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Pancreatic Cystosis and Intrahepatic Biliopathy in a Young Adult with Cystic Fibrosis.

J Pediatr. 2018 Jul 02;:

Authors: Al Qatarneh S, Michel H, Lindblad D, Ozolek J, Venkat V, Weiner D

PMID: 30041939 [PubMed - as supplied by publisher]

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The herbicide atrazine affects sperm quality and the expression of antioxidant and spermatogenesis genes in zebrafish testes.

Comp Biochem Physiol C Toxicol Pharmacol. 2018 Apr;206-207:17-22

Authors: Bautista FEA, Varela Junior AS, Corcini CD, Acosta IB, Caldas SS, Primel EG, Zanette J

Abstract
The herbicide atrazine (ATZ) is used worldwide in the control of annual grasses and broad-leaved weeds. The present study evaluated sperm quality parameters in zebrafish Danio rerio after 11-day exposure to nominal ATZ concentrations of 2, 10, and 100 μg L-1. All ATZ concentrations caused a decrease in motility, mitochondrial functionality, and membrane integrity, as measured using conventional microscopy or fluorescence microscopy with specific probes. The DNA integrity of sperm was not affected. The levels of expression of genes related to spermatogenesis, antioxidant defenses, and DNA repair were also investigated using RT-qPCR. The ATZ caused transcriptional repression of the spermatogenesis-related genes SRD5A2 and CFTR, the antioxidant defense genes SOD2 and GPX4B, and the DNA repair gene XPC. This is the first study to show that environmentally relevant concentrations of ATZ significantly affect the sperm quality in fish, possibly resulting in reduced fertility rates. In addition, we showed that the repression of genes related to spermatogenesis and cellular defense could be part of the mechanisms involved in the ATZ toxicity in the testes of male fish.

PMID: 29471151 [PubMed - indexed for MEDLINE]

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Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol. 2018 Jul 24;:

Authors: Tan AY, Zhang T, Michaeel A, Blumenfeld J, Liu G, Zhang W, Zhang Z, Zhu Y, Rennert L, Martin C, Xiang J, Salvatore SP, Robinson BD, Kapur S, Donahue S, Bobb WO, Rennert H

Abstract
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.
METHODS: We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified.
RESULTS: Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes.
CONCLUSIONS: These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

PMID: 30042192 [PubMed - as supplied by publisher]

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Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome.

Brain Dev. 2018 Jul 02;:

Authors: Takezawa Y, Fujie H, Kikuchi A, Niihori T, Funayama R, Shirota M, Nakayama K, Aoki Y, Sasaki M, Kure S

Abstract
BACKGROUND: IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations.
CASE REPORT: A 7-month-old Japanese girl presented with infantile spasms. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy and hyperintensity in the bilateral basal ganglia. Three years later, her younger sister also presented with infantile spasms. MRI revealed diffuse brain atrophy and hyperintensity of the bilateral ganglia, suggesting Leigh syndrome. The siblings were identified with compound heterozygous missense mutations in IARS2, p.[(Phe227Ser)];[(Arg817His)].
CONCLUSION: This is the first case study reporting Leigh syndrome concomitant with some features of CAGSSS in siblings with novel IARS2 mutations, thereby broadening the phenotypic spectrum of IARS2-related disorders. Further studies are warranted to elucidate the nature of these disorders.

PMID: 30041933 [PubMed - as supplied by publisher]

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Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants.

Orphanet J Rare Dis. 2018 Jul 24;13(1):125

Authors: Brasil S, Leal F, Vega A, Navarrete R, Ecay MJ, Desviat LR, Riera C, Padilla N, de la Cruz X, Couce ML, Martin-Hernández E, Morais A, Pedrón C, Peña-Quintana L, Rigoldi M, Specola N, de Almeida IT, Vives I, Yahyaoui R, Rodríguez-Pombo P, Ugarte M, Pérez-Cerda C, Merinero B, Pérez B

Abstract
BACKGROUND: Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.
RESULTS: This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.
CONCLUSIONS: The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.

PMID: 30041674 [PubMed - in process]

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Classification and molecular pathogenesis of NBIA syndromes.

Eur J Paediatr Neurol. 2018 Mar;22(2):272-284

Authors: Di Meo I, Tiranti V

Abstract
Brain iron accumulation is the hallmark of a group of seriously invalidating and progressive rare diseases collectively denominated Neurodegeneration with Brain Iron Accumulation (NBIA), characterized by movement disorder, painful dystonia, parkinsonism, mental disability and early death. Currently there is no established therapy available to slow down or reverse the progression of these conditions. Several genes have been identified as responsible for NBIA but only two encode for proteins playing a direct role in iron metabolism. The other genes encode for proteins either with various functions in lipid metabolism, lysosomal activity and autophagic processes or with still unknown roles. The different NBIA subtypes have been classified and denominated on the basis of the mutated genes and, despite genetic heterogeneity, some of them code for proteins, which share or converge on common metabolic pathways. In the last ten years, the implementation of genetic screening based on Whole Exome Sequencing has greatly accelerated gene discovery, nevertheless our knowledge of the pathogenic mechanisms underlying the NBIA syndromes is still largely incomplete.

PMID: 29409688 [PubMed - indexed for MEDLINE]

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DNA testing of pancreatic cyst fluid: is it ready for prime time?

Lancet Gastroenterol Hepatol. 2017 01;2(1):63-72

Authors: Singhi AD, Nikiforova MN, McGrath K

Abstract
Pancreatic cysts are a clinical quandary in both diagnosis and management. Although many cysts, such as pseudocysts and serous cystadenomas, are benign and can be monitored clinically, mucinous cysts, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, have the potential to progress to pancreatic cancer. Considering the poor prognosis of pancreatic cancer, the detection of a pancreatic cyst can be a source of anxiety for both the patient and physician. This diagnosis in turn can lead to expensive, invasive, and even harmful surveillance and treatment options. As a consequence, several national and international guidelines for the management of pancreatic cysts have been developed over the past decade. However, these guidelines rely on standard clinical assessment, radiographical imaging, and ancillary fluid studies that have insufficient sensitivity and specificity. The application of DNA-based molecular techniques has emerged as an adjunct to the assessment of pancreatic cysts. The cellular content of pancreatic cyst fluid aspirate is often suboptimal for analysis, but DNA isolated from lysed or exfoliated cells within the cyst can be analysed for genetic abnormalities. Moreover, whole exome sequencing and targeted sequencing of the major pancreatic cysts has identified unique mutational profiles for cyst type and genetic alterations that coincide with the development of pancreatic cancer. In this Review, we discuss the major cystic lesions of the pancreas and their underlying molecular pathology, current management guidelines for pancreatic cysts, and integration of DNA-based molecular testing within this field.

PMID: 28404017 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-DK-18-012 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement will provide support for a Human Islet Research Enhancement Centerthat will supply the infrastructure needed to support research coordination, collaboration and dissemination of advances made by the NIDDK funded Human Islet Research Network (HIRN).

Funding Opportunity RFA-HG-18-008 from the NIH Guide for Grants and Contracts. The NHGRI Ethical, Legal and Social Implications (ELSI) Research Program solicits applications to develop and implement a Center for ELSI Resources and Analysis (CERA). The proposed Center will: 1) provide ELSI researchers with an established platform to share their research tools and products related to genomics; 2) serve as a resource that curates and synthesizes ELSI research on key topics in the field, highlights new findings and provides access to these works; and 3) convene ELSI researchers for both small and large scale transdisciplinary projects and meetings to develop a more synergistic and integrated ELSI research community.

Funding Opportunity RFA-AG-19-021 from the NIH Guide for Grants and Contracts. The goal of the GEMSSTAR program is to provide support for early-career physician-scientists trained in medical or surgical specialties or early-career dentist-scientists to launch careers as future leaders in aging- or geriatric-focused research. To achieve this goal, the GEMSSTAR FOA provides small grants to conduct transdisciplinary aging research that will yield pilot data and experience for subsequent aging research projects. The GEMSSTAR program also encourages candidates to seek out a supportive research environment to achieve the program's goal of fostering the development of early-career physician- and dentist-scientists in aging- or geriatric-focused research, particularly as it applies to their clinical specialty/discipline. In selecting GEMSSTAR awardees, NIA will consider the extent to which a candidate's environment is supportive of aging- or geriatric-focused research.

Funding Opportunity RFA-RM-18-025 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support the development of innovative technologies to non-invasively label and monitor genome edited cells in vivo. The ultimate goal for these technologies is to inform on safety and efficacy of in vivo genome editing over time.

Funding Opportunity RFA-RM-18-024 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications proposing research on the development of novel and optimized alternatives to existing in vivo genome editing complexes.

Funding Opportunity RFA-RM-18-023 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to support the development and evaluation of innovative approaches to deliver genome editing machinery into somatic cells, with the ultimate goal of accelerating the development of genome editing therapeutics to treat human disease.

Funding Opportunity RFA-RM-18-022 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications that propose to develop and validate cell- and tissue-based platforms for assessing potential adverse biological consequences of somatic cell genome editing.

Funding Opportunity PA-18-876 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is twofold: (1) to stimulate basic and mechanistic science that facilitates the development of effective probiotics or pre-/probiotic combinations of relevance to human health and disease; and (2) determine biological outcomes for the evaluation of efficacy of pre/probiotics in appropriate test systems and animal models. This FOA encourages basic and mechanistic studies using in vitro, in vivo, ex vivo, and in silico models that focus on prebiotic/probiotic strain selectivity, interaction, and function. It will also encourage inter and multidisciplinary collaborations among scientists in a wide range of disciplines including nutritional science, immunology, microbiomics, genomics, other '-omic' sciences, biotechnology, and bioinformatics.

Funding Opportunity PA-18-874 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to encourage exploratory/ developmental research on biologic factors that mediate the differences in prevalence and severity of Dental, Oral, and Craniofacial (DOC)-related diseases and conditions in oral health disparities populations. It is long recognized that certain racial and ethnic populations suffer an increased burden of DOC diseases and conditions, such as oral/oropharyngeal cancers, early childhood caries (ECC), dental caries, and periodontitis. For each of these diseases, substantial racial and ethnic differences exist in prevalence, severity, persistence and/or disease progression. Biologic factors are believed to play a role in oral health disparities in addition to behavioral, social, and environmental factors. Because critical scientific gaps remain in our understanding of underlying biologic mechanisms that could contribute to these differences, it is difficult to develop targeted therapeutic regimens for those in greatest need.

Funding Opportunity PAR-18-875 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support investigator-initiated studies designed to identify and understand biologic factors (microbial, immune, genetic) that contribute to disparities in dental, oral, and craniofacial disease onset, progression, and persistence.

Notice NOT-CA-18-096 from the NIH Guide for Grants and Contracts