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Pancreatic carcinoma is one of the most lethal cancers and the absence of efficient therapeutic strategies results in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC impacts initiation, development, and survival of this tumor type. Using patient-derived xenografts of pancreatic carcinoma driven by KRAS and MYC oncogenic transcription, we show that co-inhibition of Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) synergistically induce tumor regression through targeting promoter pause-release, a rate-limiting step in transcription elongation. By comparing the nascent transcriptome with the recruitment of elongation and termination factors along genes, we found that co-inhibition of TOP1 and BRD4, while globally impairing RNA production, disturbs recruitment of proteins involved in termination. Thus, RNA polymerases continue transcribing downstream of genes for hundreds of kilobases leading to readthrough transcription. This pervasive transcription also occurs during replication, perturbing replisome progression and leading to DNA damage. The synergistic effect of TOP1 and BRD4 inhibition is specific for cancer cells leaving normal cells unharmed, highlighting the sensitivity of the tumor to these transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of high transcription and replication.One Sentence SummaryTOP1 and BRD4 inhibitors synergize to selectively kill pancreatic cancerin vivo viareadthrough transcription without emergence of drug resistance

Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients.This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26.One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented.This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.

Cytogenetic diagnostics play a crucial role in risk stratification and classification of myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), thus influencing treatment decisions. Optical genome mapping (OGM) is a novel whole genome method for the detection of cytogenetic abnormalities. Our study assessed the applicability and practicality of OGM as diagnostic tool in AML and MDS patients. In total, 27 patients with AML or MDS underwent routine diagnostics including classical karyotyping and fluorescence in situ hybridization (FISH) or real-time PCR analysis wherever indicated as well as OGM following a recently established workflow. Methods were compared regarding concordance and content of information. In 93%, OGM was concordant to classical karyotyping and a total of 61 additional variants in a predefined myeloid gene-set could be detected. In 67% of samples the karyotype could be redefined by OGM. OGM offers a whole genome approach to cytogenetic diagnostics in AML and MDS with a high concordance to classical cytogenetics. The method has the potential to enter routine diagnostics as a gold standard for cytogenetic diagnostics widely superseding FISH. Furthermore, OGM can serve as a tool to identify genetic regions of interest and future research regarding tumor biology.

Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. Methods In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. Findings Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [ Interpretation In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. Funding The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

In fractography, different fracture surfaces are examined and described with regard to their appearance and morphology. In this context, the fracture surface carries information on the fracture event and on the material, as the morphology reflects the microstructure as well as the physical properties. In the course of this work it is show that the fractographic examination may go beyond just viewing the fracture surfaces. In addition to that, some fracture appearances are presented that are rarely encountered in practice.

The hydrogen-induced damage behavior of ultra-high strength steels (UHSS) has been predicted by a combination of experimental and numerical investigations. Firstly, the resistance against hydrogen-induced failure was examined by slow strain rate tests (SSRT) using various sample geometries and hydrogen contents. Secondly, the hydrogen distribution and loading conditions during the tensile test were calculated by means of the finite element method (FEM). Finally, a combination of various damage models was applied and validated by further SSRT. The main result of this study is a failure prediction model, which considers local stress and strain conditions, as well as hydrogen content.

Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.

Friction (2020). doi:10.1007/s40544-020-0454-4, Published by Springer, Heidelberg

Importance Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. Objective To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. Design, Setting, and Participants This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. Interventions Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. Main Outcomes and Measures The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. Results Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45,P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%,P = .67) and distant metastases (18% vs 16%,P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. Conclusions and Relevance This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. Trial Registration ClinicalTrials.gov identifier:NCT02363374

The transport behavior of hydrogen in ultra-high strength steel grades (UHSS) has been analyzed by several test and evaluation methods. In particular, permeation and desorption measurements have been performed to evaluate material specific parameters such as the effective diffusion coefficient, the reversible trap density and the reversible trap activation energy. Subjects of this study were a dual phase steel grade (DP) with a ferritic-martensitic microstructure and a martensitic steel grade (MS). The results of the permeation measurements indicate that the influence of irreversible traps might be negligible for the investigated UHSS compared to other impact factors. The evaluated reversible trap densities were some orders of magnitude higher than those known for pure iron reflecting the more complex microstructure. The major influence on hydrogen trapping is attributed to reversible traps like grain boundaries and dislocations based on the results of desorption measurements.

Characterization of crystal orientation and grain boundaries is of great interest in the understanding of the mechanisms taking place during the degradation process originated by the exposure of materials to erosive media. In the present study, an austenitic stainless steel previously analyzed by electron backscatter diffraction was exposed to ultrasonic cavitation erosion. Several parameters such as crystal orientation, misorientation, coincidence site lattice, Schmid factor and twin orientation were examined in order to determine their influence on the local susceptibility to early damage induced by cavitation. Crystallographic orientation was found to play a significant role in the deformation mechanisms occurring inside grains. Furthermore, high misorientation between adjacent grains was recognized as a determining factor leading to early damage observed at random grain boundaries, while the difference in Schmid factor was identified to have a significant effect on the cavitation resistance of twin boundaries. Moreover, the effect of the deviation from the ideal orientation predicted for coherent twins was analyzed in connection with cavitation resistance.

Hydrogen can get into metallic components and damage them in very different ways. Liquid-phase metallurgical processes such as casting and welding can lead to the formation of “fish-eyes” and “flakes”. Apart from metallurgical sources, semi-finished and finished components can also absorb hydrogen from galvanic processes or as a result of corrosion. In these cases hydrogen diffuses into regions of higher stress and strain causing cracking, often unexpectedly and after significant periods of time, which is referred to as “delayed fracture” and “cathodic stress corrosion cracking”. In failure analysis the clarification of hydrogen-induced component damages is based on fractographic examinations in combination with H-analysis. However, a systematic approach of consecutive steps is required in order to clarify hydrogen-induced fractures unambiguously. In failure analysis a delayed fracture is a strong evidence for a damage caused by hydrogen. If a sample taken from the as-received component breaks delayed during a clamping test, this can only be caused by hydrogen which has been present in the component. If too much of the hydrogen has escaped in the space of time from failure to investigation, a clamping test with simultaneous hydrogen uptake can be performed. The fractographic comparison of a sample broken in a clamping test and the primary fracture of the component, as well as the final fracture is necessary. As these three fractures arise from the identical material, the comparison should lead to an unambiguous result. Finally there is the possibility to selectively detect the diffusible (damaging) hydrogen using the HCA method.

An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. Significance: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.

Bei dem vorliegenden Text handelt es sich um einen alternativen Anfang zu Schlicks im Sommersemester 1912 in Rostock gehaltener Vorlesung zur Einleitung in die Naturphilosophie. So stimmen beide Stucke darin uberein, dass Schlick in ihnen auf die antiken Ursprunge der (Natur-)Philosophie hinweist und sich in diesem Zusammenhang auf dieselbe Stelle in der Metaphysik von Aristoteles bezieht.

Bei dem vorliegenden Text handelt es sich um eine ausfuhrliche Auseinandersetzung mit Themen aus dem Bereich der Philosophie der Biologie, die zwischen 1915 und Anfang 1917 entstand, als Schlick Professor in Rostock war.

Nachdem Schlicks Habilitationsversuch an der Universitat Zurich gescheitert war, habilitierte er sich schlieslich 1911 mit der Arbeit Das Wesen der Wahrheit nach der modernen Logik in Rostock, wo er anschliesend zehn Jahre lang tatig war. Am 29. Juni 1911 hielt er seine Antrittsvorlesung „Die Aufgabe der Philosophie in der Gegenwart“, im Wintersemester 1911/12 bot er seine ersten beiden Lehrveranstaltungen mit den Titeln „Grundzuge der Erkenntnistheorie und Logik“ und „Lekture klassischer Schriften zur Erkenntnistheorie“ an.

Es handelt sich bei dem vorliegenden Text um eine Vorarbeit zu den ersten drei Blattern von Schlicks Vorlesung zur Einleitung in die Naturphilosophie, die er im Sommersemester 1912 in Rostock hielt. Sowohl in seiner Vorlesung als auch in dem hier anschliesenden Text setzt Schlick sich kritisch mit dem Naturphilosophieverstandnis des deutschen Idealismus auseinander, um in Abgrenzung dazu seine eigene Auffassung von Naturphilosophie und deren Verhaltnis zu den Naturwissenschaften zu erlautern. Schlick verwendet in seinem Text ahnliche Formulierungen und fuhrt dieselben Zitate und Beispiele an, wie er sie spater in der „Einleitung in die Naturphilosophie“ gebraucht.

Im Oktober 1921 folgt Moritz Schlick, der seit 1910 in Rostock gelebt und gelehrt hat, einem Ruf an die Universitat Kiel, wo er allerdings nur ein Jahr lang tatig sein wird. Bereits im September 1921 fragt Erich Becher vertraulich bei Schlick an, ob dieser sich vorstellen konne, eine Lehrkanzel an der Universitat Wien anzunehmen, ohne ihm jedoch allzu grose Hoffnungen auf diese Stelle zu machen. Dennoch erhalt Schlick Ende Dezember 1921 vom osterreichischen Bundesministerium fur Inneres und Unterricht die ozielle Mitteilung, dass er primo loco „fur eine erledigte ordentliche Lehrkanzel der Philosophie“ an der Universitat Wien vorgeschlagen wurde.

Im Dezember 1934 wurde in der Zeitschrift Erkenntnis ein von Moritz Schlick verfasster Aufsatz mit dem Titel „Philosophie und Naturwissenschaft“ veroffentlicht. Dieser Aufsatz stellte nach Schlicks eigenen Worten „den (nachtraglich rekonstruierten) Inhalt eines Vortrags dar, der im Jahre 1929 an der Universitat Wien als Einleitung in einen volkstumlichen Zyklus ‚Das Weltbild der Naturwissenschaftʻ gehalten wurde“. Schlick hielt diesen Vortrag am 18. Oktober 1929, kurz nachdem er via Italien von einem Aufenthalt an der Universitat Stanford nach Wien zuruckgekehrt war.