RepoMed (Medizinische Hochschule Hannover)
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Clec12a is required for the pathogenesis of NUP98::NSD1 AML.
Full text linkNUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NSD1-driven AML is associated with adverse outcomes and poor response to conventional treatments. However, limited studies have been done to identify new potential targets to develop better treatment approaches. The C-type lectin domain family 12, member A (CLEC12A) is a cell surface receptor that is differentially expressed in leukemic stem cells (LSCs) compared to healthy hematopoietic stem cells (HSCs). We demonstrated a strong overexpression of CLEC12A in both NUP98::NSD1 patients and murine AML cells transformed with NUP98::NSD1. To understand the role of Clec12a in NUP98::NSD1 AML, we depleted Clec12a expression in NUP98::NSD1+NRASG12D immortalized cells using the CRISPR/Cas9 approach. NUP98::NSD1+NRASG12D/Clec12a knockout cells showed higher levels of apoptosis and lower colony numbers in vitro compared to NUP98::NSD1+NRASG12D/Clec12a wildtype cells. Importantly, the deletion of Clec12a significantly reduced leukemic engraftment and prolonged survival of the NUP98::NSD1+NRASG12D murine model. Our data suggest to further explore CLEC12A as a potential target for the treatment of NUP98::NSD1 AML
Analyse der Überlebenszeit und Einflussgrößen bei dialysepflichtigen Patienten nach koronarer Bypasstransplantation
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Associations between neuropsychological profile and regional brain FDG uptake in progressive supranuclear palsy
No full textBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative movement disorder clinically characterized by falls, axial rigidity, vertical supranuclear gaze palsy, bradykinesia, and cognitive decline. There is a relative lack of studies on the functional neuroimaging correlates of cognitive impairment in PSP.ObjectiveThis study investigated the relationship between regional cerebral glucose metabolism as assessed by static 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with global scaling and the profile of cognitive performance according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery in a sample of PSP patients representative of clinical practice.Methods22 PSP patients from three tertiary movement disorder centers with CERAD testing and FDG-PET in close proximity were included retrospectively. Neuropsychological test performance was assessed for correlation with FDG uptake on a voxel-by-voxel basis with cluster-level correction for multiple testing, separately for each subtest.ResultsIn comparison to matched healthy controls, PSP patients showed reduced FDG uptake in the left inferior frontal gyrus and right angular gyrus. Reduced overall cognitive performance according to Montreal Cognitive Assessment was associated with reduced FDG uptake in the right frontal eye field. Word list learning correlated with FDG uptake in the left frontal eye field, while language fluency was linked to FDG uptake in the bilateral premotor and supplementary motor areas.ConclusionsReduction of FDG uptake in PSP primarily affects frontal brain regions and is linked to the performance in specific cognitive domains. These findings may have implications for the interpretation of FDG-PET to support the etiological diagnosis of PSP
In vivo RNAi screen and validation reveals Ngp, Hba-a1, and S100a8 as novel inhibitory targets on T lymphocytes in liver cancer
Full text linkBackground Hepatocellular carcinoma (HCC) represents the third deadliest cancer worldwide with limited treatment options. Immune checkpoint inhibitors (ICIs) have revolutionized HCC therapy, but immune suppression within the tumor microenvironment remains a major challenge. Therefore, in this study, we aimed to define novel ICI molecules arising on T cells during aggressive HCC development. Methods Using autochthonous HCC models, we performed microarray analyses followed by in vivo RNA interference screen and identified several new ICI molecules on CD4 and CD8 T lymphocytes in HCC-bearing mice. Short hairpin RNA (shRNA)-mediated knockdown of the ICI molecules was performed to validate their functional role in T cell activity and survival of HCC-bearing mice. Finally, we searched for the presence of the defined ICI molecules in HCC patients. Results We identified neutrophilic granule protein (Ngp), hemoglobin subunit alpha-1 (Hba-a1), and S100 calcium-binding protein a8 (S100a8) as novel inhibitory molecules of T cells in HCC. The specific shRNA-based knockdown of these inhibitory targets was safe, led to a downregulation of classical ICI molecules (PD-1, PD-L1, 4-1BBL, CD160), and kept liver parameters under control in murine HCC. Besides, we detected upregulation of S100A8 and S100A9 in blood and liver tissues in HCC patients, supporting their clinical relevance. Conclusion The obtained results pave the way for the use of the newly defined ICI molecules Ngp, Hba-a1, and S100a8 as novel immunotherapeutic targets in further preclinical and clinical studies in HCC patients
Freispruch verweigert: Eine Zeitreise zum klinisch-psychiatrischen Blick auf die Angehörigen psychisch erkrankter Menschen
Full text linkWie schaute die Anstalts- bzw. Krankenhauspsychiatrie im 19. und 20. Jahrhundert auf die Angehörigen ihrer Patientinnen und Patienten? Zur Beantwortung dieser Frage geht es auf Spurensuche in einigen psychiatrischen Lehrbüchern dieser Zeit, ergänzt um Werke der bundesdeutschen Psychiatriegeschichtsschreibung. Die Fundstellen zeichnen ein Bild, nach dem Angehörige bei der Entstehung und bei der Heilung einer psychischen Krankheit lange Zeit vor allem ein Risiko darstellten. Soziologisch-sozialpsychiatrisch inspirierte Reformen führten ab den 1970er-Jahren zur Korrektur des klinischen Blicks, die jedoch weder durchgreifend noch nachhaltig war
Influence of the BMI (<30 kg/m2 vs. ≥30 kg/m2) on the Surgical Outcome of Osteochondral Lesions of the Talus: Prospective Data from the German Cartilage Registry (KnorpelRegister DGOU)
Full text linkObjectiveAim of this study was to evaluate the 24 months follow-up data of the German Cartilage Registry (KnorpelRegister DGOU, GCR) regarding the influence of body mass index (BMI) on clinical outcomes after surgical osteochondral lesions of the talus (OCT) treatment.DesignA total of 303 patients met the inclusion criteria. Pre- and post-operative Foot and Ankle Outcome Score (FAOS) total scores, subscores, and ΔFAOS were analyzed for most frequent surgical techniques (bone marrow stimulation [BMS], matrix-augmented BMS, matrix-augmented BMS with additional bone grafting) in normal weight group (NW, BMI <30 kg/m2, n = 228) and obese weight group (OW, BMI ≥30 kg/m2, n = 75).ResultsBMI was significantly different in NW and OW (24.6 ± 2.97 [16.9-29.9] kg/m2 vs. 33.7 ± 4.0 [30.0-51.3] kg/m2, P < 0.001). Significant improvement from pre- to post-operative FAOS score and subscales was reached in both groups (NW: 64.2 ± 17.5 vs. 77.7 ± 17.8; OW: 52.3 ± 15.5 vs. 73.5 ± 20.2; P < 0.001) with higher pre- and post-operative scores in NW. No significant difference in ΔFAOS score was detected. Treatment technique did not influence the clinical outcome. OW showed an extended use of bone grafting due to greater defect depth. Age was significantly higher in OW compared to NW (35.7 ± 13.2 [18.0-69.0] years vs. 40.7 ± 13.1 [18.0-77.0] years, P = 0.005).ConclusionsPatients benefit from surgical cartilage therapy regardless of their BMI. OW showed significantly lower pre- and post-operative FAOS scores. In OW, additional bone grafting was required more frequently due to significantly deeper defects
