Circulating tumor DNA (ctDNA) in precision oncology of ovarian cancer.

Pharmacogenomics. 2019 Dec;20(18):1251-1253

Authors: Oikkonen J, Hautaniemi S

PMID: 31829836 [PubMed - in process]

Circulating tumor DNA and the future of EGFR-mutant lung cancer treatment.

Pharmacogenomics. 2019 Dec;20(18):1255-1257

Authors: Re MD, Addeo A, Passaro A, Petrini I, van Schaik RH, Danesi R

PMID: 31829835 [PubMed - in process]

Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma.

Pharmacogenomics. 2019 Dec;20(18):1283-1290

Authors: Goey AK, With M, Agema BC, Hoop EO, Singh RK, van der Veldt AA, Mathijssen RH, van Schaik RH, Bins S

Abstract
Aim: The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpatient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Patients & methods: Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for ABCB1 (3435C>T), ABCG2 (421C>A, 34G>A) and CYP3A4 (*22, 15389C>T) polymorphisms. Associations between these variants and the incidence of toxicities were studied. Results: CYP3A4*22 was significantly associated with increased risk for grade ≥3 nausea, grade 1-4 hyperbilirubinemia, and cutaneous squamous cell carcinoma. ABCB1 3435C>T was a predictor for grade ≥3 toxicity. Conclusion: Genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities.

PMID: 31829834 [PubMed - in process]

A Deep Learning Framework for Predicting Response to Therapy in Cancer.

Cell Rep. 2019 Dec 10;29(11):3367-3373.e4

Authors: Sakellaropoulos T, Vougas K, Narang S, Koinis F, Kotsinas A, Polyzos A, Moss TJ, Piha-Paul S, Zhou H, Kardala E, Damianidou E, Alexopoulos LG, Aifantis I, Townsend PA, Panayiotidis MI, Sfikakis P, Bartek J, Fitzgerald RC, Thanos D, Mills Shaw KR, Petty R, Tsirigos A, Gorgoulis VG

Abstract
A major challenge in cancer treatment is predicting clinical response to anti-cancer drugs on a personalized basis. Using a pharmacogenomics database of 1,001 cancer cell lines, we trained deep neural networks for prediction of drug response and assessed their performance on multiple clinical cohorts. We demonstrate that deep neural networks outperform the current state in machine learning frameworks. We provide a proof of concept for the use of deep neural network-based frameworks to aid precision oncology strategies.

PMID: 31825821 [PubMed - in process]

Recent advances in understanding of attention deficit hyperactivity disorder (ADHD): how genetics are shaping our conceptualization of this disorder.

F1000Res. 2019;8:

Authors: Zayats T, Neale BM

Abstract
Attention deficit hyperactivity disorder (ADHD) is a clinically defined disorder, and inattention and hyperactivity/impulsivity are its main symptom domains. The presentation, lifelong continuation and treatment response of ADHD symptoms, however, is highly heterogeneous. To better define, diagnose, treat and prevent ADHD, it is essential that we understand the biological processes underlying all of these elements. In this review, given the high heritability of ADHD, we discuss how and why genetics can foster such progress. We examine what genetics have taught us so far with regard to ADHD definition, classification, clinical presentation, diagnosis and treatment. Finally, we offer a prospect of what genetic studies on ADHD may bring in the future.

PMID: 31824658 [PubMed - in process]

Fear not: recent advances in understanding the neural basis of fear memories and implications for treatment development.

F1000Res. 2019;8:

Authors: Milton AL

Abstract
Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. However, maladaptive expression of fear can lead to debilitating stressor-related and anxiety disorders such as post-traumatic stress disorder. Although the neural basis of fear has been extensively researched for several decades, recent technological advances in pharmacogenetics and optogenetics have allowed greater resolution in understanding the neural circuits that underlie fear. Alongside conceptual advances in the understanding of fear memory, this increased knowledge has clarified mechanisms for some currently available therapies for post-traumatic stress disorder and has identified new potential treatment targets.

PMID: 31824654 [PubMed - in process]

Informing Integration of Genomic Medicine Into Primary Care: An Assessment of Current Practice, Attitudes, and Desired Resources.

Front Genet. 2019;10:1189

Authors: Carroll JC, Allanson J, Morrison S, Miller FA, Wilson BJ, Permaul JA, Telner D

Abstract
Introduction: Preparing primary care providers for genomic medicine (GM) first requires assessment of their educational needs in order to provide clear, purposeful direction and justify educational activities. More understanding is needed about primary care providers' perspectives on their role in newer areas of GM and what resources would be helpful in practice. Our objective was to determine family physicians' (FP) current involvement and confidence in GM, attitudes regarding its clinical value, suggestions for integration of GM into practice, and resources and education required. Methods: A self-complete anonymous questionnaire was mailed to a random sample of 2,000 FPs in Ontario, Canada in September 2012. Results: Adjusted response rate was 26% (361/1,365), mean age was 51, and 53% were male. FPs reported many aspects of traditional GM as part of current practice (eliciting family history: 93%; deciding who to refer to genetics: 94%; but few reported confidence (44%, 32% respectively). Newer areas of GM were not part of most FPs' current practice and confidence was low (pharmacogenetics: 28% part of practice, 5% confident; direct-to-consumer genetic testing: 14%/2%; whole genome sequencing: 8%/2%). Attitudes were mixed with 59% agreeing that GM would improve patient health outcomes, 41% seeing benefits to genetic testing, but only 36% agreeing it was their responsibility to incorporate GM into practice. Few could identify useful sources of genetic information (22%) or find information about genetic tests (21%). Educational resources participants anticipated would be useful included contact information for local genetics clinics (89%), summaries of genetic disorders (86%), and genetic referral (85%) and testing (86%) criteria. About 58% were interested in learning about new genetic technologies. Most (76%) wanted to learn through in-person teaching (lectures, seminars etc.), 66% wanted contact with a local genetic counselor to answer questions, and 59% were interested in a genetics education website. Conclusion: FPs lack confidence in GM skills needed for practice, particularly in emerging areas of GM. They see their role as making appropriate referrals, are somewhat optimistic about the contribution GM may make to patient care, but express caution about its current clinical benefits. There is a need for evidence-based educational resources integrated into primary care and improved communication with genetic specialists.

PMID: 31824576 [PubMed]

The multi-faceted functioning portrait of LRF/ZBTB7A.

Hum Genomics. 2019 Dec 10;13(1):66

Authors: Constantinou C, Spella M, Chondrou V, Patrinos GP, Papachatzopoulou A, Sgourou A

Abstract
Transcription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A's orchestrated action.

PMID: 31823818 [PubMed - in process]

Genetic variation in EPHA contributes to sensitivity to paclitaxel-induced peripheral neuropathy.

Br J Clin Pharmacol. 2019 Dec 10;:

Authors: Marcath LA, Kidwell KM, Vangipuram K, Gersch CL, Rae JM, Burness ML, Griggs JJ, Van Poznak C, Hayes DF, Lavoie Smith EM, Henry NL, Beutler AS, Hertz DL

Abstract
AIMS: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold).
METHODS: Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for three genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption.
RESULTS: EPHA5 rs7349683 (minor allele frequency=0.32) was associated with increased PN sensitivity (ß-coefficient=0.39, 95% confidence interval (CI) 0.11-0.67, p=0.007). Setting a maximum tolerable threshold of CIPN8=30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 hrs) than heterozygous (12.6 hrs) or wild-type (13.6 hrs) patients. Total number of missense variants (median=0, range 0-2) was associated with decreased PN sensitivity (beta coefficient: -0.42, 95% CI -0.72 - -0.12, p=0.006). No association with treatment disruption was detected for the total number of missense variants and rs7349683.
CONCLUSIONS: Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.

PMID: 31823378 [PubMed - as supplied by publisher]

Human genetics and genomics research in Ecuador: historical survey, current state, and future directions.

Hum Genomics. 2019 Dec 10;13(1):64

Authors: Zambrano-Mila MS, Agathos SN, Reichardt JKV

Abstract
BACKGROUND: In South America, the history of human genetics is extensive and its beginnings go back to the onset of the twentieth century. In Ecuador, the historical record of human genetics and genomics research is limited. In this context, our work analyzes the current status and historical panorama of these fields, based on bibliographic searches in Scopus, Google Scholar, PubMed, and Web of Science.
RESULTS: Our results determined that the oldest paper in human genetics coauthored by an Ecuadorian institution originates from the Central University of Ecuador in 1978. From a historical standpoint, the number of articles has increased since the 1990s. This growth has intensified and it is reflected in 137 manuscripts recorded from 2010 to 2019. Areas such as human population genetics, phylogeography, and forensic sciences are the core of genetics and genomics-associated research in Ecuador. Important advances have been made in the understanding of the bases of cancer, some genetic diseases, and congenital disorders. Fields such as pharmacogenetics and pharmacogenomics have begun to be explored during the last years.
CONCLUSIONS: This work paints a comprehensive picture and provides additional insights into the future panorama of human genetic and genomic research in Ecuador as an example of an emerging, resource-limited country with interesting phylogeographic characteristics and public health implications.

PMID: 31822297 [PubMed - in process]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/12/11

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.

Pharmacogenomic phase transition from personalized medicine to patient-centric customized delivery.

Pharmacogenomics J. 2019 Dec 10;:

Authors: Radhakrishnan A, Kuppusamy G, Ponnusankar S, Shanmukhan NK

Abstract
Personalized medicine has been a booming area in clinical research for the past decade, in which the detailed information about the patient genotype and clinical conditions were collected and considered to optimize the therapy to prevent adverse reactions. However, the utility of commercially available personalized medicine has not yet been maximized due to the lack of a structured protocol for implementation. In this narrative review, we explain the role of pharmacogenetics in personalized medicine, next-generation personalized medicine, i.e., patient-centric personalized medicine, in which the patient's comfort is considered along with pharmacogenomics to be a primary factor. We extensively discuss the classifications, strategies, tools, and drug delivery systems that can support the implementation of patient-centric personalized medicine from an industrial perspective.

PMID: 31819163 [PubMed - as supplied by publisher]

Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer.

Pharmacogenomics J. 2019 Dec 10;:

Authors: Reynolds IS, O'Connell E, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Furney SJ, Burke JP

Abstract
Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer. A systematic search of PubMed was performed to identify papers investigating drug resistance in colorectal cancer. From this review, a list of 26 drug-resistance-associated genes was compiled. Using patient data from The Cancer Genome Atlas (TCGA), the somatic mutation rate and CNV was compared between patients with mucinous and non-mucinous colorectal cancer. Statistical analysis was carried out using GraphPad PRISM® version 5.00. Data were available on 531 patients (464 non-mucinous, 67 mucinous). A statistically significant difference in the somatic mutation rate between the two cohorts was identified in the TYMP (p = 0.0179), ATP7B (p = 0.0465), SRPK1 (p = 0.0135), ABCB1 (p = 0.0423), and ABCG2 (p = 0.0102) genes. A statistically significant difference in CNV was identified between the two cohorts in the GSTP1 (p = 0.0405), CCS (p = 0.0063), and TOP1 (p = 0.0048) genes. Differences in somatic mutation rate and CNV in genes associated with resistance to 5-FU, oxaliplatin, and irinotecan may partly account for the pattern of resistance observed in mucinous colorectal cancers. These genetic alterations may prove useful when deciding on a personalized approach to chemotherapy and may also represent potential therapeutic targets going forward.

PMID: 31819162 [PubMed - as supplied by publisher]

Cancer's epigenetic drugs: where are they in the cancer medicines?

Pharmacogenomics J. 2019 Dec 10;:

Authors: Ghasemi S

Abstract
Epigenetic modulation can affect the characteristics of cancers. Because it is likely to manipulate epigenetic genes, they can be considered as potential targets for cancer treatment. In this comprehensive study, epigenetic drugs are categorized according to anticancer mechanisms and phase of therapy. The relevant articles or databases were searched for epigenetic approaches to cancer therapy. Epigenetic drugs are divided according to their mechanisms and clinical phases that have been approved by the FDA or are undergoing evaluation phases. DNA methylation agents, chromatin remodelers specially HDACs, and noncoding RNAs especially microRNAs are the main epi-drugs for cancer. Despite many challenges, combination therapy using epi-drugs and routine therapies such as chemotherapy in various approaches have exhibited beneficial effects compared with each treatment alone. Cancer stem cell targeting and epigenetic editing have been confirmed as definitive pathways for cancer treatment. This paper reviewed the available epigenetic approaches to cancer therapy.

PMID: 31819161 [PubMed - as supplied by publisher]

Proteomic analysis to define predictors of treatment response to adalimumab or methotrexate in rheumatoid arthritis patients.

Pharmacogenomics J. 2019 Dec 10;:

Authors: Ling SF, Nair N, Verstappen SMM, Barton A, Zucht HD, Budde P, Schulz-Knappe P, MATURA consortium, Plant D

Abstract
Seropositivity for anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA), a chronic autoimmune arthritis, is associated with worse long-term disease outcomes. ACPA is ubiquitously tested in RA patients, but other autoantibodies exist (in both citrullinated and non-citrullinated form) which may provide additional information on RA subtypes and/or treatment response. We used a multiplex bead-based assay of 376 autoantibodies to test associations between these autoantibodies and treatment response in RA patients. Clusters of patients with similar autoantibody expression were defined and cluster membership was associated with treatment response. Thirty-four autoantibodies were differentially expressed in RA patients compared with healthy controls; citrullinated vimentin was associated with treatment response. A selection of citrullinated autoantibodies was found to be associated with treatment response in a subanalysis of ACPA-negative RA patients. Finer ACPA specificities in ACPA-negative RA patients may be predictive of treatment response and could represent a rich vein of future study.

PMID: 31819160 [PubMed - as supplied by publisher]

Description of an Established, Fee-for-Service, Office-Based, Pharmacist-Managed Pharmacogenomics Practice.

Sr Care Pharm. 2019 Dec 01;34(10):660-668

Authors: Schuh MJ, Crosby S

Abstract
OBJECTIVE: To describe an established, pharmacist-managed, fee-for-service, office-based pharmacogenomics (PGx) practice.<br/> SETTING: Multi-specialty, academic, tertiary care medical clinic and hospital.<br/> PRACTICE DESCRIPTION: Physician office-based PGx fee-for-service (FFS) pharmacist practice. Patients seen are complex and most are older adults.<br/> INNOVATION: Established service in a new area of ambulatory practice that is financially self-sustaining. Patients who received PGx testing were seen within the medication therapy management polypharmacy practice since 2015, with the PGx practice becoming official in 2018.<br/> MAIN OUTCOME MEASUREMENTS: Growth of practice, evaluated by referred patient consults ordered per month by providers.<br/> RESULTS: Because of insufficient third-party payment for PGx services, the practice was developed as a selfpay, FFS practice and growing because of patient and provider demand.<br/> CONCLUSION: It is quite possible pharmacists in greater numbers can expand PGx services into ambulatory and inpatient areas they may have never otherwise entered now that PGx has grown in use and relevance. PGx presents additional opportunities and service lines for pharmacists to practice how they were trained and assist them in collaborative integration onto the medical team.

PMID: 31818351 [PubMed - in process]

Aqueous Partition of Methanolic Extract of Dicranopteris linearis Leaves Protects against Liver Damage Induced by Paracetamol.

Nutrients. 2019 Dec 04;11(12):

Authors: Zakaria ZA, Kamisan FH, Mohd Nasir N, Teh LK, Salleh MZ

Abstract
This study aimed to determine the antioxidant and hepatoprotective activities of semi-purified aqueous partition obtained from the methanol extract of Dicranopteris linearis (AQDL) leaves against paracetamol (PCM)-induced liver intoxication in rats. The test solutions, AQDL (50, 250, and 500 mg/kg), were administered orally to rats (n = 6) once daily for seven consecutive days followed by the hepatotoxicity induction using 3 g/kg PCM (p.o.). Blood was collected for serum biochemical parameters analysis while the liver was collected for histopathological examination and endogenous antioxidant enzymes analysis. AQDL was also subjected to antioxidant determination and phytochemical analysis. Results obtained show that AQDL possessed high total phenolic content (TPC) value and remarkable radical scavenging activities. AQDL also significantly (p < 0.05) reduced the liver weight/body weight (LW/BW) ratio or serum level of ALT, AST, and total bilirubin while significantly (p < 0.05) increase the level of superoxide dismutase (SOD) and catalase (CAT) without affecting the malondialdehyde (MDA) in the liver indicating its hepatoprotective effect. Phytoconstituents analyses showed only the presence of saponins and triterpenes, but lack of flavonoids. In conclusion, AQDL exerts hepatoprotective activity via its high antioxidant potential and ability to modulate the endogenous enzymatic antioxidant defense system possibly via the synergistic action of saponins and triterpenes.

PMID: 31817058 [PubMed - in process]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/12/10

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

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/12/10

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.

Selective protection of murine cerebral Gi/o-proteins from inactivation by parenterally injected pertussis toxin.

J Mol Med (Berl). 2019 Dec 06;:

Authors: Vega SC, Leiss V, Piekorz R, Calaminus C, Pexa K, Vuozzo M, Schmid AM, Devanathan V, Kesenheimer C, Pichler BJ, Beer-Hammer S, Nürnberg B

Abstract
Pertussis toxin (PTX) is a potent virulence factor in patients suffering from whooping cough, but in its detoxified version, it is applied for vaccination. It is thought to contribute to the pathology of the disease including various CNS malfunctions. Based on its enzymatic activity, PTX disrupts GPCR-dependent signaling by modifying the α-subunit of heterotrimeric Gi/o-proteins. It is also extensively used as a research tool to study neuronal functions in vivo and in vitro. However, data demonstrating the penetration of PTX from the blood into the brain are missing. Here, we examined the Gαi/o-modifying activity of PTX in murine brains after its parenteral application. Ex vivo biodistribution analysis of [124I]-PTX displayed poor distribution to the brain while relatively high concentrations were visible in the pancreas. PTX affected CNS and endocrine functions of the pancreas as shown by open-field and glucose tolerance tests, respectively. However, while pancreatic islet Gαi/o-proteins were modified, their neuronal counterparts in brain tissue were resistant towards PTX as indicated by different autoradiographic and immunoblot SDS-PAGE analyses. In contrast, PTX easily modified brain Gαi/o-proteins ex vivo. An attempt to increase BBB permeability by application of hypertonic mannitol did not show PTX activity on neuronal G proteins. Consistent with these findings, in vivo MRI analysis did not point to an increased blood-brain barrier (BBB) permeability following PTX treatment. Our data demonstrate that the CNS is protected from PTX. Thus, we hypothesize that the BBB hinders PTX to penetrate into the CNS and to deliver its enzymatic activity to brain Gαi/o-proteins. KEY MESSAGES: i.p. applied PTX is poorly retained in the brain while reaches high concentration in the pancreas. Pancreatic islet Gαi/o- but not cerebral Gαi/o-proteins are modified by i.p. administered PTX. Gαi/o-proteins from isolated cerebral cell membranes were easily modified by PTX ex vivo. CNS is protected from i.p. administered PTX. PTX does not permeabilize the BBB.

PMID: 31811326 [PubMed - as supplied by publisher]