15 research outputs found
Wohnen in Wien : Vom Leben im Gemeindebau
Was vor rund 100 Jahren seinen Anfang nahm, gilt heute als weltweites Vorzeigeprojekt. In den Jahren des sogenannten „Roten Wien“ nach dem Ersten Weltkrieg war der Gemeindebau die mutige politische Antwort auf die gewaltige Wohnungsnot und auf die katastrophalen Wohnverhältnisse. Während andere Städte und Ballungsräume neoliberalen Privatisierungstrends nachgaben, hielt die Stadt Wien am bewährten Modell des Gemeindebaus fest und kann so der Bevölkerung bis heute in großem Umfang leistbaren Wohnraum zur Verfügung stellen. Der Beitrag zeichnet diese erfolgreiche Wohnungspolitik nach und wirft am Beispiel Wien(er Wohnen), aber auch darüber hinausweisend, Schlaglichter auf die gegenwärtigen gesellschaftlichen Herausforderungen und politischen Lösungsstrategien der Wohnungsfrage.What started around 100 years ago is today a global model. In the years of the so-called “Red Vienna” after the World War One, municipal housing was the courageous political answer to the enormous housing shortage and the catastrophic housing conditions. While other cities and metropolitan areas gave way to neoliberal privatization trends, the City of Vienna stuck to the tried and tested model of municipal housing and is thus able to provide the population with affordable housing on a large scale to this day. The article traces this successful housing policy and illuminates the current social challenges and political solution strategies of the housing crisis using Vienna as an example, but also pointing beyond it.
 
Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants
Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Peer reviewe
Impact of preprocessing methods on the Raman spectra of brain tissue
Delineating cancer tissue while leaving functional tissue intact is crucial in brain tumor resection. Despite several available aids, surgeons are limited by preoperative or subjective tools. Raman spectroscopy is a label-free optical technique with promising indications for tumor tissue identification. To allow direct comparisons between measurements preprocessing of the Raman signal is required. There are many recognized methods for preprocessing Raman spectra; however, there is no universal standard. In this paper, six different preprocessing methods were tested on Raman spectra (n &gt; 900) from fresh brain tissue samples (n = 34). The sample cohort included both primary brain tumors, such as adult-type diffuse gliomas and meningiomas, as well as metastases of breast cancer. Each tissue sample was classified according to the CNS WHO 2021 guidelines. The six methods include both direct and iterative polynomial fitting, mathematical morphology, signal derivative, commercial software, and a neural network. Data exploration was performed using principal component analysis, t-distributed stochastic neighbor embedding, and k-means clustering. For each of the six methods, the parameter combination that explained the most variance in the data, i.e., resulting in the highest Gap-statistic, was chosen and compared to the other five methods. Depending on the preprocessing method, the resulting clusters varied in number, size, and associated spectral features. The detected features were associated with hemoglobin, neuroglobin, carotenoid, water, and protoporphyrin, as well as proteins and lipids. However, the spectral features seen in the Raman spectra could not be unambiguously assigned to tissue labels, regardless of preprocessing method. We have illustrated that depending on the chosen preprocessing method, the spectral appearance of Raman features from brain tumor tissue can change. Therefore, we argue both for caution in comparing spectral features from different Raman studies, as well as the importance of transparency of methodology and implementation of the preprocessing. As discussed in this study, Raman spectroscopy for in vivo guidance in neurosurgery requires fast and adaptive preprocessing. On this basis, a pre-trained neural network appears to be a promising approach for the operating room.Funding Agencies|Swedish Foundation for Strategic Research; [RMX18-0056]</p
Supplementary document for Impact of Preprocessing Methods on Raman Spectra of Brain Tissue - 6137376.pdf
Supplementary Figure
Inhibition of the prohormone convertase subtilisin-kexin isoenzyme-1 induces apoptosis in human melanoma cells
noProhormone convertases (PCs) are endoproteases that process many substrates in addition to hormone precursors. Although overexpression of PCs is linked to carcinogenesis in some solid tumors, the role of subtilisin-kexin isoenzyme-1 (SKI-1) in this context is unknown. We show that SKI-1 is constitutively expressed in human pigment cells with higher SKI activity in seven out of eight melanoma cell lines compared with normal melanocytes. SKI-1 immunoreactivity is also detectable in tumor cells of melanoma metastases. Moreover, tissue samples of the latter display higher SKI-1 mRNA levels and activity than normal skin. From various stimuli tested, 12-O-tetradecanoylphorbol-13-acetate and tunicamycin affected SKI-1 expression. Importantly, SKI-1 inhibition by the cell-permeable enzyme inhibitor decanoyl-RRLL-chloromethylketone (dec-RRLL-CMK) not only suppressed proliferation and metabolic activity of melanoma cells in vitro but also reduced tumor growth of melanoma cells injected intracutaneously into immunodeficient mice. Mechanistic studies revealed that dec-RRLL-CMK induces classical apoptosis of melanoma cells in vitro and affects expression of several SKI-1 target genes including activating transcription factor 6 (ATF6). However, ATF6 gene silencing does not result in apoptosis of melanoma cells, suggesting that dec-RRLL-CMK induces cell death in an ATF6-independent manner. Our findings encourage further studies on SKI-1 as a potential target for melanoma therapy
Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer
IMPORTANCE Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. OBJECTIVES To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. DESIGN, SETTING, AND PARTICIPANTS For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. MAIN OUTCOMES AND MEASURES FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. RESULTS In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). CONCLUSIONS AND RELEVANCE Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis
BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer
Background: Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods: To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results: BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02-36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99-59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00-3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70-2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43-9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. Conclusions: To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded
Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis
High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer
Purpose To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. Results A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5 (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9 parts per thousand (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. Conclusions High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients