Acetylsalicylic Acid Reduces the Severity of Dextran Sodium Sulfate-Induced Colitis and Increases the Formation of Anti-Inflammatory Lipid Mediators

The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation

Integrated multiomic approach for identification of novel immunotherapeutic targets in AML

Background Immunotherapy of acute myeloid leukemia has experienced considerable advances, however novel target antigens continue to be sought after. To this end, unbiased approaches for surface protein detection are limited and integration with other data types, such as gene expression and somatic mutational burden, are poorly utilized. The Cell Surface Capture technology provides an unbiased, discovery-driven approach to map the surface proteins on cells of interest. Yet, direct utilization of primary patient samples has been limited by the considerable number of viable cells needed. Methods Here, we optimized the Cell Surface Capture protocol to enable direct interrogation of primary patient samples and applied our optimized protocol to a set of samples from patients with acute myeloid leukemia (AML) to generate the AML surfaceome. We then further curated this AML surfaceome to exclude antigens expressed on healthy tissues and integrated mutational burden data from hematologic cancers to further enrich for targets which are likely to be essential to leukemia biology. Finally, we validated our findings in a separate cohort of AML patient samples. Results Our protocol modifications allowed us to double the yield in identified proteins and increased the specificity from 54 to 80.4% compared to previous approaches. Using primary AML patient samples, we were able to identify a total of 621 surface proteins comprising the AML surfaceome. We integrated this data with gene expression and mutational burden data to curate a set of robust putative target antigens. Seventy-six proteins were selected as potential candidates for further investigation of which we validated the most promising novel candidate markers, and identified CD148, ITGA4 and Integrin beta-7 as promising targets in AML. Integrin beta-7 showed the most promising combination of expression in patient AML samples, and low or absent expression on healthy hematopoietic tissue. Conclusion Taken together, we demonstrate the feasibility of a highly optimized surfaceome detection method to interrogate the entire AML surfaceome directly from primary patient samples and integrate this data with gene expression and mutational burden data to achieve a robust, multiomic target identification platform. This approach has the potential to accelerate the unbiased target identification for immunotherapy of AML

Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability

Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe A.L. Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majet

Net‐Zero CO 2 Germany - A Retrospect From the Year 2050

Germany 2050: For the first time Germany reached a balance between its sources of anthropogenic CO2 to the atmosphere and newly created anthropogenic sinks. This backcasting study presents a fictional future in which this goal was achieved by avoiding (∼645 Mt CO2), reducing (∼50 Mt CO2) and removing (∼60 Mt CO2) carbon emissions. This meant substantial transformation of the energy system, increasing energy efficiency, sector coupling, and electrification, energy storage solutions including synthetic energy carriers, sector-specific solutions for industry, transport, and agriculture, as well as natural-sink enhancement and technological carbon dioxide options. All of the above was necessary to achieve a net-zero CO2 system for Germany by 2050

Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts

Acetylsalicylic acid reduces the severity of dextran sodium sulfate-induced colitis and increases the formation of anti-inflammatory lipid mediators

Im Rahmen dieser Arbeit wurde die Acetylsalicylsäure (ASS) in einem Tiermodell zu chronisch entzündlichen Darmerkrankungen untersucht. So zeigen die Versuchstiere, die mit ASS behandelt wurden, einen geringeren Gewichtsverlust, ein geringeres Ausmaß an Diarrhoen und rektalen Blutungen, ein geringeres histopathologisches Entzündungsausmaß, eine geringere Expression der mit Entzündungsreaktionen assoziierten COX-2, sowie nicht zuletzt ein hochsignifikant geringeres Entzündungsausmaß in der Magnet-Resonanz- Tomographie. Bemerkenswerterweise war in der MRT ein signifikanter Unterschied zwischen den Versuchsgruppen bereits an Tag 3 des Versuches detektierbar. In den post mortem gewonnen Kolonproben zeigten sich erhöhte Konzentration von anti- inflammatorischen omega-6 Lipidmediatoren. Hier ließen sich in der ASS- Gruppe signifikant höhere Konzentration des anti-inflammatorischen Mediators 15-epi-LXA4 nachweisen, der unter anderem als Initiatoren einer Resolutions- oder Auflösungsphase von Entzündungsreaktionen angesehen wird. Zudem ließen sich aus der Gruppe der omega-3-PUFA erhöhte Konzentrationen des anti- inflammatorischen 17-HDHA in der ASS-Gruppe detektieren. So scheint es durch die hier präsentierten Daten plausibel, dass diese Lipidmediatoren einen entscheidenden Anteil an der anti-entzündlichen Wirkung der ASS ausmachen, insbesondere da hier interessanterweise die Konzentration des pro- inflammatorischen Prostaglandin E2 zwischen den Versuchsgruppen vergleichbar hoch war. Im Kontext der in der jüngsten Zeit erneut durch Daten aus großen randomisierten Studien gezeigten Malignomprotektion durch die langfristige Einnahme von ASS scheint uns eine Reevaluation von ASS im Kontext der CED attraktiv. Hier bedarf es weiterer Studien um letztlich für diese global in ihrer Inzidenz zunehmenden Erkrankung weiter therapeutische Fortschritte zusätzlich zur kurz- oder mittelfristigen Entzündungskontrolle zu erreichen. Zudem scheint der Einsatz der Kleintier-MRT im Kontext einer longitudinalen Beobachtung des Entzündungsprozesses bei gleichzeitiger Minimierung des Einsatzes von Versuchstieren sinnvoll. Die durchgeführten Messungen waren gut reproduzierbar und ließen die Detektion von Unterschieden zwischen den Behandlungsgruppen bereits zu einem sehr frühen Zeitpunkt zu. Die Ergebnisse dieser Arbeit wurden im Jahr 2013 unter dem Titel „Acetylsalicylic Acid Reduces the Severity of Dextran Sodium Sulfate-Induced Colitis and Increases the Formation of Anti-Inflammatory Lipid Mediators“ in BioMed Research International publiziert.The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti- inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA- derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation. The results from this study were published in BioMed Research International in 2013

A Role for Lipid Mediators in Acute Myeloid Leukemia

In spite of therapeutic improvements in the treatment of different hematologic malignancies, the prognosis of acute myeloid leukemia (AML) treated solely with conventional induction and consolidation chemotherapy remains poor, especially in association with high risk chromosomal or molecular aberrations. Recent discoveries describe the complex interaction of immune effector cells, as well as the role of the bone marrow microenvironment in the development, maintenance and progression of AML. Lipids, and in particular omega-3 as well as omega-6 polyunsaturated fatty acids (PUFAs) have been shown to play a vital role as signaling molecules of immune processes in numerous benign and malignant conditions. While the majority of research in cancer has been focused on the role of lipid mediators in solid tumors, some data are showing their involvement also in hematologic malignancies. There is a considerable amount of evidence that AML cells are targetable by innate and adaptive immune mechanisms, paving the way for immune therapy approaches in AML. In this article we review the current data showing the lipid mediator and lipidome patterns in AML and their potential links to immune mechanisms