John Hardy Lockhart

John Hardy Lockhart
Moffitt Cancer Center · Department of Molecular Oncology

Ph.D. (Medical Science); M.S. (Bioinformatics and Computational Biology)
Investigating drivers of lung adenocarcinoma progression and heterogeneity using machine learning and molecular biology

About

22
Publications
13,577
Reads
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136
Citations
Introduction
My research focuses on uncovering drivers of tumor progression and heterogeneity in lung adenocarcinoma using spatial multi-omics guided by a machine learning pipeline for tumor grading. In addition, I am investigating oncogenic and tumor-suppressive long non-coding RNAs and circular RNAs that the p53 family regulates in non-small cell lung cancer.
Additional affiliations
August 2014 - October 2019
University of South Florida
Position
  • PhD Student
Description
  • Identified changes in microRNA-mediated transcript silencing after incorporation of modified nucleotides during in-vitro transcription. Developed a peptide-based nanoparticle for delivery of cell-selective synthetic mRNA to inhibit vessel blockage after angioplasty.
May 2014 - August 2014
University of South Florida
Position
  • Bioinformatics Intern
Description
  • Established a local instance of Galaxy for the Bioinformatics Core at USF Morsani College of Medicine. Used published next-generation sequencing data to examine the conservation of LTR retrotransposons and possible mRNA transcripts driven by LTRs.
May 2011 - May 2012
University of South Florida
Position
  • Undergraduate Research Assistant
Description
  • Collected and analyzed samples from black mangroves (A. germinans) for analysis of litter composition and propagule characteristics Assisted in field experiments to measure effects of vegetation on tidal dispersion and recruitment of mangrove propagules
Education
August 2014 - May 2019
University of South Florida
Field of study
  • Biomedical Science
May 2013 - July 2014
University of South Florida
Field of study
  • Bioinformatics and Computational Biology
August 2008 - May 2013
University of South Florida
Field of study
  • Biology

Publications

Publications (22)
Article
Cardiovascular disease is the leading cause of death and disability worldwide. Effective delivery of cell-selective therapies that target atherosclerotic plaques and neointimal growth while sparing the endothelium remain the Achilles heel of percutaneous interventions. The current study utilizes synthetic microRNA switch therapy that self-assembles...
Article
Full-text available
mRNA therapeutics hold great promise for the treatment of human diseases. While incorporating naturally occurring modified nucleotides during synthesis has greatly increased their potency and safety, challenges in selective expression have hindered clinical applications. MicroRNA (miRNA)-regulated in vitro-transcribed mRNAs, called miRNA switches,...
Conference Paper
Preclinical mouse models of lung adenocarcinoma are invaluable for the discovery of molecular drivers of tumor formation, progression, and therapeutic resistance. Histological analyses of these preclinical models require significant investments of time and training to ensure accuracy and consistency. Analysis by a clinical pathologist is the gold s...
Article
The heterogeneous cell types of the tumor-immune microenvironment (TIME) play key roles in determining cancer progression, metastasis, and response to treatment. We report the development of TIMEx, a novel tumor-immune microenvironment deconvolution method emphasizing on estimating infiltrating immune cells for bulk transcriptomics using pan-cancer...
Article
Full-text available
During implantation, cytotrophoblasts undergo epithelial-to-mesenchymal transition (EMT) as they differentiate into invasive extravillous trophoblasts (EVTs). The primate-specific microRNA cluster on chromosome 19 (C19MC) is exclusively expressed in the placenta, embryonic stem cells and certain cancers however, its role in EMT gene regulation is u...
Poster
Preclinical mouse models of lung adenocarcinoma (LUAD) are invaluable for the discovery of molecular drivers of tumor formation, progression, and therapeutic resistance. Histological analyses of preclinical models require significant training to ensure accuracy and consistency. Clinical pathologists provide the gold standard in this approach, but r...
Article
Full-text available
The tumor immune microenvironment (TIME) encompasses many heterogeneous cell types that engage in extensive crosstalk among the cancer, immune, and stromal components. The spatial organization of these different cell types in TIME could be used as biomarkers for predicting drug responses, prognosis and metastasis. Recently, deep learning approaches...
Poster
Analysis by a clinical pathologist is the gold standard for preclinical histological analysis but may be difficult to obtain due to the cost and availability of their services. As an alternative we have developed a digital pathology pipeline to segment, grade, and analyze lung adenocarcinoma tumors. This convolutional neural network (CNN) was train...
Article
Preclinical mouse models of lung adenocarcinoma are invaluable for the discovery of molecular drivers of tumor formation, progression, and therapeutic resistance. Histological analyses of these preclinical models require significant investments of time and training to ensure accuracy and consistency. Analysis by a clinical pathologist is the gold s...
Conference Paper
P53 is frequently mutated in a wide variety of tumors; yet, the regulation and expression of downstream targets during tumor progression and response to therapy is unknown. Here, we use Kras/p53-driven lung adenocarcinoma in the mouse as a model system to identify p53-driven molecular signatures that predict lung adenocarcinoma progression. Using t...
Article
Full-text available
As one of the most widespread metabolic diseases, atherosclerosis affects nearly everyone as they age; arteries gradually narrow from plaque accumulation over time reducing oxygenated blood flow to central and periphery causing heart disease, stroke, kidney problems, and even pulmonary disease. Personalized medicine promises to bring treatments bas...
Article
Preeclampsia (PE) is a common cause of maternal morbidity, characterized by impaired trophoblast invasion and spiral artery transformation resulting in progressive uteroplacental hypoxia. Given the primary role of LIN28A and LIN28B in modulating cell metabolism, differentiation, and invasion, we hypothesized that LIN28A and/or LIN28B regulates trop...
Article
Objective: Infantile hemangiomas (IHs) are the most common benign vascular neoplasms of infancy, characterized by a rapid growth phase followed by a spontaneous involution, or triggered by propranolol treatment by poorly understood mechanisms. LIN28/let-7 axis plays a central role in the regulation of stem cell self-renewal and tumorigenesis. Howe...
Poster
Infantile hemangiomas (IH) are common benign tumors diagnosed in approximately 10% of children aged <1 year, with increased incidence in premature infants and females. IH development is characterized by rapid proliferation followed by a regressive involuting phase that leaves a fibro fatty residuum. IH is a unique model of postnatal vasculogenesis...
Poster
Current therapies for preventing restenosis following angioplasty utilize drugs, such as sirolimus or paclitaxel, that act indiscriminately on all cell-types. This leads to aberrant endothelial regrowth and contributes to an increased incidence of in-stent thrombosis and neoatherosclerosis. We have recently developed a cell-selective treatment that...
Poster
Pulmonary hypertension (PH) is characterized by remodeling of the pulmonary vasculature leading to narrowing of the blood vessels. To date, only mildly effective, non-curative treatments are available. We aim to employ a newly established microRNA based cell-selective therapy to selectively inhibit pulmonary artery smooth muscle cells (PASMCs), lun...
Conference Paper
Full-text available
Advanced treatments for cardiovascular disease (CVD) are sorely needed, given that CVD remains the leading cause of death (>30%) and disability worldwide and continues to rise in response to poor nutrition, physical inactivity and obesity. MicroRNAs (miRNAs) are now widely recognized as crucial regulators of mammalian cardiovascular development, ho...
Article
Successful use of anticancer designer drugs is likely to depend on simultaneous combinations of these drugs to minimize the development of resistant cancer cells. Considering the knowledge base of cancer signaling pathways, mechanisms of designer drug resistance should be anticipated, and early clinical trials could be designed to include arms that...
Poster
Full-text available
Microarray analysis provides researchers with a powerful, high throughput tool for measuring differentially expressed genes. Downstream analysis of microarray data is frequently carried out using proprietary software, such as Ingenuity Pathway Analysis. However, using “black box” programs can bias the results of such analysis due to lack of researc...

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Projects

Projects (3)
Project
Create a non-viral vector capable of selectively overexpressing the cyclin-dependent kinase inhibitor p27Kip1 in the smooth muscle cells and infiltrating immune cells of wounded arteries after balloon angioplasty. Sparing endothelial from cell growth arrest will promote vessel healing while simultaneously preventing restenosis.
Project
Manual analysis of histological specimens is a time consuming process that requires extensive training and experience to produce consistent results. To provide a more standardized analysis we aim to create a machine learning model that can segment and grade individual tumors in mouse models of lung adenocarcinoma.
Archived project
We have previously shown that MZT is a time when transposons (TEs) are transriptionally active in mice. We're testing if this is true for other mammals. We're also testing this phenomenon as "universal" explanation for TE propagation in "host" species.