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Su Y.A.,GenProMarkers, Inc. | Yang J.,GenProMarkers, Inc. | Tao L.,GenProMarkers, Inc. | Nguyen H.,GenProMarkers, Inc. | He P.,U.S. Food and Drug Administration
Journal of Cancer | Year: 2010

Cytogenetic aberration and loss of heterozygosity (LOH) are documented on chromosome 6 in many cancers and the introduction of a neo-tagged chromosome 6 into breast cancer cell lines mediates suppression of tumorigenicity. In this study, we described the identification of KIAA1949 (phostensin) as a putative tumor suppressor gene. Our microarray analysis screened 25,985 cDNAs between a tumorigenic and metastatic breast cancer cell line MDA-MB-231 and the chromosome 6-mediated suppressed, non-tumorigenic and non-metastatic derivative cell line MDA/H6, resulting in the identification of 651 differentially expressed genes. Using customized microarrays containing these 651 cDNAs and 117 controls, we identified 200 frequently dysregulated genes in 10 breast cancer cell lines and 5 tumor tissues using MDA/H6 as reference. Our bioinformatics analysis revealed that chromosome 6 encodes 25 of these 200 genes, with 4 downregulation and 21 upergulation. Northern analysis validated microarray results and was used to detect the size and number of RNA species of 2 downregulated (KIAA1949, PTK7) and 2 upregulated (SFRS3, HMGN3) genes in the cell lines. Particularly, the KIAA1949 gene at 6p21.33, a band region with the frequent cytogenetic aberration and LOH encodes 4 poly(A)-RNA species (4.6-, 4-, 3- and 1.5-kb) in multiple normal and breast cancer samples. Microarray analysis revealed KIAA1949 downregulation in 86.7% (n=15) of breast cancer cell lines and tumor tissues. Northern analysis demonstrated undetectable and decreased expression of KIAA1949 in 100% (n=10) of breast cancer cell lines. Taken together, these results strongly suggest KIAA1949 is a novel candidate breast cancer suppressor gene. © Ivyspring International Publisher.


China M.,Forestry and Fisheries Promotion Center | Nakamura H.,Okinawa Prefectural Sea Farming Center | Hamakawa K.,Okinawa Prefectural Fisheries Research and Extension Center | Tamaki E.,Okinawa Prefectural Sea Farming Center | And 4 more authors.
Fish Pathology | Year: 2013

In 2008, the myxosporean emaciation disease was found in cultured Malabar grouper Epinephelus malabaricus in a fish farm in Okinawa Prefecture, Japan. The disease occurred in winter when water temperature ranged from 21 to 26°C, and the cumulative mortality reached 20-50% among culture tanks. In affected fish, cranial bones were externally apparent due to severe emaciation. The intestinal wall was very thin and the liver exhibited conspicuous green color. Morphological and molecular analyses demonstrated that the causative myxosporean was Enteromyxum leei. Histopathological examinations revealed that the epithelia of the intestine and bile duct of diseased fish were heavily infected with E. leei. The common bile duct was often obstructed by severe inflammation with degenerated tissues and bacteria, suggesting that the abnormal color of the liver was caused by cholestasis. Some diseased fish recovered in a laboratory when water temperature increased naturally to 27-30°C in summer months, and the parasite was not detected in those fish. Experimental transmission of E. leei to naive Malabar grouper was successfully achieved by cohabitation with infected grouper or by feeding with the feces of infected fish. This is a new host and locality record for E. leei.


Hu T.,Kunming Medical University | Hu T.,The Third Peoples Hospital of Yunnan Province | Zhang C.,Kunming Medical University | Zhang C.,Yunnan Provincial Maternal and Child Health Hospital | And 8 more authors.
BMC Cancer | Year: 2013

Background: Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.Methods: HEM (human epidermal melanocyte) cells and human melanoma cells with the wild-type G6PD gene (A375-WT), G6PD deficiency (A375-G6PD{increment}), G6PD cDNA overexpression (A375-G6PD{increment}-G6PD-WT), and mutant G6PD cDNA (A375-G6PD{increment}-G6PD-G487A) were subcutaneously injected into 5 groups of nude mice. Expressions of G6PD, STAT3, STAT5, cell cycle-related proteins, and apoptotic proteins as well as mechanistic exploration of STAT3/STAT5 were determined by quantitative real-time PCR (qRT-PCR), immunohistochemistry and western blot.Results: Delayed formation and slowed growth were apparent in A375-G6PD{increment} cells, compared to A375-WT cells. Significantly decreased G6PD expression and activity were observed in tumor tissues induced by A375-G6PD{increment}, along with down-regulated cell cycle proteins cyclin D1, cyclin E, p53, and S100A4. Apoptosis-inhibited factors Bcl-2 and Bcl-xl were up-regulated; however, apoptosis factor Fas was down-regulated, compared to A375-WT cells. Moderate protein expressions were observed in A375-G6PD{increment}-G6PD-WT and A375-G6PD{increment}-G6PD-G487A cells.Conclusions: G6PD may regulate apoptosis and expression of cell cycle-related proteins through phosphorylation of transcription factors STAT3 and STAT5, thus mediating formation and growth of human melanoma cells. Further study will, however, be required to determine potential clinical applications. © 2013 Hu et al.; licensee BioMed Central Ltd.


Hsiao Y.-H.,Chung Shan Medical University | Hsiao Y.-H.,Changhua Christian Hospital | Su Y.A.,GenProMarkers, Inc. | Tsai H.-D.,Changhua Christian Hospital | And 3 more authors.
International Journal of Biological Sciences | Year: 2010

Our previous studies revealed that pregnancy associated breast cancer (PABC) had significantly reduced nuclear p63 expression in myoepithelia, while intense cytoplasmic p63 expression in associated epithelia. Our current study assessed these epithelia using immunohistochemistry with a panel of aggressiveness and invasiveness related markers and comparative genomic hybridization (array-CGH) with over 30,000 DNA probes. These epithelia showed several unique alterations, including (1) immunohistochemical and morphological resemblance to invasive cancer, (2) significant gain in copy numbers of DNA coding genes for morphogenesis, angiogenesis, and metastasis, and (3) significant loss in copy numbers of DNA coding genes for tumor suppressors, cell adhesion, and macromolecular complex assembly or intra-cellular trafficking. Detected array-CGH alterations correlated well with in vivo expression of a number of corresponding proteins tested. These findings suggest that aberrant sub-cellular localization of p63 expression in normal or hyperplastic appearing epithelial cells may significant contribute to increased invasiveness and aggressiveness of these cells. © Ivyspring International Publisher. All rights reserved.


Jia M.,Uniformed Services University of the Health Sciences | Meng F.,GenProMarkers, Inc. | Smerin S.E.,Uniformed Services University of the Health Sciences | Xing G.,Uniformed Services University of the Health Sciences | And 6 more authors.
Journal of Visualized Experiments | Year: 2012

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for objective diagnosis but also for the evaluation of therapeutic efficacy and resilience to trauma. Ongoing research is directed at identifying molecular biomarkers for PTSD, including traumatic stress induced proteins, transcriptomes, genomic variances and genetic modulators, using biologic samples from subjects' blood, saliva, urine, and postmortem brain tissues. However, the correlation of these biomarker molecules in peripheral or postmortem samples to altered brain functions associated with psychiatric symptoms in PTSD remains unresolved. Here, we present an animal model of PTSD in which both peripheral blood and central brain biomarkers, as well as behavioral phenotype, can be collected and measured, thus providing the needed correlation of the central biomarkers of PTSD, which are mechanistic and pathognomonic but cannot be collected from people, with the peripheral biomarkers and behavioral phenotypes, which can. Our animal model of PTSD employs restraint and tail shocks repeated for three continuous days - the inescapable tail-shock model (ITS) in rats. This ITS model mimics the pathophysiology of PTSD 17, 7, 4, 10. We and others have verified that the ITS model induces behavioral and neurobiological alterations similar to those found in PTSD subjects 17, 7, 10, 9. Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients (DSM-IV-TR PTSD Criterian D/E 13), (2) enhanced plasma corticosterone (CORT) for several days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, indicating dysfunction of metabolic regulation. The experimental paradigms employed for this model are: (1) a learned helplessness paradigm in the rat assayed by measurement of acoustic startle response (ASR) and a charting of body mass; (2) microdissection of the rat brain into regions and nuclei; (3) enzyme-linked immunosorbent assay (ELISA) for blood levels of CORT; (4) a gene expression microarray plus related bioinformatics tools 18. This microarray, dubbed rMNChip, focuses on mitochondrial and mitochondria-related nuclear genes in the rat so as to specifically address the neuronal bioenergetics hypothesized to be involved in PTSD. © 2012 Creative Commons Attribution-NonCommercial License.


Li H.,Uniformed Services University of the Health Sciences | Li X.,Georgetown University | Smerin S.E.,Uniformed Services University of the Health Sciences | Zhang L.,Uniformed Services University of the Health Sciences | And 6 more authors.
Frontiers in Neurology | Year: 2014

The metabolic mechanisms underlying the development of exaggerated fear in posttraumatic stress disorder (PTSD) are not well defined. In the present study, alteration in the expression of genes associated with mitochondrial function in the amygdala of an animal model of PTSD was determined. Amygdala tissue samples were excised from 10 nonstressed control rats and10 stressed rats, 14 days post stress treatment.. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined using a cDNA microarray. During the development of the exaggerated fear associated with PTSD, 48 genes were found to be significantly upregulated and 37 were significantly downregulated in the amygdala complex based on stringent criteria (p<0.01). Ingenuity Pathway Analysis (IPA) revealed up or down regulation in the amygdala complex of four signaling networks - one associated with inflammatory and apoptotic pathways, one with immune mediators and metabolism, one with transcriptional factors, and one with chromatin remodeling. Thus, informatics of a neuronal gene array allowed us to determine the expression profile of mitochondrial genes in the amygdala complex of an animal model of PTSD. The result is a further understanding of the metabolic and neuronal signaling mechanisms associated with delayed and exaggerated fear. © 2014 Li, Li, Smerin, Zhang, Jia, Xing, Su, Wen, Benedek and Ursano.


PubMed | Georgetown University, Uniformed Services University of the Health Sciences and GenProMarkers, Inc.
Type: | Journal: Frontiers in neurology | Year: 2014

The metabolic mechanisms underlying the development of exaggerated fear in post-traumatic stress disorder (PTSD) are not well defined. In the present study, alteration in the expression of genes associated with mitochondrial function in the amygdala of an animal model of PTSD was determined. Amygdala tissue samples were excised from 10 non-stressed control rats and 10 stressed rats, 14days post-stress treatment. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined using a cDNA microarray. During the development of the exaggerated fear associated with PTSD, 48 genes were found to be significantly upregulated and 37 were significantly downregulated in the amygdala complex based on stringent criteria (p<0.01). Ingenuity pathway analysis revealed up- or downregulation in the amygdala complex of four signaling networks - one associated with inflammatory and apoptotic pathways, one with immune mediators and metabolism, one with transcriptional factors, and one with chromatin remodeling. Thus, informatics of a neuronal gene array allowed us to determine the expression profile of mitochondrial genes in the amygdala complex of an animal model of PTSD. The result is a further understanding of the metabolic and neuronal signaling mechanisms associated with delayed and exaggerated fear.


Su Y.A.,GenProMarkers, Inc. | Zhang Q.,GenProMarkers, Inc. | Su D.M.,GenProMarkers, Inc. | Tang M.X.,GenProMarkers, Inc.
International Journal of Biological Sciences | Year: 2011

Mitochondrial function is of particular importance in brain because of its high demand for energy (ATP) and efficient removal of reactive oxygen species (ROS). We developed rat mitochondrion-neuron focused microarray (rMNChip) and integrated bioinformatics tools for rapid identification of differential pathways in brain tissues. rMNChip contains 1,500 genes involved in mitochondrial functions, stress response, circadian rhythms and signal transduc-tion. The bioinformatics tool includes an algorithm for computing of differentially expressed genes, and a database for straightforward and intuitive interpretation for microarray results. Our application of these tools to RNA samples derived from rat frontal cortex (FC), hip-pocampus (HC) and hypothalamus (HT) led to the identification of differentially-expressed signal-transduction-bioenergenesis and neurotransmitter-synthesis pathways with a dominant number of genes (FC/HC = 55/6; FC/HT = 55/4) having significantly (p<0.05, FDR<10.70%) higher (≥1.25 fold) RNA levels in the frontal cortex than the others, strongly suggesting active generation of ATP and neurotransmitters and efficient removal of ROS. Thus, these tools for rapid and efficient identification of differential pathways in brain regions will greatly facilitate our systems-biological study and understanding of molecular mechanisms underlying complex and multifactorial neurodegenerative diseases.© Ivyspring International Publisher.


Grant
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2012

Our pilot study demonstrates that a novel proprietary biological dry powder/pellet (BDP) is useful for long-term preservation of nucleic acids in blood and bone marrow at room temperature (15"22 degree C). The concept of the BDP approach includes to dissolve the interested biological samples into nucleic acid protecting reagents and then to lyophilize mixture into BDP for preservation of nucleic acids at room temperature or 4 degree C for many years. To make BDP useful, we have also developed specific methods for efficient purification of high quality and quantity of RNA from BDP derived from small amount samples, for example, as low as 500 microliters of peripheral blood or 200 microliters of bone marrow. To our knowledge, BDP represents a paradigm shift in archiving biological samples for preservation of RNA and DNA at room temperature for years potentially as long as a human life span. We now apply for the DoD SBIR Phase I support to optimize the BDP methods, specifically, i) to determine preferable tissue for nucleic acid archiving, ii) to investigate sample collection protocol, processing, of the selected tissue, and iii) to initially define key potential aspects of storage conditions for preservation of nucleic acids.


Systems Biology Systems biology is a biology-based inter-disciplinary study field that focuses on complex and holistic interactions in biological systems and aims at solving fundamental molecular mechanisms underlying biological phenomena and problems that cannot be answered by conventional individual approaches. High-throughput technologies for generating enormous biological information, database for logistic organization of the information, computational methods for data mining, and comprehensive understanding of biological systems in study are all essential aspects of systems biology ...

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