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Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Since first of January 2015, the EU-regulation 1143/2014 obligates all member states to conduct costbenefit analyses in preparation of control programs for invasive alien species to minimize and mitigate their impacts. In addition, with ratification of the Rio Declaration and the amended Federal Nature Conservation Act, Germany is committed to control any further spread of invasive species. This is the first cost-benefit analysis estimating positive welfare effects and societal importance of H. mantagezzianum invasion control in Germany. The paper analyses possible control options limiting stands of giant hogweeds (H. mantegazzianum) based on survey data of n = 287 German districts. We differentiate between several control options (e.g. root destruction, mechanical cutting or mowing, chemical treatment and grazing) depending on infested area size and protection status. The calculation of benefits is based on stated preference results (choice experiment; n = 282). For the cost side, we calculate two different invasion scenarios (i) no re-infestation after successfully conducted control measures (optimistic) and (ii) re-infestation twice after conducting control measures occurring within ten years (pessimistic). Minimum costs of eradication measures including a time span of ten years and a social discount rate of 1% result in a total of 3,467,640 € for optimistic scenario and 6,254,932 € for pessimistic invasion scenario, where no success of the first eradication attempt is assumed. Benefits of invasion control in Germany result in a total of 238,063,641 € per year and overassessment-factor corrected in 59,515,910 € per year.
Prioritisation of high-impact species is becoming increasingly important for management of introduced species (‘neobiota’) because of their growing number of which, however, only a small fraction has substantial impacts. Impact scores for prioritising species may be affected by the type of effect model used. Recent studies have shown that environmental co-variation and non-linearity may be significant for effect models of biological invasions. Here, we test for differences in impact scores between simple and complex effect models of three invasive plant species (Heracleum mantegazzianum, Lupinus polyphyllus, Rosa rugosa). We investigated the effects of cover percentages of the invasive plants on species richness of invaded communities using both simple linear effect models (‘basic models’) and more complex linear or nonlinear models including environmental co-factors (‘full models’). Then, we calculated impact scores for each invasive species as the average reduction of species richness predicted by basic and full effect models. All three non-native species had negative effects on species richness, but the full effect models also indicated significant influence of habitat types. Heracleum mantegazzianum had uniform linear effects in all habitats, while effects of L. polyphyllus interacted strongly with habitat type, and R. rugosa showed a marked non-linear relationship. Impact scores were overestimated by basic effect models for H. mantegazzianum and R. rugosa due to disregard of habitat effects and non-linearity, respectively. In contrast, impact of L. polyphyllus was underestimated by the basic model that did not account for the strong interaction of invader cover and habitat type. We conclude that simple linear models will often yield inaccurate impact scores of non-native species. Hence, effect models should consider environmental co-variation and, if necessary, non-linearity of the effects of biological invasions on native ecosystems.
Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.
Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.
Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.
Conclusions: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.