Bioproduktion in dreidimensional wachsenden Zellkulturen

Die biotechnologische Produktion von Substancen wie t-PA, monoklonalen Antikörpern, lnterleukinen, Wachstumsfaktoren, Interferonen und Hormonen sollte vorzugsweise mit Säugetierzellen erfolgen, weil Bakterien diese Substanzen nicht in ihrer nativen Form herstellen können. Die dazu benötigten großen Mengen von Säugerzellen werden - je nach Zelltyp - in Monolayer- oder Suspensionskultur gezüchtet. Für Monolayerkulturen müssen große Oberflächen (Roller Bottles, Microcarrier) zur Verfügung gestellt werden, was viel Raum und Materlal beansprucht und damit kostenintensiv ist. In Suspension wachsen die Zellen voneinander isoliert, wodurch Zellkooperation unterbunden wird und interzellulärer Informationsaustausch nicht mehr möglch ist. Es gibt jedoch eine weitere Möglichkeit, Eurokaryonten zu kultivieren, welche die Nachteile der beiden anderen Methoden aufhebt. Diese bisher vorwiegend in der Krebsforschung oder bei der Untersuchung von Regulationsmechanismen von Zellen verwendete Technik läßt die Zellen zu dreidimensional angeordneten kugelförmigen Zellaggregaten - den Multizell-Sphäroiden - heranwachsen

Becoming Vigilant Subjects

Becoming Vigilant Subjects argues that practices of vigilance are key to forming individual subjectivity. The book emerged from a multi-disciplinary working group at the Collaborative Research Center for ›Cultures of Vigilance‹ at LMU Munich. The authors include anthropologists, historians, and literary scholars. They draw on historically and culturally diverse case studies to examine how individuals develop their own vigilant selves in response to being observed by (often powerful) others – be they present, absent, or imagined. The authors argue that, in the interplay between this assumed observation and individual watchfulness, subjectivity emerges. However, as shown in the case studies, this is an ambivalent process. The focus of this book is therefore on the becoming – rather than being – of subjects against the backdrop of heightened attention, which is directed towards objectives beyond individual goals and tasks. The different cases, relating to the realm of religion, citizenship, and migration, show how individuals engage with, and potentially change, the social world within which they are embedded. All of these examples emphasize that subjects are not just shaped by the context of vigilance, but have agency and the ability to transform their own circumstances. Becoming Vigilant Subjects makes a valuable contribution to the as yet understudied topics of subjectivity and vigilance, by interrogating how both inform one another

Time-discrete higher order ALE formulations: a priori error analysis

We derive optimal a priori error estimates for discontinuous Galerkin (dG) time discrete schemes of any order applied to an advection-diffusion model defined on moving domains and written in the Arbitrary Lagrangian Eulerian (ALE) framework. Our estimates hold without any restrictions on the time steps for dG with exact integration or Reynolds' quadrature. They involve a mild restriction on the time steps for the practical Runge-Kutta-Radau methods of any order. The key ingredients are the stability results shown earlier in Bonito et al. (Time-discrete higher order ALE formulations: stability, 2013) along with a novel ALE projection. Numerical experiments illustrate and complement our theoretical results.</p

Characteristics and Outcomes of IBD Patients with COVID-19 on Tofacitinib Therapy in the SECURE-IBD Registry

The coronavirus disease 2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to unprecedented loss of life and health on a global scale. COVID-19 outcomes are more severe among those with comorbid conditions, which raises concerns for patients with inflammatory bowel disease (IBD), especially given the increased infection risk with immunosuppression used for IBD therapy

Aspirin and NSAID use and lung cancer risk: a pooled analysis in the International Lung Cancer Consortium (ILCCO)

Purpose: To investigate the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) lower lung cancer risk. Methods: We analysed pooled individual-level data from seven case-control and one cohort study in the International Lung Cancer Consortium (ILCCO). Relative risks for lung cancer associated with self-reported history of aspirin and other NSAID use were estimated within individual studies using logistic regression or proportional hazards models, adjusted for packyears of smoking, age, calendar period, ethnicity and education and were combined using random effects meta-analysis. Results: A total of 4,309 lung cancer cases (mean age at diagnosis 65 years, 45% adenocarcinoma and 22% squamous-cell carcinoma) and 58,301 non-cases/controls were included. Amongst controls, 34% had used NSAIDs in the past (81% of them used aspirin). After adjustment for negative confounding by smoking, ever-NSAID use (affirmative answer to the study-specific question on NSAID use) was associated with a 26% reduction (95% confidence interval 8 to 41%) in lung cancer risk in men, but not in women (3% increase (-11% to 30%)). In men, the association was stronger in current and former smokers, and for squamous-cell carcinoma than for adenocarcinomas, but there was no trend with duration of use. No differences were found in the effects on lung cancer risk of aspirin and non-aspirin NSAIDs. Conclusions Evidence from ILCCO suggests that NSAID use in men confers a modest protection for lung cancer, especially amongst ever-smokers. Additional investigation is needed regarding the possible effects of age, duration, dose and type of NSAID and whether effect modification by smoking status or sex exists

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study

Background: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. Methods: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. Results: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for >= 20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). Conclusions: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition