A5020448123- Lymphoma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Immune Cell Function and Interaction
- Histone Deacetylase Inhibitors Research
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Peptidase Inhibition and Analysis
- CAR-T cell therapy research
- Genetic Mapping and Diversity in Plants and Animals
- Chronic Lymphocytic Leukemia Research
- Genetic Associations and Epidemiology
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Diet and metabolism studies
- Cancer-related gene regulation
- Adipose Tissue and Metabolism
- Peroxisome Proliferator-Activated Receptors
- Liver Disease Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Single-cell and spatial transcriptomics
- T-cell and B-cell Immunology
- Lung Cancer Treatments and Mutations
University Hospital Heidelberg
2025
Heidelberg University
2025
The University of Texas MD Anderson Cancer Center
2016-2023
The University of Texas Health Science Center at Houston
2021
University of Iowa
2013-2017
Hammersmith Hospital
2015
Medical Research Council
2015
Imperial College London
2015
University of California, Los Angeles
2015
Institute for Molecular Medicine Finland
2010
The mitochondrial caseinolytic protease P (ClpP) plays a central role in protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the selectively kills cancer cells, independently p53 status, selective degradation its respiratory chain substrates disrupts structure function, while it does not affect non-malignant cells. We identified imipridones as potent activators ClpP. Through biochemical studies crystallography,...
Large numbers of inbred laboratory rat strains have been developed for a range complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection these phenotypes, we sequenced genomes 27 strains, including 11 models hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, identified more than 13 million single-nucleotide variants, indels, structural variants across Analysis strain-specific selective sweeps gene...
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of yield different degrees disruption epigenome, with HAT being more severe associated inferior clinical outcome. Genes perturbed by mutation direct targets BCL6-HDAC3 onco-repressor complex. Accordingly, HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i)...
B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common B-NHL, such as diffuse large lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, mantle cell remain less extensively characterized. Furthermore, B-NHL thus far not compared using same methodology to identify conserved or subtype-specific patterns alterations. Here, we employed a targeted...
Abstract PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) NK cells. In a single-center, open-label, phase 2 trial, we tested combination pembrolizumab, an anti-PD-1 monoclonal antibody, rituximab, anti-CD20 antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles,...
The activated B cell (ABC-like) subtype of diffuse large lymphoma (DLBCL) is characterized by chronic activation signaling initiated immunoglobulin μ (IgM). By analyzing the DNA copy number profiles 1000 DLBCL tumors, we identified gains 18q21.2 as most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis matched gene expression profiling data, found that TCF4 (E2-2) transcription factor was target these alterations. Overexpression lines led to its occupancy on (IGHM)...
Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged decades. Both preclinical models and clinical data suggest the combination of lenalidomide ibrutinib may have synergy in DLBCL, particularly non-germinal center B-cell-like subset.
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to inhibition. Therefore, more potent and biomarkers predictive tumor sensitivity needed. The novel inhibitor DS-3032b is 10-fold than the first-generation nutlin-3a. mutations were resistance DS-3032b, allele frequencies negatively correlated with DS-3032b. However, varied greatly....
7519 Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the of cells in FL. In addition, blocking on NK has been shown to enhance ADCC effect cells. We reasoned that combination pembrolizumab (P), an anti-PD-1 antibody (ab), and rituximab (R), anti-CD20 ab induces ADCC, likely be synergistic through activation both innate adaptive systems result...
The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. Lyon hypertensive normotensive rats are models MetS sensitivity resistance, respectively. To identify genetic determinants mechanisms underlying MetS, an F2 intercross between was comprehensively studied.Multidimensional data were obtained genotypes 1536 single-nucleotide polymorphisms, 23 physiological traits, >150 billion nucleotides RNA-seq...
Abstract Sterile haemorrhagic cystitis ( SHC ) is a known risk of cyclophosphamide treatment. Diuresis using furosemide effective in canines when maximally tolerated dosed administered. This retrospective study aimed to determine whether orally administered decreased the incidence . Secondary aims were identify predisposing factors for One‐hundred and fifteen dogs treated with metronomic analysed retrospectively. Populations not randomized. 25 (21.7%) developed Furosemide administration...
Assays based on Förster resonance energy transfer (FRET) can be used to study many processes in cell biology. Although this is most often done with microscopy for fluorescence detection, we report two ways measure FRET living cells by flow cytometry. Using a conventional cytometer and the "3-cube method" intensity-based calculation of efficiency, measured enzymatic activity specific kinases expressing genetically-encoded reporter. For both AKT protein kinase A, method time-course,...
Abstract Background The metabolic syndrome (MetS), a complex disorder involving hypertension, obesity, dyslipidemia and insulin resistance, is major risk factor for heart disease, stroke, diabetes. Lyon Hypertensive (LH), Normotensive (LN) Low-pressure (LL) rats are inbred strains simultaneously derived from common outbred Sprague Dawley colony by selection high, normal, low blood pressure, respectively. Further studies found that LH MetS susceptible strain, while LN resistant LL has an...
Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the of cells in FL. In addition, blocking on NK has been shown to enhance ADCC effect cells. We reasoned that combination pembrolizumab, an anti-PD-1 antibody, and rituximab (R), anti-CD20 antibody induces ADCC, likely be synergistic through activation both innate adaptive systems result enhanced...
Hypertension is a major risk factor for cardiovascular disease, Type 2 diabetes, and end organ failure, often found concomitant with disorders characteristic of the Metabolic Syndrome (MetS), including obesity, dyslipidemia, insulin resistance. While associated features occur together, pathway(s) or mechanism(s) linking hypertension in MetS are not well understood. Previous work determined that genetic variation on rat chromosome 17 (RNO17) contributes to several MetS-defining traits...
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of yield different degrees disruption epigenome, with HAT being more severe associated inferior clinical outcome. Genes perturbed by mutation direct targets BCL6/HDAC3 onco-repressor complex. Accordingly, HDAC3 selective inhibitors fully reverse mutant aberrant epigenetic programming resulting in: a) growth...
ABSTRACT B-cell non-Hodgkin’s lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common B-NHL such as diffuse large (DLBCL) have been comprehensively interrogated at the genomic level. But rarer mantle cell (MCL) remain sparsely characterized. Furthermore, thus far not compared using same methodology to identify conserved or subtype-specific patterns alterations. Here, we employed a targeted hybrid-capture...
The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused their unique breeding history. These haplotypes have been recently mapped extensive sequencing key strains. Comparison genomic variation between two closely related with different phenotypes has proposed as an effective strategy for the discovery candidate strain-specific regions involved in phenotypic differences. We developed method to prioritise integrating and regulatory data predicted be...