Showing papers by "Lorenz Trümper published in 2022"

Superresolution microscopy localizes endogenous Dvl2 to Wnt signaling-responsive biomolecular condensates

Abstract: Significance Wnt signaling governs cell fate and tissue polarity across species. The Dishevelled proteins are central to Wnt signaling cascades. Wnt-mediated multiprotein complexes such as the “signalosome” and the “destruction complex” have been proposed to represent biomolecular condensates. These nonmembranous, specialized compartments have been suggested to form through liquid–liquid phase separation and ensure correctly proceeding physiological reactions. Although biomolecular condensates have increasingly been studied, key questions remain regarding, for example, their architecture and physiological regulation. Here, superresolution microscopy after endogenous labeling of Dishevelled-2 gives insights into protein functions and Wnt signaling at physiological levels. It reveals the distinct molecular architecture of endogenous Wnt condensates at single-molecule resolution and illustrates close interactions at the centrosome.

Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis

Abstract: Simple Summary This study investigated SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated (n = 49) and non-vaccinated (n = 84) cancer patients. A mild course of COVID-19 was documented more frequently in vaccinated cancer patients (49% vs. 29%), while the incidence of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%). In comparison to non-vaccinated patients, admissions to intermediate and intensive care units and the need for non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients. The median length of hospital stay was 11 days for non-vaccinated and 5 days for vaccinated patients. COVID-19 mortality was reduced by 83% in vaccinated patients. Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively. Our results provide evidence for the significant benefits of COVID-19 vaccines for cancer patients. Abstract COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.

The EHA Research Roadmap: Malignant Lymphoid Diseases

Abstract: Normal Hematopoiesis; Malignant Lymphoid Malignant Myeloid Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Transfusion in Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell- based Therapies; and analyze including immunother- apies will be increasingly implemented. These should improve the prognosis of high-risk patients but also significantly reduce treatment-related morbidity for patients of all ages, and especially for long-term survivors of childhood ALL. In addition, individualized drug dosing may prevent underdosing and hence may reduce the risk of relapse, while preventing over-dosing and associated toxic side effects. Other venues of development include ambitions to develop response adapted treatment strategies, based on MRD 66 ; incorporation of the new knowledge emerging from biology stud- ies into risk-based strategies, specifically targeting biological high-risk populations such as TP53-mutated MCL; strategies to improve outcome for BTKi-refractory disease; as well as real-world evidence studies, based on the high quality, nation-wide registers present in many European countries. supplemented with autologous serum against MALT lym- phoma of the conjunctiva. 115 Finally, first data of CAR-T-cell therapy for MZL were presented recently; assessment on a larger number of patients and longer follow-up is expected.

Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

Abstract: Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-of-function. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.

Developments in Other Haematological Malignancies: Other Lymphoid Malignancies

Abstract: Abstract Peripheral T cell lymphomas comprise a heterogeneous group of rare diseases, representing 10–15% of all non-Hodgkin lymphomas (NHLs). Upfront treatment for peripheral T cell lymphoma (pTNHL) includes CHOP-like (cyclophosphamide, adriamycin, vincristine, prednisone) multiagent chemotherapy with or without etoposide, followed by stem cell transplantation as consolidation in responsive fit patients. This approach induces durable long-term remission in approximately 40% of cases; early refractoriness during induction occurs in approximately 25% of patients, with the remaining patients typically relapsing within 24 months. With the exception of patients with anaplastic large cell lymphomas who are eligible to receive brentuximab vedotin, there is no standard of care in the relapse setting. In patients not eligible to receive high-dose chemotherapy followed by allogeneic stem cell transplantation, the prognosis is dismal.

B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens

Abstract: Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens.