The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices.

Int J Mol Sci. 2018 Sep 20;19(10):

Authors: Senthebane DA, Jonker T, Rowe A, Thomford NE, Munro D, Dandara C, Wonkam A, Govender D, Calder B, Soares NC, Blackburn JM, Parker MI, Dzobo K

Abstract
BACKGROUND: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments.
METHODS: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM; cancer cell-derived ECM; combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µM cisplatin, 3.5 µM 5-fluorouracil and 2.5 µM epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints.
RESULTS: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20⁻60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30⁻50%, and reduced colony formation and cancer cell migration.
CONCLUSION: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.

PMID: 30241395 [PubMed - in process]

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RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.

Front Physiol. 2018;9:1234

Authors: Lian X, Beer-Hammer S, König GM, Kostenis E, Nürnberg B, Gollasch M

Abstract
Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the Gi-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive. Methods: We used Gαi2- (Gnai2-/-) and Gαi3-deficient (Gnai3-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested. Results: Relaxin-2 (∼50% relaxation at 10-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2-/- mice, but not from Gnai3-/- mice. The effects were not affected by FR900359 (Gαq protein inhibitor) or PI-103 (PI3Kα inhibitor), but inhibited by TGX-221 (PI3Kβ inhibitor) or AS-252424 (PI3Kγ inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue. Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to Gi2-PI3K-eNOS pathway. Targeting vasodilatory Gi-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease.

PMID: 30233409 [PubMed]

The Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION): registry overview and protocol for a propensity score-matched study of opioid prescribing in patients with low back pain.

J Pain Res. 2018;11:1751-1760

Authors: Licciardone JC, Gatchel RJ, Phillips N, Aryal S

Abstract
Background: Low back pain is the leading cause of disability worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as the first-line pharmacologic therapy for subacute or chronic low back pain, with opioids reserved for patients who fail on NSAIDs. CYP2D6, CYP2C9, and CYP2C19 genes have variants that place patients using analgesics at risk for adverse events. However, precision medicine based on pharmacogenetically informed prescribing is becoming more feasible as genotyping costs decline. This study aims to compare opioids vs NSAIDs in treating adults with subacute or chronic low back pain under the alternative models of usual care and precision medicine.
Methods: An observational cohort study within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) will be used to simulate a randomized controlled trial. Patients using opioids and NSAIDs will be optimally matched at baseline using propensity scores. A saliva sample will also be collected to determine patient genotypes for drug metabolism based on CYP2D6 (single-gene model) and CYP2D6, CYP2C9, and CYP2C19 (multigene model). Prescribing that is concordant with pharmacogenetically informed care under these models will be considered "low risk", whereas discordant prescribing will be considered "high risk". Primary outcomes will be assessed over 6 months using a Numerical Rating Scale for pain, the Roland-Morris Disability Questionnaire, and the Drug Adverse Events Index. Secondary outcomes will be assessed using quality-of-life measures. An estimated 600 patients will be enrolled to acquire at least 400 patients after attrition and allowing for unmatched patients. This will achieve a statistical power of at least 80% in detecting the effect sizes ranging from 0.35 (small-medium effect) to 0.69 (medium-large effect).
Discussion: This PRECISION Pain Research Registry study builds on the concepts espoused in the Precision Medicine Initiative and addresses long-term goals established by the National Institutes of Health by assessing how precision medicine may prevent and treat chronic pain.

PMID: 30233232 [PubMed]

Challenging obesity, diabetes, and addiction: the potential of lorcaserin extended release.

Diabetes Metab Syndr Obes. 2018;11:469-478

Authors: Hurt RT, Mundi MS, Ebbert JO

Abstract
Obesity is a global epidemic that is a leading cause of preventable death. In addition to lifestyle modification, there are numerous obesity treatments for clinicians to consider, including medications. Lorcaserin immediate release/extended release (IR/XR) is a US Food and Drug Administration approved medication for overweight and obese patients to be used with lifestyle modifications. Lorcaserin is thought to reduce weight by targeting the serotonin (5HT2c) system to induce satiety. Lorcaserin IR has been shown to be effective in reducing weight in overweight (body mass index [BMI] > 27 kg/m2) and obese (BMI > 30 kg/m2) participants in three large Phase III trials. In addition, lorcaserin has been shown to reduce post-cessation weight gain and improved smoking cessation in a randomized placebo-controlled trial. A recent meta-analysis suggested in overweight diabetic patients lorcaserin may be added to first-line oral hypoglycemic medications to enhance reduction in glycated hemoglobin. Lorcaserin is generally well tolerated with the most common side effect being headache, which is typically self-limiting. Lorcaserin XR (once daily) was recently approved and has been shown to be bioequivalent to lorcaserin IR (twice daily) in a pivotal study. Lorcaserin XRs, main advantage over the IR formulation is the once daily dosing regimen, which likely would lead to improved adherence and thus improved clinical effectiveness. The present review will evaluate the lorcaserin clinical studies (obesity, diabetes, and addiction), XR bioequivalence studies, pharmacogenomics of the serotonin (5HT2c) system, and adherence data in once daily versus twice daily medications.

PMID: 30233224 [PubMed]

Pharmacogenetics of Antiretroviral Drug Response and Pharmacokinetic Variations in Indigenous South African Populations.

OMICS. 2018 Sep;22(9):589-597

Authors: O'Connell KS, Swart M, McGregor NW, Dandara C, Warnich L

Abstract
Interindividual and interethnic differences in response to antiretroviral drugs (ARVs) are influenced by genetic variation. The few genomic studies conducted among African-Americans and African ethnic groups do not reflect the extensive genetic diversity within African populations. ARVs are widely used in Africa. Therefore, genomic characterization of African populations is required before genotype-guided dosing becomes possible. The aim of this study was to determine and report on the frequency of genetic variants in genes implicated in metabolism and transport of ARVs in South African populations. The study comprised 48 self-reported South African Colored (SAC) and 296 self-reported Black African (BA) individuals. Allele and genotype frequency distributions for 93 variants contributing to metabolism and transport of ARVs were compared between groups, and other global populations. Fifty-three variants had significant differences in allele and genotype frequencies when comparing SAC and BA groups. Thirteen of these have strong clinical annotations, affecting efavirenz and tenofovir pharmacokinetics. This study provides a summary of the genetic variation within genes implicated in metabolism and transport of ARVs in indigenous South African populations. The observed differences between indigenous population groups, and between these groups and global populations, demonstrate that data generated from specific African populations cannot be used to infer genetic diversity within other populations on the continent. These results highlight the need for comprehensive characterization of genetic variation within indigenous African populations, and the clinical utility of these variants in ARV dosing for global precision medicine. Population pharmacogenetics is a nascent field of global health and warrants further research and education.

PMID: 30235109 [PubMed - in process]

The dawn of precision medicine in HIV: state of the art of pharmacotherapy.

Expert Opin Pharmacother. 2018 Sep 20;:1-15

Authors: Mu Y, Kodidela S, Wang Y, Kumar S, Cory TJ

Abstract
INTRODUCTION: Combination antiretroviral therapy (ART) reduces viral load to under the limit of detection, successfully decreasing HIV-related morbidity and mortality. Due to viral mutations, complex drug combinations and different patient response, there is an increasing demand for individualized treatment options for patients. Areas covered: This review first summarizes the pharmacokinetic and pharmacodynamic profile of clinical first-line drugs, which serves as guidance for antiretroviral precision medicine. Factors which have influential effects on drug efficacy and thus precision medicine are discussed: patients' pharmacogenetic information, virus mutations, comorbidities, and immune recovery. Furthermore, strategies to improve the application of precision medicine are discussed. Expert opinion: Precision medicine for ART requires comprehensive information on the drug, virus, and clinical data from the patients. The clinically available genetic tests are a good starting point. To better apply precision medicine, deeper knowledge of drug concentrations, HIV reservoirs, and efficacy associated genes, such as polymorphisms of drug transporters and metabolizing enzymes, are required. With advanced computer-based prediction systems which integrate more comprehensive information on pharmacokinetics, pharmacodynamics, pharmacogenomics, and the clinically relevant information of the patients, precision medicine will lead to better treatment choices and improved disease outcomes.

PMID: 30234392 [PubMed - as supplied by publisher]

Sleep quality in opioid-naive and opioid-dependent patientson methadone maintenance therapy in Malaysia.

Turk J Med Sci. 2016 Dec 20;46(6):1743-1748

Authors: Zahari Z, Inrahim MA, Tan SC, Mohamad N, Ismail R

Abstract
BACKGROUND/AIM: Sleep disturbances may contribute to poor treatment outcomes in opioid-dependent patients. The extent to which the sleep profiles of opioid-dependent patients differ from those of the general Malaysian population is not documented. This study compared opioid-naive subjects and opioid-dependent patients on methadone maintenance therapy (MMT) in terms of their sleep quality.
MATERIALS AND METHODS: Participants comprised Malay male opioid-naive subjects (n = 159) and opioid-dependent patients (n = 160) from MMT clinics in Kelantan, Malaysia, between March and October 2013. Sleep quality was evaluated using the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI).
RESULTS: The opioid-dependent patients exhibited higher global PSQI scores [adjusted mean (95% CI) = 5.46 (5.02, 5.90)] than the opioid-naive group [4.71 (4.26, 5.15)] [F (1, 313) = 4.77, P = 0.030].
CONCLUSION: This study confirmed the poorer sleep quality among opioid-dependent patients on MMT, as manifested by their higher global PSQI scores. The sleep complaints in this patient population are a factor to consider and, when necessary, sleep evaluation and treatment should be undertaken to improve MMT patients' quality of sleep and overall treatment outcome.

PMID: 28081321 [PubMed - indexed for MEDLINE]

NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model.

EBioMedicine. 2017 Jul;21:3-4

Authors: Nadon NL, Strong R, Miller RA, Harrison DE

PMID: 27923560 [PubMed - indexed for MEDLINE]

Losses of cytokines and chemokines are common genetic features of human cancers: the somatic copy number alterations are correlated with patient prognoses and therapeutic resistance.

Oncoimmunology. 2018;7(9):e1468951

Authors: Wong HS, Chang WC

Abstract
Intricate relationships among cytokines (including chemokines) shape the tumor microenvironment (TME) and reflect cell-cell interactions between malignant cells and other cells from the TME. Although our previous study indicated the transcriptional landscape of cytokines in 19 cancer types, the global pattern somatic copy number (SCN) alterations and the clinical relevance of cytokines have not been systematically investigated. Here, we reported a significant negative selection on cytokine genes. We also linked the SCN losses of cytokine genes to the abundance of immune infiltrates which affects cancer progression and patient prognoses. We also demonstrated and validated the correlations between SCN alterations of cytokine-containing loci and drug sensitivity. The results indicated the genomic loss of cytokines in malignant cells as a crucial theme for interrogating cancer progression, malignant cell-TME interactions, and therapeutics.

PMID: 30228934 [PubMed]

Subtype-Specific Inherited Predisposition to Pemphigus in Chinese Population.

Br J Dermatol. 2018 Sep 19;:

Authors: Zhang S, Zhou X, Zhou X, Zhang Y, Deng Y, Liao F, Yang M, Xia X, Zhou Y, Yin D, Ojaswi P, Hou Q, Wang L, Zhang D, Xia D, Deng Y, Ding L, Liu H, Yan W, Li M, Ma W, Ma JJ, Yu Q, Liu B, Yang L, Zhang W, Shu Y, Xu H, Li W

Abstract
BACKGROUND: Pemphigus is a group of rare life-threatening cutaneous autoimmune diseases, presenting mainly as two subtypes including pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but remains poorly understood.
OBJECTIVE: To identify common and specific non-genetic and genetic factors associated with pemphigus and its subtypes in Chinese population.
METHODS: Genome-wide association study was performed in 496 unrelated pemphigus patients (365 PV and 104 PF) and 1105 non-pemphigus controls.
RESULTS: Gender preference was observed only in PV (female: 57.5%) but not PF (female: 47.1%). For male patients only, the mean age at diagnosis was significantly younger in PV than in PF (P < 0.0004). The strongest association SNPs are in HLA region, rs70993900 (PV; P = 1.5 × 10-45 ) and rs9469220 (PF; P = 1.1 × 10-8 ). w ranks the top (P = 4.7 × 10-40 ; OR = 12.4) in both subtypes with significantly different risk allele frequency (RAFPV = 34.16% vs. RAFPF = 18.84% vs. RAFcontrol = 4.39%), whereas HLA-DRB1*14:01 and HLA-DRB1*04:06 exhibit PV-specific. HLA-DQB1*03:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All these associations can be validated in the replication series with 147 pemphigus cases and 604 controls. Besides, multiple novel non-HLA susceptibility loci have also been identified in GWAS.
CONCLUSIONS: This study represents the largest GWAS on pemphigus in Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus. This article is protected by copyright. All rights reserved.

PMID: 30230522 [PubMed - as supplied by publisher]

Shortcut to success? Negotiating genetic uniqueness in global biomedicine.

Soc Stud Sci. 2018 Sep 19;:306312718801165

Authors: Tarkkala H, Tupasela A

Abstract
Since the sequencing of the human genome, as well as the completion of the first Human Genome Diversity Project, the benefits of studying one human population over another has been an ongoing debate relating to the replicability of findings in other populations. The leveraging of specific populations into research markets has made headlines in cases such as deCode in Iceland, Quebec Founder Population, and Generation Scotland. In such cases, researchers and policy makers have used the genetic and historical uniqueness of their populations to attract scientific, commercial and political interest. In this article, we explore how in countries with population isolates, such as Finland, the researchers balance considerations relating to the generalization and replicability of findings in small yet unique research populations to global biomedical research interests. This highlights challenges related to forms of competition associated with genetics research markets, as well as what counts as the 'right' population for genetic research.

PMID: 30230417 [PubMed - as supplied by publisher]

Clinical Factors and Rate of Cough During Angiotensin-Converting Enzyme Inhibitor Treatment.

Clin Pharmacol Ther. 2018 Sep 18;:

Authors: Ren H, Luo JQ, Shu Y, Zhou HH, Zhang W

PMID: 30229862 [PubMed - as supplied by publisher]

Genetic validation study of protein tyrosine phosphatase receptor type D (PTPRD) gene variants and risk for antipsychotic-induced weight gain.

J Neural Transm (Vienna). 2018 Sep 18;:

Authors: Maciukiewicz M, Gorbovskaya I, Tiwari AK, Zai CC, Freeman N, Meltzer HY, Kennedy JL, Müller DJ

Abstract
Schizophrenia is a severe, debilitating disorder with a lifetime prevalence of 1% irrespective of gender or ethnicity and is typically treated with antipsychotic drugs. Antipsychotic-induced weight gain (AIWG) is a leading factor of patient non-compliance and has previously been shown to increase the risk of type 2 diabetes, metabolic syndrome, and cardiovascular events. The current study intends to replicate findings from a recent genome-wide association study in Han-Chinese patients implicating two gene variants (rs10977144 and rs10977154) of the protein tyrosine phosphatase receptor type D (PTPRD) in antipsychotic-induced weight gain (AIWG). We investigated a sample of European and African American ancestry (n = 201) and calculated percentage of weight change using linear regression corrected for type of antipsychotics, duration of treatment and principal components from ancestry checks. As secondary goal, we investigated additional gene variants of PTPRD previously not associated with AIWG. We found no association with rs10977144 and rs10977154. However, we found nominally significant results between PTPRD and AIWG with rs73398242 in Europeans (BETA = - 0.267, p = 0.002) and rs13294608 in African Americans (BETA = 0.423, p = 0.003). According to Haploreg, both SNPs are histone marks for enhancers and promoters across various brain regions including the cingulate gyrus and dorsolateral prefrontal cortex. In summary, our results tentatively suggest that PTPRD might be associated with AIWG although different SNPS might be involved in different ethnic groups.

PMID: 30229349 [PubMed - as supplied by publisher]

Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro.

Xenobiotica. 2018 Sep 19;:1-33

Authors: San SN, Matsumoto J, Saito Y, Koike M, Sakaue H, Kato Y, Fujiyoshi M, Ariyoshi N, Yamada H

Abstract
1. Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. 2. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5), and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3, or CYP3A5*3/*3. 3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. 4. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. 5. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

PMID: 30227770 [PubMed - as supplied by publisher]

RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy.

Biomed Res Int. 2018;2018:7675286

Authors: Olejarz W, Łacheta D, Głuszko A, Migacz E, Kukwa W, Szczepański MJ, Tomaszewski P, Nowicka G

Abstract
Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors' pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

PMID: 30225265 [PubMed - in process]

Vitamin D status during pregnancy and in cord blood in a large prospective French cohort.

Clin Nutr. 2018 Aug 31;:

Authors: Courbebaisse M, Souberbielle JC, Baptiste A, Taieb J, Tsatsaris V, Guibourdenche J, Senat MV, Haidar H, Jani J, Guizani M, Jouannic JM, Haguet MC, Winer N, Masson D, Elie C, Benachi A

Abstract
BACKGROUND & AIMS: Vitamin D status during pregnancy and in newborns has never been studied in France. This study aims at determining the vitamin D status during the first and third trimesters of pregnancy (T1, T3) and in cord blood (CB) in the middle-north of France.
METHODS: We conducted a prospective cohort study in five French centers (latitude 47.22 to 48.86°N). Serum 25(OH)-vitamin D (25(OH)D) concentrations were measured using a radioimmunoassay during T1, T3 and in CB. According to the French guidelines, pregnant women received cholecalciferol, 100,000 IU, in the seventh month.
RESULTS: Between April 2012 and July 2014, 2832 women were included, of whom 2803 were analyzed (mean ± SD age: 31.5 ± 5.0 years; phototypes 5-6: 21.8%). Three and 88.6% of participants received supplementation during the month before inclusion and in the seventh month, respectively. At T1, T3, and CB, mean 25(OH)D concentrations were 21.9 ± 10.4, 31.8 ± 11.5, and 17.0 ± 7.2 ng/mL, respectively, and 25(OH)D was <20 ng/mL in 46.5%, 14.0%, and 68.5%, respectively. At T1, body mass index ≥25 kg/m2, dark phototypes, sampling outside summer, and no supplementation before inclusion were independently associated with vitamin D insufficiency (25(OH)D < 20 ng/mL). Women who received cholecalciferol supplementation in month 7 had higher 25(OH)D at T3 than non-supplemented women (32.5 ± 11.4 versus 25.8 ± 11.4 ng/mL, p = <0.001) and marginally higher 25(OH)D in CB (17.2 ± 7.2 versus 15.5 ± 7.1 ng/mL, p = 0.004).
CONCLUSIONS: Despite the recommended supplementation, vitamin D insufficiency is frequent during pregnancy and in newborns in France.

PMID: 30224306 [PubMed - as supplied by publisher]

F13A1 Gene Variant (V34L) and Residual Circulating FXIIIA Levels Predict Short- and Long-Term Mortality in Acute Myocardial Infarction after Coronary Angioplasty.

Int J Mol Sci. 2018 Sep 14;19(9):

Authors: Ansani L, Marchesini J, Pestelli G, Luisi GA, Scillitani G, Longo G, Milani D, Serino ML, Tisato V, Gemmati D

Abstract
Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating relationships between FXIIIA residual levels, cardiovascular risk-factors, and inherited genetic predispositions. FXIIIA V34L was genotyped in 333 AMI patients and a five-year follow-up was performed. FXIIIA levels assessed at day-zero (d0) and four days after AMI (d4), and conventional risk factors were analyzed, focusing on the development of major adverse cardiovascular events (MACE). FXIIIA assessed at d0 and d4 was also an independent MACE predictor in the long-term follow-up (FXIIIAd0, Odds Ratio (OR) = 3.02, 1.79⁻5.1, p = 0.013; FXIIIAd4, OR = 4.46, 2.33⁻8.55, p = 0.0001). FXIIIAd4 showed the strongest MACE association, suggesting that the FXIIIA protective role is maximized when high levels are maintained for longer time. Conversely, FXIIIA levels stratified by V34L predicted MACE at a lesser extent among L34-carriers (Hazard Risk (HR)VV34 = 3.89, 2.19⁻6.87, p = 0.000003; HRL34-carriers = 2.78, 1.39⁻5.57, p = 0.0039), and V34L did not predict all MACE, only multiple-MACE occurrence (p = 0.0087). Finally, in survival analysis, heart failure and death differed significantly from stroke and recurrent ischemia (p = 0.0013), with FXIIIA levels appreciably lower in the former (p = 0.05). Overall, genetically-determined FXIIIA levels have a significant long-term prognostic role, suggesting that a pharmacogenetics approach might help to select those AMI patients at risk of poor prognosis in the need of dedicated treatments.

PMID: 30223472 [PubMed - in process]

Role of Lh polymorphisms and r-hLh supplementation in GnRh agonist treated ART cycles: A cross sectional study.

Eur J Obstet Gynecol Reprod Biol. 2018 Mar;222:119-125

Authors: G A R, Cheemakurthi R, Prathigudupu K, Balabomma KL, Kalagara M, Thota S, Kota M

Abstract
STUDY OBJECTIVES: To investigate the effect of N312S polymorphism in the LHCGR gene as a predictive pharmacogenetic marker on clinical and embryological parameters and determining the need of r-hLH supplementation combine with r-hFSH in patients undergoing ART treatment.
STUDY DESIGN: In a cross-sectional study, a retrospective analysis of women (n = 553), who underwent controlled ovarian stimulation treatment protocol was conducted during the years 2012-2014. R-hFSH (Gonal-F, Merck Serono) was administered to all patients undergoing ART cycle after initiating long luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation. R-hLH was supplemented based on P.C. Wong criteria. N312S genotype was determined using sequencing methodology. The mean r-hFSH, r-hLH doses, total number of oocytes, cleavage rates of embryos and clinical pregnancy were recorded. The association between the r-hLH supplementation and LHCGR N312S polymorphism and clinical pregnancy rates was determined using regression analysis by SPSS.
RESULTS: 19.7% of women were homozygous for A allele encoding asparagine (N/N), 45.7% were heterozygous (N/S) and 34.6% were homozygous (S/S) for G allele encoding serine. Women heterozygous (N/S) or homozygous (S/S) for serine showed a higher requirement for r-hLH (OR, 95% p-trend = <0.0001) compared to those homozygous for asparagine (N/N). Homozygous G allele was also associated with higher daily and total r-hLH dose per treatment cycle p-trend = <0.0001. Though, the total no of oocytes (14.87 ± 4.95 vs 12.98 ± 5.39 and 13.58 ± 5.45), Gr-I quality embryos (2.61 ± 1.81 vs 2.18 ± 1.96 and 1.98 ± 2.05) were significantly higher in women homozygous for A allele compared to women with heterozygous and homozygous for G allele, clinical pregnancy rates were significantly more in women with for G allele after excluding patients with PCOS and endometriosis conditions (P < 0.04).
CONCLUSION: The present findings reveal that women heterozygous and homozygous for G allele required higher doses of r-hLH supplementation and these women were shown to have higher clinical pregnancy rates.

PMID: 29408742 [PubMed - indexed for MEDLINE]

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer.

Gut. 2018 10;67(10):1780-1792

Authors: Chong IY, Aronson L, Bryant H, Gulati A, Campbell J, Elliott R, Pettitt S, Wilkerson P, Lambros MB, Reis-Filho JS, Ramessur A, Davidson M, Chau I, Cunningham D, Ashworth A, Lord CJ

Abstract
OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.
DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.
RESULTS: By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.
CONCLUSIONS: BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453).
TRIAL REGISTRATION NUMBER: NCT02884453; Pre-results.

PMID: 28830912 [PubMed - indexed for MEDLINE]