A5062809387- Acute Myeloid Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Chronic Myeloid Leukemia Treatments
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- Lymphoma Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- Immunodeficiency and Autoimmune Disorders
- Lung Cancer Treatments and Mutations
- Acute Lymphoblastic Leukemia research
- Multiple Myeloma Research and Treatments
- RNA modifications and cancer
- Blood groups and transfusion
- Complement system in diseases
- Evolution and Genetic Dynamics
- Bioinformatics and Genomic Networks
- Gene expression and cancer classification
- Radiomics and Machine Learning in Medical Imaging
- Computational Drug Discovery Methods
- Mathematical Biology Tumor Growth
- Cancer-related gene regulation
- Histone Deacetylase Inhibitors Research
- Sarcoma Diagnosis and Treatment
- Single-cell and spatial transcriptomics
Cleveland Clinic
2019-2025
Translational Research in Oncology
2024
University of Tennessee Health Science Center
2024
Cancer Institute (WIA)
2024
University of Michigan–Ann Arbor
2024
Johns Hopkins University
2024
Case Western Reserve University
2016-2023
Cleveland Clinic Lerner College of Medicine
2022-2023
Sabancı Üniversitesi
2014
ABSTRACT Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on molecular mechanisms resistance, understanding how evolves remains limited. Using an experimental model ALK positive NSCLC, we explored evolution different clinical inhibitors. We found that can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity Instead commonly assumed...
PURPOSE Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, early therapeutic interventions. PATIENTS AND METHODS We studied a multicenter, retrospective cohort of 1,008 (median follow-up 8.6 years) AA PNH to assess clinical molecular determinants clonal evolution. RESULTS Although none transplanted...
In this study, we experimentally measure the frequency-dependent interactions between a gefitinib-resistant non–small cell lung cancer population and its sensitive ancestor via evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion growth rate measurements are required. Using data, then gefitinib treatment results in ancestor, while absence likely, but not guaranteed, resistant strain. Then, using simulations, demonstrate...
The evolution of resistance remains one the primary challenges for modern medicine, from infectious diseases to cancers. Many these resistance-conferring mutations often carry a substantial fitness cost in absence treatment. As result, we would expect mutants undergo purifying selection and be rapidly driven extinction. Nevertheless, preexisting is frequently observed drug-resistant malaria targeted cancer therapies non-small-cell lung (NSCLC) melanoma. Solutions this apparent paradox have...
CBL proteins are a family of RING finger E3 ubiquitin ligases that regulate proliferative signals via ubiquitination and degradation tyrosine-phosphorylated signaling proteins, such as KIT, CSF-1, FLT3 PDGF [1].We previously described c-CBL mutations in myeloid neoplasia (MN), chiefly myelodysplastic/ myeloproliferative (MDS/MPN) syndromes chronic myelomonocytic leukemia [2, 3] juvenile [4].c-CBL mainly heterozygous, but some instances homozygous configuration can be found due to somatic...
Abstract Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk tMN is high in recipients autologous hematopoietic stem cell transplantation (aHSCT). Acquisition genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly context preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied cohort 1507 patients undergoing aHSCT 263 who developed without to determine...
Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological clinical features have dominated classical criteria for diagnosis classification, incorporation molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning identify objective clusters, irrespective anamnestic clinico-morphological features, despite complexity alterations in neoplasia. Our approach reflects disease evolution, informed...
Abstract Background TP53 mutations ( MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic subclones cases dismal prognosis. Methods We have collected clinical and molecular data 7400 patients myeloid neoplasms applied a novel model by identifying an optimal VAF cutoff using statistically robust strategy...
Abstract PHF6 mutations ( MT ) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of MN. Here we show three main findings our comprehensive genomic proteomic study. Firstly, a different pattern genes correlating with male female cases. When analyzing cases separately, only cases, RUNX1 U2AF1 co-mutated . In contrast, reveal co-occurrence ASXL1 X-chromosome deletions Next, proteomics analysis reveals direct interaction...
Advances in the treatment of Ewing's sarcoma (EWS) are desperately needed, particularly case metastatic disease. A deeper understanding collateral sensitivity, where evolution therapeutic resistance to one drug aligns with sensitivity another drug, may improve our ability effectively target this For first time a solid tumor, we produced temporal map that demonstrates and EWS. We found was predictable some drugs but had significant variation response other drugs. Using EWS, can see path...
Abstract Non-small cell lung cancer (NSCLC) brain metastasis lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC metastases with genomic annotation useful for translational mechanistic studies. Both heterotopic orthotopic intracranial xenografts were established RNA DNA sequencing was performed patient matching tumors. Morphologically, strong retention cytoarchitectural features observed between original...
The increasing knowledge of molecular genetics acute myeloid leukemia (AML) necessitated the update previous diagnostic and prognostic schemes, which resulted in development World Health Organization (WHO), International Consensus Classification (ICC), new European LeukemiaNet (ELN) recommendations 2022. We aimed to provide a real-world application models, unravel differences similarities, test their implementation clinical AML diagnosis. A total 1001 patients diagnosed with were...
Physicochemical properties of compounds have been instrumental in selecting lead with increased drug-likeness. However, the relationship between physicochemical constituent drugs and tendency to exhibit drug interaction has not systematically studied. We assembled descriptors for a set antifungal ("drugs") previously examined interaction. Analyzing molecular weight, lipophilicity, H-bond donor, acceptor values their propensity show pairwise synergy, we found that combinations two lipophilic...
Abstract Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology -7/del7q genes responsible for leukemogenic properties have not been completely elucidated. Chromosomal may create clonal vulnerabilities due haploinsufficient (HI) contained deleted regions. Therefore, HI potential targets synthetic lethal strategies. Through comprehensive multimodal...
Abstract Background Splenectomy is commonly used to treat refractory immune–mediated cytopenia, but there are no established factors that associated with response the procedure. Objectives A cohort study was conducted evaluate hematologic and surgical outcomes of splenectomy in adult patients immune cytopenias identify preoperative response. Methods Data from Cleveland Clinic Foundation for 1824 aged over 18 who underwent 2002 2020 were analyzed. Results The found most common indications...
ABSTRACT Therapeutic strategies for tumor control have traditionally assumed that maximizing reduction in volume correlates with clinical efficacy. Unfortunately, this rapid decrease burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment attempt to delay resistance via judicious treatments maintain a significant treatable subpopulation. While these shown promise recent trials, they often rely on biological conjecture and intuition derive...