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Kuo J.,Clemson University | Zhang L.,Medical University of South Carolina | Bacro T.,MUSC | Yao H.,Clemson University | Yao H.,Medical University of South Carolina
Journal of Biomechanics | Year: 2010

The objective of this study was to determine the biphasic viscoelastic properties of human temporomandibular joint (TMJ) discs, correlate these properties with disc biochemical composition, and examine the relationship between these properties and disc dynamic behavior in confined compression. The equilibrium aggregate modulus (HA), hydraulic permeability (k), and dynamic modulus were examined between five disc regions. Biochemical assays were conducted to quantify the amount of water, collagen, and glycosaminoglycan (GAG) content in each region. The creep tests showed that the average equilibrium moduli of the intermediate, lateral, and medial regions were significantly higher than for the anterior and posterior regions (69.75±11.47kPa compared to 22.0±5.15kPa). Permeability showed the inverse trend with the largest values in the anterior and posterior regions (8.51±1.36×10-15m4/Ns compared with 3.75±0.72×10-15m4/Ns). Discs were 74.5% water by wet weight, 62% collagen, and 3.2% GAG by dry weight. Regional variations were only observed for water content which likely results in the regional variation in biphasic mechanical properties. The dynamic modulus of samples during confined compression is related to the aggregate modulus and hydraulic permeability of the tissue. The anterior and posterior regions displayed lower complex moduli over all frequencies (0.01-3Hz) with average moduli of 171.8-609.3kPa compared with 454.6-1613.0kPa for the 3 central regions. The region of the TMJ disc with higher aggregate modulus and lower permeability had higher dynamic modulus. Our results suggested that fluid pressurization plays a significant role in the load support of the TMJ disc under dynamic loading conditions. © 2010 Elsevier Ltd.

Zhang X.,Medical University of South Carolina | Hyer J.M.,MUSC | Yu H.,Medical University of South Carolina | D'Silva N.J.,University of Michigan | Kirkwood K.L.,Medical University of South Carolina
Cancer Research | Year: 2014

DUSP1 is a dual-specificity phosphatase that regulates mitogen-activated protein (MAP) kinase activity. Studies have associated loss of DUSP1 expression with certain cancers, but there has been no report of a mechanism by which this supports tumor progression. In this study, we found DUSP1 mRNA and protein decreased in human head and neck squamous cell carcinoma tissues compared with adjacent nontumor controls. To evaluate the impact of this difference, we compared the susceptibility of Dusp1-deficient mice with oral squamous carcinogenesis induced by 4-nitroquinoline 1-oxide. Dusp1-deficient mice displayed enhanced disease progression, characterized by advanced onset, histologic stage, and tumor burden. In a syngeneic model of tumor progression, subcutaneous injection of EO771 cells formed faster-growing tumors in Dusp1-deficient mice, an effect abrogated by inhibition of p38 MAP kinase with SB203580. Histologic and quantitative assessments demonstrated increased inflammation and deregulated chemokine and cytokine expression in Dusp1-deficient tumor tissues. Specifically, proinflammatory cytokine IL1β was elevated. IL1β production was recapitulated ex vivo in primary bone marrow-derived macrophages from Dusp1-deficient mice. Together, our results clearly establish the role of Dusp1 as a tumor suppressor gene that regulates cancer-associated in flammation. ©2014 AACR.

Jones D.P.,Emory University | Lemasters J.J.,MUSC | Boelsterli U.A.,University of Connecticut
Molecular Interventions | Year: 2010

Mitochondria play key roles in aerobic life and in cell death. Thus, interference of normal mitochondrial function impairs cellular energy and lipid metabolism and leads to the unleashing of mediators of cell death. The role of mitochondria in cell death due to drug hepatotoxicity has been receiving renewed attention and it is therefore timely to assess the current status of this area. © 2010 by the American Society for Pharmacology and Experimental Therapeutics.

Hull B.,MUSC
Journal of the South Carolina Medical Association (1975) | Year: 2012

Measurement of TSH is a commonly used test to diagnosed thyroid dysfunction. Multiple factors can interfere with available assays. We present a case where presence of HAMA caused a falsely elevated TSH levels resulting in unneccessary and costly diagnostic evaluation. Clinicians should be aware of the various factors affecting thyroid function assays. Test results that are inconsistent with the clinical picture should prompt further testing to exclude interferences prior to initiating unneccessary and potentially harmful clinical interventions.

News Article | August 30, 2016
Site: www.biosciencetechnology.com

A research team including developmental biologist Stephen A. Duncan, D. Phil., SmartState Chair of Regenerative Medicine at the Medical University of South Carolina (MUSC), has found a better way to purify liver cells made from induced pluripotent stem cells (iPSCs). Their efforts, published August 25, 2016 in Stem Cell Reports, will aid studies of liver disease for the National Heart, Lung, and Blood Institute (NHLBI)'s $80 million Next Generation Genetic Association Studies (Next Gen) Program. The University of Minnesota (Minneapolis) and the Medical College of Wisconsin (Milwaukee) contributed to the study. This new methodology could facilitate progress toward an important clinical goal: the treatment of patients with disease-causing mutations in their livers by transplant of unmutated liver cells derived from their own stem cells. Previous attempts to generate liver-like cells from stem cells have yielded heterogeneous cell populations that bear little resemblance to diseased livers in patients. NHLBI's Next Gen was created to bank stem cell lines sourced from patients in genome-wide association studies (GWAS). The goal of the NHLBI Next Gen Lipid Conditions sub-section--a collaborative effort between Duncan and Daniel J. Rader, M.D., and Edward E. Morrisey, Ph.D., both at the University of Pennsylvania--is to help determine the genetic sources of heart, lung, or blood conditions that also encompass the liver. These GWAS studies map the genomes in hundreds of people as a way to look for genetic mutation patterns that differ from the genomes of healthy individuals. A GWAS study becomes more powerful--more likely to find the correct genetic mutations that cause a disease--as more genomes are mapped. Once a panel of suspected mutations is built, stem cells from these individuals can be "pushed" in culture dishes to differentiate into any of the body's cells, as for example liver-, heart-, or vascular-like cells. The cells can be screened in high-throughput formats (i.e., cells are expanded and cultured in many dishes) to learn more about the mutations and to test panels of drugs that might ultimately help treat patients harboring a disease. The problem arises during the "pushing." For example, iPSCs stubbornly refuse to mature uniformly into liver-like cells when fed growth factors. Traditionally, antibodies have been used to recognize features of maturity on the surfaces of cells and purify cells that are alike. This approach has been crucial to stem cell research, but available antibodies that recognize mature liver cells are few and tend to recognize many different kinds of cells. The many types of cells in mixed populations have diverse characteristics that can obscure underlying disease-causing genetic variations, which tend to be subtle. "Without having a pure population of liver cells, it was incredibly difficult to pick up these relatively subtle differences caused by the mutations, but differences that are important in the life of an individual," said Duncan. Instead of relying on antibodies, Duncan and his crew embraced a new technology called chemoproteomic cell surface capture (CSC) technology. True to its name, CSC technology allowed the group to map the proteins on the surface of liver cells that were most highly produced during the final stages of differentiation of stem cells into liver cells. The most abundant protein was targeted with an antibody labeled with a fluorescent marker and used to sort the mature liver cells from the rest. The procedure was highly successful: the team had a population of highly pure, homogeneous, and mature liver-like cells. Labeled cells had far more similar traits of mature hepatocytes than unlabeled cells. Pluripotent stem cells that had not differentiated were excluded from the group of labeled cells. "That's important," said Duncan. "If you're wanting to transplant cells into somebody that has liver disease, you really don't want to be transplanting pluripotent cells because pluripotent cells form tumors called teratocarcinomas." Duncan cautions that transplantation of iPSC-derived liver cells is not yet ready for translation to the clinic. But the technology for sorting homogeneous liver cells can be used now to successfully and accurately model and study disease in the cell culture dish. "We think that by being able to generate pure populations, it will get rid of the variability, and therefore really help us combine with GWAS studies to identify allelic variations that are causative of a disease, at least in the liver," said Duncan.

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