Context:
DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of ...multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.
Case Description:
We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.
Conclusions:
This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.
The purpose of this study was to examine the average treatment effect of preschool special education services on children's kindergarten academic skills. Using data from a nationally representative ...sample of United States children who participated in the Early Childhood Longitudinal Study—Birth Cohort, we examined the effectiveness of preschool special education services by comparing reading and math outcomes for children who received special education services at preschool-age to a propensity-score-weighted sample of children who did not receive these services. Results indicated that the receipt of these special education services had a statistically significant moderate negative effect on children's kindergarten skills in both reading (d=−0.21) and mathematics (d=−0.29). These findings have implications for the implementation and evaluation of services for young children experiencing developmental delays or disabilities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Managed colonies of European honey bees (
) are under threat from
mite infestation and infection with viruses vectored by mites. In particular, deformed wing virus (DWV) is a common viral pathogen ...infecting honey bees worldwide that has been shown to induce behavioral changes including precocious foraging and reduced associative learning. We investigated how DWV infection of bees affects the transcriptomic response of the brain. The transcriptomes of individual brains were analyzed using RNA-Seq after experimental infection of newly emerged adult bees with DWV. Two analytical methods were used to identify differentially expressed genes from the ~15,000 genes in the
genome. The 269 genes that had increased expression in DWV infected brains included genes involved in innate immunity such as antimicrobial peptides (AMPs), Ago2, and Dicer. Single bee brain NMR metabolomics methodology was developed for this work and indicates that proline is strongly elevated in DWV infected brains, consistent with the increased presence of the AMPs abaecin and apidaecin. The 1361 genes with reduced expression levels includes genes involved in cellular communication including G-protein coupled, tyrosine kinase, and ion-channel regulated signaling pathways. The number and function of the downregulated genes suggest that DWV has a major impact on neuron signaling that could explain DWV related behavioral changes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ...ovarian SLCT.
Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available.
In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2–99.3%) compared to 67.1% (95% CI: 55.2–81.6%) for all stage IC and 60.6% (95% CI: 40.3–91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99–305.85).
Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.
•Most (92%, 175/191) ovarian Sertoli-Leydig cell tumors (SLCTs) present as FIGO stage I disease with a favorable prognosis.•FIGO stage I tumors with mesenchymal heterologous elements are at higher risk for recurrence when not receiving chemotherapy.•Somatic (tumor) DICER1 RNase IIIb hotspot variants were found in 97% of intermediately and poorly differentiated SLCTs.•More than half (58%, 91/156) of individuals were found to have a germline DICER1 pathogenic/likely pathogenic variant.•DICER1 surveillance recommendations facilitated detection of asymptomatic ovarian SLCT with nearly all resected as stage IA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
5.
Hereditary pancreatitis for the endoscopist Patel, Milan R.; Eppolito, Amanda L.; Willingham, Field F.
Therapeutic advances in gastroenterology,
03/2013, Volume:
6, Issue:
2
Journal Article
Peer reviewed
Open access
Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily ...been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68–81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for genetic testing are discussed.
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To ...identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Phylogeny has long informed pteridophyte classification. As our ability to infer evolutionary trees has improved, classifications aimed at recognizing natural groups have become increasingly ...predictive and stable. Here, we provide a modern, comprehensive classification for lycophytes and ferns, down to the genus level, utilizing a community-based approach. We use monophyly as the primary criterion for the recognition of taxa, but also aim to preserve existing taxa and circumscriptions that are both widely accepted and consistent with our understanding of pteridophyte phylogeny. In total, this classification treats an estimated 11 916 species in 337 genera, 51 families, 14 orders, and two classes. This classification is not intended as the final word on lycophyte and fern taxonomy, but rather a summary statement of current hypotheses, derived from the best available data and shaped by those most familiar with the plants in question. We hope that it will serve as a resource for those wanting references to the recent literature on pteridophyte phylogeny and classification, a framework for guiding future investigations, and a stimulus to further discourse.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The homeodomain protein Fushi tarazu (Ftz) and its obligate cofactor Ftz-F1, an orphan nuclear receptor, cooperatively bind to DNA and co-regulate the transcription of genes responsible for ...segmentation in the early Drosophila embryo. Two interesting questions have arisen about these genes. The first question concerns the evolution of Ftz, which changed in arthropods from a Hox protein that likely bound its transcriptional targets with the cofactor Exd, to a pair-rule protein in Drosophila that synergistically binds DNA with its cofactor Ftz-F1. This change in function involved changes in both the expression and protein sequence of Ftz, which are being explored throughout arthropod lineages. To determine if the expression and function of ftz is conserved in Diptera, Ftz and related genes were examined in the mosquito Aedes aegypti using reverse transcriptase - PCR, in situ hybridization, and ectopic expression techniques. The second question probes the mechanisms underlying Drosophila Ftz/Ftz-F1 target site recognition in vivo. To date, direct computational attempts to identify downstream target genes and their enhancers have been inadequate. Towards this end, a microarray analysis was performed comparing wild type and ftz-f1 mutant embryos. This generated a list of Ftz/Ftz-F1 target genes whose expression was lower in ftz-f1 mutants than wild type. To identify genes among this group that are directly regulated by Ftz/Ftz-F1, potential Ftz/Ftz-F1 binding sites around these genes were identified by combining Ftz in vivo ChIP data with a computational search for candidate Ftz-F1 binding sites. Next, to test whether these regions correspond to Ftz/Ftz-F1-dependent enhancers, enhancer-lacZ reporter genes were constructed and their expression was analyzed in wild type and ftz mutant embryos. Of 10 enhancers tested, 8 generated expression patterns that overlap with Ftz and Ftz-F1 expression in early embryos and were lost in ftz mutants. The enhancers found in this study, along with previously identified Ftz/Ftz-F1-dependent enhancers, were analyzed to identify binding motifs for additional transcription factors that might co-regulate gene expression with Ftz/Ftz-F1. Four transcription factors were identified that could potentially be involved in Ftz/Ftz-F1-dependent gene regulation: Deaf-1, Dichaete, Zeste, all transcriptional activators, and GAGA factor, a repressor. Together, these studies identified five new Ftz/Ftz-F1-dependent target genes and seven new Ftz/Ftz-F1-regulated enhancers, and they suggest that other transcription factors may also play roles in the pair-rule gene regulatory system.
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently ...conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
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