponsive to colchicine.

Scand J Rheumatol. 2017 09;46(5):407-409

Authors: Pecher AC, Igney-Oertel A, Kanz L, Henes J

PMID: 28097903 [PubMed - indexed for MEDLINE]

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 2018/03/29

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.

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 2018/03/29

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.

Toward Decentralized Agrigenomic Surveillance? A Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Approach for Adaptable and Rapid Detection of User-Defined Fungal Pathogens in Potato Crops.

OMICS. 2018 Mar 27;:

Authors: Kambouris ME, Manoussopoulos Y, Kritikou S, Milioni A, Mantzoukas S, Velegraki A

Abstract
Agrigenomics is one of the emerging focus areas for omics sciences. Yet, agrigenomics differs from medical omics applications such as pharmacogenomics and precision medicine, by virtue of vastly distributed geography of applications at the intersection of agriculture, nutrition, and genomics research streams. Crucially, agrigenomics can address diagnostics and safety surveillance needs in remote and rural farming communities or decentralized food, crop, and environmental monitoring programs for prompt, selective, and differential identification of pathogens. A case in point is the potato crop that serves as a fundamental nutritional source worldwide. Decentralized potato crop and plant protection facilities are pivotal to minimize unnecessary, preemptive use of broad-spectrum fungicides, thus helping to curtail the costs, environmental burden, and the development of resistance in opportunistic human pathogenic fungi. We report here a polymerase chain reaction-restriction fragment length polymorphism approach that is sensitive and adaptable in detection and broad identification of fungal pathogens in potato crops, with a view to future decentralized agrigenomic surveillance programs. Notably, the fingerprinting patterns obtained by the method fully differentiated 12 fungal species examined in silico, with 10 of them also tested in vitro. The method can be scaled up through improvements in electrophoresis and enzyme panel for adaption to other crops and/or pathogens. We suggest that decentralized and integrated agrosurveillance programs and translational agrigenomic programs can inform future innovations in multidomain biosecurity, particularly across omics applications from agriculture and nutrition to clinical medicine and environmental biosafety.

PMID: 29584542 [PubMed - as supplied by publisher]

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer.

J Cancer. 2018;9(6):1088-1095

Authors: Luo CH, Zhao M, Tang YX, Shahabi S, Fang KN, Chen Y, Tang Y, Chen XY, Wang J, Zhou HH

Abstract
Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

PMID: 29581788 [PubMed]

Pharmacoepidemiology in pediatrics: Needs, challenges and future directions for research.

Therapie. 2018 Feb 21;:

Authors: Osokogu OU, Verhamme K, Sturkenboom M, Kaguelidou F

Abstract
Despite international initiatives to promote clinical research in pediatrics, there are still many gaps of knowledge in the use of drugs to treat this specific population. When important information cannot be derived only from clinical trials, use of available observational research tools is required. In this paper, we provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents. We also sought to underline the unique challenges and specific needs regarding this research. Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research.

PMID: 29580613 [PubMed - as supplied by publisher]

Drug evaluation in children 10years after the European pediatric regulation current challenges and perspectives.

Therapie. 2018 Feb 17;:

Authors: Élie V, Leroux S, Kaguelidou F, Jacqz-Aigrain E

Abstract
The European pediatric regulation, that entered into force in June 2007 with the objectives to improve the health of children in Europe, dramatically changed the regulatory environment of paediatric drug evaluation in Europe. The recent 10years European medicines agency (EMA) report showed that the number of paediatric trials increased and that 238 new medicines and indications for use in children were authorised in the EU. However, results remain constrated and futur developments require european collaborations beween all experts in developmental pharmacology, drug evaluation and trial conduct, training, all aspects already considered in different EU paediatric programs.

PMID: 29580612 [PubMed - as supplied by publisher]

Pharmacogenetics of oral antidiabetic therapy.

Pharmacogenomics. 2018 Mar 27;:

Authors: Ordelheide AM, de Angelis MH, Häring HU, Staiger H

Abstract
Type 2 diabetes prevalence is still on the rise worldwide. Antidiabetic drugs are widely prescribed to patients with Type 2 diabetes. Most patients start with metformin which is mostly well tolerated. However, a high percentage of patients fail to achieve glycemic control. The effectiveness of metformin as well as most other antidiabetic drugs depends among other factors on interindividual genetic differences that are up to now ignored in the treatment of Type 2 diabetes. Interestingly, many genes influencing the effectiveness of antidiabetic drugs are Type 2 diabetes risk genes making matters worse. Here, we shed light on these interindividual genetic differences.

PMID: 29580198 [PubMed - as supplied by publisher]

Effect of hydrochlorothiazide on serum uric acid concentration: a genome-wide association study.

Pharmacogenomics. 2018 Mar 27;:

Authors: Ala-Mutka EM, Rimpelä JM, Fyhrquist F, Kontula KK, Hiltunen TP

Abstract
AIM: To recognize genetic associations of hydrochlorothiazide-induced change in serum uric acid (SUA) concentration.
PATIENTS & METHODS: We conducted a genome-wide association study on hydrochlorothiazide-induced change in SUA in 214 Finnish men from the GENRES study. Replication analyses were performed in 465 Finns from the LIFE study.
RESULTS: In GENRES, we identified 31 loci associated with hydrochlorothiazide-induced change in SUA at p < 5 × 10-5. rs1002976 near VEGFC associated with the change in GENRES and in LIFE. rs950569 near BRINP3 associated with the change in SUA in GENRES and LIFE. The analysis of previously reported SNPs and candidate genes provided some proof for PADI4 and ABCC4.
CONCLUSION: We report genetic markers that may predict the increase in SUA concentration during thiazide treatment.

PMID: 29580174 [PubMed - as supplied by publisher]

From Homer and Hippocrates to modern personalized medicine: is there a role for pharmacoepigenomics in the treatment of alcohol addiction?

Pharmacogenomics. 2018 Mar 27;:

Authors: Ragia G, Manolopoulos VG

Abstract
From the earliest times to the present, alcohol has evolved as part of life and culture. For most adults, moderate alcohol use is harmless, however, it lies at one end of a range that moves through alcohol abuse to alcohol addiction. Alcohol addiction is a serious and chronic psychiatric disorder that, on top of its heavy consequences on health, also brings significant social and economic losses to individuals and society at large. Pharmacotherapy of alcohol addiction exists, but its effectiveness varies significantly among individuals. Genomic and nongenomic factors are significant contributors to interindividual variation in the clinical presentation of alcohol problems and the response to a given treatment. In addition, emerging evidence suggests pharmacoepigenomics of alcohol addiction as a novel promising area for improvement of alcohol addiction management.

PMID: 29580163 [PubMed - as supplied by publisher]

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study.

J Mol Diagn. 2017 Jul;19(4):561-566

Authors: Rasmussen-Torvik LJ, Almoguera B, Doheny KF, Freimuth RR, Gordon AS, Hakonarson H, Hawkins JB, Husami A, Ivacic LC, Kullo IJ, Linderman MD, Manolio TA, Obeng AO, Pellegrino R, Prows CA, Ritchie MD, Smith ME, Stallings SC, Wolf WA, Zhang K, Scott SA

Abstract
There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

PMID: 28502727 [PubMed - indexed for MEDLINE]

17 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 2018/03/27

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

16 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 2018/03/27

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

Risk of Clinically Relevant Pharmacokinetic-based Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration Between 2013 and 2016.

Drug Metab Dispos. 2018 Mar 23;:

Authors: Yu J, Zhou Z, Tay-Sontheimer J, Levy RH, Ragueneau-Majlessi I

Abstract
A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutnib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when co-administered with a strong inhibitor). Interestingly, approximately 75% of identified CYP3A substrates were also substrates of P-gp. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction, with only two drugs (Viekira Pak and idelalisib) showing strong inhibition of CYP3A, and one NME (lumacaftor) considered as a strong CYP3A inducer. Among drugs with large changes in exposure (≥ 5-fold), whether as victim or perpetrator, the most represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations.

PMID: 29572333 [PubMed - as supplied by publisher]

Helicase POLQ-like (HELQ) as a novel indicator of platinum-based chemoresistance for epithelial ovarian cancer.

Gynecol Oncol. 2018 Mar 20;:

Authors: Long J, Zhu JY, Liu YB, Fu K, Tian Y, Li PY, Yang WQ, Yang SY, Yin JY, Yin G, Zhang Y

Abstract
OBJECTIVE: To investigate the role of HELQ in chemo-resistance of epithelial ovarian carcinoma (EOC), which is a critical factor of patients' prognosis.
METHODS: Immunohistochemistry, survival analysis of our 87 EOC patients and bioinformatics analysis of The Cancer Genome Atlas (TCGA) datasets (Nature, 2011) disclosed the clinical importance of HELQ expression. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western Blot analyses of EOC tissue were used to confirm it. Ectopic overexpression and RNA interference knockdown of HELQ were carried out in OVCAR3 and A2780 cell lines, respectively, to determine the effect of altered HELQ expression on cellular response to cisplatin by CCK8 assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Western Blot analyses were carried out to determine the effect of HLEQ on the DNA repair genes by using cells with altered HELQ expression.
RESULTS: HELQ expression associates with response of EOC patients to platinum-based chemotherapy and their overall survival (OS), disease free survival (DFS). HELQ overexpression or knockdown, respectively, increased and decreased the cellular resistance to cisplatin, DNA repair activity, and expression of DNA repair proteins of Nucleotide excision repair (NER) pathway.
CONCLUSIONS: HELQ plays an important role in regulating the expression of DNA repair proteins NER pathway which, in turn, contributes to cellular response to cisplatin and patients' response to platinum-based chemotherapy. Our results demonstrated that HELQ could serve as a novel indicator for chemo-resistance of EOC, which can predict the prognosis of the disease.

PMID: 29572031 [PubMed - as supplied by publisher]

Comprehensive mapping of Cystic Fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site.

Proteins. 2018 Mar 23;:

Authors: Molinski SV, Shahani VM, Subramanian AS, MacKinnon SS, Woollard G, Laforet M, Laselva O, Morayniss LD, Bear CE, Windemuth A

Abstract
Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, of which over 2000 have been reported to date. Mutations have yet to be analyzed in aggregate to assess their distribution across the tertiary structure of the CFTR protein, an approach that could provide valuable insights into the structure-function relationship of CFTR. In addition, the binding site of Class I correctors (VX-809, VX-661, C18) is not well understood. In this study, exonic CFTR mutations and mutant allele frequencies described in three curated databases (ABCMdb, CFTR1 and CFTR2, comprising >130,000 data points) were mapped to two different structural models: a homology model of full-length CFTR protein in the open-channel state, and a cryo-electron microscopy core-structure of CFTR in the closed-channel state. Accordingly, residue positions of six high-frequency mutant CFTR alleles were found to spatially co-localize in CFTR protein, and a significant cluster was identified at the NBD1:ICL4 interdomain interface. In addition, immunoblotting confirmed the approximate binding site of Class I correctors, demonstrating that these small molecules act via a similar mechanism in vitro, and in silico molecular docking generated binding poses for their complex with the cryo-electron microscopy structure to suggest the putative corrector binding site is a multi-domain pocket near residues F374-L375. These results confirm the significance of interdomain interfaces as susceptible to disruptive mutation, and identify a putative corrector binding site. The structural pharmacogenomics approach of mapping mutation databases to protein models shows promise for facilitating drug discovery and personalized medicine for monogenetic diseases. This article is protected by copyright. All rights reserved.

PMID: 29569753 [PubMed - as supplied by publisher]

Future directions in pharmacogenomics discovery in cardiovascular disease.

Pharmacogenomics. 2018 Mar 23;:

Authors: Friede KA, Voora D

PMID: 29569527 [PubMed - as supplied by publisher]

Pharmacogenetics and the treatment of chronic myeloid leukemia: how relevant clinically? An update.

Pharmacogenomics. 2018 Mar 23;:

Authors: Ankathil R, Azlan H, Dzarr AA, Baba AA

Abstract
Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.

PMID: 29569526 [PubMed - as supplied by publisher]

Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations.

Mol Med Rep. 2018 Mar 16;:

Authors: Zhu YB, Luo JW, Jiang F, Liu G

Abstract
Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia‑associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen‑2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage‑gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.

PMID: 29568937 [PubMed - as supplied by publisher]