Related Articles

Genetic epidemiology of neural tube defects.

J Pediatr Rehabil Med. 2017 Dec 11;10(3-4):189-194

Authors: Lupo PJ, Agopian AJ, Castillo H, Castillo J, Clayton GH, Dosa NP, Hopson B, Joseph DB, Rocque BG, Walker WO, Wiener JS, Mitchell LE

Abstract
It has been estimated that 60-70% of neural tube defects (NTDs) have a genetic component, but few causative genes have been identified. The lack of information on genes associated with non-syndromic NTDs in humans is especially notable as the "genomic revolution" has led to new tools (e.g., genome-wide genotyping arrays, next-generation sequencing) that are helping to elucidate the full spectrum of genetic variation (from common to rare) contributing to complex traits, including structural birth defects. However, the application of modern genomic approaches to the study of NTDs has lagged behind that of some other common structural birth defects. This may be due to the difficulty of assembling large study cohorts for anencephaly or spina bifida. The purpose of this review is to outline the evolution of genetic studies of NTDs, from studies of familial aggregation to candidate gene and genome-wide association studies, through whole-exome and whole-genome sequencing. Strategies for addressing gaps in NTD genetic research are also explored.

PMID: 29125517 [PubMed - indexed for MEDLINE]

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Genetic predisposition in children with cancer - affected families' acceptance of Trio-WES.

Eur J Pediatr. 2018 Jan;177(1):53-60

Authors: Brozou T, Taeubner J, Velleuer E, Dugas M, Wieczorek D, Borkhardt A, Kuhlen M

Abstract
A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer.
CONCLUSIONS: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology. What is Known: • A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). What is New: • Knowing about an underlying CPS and, thus, the risk of recurrence in other children is of great interest to affected families.

PMID: 28929227 [PubMed - indexed for MEDLINE]

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Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review.

Diabetes Res Clin Pract. 2018 May;139:203-220

Authors: Bonaventura A, Montecucco F

Abstract
Corticosteroids are widely diffused drugs. An important side effect is the impairment of glycemic control both in patients with known diabetes and in normoglycemic ones potentially leading to steroid-induced diabetes mellitus (SIDM). In this review based on papers released on PubMed, MEDLINE, and EMBASE from January 2015 to October 2017, we summarized and discussed main updates about the definition, the diagnosis, and the pathophysiology of steroid-induced hyperglycemia (SIH), with a look to new therapies. Main alterations responsible for the diabetogenic effect of corticosteroids are a negative impact on insulin sensitivity along with a derangement on insulin secretion, explaining the typical post-prandial hyperglycemia linked to the promotion of gluconeogenesis. An early and precise diagnosis of SIH and/or SIDM is necessary, but current criteria do not seem sensible enough. As an afterthought, the treatment should be reasoned and tailored according to proposed glycemic thresholds and patient comorbidities, choosing between antidiabetic oral drugs and insulin, the latter being preferable among hospitalized patients. SIDM and SIH are frequent problems, but often underdiagnosed due to old diagnostic criteria. Dedicated guidelines universally shared are mandatory in order to harmonize the treatment of these conditions, thus overtaking single therapeutic strategies mostly arising from literature.

PMID: 29530386 [PubMed - indexed for MEDLINE]

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Pharmacokinetic drug-drug interactions in the intensive care unit - single-centre experience and literature review.

Anaesthesiol Intensive Ther. 2017;49(4):259-267

Authors: Łój P, Olender A, Ślęzak W, Krzych ŁJ

Abstract
BACKGROUND: Drug-drug interactions constitute a serious health hazard in everyday clinical practice in critically ill patients. Drug-drug interactions may be pharmacokinetic or pharmacodynamic in their nature. We aimed to investigate the quantity and quality of possible drug-drug interactions, and their possible side effects in intensive care unit patients in a 12-month period.
METHODS: This retrospective study covered data on pharmacological treatment of 43 consecutive patients (11 females, 32 males) aged 62 ± 15 years, hospitalized between January 2015 and February 2016. Pharmacokinetic DDIs were identified and graded. Only severe and clinically important drug-drug interactions were subjected for further analysis.
RESULTS: Median baseline SAPS III was 53 (IQR 38-67) points. Median intensive care unit stay was 12 (6-25) days. Subjects were treated with a median number of 22 (12-27) drugs. We identified 27 (16-41) possible drug-drug interactions per patient, including 3 (1-7) drug-drug interactions of a severe grade. The total number of severe and clinically important drug-drug interactions was 253 of which 227 were analyzed in detail. No possible side-effects of drug-drug interactions were identified.
CONCLUSIONS: DDIs as well as their side-effects are challenging regarding their precise evaluation, especially due to the need for multidrug treatment in critically ill patients. Concentration-controlled therapy should be recommended, especially for treatment with vancomycin, digoxin and valproate. Pantoprazole should be a proton pump-inhibitor of choice. Drug dose modification is necessary in combined treatment with fluconazole and amiodarone or rifampicin. From a clinical point of view, the most important impact of drug-drug interactions is on antibiotic treatment effectiveness, especially with meropenem when valproate is also prescribed.

PMID: 29027654 [PubMed - indexed for MEDLINE]

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Electrophysiological Adverse Effects of Direct-Acting Antivirals in Patients With Chronic Hepatitis C.

J Clin Pharmacol. 2017 07;57(7):931-932

Authors: Rossotti R, Garcia-Fraile Fraile LJ, Baiguera C, Puoti M

PMID: 28467638 [PubMed - indexed for MEDLINE]

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

"systems biology"

These pubmed results were generated on 2018/06/16

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

Notice NOT-AG-18-018 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-832 from the NIH Guide for Grants and Contracts. The National Institute of Mental Health (NIMH) Division of AIDS Research (DAR) encourages applications for Center Core grants (P30) to support an HIV/AIDS Research Center (ARC). The ARC is intended to provide infrastructural support that facilitates the development of high impact science in HIV/AIDS and mental health that is relevant to the NIMH mission. This FOA intends to support innovative, interdisciplinary research in several areas, including basic, neurological (i.e., neuro-HIV), behavioral and social, integrated biobehavioral, applied, clinical, translational, and implementation science.

Funding Opportunity PAR-18-833 from the NIH Guide for Grants and Contracts. The National Institute of Mental Health (NIMH) Division of AIDS Research (DAR) encourages applications for Center Core grants (P30) to support Developmental AIDS Research Centers (D-ARC). The D-ARC is intended to provide infrastructural support that facilitates the development of high impact science in HIV/AIDS and mental health that is relevant to the NIMH mission. This FOA intends to support innovative, interdisciplinary research in several areas, including basic, neurological (i.e., neuro-HIV), behavioral and social, integrated biobehavioral, applied, clinical, translational, and implementation science

Funding Opportunity RFA-HD-19-015 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to support and facilitate multidisciplinary research approaches for the development of novel nonsteroidal contraceptive products for men and women that act prior to fertilization. This FOA aims to position innovative and validated methods for future clinical development.

Notice NOT-GM-18-036 from the NIH Guide for Grants and Contracts

Notice NOT-HL-18-636 from the NIH Guide for Grants and Contracts

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

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/15

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

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

"systems biology"

These pubmed results were generated on 2018/06/15

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

Related Articles

Hydroxyurea-Induced Pneumopathy in a Patient With Myeloproliferative Syndrome.

Clin Med Insights Case Rep. 2018;11:1179547618770688

Authors: Galván OP, Moltó HP, Fabià-Mayans A, Xicoy B, Mate JL, Martí PR

Abstract
Hydroxyurea (HU) is a drug frequently used in the treatment of chronic myeloproliferative neoplasms. The most common side effects of this drug are pancytopenia, digestive and skin disorders. Respiratory complications are rare and there are less than 20 cases described, only 5 of which underwent an anatomopathological study. We present the case of a patient with chronic myeloproliferative neoplasm who developed interstitial pneumonitis probably due to HU according to histological study.

PMID: 29899671 [PubMed]

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Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis.

Breast Cancer Res. 2018 Jun 14;20(1):54

Authors: Jin K, Pandey NB, Popel AS

Abstract
BACKGROUND: Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis.
METHODS: We examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured.
RESULTS: In this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis.
CONCLUSION: Taken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients.

PMID: 29898755 [PubMed - in process]

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Prognostic, predictive and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer.

Mol Oncol. 2018 Jun 14;:

Authors: Bruun J, Sveen A, Barros R, Eide PW, Eilertsen I, Kolberg M, Pellinen T, David L, Svindland A, Kallioniemi O, Guren MG, Nesbakken A, Almeida R, Lothe RA

Abstract
We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n=403) or immunohistochemistry (n=642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and patient tumors.

PMID: 29900672 [PubMed - as supplied by publisher]

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Correction: Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma.

Br J Cancer. 2018 Jun 14;:

Authors: Lièvre A, Ouine B, Canet J, Cartier A, Amar Y, Cacheux W, Mariani O, Guimbaud R, Selves J, Lecomte T, Guyetant S, Bieche I, Berger F, de Koning L

Abstract
Supplementary Table 1 and the Supplementary Figure legends were not included when this manuscript was first published. The files are now available here.

PMID: 29899390 [PubMed - as supplied by publisher]

Related Articles

Human Genetics of Obesity and Type 2 Diabetes Mellitus: Past, Present, and Future.

Circ Genom Precis Med. 2018 Jun;11(6):e002090

Authors: Ingelsson E, McCarthy MI

Abstract
Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.

PMID: 29899044 [PubMed - in process]

Related Articles

Pharmacogenetic studies in Alzheimer disease.

Neurologia. 2018 Jun 10;:

Authors: Zúñiga Santamaría T, Yescas Gómez P, Fricke Galindo I, González González M, Ortega Vázquez A, López López M

Abstract
INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.
DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.
CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.

PMID: 29898857 [PubMed - as supplied by publisher]