Chendil Damodaran

University of Louisville, Louisville, Kentucky, United States

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Publications (50)193.3 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC); hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer.
    Current Colorectal Cancer Reports 12/2014; 10(4). DOI:10.1007/s11888-014-0252-3
  • Trinath P Das, Suman Suman, Chendil Damodaran
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    ABSTRACT: Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 07/2014; 53(7). DOI:10.1002/mc.22014 · 4.77 Impact Factor
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    ABSTRACT: Background:Autophagy is a catabolic process that has a vital role in cancer progression and treatment. Current chemotherapeutic agents, which target autophagy, result in growth inhibition in many cancer types. In this study, we examined the role of autophagy in breast cancer (BCa) patients as well as BCa cell lines.Methods:Tissue microarray was used to detect the expression of an autophagy marker, LC3B in BCa patients (normal/hyperplasia=8; grade-I=15, grade-II=84, and grade-III=27) and BCa cell lines. To modulate the activation of autophagy, we used novel herbal compound nimocinol acetate (NA) in BCa cell lines and the anticancer activity was measured by phenotypic and molecular analysis.Results:LC3B is highly expressed in tumours as compared with normal tissues. Activation of LC3B in NA-treated BCa (MCF-7 and MDA-MB-231) cells was evident as compared with other autophagy makers. Further, our results confirmed that NA-transcriptionally regulates LC3B (as confirmed by mRNA levels and reporter assay), which resulted in the formation of acidic autophagy vesicles and autolysosomes in BCa cells. Nimocinol acetate inhibited mTOR-mediated pro-survival signalling that resulted in inhibition of growth in BCa cells without affecting normal breast epithelial cells. Downregulation of LC3B expression by siRNA significantly inhibited the anticancer effects of NA in BCa cells.Conclusions:Together, our results suggest that LC3B is highly expressed in BCa tissues and increasing the threshold of LC3B activation dictates the pro-apoptotic function, which in turn, suppresses the growth of BCa cells. Nimocinol acetate could be a potential agent for treatment of BCa.British Journal of Cancer advance online publication, 19 June 2014; doi:10.1038/bjc.2014.203 www.bjcancer.com.
    British Journal of Cancer 06/2014; DOI:10.1038/bjc.2014.203 · 4.82 Impact Factor
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    ABSTRACT: Activation of the serine-threonine protein kinase AKT has emerged as a central feature of epithelial-mesenchymal transition (EMT), which is the initial step for metastasis in many cancer models, including colorectal cancer. The focus of our study was to dissect the role of AKT and its molecular regulation of EMT in colorectal cancer. HCT-116 colorectal cancer cells stably overexpressing AKT (AKT/HCT-116) showed significantly higher cell proliferation compared with vector-transfected cells (pCMV/HCT-116). Elevated expression of important EMT-related transcription factors and genes such as Snail, Slug, β-catenin, vimentin, and MMP-9 correlated with increased migration and invasion by AKT/HCT-116 cells. Further, in vivo studies confirmed that AKT/HCT-116 xenografts were highly aggressive and angiogenic in nature compared with pCMV/HCT-116 xenografts. Molecular analysis of tumor samples revealed transcriptional regulation of Snail, Slug, β-catenin, MMP-2, and MMP-9 in AKT/HCT-116 tumors. These results were supported by immunohistochemistry analysis. Low levels of E-cadherin expression with a concomitant increase in and nuclear localization of β-catenin were evident in AKT/HCT-116 tumors compared with control tumors. Increased microvessel formation coincident with high expression of Factor VIII and increased numbers of reticulocytes confirmed the angiogenic property of AKT/HCT-116 tumors. Our results confirm the potential role of AKT signaling in regulating EMT and angiogenesis in colorectal cancer and suggest that inhibition of AKT can serve as an important therapeutic strategy in modulating EMT in colorectal cancer growth and metastasis. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 02/2014; 53(S1). DOI:10.1002/mc.22076 · 4.77 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNA molecules present in all cell types, with sizes that vary from 18 to 28 nucleotides. miRNAs play significant roles in several biological processes, including development, differentiation, metabolism, initiation, and progression of cancer. In recent years, considerable research has been directed towards identifying miRNAs in peripheral blood from circulating tumor cells and disseminating tumor cells. Because these circulatory miRNAs are very stable and reproducible, their identification could be useful as prognostic markers as well as therapeutic agents for many cancers such as breast cancer. In this article, we review the role of specific circulatory miRNAs in breast cancer, with particular emphasis on their clinical importance.
    Frontiers in Bioscience 01/2014; 19:1-11. · 4.25 Impact Factor
  • Joe Luevano, Chendil Damodaran
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    ABSTRACT: Cadmium (Cd) is a toxic, heavy industrial metal that poses serious environmental health hazards to both humans and wildlife. Recently, Cd and Cd-containing compounds have been classified as known human carcinogens, and epidemiological data show causal associations with prostate, breast, and lung cancer. The molecular mechanisms involved in Cd-induced carcinogenesis are poorly understood and are only now beginning to be elucidated. The effects of chronic exposure to Cd have recently attracted great interest due to the development of malignancies in Cd-induced tumorigenesis in animals models. Briefly, various in vitro studies demonstrate that Cd can act as a mitogen, can stimulate cell proliferation and inhibit apoptosis and DNA repair, and can induce carcinogenesis in several mammalian tissues and organs. Thus, the various mechanisms involved in chronic Cd exposure and malignant transformations warrant further investigation. In this review, we focus on recent evidence of various leading general and tissue-specific molecular mechanisms that follow chronic exposure to Cd in prostate-, breast-, and lung-transformed malignancies. In addition, in this review, we consider less defined mechanisms such as epigenetic modification and autophagy, which are thought to play a role in the development of Cd-induced malignant transformation.
    Journal of Environmental Pathology Toxicology and Oncology 01/2014; 33(3):183-194. DOI:10.1615/JEnvironPatholToxicolOncol.2014011075 · 0.88 Impact Factor
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    S Suman, T P Das, C Damodaran
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    ABSTRACT: Background:Breast cancer stem cells (BCSCs) are characterized by high aldehyde dehydrogenase (ALDH) enzyme activity and are refractory to current treatment modalities, show a higher risk for metastasis, and influence the epithelial to mesenchymal transition (EMT), leading to a shorter time to recurrence and death. In this study, we focused on examination of the mechanism of action of a small herbal molecule, psoralidin (Pso) that has been shown to effectively suppress the growth of BSCSs and breast cancer cells (BCCs), in breast cancer (BC) models.Methods:ALDH(-) and ALDH(+) BCCs were isolated from MDA-MB-231 cells, and the anticancer effects of Pso were measured using cell viability, apoptosis, colony formation, invasion, migration, mammosphere formation, immunofluorescence, and western blot analysis.Results:Psoralidin significantly downregulated NOTCH1 signaling, and this downregulation resulted in growth inhibition and induction of apoptosis in both ALDH(-) and ALDH(+) cells. Molecularly, Pso inhibited NOTCH1 signaling, which facilitated inhibition of EMT markers (β-catenin and vimentin) and upregulated E-cadherin expression, resulting in reduced migration and invasion of both ALDH(-) and ALDH(+) cells.Conclusion:Together, our results suggest that inhibition of NOTCH1 by Pso resulted in growth arrest and inhibition of EMT in BCSCs and BCCs. Psoralidin appears to be a novel agent that targets both BCSCs and BCCs.British Journal of Cancer advance online publication, 15 October 2013; doi:10.1038/bjc.2013.642 www.bjcancer.com.
    British Journal of Cancer 10/2013; DOI:10.1038/bjc.2013.642 · 4.82 Impact Factor
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    ABSTRACT: Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer. Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including prostate cancer are increasing. The present study focused on the cell cycle regulatory potential of the withanolide withaferin A (1) on prostate cancer cells. Compound 1 induced G2/M arrest in both prostate cancer cell lines (PC-3 and DU-145) when treated for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee-1, phosphorylated histone H3, p21, and Aurora B. On the other hand, downregulation of cyclins (A2, B1, and E2) and a reduction in phosphorylated Cdc2 (Tyr15) were observed in 1-treated prostate cancer cells. In addition, decreased levels of phosphorylated Chk1 (Ser345) and Chk2 (Thr68) were evident in prostate cancer cells on treatment with 1. These results suggest that activation of Cdc2 leads to arrest in the M phase, with abnormal duplication, and initiation of mitotic catastrophe that results in cell death. In conclusion, these results show clearly the potential of 1 as a regulator of the G2/M phase of the cell cycle and as a therapeutic agent for prostate cancer.
    Journal of Natural Products 09/2013; 76(10). DOI:10.1021/np400441f · 3.95 Impact Factor
  • T. P. Das, C. Damodaran
    Cancer Research 08/2013; 73(8 Supplement):5457-5457. DOI:10.1158/1538-7445.AM2013-5457 · 9.28 Impact Factor
  • R. Subramani Reddy, P. Pahari, C. Damodaran
    Cancer Research 08/2013; 73(8 Supplement):1668-1668. DOI:10.1158/1538-7445.AM2013-1668 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):1479-1479. DOI:10.1158/1538-7445.AM2013-1479 · 9.28 Impact Factor
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    ABSTRACT: Deregulation of cell cycle progression is the hallmark of cancer; to this effect, several small molecules (AG-024322, AT7519, E7070, P1446A-05 and Flavopiridol) against cell cycle kinases are being developed to regulate cell cycle machinery that resulted in inhibition of tumor growth. The present study examined the effect of 3, 9-dihydroxy-2-prenylcoumestan-a furanocoumarin (Pso) on castration resistant prostate cancer cells (CRPC) cells. Treatment of CRPC (PC-3 and C4-2B) cells with Pso significantly caused irreversible G0-G1 cell cycle arrest that resulted in inhibition of cell proliferation. Protein analysis suggested that the expression of cdk inhibitors (CDKI) p21cip1 and p27kip1 were upregulated in both CRPC cell lines by Pso treatment. Studies using real-time reverse transcription-polymerase chain reaction analysis suggest that Pso transcriptionally regulates p21cip1 and p27kip1 in CRPC cells. Our immunofluorescence analysis pointed out that both p21cip1 and p27kip1 accumulated in the nucleus upon the treatment as compared to untreated CRPC cells. In addition, the cell cycle arrest was associated with decreased levels of both cyclins and cyclin-dependent kinases. However, cdk-4 appears to be more significantly downregulated when compared with either cyclins (D1, D2, D3 and Cyclin E) or other Cdk’s (cdk2/6). Also, we noted an increased hypophosphorylated level of retinoblastoma (Rb) with a decreased in Rb phosphorylation resulted in inhibition of E2F1 function. Further, transient over expression of Cdk4 overcomes the Pso-induced G0-G1 arrest in CRPC cells. Also, knockdown of p21cip1 and p27kip1 expression with small interfering RNA significantly abrogated the Pso-induced G0-G1 cell cycle arrest suggested that induction of p21cip1 and p27kip1 is required for G0-G1 cell cycle arrest by Pso. Altogether our results strongly suggest that Pso could be a potential candidate for prevention and therapy against CRPC. Our ongoing studies using xenograft models of CRPC in nude mice may reveal the in vivo efficacy of Pso.
    AACR 104th Annual Meeting 2013-- Apr6-Apr 10, 2013; Washington DC; 08/2013
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    ABSTRACT: This study examined the effect of 3, 9-dihydroxy-2-prenylcoumestan (pso), a furanocoumarin, on PC-3 and C4-2B castration-resistant prostate cancer (CRPC) cell lines. Pso caused significant G0/G1 cell cycle arrest and inhibition of cell growth. Molecular analysis of cyclin (D1, D2, D3, and E), cyclin-dependent kinase (cdk) (cdks 2, 4, and 6), and cdk inhibitor (p21 and p27) expression suggested transcriptional regulation of the cdk inhibitors and more significant downregulation of cdk4 than of cyclins or other cdks. Overexpression of cdk4, or silencing of p21 or p27, overcame pso-induced G0/G1 arrest, suggesting that G0/G1 cell cycle arrest is a potential mechanism of growth inhibition in CRPC cells.
    Cancer letters 05/2013; DOI:10.1016/j.canlet.2013.05.014 · 5.02 Impact Factor
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    ABSTRACT: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast tumors and these breast tumors are usually aggressive and highly metastatic. Unfortunately, treatment options for TNBCs are limited; we have identified a novel molecule, 2'-3'-dehydrosalannol (DHS) and in this study we investigated the anticancer effect of DHS against TNBC cells. TNBC (MDA-MB 231; MDA-MB 468) cells were treated with DHS and its effect on cell viability, apoptosis and molecular mechanisms were analyzed. DHS inhibited growth and induced apoptosis in TNBC cell lines. Molecular analysis suggested that DHS inhibited cathepsin-mediated pro-survival signaling [pAKT: phosphorylated protein kinase B; BCL-2: B-cell lymphoma 2 and cyclin D1] and induced pro-apoptotic markers such as BAX [BCL-2-associated X protein] and cleaved caspase-3. Our results demonstrate that DHS inhibits cathepsin-mediated pro-survival signaling which resulted in growth arrest of TNBC cells. These findings suggest that DHS may be a promising agent for the prevention and treatment of TNBC.
    Anticancer research 07/2012; 32(7):2801-6. · 1.87 Impact Factor
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    ABSTRACT: Radical prostectomy, radiation treatment, and/or hormone ablation therapy are the first lines of treatment for prostate cancer (CaP). Despite initial sensitivity to these treatments, CaP eventually progresses to castration-resistant CaP (CRPC), which is both aggressive and refractory to current therapeutic options. Accordingly, there is a tremendous need for a novel agent that can either retard or prevent the emergence of CRPC. Changes in reactive oxygen species (ROS) play a pivotal role in these processes. For example, a moderate increase in ROS promotes cell proliferation, but excessive amounts of ROS can induce apoptosis in cancer cells. Hence, it is possible to manipulate the redox (oxidative stress) system to selectively kill cancer cells. Psoralidin (Pso), a natural bioactive compound derived from Psoralea Corylifolia which is extensively used in Asian and African medicines, is an orally bioavailable dietary agent. We are the first group to demonstrate that Pso is non-toxic to normal prostate epithelial cells but specifically targets CaP cell lines (PC-3, DU-145, LnCaP and C4-2B) by inhibiting Akt and its downstream pro-survival signaling pathways. While dissecting the upstream events of Akt, we found that Pso generates ROS production and inhibits Akt mediated pro-survival signaling in both cell cultures and animal models of CRPC. Importantly, over expression of antioxidants, genetically (SOD/Catalase) or pharmacologically N-acetylcysteine (NAC) or treatment with ROS inhibitors Rotenone (mitochondrial) or Diphenylenel iodonium DPI (extra mitochondrial) inhibited Pso induced oxidative stress (both Intracellular and NADPH oxidase mediated) in CaP cells. Further, Pso in combination with anti-oxidants/ROS inhibitors significantly decreased the migratory and invasive property of CaP cell lines. Currently, we are delineating the role of Pso induced non-mitochondrial ROS generation, by analyzing expression patterns of NADPH oxidase and their subunits. We will apply genetic and/or pharmacological approaches to determine the key Pso target in CaP cell lines. Further, our chemopreventive and chemotherapeutic studies of Pso in both xenograft models and pilot experiments in transgenic adenocarcinoma of mouse prostate (TRAMP) model showed that Pso inhibits prostate tumor growth. These studies may suggest modulation of redox status could be a novel and powerful approach to chemoprevention and/or treatment of CaP.
    AACR 103rd Annual Meeting 2012-- Mar 31-Apr 4, 2012; Chicago, IL; 06/2012
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    ABSTRACT: In spite of early diagnosis and potent treatment modalities, breast cancer remains a leading cause of cancer related death among women. Studies have shown that breast cancer stem cells (BCSCs) are a subpopulation of tumor cells characterized by cell surface antigens CD44+/CD24-/low and high Aldehyde dehydrogenase (ALDH) enzyme activity. These cells are refractory to current treatment modalities, show higher risk of metastasis, a shorter time to recurrence, and relapse to death. Hence, it is imperative to find new effective treatments to target both BCSCs and breast cancer cells (BCs) in order to reduce mortality associated with this disease. Notch signaling is implicated in self-renewal of stem cells by transcriptional activation of its target genes such as Hes-1 and Hey-1. Hence, we screened small molecules, which target Notch signaling in ALDH+ and ALDH- breast cancer cells. We have identified a potent natural compound psoralidin that effectively inhibits ALDH+ and ALDH- breast cancer cells. Our results revealed, psoralidin significantly down-regulates Notch-1 and its target genes (Hes-1 and Hey-1), which resulted in growth inhibition and induction of apoptosis in both ALDH+ and ALDH- cells. Psoralidin significantly inhibited invasion and migration of ALDH+ (p<0.004) and ALDH- (p<0.001) cells. Interestingly, higher inhibition in invasion (MMPs, Laminin, ADAMs) and migration (E-cadherin, Vimentin, Snail, Slug, Zeb-1) was observed in case of ALDH- cells as compared to the ALDH+ cells. Our ongoing overexpression and inhibition studies on Notch-1 (in vitro and in vivo) may reveal the role of Notch-1 in ALDH+ and ALDH- cells. In addition, phenotypic and molecular analysis will help us to understand the mechanism behind tumor initiation, metastasis and recurrence of tumor growth in breast cancer. Our results may support psoralidin as a novel potent anticancer agent targeting both BCSCs and BCs.
    AACR 103rd Annual Meeting 2012-- Mar 31-Apr 4, 2012; Chicago, IL; 06/2012
  • Cancer Research 06/2012; 72(8 Supplement):2077-2077. DOI:10.1158/1538-7445.AM2012-2077 · 9.28 Impact Factor
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    ABSTRACT: Breast cancer is the leading cause of cancer-related deaths in women in the United States and many other countries. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for many cancers, but especially for breast cancer. Natural products are being tested with a hope of identifying novel potent molecules as anticancer agents. Phytochemicals and dietary compounds have been used for the treatment of various illnesses throughout history due to their safety, low toxicity, and general availability. Currently, many active phytochemicals are in clinical trials. Preclinical and clinical studies have indicated that daily consumption of dietary phytochemicals reduces the risk of several cancers. Phytochemicals can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes, by regulating inflammatory/proliferative signaling pathways, and by inducing apoptosis. This review article describes some of the potential natural cancer preventive compounds, along with a mechanistic discussion of their interactions with key cellular signal transduction pathways as well as their contribution to the suppression of breast cancer cell growth.
    Anti-cancer agents in medicinal chemistry 05/2012; DOI:10.2174/187152012803833008 · 2.94 Impact Factor
  • 102nd Annual Meeting AACR, Orange County Convention Center, Orlando, Florida; 04/2011
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    ABSTRACT: Streptomyces cyanogenus S-136 is the producer of previously reported landomycins A-D. An analysis of minor products of the strain led to isolation and structure elucidation of eight new congeners, named landomycins P-W (5, 6, 3, 17, 9, 10, 15, 7), along with 10 other known angucyclin(on)es. The structures of the new compounds were established from their NMR and mass spectrometry data. The activity of these angucyclin(on)es was determined using MCF-7 (estrogen responsive) and MDA-231 (estrogen refractory) breast cancer cell lines. Cell viability assays showed that anhydrolandomycinone (2), landomycinone (11), and landomycin A (16) showed the best combined activities in both MCF-7 and MDA-231 assays, with 2 being the most potent in the former and 11 and 16 in the latter. These data reveal that some of the aglycones are equipotent to the principle product 16, which contains the longest saccharide chain. Specifically, anhydrolandomycinone (2) was the most active against MCF-7 cells (IC(50) = 1.8 μM). Compounds with shorter saccharidal moieties were less potent against MCF-7. The fact that the most active landomycins have either long penta- or hexasaccharide chains or no sugars at all suggests that the large compounds may act by a different mode of action than their small sugar-free congeners. The results presented here provide more insights into the structure-activity relationship of landomycins.
    Journal of Natural Products 12/2010; 74(1):2-11. DOI:10.1021/np100469y · 3.95 Impact Factor

Publication Stats

320 Citations
193.30 Total Impact Points

Institutions

  • 2014
    • University of Louisville
      • Department of Urology
      Louisville, Kentucky, United States
  • 2012–2014
    • Texas Tech University Health Sciences Center
      • Department of Biomedical Sciences
      El Paso, Texas, United States
  • 2006–2010
    • University of Kentucky
      • Department of Clinical Sciences
      Lexington, Kentucky, United States