Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1α kinase inhibitor KIRA6 through HSP60 targeting

in Cell Death and Differentiation (2021)

Mounting evidence indicates that immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress favor proficient cancer cell-immune interactions, by ... [more ▼]

Mounting evidence indicates that immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress favor proficient cancer cell-immune interactions, by stimulating the release of immunomodulatory/ proinflammatory factors by stressed or dying cancer cells. UPR-driven transcription of proinflammatory cytokines/chemokines exert beneficial or detrimental effects on tumor growth and antitumor immunity, but the cell-autonomous machinery governing the cancer cell inflammatory output in response to immunogenic therapies remains poorly defined. Here, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated a NF-κB/AP-1-inflammatory stress response, which dissociated from both cell death and UPR. This stress-induced inflammation was specifically abolished by the IRE1α-kinase inhibitor KIRA6. Supernatants from immunogenic chemotherapy and KIRA6 co-treated cancer cells were deprived of proinflammatory/chemoattractant factors and failed to mobilize neutrophils and induce dendritic cell maturation. Furthermore, KIRA6 significantly reduced the in vivo vaccination potential of dying cancer cells responding to immunogenic chemotherapy. Mechanistically, we found that the anti-inflammatory effect of KIRA6 was still effective in IRE1α-deficient cells, indicating a hitherto unknown off-target effector of this IRE1α-kinase inhibitor. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry, and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the IKK-driven NF-κB pathway. In sum, our study unravels that HSP60 is a KIRA6-inhibitable upstream regulator of the NF-κB/AP-1-inflammatory stress responses evoked by immunogenic treatments. It also urges caution when interpreting the anti-inflammatory action of IRE1α chemical inhibitors. [less ▲]

Stressbewältigung

in Meinlschmidt, G.; Schneider, S.; Margraf, J. (Eds.) Lehrbuch der Verhaltenstherapie: Materialien für die Psychotherapie, 4 (2011)

Das Thema Stressbewältigung (7 Kap. II/30) hat seit den 1960er Jahren einen rasanten Aufschwung genommen. Die damals beginnende Abkehr von dem bis dahin vorherrschenden biologisch-medizinischen Modell ... [more ▼]

Das Thema Stressbewältigung (7 Kap. II/30) hat seit den 1960er Jahren einen rasanten Aufschwung genommen. Die damals beginnende Abkehr von dem bis dahin vorherrschenden biologisch-medizinischen Modell, die zunehmende Unzufriedenheit mit der traditionellen Psychiatrie und die wachsende Bedeutung psychologischer Modelle und klinisch-psychologischer Interventionen haben dazu beigetragen, dass über die letzten 50 Jahre mehr als 4.000 wissenschaft liche Artikel zu diesem Th ema veröffentlicht wurden. Dabei finden sich die unterschiedlichsten Anwendungsbereiche, z. B. Stressbewältigung im Arbeitsbereich, in der Psychotherapie, in der Gesundheitsförderung und der medizinischen Versorgung, in der Paartherapie und in der Krisenintervention. Die Breite dieser Anwendungsbereiche ist sicherlich einer unter mehreren Gründen für die Unterschiedlichkeit der Interventionsmethoden, die unter dem Begriff Stressbewältigungstraining (z. B. Kaluza 2004) zusammengefasst werden. Üblicherweise beginnen die Stressbewältigungsprogramme mit einer allgemeinen Einführung zum Thema »was ist Stress«, ergänzt um eine Darstellung psychobiologischer Zusammenhänge und körperlicher Folgen vonchronischem Stress (7 Kap. IV/19). Die einzelnen Module beziehen sich dann auf spezifische Bereiche, die auch in anderen klinischen Kontexten von Relevanz sind. Dazu gehören Entspannungsverfahren (progressive Muskelrelaxation nach Jacobson, Meditation, autogenes Training, Biofeedback, Atementspannung; 7 Kap. IV/6), klinischpsychologische Interventionen (kognitive Umstrukturierung; 7 Kap. IV/11), Problemlösetraining, Training sozialerFertigkeiten (7 Kap. IV/10), Kommunikationstraining, Genusstraining (7 Kap. IV/8), Aufb au von Aktivitäten (7 Kap. IV/34)) und edukative Maßnahmen (Beratung zu Ernährung, Bewegung und Gesundheit sowie Techniken zur Optimierung von Arbeitsabläufen, Lernen oder Zeitmanagement). Bei aller Verschiedenartigkeit haben Stressbewältigungstrainings allerdings ein gemeinsames Ziel: die Förderung der körperlichen und psychischen Gesundheit und des Wohlbefindens durch eine Verbesserung der individuellen Kompetenzen zur Stressbewältigung. Genauer gesagt besteht das Ziel in der Erhöhung der Flexibilität im Umgang mit Belastungen. Um dieses Ziel zu erreichen und den individuellen Bewältigungskompetenzen des Einzelnen gerecht zu werden, bedarf es eines breiten Angebots innerhalb eines Stressbewältigungstrainings. Deshalb integrieren die meisten Stressbewältigungstrainings mehrere unterschiedliche Interventionsmethoden in multimodale Programme. Wie bei anderen Interventionen auch, kann ein auf die einzelne Person zugeschnittenes Stressbewältigungstraining allerdings erst nach einer genauen Diagnostik der individuellen Voraussetzungen und Bedürfnisse durchgeführt werden. Im vorliegenden Kapitel werden nur wenige ausgewählte übergeordnete Materialien vorgestellt und es wird auf eine Auswahl der wichtigsten deutschsprachigen diagnostischen Verfahren zur Erfassung von Bewältigungsstrategien und therapeutischen Interventionen zur Stressbewältigung verwiesen. Verschiedene Bausteine zur Stressbewältigung können zudem – auf die individuellen Bedürfnisse eines Patienten angepasst – aus den o. g. Kapiteln zusammengestellt werden. [less ▲]

Stressimpfungstraining

in Psychologie und Sport (1995), 2(3), 83-86

Das Streßimpfungstraining (SIT) nach Meichenbaum (1991) stellt ein Verfahren dar, durch das gelernt wird, Streßsituationen bzw. emotional belastende Ereignisse angemessen zu bewältigen. Trainiert werden ... [more ▼]

Das Streßimpfungstraining (SIT) nach Meichenbaum (1991) stellt ein Verfahren dar, durch das gelernt wird, Streßsituationen bzw. emotional belastende Ereignisse angemessen zu bewältigen. Trainiert werden allgemein anwendbare Strategien. Einheitliches Merkmal dieser Strategien ist die Kompetenz, Problem- bzw. Streßsituationen frühzeitig zu erkennen und diese Situationen durch alternative/kognitive und verhaltensbezogene Bewältigungsmaßnahmen zu meistern. [less ▲]

Stretching directions in cislunar space: Applications for departures and transfer design

in Astrodynamics (2022)

Stable or nearly stable orbits do not generally possess well-distinguished manifold structures that assist in designing trajectories for departing from or arriving onto a periodic orbit. For some ... [more ▼]

Stable or nearly stable orbits do not generally possess well-distinguished manifold structures that assist in designing trajectories for departing from or arriving onto a periodic orbit. For some potential missions, the orbits of interest are selected as nearly stable to reduce the possibility of rapid departure. However, the linearly stable nature of these orbits is also a drawback for their timely insertion into or departure from the orbit. Stable or nearly stable Near Rectilinear Halo Orbits (NRHOs), Distant Retrograde Orbits (DROs), and lunar orbits offer potential long-horizon trajectories for exploration missions and demand efficient operations. The current investigation focuses on leveraging stretching directions as a tool for departure and trajectory design applications. The magnitude of the state variations along the maximum stretching direction is expected to grow rapidly and, therefore, offers information for efficient departure from the orbit. Similarly, maximum stretching in reverse time enables arrival with a minimal maneuver magnitude. [less ▲]

Streß und Streßbewältigung

in Flor, H.; Birbaumer, N.; Hahlweg, K. (Eds.) Enzyklopädie der Psychologie, 3 (1999)

Striking discrepancy of anomalous body experiences with normal interoceptive accuracy in depersonalization-derealization disorder

in PLoS ONE (2014), 9(2), 89823

BACKGROUND: Disembodiment is a core feature of depersonalization disorder (DPD). Given the narratives of DPD patients about their disembodiment and emotional numbing and neurobiological findings of an ... [more ▼]

BACKGROUND: Disembodiment is a core feature of depersonalization disorder (DPD). Given the narratives of DPD patients about their disembodiment and emotional numbing and neurobiological findings of an inhibition of insular activity, DPD may be considered as a mental disorder with specific impairments of interoceptive awareness and body perception. METHODS: We investigated cardioceptive accuracy (CA) of DPD patients (n = 24) as compared to healthy controls (n = 26) with two different heartbeat detection tasks ("Schandry heartbeat counting task" and "Whitehead heartbeat discrimination task"). Self-rated clearness of body perception was measured by questionnaire. RESULTS: Contrary to our hypothesis, DPD patients performed similarly to healthy controls on the two different heartbeat detection tasks, and they had equal scores regarding their self-rated clearness of body perception. There was no correlation of the severity of "anomalous body experiences" and depersonalization with measures of interoceptive accuracy. Only among healthy controls CA in the Schandry task was positively correlated with self-rated clearness of body perception. Depersonalization was unrelated to severity of depression or anxiety, while depression and anxiety were highly correlated. Anxiety and depression did not modify the associations of depersonalization with interoceptive accuracy. CONCLUSIONS: Our main findings highlight a striking discrepancy of normal interoception with overwhelming experiences of disembodiment in DPD. This may reflect difficulties of DPD patients to integrate their visceral and bodily perceptions into a sense of their selves. This problem may be considered an important target for psychotherapeutic treatment approaches. [less ▲]

Striving for Less: Minimally-Supervised Pseudo-Label Generation for Monocular Road Segmentation

in IEEE Robotics and Automation Letters (2022), 7(4), 10628-10634

Identifying traversable space is one of the most important problems in autonomous robot navigation and is primarily tackled using learning-based methods. To alleviate the prohibitively high annotation ... [more ▼]

Identifying traversable space is one of the most important problems in autonomous robot navigation and is primarily tackled using learning-based methods. To alleviate the prohibitively high annotation-cost associated with labeling large and diverse datasets, research has recently shifted from traditional supervised methods to focus on unsupervised and semi-supervised approaches. This work focuses on monocular road segmentation and proposes a practical, generic, and minimally-supervised approach based on task-specific feature extraction and pseudo-labeling. Building on recent advances in monocular depth estimation models, we process approximate dense depth maps to estimate pixel-wise road-plane distance maps. These maps are then used in both unsupervised and semi-supervised road segmentation scenarios. In the unsupervised case, we propose a pseudo-labeling pipeline that reaches state-of-the-art Intersection-over-Union (IoU), while reducing complexity and computations compared to existing approaches. We also investigate a semi-supervised extension to our method and find that even minimal labeling efforts can greatly improve results. Our semi-supervised experiments using as little as 1% and 10% of ground truth data, yield models scoring 0.9063 and 0.9332 on the IoU metric respectively. These results correspond to a comparative performance of 95.9% and 98.7% of a fully-supervised model's IoU score, which motivates a pragmatic approach to labeling. [less ▲]

Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages

in Cancer Letters (2021)

Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor ... [more ▼]

Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major components of the tumor microenvironment. TAMs promote tumor progression, angiogenesis and tissue remodeling. However, the impact of the molecular crosstalk of tumor cells (TCs) with CAFs and macrophages on monocyte recruitment and their phenotypic conversion is not known in detail so far. In a 3D human organotypic CRC model, we show that CAFs and normal colonic fibroblasts are critically involved in monocyte recruitment and for the establishment of a macrophage phenotype, characterized by high CD163 expression. This is in line with the steady recruitment and differentiation of monocytes to immunosuppressive macrophages in the normal colon. Cytokine profiling revealed that CAFs produce M-CSF, and IL6, IL8, HGF and CCL2 secretion was specifically induced by CAFs in co-cultures with macrophages. Moreover, macrophage/CAF/TCs co-cultures increased TC invasion. We demonstrate that CAFs and macrophages are the major producers of CCL2 and, upon co-culture, increase their CCL2 production twofold and 40-fold, respectively. CAFs and macrophages expressing high CCL2 were also found in vivo in CRC, strongly supporting our findings. CCL2, CCR2, CSF1R and CD163 expression in macrophages was dependent on active MCSFR signaling as shown by M-CSFR inhibition. These results indicate that colon fibroblasts and not TCs are the major cellular component, recruiting and dictating the fate of infiltrated monocytes towards a specific macrophage population, characterized by high CD163 expression and CCL2 production. [less ▲]

Strong asymptotic independence on Wiener chaos

in Proceedings of the American Mathematical Society (2016), 144(2), 875-886

Strong Effect ofWeak Charging in Suspensions of Anisotropic Colloids

in Soft Matter (2014)

Suspensions of hard colloidal particles frequently serve as model systems in studies on fundamental aspects of phase transitions. But often colloidal particles that are considered as ``hard'' are in fact ... [more ▼]

Suspensions of hard colloidal particles frequently serve as model systems in studies on fundamental aspects of phase transitions. But often colloidal particles that are considered as ``hard'' are in fact weakly charged. If the colloids are spherical, weak charging has a only a weak effect on the structural properties of the suspension, which can be easily corrected for. However, this does not hold for anisotropic particles. We introduce a model for the interaction potential between charged ellipsoids of revolution (spheroids) based on the Derjaguin approximation of Debye--Hückel Theory and present a computer simulation study on aspects of the system's structural properties and phase behaviour. In line with previous experimental observations, we find that even a weak surface charge has a strong impact on the correlation functions. A likewise strong impact is seen on the phase behaviour, in particular, we find stable cubatic order in suspensions of oblate ellipsoids. [less ▲]