Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1␣ (HIF-1␣), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1␣ functional activity was specifically caused by impaired HIF-1␣ binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1␣/p300 interaction and transactivation by HIF-1␣. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.deferoxamine ͉ HIF-1 ͉ hyperglycemia ͉ ischemia

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Tissue ischemia promotes vasculogenesis through chemokine-induced recruitment of bone marrow-derived endothelial progenitor cells (EPCs). Diabetes significantly impairs this process. Because hyperglycemia increases reactive oxygen species in a number of cell types, and because many of the defects responsible for impaired vasculogenesis involve HIF1-regulated genes, we hypothesized that HIF1 function is impaired in diabetes because of reactive oxygen species-induced modification of HIF1␣ by the glyoxalase 1 (GLO1) substrate methylglyoxal. Decreasing superoxide in diabetic mice by either transgenic expression of manganese superoxide dismutase or by administration of an superoxide dismutase mimetic corrected post-ischemic defects in neovascularization, oxygen delivery, and chemokine expression, and normalized tissue survival. In hypoxic fibroblasts cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the EPC mobilizing chemokine stromal cell-derived factor-1 (SDF-1) and of vascular epidermal growth factor, which modulates growth and differentiation of recruited EPCs. In hypoxic EPCs cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the SDF-1 receptor CXCR4, and endothelial nitric-oxide synthase, an enzyme essential for EPC mobilization. HIF1␣ modification by methylglyoxal reduced heterodimer formation and HIF1␣ binding to all relevant promoters. These results provide a basis for the rational design of new therapeutics to normalize impaired ischemia-induced vasculogenesis in patients with diabetes.Studies in both experimental animals and humans have shown that diabetes impairs ischemia-driven neovascularization (1, 2). Diabetic animals have a decreased vascular density following hind limb ischemia (3, 4) and impaired wound healing (5). Human angiograms demonstrate fewer collateral vessels in diabetic patients compared with non-diabetic controls (1). Clinically, this contributes to increased rates of lower limb amputation, heart failure, and increased mortality after ischemic events.Ischemic tissue selectively recruits endothelial progenitor cells (EPCs) 3 from the bone marrow compartment by up-regulating the chemokine stromal cell-derived factor-1 (SDF-1). SDF-1 expression acts as a signal indicating the presence of tissue ischemia, and its expression is directly regulated by hypoxia-inducible factor-1 (5, 6). Ischemic tissue also up-regulates expression of VEGF, which modulates growth and differentiation of recruited EPCs (7). Endothelial cell mobilization from the bone marrow compartment is mediated by the SDF-1 receptor CXCR4, and endothelial nitric-oxide synthase plays an essential role in this mobilization (8). In diabetic mice, expression of SDF-1 in peripheral wound tissue is decreased, and in diabetic mice and humans, there is a significant decrease in circulating EPCs (5, 9), which exhibit impaired proliferation, adhesion, and incorporation into vascular structures (9). The mechanisms underlying defective ischemia-induced vasculogenesis ...

Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha (HIF-1alpha), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1alpha transactivation persist even in the setting of constitutive HIF-1alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1alpha (the primary pathway regulating HIF-1alpha/p300 binding) does not alter HIF-1alpha activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.

Background: Thyroid cancer incidence is increasing worldwide at an alarming rate, yet little is known of the impact this increase will have on society. We sought to determine the clinical and economic burden of a sustained increase in thyroid cancer incidence in the United States and to understand how these burdens correlate with the National Cancer Institute's (NCI) prioritization of thyroid cancer research funding.Methods: We used the NCI's SEER 13 database (1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009) and Joinpoint regression software to identify the current clinical burden of thyroid cancer and to project future incidence through 2019. We combined Medicare reimbursement rates with American Thyroid Association guidelines, and our clinical practice to create an economic model of thyroid cancer. We obtained research-funding data from the NCI's Office of Budget and Finance.Results; By 2019, papillary thyroid cancer will double in incidence and become the third most common cancer in women of all ages at a cost of $18 to $21 billion dollars in the United States. Despite these substantial clinical and economic burdens, thyroid cancer research remains significantly underfunded by comparison, and in 2009 received only $14.7 million (ranked 30th) from the NCI.Conclusion: The impact of thyroid cancer on society has been significantly underappreciated, as is evidenced by its low priority in national research funding levels.Impact: Increased awareness in the medical community and the general public of the societal burden of thyroid cancer, and substantial increases in research on thyroid cancer etiology, prevention, and treatment are needed to offset these growing concerns. Cancer Epidemiol Biomarkers Prev; 22(7); 1252-9. Ó2013 AACR.

Background: The prevalence of thyroid cancer survivors is rising rapidly due to the combination of an increasing incidence, high survival rates, and a young age at diagnosis. The physical and psychosocial morbidity of thyroid cancer has not been adequately described, and this study therefore sought to improve the understanding of the impact of thyroid cancer on quality of life (QoL) by conducting a large-scale survivorship study. Methods: Thyroid cancer survivors were recruited from a multicenter collaborative network of clinics, national survivorship groups, and social media. Study participants completed a validated QoL assessment tool that measures four morbidity domains: physical, psychological, social, and spiritual effects. Data were also collected on participant demographics, medical comorbidities, tumor characteristics, and treatment modalities. Results: A total of 1174 participants with thyroid cancer were recruited. Of these, 89.9% were female, with an average age of 48 years, and a mean time from diagnosis of five years. The mean overall QoL was 5.56/10, with 0 being the worst. Scores for each of the sub-domains were 5.83 for physical, 5.03 for psychological, 6.48 for social, and 5.16 for spiritual well-being. QoL scores begin to improve five years after diagnosis. Female sex, young age at diagnosis, and lower educational attainment were highly predictive of decreased QoL. Conclusion: Thyroid cancer diagnosis and treatment can result in a decreased QoL. The present findings indicate that better tools to measure and improve thyroid cancer survivor QoL are needed. The authors plan to follow-up on these findings in the near future, as enrollment and data collection are ongoing.

Rates of thyroid cancer in women with a history of breast cancer are higher than expected. Similarly, rates of breast cancer in those with a history of thyroid cancer are increased. Explanations for these associations include detection bias, shared hormonal risk factors, treatment effect, and genetic susceptibility. With increasing numbers of breast and thyroid cancer survivors clinicians should be particularly cognizant of this association. Here we perform a systematic review and meta-analysis of the literature utilizing PubMed and Scopus search engines to identify all publications studying the incidence of breast cancer as a secondary malignancy following a diagnosis of thyroid cancer or thyroid cancer following a diagnosis of breast cancer. This demonstrated an increased risk of thyroid cancer as a secondary malignancy following breast cancer (OR=1.55, 95% CI [1.44,1.67]) and an increased risk of breast cancer as a secondary malignancy following thyroid cancer (OR= 1.32, 95% CI [1.23,1.42]). There is a clear increase in the odds of developing either thyroid or breast cancer as a secondary malignancy after diagnosis with the other. Here we review this association and current hypothesis as to the cause of this correlation.

PTMC is an indolent disease, but does pose a risk for LNM and local recurrence. More aggressive treatment or more frequent follow-up could be considered for patients with unfavorable features (age <45 years, multifocality, ETE), especially in the setting of involved lymph nodes at the time of surgical resection, as these patients may be at an increased risk for recurrence.