System-Aufstellungen und ihre naturwissenschaftliche Begründung

In dieser Open-Access-Publikation liefert Thomas Gehlert eine konsistente, auf aktuellen Experimenten und Theorien basierte, fundierte natur- und neurowissenschaftliche Theorie, die den zugrundeliegenden Prozess bei Intuition (Bauchgefühl) und System-Aufstellung beschreiben kann. Damit schließt er eine theoretische Lücke, die die breite Akzeptanz unzähliger experimenteller Ergebnisse in Entscheidungstheorie- und Intuitionsforschung verhinderte. Darauf aufbauend darf die System-Aufstellung als legitimierte Methode im Kontext von Unternehmensführung, strategischem Management und Entscheidungsfindung angesehen werden

Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis

Immunotherapy has evolved as a powerful tool for the treatment of B-cell malignancies, and patient outcomes have improved by combining therapeutic antibodies with conventional chemotherapy. Overexpression of antiapoptotic B-cell lymphoma 2 (Bcl-2) is associated with a poor prognosis, and increased levels have been described in patients with "double-hit" diffuse large B-cell lymphoma, a subgroup of Burkitt's lymphoma, and patients with pediatric acute lymphoblastic leukemia harboring a t(17;19) translocation. Here, we show that the addition of venetoclax (VEN), a specific Bcl-2 inhibitor, potently enhanced the efficacy of the therapeutic anti-CD20 antibody rituximab, anti-CD38 daratumumab, and anti-CD19-DE, a proprietary version of tafasitamab. This was because of an increase in antibody-dependent cellular phagocytosis by macrophages as shown in vitro and in vivo in cell lines and patient-derived xenograft models. Mechanistically, double-hit lymphoma cells subjected to VEN triggered phagocytosis in an apoptosis-independent manner. Our study identifies the combination of VEN and therapeutic antibodies as a promising novel strategy for the treatment of B-cell malignancies

Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells

Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy

Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics

Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory

Differential Cerebral Cortex Transcriptomes of Baboon Neonates Consuming Moderate and High Docosahexaenoic Acid Formulas

BACKGROUND: Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system (CNS). These nutrients are present in most infant formulas at modest levels, intended to support visual and neural development. There are no investigations in primates of the biological consequences of dietary DHA at levels above those present in formulas but within normal breastmilk levels. METHODS AND FINDINGS: Twelve baboons were divided into three formula groups: Control, with no DHA-ARA; “L”, LCPUFA, with 0.33%DHA-0.67%ARA; “L3”, LCPUFA, with 1.00%DHA-0.67%ARA. All the samples are from the precentral gyrus of cerebral cortex brain regions. At 12 weeks of age, changes in gene expression were detected in 1,108 of 54,000 probe sets (2.05%), with most showing <2-fold change. Gene ontology analysis assigns them to diverse biological functions, notably lipid metabolism and transport, G-protein and signal transduction, development, visual perception, cytoskeleton, peptidases, stress response, transcription regulation, and 400 transcripts having no defined function. PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only LCPUFA biosynthetic enzyme that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated by high DHA, while the mitochondrial proton carrier, UCP2, was upregulated. TIMM8A, also known as deafness/dystonia peptide 1, was among several differentially expressed neural development genes. LUM and TIMP3, associated with corneal structure and age-related macular degeneration, respectively, were among visual perception genes influenced by LCPUFA. TIA1, a silencer of COX2 gene translation, is upregulated by high DHA. Ingenuity pathway analysis identified a highly significant nervous system network, with epidermal growth factor receptor (EGFR) as the outstanding interaction partner. CONCLUSIONS: These data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across a wide array of processes, in addition to changes in visual and neural function normally associated with formula LCPUFA

System-Aufstellungen und ihre naturwissenschaftliche Begründung: Grundlage für eine innovative Methode zur Entscheidungsfindung in der Unternehmensführung

Mit dieser Forschung liefert Thomas Gehlert eine konsistente, auf aktuellen Experimenten und Theorien basierte, fundierte natur- und neurowissenschaftliche Theorie, die den zugrundeliegenden Prozess bei Intuition (Bauchgefühl) und System-Aufstellung beschreiben kann. Damit schließt er eine theoretische Lücke, die die breite Akzeptanz unzähliger experimenteller Ergebnisse in Entscheidungstheorie- und Intuitionsforschung verhinderte. Darauf aufbauend darf die System-Aufstellung als legitimierte Methode im Kontext von Unternehmensführung, strategischem Management und Entscheidungsfindung angesehen werden.:1 Einstieg und Orientierung 1 1.1 Einleitende Gedanken und Ausgangssituation 1 1.2 Zielsetzungen der Forschungsarbeit 6 1.3 Vorgehensweise und Methode 7 1.4 Aufbau der Arbeit 8 2 Methodologischer Zugang 13 2.1 Methodische Vorgehensweise 13 2.2 Wissenschaftliche Legitimation 26 3 Wirtschaftswissenschaftlicher Zugang 47 3.1 Unternehmensführung in der VUCA-Welt 47 3.2 Unternehmensführung und strategisches Management 58 3.3 System-Aufstellungen, als Antwort auf die VUCA-Herausforderung 106 4 Notwendige interdisziplinäre Erweiterung 141 4.1 Intuitionsforschung 141 4.2 Information und Informationsübertragung 166 5 Erklärungsansätze 229 5.1 Bewertung bisher betrachteter Experimente 229 5.2 Intuition als mögliche Erklärung für die Phänomene bei SyA 234 5.3 Erklärungsversuche im Rahmen von SyA 244 6 Zwischenresümee – Erkenntnisse und Fragen 267 7 Auf dem Weg zu einer neuen Theorie 271 7.1 Eine heuristische Betrachtung als Ausgangspunkt 271 7.2 Ausgangsbasis für eine komplementäre Theorie der SyA 276 7.3 Bedingungen für Quantenverhalten in Makrosystemen 282 7.4 Anwendung der geforderten Bedingungen auf SyA 287 8 Modellentwicklung von der Mikro- zur Makrowelt 291 8.1 Quantenphysikalische Annäherung 291 8.2 Biologische Systeme und Physik 406 8.3 Neurowissenschaften – Der Mensch als Entscheider 459 9 Homologie von QPhy–Systemtheorie–SyA 535 9.1 Verbundene Entwicklungsgeschichte 537 9.2 Gemeinsame Prinzipien und Zusammenhänge 544 9.3 Conclusio zur Homologie 549 10 Ergebnisse und Ausblick 553 10.1 Grundsätzliche Ergebnisse auf einen Blick 553 10.2 Naturwissenschaftlich begründetes Theoriemodell zur Intuition im Rahmen von SyA 556 10.3 Antworten zur wissenschaftlichen Legitimation 563 10.4 Ergebnisse in Bezug auf die wirtschaftswissenschaftliche Dimension 565 10.5 Grenzen dieser Arbeit 582 10.6 Zukünftiger Forschungsbedarf und Ausblick 584 11 Fazit und Nachwort 589 11.1 Fazit 589 11.2 Nachwort 591 Literatur 59