CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein.

Brain Behav Immun. 2017 Aug 31;:

Authors: Miller MW, Maniates H, Wolf EJ, Logue MW, Schichman SA, Stone A, Milberg W, McGlinchey R

Abstract
BACKGROUND: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD.
METHODS: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study.
RESULTS: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels.
CONCLUSIONS: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD.

PMID: 28867284 [PubMed - as supplied by publisher]

Prioritizing Possibilities for Child and Family Health: An Agenda to Address Adverse Childhood Experiences and Foster the Social and Emotional Roots of Well-being in Pediatrics.

Acad Pediatr. 2017 Sep - Oct;17(7S):S36-S50

Authors: Bethell CD, Solloway MR, Guinosso S, Hassink S, Srivastav A, Ford D, Simpson LA

Abstract
OBJECTIVE: A convergence of theoretical and empirical evidence across many scientific disciplines reveals unprecedented possibilities to advance much needed improvements in child and family well-being by addressing adverse childhood experiences (ACEs), promoting resilience, and fostering nurturance and the social and emotional roots of healthy child development and lifelong health. In this article we synthesize recommendations from a structured, multiyear field-building and research, policy, and practice agenda setting process to address these issues in children's health services.
METHODS: Between Spring of 2013 and Winter of 2017, the field-building and agenda-setting process directly engaged more than 500 individuals and comprised 79 distinct agenda-setting and field-building activities and processes, including: 4 in-person meetings; 4 online crowdsourcing rounds across 10 stakeholder groups; literature and environmental scans, publications documenting ACEs, resilience, and protective factors among US children, and commissioning of this special issue of Academic Pediatrics; 8 in-person listening forums and 31 educational sessions with stakeholders; and a range of action research efforts with emerging community efforts. Modified Delphi processes and grounded theory methods were used and iterative and structured synthesis of input was conducted to discern themes, priorities, and recommendations.
RESULTS: Participants discerned that sufficient scientific findings support the formation of an applied child health services research and policy agenda. Four overarching priorities for the agenda emerged: 1) translate the science of ACEs, resilience, and nurturing relationships into children's health services; 2) cultivate the conditions for cross-sector collaboration to incentivize action and address structural inequalities; 3) restore and reward for promoting safe and nurturing relationships and full engagement of individuals, families, and communities to heal trauma, promote resilience, and prevent ACEs; and 4) fuel "launch and learn" research, innovation, and implementation efforts. Four research areas arose as central to advancing these priorities in the short term. These are related to: 1) family-centered clinical protocols, 2) assessing effects on outcomes and costs, 3) capacity-building and accountability, and 4) role of provider self-care to quality of care. Finally, we identified 16 short-term actions to leverage existing policies, practices, and structures to advance agenda priorities and research priorities.
CONCLUSIONS: Efforts to address the high prevalence and negative effects of ACEs on child health are needed, including widespread and concrete understanding and strategies to promote awareness, resilience, and safe, stable, nurturing relationships as foundational to healthy child development and sustainable well-being throughout life. A paradigm-shifting evolution in individual, organizational, and collective mindsets, policies, and practices is required. Shifts will emphasize the centrality of relationships and regulation of emotion and stress to brain development as well as overall health. They will elevate relationship-centered methods to engage individuals, families, and communities in self-care related to ACEs, stress, trauma, and building the resilience and nurturing relationships science has revealed to be at the root of well-being. Findings reflect a palpable hope for prevention, mitigation, and healing of individual, intergenerational, and community trauma associated with ACEs and provide a road map for doing so.

PMID: 28865659 [PubMed - in process]

Wuzhi tablet (Schisandra sphenanthera extract) is a promising tacrolimus-sparing agent for renal transplant recipients who are CYP3A5 expressers: a two-phase prospective study.

Drug Metab Dispos. 2017 Sep 01;:

Authors: Li JL, Chen S, Qin X, Fu Q, Bi H, Zhang Y, Wang X, Liu L, Wang C, Huang M

Abstract
Tacrolimus is a potent but expensive first-line immunosuppressant, thus solutions to reduce tacrolimus consumption while maintain therapeutic level are in urgent need. A two-phase prospective study was conducted to assess the efficacy of an ethanolic extraction preparation of Schisandra sphenanthera (Wuzhi tablet) as a tacrolimus-sparing agent in renal transplant recipients who were high-dose tacrolimus consumers (CYP3A5*1 allele carriers, CYP3A5 expressers). A total of twelve patients were included in the Part I study. After co-administration of Wuzhi tablet, the average individual increment (%) in dose-adjusted C0, Cmax and AUC0-12 h of tacrolimus were 198.8% (95% CI 149.2, 248.3), 111.0% (95% CI 63.4, 158.6) and 126.1% (95% CI 89.4, 162.8), respectively (P<0.01), while the average individual reduction (%) in tacrolimus daily dose was 40.9% (95% CI 25.2, 56.6) (P<0.01). Subsequently, 32 patients were enrolled in a prospective, randomized, controlled study and randomly assigned to receive tacrolimus by CYP3A5 genotype plus Wuzhi tablet co-administration guided dosing (study group) or standard dosing (control group). Besides less tacrolimus dose requirement (P<0.01), a more accurate tacrolimus initial dose characterized by lower incidence of out-of-range C0 after initial dose (P<0.01) and fewer dose changes (P<0.01) was found in the study group. Moreover, no significant differences in acute rejection rate and serum creatinine levels were observed between two groups. Our results show that CYP3A5 genotype plus Wuzhi tablet co-administration guided tacrolimus dosing is a promising therapy for CYP3A5 expressers in the early post-transplant stage, while further study with a larger sample size is required to prove these findings.

PMID: 28864749 [PubMed - as supplied by publisher]

Novel Interactions between Gut Microbiome and Host Drug-processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals PBDEs.

Drug Metab Dispos. 2017 Sep 01;:

Authors: Li CY, Lee S, Cade S, Kuo LJ, Schultz IR, Bhatt DK, Prasad B, Bammler TK, Cui JY

Abstract
The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 and BDE-99, are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 mol/kg) for four days. Following BDE-47 treatment, GF mice had higher level of 5-OH-BDE-47 but lower levels of 4 other metabolites in liver than CV mice; whereas following BDE-99 treatment, GF mice had lower levels of 4 minor metabolites in liver than CV mice. RNA-Seq demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal condition, the lack of gut microbiome up-regulated the Cyp2c subfamily but down-regulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated up-regulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.

PMID: 28864748 [PubMed - as supplied by publisher]

Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics.

Drug Metab Pers Ther. 2017 Sep 01;:

Authors: Morales-Borges RH

Abstract
Methylenetetrahydrofolate reductase (MTHFR) mutations have been linked to many diseases. Evidence has been provided to prove that we need to perform pharmacogenetic studies regarding the prevalence of MTHFR mutations and diseases, risks, and the impact on folate requirement in general, but little has been published about Puerto Ricans. A multi center cross-sectional retrospective review study or a prospective pharmacogenetic study of valid genotypes and phenotypes of MTHFR mutations within the different populations of Puerto Ricans and Hispanics are recommended, because differences within them and within the general population are expected.

PMID: 28862981 [PubMed - as supplied by publisher]

Impaired calcium homeostasis is associated with sudden cardiac death and arrhythmias in a genetic equivalent mouse model of the human HRC-Ser96Ala variant.

Cardiovasc Res. 2017 Sep 01;113(11):1403-1417

Authors: Tzimas C, Johnson DM, Santiago DJ, Vafiadaki E, Arvanitis DA, Davos CH, Varela A, Athanasiadis NC, Dimitriou C, Katsimpoulas M, Sonntag S, Kryzhanovska M, Shmerling D, Lehnart SE, Sipido KR, Kranias EG, Sanoudou D

Abstract
Aims: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position.
Methods and results: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting. The HRC-Ser81Ala mice presented increased mortality in the absence of structural or histological abnormalities, indicating that early death may be arrhythmia-related. Indeed, under stress-but not baseline-conditions, the HRC-Ser81Ala mice developed ventricular arrhythmias, whilst at the cardiomyocyte level they exhibited increased occurrence of triggered activity. Cardiac contraction was decreased in vivo, ex vivo, and in vitro. Additionally, Ca2+ transients and SR Ca2+ load were both reduced suggesting that cytosolic Ca2+ overload is not the underlying proarrhythmic mechanism. Interestingly, total SR Ca2+ leak was increased in HRC-Ser81Ala cardiomyocytes, without an increase in Ca2+ spark and wave frequency. However, Ca2+ wave propagation was significantly slower and the duration of the associated Na/Ca exchange current was increased. Moreover, action potential duration was also increased. Notably, Ca2+/Calmodulin kinase II (CaMKII) phosphorylation of the ryanodine receptor was increased, whilst KN-93, an inhibitor of CaMKII, reduced the occurrence of arrhythmias.
Conclusions: The homologous mutation Ser81Ala in HRC in mice, corresponding to Ser96Ala in humans, is associated with sudden death and depressed cardiac function. Ventricular arrhythmias are related to abnormal Ca2+ cycling across the SR. The data further support a role for CaMKII with the perspective to treat arrhythmias through CaMKII inhibition.

PMID: 28859293 [PubMed - in process]

Overcoming the Roadblocks to Cardiac Cell Therapy Using Tissue Engineering.

J Am Coll Cardiol. 2017 Aug 08;70(6):766-775

Authors: Yanamandala M, Zhu W, Garry DJ, Kamp TJ, Hare JM, Jun HW, Yoon YS, Bursac N, Prabhu SD, Dorn GW, Bolli R, Kitsis RN, Zhang J

Abstract
Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality.

PMID: 28774384 [PubMed - indexed for MEDLINE]

Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment.

Rheumatol Int. 2017 Apr;37(4):531-536

Authors: Cuppen BV, Pardali K, Kraan MC, Marijnissen AC, Yrlid L, Olsson M, Bijlsma JW, Lafeber FP, Fritsch-Stork RD

Abstract
A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively. The C1236T, G2677A/T, and C3435T SNPs were determined, and the functionality of P-gp was assessed by flow cytometry (Rhodamine efflux assay). Carriage of the G2677A/T SNP was significantly associated with response (OR = 6.18, p = 0.035), the other SNPs showed trends. Stratified for received treatment, the effect was only present in methylprednisolone treated patients. Mutant allele carriage significantly decreased functionality of P-gp in B cells, though had a smaller impact in other PBMC subtypes. Carriage of a MDR1 SNP was related to a response to methylprednisolone in this study, which his suggests that RA-patients carrying wild-type alleles might benefit from P-gp inhibition or administration of glucocorticoid analogues that are non-P-gp substrates.

PMID: 28132103 [PubMed - indexed for MEDLINE]

Development and validation of a simple high-performance liquid chromatography analytical method for simultaneous determination of phytosterols, cholesterol, and squalene in parenteral lipid emulsions.

Biomed Chromatogr. 2017 Aug 30;:

Authors: Novak A, Gutiérrez-Zamora M, Domenech L, Suñé-Negre JM, Miñarro M, García-Montoya E, Llop JM, Ticó JR, Pérez-Lozano P

Abstract
A simple analytical method for simultaneous determination of phytosterols, cholesterol, and squalene in lipid emulsions was developed due to increased interest in their clinical effects. Method development was based on commonly used stationary (C18 , C8 and phenyl) and mobile phases (mixtures of acetonitrile, methanol, and water) under isocratic conditions. Differences in stationary phases resulted in peak overlapping or coelution of different peaks. The best separation of all analyzed compounds was achieved on Zorbax Eclipse XDB C8 (150 x 4.6 mm, 5 μm; Agilent) and ACN/H2 O/MeOH = 80:19.5:0.5 (v/v/v). In order to achieve a shorter time of analysis, the method was further optimized and gradient separation was established. The optimized analytical method was validated and tested for routine use in lipid emulsion analyses.

PMID: 28857206 [PubMed - as supplied by publisher]

SIRT1/HERC4 Locus Associated with Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis.

J Bone Miner Res. 2017 Aug 30;:

Authors: Yang G, Hamadeh I, Katz J, Riva A, Lakatos P, Balla B, Kosa J, Vaszilko M, Pelliccioni GA, Davis N, Langaee TY, Moreb JS, Gong Y

Abstract
Osteonecrosis of jaw (ONJ) is a rare but serious adverse drug side effect, mainly associated with the use of intravenous (IV) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with IV BPs using a whole-exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI) adjusting for age, gender and principal components for ancestry. Meta-analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case-control study of 48 patients of European ancestry treated with IV BPs (19 ONJ cases and 29 controls). The top SNPs in the exome-wide association meta-analysis were two SNPs on Chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01-0.46) (p = 3.83*10(-5) ). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10-0.88), 0.26 (0.12-0.55), and 0.26 (0.12-0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on Chromosome 10 to be associated with IV BPs related ONJ and two promoter SNPs that might be the potential genetic markers for this association. This article is protected by copyright. All rights reserved.

PMID: 28856724 [PubMed - as supplied by publisher]

Breast cancer chemoprevention pharmacogenomics: Deep sequencing and functional genomics of the ZNF423 and CTSO genes.

NPJ Breast Cancer. 2017;3:30

Authors: Liu D, Ho MF, Schaid DJ, Scherer SE, Kalari K, Liu M, Biernacka J, Yee V, Evans J, Carlson E, Goetz MP, Kubo M, Wickerham DL, Wang L, Ingle JN, Weinshilboum RM

Abstract
Our previous GWAS using samples from the NSABP P-1 and P-2 selective estrogen receptor modulator (SERM) breast cancer prevention trials identified SNPs in ZNF423 and near CTSO that were associated with breast cancer risk during SERM chemoprevention. We have now performed Next Generation DNA sequencing to identify additional SNPs that might contribute to breast cancer risk and to extend our observation that SNPs located hundreds of bp from estrogen response elements (EREs) can alter estrogen receptor alpha (ERα) binding in a SERM-dependent fashion. Our study utilized a nested case-control cohort selected from patients enrolled in the original GWAS, with 199 cases who developed breast cancer during SERM therapy and 201 matched controls who did not. We resequenced approximately 500 kb across both ZNF423 and CTSO, followed by functional genomic studies. We identified 4079 SNPs across ZNF423 and 3876 across CTSO, with 9 SNPs in ZNF423 and 12 in CTSO with p < 1E-02 that were within 500 bp of an ERE motif. The rs746157 (p = 8.44E-04) and rs12918288 SNPs (p = 3.43E-03) in intron 5 of ZNF423, were in linkage equilibrium and were associated with alterations in ER-binding to an ERE motif distant from these SNPs. We also studied all nonsynonymous SNPs in both genes and observed that one nsSNP in ZNF423 displayed decreased protein expression. In conclusion, we identified additional functional SNPs in ZNF423 that were associated with SNP and SERM-dependent alternations in ER binding and transcriptional regulation for an ERE at a distance from the SNPs, thus providing novel insight into mechanisms of SERM effect.

PMID: 28856246 [PubMed]

[Association of ITGB3, P2RY12, and CYP2C19 gene polymorphisms with platelet functional activity in patients with coronary heart disease during dual antiplatelet therapy].

Ter Arkh. 2017;89(5):74-78

Authors: Muslimova EF, Afanasiev SA, Rebrova TY, Sergienko TN, Repin AN

Abstract
AIM: To assess the association of CYP2C19 G681A, P2RY12 H1/H2, and ITGB3 T1565C polymorphisms with the extent of platelet aggregation in patients with coronary heart disease (CHD) during antiplatelet therapy.
SUBJECTS AND METHODS: 166 male patients with CHD, living in the Western Siberian Region, were examined. All the patients underwent a test for platelet aggregation induced by ADP (2.5 and 5.0 µm) and epinephrine (0.2 µm). Genotyping was performed using an allele-specific polymerase chain reaction technique.
RESULTS: The polymorphic variants of the P2RY12 and ITGB3 genes were ascertained to have no impact on the extent of platelet aggregation in patients receiving clopidogrel and acetylsalicylic acid. An association was found between CYP2C19 681A allele carriage and the increased extent of platelet aggregation induced by ADP.
CONCLUSION: The carriage of the cytochrome P450 CYP2C19 681A allele rather than platelet receptor gene polymorphisms determines a risk for clopidogrel resistance in patients with CHD.

PMID: 28631703 [PubMed - indexed for MEDLINE]

Cost-Effectiveness of Pharmacogenomic and Pharmacogenetic Test-Guided Personalized Therapies: A Systematic Review of the Approved Active Substances for Personalized Medicine in Germany.

Adv Ther. 2016 Sep;33(9):1461-80

Authors: Plöthner M, Ribbentrop D, Hartman JP, Frank M

Abstract
BACKGROUND: The use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost-effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing.
METHODS: A systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument.
RESULTS: In the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost-effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost-savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated.
CONCLUSION: Pharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.

PMID: 27406232 [PubMed - indexed for MEDLINE]

Secretory leukocyte protease inhibitor is a survival and proliferation factor for castration-resistant prostate cancer.

Oncogene. 2016 Sep 08;35(36):4807-15

Authors: Zheng D, Gui B, Gray KP, Tinay I, Rafiei S, Huang Q, Sweeney CJ, Kibel AS, Jia L

Abstract
Androgen receptor (AR)-mediated gene expression continues to have a critical role in promoting castration-resistant prostate cancer (CRPC) survival and growth even after androgen deprivation therapy. AR cistrome analyses in CRPC cells have identified a large number of AR target genes involved in proliferative and cell cycle-related functions, and hold promise for development of novel therapeutic approaches for CRPC. However, there is little understanding of how these genes function in vivo and what the clinical implications are. We previously reported that secretory leukocyte peptidase inhibitor (SLPI) is regulated by the AR in a ligand-independent manner in CRPC cells and required for CRPC cell proliferation under androgen-deprived conditions. SLPI is a secreted serine protease inhibitor, which is overexpressed in a number of cancers, including lung, breast and ovarian cancer, and involved in tumor progression. However, the oncogenic potential of SLPI in prostate cancer remains unknown. Here we provide the first evidence that SLPI is upregulated in a subset of CRPC cell lines and CRPC patient tumors. In addition, serum SLPI levels are significantly elevated in metastatic CRPC patients compared with hormone naive patients, raising the possibility that this could serve as a biomarker. We demonstrated that SLPI expression has functional significance, as it promotes CRPC cell survival and growth after androgen withdrawal in vivo and in vitro. Last, we demonstrated that the oncogenic effect of SLPI may be due to protection of growth factor progranulin from enzymatic cleavage or suppression of CRPC cell apoptosis independent of anti-protease activity of SLPI. These findings implicate SLPI as a potential biomarker of resistance to AR inhibition and therapeutic target for CRPC treatment.

PMID: 26876202 [PubMed - indexed for MEDLINE]

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Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial.

ESMO Open. 2016;1(6):e000086

Authors: Martinelli E, Cardone C, Troiani T, Normanno N, Pisconti S, Sforza V, Bordonaro AR, Rachiglio AM, Lambiase M, Latiano TP, Modoni G, Cordio S, Giuliani F, Biglietto M, Montesarchio V, Barone C, Tonini G, Cinieri S, Febbraro A, Rizzi D, De Vita F, Orditura M, Colucci G, Maiello E, Ciardiello F

Abstract
BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.
METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years).
RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years.
CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years.
TRIAL REGISTRATION NUMBER: 2009-014041-81.

PMID: 28848656 [PubMed]

Genetically driven antioxidant capacity in a Caucasian Southeastern European population.

Mech Ageing Dev. 2017 Aug 24;:

Authors: Katsarou MS, Giakoumaki M, Papadimitriou A, Demertzis N, Androutsopoulos V, Drakoulis N

Abstract
Previous studies have underlined the function of specific xenobiotic metabolizing phase-I or phase-II enzymes and endogenous antioxidant-related enzymes in the reduction and/or progression of oxidative stress and consequently the incidence of several diseases. In the present study, 10 polymorphic variants (rs4880, rs1799895, rs660339, rs1050450, rs1001179, rs28665122, rs1695, rs1138272, rs1051740 and rs2234922) were investigated in 1,132 individuals of a Caucasian Southeastern European population. The frequency distribution of alleles and genotypes was compared to data of European (Northern, Central, Northwestern and Southwestern) and Global populations, extracted from the ensembl genome browser. The allele frequencies in the case of rs1051740 were similar to the frequencies noted in the global population. The majority of the present study allelic polymorphisms showed similar frequency distribution to those of the European or the Global populations (0.88≤OR≤1.14). The rs1051740 polymorphism demonstrated similar to the Global population frequencies (OR=1.09). In conclusion, observed distributions of the polymorphisms studied in the Southeastern population demonstrate a positive impact (rs4880, rs1799895, rs660339, rs28665122) and a negative impact (rs1050450, rs1138272, rs109179, rs1695) against oxidative stress when compared to other population groups.

PMID: 28844971 [PubMed - as supplied by publisher]

The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes.

Mol Cell. 2017 Aug 17;:

Authors: Conrad RJ, Fozouni P, Thomas S, Sy H, Zhang Q, Zhou MM, Ott M

Abstract
BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells, and it was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and this isoform was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using chromatin immunoprecipitation sequencing (ChIP-seq) combined with assay for transposase-accessible chromatin coupled to high-throughput sequencing (ATAC-seq) data, we found that the latent HIV-1 promoter phenotypically resembles endogenous long terminal repeat (LTR) sequences, pointing to a select role of BRD4S-BRG1 complexes in genomic silencing of invasive retroelements.

PMID: 28844864 [PubMed - as supplied by publisher]

Sequencing brain metastases and opportunities for targeted therapies.

Pharmacogenomics. 2017 Apr;18(6):585-594

Authors: Chukwueke UN, Brastianos PK

Abstract
CNS metastases have long been recognized as a common and late complication of systemic malignancies. They represent the most common tumor of the brain. As outcomes and overall survival improve with better tolerated and more durable responses from therapies for systemic cancers, the incidence and prevalence of brain metastases is likely to increase. Among the most common systemic cancers leading to brain metastases include lung, melanoma, breast (triple-negative histology) and renal cell cancers. To date, there has been infrequent involvement of gastrointestinal and gynecologic malignancies; however, this may also change, reflecting improvement in overall survival and therapeutic regimens. Traditional therapy of brain metastases has focused on surgery, radiation therapy or best supportive/palliative care. The advent of modern genomic techniques, including next-generation and whole-exome sequencing, has allowed for the identification of unique markers and potential drivers of metastatic pathways. This review aims to discuss and highlight the known drivers of disease and the opportunities for ultimate development of targeted therapies.

PMID: 28290769 [PubMed - indexed for MEDLINE]

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity.

Diabetologia. 2016 Dec;59(12):2622-2631

Authors: Heni M, Kullmann S, Ahlqvist E, Wagner R, Machicao F, Staiger H, Häring HU, Almgren P, Groop LC, Small DM, Fritsche A, Preissl H

Abstract
AIMS/HYPOTHESIS: Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity.
METHODS: Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration.
RESULTS: We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors.
CONCLUSIONS/INTERPRETATION: The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.

PMID: 27600277 [PubMed - indexed for MEDLINE]