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Comparing the adverse effects of platinum in combination with etoposide or irinotecan in previously untreated small-cell lung cancer patients with extensive disease: A network meta-analyses.

Thorac Cancer. 2017 May;8(3):170-180

Authors: Chen Y, Chen L, Zhong D

Abstract
BACKGROUND: The safety of front-line chemotherapies for the treatment of extensive stage small-cell lung cancer (ED-SCLC) is uncertain. We carried out a network meta-analysis to compare the toxicity of different therapies for ED-SCLC.
METHODS: We searched EMBASE, PubMed, CENTRAL and clinicaltrials.gov. We performed network meta-analysis on hematological (anemia, leukopenia, neutropenia, and thrombocytopenia) and non-hematological toxicities (diarrhea, infection, and nausea and vomiting).
RESULTS: Nine studies with 2317 patients were included. Etoposide with carboplatin (EC) was associated with a higher incidence of anemia (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.13-3.63), leukopenia (OR 2.67, 95% CI 1.25-5.72), neutropenia (OR 12.08, 95% CI 2.13-68.66), and thrombocytopenia (OR 2.73, 95% CI 1.27-5.85) compared with irinotecan with carboplatin (IC). Similarly, etoposide with cisplatin (EP) was associated with a higher incidence of anemia (OR 1.70, 95% CI 1.13-2.56), leukopenia (OR 2.65, 95% CI 1.34-5.28), neutropenia (OR 5.70, 95% CI 2.93-11.10), and thrombocytopenia (OR 3.26, 95% CI 1.66-6.38) compared with irinotecan with cisplatin (IP). EC was associated with a lower incidence of diarrhea (OR 0.26, 95% CI 0.10-0.68) compared with IC, and EP was associated with a lower incidence of diarrhea (OR 0.09, 95% CI 0.03-0.25) and nausea and vomiting (OR 0.53, 95% CI 0.33-0.84) than IP.
CONCLUSIONS: Hematological toxicities were most common in EC-treated patients, while the lowest incidence occurred with IP treatment. The IP regimen was associated with the highest incidence of toxicities of the digestive tract, while the lowest incidence occurred with EC treatment.

PMID: 28263036 [PubMed - indexed for MEDLINE]

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Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer.

Oncologist. 2017 03;22(3):245-254

Authors: Vahdat LT, Layman R, Yardley DA, Gradishar W, Salkeni MA, Joy AA, Garcia AA, Ward P, Khatcheressian J, Sparano J, Rodriguez G, Tang S, Gao L, Dalal RP, Kauh J, Miller K

Abstract
BACKGROUND: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
METHODS: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.
RESULTS: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.
CONCLUSION: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

PMID: 28220020 [PubMed - indexed for MEDLINE]

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Efficacy and Safety of FOLFIRI Regimen in Elderly Versus Nonelderly Patients with Metastatic Colorectal or Gastric Cancer.

Oncologist. 2017 Mar;22(3):293-303

Authors: Kim JW, Lee KW, Kim KP, Lee JH, Hong YS, Kim JE, Kim SY, Park SR, Nam BH, Cho SH, Chung IJ, Park YS, Oh HS, Lee MA, Kang HJ, Park YI, Song EK, Han HS, Lee KT, Shin DB, Kang JH, Zang DY, Kim JH, Kim TW

Abstract
BACKGROUND: Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients.
PATIENTS AND METHODS: Using the patient cohort (n = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (n = 934) or GC (n = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy.
RESULTS: Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; p = .244, and HR, 0.989; 95% CI, 0.774-1.264; p = .931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; p = .479, and HR, 1.188; 95% CI, 0.891-1.585; p = .241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients.
CONCLUSION: The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status.

PMID: 28209749 [PubMed - indexed for MEDLINE]

Related Articles

OntoADR a semantic resource describing adverse drug reactions to support searching, coding, and information retrieval.

J Biomed Inform. 2016 Oct;63:100-107

Authors: Souvignet J, Declerck G, Asfari H, Jaulent MC, Bousquet C

Abstract
INTRODUCTION: Efficient searching and coding in databases that use terminological resources requires that they support efficient data retrieval. The Medical Dictionary for Regulatory Activities (MedDRA) is a reference terminology for several countries and organizations to code adverse drug reactions (ADRs) for pharmacovigilance. Ontologies that are available in the medical domain provide several advantages such as reasoning to improve data retrieval. The field of pharmacovigilance does not yet benefit from a fully operational ontology to formally represent the MedDRA terms. Our objective was to build a semantic resource based on formal description logic to improve MedDRA term retrieval and aid the generation of on-demand custom groupings by appropriately and efficiently selecting terms: OntoADR.
METHODS: The method consists of the following steps: (1) mapping between MedDRA terms and SNOMED-CT, (2) generation of semantic definitions using semi-automatic methods, (3) storage of the resource and (4) manual curation by pharmacovigilance experts.
RESULTS: We built a semantic resource for ADRs enabling a new type of semantics-based term search. OntoADR adds new search capabilities relative to previous approaches, overcoming the usual limitations of computation using lightweight description logic, such as the intractability of unions or negation queries, bringing it closer to user needs. Our automated approach for defining MedDRA terms enabled the association of at least one defining relationship with 67% of preferred terms. The curation work performed on our sample showed an error level of 14% for this automated approach. We tested OntoADR in practice, which allowed us to build custom groupings for several medical topics of interest.
DISCUSSION: The methods we describe in this article could be adapted and extended to other terminologies which do not benefit from a formal semantic representation, thus enabling better data retrieval performance. Our custom groupings of MedDRA terms were used while performing signal detection, which suggests that the graphical user interface we are currently implementing to process OntoADR could be usefully integrated into specialized pharmacovigilance software that rely on MedDRA.

PMID: 27369567 [PubMed - indexed for MEDLINE]

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Differences in reproductive toxicology between alopecia drugs: an analysis on adverse events among female and male cases.

Oncotarget. 2016 Dec 13;7(50):82074-82084

Authors: Wu M, Yu Q, Li Q

Abstract
Alopecia is a dermatological condition with limited therapeutic options. Only two drugs, finasteride and minoxidil, are approved by FDA for alopecia treatment. However, little is known about the differences in adverse effects between these two drugs. We examined the clinical reports submitted to the FDA Adverse Event Reporting System (FAERS) from 2004 to 2014. For both female and males, finasteride was found to be more associated with reproductive toxicity as compared to minoxidil. Among male alopecia cases, finasteride was significantly more concurrent with several forms of sexual dysfunction. Among female alopecia cases, finasteride was significantly more concurrent with harm to fetus and disorder of uterus. In addition, drug-gene network analysis indicated that finasteride could profoundly disturb pathways related to sex hormone signaling and oocyte maturation. These findings could provide clues for subsequent toxicological research. Taken together, this analysis suggested that finasteride could be more liable to various reproductive adverse effects. Some of these adverse effects have yet to be warned in FDA-approved drug label. This information can help improve the treatment regimen of alopecia and post-marketing regulation of drug products.

PMID: 27738338 [PubMed - indexed for MEDLINE]

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Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

J Nucl Cardiol. 2017 Feb;24(1):57-65

Authors: Townsend R, Desai A, Rammelsberg D, Kowalski D, Simmons N, Kitt TM

Abstract
BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed.
METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 μg (3 doses), 200 μg (3 doses), or 400 μg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects.
CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

PMID: 26607361 [PubMed - indexed for MEDLINE]

Funding Opportunity PA-18-671 from the NIH Guide for Grants and Contracts. The purpose of the Kirschstein-NRSA predoctoral fellowship (F31) award is to enable promising predoctoral students to obtain individualized, mentored research training from outstanding faculty sponsors while conducting dissertation research in scientific health-related fields relevant to the missions of the participating NIH Institutes and Centers. The proposed mentored research training must reflect the applicants dissertation research project and is expected to clearly enhance the individuals potential to develop into a productive, independent research scientist. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing research that does not involve leading an independent clinical trial, a clinical trial feasibility study, or an ancillary study to a clinical trial, but does allow applicants to propose research experience in a clinical trial led by a sponsor or co-sponsor.

Funding Opportunity PA-18-668 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) will support students at institutions with NIH-funded institutional predoctoral dual-degree training programs. The purpose of the Kirschstein-NRSA, dual-doctoral degree, predoctoral fellowship (F30) is to enhance the integrated research and clinical training of promising predoctoral students, who are matriculated in a combined MD/PhD or other dual-doctoral degree training program (e.g. DO/PhD, DDS/PhD, AuD/PhD, DVM/PhD), and who intend careers as physician/clinician-scientists. Applicants must propose an integrated research and clinical training plan and a dissertation research project in scientific health-related fields relevant to the missions of the participating NIH Institutes and Centers. The fellowship experience is expected to clearly enhance the individual's potential to develop into a productive, independent physician/clinician-scientist. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing research that does not involve leading an independent clinical trial, a clinical trial feasibility study, or an ancillary study to a clinical trial, but does allow applicants to propose research experience in a clinical trial led by a sponsor or co-sponsor

Funding Opportunity RFA-RM-18-004 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite applications for the second phase of the NIH National Research Mentoring Network (NRMN) efforts. The NRMN is a nationwide consortium that was designed to enhance mentoring and career development of individuals from groups underrepresented in the biomedical research workforce. This new cycle of NRMN will expand the scientific scope of the program to encourage grants with varied approaches aimed at the science of mentorship, networking, and navigating critical career transition points. The NRMN will be a set of cooperative agreements in which the Program Directors/Principal Investigators (PDs/PIs) will work through a NRMN Coordination Center and the NRMN Resource Center to disseminate effective resources. The NRMN research is expected to align with the hallmarks of success that have been defined by the Diversity Program Consortium and the Center for Evaluation and Coordination (CEC).

Funding Opportunity RFA-RM-18-002 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite applications from qualified institutions for the NIH National Research Mentoring Network (NRMN) Resource Center. The NRMN is a nationwide consortium intended to enhance the training and career development of biomedical researchers from diverse backgrounds, through enhanced networking and mentorship experiences. One grant will be awarded for the development and management of a NRMN Resource Center, which will provide a web-based mentoring tool to facilitate real-time mentor/mentee engagement and networking. The awardee will also oversee the management of the NRMN website, report on outputs from NRMN components, and serve as a repository for publicly available mentoring resources and tools.

Funding Opportunity RFA-RM-18-003 from the NIH Guide for Grants and Contracts. The National Research Mentoring Network (NRMN) is a nationwide consortium developed to enhance the training and career development of individuals from diverse backgrounds who are pursuing biomedical research careers by providing networking and mentorship experiences. The NRMN Coordination Center will provide infrastructure and expertise that supports the collection, secure storage, and reporting of data generated by the individual NRMN component projects. Building upon the instruments and processes developed to assess the impact of NRMN activities in the previous Diversity Program Consortium (DPC) funding period, the NRMN Coordination Center will coordinate the early stages of collection of data in an ongoing way, and provide feedback to the consortium to maximize the research benefit of the various NRMN activities. The NRMN Coordination Center will also be responsible for promoting synergistic interactions with the DPC Center for Evaluation and Coordination (CEC) for the long-term collection and storage of data.

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Calcium Channel Blockers as Drug Repurposing Candidates for Gestational Diabetes: Mining large scale genomic and electronic health records data to repurpose medications.

Pharmacol Res. 2018 Feb 12;:

Authors: Goldstein JA, Bastarache LA, Denny JC, Roden DM, Pulley JM, Aronoff DM

Abstract
New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-gram glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and Serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86 to 5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.

PMID: 29448118 [PubMed - as supplied by publisher]

Anticancer Drugs as Antibiofilm Agents in Candida albicans: Potential Targets.

Assay Drug Dev Technol. 2018 Feb 15;:

Authors: Wakharde AA, Halbandge SD, Phule DB, Karuppayil SM

Abstract
The human pathogen Candida albicans can grow as a biofilm on host tissues and on the surfaces of different prosthetic devices in a patient's body. Various studies have reported that biofilms formed by C. albicans are resistant to most of the currently used antibiotics including the widely prescribed drug, fluconazole. As such, novel strategies for the treatment of drug-resistant biofilms are required. Drug repositioning or the use of drugs outside their unique indication has the potential to radically change drug development. We have tested 16 anticancer drugs for their activities against C. albicans. For the first time, we are reporting repositioning of anticancer drugs as potential antibiofilm agents in C. albicans. Nine categories of drugs with different chemical modes of action effectively inhibited biofilms at a concentration range of 0.25-4 mg/mL, establishing their potential for the inhibition of biofilms. Human genes targeted by these drugs show significant identity with their homologous genes in C. albicans at the amino acid as well as nucleotide levels. This study indicates that anticancer drugs could be potential candidates for repositioning as anti-Candida biofilm agents.

PMID: 29446984 [PubMed - as supplied by publisher]

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I Am That Parent.

JAMA. 2018 Feb 06;319(5):445

Authors: Rule ARL

PMID: 29411036 [PubMed - indexed for MEDLINE]

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The decision-making process and criteria in selecting candidate drugs for progeria clinical trials.

EMBO Mol Med. 2016 07;8(7):685-7

Authors: Gordon LB, Kieran MW, Kleinman ME, Misteli T

PMID: 27234439 [PubMed - indexed for MEDLINE]

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[Aplasia cutis congenita is a rare and possibly overlooked congenital anomaly].

Ugeskr Laeger. 2014 Nov 24;176(48):

Authors: E Rogvi R, Sommerlund M, Vestergaard ET

Abstract
Aplasia cutis congenita (ACC) is a rare congenital defect of the skin. In this study we present the diagnosis and management of the condition. In 1997-2009 a total of 65 ACC cases were registered in the Danish National Patient Registry (1:13.000 births). The mortality among these cases was 1.6% (one case) though the death was not attributable to ACC, which is far lower than described in international studies.

PMID: 25430571 [PubMed - indexed for MEDLINE]

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using next generation sequencing platform.

Ann Hum Biol. 2018 Feb 15;:1-12

Authors: Ang GY, Yu CY, Johari James R, Ahmad A, Abdul Rahman T, Mohd Nor F, Shaari SA, Ismail AI, Teh LK, Salleh MZ

Abstract
CYP3A5 is the predominant subfamily of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of interindividual and interethnic differences in CYP3A-mediated drug disposition and response. This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using next generation sequencing platform. Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed. A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524 which is in the 3'UTR and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3). The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unraveled and the findings in this study may serve as a guide for the optimiszation of pharmacotherapy for the Orang Asli community.

PMID: 29447003 [PubMed - as supplied by publisher]

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

Genet Test Mol Biomarkers. 2018 Feb 15;:

Authors: Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K

Abstract
AIM: Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority of them will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype.
METHODS: Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group.
RESULTS: Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression.
CONCLUSIONS: The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

PMID: 29446656 [PubMed - as supplied by publisher]

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Significant Prevalence of NR3C1 Mutations in incidentally discovered Bilateral Adrenal Hyperplasia: Results of the French MUTA-GR Study.

Eur J Endocrinol. 2018 Feb 14;:

Authors: Vitellius G, Trabado S, Hoeffel-Fornes C, Bouligand J, Bennet A, Castinetti F, Decoudier B, Guiochon-Mantel A, Lombes M, Delemer B

Abstract
Recently discovered mutations of NR3C1 gene, encoding for the Glucocorticoid Receptor (GR), in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia.
OBJECTIVE: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.
RESULTS: One hundred patients were included in whom NR3C1 sequencing revealed five original heterozygous GR mutations that impaired GR signaling in vitro. Mutated patients presented with mild glucocorticoid resistance defined as elevated Urinary-Free Cortisol (1.7±0.7 vs 0.9±0.8 upper limit of normal range, P=0.006), incomplete 1mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9±31.2 vs 16.2±17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6±0.2 vs 4.1±0.5 mmol/L, P=0.01, and 17.3±9.9 vs 98.6±115.4 pg/mL, P=0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. Ex-vivo characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of FKBP5 gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of BclI polymorphism.
CONCLUSION: The 5% prevalence of heterozygous NR3C1 mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.

PMID: 29444898 [PubMed - as supplied by publisher]