RepoMed (Medizinische Hochschule Hannover)
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A lentiviral vaccine against human cytomegalovirus: testing in HLA-matched humanized mouse models
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Entwicklung und Vergleich von Tests zum Nachweis von Ferritin-Autoantikörpern bei der Riesenzellarteriitis
Get PDFCharacterization and Classification of Postoperative Cysts After Strabismus Surgery: Clinical, Histological, and Anterior Segment OCT Analysis in a Large German Cohort
Get PDFIntroduction In this work, we provide a detailed characterization of a rare complication-subconjunctival cyst formation after strabismus surgery-in a large German cohort. Methods We conducted a retrospective analysis of 822 consecutive patients who underwent strabismus surgery between 2015 and 2022. The patients received comprehensive eye and orthoptic examinations preoperatively, at 1 day, and at 3 months postoperatively. Cysts were analyzed with slit-lamp examination, anterior segment optical coherence tomography (AS-OCT), and histopathological subsumption. Results Nineteen cases of postoperative cysts were observed (2.3%), 12 of which underwent surgical revision. Clinical evaluation including slit-lamp and AS-OCT as well as histological analysis resulted in a classification of three types of cysts: type 1, which is a single hyporeflective cyst, type 2, which is a multilobular hyporeflective cyst, and type 3, a dense hyperreflective granulomatous-like cyst. Eta (η) correlation ratio analysis could show a correlation between time of clinical appearance and type of cyst (Eta = 0.63). Most cysts developed within 20 days after surgery. Not only did cysts more frequently affect the medial rectus muscle, which in most cases underwent a shortening procedure (11/19 tucks, 4/19 resections) for intermittent exotropia (X(T)), but the cyst also formed earlier than in the lateral rectus muscle (Eta = 0.45). No correlation could be shown between the type of surgical procedure and time of cyst occurrence (Eta = 0.1). Patient age and cyst type correlated strongly (Eta = 0.47). The underlying type of strabismus did not correlate with the type of cyst observed. Conclusions Our cases showed a strong positive correlation to the type of strabismus (X(T)), age (young patients), and the procedure (tuck/resection). We introduce a grading system for postoperative cysts after strabismus surgery, complementing histopathology and slit-lamp aspects with AS-OCT information
Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia
Get PDFTreatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) with or without venetoclax in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLA-IDA treated patients (78% vs. 47%; P=0.001), while MRD was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eightyone percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation (alloHCT) or donor lymphocyte infusion (DLI) after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA and FLA-IDA treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing MRD negative remission in a high proportion of R/R AML patients
CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate specific elimination of malignant cells from leukemia and solid tumors.
Get PDFIntroduction Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "on-target/off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity. Results Specific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific. Discussion Genetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity
Alterations in voxel based morphometry and resting state functional connectivity in men with compulsive sexual behavior disorder in the Sex@Brain study.
Get PDFCompulsive Sexual Behavior Disorder (CSBD) is a new category in ICD-11. Research examining underlying brain mechanisms is sparse. Research into neurobiological differences can be helpful in advancing the possibilities of new diagnostic approaches and therapeutic methods. The present study aimed to examine brain matter volume and resting state functional connectivity (rs-FC) in CSBD. Methods Structural and rs-FC magnetic resonance imaging and data from questionnaires were collected in 30 men with CSBD and 32 age- and education-matched controls. Whole brain voxel based morphometry (VBM) and seed based rs-FC in a-priori defined seeds were analyzed. Results Structural analyses showed that men with CSBD had significantly increased gray matter volume in the right cerebellum, middle occipital and superior frontal lobe. No differences in rs-FC could be detected when using these brain structures as seed regions in rs-FC. In contrast, literature based rs-FC analysis revealed decreased rs-FC between the right orbital middle frontal cortex (mOFC) and the right gyrus rectus, as well as between left pallidum and right post/precentral gyrus in men with CSBD. In the left amygdala we observed increased rs-FC with precuneus in this group. In addition, most of these measures correlated with symptom severity. Conclusion Structural findings may underscore the idea that the cerebellum plays an important role in sexual arousal and CSBD. Perhaps, a simultaneous activation of the left amygdala and the precuneus reflects a constant sexual occupation of men with CSBD. Furthermore, lower connectivity between mOFC and gyrus rectus in CSBD may support the assumption that sexual stimuli are evaluated more positively because inhibition is decreased
Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19
No full textPurpose: Post-acute sequelae of COVID-19 (PASC) affect approximately 10% of convalescent patients. The spectrum of symptoms is broad and heterogenous with fatigue being the most often reported sequela. Easily accessible blood biomarkers to determine PASC severity are lacking. Thus, our study aimed to correlate immune phenotypes with PASC across the severity spectrum of COVID-19. Methods: 176 originally immunonaïve, convalescent COVID-19 patients from a prospective cohort during the first pandemic phase were stratified by initial disease severity and underwent clinical, psychosocial, and immune phenotyping around 10 weeks after first COVID-19 symptoms. COVID-19 associated fatigue dynamics were assessed and related to clinical and immune phenotypes. Results: Fatigue and severe fatigue were commonly reported irrespective of initial COVID-19 severity or organ-specific PASC. A clinically relevant increase in fatigue severity after COVID-19 was detected in all groups. Neutralizing antibody titers were higher in patients with severe acute disease, but no association was found between antibody titers and PASC. While absolute peripheral blood immune cell counts in originally immunonaïve PASC patients did not differ from unexposed controls, peripheral CD3+CD4+ T cell counts were independently correlated with fatigue severity across all strata in multivariable analysis. Conclusions: Patients were at similar risk of self-reported PASC irrespective of initial disease severity. The independent correlation between fatigue severity and blood T cell phenotypes indicates a possible role of CD4+ T cells in the pathogenesis of post-COVID-19 fatigue, which might serve as a blood biomarker. Immunophenotyping: Quantification of blood immune cell phenotypes of peripheral venous EDTA-whole blood was performed using the BD Trucount™ System (Multitest™ 6-Color TBNK: CD3-FITC, CD16-PE, CD56-PE, CD45-PerCP-Cy5.5, CD4-Pe-Cy7, CD19-APC, CD8-APC-Cy7 (Trucount) with tubes; BD Biosciences cat #337166) according to manufacturer’s instructions. In brief, 20 μL of BD Multitest 6-Color TBNK antibody solution was mixed with 50 μL of whole blood in Trucount tubes. The solution was vortexed and incubated for 15 min at RT in the dark. Next, 450 μL of BD FACS Lysing Solution (1x), which was previously diluted 1:10 from the 10x stock solution in distilled aqua, was added to the sample, vortexed, and incubated again for 15 min at RT in the dark to allow lysis of the erythrocytes. Samples were immediately measured on the LSR-II flow cytometer by recording 200,000 cell events and analyzed using FACSDiva software (version 8.0.1)
CSF-1 and Notch signaling cooperate in macrophage instruction and tissue repair during peripheral limb ischemia
Get PDFIschemia causes an inflammatory response featuring monocyte-derived macrophages (MF) involved in angiogenesis and tissue repair. Angiogenesis and ischemic macrophage differentiation are regulated by Notch signaling via Notch ligand Delta-like 1 (Dll1). Colony stimulating factor 1 (CSF-1) is an essential MF lineage factor, but its role in ischemic macrophage development and the interaction with Notch signaling is so far unclear. Using a mouse model of hind limb ischemia with CSF-1 inhibitor studies and Dll1 heterozygous mice we show that CSF-1 is induced in the ischemic niche by a subpopulation of stromal cells expressing podoplanin, which was paralleled by the development of ischemic macrophages. Inhibition of CSF-1 signaling with small molecules or blocking antibodies impaired macrophage differentiation but prolonged the inflammatory response, resulting in impaired perfusion recovery and tissue regeneration. Yet, despite high levels of CSF-1, macrophage maturation and perfusion recovery were impaired in mice with Dll1 haploinsufficiency, while inflammation was exaggerated. In vitro, CSF-1 was not sufficient to induce full MF differentiation from donor monocytes in the absence of recombinant DLL1, while the presence of DLL1 in a dose-dependent manner stimulated MF differentiation in combination with CSF-1. Thus, CSF-1 is an ischemic niche factor that cooperates with Notch signaling in a non-redundant fashion to instruct macrophage cell fate and maturation, which is required for ischemic perfusion recovery and tissue repair
