Zaytseva Y.Y.,Markey Cancer Center |
Elliott V.A.,Markey Cancer Center |
Rychahou P.,Markey Cancer Center |
Kim J.T.,Markey Cancer Center |
And 4 more authors.
Carcinogenesis | Year: 2014
Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Etter N.M.,Pennsylvania State University |
Dressler E.V.,Markey Cancer Center |
Andreatta R.D.,University of Kentucky
International Journal of Speech-Language Pathology | Year: 2016
Purpose: Orofacial anatomy is unique from other body systems in that oral musculature inserts directly into the underlying cutaneous skin, allowing for tight temporal synchronicity between somatosensory and auditory performance feedback to maintain correct orofacial behaviours across the lifespan. Unfortunately, little is currently known regarding the changes in orofacial sensory capacities associated with ageing and how these somatosensory and auditory changes may impact feedback during functional behaviours such as speech or swallowing. The purpose of this descriptive study was to begin assessing the relationship between the auditory and labial somatosensory system in healthy ageing adults. Method: Pure-tone hearing thresholds were determined for 500, 1000, 2000 and 4000 Hz. Using a 2-alternative forced choice paradigm, 60 adults (19-84 years) completed vibrotactile detection thresholds (VDT) at the 5 and 10 Hz test frequencies. Result: A significant difference for age by group was identified at the 5 Hz test frequency. Spearman Correlations identified a significant correlation between age and pure tone hearing thresholds and the 5 Hz test frequency threshold. Conclusion: A relationship between pure tone hearing thresholds and labial somatosensory was identified. Future studies will begin the processing of modelling the complex multivariate sensorimotor relationship in healthy individuals before moving to a disordered population. © 2015 The Speech Pathology Association of Australia Limited.
Ely G.E.,University of Kentucky |
Fields M.,University of Louisville |
Dignan M.,Markey Cancer Center
Social Work in Public Health | Year: 2014
The purpose of this article is to describe a pilot study of 16 Appalachian Kentucky school districts designed to gather information about their school vaccination and health education programs in relation to the Human Papillomavirus (HPV) vaccine. School district administrators were contacted by a professional telephone interviewer and asked to participate in a structured interview that also included open-ended questions. Results suggest that few schools have school-based vaccination programs, and of those that do, very few programs include the HPV vaccine. A majority of respondents reported that information leaflets about HPV are available in the schools, whereas few schools include discussions of HPV in their health programs. Almost all respondents reported an excellent relationship with their county health departments, school nurses, and school social workers, although most schools lacked the presence of a school social worker. Implications for social work practice and policy and directions for future research are also discussed. © Taylor and Francis.
Starr M.E.,University of Kentucky |
Saito M.,Markey Cancer Center |
Evers B.M.,University of Kentucky |
Evers B.M.,Markey Cancer Center |
And 2 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2015
Expression of interleukin-6 (IL-6) upon acute inflammatory stress is significantly augmented by aging in adipose tissue, a major source of this cytokine. In the present study, we examined the mechanism of age-dependent IL-6 overproduction using visceral white adipose tissue from C57BL/6 mice. Upon treatment with lipopolysaccharide (LPS) in vitro, IL-6 was produced by adipose tissue explants, and secreted levels were significantly higher in cultures from aged (24 months) mice compared to young (4 months). Interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα), two inducers of IL-6, were mainly produced by the lungs and spleen rather than adipose tissue in mice after LPS injection. Treatment of adipose explants with physiological levels of IL-1β induced significant age-dependent secretion of IL-6, while treatment with TNFα had little effect, demonstrating an augmented response of adipose tissues to IL-1β in the aged. In vitro experiments utilizing a neutralizing antibody against IL-1β and in vivo experiments utilizing IL-1-receptor-1 deficient mice, confirmed that IL-6 overproduction in the aged is regulated by autocrine/paracrine action of IL-1β which specifically occurs in aged adipose tissues. These findings indicate an elevated inflammatory potential of adipose tissue in the aged and a unique IL-1β-mediated mechanism for IL-6 overproduction, which may impact age-associated vulnerability to acute inflammatory diseases such as sepsis. © 2015 The Author.
Miyamoto S.,University of California at San Diego |
Purcell N.H.,University of California at San Diego |
Smith J.M.,University of California at San Diego |
Gao T.,Markey Cancer Center |
And 7 more authors.
Circulation Research | Year: 2010
Rationale: The recently discovered PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) selectively dephosphorylates Akt at Ser473 and terminates Akt signaling in cancer cells. The regulatory role of PHLPP-1 in the heart has not been considered. Objective: To test the hypothesis that blockade/inhibition of PHLPP-1 could constitute a novel way to enhance Akt signals and provide cardioprotection. Methods and Results: PHLPP-1 is expressed in neonatal rat ventricular myocytes (NRVMs) and in adult mouse ventricular myocytes (AMVMs). PHLPP-1 knockdown by small interfering RNA significantly enhances phosphorylation of Akt (p-Akt) at Ser473, but not at Thr308, in NRVMs stimulated with leukemia inhibitory factor (LIF). The increased phosphorylation is accompanied by greater Akt catalytic activity. PHLPP-1 knockdown enhances LIF-mediated cardioprotection against doxorubicin and also protects cardiomyocytes against H2O2. Direct Akt effects at mitochondria have been implicated in cardioprotection and mitochondria/cytosol fractionation revealed a significant enrichment of PHLPP-1 at mitochondria. The ability of PHLPP-1 knockdown to potentiate LIF-mediated increases in p-Akt at mitochondria and an accompanying increase in mitochondrial hexokinase-II was demonstrated. We generated PHLPP-1 knockout (KO) mice and demonstrate that AMVMs isolated from KO mice show potentiated p-Akt at Ser473 in response to agonists. When isolated perfused hearts are subjected to ischemia/reperfusion, p-Akt in whole-heart homogenates and in the mitochondrial fraction is significantly increased. Additionally in PHLPP-1 KO hearts, the increase in p-Akt elicited by ischemia/reperfusion is potentiated and, concomitantly, infarct size is significantly reduced. Conclusions: These results implicate PHLPP-1 as an endogenous negative regulator of Akt activity and cell survival in the heart. © 2010 American Heart Association. All rights reserved.
Flaherty C.,University of Kentucky |
Ely G.E.,University of Kentucky |
Akers L.S.,Volunteers of America of Kentucky Inc. |
Dignan M.,Markey Cancer Center |
Bonistall Noland T.,University of Kentucky
Social Work in Health Care | Year: 2012
The purpose of the current study was to examine social work student attitudes toward the social work profession's perspective on certain aspects of reproductive health in the United States: contraception, emergency contraception, and the Human Papillomavirus (HPV) vaccine. Students at a large, public, land grant university were surveyed to determine whether their personal attitudes were in line with the National Association of Social Workers (NASW) stance on reproductive health outlined in the NASW policy statement on family planning and reproductive health. The relationship between levels of religious activity and attitudes toward these aspects of reproductive health was also examined. Results suggest that almost all of the respondents support public funding for family planning. Furthermore, almost all students indicate willingness to refer clients for general contraception. However, results related to emergency contraception indicate that 72% of students disagree that it should be available for adolescents over the counter, even with parental consent, which is inconsistent with the NASW perspective. Sixty-four percent of students report believing that the HPV vaccine is unsafe. Further, as levels of religious activity increased, acceptance of some of these aspects of reproductive health decreased. Implications for social work practice, education, and directions for future research are discussed. © 2012 Copyright Taylor and Francis Group, LLC.
Kohler H.,Markey Cancer Center
Immunotherapy | Year: 2013
This review recalls the history of homophilic antibody discovery and adaptation for cancer immunotherapy. Homophilic antibodies are a rare type of murine monoclonal antibody produced by plasmacytomas. They are self-binding in solid-phase assays and, in solution, are in an equilibrium of monomers and dimers. This equilibrium is controlled by antibody concentration and temperature, whereby low concentration and high temperature promote dimerization. The antibody domain that induces homophilic binding resides in the Vh region of the prototype T15 antibody. A peptide representing this domain can confer homophilicity to antibodies as a covalent conjugate. Homophilized antibodies have enhanced potency in target binding, induction of apoptosis, complement fixation and receptor-mediated signal growth inhibition. Titration of homophilic antibodies reveals a dose response skewed toward lower concentrations. The immunotherapeutic utility of homophilized antibodies has been demonstrated in vitro and in animal models. Clinical studies are needed to establish homophilic antibodies as novel, potent, immunotherapeutic agents. © 2013 Future Medicine Ltd.
Zhu J.,Markey Cancer Center |
Xiong G.,Markey Cancer Center |
Trinkle C.,University of Kentucky |
Xu R.,Markey Cancer Center
Histology and Histopathology | Year: 2014
Extracellular matrix (ECM), a major component of the cellular microenvironment, plays critical roles in normal tissue morphogenesis and disease progression. Binding of ECM to membrane receptor proteins, such as integrin, discoidin domain receptors, and dystroglycan, elicits biochemical and biomechanical signals that control cellular architecture and gene expression. These ECM signals cooperate with growth factors and hormones to regulate cell migration, differentiation, and transformation. ECM signaling is tightly regulated during normal mammary gland development. Deposition and alignment of fibrillar collagens direct migration and invasion of mammary epithelial cells during branching morphogenesis. Basement membrane proteins are required for polarized acinar morphogenesis and milk protein expression. Deregulation of ECM proteins in the long run is sufficient to promote breast cancer development and progression. Recent studies demonstrate that the integrated biophysical and biochemical signals from ECM and soluble factors are crucial for normal mammary gland development as well as breast cancer progression.
PubMed | University of Kentucky, Markey Cancer Center, University of Maryland, Baltimore and King Faisal Specialist Hospital And Research Center
Type: Journal Article | Journal: Journal of radiation oncology | Year: 2015
This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN).We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles.Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively.Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation.
PubMed | Markey Cancer Center
Type: Journal Article | Journal: Asian Pacific journal of cancer prevention : APJCP | Year: 2017
Objective: Dorema glabrum Fisch. & C.A. Mey is a perennial plant that has several curative properties. Anti-proliferative activity of seeds of this plant has been demonstrated in a mouse fibrosarcoma cell line. The aim of the present study was to evaluate cytotoxicity of D. glabrum root extracts in a human gastric adenocarcinoma (AGS) cell line and explore mechanisms of apoptosis induction, cell cycle arrest and altered gene expression in cancer cells. Materials and Methods: The MTT assay was used to evaluate IC50 values, EB/AO staining to analyze the mode of cell death, and flow cytometry to assess the cell cycle. Quantitative real-time polymerase chain reaction (qRT-PCR) amplification was performed with apoptosis and cell cycle-related gene primers, for cyclin D1, c-myc, survivin, VEGF, Bcl-2, Bax, and caspase-3 to determine alteration of gene expression. Results: Our results showed that n-hexane and chloroform extracts had greatest toxic effects on gastric cancer cells with IC50 values of 6.4 g/ml and 4.6 g/ml, respectively, after 72 h. Cell cycle analysis revealed that the population of treated cells in the G1 phase was increased in comparison to controls. Cellular morphological changes indicated induction of apoptosis. In addition, mRNA expression levels of Bax and caspase-3 were increased, and of bcl-2 survivin, VEGF, c-myc and cyclin D1 were decreased. Conclusion: Our study results suggest that D. glabrum has cytotoxic effects on AGS cells, characterized by enhanced apoptosis, reduced cell viability and arrest of cell cycling.