31 research outputs found

    Renal Tubular Dysgenesis in a Case of Fetus Acardius Amorphus

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    Fetus acardius amorphus is a rare congenital malformation characterized by the lack of a functional heart, the presence of a bivascular umbilical cord, as well as a developed and organized skeletal system and partially organized inner organs. Fetus acardii mostly occur in multiple gestations. The pathogenesis of this entity is not clarified yet. It has been hypothesized that, although formation of anastomosing vessels between the co-twin and the anomalous embryo as well as reverse directed blood flow within the umbilical arteries of the weaker twin may allow sufficient blood flow to form rudimentary internal organs, it is insufficient to develop a fully functional heart. We had a case of fetus acardius amorphus, where we performed autopsy as well as routine histology assessment to identify different types of tissues. We showed that our fetus acardius amorphus demonstrated histomorphological features of renal tubular dysgenesis, confirmed by lack of proximal tubules, extramedullary hematopoiesis and increased number of smooth muscle actin positive vessels. This is a novel finding and has not been reported previously.Peer Reviewe

    Mutation screen in the GWAS derived obesity gene <em>SH2B1</em> including functional analyses of detected variants.

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    BACKGROUND: The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation. METHODS: We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro. RESULTS: We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (&beta;Thr656Ile) and gamma (&gamma;Pro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3&#39; end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p&thinsp;=&thinsp;0.009, OR&thinsp;=&thinsp;1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p&thinsp;=&thinsp;0.042, OR&thinsp;=&thinsp;1.23). The obesity risk-alleles at Thr484Ala and &beta;Thr656Ile/&gamma;Pro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants &beta; and &gamma;. CONCLUSION: The rare coding mutation &beta;Thr656Ile/&gamma;Pro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1

    Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

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    Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&amp;E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification. TCC was analyzed in 120 H&amp;E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath). Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&amp;E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&amp;E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%. Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions
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