105 results on '"John F. McDonald"'
Search Results
2. Label-free microfluidic enrichment of cancer cells from non-cancer cells in ascites
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A. Raj, Katherine M. Young, Benedict B. Benigno, Todd Sulchek, Alexander Alexeev, Budd A. Tucker, Nicholas Stone, Adam P. DeLuca, Fatima Ezahra Chrit, and John F. McDonald
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Cell biology ,Science ,Cell ,Gene Expression ,Cell Separation ,Models, Biological ,Article ,medicine ,Biomarkers, Tumor ,Ascitic Fluid ,Humans ,Neoplasm Invasiveness ,Liquid biopsy ,Precision Medicine ,Cancer ,Ovarian Neoplasms ,Multidisciplinary ,Magnetic-activated cell sorting ,business.industry ,Liquid Biopsy ,Ascites ,High-Throughput Nucleotide Sequencing ,Cell sorting ,Microfluidic Analytical Techniques ,Translational research ,medicine.disease ,Neoplastic Cells, Circulating ,Biomechanical Phenomena ,medicine.anatomical_structure ,Cancer cell ,Mutation ,Cancer research ,Medicine ,Female ,Personalized medicine ,Tumor Suppressor Protein p53 ,Ovarian cancer ,business ,Multiplex Polymerase Chain Reaction ,Biomarkers - Abstract
The isolation of a patient's metastatic cancer cells is the first, enabling step toward treatment of that patient using modern personalized medicine techniques. Whereas traditional standard-of-care approaches select treatments for cancer patients based on the histological classification of cancerous tissue at the time of diagnosis, personalized medicine techniques leverage molecular and functional analysis of a patient's own cancer cells to select treatments with the highest likelihood of being effective. Unfortunately, the pure populations of cancer cells required for these analyses can be difficult to acquire, given that metastatic cancer cells typically reside in fluid containing many different cell populations. Detection and analyses of cancer cells therefore require separation from these contaminating cells. Conventional cell sorting approaches such as Fluorescence Activated Cell Sorting or Magnetic Activated Cell Sorting rely on the presence of distinct surface markers on cells of interest which may not be known nor exist for cancer applications. In this work, we present a microfluidic platform capable of label-free enrichment of tumor cells from the ascites fluid of ovarian cancer patients. This approach sorts cells based on differences in biomechanical properties, and therefore does not require any labeling or other pre-sort interference with the cells. The method is also useful in the cases when specific surface markers do not exist for cells of interest. In model ovarian cancer cell lines, the method was used to separate invasive subtypes from less invasive subtypes with an enrichment of ~ sixfold. In ascites specimens from ovarian cancer patients, we found the enrichment protocol resulted in an improved purity of P53 mutant cells indicative of the presence of ovarian cancer cells. We believe that this technology could enable the application of personalized medicine based on analysis of liquid biopsy patient specimens, such as ascites from ovarian cancer patients, for quick evaluation of metastatic disease progression and determination of patient-specific treatment.
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- 2021
3. Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy
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Dario I. Carrasco, Paul Nardelli, John F. McDonald, Emily Pfahl, Timothy C. Cope, Stephen N. Housley, Lilya V. Matyunina, and Travis M. Rotterman
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Male ,0301 basic medicine ,Cancer Research ,Sensory Receptor Cells ,medicine.medical_treatment ,Antineoplastic Agents ,Sensory system ,Article ,03 medical and health sciences ,0302 clinical medicine ,Chemotherapy induced ,Biomarkers, Tumor ,medicine ,Animals ,Differential expression ,Chemotherapy ,business.industry ,Gene Expression Profiling ,Peripheral Nervous System Diseases ,medicine.disease ,Rats, Inbred F344 ,Sensory neuron ,Rats ,Gene Expression Regulation, Neoplastic ,Oxaliplatin ,Disease Models, Animal ,030104 developmental biology ,Peripheral neuropathy ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Sensory neuropathy ,Forelimb ,Colorectal Neoplasms ,business ,Neuroscience - Abstract
For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. Significance: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.
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- 2020
4. The ability of miRNAs to induce mesenchymal-to-epithelial transition (MET) in cancer cells is highly dependent upon genetic background
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Amber Akbar, Lilya V. Matyunina, Mengnan Zhang, John F. McDonald, and Yuehua Wang
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Male ,0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Biology ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Gene expression ,Biomarkers, Tumor ,medicine ,Humans ,Gene ,Ovarian Neoplasms ,Binding Sites ,Transition (genetics) ,Mesenchymal stem cell ,Prostatic Neoplasms ,Cancer ,medicine.disease ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,PC-3 Cells ,Cancer cell ,Female ,Cancer cell lines - Abstract
Understanding of the molecular basis of host cell-miRNA interactions is prerequisite to the successful application of miRNAs as potential therapeutic agents. We studied the morphological and molecular consequences of over expression of three sequence divergent miRNAs previously implicated in the mesenchymal-to-epithelial transition process (MET) in three distinct mesenchymal-like cancer cell lines. The ability of miRNAs to induce morphological changes characteristic of MET positively correlated with induced changes in the expression of genes previously implicated in the process. Variability in the responses of different mesenchymal-like cells to over expression of the same miRNAs was attributable to inherent differences in trans-regulatory profiles pre-disposing these cells to miRNA-induced MET. Collectively our results indicate that miRNA-mediated regulation of MET is a highly integrated process that is significantly modulated by the molecular background of individual cells.
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- 2020
5. Tumor suppressor genes and allele-specific expression: mechanisms and significance
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Lu Wang, Dongjo Ban, I. King Jordan, Shareef Khalid, John F. McDonald, and Evan A. Clayton
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0301 basic medicine ,Tumor suppressor gene ,allele-specific expression ,Biology ,law.invention ,03 medical and health sciences ,alternative splicing ,tumor-suppressor genes ,0302 clinical medicine ,law ,medicine ,cancer ,Allele ,Gene ,antisense RNA ,Genetics ,Alternative splicing ,Cancer ,Heterozygote advantage ,medicine.disease ,Antisense RNA ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Suppressor ,Research Paper - Abstract
Recent findings indicate that allele-specific expression (ASE) at specific cancer driver gene loci may be of importance in onset/progression of the disease. Of particular interest are loss-of-function (LOF) of tumor suppressor gene (TSGs) alleles. While LOF tumor suppressor mutations are typically considered to be recessive, if these mutant alleles can be significantly differentially expressed relative to wild-type alleles in heterozygotes, the clinical consequences could be significant. LOF TSG alleles are shown to be segregating at high frequencies in world-wide populations of normal/healthy individuals. Matched sets of normal and tumor tissues isolated from 233 cancer patients representing four diverse tumor types demonstrate functionally important changes in patterns of ASE in individuals heterozygous for LOF TSG alleles associated with cancer onset/progression. While a variety of molecular mechanisms were identified as potentially contributing to changes in ASE patterns in cancer, changes in DNA copy number and allele-specific alternative splicing possibly mediated by antisense RNA emerged as predominant factors. In conclusion, LOF TSGs are segregating in human populations at significant frequencies indicating that many otherwise healthy individuals are at elevated risk of developing cancer. Changes in ASE between normal and cancer tissues indicates that LOF TSG alleles may contribute to cancer onset/progression even when heterozygous with wild-type functional alleles.
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- 2020
6. Changes in gene-gene interactions associated with cancer onset and progression are largely independent of changes in gene expression
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John F. McDonald and Zainab Arshad
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Multidisciplinary ,Cancer systems biology ,Transition (genetics) ,Science ,Cancer ,Biology ,medicine.disease ,Article ,chemistry.chemical_compound ,Classification Description ,chemistry ,Housekeeping ,Gene expression ,Cancer research ,medicine ,Cancer development ,sense organs ,skin and connective tissue diseases ,Systems biology ,Transcriptomics ,Gene ,DNA - Abstract
Summary Recent findings indicate that changes underlying cancer onset and progression are not only attributable to changes in DNA structure and expression of individual genes but to changes in interactions among these genes as well. We examined co-expression changes in gene-network structure occurring during the onset and progression of nine different cancer types. Network complexity is generally reduced in the transition from normal precursor tissues to corresponding primary tumors. Cross-tissue cancer network similarity generally increases in early-stage cancers followed by a subsequent loss in cross-tissue cancer similarity as tumors reacquire cancer-specific network complexity. Gene-gene connections remaining stable through cancer development are enriched for “housekeeping” gene functions, whereas newly acquired interactions are associated with established cancer-promoting functions. Surprisingly, >90% of changes in gene-gene network interactions in cancers are not associated with changes in the expression of network genes relative to normal precursor tissues., Graphical abstract, Highlights • Gene-gene network complexity is reduced in the transition from normal to cancer • Network similarity across cancer types is higher in early-stage versus late-stage cancers • Network interactions among housekeeping genes are stable through cancer development •, Classification Description: Systems biology; Cancer systems biology; Transcriptomics
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- 2021
7. Sequence diverse miRNAs converge to induce mesenchymal-to-epithelial transition in ovarian cancer cells through direct and indirect regulatory controls
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Minati Satpathy, Lilya V. Matyunina, John F. McDonald, Mengnan Zhang, Yuehua Wang, L. DeEtte McDonald, and Neda Jabbari
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Biology ,Transfection ,Wnt-5a Protein ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Gene expression ,microRNA ,medicine ,Humans ,Gene Regulatory Networks ,Gene ,Ovarian Neoplasms ,Base Sequence ,Transition (genetics) ,Phylogenetic tree ,Mesenchymal stem cell ,Zinc Finger E-box-Binding Homeobox 1 ,medicine.disease ,Cell biology ,Gene Expression Regulation, Neoplastic ,WNT5A ,MicroRNAs ,030104 developmental biology ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Female ,Ovarian cancer - Abstract
Epithelial-to-mesenchymal transition (EMT) has been shown to be similarly regulated by multiple miRNAs, some displaying little or no sequence identity. While alternate models have been proposed to explain the functional convergence of sequence divergent miRNAs, little experimental evidence exists to elucidate the underlying mechanisms involved. Representative members of the miR-200 family of miRNAs and the sequence divergent miR-205 miRNA were independently over expressed in mesenchymal-like ovarian cancer (OC) cells resulting in mesenchymal-to-epithelial transition (MET). The miR-205 and the miR-200 family of miRNAs were found to coordinately induce MET in mesenchymal-like OC cells by affecting both direct and indirect changes in the expression of genes previously associated with EMT/MET. Only two direct targets of these miRNAs (ZEB 1 and WNT5A) are commonly down regulated in response to over-expression of miR-205 and/or the miR-200 family of miRNAs. Down-regulation of these genes, alone or in combination, only partially recapitulates the changes induced by the miRNAs indicating an additional contribution of indirect changes regulated by the miRNAs. Combined gene expression analyses and phylogenetic comparisons suggest an evolutionarily more recent involvement of miR-205 in the EMT/MET process.
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- 2019
8. Hybrid negative enrichment of circulating tumor cells from whole blood in a 3D-printed monolithic device
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Tevhide Ozkaya-Ahmadov, John F. McDonald, Chia-Heng Chu, Brandi E. Swain, Mert Boya, Mehmet Asim Bilen, A. Fatih Sarioglu, Ruxiu Liu, Enerelt Burentugs, and Jacob M Owens
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Cell ,Microfluidics ,Biomedical Engineering ,Bioengineering ,Cell Separation ,02 engineering and technology ,Immunofluorescence ,01 natural sciences ,Biochemistry ,Jurkat cells ,Jurkat Cells ,Prostate cancer ,Circulating tumor cell ,Lab-On-A-Chip Devices ,Leukocytes ,medicine ,Humans ,Whole blood ,medicine.diagnostic_test ,biology ,Chemistry ,010401 analytical chemistry ,General Chemistry ,Neoplastic Cells, Circulating ,021001 nanoscience & nanotechnology ,medicine.disease ,0104 chemical sciences ,medicine.anatomical_structure ,Printing, Three-Dimensional ,biology.protein ,Antibody ,0210 nano-technology ,Antibodies, Immobilized ,Biomedical engineering - Abstract
Isolation and analysis of circulating tumor cells (CTCs) from blood samples present exciting opportunities for basic cancer research and personalized treatment of the disease. While microchip-based negative CTC enrichment offers both sensitive microfluidic cell screening and unbiased selection, conventional microchips are inherently limited by their capacity to deplete a large number of normal blood cells. In this paper, we use 3D printing to create a monolithic device that combines immunoaffinity-based microfluidic cell capture and a commercial membrane filter for negative enrichment of CTCs directly from whole blood. In our device, stacked layers of chemically-functionalized microfluidic channels capture millions of white blood cells (WBCs) in parallel without getting saturated and the leuko-depleted blood is post-filtered with a 3 μm-pore size membrane filter to eliminate anucleated blood cells. This hybrid negative enrichment approach facilitated direct extraction of viable CTCs off the chip on a membrane filter for downstream analysis. Immunofluorescence imaging of enriched cells showed ∼90% tumor cell recovery rate from simulated samples spiked with prostate, breast or ovarian cancer cells. We also demonstrated the feasibility of our approach for processing clinical samples by isolating prostate cancer CTCs directly from a 10 mL whole blood sample.
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- 2019
9. Machine learning predicts individual cancer patient responses to therapeutic drugs with high accuracy
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Lilya V. Matyunina, John F. McDonald, Cai Huang, Benedict B. Benigno, L. DeEtte McDonald, Evan A. Clayton, and Fredrik O. Vannberg
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0301 basic medicine ,Antimetabolites, Antineoplastic ,Support Vector Machine ,Databases, Factual ,lcsh:Medicine ,Machine learning ,computer.software_genre ,Deoxycytidine ,Article ,Machine Learning ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Cancer Medicine ,Predictive Value of Tests ,Neoplasms ,Biomarkers, Tumor ,Drug response ,Humans ,Medicine ,Precision Medicine ,lcsh:Science ,Ovarian Neoplasms ,Multidisciplinary ,Genome, Human ,business.industry ,lcsh:R ,Computational Biology ,Cancer ,medicine.disease ,Gemcitabine ,Support vector machine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,lcsh:Q ,Fluorouracil ,Chemotherapeutic drugs ,Artificial intelligence ,Transcriptome ,business ,computer ,Algorithms - Abstract
Precision or personalized cancer medicine is a clinical approach that strives to customize therapies based upon the genomic profiles of individual patient tumors. Machine learning (ML) is a computational method particularly suited to the establishment of predictive models of drug response based on genomic profiles of targeted cells. We report here on the application of our previously established open-source support vector machine (SVM)-based algorithm to predict the responses of 175 individual cancer patients to a variety of standard-of-care chemotherapeutic drugs from the gene-expression profiles (RNA-seq or microarray) of individual patient tumors. The models were found to predict patient responses with >80% accuracy. The high PPV of our algorithms across multiple drugs suggests a potential clinical utility of our approach, particularly with respect to the identification of promising second-line treatments for patients failing standard-of-care first-line therapies.
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- 2018
10. Leveraging TCGA gene expression data to build predictive models for cancer drug response
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John F. McDonald, Toyya A Pujol, Evan A. Clayton, and Peng Qiu
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Matching (statistics) ,Drug response ,Antineoplastic Agents ,Computational biology ,lcsh:Computer applications to medicine. Medical informatics ,Biochemistry ,Deoxycytidine ,Predictive models ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Neoplasms ,Databases, Genetic ,Machine learning ,medicine ,Cluster Analysis ,Humans ,Cluster analysis ,Molecular Biology ,lcsh:QH301-705.5 ,030304 developmental biology ,0303 health sciences ,business.industry ,Applied Mathematics ,Research ,medicine.disease ,Primary tumor ,Gemcitabine ,Personalized oncology ,Computer Science Applications ,Random forest ,Clinical trial ,Gene Expression Regulation, Neoplastic ,lcsh:Biology (General) ,ROC Curve ,Sample size determination ,030220 oncology & carcinogenesis ,Area Under Curve ,lcsh:R858-859.7 ,Fluorouracil ,DNA microarray ,business ,medicine.drug - Abstract
Background Machine learning has been utilized to predict cancer drug response from multi-omics data generated from sensitivities of cancer cell lines to different therapeutic compounds. Here, we build machine learning models using gene expression data from patients’ primary tumor tissues to predict whether a patient will respond positively or negatively to two chemotherapeutics: 5-Fluorouracil and Gemcitabine. Results We focused on 5-Fluorouracil and Gemcitabine because based on our exclusion criteria, they provide the largest numbers of patients within TCGA. Normalized gene expression data were clustered and used as the input features for the study. We used matching clinical trial data to ascertain the response of these patients via multiple classification methods. Multiple clustering and classification methods were compared for prediction accuracy of drug response. Clara and random forest were found to be the best clustering and classification methods, respectively. The results show our models predict with up to 86% accuracy; despite the study’s limitation of sample size. We also found the genes most informative for predicting drug response were enriched in well-known cancer signaling pathways and highlighted their potential significance in chemotherapy prognosis. Conclusions Primary tumor gene expression is a good predictor of cancer drug response. Investment in larger datasets containing both patient gene expression and drug response is needed to support future work of machine learning models. Ultimately, such predictive models may aid oncologists with making critical treatment decisions.
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- 2020
11. An atlas of transposable element-derived alternative splicing in cancer
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Evan A. Clayton, Dongjo Ban, I. King Jordan, Lavanya Rishishwar, John F. McDonald, Tzu-Chuan Huang, and Saurabh Gulati
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Transposable element ,Gene isoform ,Regulation of gene expression ,Genome, Human ,Alternative splicing ,Computational biology ,Articles ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Alternative Splicing ,Neoplasms ,medicine ,DNA Transposable Elements ,Humans ,Human genome ,splice ,General Agricultural and Biological Sciences ,Carcinogenesis ,Gene - Abstract
Transposable element (TE)-derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially used in normal versus cancer tissues. We analysed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumour tissue pairs across 13 cancer types, resulting in the discovery of 4820 TE-generated alternative splice events distributed among 723 cancer-associated genes. Short interspersed nuclear elements (Alu) and long interspersed nuclear elements (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes, including MYH11 , WHSC1 and CANT1 , were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans -splicing mediated by dispersed TE repeats. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation'.
- Published
- 2020
12. Towards a Model of Optimal Social Distancing During a Pandemic
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John F. McDonald and Steven Balkin
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,media_common.quotation_subject ,Social distance ,Public health ,Developing country ,Harm ,Development economics ,Pandemic ,Unemployment ,medicine ,Economics ,Mandate ,media_common - Abstract
The approach to reducing the current harm from the COVID-19 disease is to mandate or encourage an array of social distancing behaviors. These behaviors have the negative effects of reducing GDP, personal incomes, and increasing unemployment leading to calls for opening up the economy and thereby reducing social distancing. This makes more sense to do in developing economies which lack the private and public safety nets to compensate for the lost income. However, if this opening-up policy is followed, we suggest that social distancing be maintained at the level that minimizes deaths.
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- 2020
13. Time-course analysis of microRNA-induced mesenchymal-to-epithelial transition underscores the complexity of the underlying molecular processes
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Loukia N. Lili, Minati Satpathy, Andrew D. Huang, L. DeEtte McDonald, Lilya V. Matyunina, John F. McDonald, Mengnan Zhang, and Lijuan Wang
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Intravital Microscopy ,Microarray ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,microRNA ,Gene expression ,medicine ,Humans ,RNA, Small Interfering ,Gene ,Oligonucleotide Array Sequence Analysis ,Zinc Finger E-box Binding Homeobox 2 ,Ovarian Neoplasms ,Transition (genetics) ,Gene Expression Profiling ,Mesenchymal stem cell ,Zinc Finger E-box-Binding Homeobox 1 ,medicine.disease ,Phenotype ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Oncology ,Gene Knockdown Techniques ,Female ,Ovarian cancer - Abstract
Expression levels of the miR-200 family of miRNAs are significantly reduced during the epithelial-to-mesenchymal transition (EMT) and consequent metastasis of ovarian and other cancers. Consistently, ectopic over-expression of miR-200 family miRNAs in mesenchymal-like cells reverses the process by converting treated cells to an epithelial phenotype, thereby reducing invasiveness and increasing sensitivity to chemotherapeutic drugs. To better understand the dynamics and molecular processes underlying miRNA-induced mesenchymal-to mesenchymal transition (MET), a time-course study was conducted where miRNA-induced morphological and molecular changes associated with MET were monitored over a period of 144 h. Morphological transition from an elongated mesenchymal-like to a cuboidal epithelial-like phenotype is maximized at 48 h with cells returning to the elongated phenotype by 144 h. Changes in the expression of >3000 genes, including many previously associated with epithelial-to-mesenchymal transition (EMT), are most pronounced at 48 h, and approach starting levels of expression by 144 h. The majority of these genes are not direct targets of miR-429. Targeted (siRNA) inhibition of key miR-429 regulated genes previously implicated as drivers of EMT/MET, do not recapitulate miR-429 induced MET indicating that the underlying molecular processes are complex.
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- 2018
14. Population and clinical genetics of human transposable elements in the (post) genomic era
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Evan A. Clayton, Leonardo Mariño-Ramírez, Lavanya Rishishwar, John F. McDonald, Lu Wang, and I. King Jordan
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0301 basic medicine ,Transposable element ,medicine.medical_specialty ,Population ,Genomics ,Review ,Biology ,Biochemistry ,Germline ,03 medical and health sciences ,medicine ,Clinical genetic ,genomics ,transposition ,genetics ,human ,education ,Genetics ,education.field_of_study ,disease ,Natural selection ,health ,natural selection ,bioinformatics ,030104 developmental biology ,Human evolution ,Evolutionary biology ,Medical genetics ,transposable elements ,polymorphisms - Abstract
Recent technological developments—in genomics, bioinformatics and high-throughput experimental techniques—are providing opportunities to study ongoing human transposable element (TE) activity at an unprecedented level of detail. It is now possible to characterize genome-wide collections of TE insertion sites for multiple human individuals, within and between populations, and for a variety of tissue types. Comparison of TE insertion site profiles between individuals captures the germline activity of TEs and reveals insertion site variants that segregate as polymorphisms among human populations, whereas comparison among tissue types ascertains somatic TE activity that generates cellular heterogeneity. In this review, we provide an overview of these new technologies and explore their implications for population and clinical genetic studies of human TEs. We cover both recent published results on human TE insertion activity as well as the prospects for future TE studies related to human evolution and health.
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- 2017
15. Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes
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Roman Mezencev, G T Wagner, Lilya V. Matyunina, and John F. McDonald
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0301 basic medicine ,Cancer Research ,endocrine system diseases ,DNA damage ,DNA repair ,Cell ,Antineoplastic Agents ,Drug resistance ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Humans ,Molecular Biology ,Cisplatin ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Computational Biology ,medicine.disease ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Molecular Medicine ,Original Article ,medicine.drug ,Signal Transduction - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of malignancies, in large measure, due to the propensity of PDAC cells to acquire resistance to chemotherapeutic agents. A better understanding of the molecular basis of acquired resistance is a major focus of contemporary PDAC research. We report here the results of a study to independently develop cisplatin resistance in two distinct parental PDAC cell lines, AsPC1 and BxPC3, and to subsequently examine the molecular mechanisms associated with the acquired resistance. Cisplatin resistance in both resistant cell lines was found to be multifactorial and to be associated with mechanisms related to drug transport, drug inactivation, DNA damage response, DNA repair and the modulation of apoptosis. Our results demonstrate that the two resistant cell lines employed alternative molecular strategies in acquiring resistance dictated, in part, by pre-existing molecular differences between the parental cell lines. Collectively, our findings indicate that strategies to inhibit or reverse acquired resistance of PDAC cells to cisplatin, and perhaps other chemotherapeutic agents, may not be generalized but will require individual molecular profiling and analysis to be effective.
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- 2016
16. Bioinformatics analysis of circulating miRNAs related to cancer following spinal cord injury
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Alberto Cliquet, Wilson Nadruz, Roberto Schreiber, Décio Roberto Calegari, Layde R. Paim, Elisangela C.P. Lopes, José Irineu Gorla, José R. Matos-Souza, Carmen Silvia Passos Lima, and John F. McDonald
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Adult ,Male ,0301 basic medicine ,Esophageal Neoplasms ,In silico ,Biophysics ,Spinal cord injury ,Disease ,medicine.disease_cause ,Bioinformatics ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,medicine ,cancer ,Humans ,Molecular Biology ,Gene ,Research Articles ,Spinal Cord Injuries ,business.industry ,Computational Biology ,Cancer ,Cell Biology ,Esophageal cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Urinary Bladder Neoplasms ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,miRNAs ,KRAS ,Sedentary Behavior ,business ,Cell-Free Nucleic Acids ,Research Article - Abstract
Patients with spinal cord injury (SCI) have an increased risk of developing esophageal, bladder and hematologic malignancies compared with the normal population. In the present study, we aimed to identify, through in silico analysis, miRNAs and their target genes related to the three most frequent types of cancer in individuals with SCI. In a previous study, we reported a pattern of expression of miRNAs in 17 sedentary SCI males compared with 22 healthy able-bodied males by TaqMan OpenArray. This list of miRNAs deregulated in SCI patients was uploaded to miRWALK2.0 to predict the target genes and pathways of selected miRNAs. We used Cytoscape software to construct the network displaying the miRNAs and their gene targets. Among the down-regulated miRNAs in SCI, 21, 19 and 20 miRNAs were potentially associated with hematological, bladder and esophageal cancer, respectively, and three target genes (TP53, CCND1 and KRAS) were common to all three types of cancer. The three up-regulated miRNAs were potentially targeted by 18, 15 and 10 genes associated with all three types of cancer. Our current bioinformatics analysis suggests the potential influence of several miRNAs on the development of cancer in SCI. In general, these data may provide novel information regarding potential molecular mechanisms involved in the development of cancer among individuals with SCI. Further studies aiming at understanding how miRNAs contribute to the development of the major cancers that affect patients after SCI may help elucidate the role of these molecules in the pathophysiology of the disease.
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- 2019
17. Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy
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Emily Pfahl, Lilya V. Matyunina, Dario I. Carrasco, Stephen N. Housley, Paul Nardelli, John F. McDonald, and Timothy C. Cope
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0303 health sciences ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Sensory system ,medicine.disease ,Sensory neuron ,Potassium channel ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Peripheral neuropathy ,Chemotherapy induced ,Chemotherapy-induced peripheral neuropathy ,medicine ,Sensory neuropathy ,business ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
For the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.
- Published
- 2019
18. Analyzing Mechanisms of Metastatic Cancer Cell Adhesive Phenotype Leveraging Preparative Adhesion Chromatography Microfluidic
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Dongjo Ban, Meghan J. O'Melia, John F. McDonald, Janna K. Mouw, Katherine G. Birmingham, Susan N. Thomas, Erin E. Edwards, and Adam I. Marcus
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Biomedical Engineering ,Mice, SCID ,General Biochemistry, Genetics and Molecular Biology ,Article ,Flow cytometry ,Biomaterials ,Mice ,Carcinoembryonic antigen ,Cancer stem cell ,Cell Line, Tumor ,E-selectin ,medicine ,Cell Adhesion ,Animals ,Humans ,Neoplasm Metastasis ,Chromatography ,biology ,medicine.diagnostic_test ,Chemistry ,CD44 ,Adhesion ,Equipment Design ,Microfluidic Analytical Techniques ,Cell biology ,Phenotype ,Cancer cell ,Colonic Neoplasms ,biology.protein ,E-Selectin ,Cell Adhesion Molecules ,Selectin - Abstract
An integrated, parallel-plate microfluidic device was engineered to interrogate and fractionate cells based on their adhesivity to a substrate surface functionalized with adhesive ligand in a tightly controlled flow environment to elucidate associated cell-intrinsic pathways. Wall shear stress levels and endothelial presentation of E-selectin were modeled after the inflamed vasculature microenvironment in order to simulate in vitro conditions under which in vivo hematogenous metastasis occurs. Based on elution time from the flow channel, the collection of separate fractions of cells – non-interacting and interacting – at high yields and viabilities enabled multiple post-perfusion analyses, including flow cytometry, in vivo metastasis modeling, and transcriptomic analysis. This platform enabled the interrogation of flow-regulated cell molecular profiles, such as (co)expression levels of natively expressed selectin ligands sLe(x), CD44, and carcinoembryonic antigen, and cancer stem cell marker CD24. This additionally revealed E-selectin adhesivity exhibited by metastatic human colon carcinoma cells to be a transient phenotype. Facile and rapid, this methodology for unbiased, label free sorting of large populations of cells based on their adhesion in flow represents a method of studying flow-regulated adhesion in vitro for the identification of molecular drug targets for development as anti-metastatic cancer therapeutics.
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- 2019
19. Abstract PO-002: The effect of genetic ancestry and molecular signatures on cancer survival disparities: A pan-cancer analysis
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Kara Keun Lee, King I. Jordan, and John F. McDonald
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Oncology ,medicine.medical_specialty ,Pan cancer ,Epidemiology ,Genetic genealogy ,Internal medicine ,medicine ,Cancer survival ,Biology - Abstract
Cancer incidence and mortality rates in the United States (US) are not equitably distributed among all population groups, especially for racial and ethnic minorities. While non-genetic factors, including socioeconomic and environmental differences, have long been cited as the main contributors to cancer health disparities (CHD), new evidence points to a possible role of genetic and biological differences in CHD but with limited understanding and remain largely undiscovered. In this study, disparities in cancer survival outcome among US population groups were characterized based on self-identified race and ethnicity (SIRE) and genetic ancestry (GA), using univariate and multivariate survival analyses. Moreover, group-specific gene expression and mutation signatures that contribute to cancer survivorship disparities were systematically analyzed using feature selection and multiple and generalized linear regression models. Kaplan-Meier analysis of overall survival of The Cancer Genome Atlas (TCGA) cohort showed significantly different survival probability for the following GA groups: East Asian (EA) vs. European (EU) in head and neck squamous cell carcinoma (HNSC), African (AF), EA and EU vs. Admixed American (AA) in kidney renal clear cell carcinoma (KIRC), and EA, AA vs. EU and EA vs. AA in skin cutaneous carcinoma (SKCM). Multivariate Cox proportional hazard modeling using GA showed significantly greater risk of mortality for AF compared to EU (hazard ratio(HR)= 1.838, p= 0.021) with breast invasive carcinoma (BRCA) and HNSC (HR= 2.01, p= 0.005), Native Americans (NA) compared to EU (HR= 1.36, p= Citation Format: Kara Keun Lee, John F. McDonald, King I. Jordan. The effect of genetic ancestry and molecular signatures on cancer survival disparities: A pan-cancer analysis [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-002.
- Published
- 2020
20. Evidence for the role of microRNA 374b in acquired cisplatin resistance in pancreatic cancer cells
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Roman Mezencev, Lilya V. Matyunina, John F. McDonald, and Roberto Schreiber
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0301 basic medicine ,Cancer Research ,Genetic enhancement ,Gene Expression ,Antineoplastic Agents ,Drug resistance ,Biology ,Bioinformatics ,Ectopic Gene Expression ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,Pancreatic cancer ,microRNA ,medicine ,Humans ,Position-Specific Scoring Matrices ,RNA, Messenger ,Nucleotide Motifs ,Molecular Biology ,Cisplatin ,Binding Sites ,Gene Expression Profiling ,Computational Biology ,Cancer ,medicine.disease ,Phenotype ,Pancreatic Neoplasms ,MicroRNAs ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Original Article ,medicine.drug - Abstract
Recent evidence has implicated microRNAs (miRNAs) as potentially significant players in the acquisition of cancer-drug resistance in pancreatic and other cancers. To evaluate the potential contribution of miRNAs in acquired resistance to cisplatin in pancreatic cancer, we compared levels of more than 2000 human miRNAs in a cisplatin-resistant cell line (BxPC3-R) derived from parental (BxPC3) cells by step-wise exposure to increasing concentrations of the drug over more than 20 passages. The acquired drug resistance was accompanied by significant changes in the expression of 57 miRNAs, of which 23 were downregulated and 34 were upregulated. Employing a hidden Markov model (HMM) algorithm, we identified downregulation of miR-374b as likely being directly involved in acquisition of the drug-resistant phenotype. Consistent with this prediction, ectopic overexpression of miR-374b in the resistant BxPC3-R cells restored cisplatin sensitivity to levels approaching those displayed by the BxPC3 parental cells. The results are consistent with a growing body of evidence implicating miRNAs in acquired cancer-drug resistance and with the potential therapeutic value of these small regulatory RNAs in blocking and/or reversing the process.
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- 2016
21. Abstract 2115: An atlas of transposable element derived alternative splicing in cancer
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John F. McDonald, Lavanya Rishishwar, Dongjo Ban, Saurabh Gulati, Evan A. Clayton, Tzu-Chuan Huang, and I. King Jordan
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Transposable element ,Cancer Research ,medicine.anatomical_structure ,Oncology ,Atlas (anatomy) ,Alternative splicing ,medicine ,Computational biology ,Biology - Abstract
Transposable element (TE) derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially utilized in normal versus cancer tissues. We analyzed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumor tissue pairs across 13 cancer types, resulting in the discovery of 4,820 TE-generated alternative splice events distributed among 723 cancer-associated genes. SINEs (Alu) and LINEs (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes - including MYH11, WHSC1, and CANT1 - were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans-splicing mediated by dispersed TE repeats. Citation Format: Evan A. Clayton, Lavanya Rishishwar, Tzu-Chuan Huang, Saurabh Gulati, Dongjo Ban, John F. McDonald, I. King Jordan. An atlas of transposable element derived alternative splicing in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2115.
- Published
- 2020
22. Back to the future - The integration of big data with machine learning is re-establishing the importance of predictive correlations in ovarian cancer diagnostics and therapeutics
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John F. McDonald
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0301 basic medicine ,Big data ,MEDLINE ,Datasets as Topic ,Machine learning ,computer.software_genre ,Genetic therapy ,Machine Learning ,03 medical and health sciences ,Text mining ,Predictive Value of Tests ,Databases, Genetic ,medicine ,Humans ,Ovarian Neoplasms ,business.industry ,Obstetrics and Gynecology ,Genetic Therapy ,medicine.disease ,030104 developmental biology ,Oncology ,Predictive value of tests ,Female ,Artificial intelligence ,Ovarian cancer ,business ,computer - Abstract
• Scientific predictions may be based on known cause-effect relationships or simply correlations.
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- 2018
23. Glycomic Analysis of Membrane Glycoproteins with Bisecting Glycosylation from Ovarian Cancer Tissues Reveals Novel Structures and Functions
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Kazuhiro Aoki, Benedict B. Benigno, Samuel G. Mackintosh, Karen L. Abbott, Michael Tiemeyer, Heba Allam, and John F. McDonald
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Glycan ,endocrine system ,Glycosylation ,endocrine system diseases ,N-Acetylglucosaminyltransferases ,Biochemistry ,Article ,Glycomics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tandem Mass Spectrometry ,medicine ,Biomarkers, Tumor ,Humans ,RNA, Small Interfering ,glycoproteins ,Chromatography, High Pressure Liquid ,030304 developmental biology ,mass spectrometry ,chemistry.chemical_classification ,Ovarian Neoplasms ,0303 health sciences ,Membrane Glycoproteins ,biology ,Lectin ,biomarkers ,General Chemistry ,medicine.disease ,Molecular biology ,female genital diseases and pregnancy complications ,human tissue ,3. Good health ,Membrane glycoproteins ,Serous fluid ,bisecting N-linked glycans ,ovarian cancer ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Glycoprotein ,Ovarian cancer - Abstract
Biomarkers capable of detecting and targeting epithelial ovarian cancer cells for diagnostics and therapeutics would be extremely valuable. Ovarian cancer is the deadliest reproductive malignancy among women in the U.S., killing over 14 000 women each year. Both the lack of presenting symptoms and high mortality rates illustrate the need for earlier diagnosis and improved treatment of this disease. The glycosyltransferase enzyme GnT-III encoded by the Mgat3 gene is responsible for the addition of GlcNAc (N-acetylglucosamine) to form bisecting N-linked glycan structures. GnT-III mRNA expression is amplified in ovarian cancer tissues compared with normal ovarian tissue. We use a lectin capture strategy coupled to nano-ESI-RPLC-MS/MS to isolate and identify the membrane glycoproteins and unique glycan structures associated with GnT-III amplification in human ovarian cancer tissues. Our data illustrate that the majority of membrane glycoproteins with bisecting glycosylation are common to both serous and endometrioid histological subtypes of ovarian cancer, and several have been reported to participate in signaling pathways such as Notch, Wnt, and TGFβ.
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- 2014
24. Evidence for the importance of post-transcriptional regulatory changes in ovarian cancer progression and the contribution of miRNAs
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L. DeEtte Walker, Lilya V. Matyunina, Benedict B. Benigno, Haopeng Xiao, Weixuan Chen, Ronghu Wu, John F. McDonald, and Mengnan Zhang
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0301 basic medicine ,Science ,Biology ,Bioinformatics ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,microRNA ,Protein biosynthesis ,Humans ,RNA, Messenger ,RNA Processing, Post-Transcriptional ,skin and connective tissue diseases ,Neoplasm Staging ,Regulation of gene expression ,Ovarian Neoplasms ,Messenger RNA ,Multidisciplinary ,Gene Expression Profiling ,Ovary ,RNA ,Computational Biology ,3. Good health ,Cell biology ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Protein Biosynthesis ,Disease Progression ,Medicine ,Female ,RNA Interference ,sense organs ,Neoplasm Grading - Abstract
High-throughput technologies have identified significant changes in patterns of mRNA expression over cancer development but the functional significance of these changes often rests upon the assumption that observed changes in levels of mRNA accurately reflect changes in levels of their encoded proteins. We systematically compared the expression of 4436 genes on the RNA and protein levels between discrete tumor samples collected from the ovary and from the omentum of the same OC patient. The overall correlation between global changes in levels of mRNA and their encoding proteins is low (r = 0.38). The majority of differences are on the protein level with no corresponding change on the mRNA level. Indirect and direct evidence indicates that a significant fraction of the differences may be mediated by microRNAs.
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- 2017
25. Feasibility of Detecting Prostate Cancer by Ultraperformance Liquid Chromatography–Mass Spectrometry Serum Metabolomics
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Facundo M. Fernández, Manshui Zhou, Xiaoling Zang, Roman Mezencev, Tran Q. Long, Alexander G. Gray, Christina M. Jones, L. DeEtte Walker, John F. McDonald, and María Eugenia Monge
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MASS SPECTROMETRY ,Male ,Metabolite ,Tandem mass spectrometry ,Mass spectrometry ,PROSTATE CANCER ,Biochemistry ,chemistry.chemical_compound ,Prostate cancer ,IVDMIA ,Metabolomics ,Antigen ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,Biomarkers, Tumor ,medicine ,Humans ,Overdiagnosis ,IN VITRO DIAGNOSTIC MULTIVARIATE INDEX ASSAY ,Chromatography, High Pressure Liquid ,Aged ,Chromatography ,Chemistry ,Otras Ciencias Químicas ,Ciencias Químicas ,Prostatic Neoplasms ,General Chemistry ,PROSTATE CANCER DETECTION ,Middle Aged ,medicine.disease ,SUPPORT VECTOR MACHINES ,ULTRAPERFORMANCE LIQUID CHROMATOGRAPHY ,Case-Control Studies ,ONCOMETABOLOMICS ,Feasibility Studies ,MACHINE LEARNING METHODS ,UNTARGETED METABOLOMICS ,CIENCIAS NATURALES Y EXACTAS - Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men. The prevalent diagnosis method is based on the serum prostate-specific antigen (PSA) screening test, which suffers from low specificity, overdiagnosis, and overtreatment. In this work, untargeted metabolomic profiling of age-matched serum samples from prostate cancer patients and healthy individuals was performed using ultraperformance liquid chromatography coupled to high-resolution tandem mass spectrometry (UPLC-MS/MS) and machine learning methods. A metabolite-based in vitro diagnostic multivariate index assay (IVDMIA) was developed to predict the presence of PCa in serum samples with high classification sensitivity, specificity, and accuracy. A panel of 40 metabolic spectral features was found to be differential with 92.1% sensitivity, 94.3% specificity, and 93.0% accuracy. The performance of the IVDMIA was higher than the prevalent PSA test. Within the discriminant panel, 31 metabolites were identified by MS and MS/MS, with 10 further confirmed chromatographically by standards. Numerous discriminant metabolites were mapped in the steroid hormone biosynthesis pathway. The identification of fatty acids, amino acids, lysophospholipids, and bile acids provided further insights into the metabolic alterations associated with the disease. With additional work, the results presented here show great potential toward implementation in clinical settings. Fil: Zang, Xiaoling. Georgia Institute of Techology; Estados Unidos Fil: Jones, Christina M.. Georgia Institute of Techology; Estados Unidos Fil: Long, Tran Q.. Georgia Institute of Techology; Estados Unidos Fil: Monge, Maria Eugenia. Georgia Institute of Techology; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Zhou, Manshui. Georgia Institute of Techology; Estados Unidos Fil: DeEtte Walker, L.. Georgia Institute of Techology; Estados Unidos Fil: Mezencev, Roman. Georgia Institute of Techology; Estados Unidos Fil: Gray, Alexander. Georgia Institute of Techology; Estados Unidos Fil: McDonald, John F.. Georgia Institute of Techology; Estados Unidos Fil: Fernandez, Facundo M.. Georgia Institute of Techology; Estados Unidos
- Published
- 2014
26. Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer
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George W. Daneker, Loukia N. Lili, Lilya V. Matyunina, L. DeEtte Walker, and John F. McDonald
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Male ,Endocrinology, Diabetes and Metabolism ,Disease ,Biology ,Endocrinology ,Pancreatic cancer ,Gene expression ,Internal Medicine ,medicine ,Cluster Analysis ,Humans ,Epigenetics ,Molecular Targeted Therapy ,Precision Medicine ,Gene ,Genetic association ,Aged ,Oligonucleotide Array Sequence Analysis ,Genetics ,Hepatology ,cancer diagnostics ,business.industry ,Gene Expression Profiling ,Original Articles ,Middle Aged ,medicine.disease ,Gene expression profiling ,personalized cancer profiling ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,gene expression ,Female ,Personalized medicine ,business ,microarray ,Signal Transduction - Abstract
Supplemental digital content is available in the text., Objectives There is a growing body of evidence that targeted gene therapy holds great promise for the future treatment of cancer. A crucial step in this therapy is the accurate identification of appropriate candidate genes/pathways for targeted treatment. One approach is to identify variant genes/pathways that are significantly enriched in groups of afflicted individuals relative to control subjects. However, if there are multiple molecular pathways to the same cancer, the molecular determinants of the disease may be heterogeneous among individuals and possibly go undetected by group analyses. Methods In an effort to explore this question in pancreatic cancer, we compared the most significantly differentially expressed genes/pathways between cancer and control patient samples as determined by group versus personalized analyses. Results We found little to no overlap between genes/pathways identified by gene expression profiling using group analyses relative to those identified by personalized analyses. Conclusions Our results indicate that personalized and not group molecular profiling is the most appropriate approach for the identification of putative candidates for targeted gene therapy of pancreatic and perhaps other cancers with heterogeneous molecular etiology.
- Published
- 2014
27. Patterns of Transposable Element Expression and Insertion in Cancer
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Evan A Clayton, Lu Wang, Lavanya Rishishwar, Jianrong Wang, John F McDonald, and I. King Jordan
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0301 basic medicine ,Transposable element ,Tumor suppressor gene ,Alu ,Alu element ,Retrotransposon ,Biology ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,03 medical and health sciences ,Exon ,LINE-1 ,medicine ,Molecular Biosciences ,Molecular Biology ,lcsh:QH301-705.5 ,Original Research ,Genetics ,bioinformatics ,L1 ,medicine.disease ,Primary tumor ,retrotransposons ,SVA ,tumorigenesis ,030104 developmental biology ,lcsh:Biology (General) ,Adenocarcinoma ,mutation ,Carcinogenesis - Abstract
Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.
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- 2016
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28. Abstract 4306: JunD-induced cell proliferation requires MYC signaling in prostate cancer cells
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Nathan J. Bowen, Mengnan Zhang, Gabrielle Webb, Guangdi Wang, Jin Zou, Shafiq A. Khan, Bethtrice Thompson, Qiang Zhang, Ana Cecilia Millena, Shadyra Thompson, Lilya V. Matyunina, John F. McDonald, and Vanessa Eaton
- Subjects
Cancer Research ,integumentary system ,Cell growth ,Cyclin-dependent kinase 2 ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,PRDX3 ,Gene expression profiling ,Oncology ,Apoptosis ,biology.protein ,medicine ,Cancer research ,Carcinogenesis ,Transcription factor - Abstract
JunD, a member of the AP-1 transcription factor family, is involved in a variety of biological processes including cell proliferation, inflammation, differentiation, apoptosis, and carcinogenesis. We previously showed that JunD is essential for cell proliferation and demonstrated that the knock-down (KD) of JunD in PCa cells resulted in cell cycle arrest in G1-phase concomitant with a decrease in the levels of Id1, c-MYC, and Ki67, but an increased in p21 protein levels. Furthermore, the over-expression of JunD significantly increased proliferation in these cells suggesting that JunD regulates the expression of genes which are required for cell cycle progression. In this present study, employing gene expression profiling, quantitative proteomics, and validation approaches, we demonstrated that JunD KD is associated with distinct gene and protein expression patterns. Comparison integrative analysis by Ingenuity Pathway Analysis (IPA) identified 1) cell cycle control/regulation as the top canonical pathway whose members exhibited a significant decrease in their expression following JunD KD including PRDX3, PEA15, KIF2C, and CDK2, and 2) JunD target genes are involved in cell proliferation, with MYC as the key downstream regulator. Conversely, JunD over-expression induced cell proliferation and the expression of the above JunD target genes including c-MYC. When treated with JQ1, a c-MYC inhibitor, these cells exhibited a significant reduction in cell proliferation and a decrease in JunD target genes. Our data suggest that JunD-mediated cell proliferation involves MYC signaling and inhibiting its target genes may be an effective approach to blocking prostate carcinogenesis Citation Format: Bethtrice Thompson (Elliott), Ana Cecilia Millena, Lilya Matyunina, Mengnan Zhang, Jin Zou, Guangdi Wang, Qiang Zhang, Nathan Bowen, Vanessa Eaton, Gabrielle Webb, Shadyra Thompson, John McDonald, Shafiq Khan. JunD-induced cell proliferation requires MYC signaling in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4306.
- Published
- 2019
29. Chemotherapy-induced neuronal dysfunction in the absence of axon degeneration
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Eric J. Perreault, Paul Nardelli, John F. McDonald, Ann Marie Flores, Allison B. Wang, Stephen N. Housley, Lilya V. Matyunina, Timothy C. Cope, and Dario I. Carrasco
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,Mortality rate ,medicine.disease ,nervous system ,Chemotherapy induced ,Internal medicine ,medicine ,business ,Axon degeneration - Abstract
e15091 Background: Colorectal cancer is one of the three most prevalent cancers. Mortality rates have largely decreased due, in part, to advanced treatments such as platinum-based chemotherapy (e.g. oxaliplatin – OX). Unfortunately, OX induces severe off-target, neurotoxic side-effects in the sensory nervous system that can limit or end treatment and diminish patient quality of life for years. Patient symptoms are often attributed to dying-back degeneration of primary sensory axons despite the absence of conclusive evidence. We tested the hypothesis that proprioceptive disorders persisting after chemotherapy result solely from axon degeneration of muscle proprioceptors. Methods: We used a rat model to test our hypothesis. In a rodent model of OX clinical cancer treatment, one that exhibits sensorimotor deficits in a test of proprioceptive behavior, we performed single-neuron in vivo electrophysiological and immunohistological experiments. We then profiled transcriptomes of sensory neurons to gain unbiased insight into molecular evidence of degeneration. We compared the OX group of rats (n = 18) to healthy, control rats (n = 6) using hierarchical Bayesian analysis. Results: We found no evidence for sensory axon degeneration in electrophysiologic measures of axon conduction or in immunohistochemical analysis of the axon terminals of sensory neurons, OX and control rats were indistinguishable by these measures. Unbiased transcriptional profiling gave little evidence of neuronal degeneration, although genes related to axon transport showed signs of dysregulation. Structural degeneration was also ruled out by finding that all sensory neurons fired in response to stretch. Nonetheless, anomalous firing patterns were observed, e.g. decreased spike activity in response to mechanosensory stimulation, consistent with changes in ion channel physiology. Conclusions: Our findings reject the hypothesis that nerve degeneration is required to explain OX-related sensorimotor disorders. Our research suggests biological mechanisms that are alternative to axon degeneration in explaining sensorimotor changes due to OX.
- Published
- 2019
30. Molecular Profiling Predicts the Existence of Two Functionally Distinct Classes of Ovarian Cancer Stroma
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L. DeEtte Walker, Lilya V. Matyunina, Loukia N. Lili, Benedict B. Benigno, and John F. McDonald
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Cell signaling ,Stromal cell ,Article Subject ,lcsh:Medicine ,Receptors, Cell Surface ,Biology ,Ligands ,General Biochemistry, Genetics and Molecular Biology ,Stroma ,medicine ,Cluster Analysis ,Humans ,Aged ,Laser capture microdissection ,Ovarian Neoplasms ,General Immunology and Microbiology ,Microarray analysis techniques ,Gene Expression Profiling ,lcsh:R ,Ovary ,Epithelial Cells ,General Medicine ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Cancer cell ,Cancer research ,Female ,Stromal Cells ,Ovarian cancer ,Research Article - Abstract
Although stromal cell signaling has been shown to play a significant role in the progression of many cancers, relatively little is known about its importance in modulating ovarian cancer development. The purpose of this study was to investigate the process of stroma activation in human ovarian cancer by molecular analysis of matched sets of cancer and surrounding stroma tissues. RNA microarray profiling of 45 tissue samples was carried out using the Affymetrix (U133 Plus 2.0) gene expression platform. Laser capture microdissection (LCM) was employed to isolate cancer cells from the tumors of ovarian cancer patients (Cepi) and matched sets of surrounding cancer stroma (CS). For controls, ovarian surface epithelial cells (OSE) were isolated from the normal (noncancerous) ovaries and normal stroma (NS). Hierarchical clustering of the microarray data resulted in clear separations between the OSE, Cepi, NS, and CS samples. Expression patterns of genes encoding signaling molecules and compatible receptors in the CS and Cepi samples indicate the existence of two subgroups of cancer stroma (CS) with different propensities to support tumor growth. Our results indicate that functionally significant variability exists among ovarian cancer patients in the ability of the microenvironment to modulate cancer development.
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- 2013
31. Targeted in vivo delivery of EGFR siRNA inhibits ovarian cancer growth and enhances drug sensitivity
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Minati Satpathy, Roman Mezencev, Lijuan Wang, and John F. McDonald
- Subjects
0301 basic medicine ,Drug ,Oncology ,medicine.medical_specialty ,endocrine system diseases ,Organoplatinum Compounds ,media_common.quotation_subject ,Antineoplastic Agents ,Mice, SCID ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Clinical significance ,Epidermal growth factor receptor ,RNA, Small Interfering ,media_common ,Cell Proliferation ,Ovarian Neoplasms ,Gene knockdown ,Multidisciplinary ,biology ,business.industry ,medicine.disease ,female genital diseases and pregnancy complications ,3. Good health ,ErbB Receptors ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,biology.protein ,Female ,RNA Interference ,Delivery system ,Ovarian cancer ,business - Abstract
A functionalized nanohydrogel siRNA delivery system and a mouse model of serous ovarian cancer were used to test predictions from previous cell line studies that knockdown of EGFR (epidermal growth factor receptor) may be of clinical significance in the treatment of epithelial tumors especially with respect to the enhancement of platinum based therapies. Our results support these predictions and suggest that targeted delivery of EGFR siRNA may be an effective strategy for the treatment of ovarian and other epithelial tumors associated with elevated levels of EGFR and especially those demonstrating resistance to platinum-based therapies.
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- 2016
32. Depression, War, and aftermath
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John F. McDonald
- Subjects
medicine.medical_specialty ,Depression (economics) ,medicine ,Psychology ,Psychiatry - Published
- 2016
33. Highly-accurate metabolomic detection of early-stage ovarian cancer
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David A. Gaul, Benedict B. Benigno, Christina M. Jones, John F. McDonald, Facundo M. Fernández, Roman Mezencev, Alexander G. Gray, and Tran Q. Long
- Subjects
Adult ,Support Vector Machine ,Biology ,Bioinformatics ,Sensitivity and Specificity ,Article ,chemistry.chemical_compound ,Metabolomics ,Tandem Mass Spectrometry ,Biomarkers, Tumor ,medicine ,Metabolome ,Humans ,Stage (cooking) ,Chromatography, High Pressure Liquid ,Early Detection of Cancer ,Aged ,Ovarian Neoplasms ,Principal Component Analysis ,Multidisciplinary ,Fatty acid metabolism ,Case-control study ,Diagnostic test ,Middle Aged ,medicine.disease ,chemistry ,CA-125 Antigen ,Case-Control Studies ,Cohort ,Female ,Lysophospholipids ,Ovarian cancer - Abstract
High performance mass spectrometry was employed to interrogate the serum metabolome of early-stage ovarian cancer (OC) patients and age-matched control women. The resulting spectral features were used to establish a linear support vector machine (SVM) model of sixteen diagnostic metabolites that are able to identify early-stage OC with 100% accuracy in our patient cohort. The results provide evidence for the importance of lipid and fatty acid metabolism in OC and serve as the foundation of a clinically significant diagnostic test.
- Published
- 2015
34. Evidence for the Importance of Post-transcriptional Regulatorychanges in ovarian cancer metastasis and the contribution of miRNAs
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L. Walker, John F. McDonald, Ronghu Wu, Lilya V. Matyunina, Mengnan Zhang, Benedict B. Benigno, Haopeng Xiao, and Weixuan Chen
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,microRNA ,Obstetrics and Gynecology ,Medicine ,business ,medicine.disease ,Ovarian cancer ,Metastasis - Published
- 2017
35. Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells
- Author
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Christopher G. Hill, John F. McDonald, Lilya V. Matyunina, Lijuan Wang, and Jing Chen
- Subjects
Oncology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Cell Growth Processes ,Biology ,Transfection ,Metastasis ,Cell Line, Tumor ,Internal medicine ,microRNA ,Cell Adhesion ,medicine ,Humans ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Ovarian Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Mesenchymal stem cell ,Obstetrics and Gynecology ,medicine.disease ,Reverse transcription polymerase chain reaction ,Gene expression profiling ,MicroRNAs ,Female ,Ovarian cancer - Abstract
Objective Ovarian cancer (OC) is the most lethal of all gynecological malignancies primarily due to the sloughing-off of highly metastatic cells from primary tumors and their subsequent spread throughout the peritoneal cavity. Since the epithelial-to-mesenchymal transition (EMT) of OC cells located at the periphery of primary tumors is essential to this process, molecular interventions that can block EMT are of potential clinical significance. Members of the miR200 family of microRNAs have been implicated in EMT in other cancers. Our purpose was to determine if miR200 family microRNAs may be involved in EMT in OC and of potential therapeutic value in reducing OC metastasis. Methods Gene expression profiles of two OC cell lines with different metastatic potentials were monitored using qRT-PCR (quantitative reverse transcription polymerase chain reaction). The effect of over-expression of a miR-200 family microRNA (miR-429) in metastatic OC cells was monitored on molecular (qRT-PCR and microarray) and functional (morphology, migration, invasiveness and anchorage independence assays) levels. Results Molecular profiling of two OC cell lines with differing metastatic potentials identified significant differences in previously established epithelial and mesenchymal cell biomarkers including E-cadherin, ZEB1, ZEB2, miR-205 and miR-200 family microRNAs. Ectopic overexpression of miR-429, a member of the miR-200 family of microRNAs, in mesenchymal-like OC cells resulted in reversal of the mesenchymal phenotype (mesenchymal–epithelial transition, MET). Conclusions Our results indicate that miR-429 may not only be a useful biomarker of EMT in ovarian cancer, but also of potential therapeutic value in abating OC metastasis.
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- 2011
36. Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules
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Todd C. McDevitt, Ross A. Marklein, Richard L. Carpenedo, John F. McDonald, Andrés M. Bratt-Leal, Nathan J. Bowen, and Scott A. Seaman
- Subjects
animal structures ,Cellular differentiation ,Biophysics ,Retinoic acid ,Tretinoin ,Bioengineering ,Embryoid body ,Biology ,Article ,Biomaterials ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Cells, Cultured ,Embryonic Stem Cells ,Gene Expression Profiling ,Embryogenesis ,Cell Differentiation ,Embryonic stem cell ,Molecular biology ,Microspheres ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,Mechanics of Materials ,embryonic structures ,Microscopy, Electron, Scanning ,Ceramics and Composites ,Stem cell ,Endoderm ,Morphogen - Abstract
Cell specification and tissue formation during embryonic development are precisely controlled by the local concentration and temporal presentation of morphogenic factors. Similarly, pluripotent embryonic stem cells can be induced to differentiate in vitro into specific phenotypes in response to morphogen treatment. Embryonic stem cells (ESCs) are commonly differentiated as 3D spheroids referred to as embryoid bodies (EBs); however, differentiation of cells within EBs is typically heterogeneous and disordered. In this study, we demonstrate that in contrast to soluble morphogen treatment, delivery of morphogenic factors directly within EB microenvironments in a spatiotemporally controlled manner using polymer microspheres yields homogeneous, synchronous and organized ESC differentiation. Degradable PLGA microspheres releasing retinoic acid were incorporated directly within EBs and induced the formation of cystic spheroids uniquely resembling the phenotype and structure of early streak mouse embryos (E6.75), with an exterior of FOXA2+ visceral endoderm enveloping an epiblast-like layer of OCT4+ cells. These results demonstrate that controlled morphogen presentation to stem cells using degradable microspheres more efficiently directs cell differentiation and tissue formation than simple soluble delivery methods and presents a unique route to study the spatiotemporal effects of morphogenic factors on embryonic developmental processes in vitro.
- Published
- 2009
37. Magnetic Nanoparticle−Peptide Conjugates for in Vitro and in Vivo Targeting and Extraction of Cancer Cells
- Author
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John F. McDonald, Kenneth E. Scarberry, Erin B. Dickerson, and Z. John Zhang
- Subjects
Metal Nanoparticles ,Peptide ,Cell Separation ,Biochemistry ,Catalysis ,Magnetics ,Mice ,Peritoneal cavity ,Drug Delivery Systems ,Colloid and Surface Chemistry ,In vivo ,medicine ,Animals ,Neoplasm Metastasis ,Receptor ,Ovarian Neoplasms ,chemistry.chemical_classification ,Chemistry ,Receptor, EphA2 ,General Chemistry ,equipment and supplies ,medicine.disease ,In vitro ,Neoplasm Proteins ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,Magnetic nanoparticles ,Female ,Peptides ,Ovarian cancer ,human activities - Abstract
Magnetic cobalt spinel ferrite nanoparticles coated with biocompatible polygalacturonic acid were functionalized with ligands specific for targeting expressed EphA2 receptors on ovarian cancer cells. By using such magnetic nanoparticle-peptide conjugates, targeting and extraction of malignant cells were achieved with a magnetic field. Targeting ovarian cancer cells with receptor specific peptide-modified magnetic nanoparticles resulted in cell capture from a flow stream in vitro and from the peritoneal cavity of mice in vivo. Successful removal of metastatic cancer cells from the abdominal cavity and circulation using magnetic nanoparticle conjugates indicate the feasibility of a dialysis-like treatment and may improve long-term survival rates of ovarian cancer patients. This approach can be applied for fighting other cancers, such as leukemia, once the receptors on malignant cells are identified and the efficacy of targeting ligands is established.
- Published
- 2008
38. Emerging roles for PAX8 in ovarian cancer and endosalpingeal development
- Author
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Nathan J. Bowen, Benedict B. Benigno, Sanjay Logani, Mariam Akhtar, Erin B. Dickerson, Laura B. Kapa, and John F. McDonald
- Subjects
endocrine system ,endocrine system diseases ,Microarray ,Biology ,PAX8 Transcription Factor ,medicine ,Humans ,Paired Box Transcription Factors ,Fallopian Tubes ,Ovarian Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Ovary ,Obstetrics and Gynecology ,medicine.disease ,Immunohistochemistry ,female genital diseases and pregnancy complications ,Serous fluid ,medicine.anatomical_structure ,Oncology ,Cancer research ,Homeobox ,Female ,Ovarian cancer ,PAX8 ,Clear cell ,Fallopian tube - Abstract
Objectives. Epithelial ovarian carcinomas develop from ovarian surface epithelia that undergo complex differentiation to form distinguishable phenotypes resembling those of the epithelia of the female urogenital regions. While previous studies have implicated regulatory developmental homeobox (HOX) genes in this process, other factors responsible for this differentiation are largely unknown. Aberrant transcriptional expression of PAX8 has been reported in epithelial ovarian cancer, prompting us to initiate the molecular characterization of this master regulatory gene in ovarian cancer development. Methods. Immunohistochemistry, immunoblotting and RT-PCR were used to investigate the presence of PAX8 and its protein products in epithelial ovarian cancer subtypes, normal ovarian surface epithelia, ovarian inclusion cysts and normal endosalpingeal epithelia. Results. In this report, we confirm microarray results indicating that the transcription factor, PAX8, is highly expressed in epithelial ovarian cancer but absent from the precursor ovarian surface epithelia of healthy individuals. Furthermore, we report that PAX8 is localized to the nucleus of non-ciliated epithelia in simple ovarian epithelial inclusion cysts and in three epithelial ovarian cancer subtypes (serous, endometrioid and clear cell). We also determined that PAX8 is expressed in the non-ciliated, secretory cells of healthy fallopian tube mucosal linings but not in the adjacent ciliated epithelia. Conclusion. These findings support the hypothesis that PAX8 plays parallel roles in the development of epithelial ovarian cancer and in the developmental differentiation of coelomic epithelia into endosalpingeal epithelia.
- Published
- 2007
39. Depression and war
- Author
-
John F. McDonald
- Subjects
medicine.medical_specialty ,business.industry ,medicine ,Psychiatry ,business ,Depression (differential diagnoses) - Published
- 2015
40. Integrated sequence and expression analysis of ovarian cancer structural variants underscores the importance of gene fusion regulation
- Author
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Vinay K. Mittal and John F. McDonald
- Subjects
Biology ,Germline ,Fusion gene ,Gene expression ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Gene ,Genetics (clinical) ,Ovarian Neoplasms ,Gene Expression Profiling ,Chromosome Mapping ,Genetic Variation ,Chromosome Breakage ,Sequence Analysis, DNA ,medicine.disease ,Introns ,3. Good health ,Systems Integration ,Gene expression profiling ,Disease Progression ,Female ,Gene Fusion ,Chromosome breakage ,DNA microarray ,Ovarian cancer ,Research Article - Abstract
Background Genomic rearrangements or structural variants (SVs) are one of the most common classes of mutations in cancer. Methods An integrated DNA sequencing and transcriptional profiling (RNA sequence and microarray gene expression data) analysis was performed on six ovarian cancer patient samples. Matched sets of control (whole blood) samples from these same patients were used to distinguish cancer SVs of germline origin from those arising somatically in the cancer cell lineage. Results We detected 10,034 ovarian cancer SVs (5518 germline derived; 4516 somatically derived) at base-pair level resolution. Only 11 % of these variants were shown to have the potential to form gene fusions and, of these, less than 20 % were detected at the transcriptional level. Conclusions Collectively our results are consistent with the view that gene fusions and other SVs can be significant factors in the onset and progression of ovarian cancer. The results further indicate that it may not only be the occurrence of these variants in cancer but their regulation that contributes to their biological and clinical significance. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0118-9) contains supplementary material, which is available to authorized users.
- Published
- 2015
41. Design and Structure Activity Relationship of Tumor-Homing Histone Deacetylase Inhibitors Conjugated to Folic and Pteroic Acids
- Author
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James R. Kornacki, Milan Mrksich, Quaovi H. Sodji, Adegboyega K. Oyelere, and John F. McDonald
- Subjects
Models, Molecular ,Cell Survival ,Antineoplastic Agents ,Histone Deacetylase 1 ,Pharmacology ,Article ,KB Cells ,Romidepsin ,Structure-Activity Relationship ,Folic Acid ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Vorinostat ,Cell Proliferation ,Cardiotoxicity ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Cancer ,General Medicine ,medicine.disease ,HDAC1 ,Pterins ,Histone Deacetylase Inhibitors ,Folate receptor ,Drug Design ,Cancer cell ,Histone deacetylase ,Drug Screening Assays, Antitumor ,Reactive Oxygen Species ,medicine.drug ,HeLa Cells - Abstract
Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) – Vorinostat and Romidepsin – have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency.
- Published
- 2015
42. Functional and Evolutionary Significance of Human MicroRNA Seed Region Mutations
- Author
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Lilya V. Matyunina, John F. McDonald, Christopher G. Hill, and Neda Jabbari
- Subjects
Evolutionary Genetics ,lcsh:Medicine ,Gene Expression ,medicine.disease_cause ,Protein Engineering ,Conserved sequence ,Mice ,lcsh:Science ,Macromolecular Engineering ,Genome Evolution ,Conserved Sequence ,Genetics ,Regulation of gene expression ,Mutation ,Multidisciplinary ,DNA microarray ,Research Article ,Biotechnology ,Directed Evolution ,Evolutionary Processes ,Sequence analysis ,Molecular Sequence Data ,Sequence alignment ,Bioengineering ,Biology ,Genome Complexity ,Molecular Evolution ,Molecular Genetics ,Evolution, Molecular ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Computer Simulation ,Gene ,Molecular Biology ,Evolutionary Biology ,Base Sequence ,Models, Genetic ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Genome Analysis ,Microarray Analysis ,MicroRNAs ,Gene Expression Regulation ,Synthetic Bioengineering ,lcsh:Q ,Sequence Alignment - Abstract
MicroRNAs have emerged in recent years as important regulators of cell function in both normal and diseased cells. MiRNAs coordinately regulate large suites of target genes by mRNA degradation and/or translational inhibition. The mRNA target specificities of miRNAs in animals are primarily encoded within a 7 nt “seed region” mapping to positions 2–8 at the molecule's 5′ end. We here combine computational analyses with experimental studies to explore the functional significance of sequence variation within the seed region of human miRNAs. The results indicate that a substitution of even a single nucleotide within the seed region changes the spectrum of mRNA targets by >50%. The high functional cost of even single nucleotide changes within seed regions is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control.
- Published
- 2014
43. Transcriptional profiling of initial differentiation events in human embryonic stem cells
- Author
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Raj R. Rao, Susanne Warrenfeltz, Romdhane Rekaya, Stephen Dalton, Steven L. Stice, John D. Calhoun, and John F. McDonald
- Subjects
Mesoderm ,Carcinoma, Hepatocellular ,Cellular differentiation ,Cell Culture Techniques ,Biophysics ,Nodal signaling ,Biology ,Biochemistry ,medicine ,Humans ,Nodal signaling pathway ,Molecular Biology ,Cells, Cultured ,Tissue Engineering ,Primitive streak ,Stem Cells ,Cell Differentiation ,Cell Biology ,Molecular biology ,Embryonic stem cell ,Culture Media ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Culture Media, Conditioned ,embryonic structures ,Mesoderm formation ,NODAL ,Transcription Factors - Abstract
Currently, there are no differentiation strategies for human embryonic stem cells (hESCs) that efficiently produce one specific cell type, possibly because of lack of understanding of the genes that control signaling events prior to overt differentiation. sed HepG2 cell conditioned medium (MEDII), which induces early differentiation in mouse ES cells while retaining pluripotent markers, to query gene expression in hESCs. Treatment of adherent hESCs with 50% MEDII medium effected differentiation to a cell type with gene expression similar to primitive streak stage cells of mouse embryos. MEDII treatment up-regulates TDGF1 (Cripto), a gene essential for anterior-posterior axis and mesoderm formation in mouse embryos and a key component of the TGFB1/NODAL signaling pathway. LEFTYA, an antagonist of NODAL/TDGF1 signaling expressed in anterior visceral endoderm, is down-regulated with MEDII treatment, as is FST, an inhibitor of mesoderm induction via the related INHBE1 pathway. In summary, the TGFB1/NODAL pathway is important for primitive-streak and mesoderm formation and in using MEDII, we present a means for generating an in vitro cell population that maintains pluripotent gene expression (POU5F1, NANOG) and SSEA-4 markers while regulating genes in the TGFB1/NODAL pathway, which may lead to more uniform formation of mesoderm in vitro.
- Published
- 2004
44. Open source machine-learning algorithms for the prediction of optimal cancer drug therapies
- Author
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Fredrik O. Vannberg, Roman Mezencev, Cai Huang, and John F. McDonald
- Subjects
0301 basic medicine ,Microarrays ,Economics ,Computer science ,Cancer drugs ,Gene Expression ,Social Sciences ,lcsh:Medicine ,computer.software_genre ,Machine Learning ,Mathematical and Statistical Techniques ,Open Science ,0302 clinical medicine ,Neoplasms ,Gene expression ,Medicine and Health Sciences ,Feature (machine learning) ,Precision Medicine ,lcsh:Science ,media_common ,Multidisciplinary ,Pharmaceutics ,Ovarian Cancer ,Bioassays and Physiological Analysis ,Oncology ,030220 oncology & carcinogenesis ,Physical Sciences ,DNA microarray ,Algorithm ,Statistics (Mathematics) ,Open Source Software ,Algorithms ,Research Article ,Employment ,Drug ,Computer and Information Sciences ,Science Policy ,media_common.quotation_subject ,MEDLINE ,Antineoplastic Agents ,Research and Analysis Methods ,Machine learning ,Computer Software ,03 medical and health sciences ,Pharmacotherapy ,Drug Therapy ,Cancer Medicine ,Artificial Intelligence ,Support Vector Machines ,Cell Line, Tumor ,Component (UML) ,Genetics ,medicine ,Humans ,Statistical Methods ,Gene ,business.industry ,lcsh:R ,Biology and Life Sciences ,Cancers and Neoplasms ,Cancer ,medicine.disease ,Precision medicine ,Expression (mathematics) ,Support vector machine ,030104 developmental biology ,Cell culture ,Labor Economics ,Cancer cell ,lcsh:Q ,Artificial intelligence ,Ovarian cancer ,business ,Gynecological Tumors ,computer ,Mathematics ,Forecasting - Abstract
Precision medicine is a rapidly growing area of modern medical science and open source machine-learning codes promise to be a critical component for the successful development of standardized and automated analysis of patient data. One important goal of precision cancer medicine is the accurate prediction of optimal drug therapies from the genomic profiles of individual patient tumors. We introduce here an open source software platform that employs a highly versatile support vector machine (SVM) algorithm combined with a standard recursive feature elimination (RFE) approach to predict personalized drug responses from gene expression profiles. Drug specific models were built using gene expression and drug response data from the National Cancer Institute panel of 60 human cancer cell lines (NCI-60). The models are highly accurate in predicting the drug responsiveness of a variety of cancer cell lines including those comprising the recent NCI-DREAM Challenge. We demonstrate that predictive accuracy is optimized when the learning dataset utilizes all probe-set expression values from a diversity of cancer cell types without pre-filtering for genes generally considered to be "drivers" of cancer onset/progression. Application of our models to publically available ovarian cancer (OC) patient gene expression datasets generated predictions consistent with observed responses previously reported in the literature. By making our algorithm "open source", we hope to facilitate its testing in a variety of cancer types and contexts leading to community-driven improvements and refinements in subsequent applications.
- Published
- 2017
45. Integrated cancer systems biology: current progress and future promise
- Author
-
John F. McDonald
- Subjects
Cancer Research ,Systems Biology ,Systems biology ,Cancer ,General Medicine ,Computational biology ,Biology ,medicine.disease ,Oncology ,Neoplasms ,Cancer systems biology ,medicine ,Humans ,Current (fluid) ,Signal Transduction - Published
- 2011
46. Histone h1.3 suppresses h19 noncoding RNA expression and cell growth of ovarian cancer cells
- Author
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Chenyi Pan, Eric E. Bouhassira, Kaixiang Cao, Magdalena Medrzycki, Yunzhe Zhang, Yuhong Fan, Weijia Zhang, Nathalie Lailler, and John F. McDonald
- Subjects
Cancer Research ,endocrine system diseases ,Article ,Histones ,Histone H1 ,Cell Line, Tumor ,medicine ,Humans ,Cancer epigenetics ,Cell Proliferation ,Regulation of gene expression ,Ovarian Neoplasms ,Gene knockdown ,biology ,Oncogene ,DNA Methylation ,medicine.disease ,Molecular biology ,female genital diseases and pregnancy complications ,Gene Expression Regulation, Neoplastic ,Histone ,Oncology ,DNA methylation ,biology.protein ,Cancer research ,Female ,RNA, Long Noncoding ,Ovarian cancer - Abstract
Ovarian cancer is a deadly gynecologic malignancy for which novel biomarkers and therapeutic targets are imperative for improving survival. Previous studies have suggested the expression pattern of linker histone variants as potential biomarkers for ovarian cancer. To investigate the role of histone H1 in ovarian cancer cells, we characterize individual H1 variants and overexpress one of the major somatic H1 variants, H1.3, in the OVCAR-3 epithelial ovarian cancer cell line. We find that overexpression of H1.3 decreases the growth rate and colony formation of OVCAR-3 cells. We identify histone H1.3 as a specific repressor for the noncoding oncogene H19. Overexpression of H1.3 suppresses H19 expression, and knockdown of H1.3 increases its expression in multiple ovarian epithelial cancer cell lines. Furthermore, we demonstrate that histone H1.3 overexpression leads to increased occupancy of H1.3 at the H19 regulator region encompassing the imprinting control region (ICR), concomitant with increased DNA methylation and reduced occupancy of the insulator protein CTCF at the ICR. Finally, we demonstrate that H1.3 overexpression and H19 knockdown synergistically decrease the growth rate of ovarian cancer cells. Our findings suggest that H1.3 dramatically inhibits H19 expression, which contributes to the suppression of epithelial ovarian carcinogenesis. Cancer Res; 74(22); 6463–73. ©2014 AACR.
- Published
- 2014
47. SNAIL-induced epithelial-to-mesenchymal transition produces concerted biophysical changes from altered cytoskeletal gene expression
- Author
-
Quang Minh N. Kieu, Roman Mezencev, John F. McDonald, Daniel J. McGrail, and Michelle R. Dawson
- Subjects
Epithelial-Mesenchymal Transition ,Cell ,Gene Expression ,Breast Neoplasms ,Biology ,Biochemistry ,Biophysical Phenomena ,Transformation, Genetic ,Mesenchymal cell proliferation ,Genetics ,medicine ,Humans ,Epithelial–mesenchymal transition ,Cytoskeleton ,Molecular Biology ,Actin ,Oligonucleotide Array Sequence Analysis ,Cell Nucleus ,Actins ,Recombinant Proteins ,Cell biology ,Cytoskeletal Gene ,medicine.anatomical_structure ,Phenotype ,Cancer cell ,MCF-7 Cells ,Female ,Snail Family Transcription Factors ,Intracellular ,Biotechnology ,Transcription Factors - Abstract
A growing body of evidence suggests that the developmental process of epithelial-to-mesenchymal transition (EMT) is co-opted by cancer cells to metastasize to distant sites. This transition is associated with morphologic elongation and loss of cell-cell adhesions, though little is known about how it alters cell biophysical properties critical for migration. Here, we use multiple-particle tracking (MPT) microrheology and traction force cytometry to probe how genetic induction of EMT in epithelial MCF7 breast cancer cells changes their intracellular stiffness and extracellular force exertion, respectively, relative to an empty vector control. This analysis demonstrated that EMT alone was sufficient to produce dramatic cytoskeletal softening coupled with increases in cell-exerted traction forces. Microarray analysis revealed that these changes corresponded with down-regulation of genes associated with actin cross-linking and up-regulation of genes associated with actomyosin contraction. Finally, we show that this loss of structural integrity to expedite migration could inhibit mesenchymal cell proliferation in a secondary tumor as it accumulates solid stress. This work demonstrates that not only does EMT enable escape from the primary tumor through loss of cell adhesions but it also induces a concerted series of biophysical changes enabling enhanced migration of cancer cells after detachment from the primary tumor.
- Published
- 2014
48. Ectopic over-expression of miR-429 induces mesenchymal-to-epithelial transition (MET) and increased drug sensitivity in metastasizing ovarian cancer cells
- Author
-
Marián Švajdler, Lijuan Wang, Benedict B. Benigno, John F. McDonald, and Roman Mezencev
- Subjects
Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Mice, Nude ,Antineoplastic Agents ,Metastasis ,Mice ,Cell Line, Tumor ,microRNA ,Ascites ,medicine ,Animals ,Humans ,Aged ,Cisplatin ,Ovarian Neoplasms ,business.industry ,Mesenchymal stem cell ,Obstetrics and Gynecology ,medicine.disease ,Xenograft Model Antitumor Assays ,MicroRNAs ,Oncology ,Cell culture ,Concomitant ,Cancer research ,Female ,medicine.symptom ,Drug Screening Assays, Antitumor ,Ovarian cancer ,business ,medicine.drug - Abstract
Objective We recently determined that the ectopic over-expression of miR-429 and other members of the miR-200 family of microRNAs in ovarian cancer (OC) mesenchymal-like cell lines induces mesenchymal-to-epithelial transition (MET) with a concomitant increase in sensitivity to platinum drugs. We sought to determine if metastasizing OC cells isolated from an OC patient could also be induced by miR-429 to undergo MET and become sensitized to established first-line platinum-based therapies. Methods We established and characterized a new primary cell line (OCI-984) from free-floating OC cells isolated from the ascites fluid of an advanced stage OC patient. miR-429 was ectopically over-expressed in these cells. Results The over-expression of miR-429 in OCI-984 cells induced morphological, functional and molecular changes consistent with MET and a concomitant significant increase in the sensitivity of the converted cells to cisplatin. Conclusions Our findings indicate that the miR-200 family of microRNAs, and miR-429 in particular, play a critical role in the functioning of OC metastasizing cells and that targeted delivery of miR-429, and perhaps other miR-200 family members, in combination with platinum-based chemotherapies may be an effective strategy in reducing OC metastasis and tumor recurrence.
- Published
- 2014
49. Cloning, expression, and characterization of a nitric oxide synthase protein from Deinococcus radiodurans
- Author
-
Kulwant S. Aulak, Brian R. Crane, John F. McDonald, John A. Tainer, Elizabeth D. Getzoff, David J. Hosfield, Koustubh Panda, Subrata Adak, Dennis J. Stuehr, and Alexandrine M. Bilwes
- Subjects
inorganic chemicals ,Models, Molecular ,Time Factors ,Hemeprotein ,Protein Conformation ,Molecular Sequence Data ,Electrons ,Heme ,Arginine ,Ligands ,Nitric Oxide ,Catalysis ,Cofactor ,chemistry.chemical_compound ,Protein structure ,medicine ,Animals ,Amino Acid Sequence ,Cloning, Molecular ,Thermus ,Peptide sequence ,Multidisciplinary ,Dose-Response Relationship, Drug ,Sequence Homology, Amino Acid ,biology ,Deinococcus radiodurans ,Hydrogen Peroxide ,Tetrahydrobiopterin ,Biological Sciences ,biology.organism_classification ,Biopterin ,Molecular biology ,Protein Structure, Tertiary ,Nitric oxide synthase ,Dithiothreitol ,Kinetics ,Zinc ,Models, Chemical ,chemistry ,Biochemistry ,biology.protein ,Citrulline ,Nitric Oxide Synthase ,Dimerization ,Oxidation-Reduction ,NADP ,Protein Binding ,medicine.drug - Abstract
We cloned, expressed, and characterized a hemeprotein from Deinococcus radiodurans ( D. radiodurans NO synthase, deiNOS) whose sequence is 34% identical to the oxygenase domain of mammalian NO synthases (NOSoxys). deiNOS was dimeric, bound substrate Arg and cofactor tetrahydrobiopterin, and had a normal heme environment, despite its missing N-terminal structures that in NOSoxy bind Zn 2+ and tetrahydrobiopterin and help form an active dimer. The deiNOS heme accepted electrons from a mammalian NOS reductase and generated NO at rates that met or exceeded NOSoxy. Activity required bound tetrahydrobiopterin or tetrahydrofolate and was linked to formation and disappearance of a typical heme-dioxy catalytic intermediate. Thus, bacterial NOS-like proteins are surprisingly similar to mammalian NOSs and broaden our perspective of NO biochemistry and function.
- Published
- 2001
50. End-stage renal disease in liver transplants
- Author
-
Kenneth Abreo, Melissa Lynn, Gazi B. Zibari, and John F. McDonald
- Subjects
Transplantation ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Urology ,urologic and male genital diseases ,medicine.disease ,End stage renal disease ,Nephrotoxicity ,Diabetic nephropathy ,Liver disease ,Focal segmental glomerulosclerosis ,Membranous nephropathy ,Medicine ,Renal biopsy ,business ,Dialysis - Abstract
Renal dysfunction is one of the most significant problems following orthotopic liver transplantation (OLTx). Since the major risk factor for delayed renal dysfunction following OLTx is presumed to be cyclosporine (CsA) nephrotoxicity, it has been suggested that CsA is the most probably cause of end-stage renal disease (ESRD) in this population of patients. To test this hypothesis the records of OLTx patients in our center who developed ESRD requiring dialysis were reviewed. There were 132 consecutive adult patients with end-stage liver disease (ESLD) who received 146 OLTxs between 1990 and 2000. Five patients (3.4%) developed ESRD requiring dialysis. Four of the five patients developed nephrotic range proteinuria prior to reaching ESRD. Renal biopsy in four patients showed focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy and cyclosporine toxicity. The underlying hepatic and metabolic disease may have played a role in the genesis of glomerular diseases in these OLTx patients. Perhaps if more renal biopsies are performed in OLTx patients with chronic renal failure, we might discover that, although CsA/tacrolimus therapy is a definite risk factor for post-transplantation chronic renal failure, other disease processes may also play a significant role.
- Published
- 2001
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