DNA Methylation and Regulatory Elements during Chicken Germline Stem Cell Differentiation.

Stem Cell Reports. 2018 Apr 17;:

Authors: He Y, Zuo Q, Edwards J, Zhao K, Lei J, Cai W, Nie Q, Li B, Song J

Abstract
The production of germ cells in vitro would open important new avenues for stem biology and human medicine, but the mechanisms of germ cell differentiation are not well understood. The chicken, as a great model for embryology and development, was used in this study to help us explore its regulatory mechanisms. In this study, we reported a comprehensive genome-wide DNA methylation landscape in chicken germ cells, and transcriptomic dynamics was also presented. By uncovering DNA methylation patterns on individual genes, some genes accurately modulated by DNA methylation were found to be associated with cancers and virus infection, e.g., AKT1 and CTNNB1. Chicken-unique markers were also discovered for identifying male germ cells. Importantly, integrated epigenetic mechanisms were explored during male germ cell differentiation, which provides deep insight into the epigenetic processes associated with male germ cell differentiation and possibly improves treatment options to male infertility in animals and humans.

PMID: 29681542 [PubMed - as supplied by publisher]

CYP2C19⁎2 Polymorphism in Chilean Patients with In-Stent Restenosis Development and Controls.

Biomed Res Int. 2017;2017:5783719

Authors: Ruedlinger J, Prado Y, Zambrano T, Saavedra N, Bobadilla B, Potthoff M, Pérez L, Lanas F, Salazar LA

Abstract
Clopidogrel is an antiplatelet drug especially used in patients undergoing percutaneous coronary interventions (PCI). Polymorphisms within CYP2C19 can result in important interindividual variations regarding therapeutic efficacy. Therefore, we aimed to evaluate the impact of the CYP2C19⁎2 variant (rs4244285) on in-stent restenosis occurrence in Chilean patients who underwent PCI and received clopidogrel. A total of 77 cases with stenosis >50% in the angioplasty site (62.75 ± 9.8 years, 80.5% males) and 86 controls (65.45 ± 9.8 years, 72.1% males) were studied. The polymorphism was genotyped using TaqMan® Drug Metabolism Genotyping Assays. Overall, CYP2C19⁎2 allele frequency was 8.3%. Diabetes, chronic lesions, and bare metal stents (BMS) were observed more often in cases than in controls (p = 0.05, p = 0.04, and p = 0.02, resp.). Genotypic frequencies did not differ significantly between the groups (p = 0.15). Nonetheless, the mutated allele was observed in a greater proportion in patients without in-stent restenosis (p = 0.055). There was no significant association between the rs4244285 variant and the occurrence of in-stent restenosis after PCI (OR = 0.44; 95% CI: 0.19 to 1.04; p = 0.06). In summary, no association was identified between the CYP2C19⁎2 variant and the development of coronary in-stent restenosis.

PMID: 28785581 [PubMed - indexed for MEDLINE]

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability.

Sci Rep. 2016 10 19;6:35434

Authors: Hendriks DF, Fredriksson Puigvert L, Messner S, Mortiz W, Ingelman-Sundberg M

Abstract
Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound's potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability.

PMID: 27759057 [PubMed - indexed for MEDLINE]

Influence of Transporter Polymorphisms on Drug Disposition and Response: A Perspective from the International Transporter Consortium.

Clin Pharmacol Ther. 2018 Apr 21;:

Authors: Yee SW, Brackman DJ, Ennis EA, Sugiyama Y, Kamdem LK, Blanchard R, Galetin A, Zhang L, Giacomini KM

Abstract
Advances in genomic technologies have led to a wealth of information identifying genetic polymorphisms in membrane transporters, specifically how these polymorphisms affect drug disposition and response. This review describes the current perspective of the International Transporter Consortium (ITC) on clinically important polymorphisms in membrane transporters. ITC suggests that in addition to previously recommended polymorphisms in ABCG2 (BCRP) and SLCO1B1 (OATP1B1), polymorphisms in the emerging transporter, SLC22A1 (OCT1), be considered during drug development. Collectively, polymorphisms in these transporters are important determinants of interindividual differences in the levels, toxicities, and response to many drugs. This article is protected by copyright. All rights reserved.

PMID: 29679469 [PubMed - as supplied by publisher]

Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment.

Best Pract Res Clin Endocrinol Metab. 2018 Apr;32(2):189-200

Authors: Santi D, Potì F, Simoni M, Casarini L

Abstract
Infertility treatment may represent a paradigmatic example of precision medicine. Follicle-stimulating hormone (FSH) has been proposed as a valuable therapeutic option both in males and in females, even if a standardized approach is far to be established. To date, several genetic mutations as well as polymorphisms have been demonstrated to significantly affect the pathophysiology of FSH-FSH receptor (FSHR) interaction, although the underlying molecular mechanisms remain unclear. This review aims to highlight possible aspects of FSH therapy that could benefit from a pharmacogenetic approach, providing an up-to-date overview of the variability of the response to FSH treatment in both sexes. Specific sections are dedicated to the clinical use of FSH in infertility and how FSHR polymorphisms may affect the therapeutic endpoints.

PMID: 29678285 [PubMed - in process]

Towards Pharmacogenomics-Driven Medication Risk Assessment in People with Polypharmacy.

Stud Health Technol Inform. 2018;247:880-884

Authors: Liu J, Finkelstein J

Abstract
The main objective of this project was to introduce approaches for comprehensive medication risk assessment in people with polypharmacy that simultaneously account for multiple drug and gene effects. To achieve this goal, we developed an integrated knowledge repository of actionable pharmacogenes and a scoring algorithm that was pilot-tested using a data set containing pharmacogenomic information of people with polypharmacy. Metabolic phenotyping using resulting database demonstrated recall of 83.6% and precision of 87.1%. The final scoring algorithm yielded medication risk scores that allowed distinguish frequently hospitalized older adults with polypharmacy and older adults with polypharmacy with low hospitalization rate (average scores respectively: 75.89±15.45 and 10.51±1.82, p<0.05). The initial prototype assessment demonstrated feasibility of our approach and identified steps for improving risk scoring algorithms. Pharmacogenomics-driven medication risk assessment in patient with polypharmacy has potential in identifying inadequate drug regimens and preventing adverse drug events.

PMID: 29678087 [PubMed - in process]

Implementing Pharmacogenomic Clinical Decision Support into German Hospitals.

Stud Health Technol Inform. 2018;247:870-874

Authors: Hinderer M, Boerries M, Boeker M, Neumaier M, Loubal FP, Acker T, Brunner M, Prokosch HU, Christoph J

Abstract
BACKGROUND: Pharmacogenomic Clinical Decision Support Systems (CDSS) are considered to be the most feasible tool for adopting pharmacogenomic testing into clinical routine.
OBJECTIVE: To discuss important factors for implementing pharmacogenomic CDSS into German hospitals.
METHODS: We analyzed two relevant studies. Furthermore, we interviewed data privacy officers of three German university hospitals and examined relevant legal regulations in literature.
RESULTS: There are three major barriers for implementing pharmacogenomic CDSS into German hospitals: (i) the legal uncertainty; (ii) the lack of machine-readable data; (iii) the remaining knowledge gap of both genetics and pharmacogenomics among physicians.
CONCLUSION: The implementation of passive clinical decision support (CDS) for somatic mutations in the form of structured pharmacogenomic reports might be the most feasible CDS feature for clinicians in German hospitals.

PMID: 29678085 [PubMed - in process]

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A Novel Fibroblast Growth Factor 15 Dependent- and Bile Acid Independent-Promotion of Liver Regeneration in Mice.

Hepatology. 2018 Apr 19;:

Authors: Kong B, Sun R, Huang M, Chow MD, Zhong XB, Xie W, Lee YH, Guo GL

Abstract
The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy (PHx) are not entirely known, but bile acids (BAs) and fibroblast growth factor 15 (Fgf15) that is highly expressed in the mouse ileum could promote hepatocyte proliferation. Fgf15 strongly suppresses the synthesis of BAs and emerging evidence indicates that Fgf15 is important for liver regeneration. The mechanisms by which Fgf15 promotes liver regeneration are unclear, but Fgf15 may do so indirectly by reducing BA levels and/or directly by promoting cell proliferation. However, it's undetermined whether these two mechanisms are independent or integrated. In this study, we aimed to clarify these relationships by generating novel Fgf15 tet-off, transgenic mice (Fgf15 Tg) that had very low BA levels resulted from overexpressed Fgf15-mediated suppression of BA synthesis. Compared to wild-type mice, the Fgf15 Tg mice showed increased hepatocyte proliferation even without surgery, and a further induction of the genes in cell-cycle progression after PHx. Moreover, overexpression of Fgf15 by AAV-Fgf15 transduction or treatment with the recombinant Fgf15 protein led to increased cell proliferation in vivo. Furthermore, Fgf15 Tg mice exhibited an earlier and greater activation of MAPK, Stat3, and NF-κB signaling pathways in the priming stage, and a disruption of the hippo signaling pathway in the termination stage of liver regeneration.
CONCLUSION: Direct in-vivo evidence demonstrates that Fgf15 is critical in stimulating the phases of priming and termination of liver regeneration that are critical for cell survival and liver-size determination, independent of BA levels. This article is protected by copyright. All rights reserved.

PMID: 29672888 [PubMed - as supplied by publisher]

Community Dissemination in a Tribal Health Setting: A Pharmacogenetics Case Study.

Am Indian Alsk Native Ment Health Res. 2018;25(1):80-94

Authors: Beans JA, Hiratsuka VY, Apok CR, Caindec K, Dillard DA, Robinson RF

Abstract
Alaska Native and American Indian (AN/AI) people experience a disproportionate burden of health disparities in the United States. Including AN/AI people in pharmacogenetic research offers an avenue to address these health disparities, however the dissemination of pharmacogenetic research results in the community context can be a challenging task. In this paper, we describe a case-study that explores the preferences of AN/AI community members regarding pharmacogenetic research results dissemination. Results were presented as a PowerPoint presentation at the 2016 Alaska Native Health Research Forum (Forum). An audience response system and discussion groups were used to gather feedback from participants. Descriptive statistics were used to assess attendee understanding of the presentation content. Thematic analysis was used to analyze discussion group data. Forum attendees needed time to work through the concept of pharmacogenetics and looked for ways pharmacogenetics could apply to their daily life. Attendees found pharmacogenetics interesting, but wanted a simple description of pharmacogenetics. Community members were optimistic about the potential benefit pharmacogenetic medicine could have in the delivery of health care and expressed excitement this research was taking place. Researchers were urged to communicate throughout the study, not just end research results, to the community. Furthermore, attendees insisted their providers stay informed of research results that may have an impact on health care delivery. Conversational forms of dissemination are recommended when disseminating pharmacogenetic research results at the community level.

PMID: 29671859 [PubMed - in process]

Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

Nature. 2018 Apr 18;:

Authors: Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, Duncan D, Bregman H, Keskin A, Santeford A, Apte RS, Sehgal R, Johnson B, Amarasinghe GK, Soares MP, Satoh T, Akira S, Hai T, de Guzman Strong C, Auclair K, Roddy TP, Biller SA, Jovanovic M, Klechevsky E, Stewart KM, Randolph GJ, Artyomov MN

Abstract
Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.

PMID: 29670287 [PubMed - as supplied by publisher]

Frizzled-related proteins 4 (SFRP4) rs1802073G allele predicts the elevated serum lipid levels during acitretin treatment in psoriatic patients from Hunan, China.

PeerJ. 2018;6:e4637

Authors: Zhou X, Zhu W, Shen M, He Y, Peng C, Kuang Y, Su J, Zhao S, Chen X, Chen W

Abstract
Background: Acitretin is a second-generation synthetic retinoid, and is widely used for treating the severe psoriasis vulgaris. However, it should be chosen with caution for its cardiovascular risk, and it is reported that acitretin may increase the serum lipids. The purpose of this study is to investigate the relationship between the Frizzled-related proteins 4 (SFRP4) rs1802073 polymorphism and the changes of serum lipids in Chinese psoriatic patients during the treatment with acitretin.
Methods: In our study, 100 psoriatic patients were recruited systematically treated with acitretin (30 mg/day) for at least eight weeks. Data of the patients' demographic and clinical characteristics and the results of serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were collected pre- and post-treatment.
Results: A total of 84 psoriatic patients were enrolled and divided into three groups by SFRP4 rs1802073 genotypes. The patients who carried with TT genotype had maintained levels of TG and LDL-C after acitretin treatment, while patients with GG/GT genotypes had significantly elevated levels of serum TG and LDL-C compared to the TT genotype (ΔTG%: 27.53 ± 59.13 vs -1.47 ± 37.79, p = 0.026, ΔLDL-C%: 10.62 ± 26.57 vs -1.29 ± 17.07, p = 0.042). The association of rs1802073 with TG and LDL-C profiles remained significant after adjusting for age, gender, and body mass index. Although without significance, the pre-post change in serum level of TC across rs1802073 GG/GT genotypes demonstrated a trend similar to TG and LDL, and the serum level of HDL-C demonstrated a trend opposite to TG, TC and LDL.
Conclusions: Our results demonstrated that SFRP4 rs1802073 polymorphism was found to be associated with elevated serum lipid levels after acitretin treatment, and it may serve as a genetic marker of safe and precise treatment for individual psoriatic patients.

PMID: 29666772 [PubMed]

Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion.

Oncotarget. 2016 Sep 27;7(39):63342-63351

Authors: Feng F, Jiang Y, Lu H, Lu X, Wang S, Wang L, Wei M, Lu W, Du Z, Ye Z, Yang G, Yuan F, Ma Y, Lei X, Lu Z

Abstract
Recent evidences have unveiled critical roles of cancer stem cells (CSCs) in tumorigenicity, but how interactions between CSC and tumor environments help maintain CSC initiation remains obscure. The small GTPases Rab27A regulates autocrine and paracrine cytokines by monitoring exocytosis of extracellular vesicles, and is reported to promote certain tumor progression. We observe that overexpression of Rab27A increased sphere formation efficiency (SFE) by increasing the proportion of CD44+ and PKH26high cells in HT29 cell lines, and accelerating the growth of colosphere with higher percentage of cells at S phase. Mechanism study revealed that the supernatant derived from HT29 sphere after Rab27A overexpression was able to expand sphere numbers with elevated secretion of VEGF and TGF-β. In tumor implanting nude mice model, tumor initiation rates and tumor sizes were enhanced by Rab27A with obvious angiogenesis. As a contrast, knocking down Rab27A impaired the above effects. More importantly, the correlation between higher p65 level and Rab27A in colon sphere was detected, p65 was sufficient to induce up-regulation of Rab27A and a functional NF-κB binding site in the Rab27A promoter was demonstrated. Altogether, our findings reveal a unique mechanism that tumor environment related NF-κB signaling promotes various colon cancer stem cells (cCSCs) properties via an amplified paracrine mechanism regulated by higher Rab27A level.

PMID: 27556511 [PubMed - indexed for MEDLINE]

Sepsis Diagnostics in the Era of "Omics" Technologies.

Prague Med Rep. 2018;119(1):9-29

Authors: Průcha M, Zazula R, Russwurm S

Abstract
Sepsis is a multifactorial clinical syndrome with an extremely dynamic clinical course and with high diverse clinical phenotype. Early diagnosis is crucial for the final clinical outcome. Previous studies have not identified a biomarker for the diagnosis of sepsis which would have sufficient sensitivity and specificity. Identification of the infectious agents or the use of molecular biology, next gene sequencing, has not brought significant benefit for the patient in terms of early diagnosis. Therefore, we are currently searching for biomarkers, through "omics" technologies with sufficient diagnostic specificity and sensitivity, able to predict the clinical course of the disease and the patient response to therapy. Current progress in the use of systems biology technologies brings us hope that by using big data from clinical trials such biomarkers will be found.

PMID: 29665344 [PubMed - in process]

Predicting Pharmacokinetics/Pharmacodynamics in the Individual Patient: Separating Reality From Hype.

J Clin Pharmacol. 2018 Apr 17;:

Authors: Benet LZ

Abstract
Individualization of patient drug dosing to maximize efficacy and minimize toxicity is the goal of clinical pharmacology. Here we review the history of drug dosing individualization from early predictions for renally eliminated drugs based on kidney function through the introduction of clearance concepts for metabolic processes, the differentiation of volume of distribution between pharmacokinetics and chemistry, the role of transporters, the unique pharmacokinetic aspects of oral dosing, and the relevance of protein binding to the emergence of pharmacogenomics. The Food and Drug Administration listing of pharmacogenomic markers in approved drug labeling is analyzed with respect to the promise of genomics in terms of picking the right drug for the patient based on genetic information vs selecting or adjusting the dosage regimen based on genetic information: the former resulting in a great advance, whereas the latter has shown less convincing evidence of clinical relevance. Finally, new information on individualized predictive methodologies based on marker drugs for enzymes and transporters is reviewed. We conclude that although individualization of drug dosing will work for most drugs primarily excreted unchanged in the urine, individualization of dosing regimens is not critical for wide-therapeutic-index drugs, whereas for narrow-therapeutic-index drugs predictions are most often more hype than reality, with therapeutic drug monitoring required. However, continuing advances in discovering and validating biomarkers will lead to predictions of pharmacokinetics/pharmacodynamics in the individualized patient that should result in shifting the hype to reality with time.

PMID: 29663413 [PubMed - as supplied by publisher]

5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer.

Oncotarget. 2018 Mar 27;9(23):16437-16450

Authors: Toffalorio F, Santarpia M, Radice D, Jaramillo CA, Spitaleri G, Manzotti M, Catania C, Jordheim LP, Pelosi G, Peters GJ, Tibaldi C, Funel N, Spaggiari L, de Braud F, De Pas T, Giovannetti E

Abstract
A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

PMID: 29662657 [PubMed]

Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients.

Pharmacogenomics J. 2018 Apr 17;:

Authors: Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, Villar E, Valdivia-Bautista J, Faus-Dáder MJ, Calleja-Hernández MÁ

Abstract
Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI95% = 1.12-5.69) and XRCC1 rs25487-GG (p = 0.0161; OR = 2.99; CI95% = 1.26-7.62) genotype showed significantly better ORR. Cox survival analysis revealed that patients carrying the MDM2 rs1690924-GG genotype (p = 0.0345; HR = 1.99; CI95% = 1.05-3.80) presented higher risk of death. Furthermore, carriers of MTR rs1805087-A alleles (p = 0.0060; HR = 8.91; CI95% = 1.87-42.42) and SLC19A1 rs1051266-AA genotype (p = 0.0130; HR = 1.74; CI95% = 1.12-2.68) showed greater risk of progression. No influence of ERCC1 rs11615, ERCC2 rs13181, ERCC2 rs1799793, XRCC1 rs1799782, MDM2 rs1470383, MTHFR rs1801131, and MTHFR rs1801133 on platinum-based chemotherapy clinical outcomes was found. In conclusion, our results suggest that ERCC1 rs3212986, XRCC1 rs25487, MDM2 rs1690924, MTR rs1805087, and SLC19A1 rs1051266 gene polymorphisms may significantly act as predictive factors in NSCLC patients treated with platinum-based chemotherapy.

PMID: 29662106 [PubMed - as supplied by publisher]

Introduction to Nephropharmacology for the Clinician: A New CJASN Series.

Clin J Am Soc Nephrol. 2018 Apr 16;:

Authors: Nolin TD, Perazella MA

PMID: 29661769 [PubMed - as supplied by publisher]

Neuroendocrine factors: The missing link in non‑melanoma skin cancer (Review).

Oncol Rep. 2017 Sep;38(3):1327-1340

Authors: Lupu M, Caruntu A, Caruntu C, Papagheorghe LML, Ilie MA, Voiculescu V, Boda D, Constantin C, Tanase C, Sifaki M, Drakoulis N, Mamoulakis C, Tzanakakis G, Neagu M, Spandidos DA, Izotov BN, Tsatsakis AM

Abstract
Non‑melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun‑protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun‑exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well‑known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene‑related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α‑melanocyte‑stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.

PMID: 28713981 [PubMed - indexed for MEDLINE]

Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males.

Pain Pract. 2017 Sep;17(7):930-940

Authors: Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, Tan SC, Mohamad N, Ismail R

Abstract
BACKGROUND: Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males.
METHODS: Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction.
RESULTS: A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype.
CONCLUSION: The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males.

PMID: 27996183 [PubMed - indexed for MEDLINE]