Biomedical Sciences publications (MU)

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https://hdl.handle.net/10355/8663

Items in this collection are the scholarly output of the Department of Biomedical Sciences faculty, staff, and students, either alone or as co-authors, and which may or may not have been published in an alternate format. Items may contain more than one file type.

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APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
(Dove Medical Press Ltd., 2019) Liang, Y.; Besch-Williford, C.; Cook, M.T.; Belenchia, A.; Brekken, R.A.; Hyder, S.M.; Biomedical Sciences
Background: Approximately 15-20 percent of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80 percent of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis. Methods: APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models. Results: APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone. Conclusion: Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.
Endurance exercise training does not limit coronary atherosclerosis in familial hypercholesterolemic swine
(American Physiological Society, 2019) Tharp, D.L.; Masseau, I.; Ivey, J.; Laughlin, M.H.; Bowles, D.K.; Biomedical Sciences
Human studies demonstrate that physical activity reduces both morbidity and mortality of coronary heart disease (CHD) including decreased progression and/or regression of CHD with life-style modification which includes exercise. However, evidence supporting an intrinsic, direct effect of exercise in attenuating the development of CHD is equivocal. One limitation has been the lack of a large animal model with clinically evident CHD disease. Thus, we examined the role of endurance exercise in CHD development in a swine model of familial hypercholesterolemia (FH) that exhibits robust, complex atherosclerosis. FH swine were randomly assigned to either sedentary (Sed) or exercise trained (Ex) groups. At 10 months of age, Ex pigs began a 10 months, moderate-intensity treadmill-training intervention. At 14 months, all pigs were switched to a high-fat, high-cholesterol diet. CHD was assessed by intravascular ultrasound (IVUS) both prior to and after completion of 6 months on the HFC diet. Prior to HFC diet, Ex resulted in a greater coronary artery size in the proximal and mid sections of the LCX compared to SED, with no effect in the LAD. After 6 months on HFC diet, there was a 5–6 fold increase in absolute plaque volume in all segments of the LCX and LAD in both groups. At 20 months, there was no difference in vessel volume, lumen volume, absolute or relative plaque volume in either the LCX or LAD between Sed and Ex animals. These findings fail to support an independent, direct effect of exercise in limiting CHD progression in familial hypercholesterolemia.
Rats selectively bred for high voluntary physical activity behavior are not protected from the deleterious metabolic effects of a Western diet when sedentary
(Oxford University Press, 2019) Heese, A. J.; Roberts, C. K.; Hofheins, J. C.; Brown, J. D.; Ruegsegger, G. N.; Toedebusch, R. G.; Booth, F. W.; Biomedical Sciences
Background: Physical activity and diet are well-established modifiable factors that influence chronic disease risk. We developed a selectively bred, polygenic model for high and low voluntary running (HVR and LVR, respectively) distances. After 8 generations, large differences in running distance were noted. Despite these inherent behavioral differences in physical activity levels, it is unknown whether HVR rats would be inherently protected from diet-induced metabolic dysfunction. Objectives: The aim of this study was to determine whether HVR rats without voluntary running wheels would be inherently protected from diet-induced metabolic dysfunction. Methods: Young HVR, LVR, and a wild-type (WT) control group were housed with no running wheel access and fed either a normal diet (ND) or a high-sugar/fat Western diet (WD) for 8 wk. Body weight, percentage body fat (by dual-energy X-ray absorptiometry scan), blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), nonesterified fatty acids], and hepatic TG content were measured, and indices of insulin sensitivity were determined via an intravenous glucose tolerance test. Additionally, weekly energy intake and feed efficiency were calculated. Results: After 8 wk, significant differences in body weight and body fat percentage were noted in all WD animals compared with ND animals, with the LVR-WD exhibiting the greatest increase due, in part, to their enhanced feed efficiency. Lipid dysregulation was present in all WD rat lines compared with ND counterparts. Furthermore, LVR-WD rats had higher total cholesterol, HDL cholesterol, and TG concentrations, and higher areas under the curve (AUC) for insulin than HVR-WD and WT-WD, although HVR-WD animals had higher AUCglucose than both LVR-WD and WT-WD and higher LDL than WT-WD. Conclusions: In the absence of high voluntary running behavior, the genetic predisposition for high running in HVR did not largely protect them from the deleterious effects of a WD compared with LVR, suggesting genetic factors influencing physical activity levels may, in part, be independent from genes influencing metabolism.
A BAC transgene expressing human CFTR under control of its regulatory elements rescues Cftr knockout mice
(Nature Publishing Group, 2019) Gawenis L. R.; Hodges C. A.; McHugh D. R.; Valerio D. M.; Miron A.; Cotton C. U.; Liu J.; Walker N. M.; Strubberg A. M.; Gillen A. E.; Mutolo M. J.; Kotzamanis G.; Bosch J.; Harris A.; Drumm M. L.; Clarke L. L.; Biomedical Sciences
Small-molecule modulators of cystic fibrosis transmembrane conductance regulator (CFTR) biology show promise in the treatment of cystic fibrosis (CF). A Cftr knockout (Cftr KO) mouse expressing mutants of human CFTR would advance in vivo testing of new modulators. A bacterial artificial chromosome (BAC) carrying the complete hCFTR gene including regulatory elements within 40.1 kb of DNA 5? and 25 kb of DNA 3? to the gene was used to generate founder mice expressing hCFTR. Whole genome sequencing indicated a single integration site on mouse chromosome 8 (8qB2) with ~6 gene copies. hCFTR+ offspring were bred to murine Cftr KO mice, producing hCFTR+/mCftr? (H+/m?) mice, which had normal survival, growth and goblet cell function as compared to wild-type (WT) mice. Expression studies showed hCFTR protein and transcripts in tissues typically expressing mCftr. Functionally, nasal potential difference and large intestinal short-circuit (Isc) responses to cAMP stimulation were similar in magnitude to WT mice, whereas small intestinal cAMP ?Isc responses were reduced. A BAC transgenic mouse with functional hCFTR under control of its regulatory elements has been developed to enable the generation of mouse models of hCFTR mutations by gene editing for in vivo testing of new CF therapies.
Sedentary death syndrome is what researchers now call America's second largest threat to public health
(2001) Booth, Frank W., Ph. D.; Krupa, Donna J.
Obesity has doubled, Type 2 diabetes has increased nine-fold, and heart disease remains the number one cause of death for Americans. Sedentary Death Syndrome, or "SeDS," is a growing list of health disorders that are exacerbated by lack of physical activity, causing premature disability and death. Sixty percent of all Americans are at risk, including children. SeDS is expected to add as much as $3 trillion to healthcare costs over ten years, more than twice the tax cut passed by the US Senate.

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