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Aluminum alloys have a strong tendency to form alumina layers on their surfaces when exposed to atmospheric air, even at room temperature. This is a severe challenge for brazing aluminum alloys as the alumina layer acts as a diffusion barrier and hinders the interactions between the filler metal and the base material. In order to achieve a good metallurgical bond between the filler metal and the aluminum alloy, it is of crucial importance to remove the alumina layer as well as to simultaneously prevent further oxidation of the aluminum alloy. The current investigation focuses on the detailed micro-structural changes that occur during in-situ brazing of liquid filler metal, 95Sn-5Cu (wt.%) on an aluminum alloy, Al-7Si-0.3Mg. These in-situ studies were performed in a large chamber scanning electron microscope in order to monitor the interactions of the filler metal and the base material, particularly the role of Cu on alumina detachment. After the in-situ experiments, the local surface and cross-sectional regions were analyzed by scanning electron microscopy in conjunction with energy dispersive X-ray spectroscopy to understand the variation in chemistry across the wetted region, which includes the interfacial region between filler metal and the base material. As the alumina scale present on the aluminum alloy is very thin (2Cu intermetallic precipitates.

The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced β-catenin binding resulting in increased cytosolic and nuclear β-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/β-catenin signaling.

Background PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. Methods This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. Results A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. Conclusions Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Functional mitochondria are essential for cell viability and depend on protein import from the cytosol. Impaired protein import initiates various well-characterized cellular programs that rescue or remove dysfunctional mitochondria. However, the molecular mechanism that underlies the initial reduction of protein import into defective mitochondria remained unknown. Here, we found that the redistribution of mtHsp70, mitochondrial chaperone that is involved in both protein import and protein folding, regulates the efficiency of protein import. During early mitochondrial stress, before rescue programs are initiated and membrane potential is affected, mtHsp70-dependent import was specifically impaired and association of mtHsp70 with the import complex reduced. Even under non-stress conditions, the majority of mtHsp70 is found in a substrate-bound state. We propose that the availability of free mtHsp70 limits protein import into mitochondria during stress.

When employed according to specific doses and fractionation schedules, radiation therapy (RT) elicits potent tumor-targeting immune responses that rely on the secretion of type I interferon (IFN) by irradiated cancer cells. Most often, this is initiated by the ability of RT to promote the cytosolic accumulation of double-stranded DNA (dsDNA) molecules, which are detected by cyclic GMP-AMP synthase (CGAS) to engage the stimulator of interferon response cGAMP interactor 1 (STING1)-dependent transactivation of type I IFN-coding genes via interferon regulatory factor 3 (IRF3). Here, we describe a simple protocol for the quantification of cytosolic dsDNA species by immunofluorescence microscopy coupled to automated image analysis, as enabled by precise sample processing conditions that permeabilize plasma-but not nuclear or inner mitochondrial-membranes. As compared to subcellular fractionation-based techniques, this approach is compatible with assessments in individual cells aimed at gauging inter-cellular heterogeneity, as well as subcellular tests including co-localization studies.

Radiation therapy (RT) is well known for its capacity to mediate cytostatic and cytotoxic effects on malignant cells, largely reflecting the ability of ionizing radiation to cause direct and indirect damage to macromolecules including DNA and lipids. While low-dose RT generally causes limited cytotoxicity in an acute manner (as it imposes insufficient cellular damage to compromise homeostasis, or instead induces the delayed demise of cells that fail to complete mitosis successfully), high RT doses can mediate an acute wave of cell death that begins to manifest shortly (24-72h) after irradiation. Here, we provide two straightforward techniques to assess the acute cytotoxic effects of RT by the flow cytometry-assisted quantification of plasma membrane permeabilization (PMP, a late-stage manifestation of cell death) and either mitochondrial outer membrane permeabilization (MOMP) or phosphatidylserine (PS) externalization (two early-stage signs of cell death) in mouse mammary adenocarcinoma TS/A cells. With minor variations, the same protocols can be straightforwardly adapted to measure acute cell death responses as elicited by RT in a large panel of human and mouse cancer cells lines of different histological derivation.

Katholische Persönlichkeiten haben das politische, soziale und kulturelle Leben Deutschlands vielfältig mitgeprägt und prägen es noch immer. Kamen früher die konfessionellen Zuordnungen noch eindeutiger zum Ausdruck, mag für die neueste Zeit die Bindung an das Katholische bei Manchem überraschen, zeigen sich bei näherem Hinsehen dann aber doch neue und differenziertere Formen eines „Katholischseins“. Die Reihe „Zeitgeschichte in Lebensbildern“ spürt seit 1973 in Form wissenschaftlich fundierter und gleichzeitig leserfreundlich formulierter biographischer Abrisse dem katholischen Anteil an der neueren deutschen Geschichte nach. Die bisher vorliegenden zwölf Bände werden hier, unter teils neuer Herausgeberschaft, um einen dreizehnten ergänzt. Er enthält, wie stets von ausgewiesenen Fachleuten verfasst, 17 Lebensbilder katholischer Persönlichkeiten des 20. und 21. Jahrhunderts, darunter Joseph Beuys, Wolfgang Clement, Helmut Kohl, Hanna-Renate Laurien, Karl Lehmann, Isa Vermehren und Hans-Jochen Vogel.

The energy transition requires a restructuring of the energy system and, as a result of decentralisation, also increasing digitalisation to integrate all actors and make them more flexible. However, digitalisation can be shaped and should happen under ecological and social premises.

Meer bewegen is de kern van het beleid bij COPD en verbeteren van het inspanningsvermogenis een van de belangrijkste doelstellingen. Dat geldt ook voor patiënten met lichte tot matigeCOPD in de huisartsenpraktijk. Een beweegprogramma blijkt inderdaad de inspanningscapaciteit enigszins te verbeteren, maar leidt niet automatisch tot actiever beweeggedrag. Hiervoorzou naast het trainingsprogramma een meer gedragsgeoriënteerde benadering nodig zijn.

Das kolorektale Karzinom (KRK) stellt in Deutschland die dritthaufigste Krebsart in der Gesamtbevolkerung dar. Bei etwa 5 % der Patienten mit einem KRK besteht ein gut definiertes erbliches Tumorsyndrom (hereditarer Darmkrebs). Es handelt sich um eine selektive Literaturrecherche und eigene Arbeiten zum Thema erblicher Darmkrebs und gastrointestinale Polyposis. Zu den hereditaren Darmkrebs-Syndromen gehoren insbesondere das Lynch-Syndrom/hereditare nichtpolypose Kolonkarzinom (HNPCC), die familiare adenomatose Polyposis (FAP), die MUTYH-assoziierte Polyposis (MAP) und verschiedene hamartomatose Polyposissyndrome (Peutz-Jeghers-Syndrom, juvenile Polyposis, Cowden-Syndrom). Ursachlich sind Keimbahnmutationen in verschiedenen Genen, die meist mit einem autosomal-dominanten Erbgang und einer auffalligen individuellen und/oder familiaren Tumoranamnese hinsichtlich Darmkrebs und anderer Karzinome einhergehen. Die Ursache des serratierten Polyposissyndroms (SPS) ist noch weitgehend unbekannt. Der Nachweis einer ursachlichen Keimbahnmutation bei einem erkrankten Familienmitglied und die Identifikation von weiteren Anlagetragern der Familie sind entscheidend, da Betroffenen eine an das jeweilige Tumorrisiko angepasste lebenslange Uberwachungsstrategie angeboten wird, die neben engmaschigen Vorsorgekoloskopien auch andere Fruherkennungsmasnahmen umfasst. Bei einigen hereditaren Syndromen kann eine prophylaktische Operation das Tumorrisiko deutlich senken.

The anticoagulation treatment of cardiovascular patients, which is mandatory after implantation of heart valves or stents, has significantly adverse effects on life quality. This treatment can be reduced or even circumvented by developing novel antithrombogenic surfaces of blood-contacting implants. Thus, we aim to discover materials exhibiting outstanding hemocompatibility compared to other available synthetic materials. We present promising surficial characteristics of single crystalline alumina in terms of platelet activation inhibition. In order to elucidate the relation between its crystallographic properties including the plane orientation and blood cell behavior, we examined endothelialization, cytocompatibility, and platelet activation at the blood-alumina interfaces in a controlled experimental setup. We observed that the cell response is highly sensitive to the plane orientation and differs significantly for (0001) and (11-20) planes of Al2O3. Our results reveal for the first time the dependence of platelet activation on crystallographic orientation, which is assumed to be a critical condition controlling the thrombogenicity. Additionally, we used an endothelial cell monolayer as an internal control since endothelial cells have an impact on vessel integrity and implant acceptance. We successfully demonstrate that Al2O3(11-20) exhibits enhanced hemocompatibility in contrast to Al2O3(0001) and is comparable to the physiological endothelial monolayer in vitro.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the \(\textit {German Consortium for Familial Intestinal Cancer}\). In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. \(\it MLH1\) (n = 21) and \(\it MSH2\) (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; \(\it P\) = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.

Das Lynch-Syndrom (LS) ist eines der haufigsten erblichen Tumorsyndrome. Bei betroffenen Frauen tritt als erstes Malignom (Sentinelkarzinom) haufig ein Endometrium- und/oder Ovarialkarzinom auf, meistens im jungeren Lebensalter als bei sporadischen Fallen. Diese haben meist eine gute Prognose, sollten aber von den betreuenden Gynakologen als Hinweis auf ein LS erkannt werden und eine Abklarungsdiagnostik (molekularpathologische Untersuchungen, ggf. genetische Beratung und Keimbahntestung) zur Folge haben. Bei gesichertem LS sind eine intensivierte gastroenterologische Fruherkennung sowie eine genetische Beratung und Testung (Kaskadentestung) der Angehorigen indiziert. Die Moglichkeiten und Limitationen einer intensivierten gynakologischen Fruherkennung und prophylaktische Operationen sollten mit den betroffenen Frauen besprochen werden. Sie sollten von einer Institution, die uber Kompetenz in der Diagnostik, Therapie und Pravention bei Patientinnen mit hereditaren Tumorerkrankungen verfugt, mitbetreut werden.

Das kolorektale Karzinom (KRK) stellt in Deutschland die dritthaufigste Krebsart in der Gesamtbevolkerung dar. Bei 3–5 % der Patienten mit einem KRK liegt ein gut definiertes erbliches Syndrom (hereditarer Darmkrebs) vor. Zu den hereditaren Darmkrebssyndromen gehoren unter anderem das Lynch-Syndrom (auch als HNPCC bezeichnet), die familiare adenomatose Polyposis (FAP), die MUTYH-assoziierte Polyposis (MAP) und verschiedene hamartomatose Polyposissyndrome (Peutz-Jeghers-Syndrom, juvenile Polyposis, Cowden-Syndrom). Ursachlich sind Keimbahnmutationen in verschiedenen Genen, die in der Regel mit einem autosomal-dominanten Erbgang und einer auffalligen individuellen und familiaren Tumoranamnese im Sinne eines deutlich erhohten Risikos fur Darmkrebs und andere Karzinome einhergehen. Die Identifikation von Risikopersonen und der Nachweis einer Mutation durch geeignete Gentests sind entscheidend, da hierdurch Betroffenen eine an das jeweilige Tumorrisiko angepasste lebenslange Uberwachungsstrategie angeboten werden kann, die neben engmaschigen Vorsorgekoloskopien auch andere Fruherkennungsmasnahmen umfasst.

International audience; Purpose: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases.Methods: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature.Results: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%).Conclusion: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

Background Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population. Methods Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX. Results The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX. Conclusions The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.

In the present work, the analytical model proposed by Van Houtte et al. (1993) is applied to predict geometric earing in cup drawing using a non-circular blank geometry. In order to validate the theoretical results, non-linear finite element simulations were carried out. It is observed that the predictions of the theoretical model are in close agreement with the results of the finite element simulations, even for unusual blank contours. Based on this confidence, the analytical earing model is paired with a simple iterative earing compensation procedure in order to calculate the blank contour which is required to obtain an earing-free cup. These results, in turn, are confronted with those obtained by means of the analytical earing compensation approach proposed by Engler et al. (2011). Very good agreement between both approaches is found. Practical applications of the analytical earing compensation approach involving anisotropic materials demonstrate its very good performance.