Publications by authors named "P Winnard"

67 Publications

Targeting host DEAD-box RNA helicase DDX3X for treating viral infections.

Antiviral Res 2021 01 7;185:104994. Epub 2020 Dec 7.

Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Sciences, USA; Department of Oncology, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

DDX3X or DDX3, a member of the DEAD (asp, glu, ala, asp) box RNA helicase family of proteins, is a multifunctional protein, which is usurped by several viruses and is vital to their production. To date, 18 species of virus from 12 genera have been demonstrated to be dependent on DDX3 for virulence. In addition, DDX3 has been shown to function within 7 of 10 subcellular regions that are involved in the metabolism of viruses. As such, due to its direct interaction with viral components across most or all stages of viral life cycles, DDX3 can be considered an excellent host target for pan-antiviral drug therapy and has been reported to be a possible broad-spectrum antiviral target. Along these lines, it has been demonstrated that treatment of virally infected cells with small molecule inhibitors of DDX3 blunts virion productions. On the other hand, DDX3 bolsters an innate immune response and viruses have evolved capacities to sequester or block DDX3, which dampens an innate immune response. Thus, enhancing DDX3 production or co-targeting direct viral products that interfere with DDX3's modulation of innate immunity would also diminish virion production. Here we review the evidence that supports the hypothesis that modulating DDX3's agonistic and antagonistic functions during viral infections could have an important impact on safely and efficiently subduing a broad-spectrum of viral infections.
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http://dx.doi.org/10.1016/j.antiviral.2020.104994DOI Listing
January 2021

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity.

PLoS One 2020 16;15(11):e0242384. Epub 2020 Nov 16.

Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: Monitoring and treating metastatic progression remains a formidable task due, in part, to an inability to monitor specific differential molecular adaptations that allow the cancer to thrive within different tissue types. Hence, to develop optimal treatment strategies for metastatic disease, an important consideration is the divergence of the metastatic cancer growing in visceral organs from the primary tumor. We had previously reported the establishment of isogenic human metastatic breast cancer cell lines that are representative of the common metastatic sites observed in breast cancer patients.

Methods: Here we have used proteomic, RNAseq, and metabolomic analyses of these isogenic cell lines to systematically identify differences and commonalities in pathway networks and examine the effect on the sensitivity to breast cancer therapeutic agents.

Results: Proteomic analyses indicated that dissemination of cells from the primary tumor sites to visceral organs resulted in cell lines that adapted to growth at each new site by, in part, acquiring protein pathways characteristic of the organ of growth. RNAseq and metabolomics analyses further confirmed the divergences, which resulted in differential efficacies to commonly used FDA approved chemotherapeutic drugs. This model system has provided data that indicates that organ-specific growth of malignant lesions is a selective adaptation and growth process.

Conclusions: The insights provided by these analyses indicate that the rationale of targeted treatment of metastatic disease may benefit from a consideration that the biology of metastases has diverged from the primary tumor biology and using primary tumor traits as the basis for treatment may not be ideal to design treatment strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242384PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668614PMC
January 2021

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

J Cachexia Sarcopenia Muscle 2020 12 2;11(6):1487-1500. Epub 2020 Oct 2.

Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes.

Methods: We quantified metabolites, detected with high-resolution H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05.

Results: The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism.

Conclusions: Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.
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http://dx.doi.org/10.1002/jcsm.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749557PMC
December 2020

Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33.

Transl Oncol 2019 Jan 3;12(1):96-105. Epub 2018 Oct 3.

Division of Cancer Imaging Research, Department of Radiology and Radiology Science, Johns Hopkins University, School of Medicine, Baltimore, MD; Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Medulloblastoma is the most common malignant tumor that arises from the cerebellum of the central nervous system. Clinically, medulloblastomas are treated by surgery, radiation, and chemotherapy, all of which result in toxicity and morbidity. Recent reports have identified that DDX3, a member of the RNA helicase family, is mutated in medulloblastoma. In this study, we demonstrate the role of DDX3 in driving medulloblastoma. With the use of a small molecule inhibitor of DDX3, RK-33, we could inhibit growth and promote cell death in two medulloblastoma cell lines, DAOY and UW228, with IC50 values of 2.5 μM and 3.5 μM, respectively. Treatment of DAOY and UW228 cells with RK-33 caused a G1 arrest, resulted in reduced TCF reporter activity, and reduced mRNA expression levels of downstream target genes of the WNT pathway, such as Axin2, CCND1, MYC, and Survivin. In addition, treatment of DAOY and UW228 cells with a combination of RK-33 and radiation exhibited a synergistic effect. Importantly, the combination of RK-33 and 5 Gy radiation caused tumor regression in a mouse xenograft model of medulloblastoma. Using immunohistochemistry, we observed DDX3 expression in both pediatric (55%) and adult (66%) medulloblastoma patients. Based on these results, we conclude that RK-33 is a promising radiosensitizing agent that inhibits DDX3 activity and down-regulates WNT/β-catenin signaling and could be used as a frontline therapeutic strategy for DDX3-expressing medulloblastomas in combination with radiation.
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http://dx.doi.org/10.1016/j.tranon.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171097PMC
January 2019
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