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Papers by Dorothy Teegarden

Current developments in nutrition, Jun 1, 2019

Objectives: Loss of vitamin D receptor (VDR) is reported during tumor progression in cancer cells... more Objectives: Loss of vitamin D receptor (VDR) is reported during tumor progression in cancer cells, including breast cancer, with the implication that vitamin D may not be effective in inhibiting metastasis. The purpose of these studies was to investigate the expression and activity of the VDR in breast cancer cells at different stages of progression and the response to treatment with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). We hypothesized that although constitutive expression of VDR is downregulated during cancer progression, 1,25(OH) 2 D induces an increase in VDR transcriptional activity and VDR expression in metastatic breast cancer cells. Methods: We employed a series of human cells representing different stages of breast cancer, the MCF-10A series which includes untransformed MCF10A, Harvey-ras oncogene transfected early progression model (MCF10A-ras), and metastatic MCF10CA1a cells. Cells

Humana Press eBooks, Nov 9, 2007

Recently, research efforts have grown to better understand the mechanism of the metabolic syndrom... more Recently, research efforts have grown to better understand the mechanism of the metabolic syndrome, otherwise known as “syndrome X,” or the insulin-resistance syndrome. The metabolic syndrome leads to an increased risk for type 2 diabetes and cardiovascular disease (1,2). A conference sponsored by the National Heart, Lung and Blood Institute in collaboration with the American Heart Association (3) recently defined the metabolic syndrome as a complex of three out of five criteria: abdominal obesity, elevated triglycerides, lower high-density lipoprotein (HDL), hypertension, and elevated fasting plasma glucose (Fig. 1). The World Health Organization also required insulin resistance for diagnosis of the syndrome (3). It is estimated that 47 million Americans have been diagnosed with the metabolic syndrome, as established from census data from 2000 (1). According to the American Association of Clinical Endocrinologists, the prevalence of insulin-resistance syndrome has risen more than 60% over the past decade (4). Insulin resistance is present in the majority of people with the metabolic syndrome, is strongly associated with risk factors for cardiovascular disease (CVD), and is considered a prediabetic condition (3). Clinical measures that often cluster with the metabolic syndrome are other dyslipidemias, including elevated apolipoprotein B levels and small low-density lipoprotein particles; proinflammatory states as represented by elevated C-reactive protein; and prothrombotic states including plasma fibrinogen and decreased fibrolysis potentially through elevated plasminogen activator inhibitor1. Thus, the metabolic syndrome is a complex cluster of symptoms which puts individuals at greatly increased risk for the development of debilitating chronic diseases such as CVD and diabetes.

Journal of Nutrition, Sep 1, 2004

Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH) 2 D... more Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH) 2 D 3 ], may inhibit carcinogenesis. Because angiogenesis is crucial to carcinogenesis, 1,25(OH) 2 D 3 regulation of proangiogenic vascular endothelial growth factor (VEGF) secretion was investigated in cellular models for multistage carcinogenesis. Conditioned media from 1,25(OH) 2 D 3-treated C3H10T 1 ⁄2 mouse fibroblasts and their Harvey ras-oncogene transfected counterparts (rasneo11a cells) induced human umbilical vein endothelial cell (HUVEC) proliferation (1.3 and 0.3 times, respectively, P Ͻ 0.05), suggesting that 1,25(OH) 2 D 3 altered the angiogenic phenotype of the cells. Although rasneo11a cells secreted less VEGF than C3H10T 1 ⁄2 cells (97%, P Ͻ 0.005), 1,25(OH) 2 D 3 induced C3H10T 1 ⁄2 and rasneo11a cells to secrete 2 and 3 times, respectively, more VEGF than controls (P Ͻ 0.05). Similar effects on VEGF release occurred after 1,25(OH) 2 D 3 treatment of MCF10A and MCF10Aras cells, a human breast epithelial cell model for multistage carcinogenesis. In C3H10T 1 ⁄2 cells, 1,25(OH) 2 D 3 activated the VEGF promoter in a dose-dependent (5-100 nmol/L) manner (maximum 60%) and all doses induced VEGF secretion (P Ͻ 0.05). 1,25(OH) 2 D 3 induced VEGF mRNA expression (ϳ50%) from 2 through 24 h; VEGF release was significantly increased at 8 h and sustained for 24 h. VEGF mRNA expression and release declined as C3H10T 1 ⁄2 cells grew more confluent, whereas the magnitude of 1,25(OH) 2 D 3-stimulated changes in VEGF was greater in confluent (3.3 times RNA; 3.5 times release) than in subconfluent (50% RNA; 100% release) cultures (P Ͻ 0.05). Thus, 1,25(OH) 2 D 3 increases VEGF secretion, and in C3H10T 1 ⁄2 cells, this is likely through activation of the VEGF promoter and induction of gene expression. These data contribute to understanding the role 1,25(OH) 2 D 3 plays in regulation of angiogenesis in normal compared with disease states.

Journal of Nutrition, 2003

The area of dairy product components and weight regulation is attracting increasing interest with... more The area of dairy product components and weight regulation is attracting increasing interest with the rapid rise in related publications. The collection of reviews and original research in this symposium add to our understanding and potential impact of dairy products on the incidence of obesity and insulin resistance. Barr begins the symposium with a retrospective review of a number of dairy product and calcium supplementation trials conducted for reasons other than body weight or body composition (e.g., skeletal endpoints, blood pressure endpoints) (Barr 2002). This report exemplifies potential reasons that the relationship between calcium intake and changes in weight or body fat has not been previously observed. Calcium intake or calcium supplementation alone as the independent variable is unlikely to demonstrate the effects on weight because calorie intake must also be factored into the model. This is shown in the analysis by Lin et al. (2000), in which the relationship of calcium intake to changes in body fat is obscured unless calcium corrected for calories is used as the independent variable. In addition, many of the trials analyzed by Barr were completed in normal weight individuals whose weight was stable, given that these factors are often inclusionary criteria for studies designed with bone as the endpoint. The impact of calcium or dairy products may well be greatest in individuals whose adipocyte status is changing, such as during weight loss

Journal of Cell Biology, Aug 15, 1991

Expression of the oncogenic form of H-ras p21 in the mouse myogenic cell line, 23A2, blocks myoge... more Expression of the oncogenic form of H-ras p21 in the mouse myogenic cell line, 23A2, blocks myogenesis and inhibits expression of the myogenic regulatory factor gene, MyoDl. Previous studies from a number of laboratories have demonstrated that the activation of ras p21 is associated with changes in phospholipid metabolism that directly, or indirectly, lead to elevated levels of intracellular diacylglycerol and the subsequent activation of protein kinase C (PKC). To assess the importance of PKC activity to the ras-induced inhibition of skeletal myogenesis, we examined the levels of PKC activity associated with the terminal differentiation of wild-type myoblasts and with the differentiation-defective phenotype of 23A2 ras cells. We demonstrate that there is a 50% reduction in PKC activity during normal myogenesis and that PKC activity

Biosensors and Bioelectronics, 2011

Glucose is the central molecule in many biochemical pathways, and numerous approaches have been d... more Glucose is the central molecule in many biochemical pathways, and numerous approaches have been developed for fabricating micro biosensors designed to measure glucose concentration in/ near cells and/or tissues. An inherent problem for microsensors used in physiological studies is a low signal-to-noise ratio, which is further complicated by concentration drift due to the metabolic activity of cells. A microsensor technique designed to filter extraneous electrical noise and provide direct quantification of active membrane transport is known as self-referencing. Self-referencing involves oscillation of a single microsensor via computer-controlled stepper motors within a stable gradient formed near cells/tissues (i.e., within the concentration boundary layer). The non-invasive technique provides direct measurement of trans-membrane (or trans-tissue) analyte flux. A glucose micro biosensor was fabricated using deposition of nanomaterials (platinum black, multiwalled carbon nanotubes, Nafion) and glucose oxidase on a platinum/iridium microelectrode. The highly sensitive/selective biosensor was used in the self-referencing modality for cell/tissue physiological transport studies. Detailed analysis of signal drift/noise filtering via phase sensitive detection (including a post-measurement analytical technique) are provided. Using this highly sensitive technique, physiological glucose uptake is demonstrated in a wide range of metabolic and pharmacological studies. Use of this technique is demonstrated for cancer cell physiology, bioenergetics, diabetes, and microbial biofilm physiology. This robust and versatile biosensor technique will provide much insight into biological transport in biomedical, environmental, and agricultural research applications.

Medicine and Science in Sports and Exercise, 1996

Exercise may increase accretion of bone, potentially reducing the risk of osteoporosis. Previous ... more Exercise may increase accretion of bone, potentially reducing the risk of osteoporosis. Previous physical activity was assessed in 204 minimally active young women (18-31 yr). Bone mineral content (BMC) and bone mineral density (BMD) for the total body, femoral neck, and spine were assessed by a dual x-ray absorptiometer, and the radius by a single photon absorptiometer. Self-reported occupation and leisure activity for the 5 yr before enrollment in the study, as well as high school and college sports participation, were assigned energy expenditure (EE) values. From this information, EE variables were created as follows: 1) occupation EE + leisure EE + high school sport and/or college sport EE if within prior 5 yr (5-yr EE); 2) occupation EE + leisure EE (occupation + leisure EE); and 3) high school sport EE (high school EE). These variables were correlated with bone mineral measures and significant results follow (P < 0.05). Five-year EE and occupation + leisure EE correlated with all measures of bone health (r from 0.13 to 0.39). High school EE correlated with total body BMD (r = 0.25) and BMC (r = 0.28), femoral neck BMD (r = 0.28), radius BMC (r = 0.20), as well as spine BMD (r = 0.20) and BMC (r = 0.27). When weight was controlled, 5-yr EE and occupation + leisure EE remained correlated with all BMC measures (r from 0.14 to 0.22). When controlled for weight, high school EE remained associated with femoral neck BMD (r = 0.24), total body BMD (r = 0.20) and BMC (r = 0.26), and spine BMC (r = 0.17). To partially control for selection bias, data were also controlled for total body BMD. Five-year EE and occupation + leisure EE remained positively correlated with all measures of BMC. High school EE remained correlated both with femoral neck BMD and total body BMC. In multiple regression analyses, 5-yr EE or occupation + leisure EE were significant predictors of all measures of bone health, except femoral neck BMD. High school EE was a significant predictor for total body BMD and BMC, femoral neck BMD, and spine BMC.

Journal of Nutrition, 2003

Obesity is a growing epidemic with subsequent health consequences leading not only to reduced qua... more Obesity is a growing epidemic with subsequent health consequences leading not only to reduced quality of life but also to increased medical costs. Growing evidence supports a relationship between increased calcium intakes and reductions in body weight specific to fat mass. Since the first observations in rats Ͼ10 y ago, several recently published clinical studies support this relationship as well. The impact of calcium intake on weight loss or prevention of weight gain has been demonstrated in a wide age range of Caucasian and African-Americans of both genders. This review focuses on the results of clinical trials that have investigated the impact of calcium and dairy products on prevention of weight gain, weight loss or development of the insulin resistance syndrome. The implications of these results are that calcium may play a substantial contributing role in reducing the incidence of obesity and prevalence of the insulin resistance syndrome.

The American Journal of Clinical Nutrition, May 1, 1999

Background: Dietary calcium and milk intakes at specific ages may influence bone mineral measures... more Background: Dietary calcium and milk intakes at specific ages may influence bone mineral measures at specific sites during development of peak bone mass. Objective: Relations of previous milk intake and current calcium intake to current bone mineral measures were investigated in young women. Design: A food-frequency interview and recall of previous milk intake from early childhood to 12 y of age and during adolescence (13-19 y) were completed in a cross-sectional analysis in young women (age 18-31 y; n = 224). Three levels of previous milk intake were defined: 1) infrequently or never, 2) sometimes, and 3) at every or almost every meal. Total body (TB), femoral neck, radius (R), and spine (S) bone mineral density (BMD) and bone mineral content (BMC) were determined by using dual-energy Xray absorptiometry. Results: Childhood and adolescent milk intakes were positively correlated (r = 0.66). Childhood and adolescent milk intakes correlated with current calcium intakes (r = 0.26 and 0.33, respectively). Adolescent milk intake correlated with RBMD (r = 0.16). When weight was controlled for, adolescent milk intake correlated with TBBMD (r = 0.16), TBBMC (r = 0.21), SBMC (r = 0.16), RBMD (r = 0.18), and RBMC (r = 0.15). Current calcium intakes correlated with SBMC (r = 0.17). Regression analyses supported these results. Conclusions: Results were consistent with the hypothesis that higher milk intake during adolescence is associated with greater total body, spine, and radial bone mineral measures during development of peak bone mass, whereas current calcium intakes may influence SBMC. In addition, milk intake at a younger age may contribute to similar habits of milk intake later in life.

Journal of The American College of Nutrition, Dec 1, 2000

Relationships between micronutrients and dairy product intake and changes in body weight and comp... more Relationships between micronutrients and dairy product intake and changes in body weight and composition over two years were investigated. Two year prospective non-concurrent analysis of the effect of calcium intake on changes in body composition during a two year exercise intervention. 54 normal weight young women, 18 to 31 years of age. Mean intakes of nutrients of interest were determined from three-day diet records completed at baseline and every six months for two years. The change in total body weight and body composition (assessed by dual x-ray absorptiometry) from baseline to two years was also determined. Total calcium/kilocalories and vitamin A together predicted (negatively and positively, respectively) changes in body weight (R2 = 0.19) and body fat (R2 = 0.27). Further, there was an interaction of calcium and energy intake in predicting changes in body weight, such that, only at lower energy intakes, calcium intake (not adjusted for energy) predicted changes in body weight. Regardless of exercise group assignment, calcium adjusted for energy intake had a negative relationship and vitamin A intake a positive relationship with two year changes in total body weight and body fat in young women aged 18 to 31 years. Thus, subjects with high calcium intake, corrected by total energy intake, and lower vitamin A intake gained less weight and body fat over two years in this randomized exercise intervention trial.

The FASEB Journal, Apr 1, 2010

The FASEB Journal, Apr 1, 2009

Medicine and Science in Sports and Exercise, May 1, 1998

Medicine and Science in Sports and Exercise, Jun 1, 2001

Purpose: The effect of quantified resistance and high impact exercise training on bone mass as mo... more Purpose: The effect of quantified resistance and high impact exercise training on bone mass as modified by age and oral contraceptive (OCont) use in young women was studied. Methods: Women were categorized by age (18-23 vs 24-31 yr) and OCont use, and were then randomized into either three sessions of resistance exercise plus 60 min•wk-1 of jumping rope or a control group for 24 months. Total body, spine, femoral neck, greater trochanter, Ward's area, and radial bone mineral density (BMD) and/or content (BMC), biochemical markers of bone turnover, dietary intake of calcium, lean body mass, maximal oxygen uptake, and strength were determined at baseline and every 6 months. Results: Total body (TB) BMC percent change from baseline was higher in exercisers compared with nonexercisers at 6 and 24 months. OCont users had lower bone turnover at baseline and a decrease in TBBMC from baseline compared with non-OCont users at 24 months. Spine BMC and BMD decreased in the exercise and OCont group at 6 months and remained significantly below nonexercisers who used oral contraceptives at 2 yr. Femoral neck BMD also decreased in the exercise and oral contraceptive group at 6 months. Conclusions: Exercise prevented a decline in TBBMC seen in the nonexercisers. On the other hand, exercise in oral contraceptive users prevented the increase observed in the spine of the nonexercise plus OCont group.

Journal of Nutrition, Dec 1, 2005

Recent epidemiologic research suggests that dairy product intake or its components (calcium, vita... more Recent epidemiologic research suggests that dairy product intake or its components (calcium, vitamin D, and amount or source of protein) are associated with lower body weight or body fat. Clinical intervention trials designed to test this association during weight loss are promising, but still controversial. Few data are available on the effect of calcium or dairy products on prevention of weight gain in long-term trials. The mechanisms proposed to mediate the putative effect of dietary calcium are primarily the formation of fecal fatty acid complexes to reduce fat absorption and the regulation of energy metabolism, including lipolysis from adipocytes and fatty acid oxidation, through the calciotropic hormones, parathyroid hormone, and 1,25-dihydroxyvitamin D. Increased energy expenditure, increased satiety, or a shift from fat to lean mass must accompany these changes in lipid metabolism to achieve changes in fat mass; however, measurable changes in these other parameters either have not been tested or have not been noted uniformly. If dairy products or their components have an effect on altering fat mass, it is likely to be a small change that may have a substantial effect on the incidence of obesity over time.

Molecular and Cellular Biology/Genetics, Jul 1, 2021

Introduction: Breast cancer (BC) is the second deadliest cancer amongst women in the US, with met... more Introduction: Breast cancer (BC) is the second deadliest cancer amongst women in the US, with metastatic breast cancer being particularly deadly. Pyruvate carboxylase (PC) catalyzes the conversion of pyruvate to oxaloacetate for anaplerotic refilling of TCA intermediates, feeding numerous energetic and biosynthetic pathways. Upregulation of PC is an important contributor to metabolic reprogramming in both primary and metastatic BC. In this study, we investigate whether suppression of PC alters metabolism and drives microenvironmental adaptation in a primary tumor model of BC. Methods: C57/Bl6 mice were injected with M-Wnt cells transduced with doxycycline-inducible ShRNA targeting PC. Doxycycline treatment began once tumors were palpable. Tumors were harvested 4 weeks following injection. Tumor transcriptomic analysis was conducted via GSEA and enrichment mapping. Digital cytometry using CIBORSORTx was conducted to determine tumor microenvironment immune cell composition. In vitro metabolic adaptation to PC suppression in BC cell lines following knockdown of PC was analyzed. Perturbations of mitochondrial metabolism and respiration were assessed by extracellular flux analysis. Assays of extracellular lactate and glucose concentrations determined changes in the production and utilization of carbon sources in the context of loss of PC Results: Metabolic assays revealed that cells with PC knockdown export more lactate into their environment and respire less efficiently, without consuming additional glucose. This indicates potential mitochondrial dysfunction with loss of PC-derived anaplerosis. In vivo suppression of PC resulted in increased tumor mass and volume relative to control. Gene expression data from PC knockdown tumors revealed distinct transcriptomic profiles between groups. GSEA analysis further showed profound suppression of immunological pathways following loss of PC, indicating that PC knockdown resulted in a diminished immune response. Digital cytometry supported this finding with PC suppression resulting in decreased proportions of critical innate and adaptive immune cell populations. Conclusion: Metabolic assays revealed increased flux through lactate production with a decrease in mitochondrial respiration, suggesting that diminished PC-mediated anaplerosis is altering the fate of carbon sources and contributing to metabolic reprogramming. Suppression of PC resulted in tumors with distinct transcriptomic profiles versus control, with immune response signatures being diminished in response to loss of PC. We conclude that PC knockdown promotes a metabolically altered tumor microenvironment associated with immunosuppression, tumor progression, and increased metastatic potential. This work was supported by R35CA197627 to S. Hursting, and R01CA232589 to D. Teegarden and S. Hursting. Citation Format: Michael F. Coleman, Alexander J. Pfeil, Violet Kiesel, Suhas K. Etigunta, Michael K. Wendt, Dorothy Teegarden, Stephen D. Hursting. Mammary tumor microenvironment reprogramming in response to pyruvate carboxylase modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2323.

The FASEB Journal, Apr 1, 2009

The FASEB Journal, Mar 1, 2008

CRC Press eBooks, Jul 29, 2013

The FASEB Journal, Apr 1, 2010

Current developments in nutrition, Jun 1, 2019

Objectives: Loss of vitamin D receptor (VDR) is reported during tumor progression in cancer cells... more Objectives: Loss of vitamin D receptor (VDR) is reported during tumor progression in cancer cells, including breast cancer, with the implication that vitamin D may not be effective in inhibiting metastasis. The purpose of these studies was to investigate the expression and activity of the VDR in breast cancer cells at different stages of progression and the response to treatment with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). We hypothesized that although constitutive expression of VDR is downregulated during cancer progression, 1,25(OH) 2 D induces an increase in VDR transcriptional activity and VDR expression in metastatic breast cancer cells. Methods: We employed a series of human cells representing different stages of breast cancer, the MCF-10A series which includes untransformed MCF10A, Harvey-ras oncogene transfected early progression model (MCF10A-ras), and metastatic MCF10CA1a cells. Cells

Humana Press eBooks, Nov 9, 2007

Recently, research efforts have grown to better understand the mechanism of the metabolic syndrom... more Recently, research efforts have grown to better understand the mechanism of the metabolic syndrome, otherwise known as “syndrome X,” or the insulin-resistance syndrome. The metabolic syndrome leads to an increased risk for type 2 diabetes and cardiovascular disease (1,2). A conference sponsored by the National Heart, Lung and Blood Institute in collaboration with the American Heart Association (3) recently defined the metabolic syndrome as a complex of three out of five criteria: abdominal obesity, elevated triglycerides, lower high-density lipoprotein (HDL), hypertension, and elevated fasting plasma glucose (Fig. 1). The World Health Organization also required insulin resistance for diagnosis of the syndrome (3). It is estimated that 47 million Americans have been diagnosed with the metabolic syndrome, as established from census data from 2000 (1). According to the American Association of Clinical Endocrinologists, the prevalence of insulin-resistance syndrome has risen more than 60% over the past decade (4). Insulin resistance is present in the majority of people with the metabolic syndrome, is strongly associated with risk factors for cardiovascular disease (CVD), and is considered a prediabetic condition (3). Clinical measures that often cluster with the metabolic syndrome are other dyslipidemias, including elevated apolipoprotein B levels and small low-density lipoprotein particles; proinflammatory states as represented by elevated C-reactive protein; and prothrombotic states including plasma fibrinogen and decreased fibrolysis potentially through elevated plasminogen activator inhibitor1. Thus, the metabolic syndrome is a complex cluster of symptoms which puts individuals at greatly increased risk for the development of debilitating chronic diseases such as CVD and diabetes.

Journal of Nutrition, Sep 1, 2004

Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH) 2 D... more Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH) 2 D 3 ], may inhibit carcinogenesis. Because angiogenesis is crucial to carcinogenesis, 1,25(OH) 2 D 3 regulation of proangiogenic vascular endothelial growth factor (VEGF) secretion was investigated in cellular models for multistage carcinogenesis. Conditioned media from 1,25(OH) 2 D 3-treated C3H10T 1 ⁄2 mouse fibroblasts and their Harvey ras-oncogene transfected counterparts (rasneo11a cells) induced human umbilical vein endothelial cell (HUVEC) proliferation (1.3 and 0.3 times, respectively, P Ͻ 0.05), suggesting that 1,25(OH) 2 D 3 altered the angiogenic phenotype of the cells. Although rasneo11a cells secreted less VEGF than C3H10T 1 ⁄2 cells (97%, P Ͻ 0.005), 1,25(OH) 2 D 3 induced C3H10T 1 ⁄2 and rasneo11a cells to secrete 2 and 3 times, respectively, more VEGF than controls (P Ͻ 0.05). Similar effects on VEGF release occurred after 1,25(OH) 2 D 3 treatment of MCF10A and MCF10Aras cells, a human breast epithelial cell model for multistage carcinogenesis. In C3H10T 1 ⁄2 cells, 1,25(OH) 2 D 3 activated the VEGF promoter in a dose-dependent (5-100 nmol/L) manner (maximum 60%) and all doses induced VEGF secretion (P Ͻ 0.05). 1,25(OH) 2 D 3 induced VEGF mRNA expression (ϳ50%) from 2 through 24 h; VEGF release was significantly increased at 8 h and sustained for 24 h. VEGF mRNA expression and release declined as C3H10T 1 ⁄2 cells grew more confluent, whereas the magnitude of 1,25(OH) 2 D 3-stimulated changes in VEGF was greater in confluent (3.3 times RNA; 3.5 times release) than in subconfluent (50% RNA; 100% release) cultures (P Ͻ 0.05). Thus, 1,25(OH) 2 D 3 increases VEGF secretion, and in C3H10T 1 ⁄2 cells, this is likely through activation of the VEGF promoter and induction of gene expression. These data contribute to understanding the role 1,25(OH) 2 D 3 plays in regulation of angiogenesis in normal compared with disease states.

Journal of Nutrition, 2003

The area of dairy product components and weight regulation is attracting increasing interest with... more The area of dairy product components and weight regulation is attracting increasing interest with the rapid rise in related publications. The collection of reviews and original research in this symposium add to our understanding and potential impact of dairy products on the incidence of obesity and insulin resistance. Barr begins the symposium with a retrospective review of a number of dairy product and calcium supplementation trials conducted for reasons other than body weight or body composition (e.g., skeletal endpoints, blood pressure endpoints) (Barr 2002). This report exemplifies potential reasons that the relationship between calcium intake and changes in weight or body fat has not been previously observed. Calcium intake or calcium supplementation alone as the independent variable is unlikely to demonstrate the effects on weight because calorie intake must also be factored into the model. This is shown in the analysis by Lin et al. (2000), in which the relationship of calcium intake to changes in body fat is obscured unless calcium corrected for calories is used as the independent variable. In addition, many of the trials analyzed by Barr were completed in normal weight individuals whose weight was stable, given that these factors are often inclusionary criteria for studies designed with bone as the endpoint. The impact of calcium or dairy products may well be greatest in individuals whose adipocyte status is changing, such as during weight loss

Journal of Cell Biology, Aug 15, 1991

Expression of the oncogenic form of H-ras p21 in the mouse myogenic cell line, 23A2, blocks myoge... more Expression of the oncogenic form of H-ras p21 in the mouse myogenic cell line, 23A2, blocks myogenesis and inhibits expression of the myogenic regulatory factor gene, MyoDl. Previous studies from a number of laboratories have demonstrated that the activation of ras p21 is associated with changes in phospholipid metabolism that directly, or indirectly, lead to elevated levels of intracellular diacylglycerol and the subsequent activation of protein kinase C (PKC). To assess the importance of PKC activity to the ras-induced inhibition of skeletal myogenesis, we examined the levels of PKC activity associated with the terminal differentiation of wild-type myoblasts and with the differentiation-defective phenotype of 23A2 ras cells. We demonstrate that there is a 50% reduction in PKC activity during normal myogenesis and that PKC activity

Biosensors and Bioelectronics, 2011

Glucose is the central molecule in many biochemical pathways, and numerous approaches have been d... more Glucose is the central molecule in many biochemical pathways, and numerous approaches have been developed for fabricating micro biosensors designed to measure glucose concentration in/ near cells and/or tissues. An inherent problem for microsensors used in physiological studies is a low signal-to-noise ratio, which is further complicated by concentration drift due to the metabolic activity of cells. A microsensor technique designed to filter extraneous electrical noise and provide direct quantification of active membrane transport is known as self-referencing. Self-referencing involves oscillation of a single microsensor via computer-controlled stepper motors within a stable gradient formed near cells/tissues (i.e., within the concentration boundary layer). The non-invasive technique provides direct measurement of trans-membrane (or trans-tissue) analyte flux. A glucose micro biosensor was fabricated using deposition of nanomaterials (platinum black, multiwalled carbon nanotubes, Nafion) and glucose oxidase on a platinum/iridium microelectrode. The highly sensitive/selective biosensor was used in the self-referencing modality for cell/tissue physiological transport studies. Detailed analysis of signal drift/noise filtering via phase sensitive detection (including a post-measurement analytical technique) are provided. Using this highly sensitive technique, physiological glucose uptake is demonstrated in a wide range of metabolic and pharmacological studies. Use of this technique is demonstrated for cancer cell physiology, bioenergetics, diabetes, and microbial biofilm physiology. This robust and versatile biosensor technique will provide much insight into biological transport in biomedical, environmental, and agricultural research applications.

Medicine and Science in Sports and Exercise, 1996

Exercise may increase accretion of bone, potentially reducing the risk of osteoporosis. Previous ... more Exercise may increase accretion of bone, potentially reducing the risk of osteoporosis. Previous physical activity was assessed in 204 minimally active young women (18-31 yr). Bone mineral content (BMC) and bone mineral density (BMD) for the total body, femoral neck, and spine were assessed by a dual x-ray absorptiometer, and the radius by a single photon absorptiometer. Self-reported occupation and leisure activity for the 5 yr before enrollment in the study, as well as high school and college sports participation, were assigned energy expenditure (EE) values. From this information, EE variables were created as follows: 1) occupation EE + leisure EE + high school sport and/or college sport EE if within prior 5 yr (5-yr EE); 2) occupation EE + leisure EE (occupation + leisure EE); and 3) high school sport EE (high school EE). These variables were correlated with bone mineral measures and significant results follow (P < 0.05). Five-year EE and occupation + leisure EE correlated with all measures of bone health (r from 0.13 to 0.39). High school EE correlated with total body BMD (r = 0.25) and BMC (r = 0.28), femoral neck BMD (r = 0.28), radius BMC (r = 0.20), as well as spine BMD (r = 0.20) and BMC (r = 0.27). When weight was controlled, 5-yr EE and occupation + leisure EE remained correlated with all BMC measures (r from 0.14 to 0.22). When controlled for weight, high school EE remained associated with femoral neck BMD (r = 0.24), total body BMD (r = 0.20) and BMC (r = 0.26), and spine BMC (r = 0.17). To partially control for selection bias, data were also controlled for total body BMD. Five-year EE and occupation + leisure EE remained positively correlated with all measures of BMC. High school EE remained correlated both with femoral neck BMD and total body BMC. In multiple regression analyses, 5-yr EE or occupation + leisure EE were significant predictors of all measures of bone health, except femoral neck BMD. High school EE was a significant predictor for total body BMD and BMC, femoral neck BMD, and spine BMC.

Journal of Nutrition, 2003

Obesity is a growing epidemic with subsequent health consequences leading not only to reduced qua... more Obesity is a growing epidemic with subsequent health consequences leading not only to reduced quality of life but also to increased medical costs. Growing evidence supports a relationship between increased calcium intakes and reductions in body weight specific to fat mass. Since the first observations in rats Ͼ10 y ago, several recently published clinical studies support this relationship as well. The impact of calcium intake on weight loss or prevention of weight gain has been demonstrated in a wide age range of Caucasian and African-Americans of both genders. This review focuses on the results of clinical trials that have investigated the impact of calcium and dairy products on prevention of weight gain, weight loss or development of the insulin resistance syndrome. The implications of these results are that calcium may play a substantial contributing role in reducing the incidence of obesity and prevalence of the insulin resistance syndrome.

The American Journal of Clinical Nutrition, May 1, 1999

Background: Dietary calcium and milk intakes at specific ages may influence bone mineral measures... more Background: Dietary calcium and milk intakes at specific ages may influence bone mineral measures at specific sites during development of peak bone mass. Objective: Relations of previous milk intake and current calcium intake to current bone mineral measures were investigated in young women. Design: A food-frequency interview and recall of previous milk intake from early childhood to 12 y of age and during adolescence (13-19 y) were completed in a cross-sectional analysis in young women (age 18-31 y; n = 224). Three levels of previous milk intake were defined: 1) infrequently or never, 2) sometimes, and 3) at every or almost every meal. Total body (TB), femoral neck, radius (R), and spine (S) bone mineral density (BMD) and bone mineral content (BMC) were determined by using dual-energy Xray absorptiometry. Results: Childhood and adolescent milk intakes were positively correlated (r = 0.66). Childhood and adolescent milk intakes correlated with current calcium intakes (r = 0.26 and 0.33, respectively). Adolescent milk intake correlated with RBMD (r = 0.16). When weight was controlled for, adolescent milk intake correlated with TBBMD (r = 0.16), TBBMC (r = 0.21), SBMC (r = 0.16), RBMD (r = 0.18), and RBMC (r = 0.15). Current calcium intakes correlated with SBMC (r = 0.17). Regression analyses supported these results. Conclusions: Results were consistent with the hypothesis that higher milk intake during adolescence is associated with greater total body, spine, and radial bone mineral measures during development of peak bone mass, whereas current calcium intakes may influence SBMC. In addition, milk intake at a younger age may contribute to similar habits of milk intake later in life.

Journal of The American College of Nutrition, Dec 1, 2000

Relationships between micronutrients and dairy product intake and changes in body weight and comp... more Relationships between micronutrients and dairy product intake and changes in body weight and composition over two years were investigated. Two year prospective non-concurrent analysis of the effect of calcium intake on changes in body composition during a two year exercise intervention. 54 normal weight young women, 18 to 31 years of age. Mean intakes of nutrients of interest were determined from three-day diet records completed at baseline and every six months for two years. The change in total body weight and body composition (assessed by dual x-ray absorptiometry) from baseline to two years was also determined. Total calcium/kilocalories and vitamin A together predicted (negatively and positively, respectively) changes in body weight (R2 = 0.19) and body fat (R2 = 0.27). Further, there was an interaction of calcium and energy intake in predicting changes in body weight, such that, only at lower energy intakes, calcium intake (not adjusted for energy) predicted changes in body weight. Regardless of exercise group assignment, calcium adjusted for energy intake had a negative relationship and vitamin A intake a positive relationship with two year changes in total body weight and body fat in young women aged 18 to 31 years. Thus, subjects with high calcium intake, corrected by total energy intake, and lower vitamin A intake gained less weight and body fat over two years in this randomized exercise intervention trial.

The FASEB Journal, Apr 1, 2010

The FASEB Journal, Apr 1, 2009

Medicine and Science in Sports and Exercise, May 1, 1998

Medicine and Science in Sports and Exercise, Jun 1, 2001

Purpose: The effect of quantified resistance and high impact exercise training on bone mass as mo... more Purpose: The effect of quantified resistance and high impact exercise training on bone mass as modified by age and oral contraceptive (OCont) use in young women was studied. Methods: Women were categorized by age (18-23 vs 24-31 yr) and OCont use, and were then randomized into either three sessions of resistance exercise plus 60 min•wk-1 of jumping rope or a control group for 24 months. Total body, spine, femoral neck, greater trochanter, Ward's area, and radial bone mineral density (BMD) and/or content (BMC), biochemical markers of bone turnover, dietary intake of calcium, lean body mass, maximal oxygen uptake, and strength were determined at baseline and every 6 months. Results: Total body (TB) BMC percent change from baseline was higher in exercisers compared with nonexercisers at 6 and 24 months. OCont users had lower bone turnover at baseline and a decrease in TBBMC from baseline compared with non-OCont users at 24 months. Spine BMC and BMD decreased in the exercise and OCont group at 6 months and remained significantly below nonexercisers who used oral contraceptives at 2 yr. Femoral neck BMD also decreased in the exercise and oral contraceptive group at 6 months. Conclusions: Exercise prevented a decline in TBBMC seen in the nonexercisers. On the other hand, exercise in oral contraceptive users prevented the increase observed in the spine of the nonexercise plus OCont group.

Journal of Nutrition, Dec 1, 2005

Recent epidemiologic research suggests that dairy product intake or its components (calcium, vita... more Recent epidemiologic research suggests that dairy product intake or its components (calcium, vitamin D, and amount or source of protein) are associated with lower body weight or body fat. Clinical intervention trials designed to test this association during weight loss are promising, but still controversial. Few data are available on the effect of calcium or dairy products on prevention of weight gain in long-term trials. The mechanisms proposed to mediate the putative effect of dietary calcium are primarily the formation of fecal fatty acid complexes to reduce fat absorption and the regulation of energy metabolism, including lipolysis from adipocytes and fatty acid oxidation, through the calciotropic hormones, parathyroid hormone, and 1,25-dihydroxyvitamin D. Increased energy expenditure, increased satiety, or a shift from fat to lean mass must accompany these changes in lipid metabolism to achieve changes in fat mass; however, measurable changes in these other parameters either have not been tested or have not been noted uniformly. If dairy products or their components have an effect on altering fat mass, it is likely to be a small change that may have a substantial effect on the incidence of obesity over time.

Molecular and Cellular Biology/Genetics, Jul 1, 2021

Introduction: Breast cancer (BC) is the second deadliest cancer amongst women in the US, with met... more Introduction: Breast cancer (BC) is the second deadliest cancer amongst women in the US, with metastatic breast cancer being particularly deadly. Pyruvate carboxylase (PC) catalyzes the conversion of pyruvate to oxaloacetate for anaplerotic refilling of TCA intermediates, feeding numerous energetic and biosynthetic pathways. Upregulation of PC is an important contributor to metabolic reprogramming in both primary and metastatic BC. In this study, we investigate whether suppression of PC alters metabolism and drives microenvironmental adaptation in a primary tumor model of BC. Methods: C57/Bl6 mice were injected with M-Wnt cells transduced with doxycycline-inducible ShRNA targeting PC. Doxycycline treatment began once tumors were palpable. Tumors were harvested 4 weeks following injection. Tumor transcriptomic analysis was conducted via GSEA and enrichment mapping. Digital cytometry using CIBORSORTx was conducted to determine tumor microenvironment immune cell composition. In vitro metabolic adaptation to PC suppression in BC cell lines following knockdown of PC was analyzed. Perturbations of mitochondrial metabolism and respiration were assessed by extracellular flux analysis. Assays of extracellular lactate and glucose concentrations determined changes in the production and utilization of carbon sources in the context of loss of PC Results: Metabolic assays revealed that cells with PC knockdown export more lactate into their environment and respire less efficiently, without consuming additional glucose. This indicates potential mitochondrial dysfunction with loss of PC-derived anaplerosis. In vivo suppression of PC resulted in increased tumor mass and volume relative to control. Gene expression data from PC knockdown tumors revealed distinct transcriptomic profiles between groups. GSEA analysis further showed profound suppression of immunological pathways following loss of PC, indicating that PC knockdown resulted in a diminished immune response. Digital cytometry supported this finding with PC suppression resulting in decreased proportions of critical innate and adaptive immune cell populations. Conclusion: Metabolic assays revealed increased flux through lactate production with a decrease in mitochondrial respiration, suggesting that diminished PC-mediated anaplerosis is altering the fate of carbon sources and contributing to metabolic reprogramming. Suppression of PC resulted in tumors with distinct transcriptomic profiles versus control, with immune response signatures being diminished in response to loss of PC. We conclude that PC knockdown promotes a metabolically altered tumor microenvironment associated with immunosuppression, tumor progression, and increased metastatic potential. This work was supported by R35CA197627 to S. Hursting, and R01CA232589 to D. Teegarden and S. Hursting. Citation Format: Michael F. Coleman, Alexander J. Pfeil, Violet Kiesel, Suhas K. Etigunta, Michael K. Wendt, Dorothy Teegarden, Stephen D. Hursting. Mammary tumor microenvironment reprogramming in response to pyruvate carboxylase modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2323.

The FASEB Journal, Apr 1, 2009

The FASEB Journal, Mar 1, 2008

CRC Press eBooks, Jul 29, 2013

The FASEB Journal, Apr 1, 2010