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  • 1
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    TAMI-02. ALTERATIONS IN C-X3-C MOTIF CHEMOKINE RECEPTOR 1 (CX3CR1) EXPRESSION INFLUENCE MICROGLIAL AND MACROPHAGE RESPONSE IN DIFFERENT STEPS OF CEREBRAL METASTASIS FORMATION
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii213-ii213
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii213-ii213
    Abstract: Metastasis to the brain is a frequent complication in lung cancer and is still associated with a dismal prognosis. Current treatment strategies not only target tumor cells but also focus on cells of the tumor microenvironment like tumor associated microglia/macrophages (TAMs). The interactions between tumor cells and TAMs during different steps of cerebral metastasis formation of lung cancer brain metastasis are poorly characterized. Moreover, the role of CX3CR1 in this process remains unclear. We established a syngeneic cerebral metastasis mouse model by combining a chronic cranial window and two-photon laser scanning microscopy (TPLSM), which allows the tracking of single fluorescent metastasizing tumor cells and the tumor microenvironment on a cellular resolution in vivoover time for a period of weeks. Transgenic CX3CR1 proficient and deficient mice (CX3CRGFP/wt and CX3CR1GFP/GFP) were injected with red fluorescent Lewis lung carcinoma cells. During different steps of metastasis formation (extravasation, formation of micro- and macrometastasis) the density and cell body volume of TAMs, their interaction with tumor cells and possible influence on the fate of single metastatic tumor cells were investigated using serial TPLSM. We found that during metastasis formation TAM density was significantly lower in CX3CR1 deficient mice. However, activation as assessed by TAM morphology did not differ in the absence of CX3CR1. Strikingly, CX3CR1 deficiency was associated with a significant increase of tumor cells successfully extravasating the cerebral vasculature. However, subsequent steps (mirco- and macrometastasis formation) were observed less frequent in CX3CR1 deficient mice. In summary, our results highlight a complex role of CX3CR1 for TAMs during cerebral metastasis formation, indicating anti-tumorous properties of CX3CR1 at early steps and possible pro-tumorous effects at later stages (micro- and macrometastasis formation).
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa215.891
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Image_2.TIF
    Frontiers Media SA ; 2020
    In:  Frontiers in Oncology Vol. 10 ( 2020-5-27)
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    In: Frontiers in Oncology, Frontiers Media SA, Vol. 10 ( 2020-5-27)
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2020.00682
    DOI: 10.3389/fonc.2020.00682.s001
    DOI: 10.3389/fonc.2020.00682.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2649216-7
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  • 3
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    TAMI-02. DEPLETION OF INTRATUMORAL TUMOR-ASSOCIATED MACROPHAGES AND MICROGLIA (TAM/M) IMPROVES CHECKPOINT-INHIBITION THERAPY FOR BRAIN METASTASIS FROM LUNG CANCER
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi198-vi198
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi198-vi198
    Abstract: Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors. METHODS Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1GFP/wt-mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks. RESULTS Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm2 (PD1-inhibition only) versus 0.9 mm2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm2 (PD1-inhibition + small molecular CSF1R-inhibitor)) (p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody. CONCLUSION Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.786
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 4
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    BSCI-08. In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Advances Vol. 3, No. Supplement_3 ( 2021-08-09), p. iii2-iii3
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 3, No. Supplement_3 ( 2021-08-09), p. iii2-iii3
    Abstract: Brain metastases represent a common complication of lung cancer and dramatically limit prognosis in affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized, but might be of therapeutic relevance. Methods We established an orthotopic cerebral metastasis model using CX3CR1-proficient (CX3CR1GFP/wt) and -deficient (CX3CR1GFP/GFP) mice with green-fluorescent TAM/M. A cranial window was prepared, and intracarotid injection of red-fluorescent Lewis Lung Carcinoma-cells (tdtLLC) was performed two weeks later. Formation of brain metastases was followed by repetitive two-photon laser scanning microscopy. Results After intracarotid injection, intravascular tumor cells extravasated into the cerebral parenchyma and eventually formed micrometastases (≤50 cells) and mature macrometastases ( & gt;50 cells). We observed phagocytosis of extravasated tumor cells by TAM/M during early steps of metastatic growth. Notably, these anti-tumor effects of TAM/M diminished during later steps of metastasis formation and were accompanied by TAM/M accumulation and activation. CX3CR1-deficiency resulted in a lower number of extravasated tumor cells, and only a small number of TAM/M were visualized during early steps of metastasis formation (extravasation, formation of micrometastases) in such mice. In contrast, progression of extravasated tumor cells into micrometastases was more frequently found in CX3CR1-deficient mice. Overall, these mechanisms resulted in a comparable number of mature macrometastases between CX3CR1-deficient and -proficient mice. Conclusion Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic approach to prevent cerebral dissemination of lung cancer cells. Given the close interaction between TAM/M and tumour cells during metastasis formation, other therapeutic approaches targeting TAM/M function warrant evaluation. Such concepts might be evaluated in vivo using the herein established orthotopic mouse model.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdab071.007
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3009682-0
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  • 5
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    Online Resource
    P2X7R antagonists in chronic stress-based depression models: a review
    Springer Science and Business Media LLC ; 2021
    In:  European Archives of Psychiatry and Clinical Neuroscience Vol. 271, No. 7 ( 2021-10), p. 1343-1358
    Details
    In: European Archives of Psychiatry and Clinical Neuroscience, Springer Science and Business Media LLC, Vol. 271, No. 7 ( 2021-10), p. 1343-1358
    Abstract: Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.
    Type of Medium: Online Resource
    ISSN: 0940-1334 , 1433-8491
    URL: Article
    DOI: 10.1007/s00406-021-01306-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2793981-9
    detail.hit.zdb_id: 1459045-1
    SSG: 2,1
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  • 6
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    Online Resource
    Combined Fainting and Psychogenic Non-epileptic Seizures as Significant Therapy Hurdles in Blood-Injury-Injection Phobia: A Mini-Review and Case Report
    Frontiers Media SA ; 2022
    In:  Frontiers in Psychiatry Vol. 13 ( 2022-7-12)
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    In: Frontiers in Psychiatry, Frontiers Media SA, Vol. 13 ( 2022-7-12)
    Abstract: Anxiety disorders are the most frequent mental disorders. Among the different subtypes, specific phobias are the commonest. Due to the ongoing SARS-CoV-19 pandemic, blood-injury-injection phobia (BII) has gained wider attention in the context of large-scale vaccination campaigns and public health. In this BII phobia mini-review and case report, we describe the successful treatment of a severe BII phobia case with combined fainting and psychogenic non-epileptic seizures (PNES) and demonstrate the role of specialized outpatient care. Case Report The patient was a 28-year-old woman. She suffered from intense fear and recurrent fainting with regard to needles, injections, injuries, and at the sight of blood since early childhood. Medical history revealed infrequent events suggestive of PNES following panic attacks after sustained exposure to phobic stimuli. Family history was positive for circulation problems and BII fears. Psychopathological evaluation confirmed BII phobia symptoms and diagnosis was made according to the DSM-5. The Multidimensional Blood/Injury Phobia Inventory short version (MBPI-K) revealed severe manifestation of the disease. Neurological examination was ordinary. Repeated electroencephalography detected no epileptic pattern. Cranial magnetic resonance imaging showed normal morphology. Treatment was carried out by a seasoned, multidisciplinary team. Cognitive behavior therapy and exposure were performed. Modification of standard treatment protocol was necessary due to hurdles posed by recurrent fainting and a severe panic-triggered dissociative PNES during in vivo exposure. Modification was implemented by limiting in vivo exposure intensity to moderate anxiety levels. In addition to applied muscle tension and ventilation techniques, increased psychoeducation, cognitive restructuring, and distress tolerance skills (e.g., ice pack, verbal self-instructions) were used to strengthen the patient's situational control during in vivo exposure. A total of 15 sessions were performed. Therapy success was proven by 83% reduction in MBPI-K rating, SARS-CoV-19 vaccination, and a blood draw without psychological assistance, fainting, or seizure. Conclusion Taken together, this case demonstrates the potential of and need for specialized outpatient care and individualized treatment for severe BII phobia patients in order to provide them the perspective to have necessary medical procedures done and get vaccinated.
    Type of Medium: Online Resource
    ISSN: 1664-0640
    URL: Article
    DOI: 10.3389/fpsyt.2022.915058
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2564218-2
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  • 7
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    Online Resource
    DataSheet1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Pharmacology Vol. 14 ( 2023-4-10)
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    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 14 ( 2023-4-10)
    Abstract: Introduction: In recent years, purinergic signaling via the P2X7 receptor (P2X7R) on microglia has repeatedly been implicated in depression genesis. However, it remains unclear which role the human P2X7R (hP2X7R) plays in regulating both microglia morphology and cytokine secretion upon different environmental and immune stimuli, respectively. Methods: For this purpose, we used primary microglial cultures derived from a humanized microglia-specific conditional P2X7R knockout mouse line to emulate different gene-environment interactions between microglial hP2X7R and molecular proxies of psychosocial and pathogen-derived immune stimuli. Microglial cultures were subjected to treatments with the agonists 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP) and lipopolysaccharides (LPS) combined with specific P2X7R antagonists (JNJ-47965567, A-804598). Results: Morphotyping revealed overall high baseline activation due to the in vitro conditions. Both BzATP and LPS + BzATP treatment increased round/ameboid microglia and decreased polarized and ramified morphotypes. This effect was stronger in hP2X7R-proficient (CTRL) compared to knockout (KO) microglia. Aptly, we found antagonism with JNJ-4796556 and A-804598 to reduce round/ameboid microglia and increase complex morphologies only in CTRL but not KO microglia. Single cell shape descriptor analysis confirmed the morphotyping results. Compared to KO microglia, hP2X7R-targeted stimulation in CTRLs led to a more pronounced increase in microglial roundness and circularity along with an overall higher decrease in aspect ratio and shape complexity. JNJ-4796556 and A-804598, on the other hand, led to opposite dynamics. In KO microglia, similar trends were observed, yet the magnitude of responses was much smaller. Parallel assessment of 10 cytokines demonstrated the proinflammatory properties of hP2X7R. Following LPS + BzATP stimulation, IL-1β, IL-6, and TNFα levels were found to be higher and IL-4 levels lower in CTRL than in KO cultures. Vice versa, hP2X7R antagonists reduced proinflammatory cytokine levels and increased IL-4 secretion. Discussion: Taken together, our results help disentangle the complex function of microglial hP2X7R downstream of various immune stimuli. In addition, this is the first study in a humanized, microglia-specific in vitro model identifying a so far unknown potential link between microglial hP2X7R function and IL-27 levels.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2023.1148190
    DOI: 10.3389/fphar.2023.1148190.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 8
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    Online Resource
    Multiomics and blood-based biomarkers of electroconvulsive therapy in severe and treatment-resistant depression: study protocol of the DetECT study
    Springer Science and Business Media LLC ; 2023
    In:  European Archives of Psychiatry and Clinical Neuroscience
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    In: European Archives of Psychiatry and Clinical Neuroscience, Springer Science and Business Media LLC
    Abstract: Electroconvulsive therapy (ECT) is commonly used to treat treatment-resistant depression (TRD). However, our knowledge of the ECT-induced molecular mechanisms causing clinical improvement is limited. To address this issue, we developed the single-center, prospective observational DetECT study (“Multimodal Biomarkers of ECT in TRD”; registered 18/07/2022, www.clinicalTrials.gov , NCT05463562). Its objective is to identify molecular, psychological, socioeconomic, and clinical biomarkers of ECT response in TRD. We aim to recruit n  = 134 patients in 3 years. Over the course of 12 biweekly ECT sessions (± 7 weeks), participant blood is collected before and 1 h after the first and seventh ECT and within 1 week after the twelfth session. In pilot subjects (first n  = 10), additional blood draws are performed 3 and 6 h after the first ECT session to determine the optimal post-ECT blood draw interval. In blood samples, multiomic analyses are performed focusing on genotyping, epigenetics, RNA sequencing, neuron-derived exosomes, purines, and immunometabolics. To determine clinical response and side effects, participants are asked weekly to complete four standardized self-rating questionnaires on depressive and somatic symptoms. Additionally, clinician ratings are obtained three times (weeks 1, 4, and 7) within structured clinical interviews. Medical and sociodemographic data are extracted from patient records. The multimodal data collected are used to perform the conventional statistics as well as mixed linear modeling to identify clusters that link biobehavioural measures to ECT response. The DetECT study can provide important insight into the complex mechanisms of ECT in TRD and a step toward biologically informed and data-driven-based ECT biomarkers.
    Type of Medium: Online Resource
    ISSN: 0940-1334 , 1433-8491
    URL: Article
    DOI: 10.1007/s00406-023-01647-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2793981-9
    detail.hit.zdb_id: 1459045-1
    SSG: 2,1
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  • 9
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    Online Resource
    Free-viewing gaze patterns reveal a mood-congruency bias in MDD during an affective fMRI/eye-tracking task
    Springer Science and Business Media LLC ; 2023
    In:  European Archives of Psychiatry and Clinical Neuroscience
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    In: European Archives of Psychiatry and Clinical Neuroscience, Springer Science and Business Media LLC
    Abstract: Major depressive disorder (MDD) has been related to abnormal amygdala activity during emotional face processing. However, a recent large-scale study ( n  = 28,638) found no such correlation, which is probably due to the low precision of fMRI measurements. To address this issue, we used simultaneous fMRI and eye-tracking measurements during a commonly employed emotional face recognition task. Eye-tracking provide high-precision data, which can be used to enrich and potentially stabilize fMRI readouts. With the behavioral response, we additionally divided the active task period into a task-related and a free-viewing phase to explore the gaze patterns of MDD patients and healthy controls (HC) and compare their respective neural correlates. Our analysis showed that a mood-congruency attentional bias could be detected in MDD compared to healthy controls during the free-viewing phase but without parallel amygdala disruption. Moreover, the neural correlates of gaze patterns reflected more prefrontal fMRI activity in the free-viewing than the task-related phase. Taken together, spontaneous emotional processing in free viewing might lead to a more pronounced mood-congruency bias in MDD, which indicates that combined fMRI with eye-tracking measurement could be beneficial for our understanding of the underlying psychopathology of MDD in different emotional processing phases. Trial Registration : The BeCOME study is registered on ClinicalTrials (gov: NCT03984084) by the Max Planck Institute of Psychiatry in Munich, Germany.
    Type of Medium: Online Resource
    ISSN: 0940-1334 , 1433-8491
    URL: Article
    DOI: 10.1007/s00406-023-01608-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2793981-9
    detail.hit.zdb_id: 1459045-1
    SSG: 2,1
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  • 10
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    Online Resource
    The P2X7 receptor in mood disorders: Emerging target in immunopsychiatry, from bench to bedside
    Elsevier BV ; 2023
    In:  Neuropharmacology Vol. 224 ( 2023-02), p. 109366-
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    In: Neuropharmacology, Elsevier BV, Vol. 224 ( 2023-02), p. 109366-
    Type of Medium: Online Resource
    ISSN: 0028-3908
    URL: Article
    DOI: 10.1016/j.neuropharm.2022.109366
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1500655-4
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