The Effects of Exercise Training on Insulin Supply and Demand in Breast Cancer Survivors

Elevated insulin concentrations may influence cancer and cardiometabolic disease onset and prognosis, and lower insulin levels after exercise may contribute to disease prevention and overall health. The effect of exercise training on systemic and tissue-specific insulin supply and demand in breast cancer survivors and adults at risk for cardiometabolic disease is unclear. The objective of this dissertation was to evaluate the effects of exercise training on postmeal insulin concentrations in breast cancer survivors, and identify mechanisms responsible for changes to insulin supply and demand following exercise training in breast cancer survivors and adults at risk for cardiometabolic disease. Study 1 investigated differences between systemic and tissue-specific responses to exercise training and/or the anti-diabetes drug metformin in adults with prediabetes. Fasting proinsulin concentrations were lower following combined exercise and metformin (-24%), and insulin clearance was higher in the metformin and combined exercise and metformin groups (+19% and +17%). There were no differences in the exercise or placebo group, and taken together with previous work from our lab, suggests that exercise regulates insulin supply and demand systemically, while pharmacological adaptations may be tissue-specific. Study 2 evaluated the effects of physical activity on postmeal insulin concentrations in breast cancer survivors. Fifteen women completed 12 weeks of exercise training with pre- and post-intervention oral glucose tolerance testing. Insulin concentrations 120 minutes following glucose ingestion decreased (68.8±34.5 vs. 56.2±31.9 uU/ml, p Study 3 assessed the specific components of insulin supply and demand that may contribute to the blunted or absent postmeal insulin response observed in study 2. There was a significant increase in estimated skeletal muscle glucose uptake following exercise training (5.7±1.8 vs. 7.2 ±1.8, mmo*pmol*kg/m2

Malignant peripheral nerve sheath tumors in neurofibromatosis type 1: a multicenter project with 3 clinical trials

ReportA major goal of this CTDA proposal is to optimize subject recruitment in each of the clinical trials. Using the prevalence estimate for NF1 as 1 in 3,500 individuals in the population at large coupled with the cross-sectional estimate of 5% affected by MPNST, we acknowledge that few centers will have more than 2 patients with MPNST and NF1 in any given year. We anticipate 1 in 1,750,000 people will develop MPNST and NF1 on an annual basis, thus the populations of the US, Canada, and Europe will provide a maximum of 50 cases per year. Our goal is to recruit at least 2/3 of this cohort for enrollment in at least 1 of the 3 clinical trials. By developing a well-publicized network of NF1 Clinic Centers and Sarcoma Centers, we plan to offer enrollment to every individual in North America and Europe who has MPNST and NF1 into the case-control trial to identify risk factors for MPNST (clinical trial project 1). Based on inclusion and exclusion criteria, some individuals will be eligible for the clinical trial of neoadjuvant chemotherapy, and this will be offered to them as a treatment option (clinical trial project 3)

Nursing Poster - 2019

Nursing Posters - 2019https://scholarlycommons.libraryinfo.bhs.org/research_education/1007/thumbnail.jp

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Modulation of neurofibromatosis type 1 gene expression during in vitro myoblast differentiation

Neurofibromin, the protein product of the neurofibromatiosis type 1 (NF1) gene, has two alternate isoforms which are generated by alternative splicing of two exons. One of these isoforms containing exon 48a is expressed at highest levels in muscle. Since neurofibromin is a p21-ras regulator and has been recently shown to be modulated during Schwann cell differentiation, we examined the expression of the NF1 gene product during in vitro muscle differentiation. Previous work demonstrated that C 2 © 1994 Wiley-Liss, Inc. C 12 murine myoblast cell differentiation could be blocked by the introduction of an activated p21-ras protein. Using this model system, we demonstrate that differentiationg C 2 C 12 cells upregulate the expression of NF1 mRNA by 2 days of serum starvation concomitant with increased expression of nicotinic acetylcholine receptor mRNA. This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation. The increase in neurofibromin levels paralleled a decrease in the levels of activated p21-ras as assayed by in vivo 32 Porthophosphate incorporation into p21-ras. These results suggest that in vitro C 2 C 12 cell differentiation is associated with a concomitant increase in NF1 gene expression and decrease in the proportion of activated p21-ras. © 1994 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50229/1/490370312_ftp.pd

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene.

BACKGROUND: In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise. OBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism. METHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5. RESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome. DISCUSSION: ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis. CONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF

Pilot study of impact of a pedal desk on postprandial responses in sedentary workers

Physical inactivity has been linked to rates of obesity, diabetes, and heart disease through insulin resistance and other mechanisms. Although sedentary workplace environments have unintentionally contributed to the risk for chronic diseases, innovations in the workplace environment could potentially rectify this public and occupational health problem. Purpose: To evaluate the effects of light-intensity physical activity using a pedal desk (PD) compared with a standard desk (STD) in a pilot study on postprandial metabolic responses and work skills. Methods: Twelve overweight/obese full-time sedentary office workers (six men and six women; body mass index, 28.7 +/- 3.6 kg m-2) were tested in two conditions: 1) PD, pedaling at self-selected light-intensity pace for 2 h and 2) STD, remaining seated for 2 h in a conventional workstation setup while performing scripted computer-based work tasks. Blood samples were analyzed for plasma glucose, insulin, and free-fatty acids in response to a standardized meal and work skills were evaluated. Paired samples t-tests were used to examine the differences in metabolic responses and work performance tasks between the conditions. Results: Pedal desk use required significantly less insulin to maintain glucose concentrations compared with STD condition (peak insulin concentration, 42.1 uU mL-1 vs 66.9 uU mL-1; P = 0.03; and area under the curve, 302.6 vs 441.8 uU min-1 mL-1; P 0.05). In addition, pedaling at a self-paced rate caused no adverse effects on work skills (P > 0.05). Conclusions: The PD resulted in lower postmeal insulin concentrations without an overall negative impact on work skills. Thus, the PD could have the potential to achieve public and occupational health goals in sedentary work environments.Peer reviewedCommunity Health Sciences, Counseling and Counseling Psycholog