Digital Commons Network^™

Genetic And Genomic Characterization Of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, And Cell Lines., Bradley Garman, Ioannis N. Anastopoulos, Clemens Krepler, Patricia Brafford, Katrin Sproesser, Yuchao Jiang, Bradley Wubbenhorst, Ravi Amaravadi, Joseph Bennett, Marilda Beqiri, David Elder, Keith T. Flaherty, Dennie T. Frederick, Tara C. Gangadhar, Michael Guarino, David Hoon, Giorgos Karakousis, Qin Liu, Nandita Mitra, Nicholas J. Petrelli, Lynn Schuchter, Batool Shannan, Carol L. Shields, Jennifer Wargo, Brandon Wenz, Melissa A. Wilson, Min Xiao, Wei Xu, Xaiowei Xu, Xiangfan Yin, Nancy R. Zhang, Michael A. Davies, Meenhard Herlyn, Katherine L. Nathanson

Wills Eye Hospital Papers

Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized …

Investigating The Mechanistic Mode Of Action Of Novel Cu(Ii) Complexes As Potential Chemotherapeutics Drugs, Garret Rochford

Doctoral

A new class of Cu(II) phenanthroline-phenazine complexes (developed in Dublin City University) have recently been reported to have the highest DNA binding constants of any copper therapeutic complex and at a similar level to Actinomycin. These new complexes show great clinical potential with their high activity against a range of in-vitro mammalian cell lines including those with cisplatin resistance however the underlying biological mechanism of their action has yet to be explored in-depth. The biological data generated in this project has examined the activity of the Cu(II) phenanthroline-phenazine complexes in selected mammalian cells lines in-vitro and demonstrated that the Cu(II) …

Phosphoproteomics Profiling Of Nonsmall Cell Lung Cancer Cells Treated With A Novel Phosphatase Activator, Danica Wiredja, Marzieh Ayati, Sahar Mazhar, Jaya Sangodkar, Sean Maxwell, Daniela Schlatzer, Goutham Narla, Mehmet Koyutürk, Mark R. Chance

Computer Science Faculty Publications

Activation of protein phosphatase 2A (PP2A) is a promising anti-cancer therapeutic strategy, as this tumor suppressor has the ability to coordinately downregulate multiple pathways involved in the regulation of cellular growth and proliferation. In order to understand the systems-level perturbations mediated by PP2A activation, we carried out mass spectrometry-based phosphoproteomic analysis of two KRAS mutated non-small cell lung cancer (NSCLC) cell lines (A549 and H358) treated with a novel Small Molecule Activator of PP2A (SMAP). Overall, this permitted quantification of differential signaling across over 1,600 phosphoproteins and 3,000 phosphosites. Kinase activity assessment and pathway enrichment implicated collective downregulation of RAS …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Complete Genome Sequence Of A Colistin-Resistant Escherichia Coli Strain Harboring Mcr-1 On An Inchi2 Plasmid In The United States, V Gilrane, S Lobo, Weihua Huang, J Zhuge, Changhong Yin, Donald Chen, K Alvarez, Alexandra Budhai, I Nadelman, Nevenka Dimitrova, John Fallon, Guiqing Wang

NYMC Faculty Publications

We report here the incidental detection and complete genome sequence of a urinary Escherichia coli strain harboring mcr-1 and resistant to colistin in a New York patient returning from Portugal in 2016. This strain, with sequence type 1485 (ST1485), was a non-extended-spectrum beta-lactamase (ESBL) and non-carbapenemase producer and carried the mcr-1 gene on an IncHI2 plasmid.

Ormeloxifene Suppresses Prostate Tumor Growth And Metastatic Phenotypes Via Inhibition Of Oncogenic Β-Catenin Signaling And Emt Progression, Bilal B. Hafeez, Aditya Ganju, Mohammed Sikander, Vivek K. Kashyap, Zubair Bin Hafeez, Neeraj Chauhan, Shabnam Malik, Andrew Massey, Manish Tripathi, Fathi T. Halaweish, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi

School of Medicine Publications

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and …

Insights Into Onchocerca Volvulus Population Biology Through Multilocus Immunophenotyping, Carmelle T Norice-Tra, José Ribeiro, Sasisekhar Bennuru, Michael P Fay, Rahul Tyagi, Makedonka Mitreva, Thomas B Nutman

2010-2019 OA Pubs

We have developed a serologically based immunophenotyping approach to study Onchocerca volvulus (Ov) population diversity. Using genomic sequence data and polymerase chain reaction-based genotyping, we identified nonsynonymous single-nucleotide polymorphisms (SNPs) in the genes of 16 major immunogenic Ov proteins: Ov-CHI-1/Ov-CHI-2, Ov16, Ov-FAR-1, Ov-CPI-1, Ov-B20, Ov-ASP-1, Ov-TMY-1, OvSOD1, OvGST1, Ov-CAL-1, M3/M4, Ov-RAL-1, Ov-RAL-2, Ov-ALT-1, Ov-FBA-1, and Ov-B8. We assessed the immunoreactivity of onchocerciasis patient sera (n = 152) from the Americas, West Africa, Central Africa, and East Africa against peptides derived from 10 of these proteins containing SNPs. Statistically significant variation in immunoreactivity among the regions was seen in SNP-containing peptides …

Cross-Reactive Immunity To Porcine Reproductive And Respiratory Syndrome Virus And Its Contribution To Protection, Ignacio Correas

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

Due to the vast geographical distribution and significant economic losses generated, porcine reproductive and respiratory syndrome virus (PRRSV) can be considered the most important swine pathogen of contemporary times. Current control and eradication strategies against PRRSV have difficulty succeeding because of their complex nature and the absence of an effective vaccine. A major obstacle for PRRSV vaccine development is the broad heterogeneity of the virus, both at the genetic and antigenic level, its rapid evolution, and an incomplete knowledge of the immune responses responsible for clearing the virus from the host. Specifically, how known correlates of protection against PRRSV—neutralizing antibodies …

Colonizing Opportunistic Pathogens (Cops): The Beasts In All Of Us., Lance B Price, Bruce A Hungate, Benjamin J Koch, Gregg S Davis, Cindy M Liu

Environmental and Occupational Health Faculty Publications

Colonizing opportunistic pathogens (COPs) are microbes that asymptomatically colonize the human body and, when the conditions are right, can cause infections. Their ability to persist indefinitely and to be transmitted without detection [1] gives COPs a unique epidemiology that warrants special consideration. There are examples of COPs among bacteria, fungi (e.g., Candida albicans [2]), protozoa (e.g., Blastocystis [3, 4]), and viruses (e.g., Rhinovirus [5]), but bacterial COPs are of particular relevance because of their major contribution to today’s antibiotic resistance crisis. The COPs include a long list of notorious bacteria that …

Colonizing Opportunistic Pathogens (Cops): The Beasts In All Of Us., Lance B Price, Bruce A Hungate, Benjamin J Koch, Gregg S Davis, Cindy M Liu

Environmental and Occupational Health Faculty Publications

Colonizing opportunistic pathogens (COPs) are microbes that asymptomatically colonize the human body and, when the conditions are right, can cause infections. Their ability to persist indefinitely and to be transmitted without detection [1] gives COPs a unique epidemiology that warrants special consideration. There are examples of COPs among bacteria, fungi (e.g., Candida albicans [2]), protozoa (e.g., Blastocystis [3, 4]), and viruses (e.g., Rhinovirus [5]), but bacterial COPs are of particular relevance because of their major contribution to today’s antibiotic resistance crisis. The COPs include a long list of notorious bacteria that …

Deconstructing Medicine: The Intersections Of Racism And Health Disparities Within Pre-Medical Education, Allison F. Dormanesh

Ethnic Studies

The purpose of this project is to evaluate ways in which historical racism and lack of it in pre- medical curriculum shapes future health professionals and results in negative medical treatment of under-represented groups. Research found in the literature review reveals a strong history of racism within medical practice and medical research, as well as unconscious bias that follows knowledge taught during undergraduate education and onwards. An intersectionality approach is used to show the affect of race and class on health disparities and unethical abuse. This research includes data analyzing the pre-medical curriculums of the ten pre-medical universities that produce …

Community Living Integration Club For Women In Recovery From Sex Trafficking, Toni Thompson

Occupational Therapy Program Student Theses, Dissertations and Capstones

Sex trafficking is one form of human trafficking, a heinous human rights violation that transcends international borders. People who have been trafficked often present with complex neurobehavioral, psychological, emotional, physiological, sensory, and developmental difficulties. The United Nations developed the international 3 p protocol to guide governmental agencies, non-governmental groups, and individuals in developing programs and legal actions of trafficking prevention, protection, and prosecution. Protection encompasses the recovery of trafficking survivors and community integration has been identified as an essential foundation for successful recovery. Measurable components of community integration include safe housing, stable employment, and vocation-focused education. This Capstone describes the …

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory cytokines such …

Comparative Analyses Of Zebrafish Anxiety-Like Behavior Using Conflict-Based Novelty Tests, Elana V. Kysil, Darya A. Meshalkina, Erin E. Frick, David J. Echevarria, Denis B. Rosemberg, Caio Maximino, Monica Gomes Lima, Murilo S. Abreu, Ana C. Giacomini, Leonardo J.G. Barcellos, Cai Song, Allan V. Kalueff

Faculty Publications

Modeling of stress and anxiety in adult zebrafish (Danio rerio) is increasingly utilized in neuroscience research and central nervous system (CNS) drug discovery. Representing the most commonly used zebrafish anxiety models, the novel tank test (NTT) focuses on zebrafish diving in response to potentially threatening stimuli, whereas the light-dark test (LDT) is based on fish scototaxis (innate preference for dark vs. bright areas). Here, we systematically evaluate the utility of these two tests, combining meta-analyses of published literature with comparative in vivo behavioral and whole-body endocrine (cortisol) testing. Overall, the NTT and LDT behaviors demonstrate a generally good cross-test correlation …

The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton

Dissertations and Theses (Open Access)

DIRAS3 is a maternally imprinted tumor suppressor gene that is downregulated by multiple mechanisms across several tumor types. When re-expressed, DIRAS3 decreases proliferation, inhibits motility, and induces autophagy and tumor dormancy. DIRAS3 encodes a 26 kDa small GTPase with 60% homology to Ras and Rap, differing from oncogenic Ras family members by a 34-amino acid N-terminal extension that is required for its tumor suppressive function in ovarian cancer. By assessing the structure-function relationship, I found that DIRAS3 inhibits Ras-induced transformation and is a natural antagonist of Ras/MAPK signaling. DIRAS3 binds directly to Ras and disrupts cluster formation inhibiting the activation …

Statistical Methods For Assessing Structural Change In Human & Microbial Genomes, Xuan Zhu

Dissertations and Theses (Open Access)

Genetic sequencing has been recognized as an effective approach to accurately address biological problems, such as clinical detection of disease, mutation discovery, and targeting specific biomarkers associated with complex diseases. Compared with conventional Sanger sequencing, next-generation sequencing costs much less due to massively parallel high-throughput sequencing. However, due to large numbers of short read sequences, the accuracy of high-throughput sequencing data remains a challenge in that the data obtained from next-generation sequencing often has higher error rates, which may impact downstream genomic analysis. Even if the downstream genomic analysis performs well, the quality of the result will still be impacted …

Genome-Scale Precision Proteomics Identifies Cancer Signaling Networks And Therapeutic Vulnerabilities, Hong Wang

Theses and Dissertations (ETD)

Mass spectrometry (MS) based-proteomics technology has been emerging as an indispensable tool for biomedical research. But the highly diverse physical and chemical properties of the protein building blocks and the dramatic human proteome complexity largely limited proteomic profiling depth. Moreover, there was a lack of high-throughput quantitative strategies that were both precise and parallel to in-depth proteomic techniques. To solve these grand challenges, a high resolution liquid chromatography (LC) system that coupled with an advanced mass spectrometer was developed to allow genome-scale human proteome identification. Using the combination of pre-MS peptide fractionation, MS2-based interference detection and post-MS computational interference correction, …

Validation Of Standard Operating Procedures In A Multicenter Retrospective Study To Identify-Omics Biomarkers For Chronic Low Back Pain, Concetta Dagostino, Manuela De Gregori, Christian Gieger, Judith Manz, Ivan Gudelj, Gordon Lauc, Laura Divizia, Wei Wang, Moira Sim, Iain K. Pemberton, Jane Macdougall, Frances Williams, Jan Vn Zundeert, Dragan Primorac, Yurii Aulchenko, Leonardo Kapural, Massimo Allegri

Research outputs 2014 to 2021

Chronic low back pain (CLBP) is one of the most common medical conditions, ranking as the greatest contributor to global disability and accounting for huge societal costs based on the Global Burden of Disease 2010 study.

Large genetic and -omics studies provide a promising avenue for the screening, development and validation of biomarkers useful for personalized diagnosis and treatment (precision medicine). Multicentre studies are needed for such an effort, and a standardized and homogeneous approach is vital for recruitment of large numbers of participants among different centres (clinical and laboratories) to obtain robust and reproducible results. To date, no validated …

Network Exploration Of Correlated Multivariate Protein Data For Alzheimer's Disease Association, Matthew J. Lane

Theses

Alzheimer Disease (AD) is difficult to diagnose by using genetic testing or other traditional methods. Unlike diseases with simple genetic risk components, there exists no single marker determining as to whether someone will develop AD. Furthermore, AD is highly heterogeneous and different subgroups of individuals develop the disease due to differing factors. Traditional diagnostic methods using perceivable cognitive deficiencies are often too little too late due to the brain having suffered damage from decades of disease progression. In order to observe AD at early stages prior to the observation of cognitive deficiencies, biomarkers with greater accuracy are required. By using …

Medical School Watercooler Newsletter - April 9, 2017, Lindsey Lyle

Watercooler Newsletter

This is the April 9, 2017 edition of the Frederick P. Whiddon College of Medicine's Newsletter - Watercooler.

Contents Include:

2017 Gumbo Chili Showdown a Success

Dr. Steve Lim Awarded $1.52M NIH Research Grant

April 13 DSS to Feature Dr. Roderick O’Sullivan

USA Libraries Hosting Book Drive for Pediatrics

Significance Of Animal Model Research In Homoeopathy, Raj Manchanda

Indian Journal of Research in Homoeopathy

No abstract provided.

Hic1 (Hypermethylated In Cancer 1) Sumoylation Is Dispensable For Dna Repair But Is Essential For The Apoptotic Dna Damage Response (Ddr) To Irreparable Dna Double-Strand Breaks (Dsbs)., Sonia Paget, Marion Dubuissez, Vanessa Dehennaut, Joe Nassour, Brennan T Harmon, Nathalie Spruyt, Ingrid Loison, Corinne Abbadie, Brian R Rood, Dominique Leprince

Surgery Faculty Publications

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation …

Inhibition Of Mammalian Glycoprotein Ykl-40 Identification Of The Physiological Ligand, Abhishek A. Kognole, Christina M. Payne

Chemical and Materials Engineering Faculty Publications

YKL-40 is a mammalian glycoprotein associated with progression, severity, and prognosis of chronic inflammatory diseases and a multitude of cancers. Despite this well documented association, identification of the lectin′s physiological ligand and, accordingly, biological function has proven experimentally difficult. YKL-40 has been shown to bind chito-oligosaccharides; however, the production of chitin by the human body has not yet been documented. Possible alternative ligands include proteoglycans, polysaccharides, and fibers like collagen, all of which makeup the extracellular matrix. It is likely that YKL-40 is interacting with these alternative polysaccharides or proteins within the body, extending its function to cell biological roles …

Characterization, Regulation, And Targeting Of Erythroid Progenitors In Normal And Disordered Human Erythropoiesis, B. M. Dulmovits, J. Hom, A. Narla, N. Mohandas, L. Blanc

Journal Articles

No abstract provided.

Human Liver Sinusoid On A Chip For Hepatitis B Virus Replication Study, Young Bok (Abraham) Kang, Siddhartha Rawat, Nicholas Duchemin, Michael Bouchard, Moses Noh

Faculty Publications - Biomedical, Mechanical, and Civil Engineering

We have developed a miniature human liver (liver-sinusoid-on-a-chip) model using a dual microchannel separated by a porous membrane. Primary human hepatocytes and immortalized bovine aortic endothelial cells were co-cultured on opposite sides of a microporous membrane in a dual microchannel with continuous perfusion. Primary human hepatocytes in this system retained their polygonal morphology for up to 26 days, while hepatocytes cultured in the absence of bovine aortic endothelial cells lost their morphology within a week. In order to demonstrate the utility of our human-liver-sinusoid-on-a-chip, human hepatocytes in this system were directly infected by Hepatitis B Virus (HBV). Expression of the …

Antimicrobial Resistance (Amr) And Multidrug Resistance (Mdr): Overview Of Current Approaches, Consortia And Intellectual Property Issues, Andrew Jenner, Niresh Bhagwandin, Stanley P. Kowalski

Law Faculty Scholarship

The supply of new diagnostics and treatments is insufficient to keep up with the increase in antimicrobial resistance (AMR) and multidrug resistance (MDR) as older medicines are used more widely and microbes develop resistance to them. At the same time, significant quantities of antibiotics are used on patients and animals that do not need them, while others who do need them lack access.

Effective responses to AMR/MDR require effort by both the public and private sectors to develop and disseminate new diagnostics, vaccines and treatments on a global scale, as well as to adapt them to local needs. This calls …

Neuroendocrine Disorder In Chronic Fatigue Syndrome, Slavica Tomic, Snezana Brkic, Dajana Lendak, Daniela Maric, Milica Medic-Stojanoska, Aleksandra Novakov-Mikic

Turkish Journal of Medical Sciences

Background/aim: Neuroendocrine disorders are considered a possible pathogenetic mechanism in chronic fatigue syndrome (CFS). The aim of our study was to determine the function of the hypothalamic-pituitary-adrenal axis (HPA) and thyroid function in women of reproductive age suffering from CFS. Materials and methods: The study included 40 women suffering from CFS and 40 healthy women (15-45 years old). Serum levels of cortisol (0800 and 1800 hours), ACTH, total T4, total T3, and TSH were measured in all subjects. The Fibro Fatigue Scale was used for determination of fatigue level. Results: Cortisol serum levels were normal in both groups. The distinctively …

The Promise Of Systems Biology Approaches For Revealing Host Pathogen Interactions In Malaria., Meghan Zuck, Laura S Austin, Samuel A Danziger, John D Aitchison, Alexis Kaushansky

Articles, Abstracts, and Reports

Despite global eradication efforts over the past century, malaria remains a devastating public health burden, causing almost half a million deaths annually (WHO, 2016). A detailed understanding of the mechanisms that control malaria infection has been hindered by technical challenges of studying a complex parasite life cycle in multiple hosts. While many interventions targeting the parasite have been implemented, the complex biology of

Microfluidics-Based Single Cell Isolation And Trapping Of Canine Cutaneous Mast Cell Tumor Cells, Dettachai Ketpun

Chulalongkorn University Theses and Dissertations (Chula ETD)

In this research, the primary objective was to develop a microfluidic platform utilized for the size-based single cell sorting of canine cutaneous mast cell tumor (MCT) cells which were categorized into 4 groups; I, II, III and IV, upon their individual sizes ranged from 5-9, 10-14, 15-19, and equal to or over than 20 mm respectively. And the secondary aim was to establish the microfluidic-based entrapping microdevice which had a capacity to ensnare single MCT cells into its triangular microwell array at the ratio of one cell per one microwell. The study consequence consistently indicated the accomplishment of device developments. …

An Exploratory Statistical Method For Finding Interactions In A Large Dataset With An Application Toward Periodontal Diseases, Joshua Lambert

Theses and Dissertations--Epidemiology and Biostatistics

It is estimated that Periodontal Diseases effects up to 90% of the adult population. Given the complexity of the host environment, many factors contribute to expression of the disease. Age, Gender, Socioeconomic Status, Smoking Status, and Race/Ethnicity are all known risk factors, as well as a handful of known comorbidities. Certain vitamins and minerals have been shown to be protective for the disease, while some toxins and chemicals have been associated with an increased prevalence. The role of toxins, chemicals, vitamins, and minerals in relation to disease is believed to be complex and potentially modified by known risk factors. A …