A5060435781- Cancer-related gene regulation
- Extracellular vesicles in disease
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cytokine Signaling Pathways and Interactions
- MicroRNA in disease regulation
- Nanopore and Nanochannel Transport Studies
- Cancer Genomics and Diagnostics
- Pancreatic and Hepatic Oncology Research
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Chromatin Remodeling and Cancer
- Protein Degradation and Inhibitors
- Cancer Cells and Metastasis
- Kruppel-like factors research
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- CRISPR and Genetic Engineering
- Mechanisms of cancer metastasis
- Medical Imaging and Pathology Studies
- Immune Cell Function and Interaction
- RNA modifications and cancer
- Rheumatoid Arthritis Research and Therapies
- Epigenetics and DNA Methylation
- Advanced biosensing and bioanalysis techniques
Resolve Therapeutics (United States)
2020-2024
University of Pennsylvania
2015-2024
Memorial Sloan Kettering Cancer Center
2009-2023
Kettering University
2010-2023
Actelion (Switzerland)
2023
San Jose State University
2019-2021
California University of Pennsylvania
2017
Philadelphia University
2017
Cancer Research Institute
2016
Novartis (Switzerland)
2012
Abstract The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms myelofibrosis improves overall survival; however, mechanism by which inhibitors achieve efficacy not been delineated. Patients MPN present increased levels circulating proinflammatory cytokines, are mitigated inhibitor therapy. We sought elucidate...
Circulating exosomes contain a wealth of proteomic and genetic information, presenting an enormous opportunity in cancer diagnostics. While microfluidic approaches have been used to successfully isolate cells from complex samples, scaling these for exosome isolation has limited by the low throughput susceptibility clogging nanofluidics. Moreover, analysis exosomal biomarkers is confounded substantial heterogeneity between patients within tumor itself. To address challenges, we developed...
JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following discovery activating mutations in majority patients with MPN. However, to date inhibitor has shown limited efficacy and apparent toxicities clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated cell line mouse models MPN polycythemia vera (PV) essential thrombocytosis (ET) by disrupting protein stability. physically associated both PU-H71 was degraded vitro vivo,...
Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most these drugs target ATP-binding pocket stabilize active conformation JAK kinases. This type I binding mode can lead to an increase in activation loop phosphorylation, despite blockade function. Here we report that stabilizing inactive state via II inhibition acts opposite manner, leading a loss phosphorylation. We used X-ray crystallography...
Abstract Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour determine efficacy chemotherapy in adjuvant (micrometastatic) setting. Here we delineate natural history metastasis an autochthonous model pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine evolution disseminated cancer cells and their associated microenvironment. With increasing...
Abstract Detection of disease-associated, cell-free nucleic acids in body fluids enables early diagnostics, genotyping and personalized therapy, but is challenged by the low concentrations clinically significant their sequence homology with abundant wild-type acids. We describe a novel approach, dubbed NAVIGATER, for increasing fractions Nucleic Acids clinical interest Via DNA-Guided Argonaute from Thermus thermophilus (TtAgo). TtAgo cleaves specifically guide-complementary DNA RNA single...
Abstract Purpose: To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC). Experimental Design: We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC disease, 89 PDAC) for following biomarkers: tumor-associated extracellular vesicle miRNA mRNA isolated on nanomagnetic platform that we developed measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration ccfDNA KRAS G12D/V/R...
Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation excessive production of proinflammatory cytokines leading to tissue damage multisystem organ failure. There an urgent need for the discovery novel targets development therapeutic strategies treat this deadly syndrome. Protein Arginine Methyltransferase 5 (PRMT5) mediates T cell-based inflammatory responses, making it potential...
Mutations in RNA splicing factor genes are common patients with myelodysplastic neoplasms (MDS) and secondary acute myeloid leukemia (AML) [1][2][3].Cells bearing these mutations have been shown to be preferentially sensitive pharmacologic modulation of compared wild-type (WT) cells [4,5].Protein arginine methyltransferase 5 (PRMT5) is an which utilizes the methyl donor S-adenosylmethionine (SAM) symmetrically methylate residues on a variety proteins [6,7].PRMT5-dependent symmetric di-methyl...
The incorporation of unsaturated acyl chains into phospholipids during de novo synthesis is primarily mediated by the 1-acyl-sn-glycerol-3-phosphate acyltransferase reaction. In Saccharomyces cerevisiae, Slc1 has been shown to mediate this reaction, but distinct activity remains after its removal from genome. To identify enzyme that mediates remaining activity, we performed synthetic genetic array analysis using a slc1Delta strain. One genes identified screen, LPT1, was found encode for an...
Abstract Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and guide treatments is crucial progress against this disease. The development of a liquid biopsy PDAC has proven challenging due sparsity variable phenotypic expression circulating biomarkers. Here we report methods developed isolating specific subsets extracellular vesicles (EV) from plasma using novel magnetic nanopore capture technique. In addition, present workflow...
Comprehensive molecular analysis of rare circulating tumor cells (CTCs) and cell clusters is often hampered by low throughput purity, as well loss. To address this, we developed a fully integrated platform for flow cytometry-based isolation CTCs from blood that can be combined with whole transcriptome or targeted RNA transcript quantification. Downstream signature linked to phenotype through index sorting. This newly utilizes in-line magnetic particle-based leukocyte depletion, acoustic...
We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key targets contributing MPN maintenance. is overexpressed primary cells, inhibition potently reduced cell proliferation ex vivo. was efficacious at reversing elevated hematocrit, leukocytosis, splenomegaly a model JAK2V617F+ polycythemia vera leukocyte platelet counts, hepatosplenomegaly, fibrosis MPLW515L myelofibrosis. Dual targeting JAK superior or inhibitor monotherapy, further...
Expression of protein arginine methyltransferase 5 (PRMT5) is highly positively correlated to DNA damage repair (DDR) and replication pathway genes in many types cancer cells, including ovarian breast cancer. In the current study, we investigated whether pharmacologic inhibition PRMT5 downregulates DDR/DNA sensitizes cells chemotherapy PARP inhibition. Potent selective inhibitors significantly downregulate expression multiple DDR cells. Mechanistically, reduces presence H4R3me2s on promoter...
The use of microtechnology for the highly selective isolation and sensitive detection circulating tumor cells has shown enormous promise. One challenge this technology is that small feature sizes - which are key to technology's performance can result in low sample throughput susceptibility clogging. Additionally, conventional molecular analysis CTCs often requires be taken off-chip preparation purification before analysis, leading loss rare cells. To address these challenges, we have...
Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA and have not been examined. Here we investigate KRAS (ctKRAS) associations overall progression-free (OS/PFS) first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), an independent cohort standard care (SOC) chemotherapy. For PRINCE, higher baseline plasma...
A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models disorders, including mice with defective cholesterol efflux pathways and two based on expression human leukemia disease alleles, we uncovered mechanism by which proliferating inflammatory myeloid cells take up oxidize glucose during feeding period, contributing to energy dissipation subsequent loss adipose...