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Aim: Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Methods: Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. Results: We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. Conclusions: IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.

Precision, accuracy, and temporal resolution are key to making full use of atmospheric trace gas records in ice cores. These aspects will become especially crucial for ice cores that aim to extend the ice core record to the last 1.5 Myr, i.e., across the Mid-Pleistocene Transition (as currently drilled within the European project Beyond EPICA – Oldest Ice Core (BE-OIC)). The ice from this period is expected to be close to bedrock and, due to glacier flow, extremely thinned with 15 000 years of climate history contained in only 1 m of ice. Accordingly, for a century-scale resolution, the sample vertical extent must be reduced to a few centimeters containing only about 1–2 mL air STP. We present a novel combined system for the extraction and the simultaneous measurement of CO2, CH4, and N2O concentrations, as well as δ13CO2, which achieves a vertical resolution of 1–2 cm (3.5×3.5 cm cross section) with precisions of 0.4 ppm, 3 ppb, 1 ppb, and 0.04 ‰, respectively, in sublimation tests with standard gas over gas-free ice. This is accomplished by employing a directional and continuous laser-induced sublimation followed by analysis of the sample gas by a quantum cascade laser absorption spectrometer (QCLAS). Besides the low sample volume requirements and the vertical resolution capabilities, the described method holds additional advantages over previous methods, including the immunity of the highly specific QCLAS analysis to drilling fluid contamination as well as the non-destructive nature of the spectroscopic gas analysis. The combined extraction and analysis system was extensively tested by sublimating gas-free ice with introduction of a standard gas to determine the accuracy and characterize potential artifacts. Moreover, Antarctic ice samples were measured to confirm the measurement performance, covering the range of variability expected in Pleistocene ice and highlighting the vertical resolution capabilities critical for its application within BE-OIC.

e15524 Background: Biomarker discovery and development are essential for stratifying cancer patients in order to improve treatment outcomes. In colorectal cancer (CRC), mutations in the TGF-β/BMP pathway, especially in the SMAD4 gene have been correlated with decreased overall survival and are suspected to modulate drug sensitivity on the cellular level, hence SMAD4 mutations are worthwile targets for novel targeted therapy aproaches. Methods: In the present study, we uncover the mechanistic role of a loss-of-function mutation in SMAD4 in syngeneic patient-derived organoids (PDOs). CRISPR-engineered SMAD4R361H PDOs were subjected to a comparative drug screening, RNA-Sequencing and multiplex protein profiling analysis (DigiWest®). We have confirmed the response towards MEK inhibition of the initial model in an additional set of 62 PDOs with known mutational status. Results: We show that acquisition of SMAD4 loss-of-function mutations renders PDOs sensitive to MEK-inhibitors. Further, an activation of the TGF-β/BMP signaling pathway, specifically of the BMP branch was observed in SMAD4wt PDOs; indicating that BMP signaling is likely responsible for the resistance towards MEK inhibition. It is plausible that functional loss of SMAD4 and thus loss of BMP signaling renders SMAD4 mutated tumors more sensitive to MEK-inhibitors. By looking at additional genes involved in TGF-β/BMP signaling that are frequently mutated in CRC, we identified the novel gene mutational SFAB-signature ( SMAD4, FBXW7, ARID1A, or BMPR2), when at least one pathogenic mutation is present in these genes. The frequency of SFAB in CRC patient cohort (TCGA, n = 594) was comparable to the frequency of SFAB in our PDOs. For PDOs with SFAB-signature, we found up to 95% and 70% significant positive prediction for cobimetinib and selumetinib, respectively and also up to 70% positive prediction for trametinib. Thus, the SFAB-signature predicts response to MEK inhibition in PDOs with a very high confidence. We further investigated whether the RAS status of CRC PDOs does predict sensitivity to MEK inhibition. The RAS status alone and in combination with SFAB-signature failed to yield better prediction sensitivity to MEK-inhibitors. Conclusions: The present study is a significant step forward to more personalized treatment regimens for CRC patients by early inclusion of MEK-inhibitors. The SFAB-signature should be put to clinical testing as a RAS-independent biomarker for stratification of patients providing a valuable alternative treatment option against CRC, thus ensuring that all patients receive effective and specific therapies as early as possible.

Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient’s tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient’s treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.

Der Titel "Big Business in Asia and its Impact on Economy and Society: The Cases of Ayala and Samsung" enthält im Prinzip schon die Forschungsfrage, nämlich welchen Einfluss und Wirkung haben große Unternehmen auf die Wirtschaft und Gesellschaft des Landes, in dem sie agieren. An den Beispielen der Firmen Ayala Corporation in den Philippinen und Samsung Group in Südkorea werden diese Einflüsse dann konkret beschrieben und analysiert. Zuerst ist es notwendig zu erklären, was "big business" oder große Unternehmen wirklich ausmacht. Im theoretischen Teil der Arbeit werden daher bestimmte Kriterien für die Beurteilung des Marktes festgelegt, die Firma definiert und die Voraussetzungen für Dominanz und Einfluss von großen Unternehmen aufgelistet. Da diese in Asien oft Mischkonzerne und auch Familienfirmen sind, werden deren Besonderheiten ebenfalls beschrieben. Nachdem nun deutlich ist, was "big business" bedeutet, sind die Gebiete festzulegen, wo der Einfluss oder die Wirkung großer Unternehmen spürbar werden. WBCSD, der "World Business Council for Sustainable Development" oder "Weltwirtschaftsrat für Nachhaltige Entwicklung", eine Versammlung von über 200 internationalen Firmen aus diversen Geschäftsgebieten und über 30 Ländern, hat einen Rahmen erarbeitet (2008: "Measuring Impact: Framework Methodolgy"), der die zehn wichtigsten Wirkungsbereiche definiert: 1. Leistungsbildung (capacity building) 2. Wirtschaftswachstum (economic growth) 3. Erziehung (education) 4. Untenehmensentwicklung (enterprise development) 5. Umweltschutz (environmental sustainability) 6. Unternehmenskontrolle (governance) 7. Menschenrechte (human rights) 8. Armutsreduktion (poverty alleviation) 9. Gesundheit (public health) 10. Soziales Gleichgewicht (social stability) Der empirische Teil beschreibt dann zuerst den Markt in den Philippinen und in Südkorea sowie die beiden Großunternehmen, Mischkonzerne und Familienfirmen Ayala und Samsung. In der Folge werden detailliert die Wirkungen aufgeführt, die diese Unternehmen in den von WBCSD bestimmten zehn Bereichen zur Folge haben. Durch die genaue Analyse dieser zwei Beispiele soll letztendlich bewiesen werden, dass große Unternehmen einen entscheidenden Einfluss auf Wirtschaft und Gesellschaft haben können, sowohl positiv wie negativ. Und da große, dominante Unternehmen laufend und in verschiedenen Ländern und Märkten entstehen, kann diese Analyse helfen, eine entsprechende Wirtschaftspolitik gegenüber solchen Unternehmen zu formulieren. Das Ziel ist, dass "big business" die Bedeutung des Gleichgewichts von finanziellem, sozialen und ökologischen Nutzen erkennt, die sogenannte "Triple Bottom Line", u.zw. sowohl aus Gründen des Eigennutzes als auch gesellschaftlicher Verantwortung.

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Trauerschrift auf Curt Reinicke Graf von Calenberg, +20. April 1709