Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile.

PURPOSE: Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. METHODS: Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy-Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-α, IL-6), and adipokine profile (leptin, adiponectin, insulin). RESULTS: Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p < 0.05) than the control group. The intervention group also improved quality of life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p < 0.05). CONCLUSIONS: Exercise and dietary counseling led to loss of body fat and improved quality of life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a change in adiposity with intervention. Exercise and healthy eating may be equally effective in this high-risk population as in other breast cancer survivors and should be encouraged as a part of a cancer survivorship program.

"Don't know" and accuracy of breast cancer risk perceptions among Appalachian women attending a mobile mammography program: implications for educational interventions and patient empowerment.

Risk perceptions are motivating factors for engaging in preventive health behaviors. Yet, almost one third of women attending a mobile mammography program targeted to rural and medically underserved Appalachian women respond "don't know" to their perceived 5-year risk of breast cancer. This study used cross-sectional data from women aged >40 years participating in Bonnie's Bus Mammography Screening and Preventive Care Survey from 2009 to 2011 to identify factors associated with "don't know" responses and accuracy of perceived risk according to constructs of the health belief model and sociodemographic characteristics. Women who responded "don't know" were more likely to be less educated, of lower income, insured by Medicaid, and less knowledgeable about breast cancer. Conversely, women who accurately perceived their risk were more likely to be of higher education, more knowledgeable about breast cancer, and have a family history of breast cancer. However, women with a high objective 5-year risk of breast cancer and older age at childbirth or were nulliparous were less likely to accurately perceive their risk. These findings suggest that women who indicate "don't know" responses and hold inaccurate risk perceptions are a population vulnerable to health disparities and may benefit from educational interventions focused on improving breast cancer knowledge and perceptions to empower them to take an active role in their preventive health and make informed decisions based on their individual level of risk.

The obesity-inflammation-eicosanoid axis in breast cancer.

Inflammation of the adipose tissues occurs in association with obesity. This inflammatory process leads to the induction of cyclooxygenase-2 (COX-2) expression and a consequent elevation in prostaglandin (PG) production, which, together with proinflammatory cytokines, induce aromatase expression and estrogen synthesis. Infiltrating macrophages support the growth of breast epithelial cells and vascular endothelial cells by producing a milieu of cytokines and growth factors. This scenario creates a microenvironment favorable to breast cancer growth and invasion. The eicosanoids promote further development and growth of breast cancers indirectly by the induction of aromatase, particularly in estrogen positive breast cancers, or by direct stimulatory effect of PGE2 and lipoxygenase (LOX) products on the more aggressive, estrogen-independent tumors. Beyond this, the local production of estrogens and proinflammatory cytokines which occurs in association with breast adipose tissue inflammation, and consequent activation of the estrogen receptor and nuclear factor-κB, provides a mechanism by which breast cancers develop resistance to selective estrogen receptor modulation and aromatase inhibitor therapy. The obesity-inflammation-eicosanoid axis in breast cancer does offer a therapeutic target for the prevention of relapse in breast cancer by improving the efficacy of antiaromatase therapy using COX/LOX inhibitors; however, careful consideration of menopausal status and obesity in patients is warranted.

Factors influencing adherence to mammography screening guidelines in Appalachian women participating in a mobile mammography program.

The objectives of this study were to evaluate the characteristics (demographic, access to care, health-related behavioral, self and family medical history, psychosocial) of women age 40 years and above who participated in a mobile mammography screening program conducted throughout West Virginia (WV) to determine the factors influencing their self-reported adherence to mammography screening guidelines. Data were analyzed using the Andersen Behavioral Model of Healthcare Utilization framework to determine the factors associated with adherence to mammography screening guidelines in these women. Of the 686 women included in the analysis, 46.2% reported having had a mammogram in the past 2 years. Bivariate analyses showed predisposing factors such as older age and unemployed status, visit to a obstetrician/gynecologist (OB/GYN) in the past year (an enabling factor) and need-related factors such as having a family history of breast cancer (BC), having had breast problems in the past, having had breast biopsy in the past, having had a Pap test in past 2 years, and having had all the screenings for cholesterol, blood glucose, bone mineral density and high blood pressure in past 2 years to be significant predictors of self-reported adherence to mammography guidelines. In the final model, being above 50 years (OR=2.132), being morbidly obese (OR=2.358), having BC-related events and low knowledge about mammography were significant predictors of self-reported adherence. Breast cancer related events seem to be associated with mammography screening adherence in this rural Appalachian population. Increasing adherence to mammography screening may require targeted, community-based educational interventions that precede and complement visits by the mobile mammography unit.

Factors Predictive of Publication Among Medical Students Participating in School-Sponsored Research Programs.

INTRODUCTION: Publishing research is an important component of medical students' career development and becoming a more competitive residency applicant. Many medical schools offer structured programs to enable students to participate in research during their preclinical and clinical years, but the majority of student-mentor partnerships do not culminate in publication across a variety of institutions and medical specialties. The primary objective of this study is to determine if any factors associated with mentee-mentor partnerships are predictive of publication from two school-sponsored research programs at a single US medical school. METHODS: The PubMed-indexed publications of all student-mentor pairings from a summer internship (after year 1 of medical school) or research elective (during year 4 of medical school) at a single institution from 2008 to 2018 were retrospectively reviewed. Student/mentor demographic information was associated with the probability of publication. RESULTS: A total of 124 students participated in the summer internship with 32 (26%) achieving publication. The publication was significantly more likely for students that were from highly ranked undergraduate institutions (p = 0.04; likelihood ratio (LR) = 5.788), were future Alpha Omega Alpha (AOA) members (p = 0.03; LR = 4.597), or worked with a mentor focused on clinical rather than basic science research (p = 0.02; LR = 5.662). Forty-four students participated in the fourth-year elective with 11 (25%) achieving publication. The publication was more likely if the student worked with a mentor without a Doctor of Medicine (MD)/Doctor of Osteopathic Medicine (DO) degree (p = 0.001; LR = 7.051), with a PhD degree (p = 0.002; LR = 7.820), or a mentor with prior publication(s) with prior mentee(s) (p = 0.03; LR = 5.368). CONCLUSION: Only one-quarter of mentor-mentee research pairings resulted in publication, with student-related factors more predictive for publication from the internship and mentor-related factors more predictive of publication from the elective. Approaches to promote successful completion of medical student research projects should be considered to yield the greatest value from students' work and strengthen the development of future physician-scientists.

Triple-negative breast cancer in West Virginia.

In 2007, the American Cancer Society ranked West Virginia 43rd in breast cancer incidence rates for individual states. Despite our improvements in medical care, the advanced pathological characteristics of breast cancer at diagnosis receive little attention. Consequently, we compared the changing pattern of early breast cancer in several cohort studies conducted at regional medical centers in West Virginia. The data used in this analysis was derived from 320 women presenting at West Virginia University Hospital (WVUH) in Morgantown between 1999 and 2004, with a diagnosis of invasive breast cancer. Details of age, tumor size and axillary lymph node status were compared with tumor registry information published from a cohort study of 191 patients from the Charleston Area Medical Center (CAMC) between 1990 and 1991. Only histologically documented adenocarcinomas of the breast were included. Tumor size was characterized using the TNM system and staged according to AJCC criteria. For comparative purposes, details from the two regional centers were compared with tumor characteristics from a large longitudinal cohort of 2,484 breast cancers from the Women's Health Initiative (WHI) study. Baseline median age at diagnosis of women screened at WVUH was younger than patients at CAMC (52 vs. 60). Women diagnosed with triple-negative breast cancer at WVUH and CAMC had similar age distributions. Within the triple-negative patients at WVUH, 44% of patients were less than 50 years of age and 20% were less than 40 years of age. At CAMC, 35% were less than 50 years of age and 7% were less than 40 years of age. For women at WVUH, 61.5% presented with T1 tumors compared to 65.5% at CAMC. These figures were lower than the WHI average of 80.3%. In contrast, more women presented with larger T2 tumors at our medical centers compared with the national study, 32.6% versus 17.4% respectively. At WVUH, 2.3% of women had T3 tumors (> or =5 cm) compared with 1% at CAMC. Similar to the WHI study, 35-42% of women at WVUH and CAMC were diagnosed at the T1c stage. Approximately, 30% were diagnosed with positive lymph nodes, compared to 23% in the national study. Combined breast cancer data from our medical centers show an increase in more advanced tumors and positive regional lymph node involvement at the time of diagnosis compared to national reports. Other factors such as obesity, diabetes, poverty and access to mammography screening could be influencing the poorer outcomes for women with breast cancer in West Virginia.

Triple-negative breast cancer and obesity in a rural Appalachian population.

BACKGROUND: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States. METHODS: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status. Body mass index was calculated and a value of > or = 30 was considered indicative of obesity. RESULTS: Triple-negative tumors occurred in 117 (18.9%) of the 620 patients, most often in association with invasive ductal carcinomas. Patients with triple-negative tumors were younger than those with other receptor types, 44.5% and 26.7%, respectively, being diagnosed at age <50 years (P = 0.0004). The triple-negative tumors were larger (P = 0.0003), most notably in the younger women, but small tumors (<2.0 cm) were more often accompanied by lymph node metastases. Obesity was present in 49.6% of those with triple-negative tumors but in only 35.8% of those with non-triple-negative tumors (P = 0.0098). Lymph node metastases were more frequently associated with T(2) tumors in obese patients (P = 0.032) regardless of their receptor status. CONCLUSIONS: Triple-negative breast cancers within a White, socioeconomically deprived, population occurred in younger women, with later stage at diagnosis, and in association with obesity, which itself has been associated with a poor prognosis in breast cancer.

Hyperspectral Imaging and K-Means Classification for Histologic Evaluation of Ductal Carcinoma In Situ.

Hyperspectral imaging (HSI) is a non-invasive optical imaging modality that shows the potential to aid pathologists in breast cancer diagnoses cases. In this study, breast cancer tissues from different patients were imaged by a hyperspectral system to detect spectral differences between normal and breast cancer tissues. Tissue samples mounted on slides were identified from 10 different patients. Samples from each patient included both normal and ductal carcinoma tissue, both stained with hematoxylin and eosin stain and unstained. Slides were imaged using a snapshot HSI system, and the spectral reflectance differences were evaluated. Analysis of the spectral reflectance values indicated that wavelengths near 550 nm showed the best differentiation between tissue types. This information was used to train image processing algorithms using supervised and unsupervised data. The K-means method was applied to the hyperspectral data cubes, and successfully detected spectral tissue differences with sensitivity of 85.45%, and specificity of 94.64% with true negative rate of 95.8%, and false positive rate of 4.2%. These results were verified by ground-truth marking of the tissue samples by a pathologist. In the hyperspectral image analysis, the image processing algorithm, K-means, shows the greatest potential for building a semi-automated system that could identify and sort between normal and ductal carcinoma in situ tissues.

Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression.

Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk. In this review, we discuss the direct and indirect effects of these protein factors on the biological and clinical aspects of breast cancer biology, and emphasize their distinctive modes of action through endocrine-, paracrine-, and autocrine-mediated pathways. The stimulatory effects of leptin on breast cancer growth were considered to occur primarily via activation of the estrogen receptor; however, new evidence suggests that leptin may be acting on downstream cell signaling pathways in both estrogen-dependent and -independent cell types. Another secretory adipokine, HGF, may act largely not only to promote tumor cell invasion, but also to enhance tumor growth indirectly by stimulating angiogenesis. In contrast, adiponectin, an endogenous insulin sensitizer, exerts a direct growth-inhibitory effect on tumor cells by downregulating cell proliferation and upregulating apoptosis, and also inhibits tumor-related angiogenesis.

PYY and the pancreas: inhibition of tumor growth and inflammation.

Peptide YY (PYY) orchestrates function of the gut and pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still not fully understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors in the proliferation of pancreatic cancer. The present paper reviews our current findings with PYY and examines the therapeutic implications of its utility in treating inflammation and cancer.

Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology.

Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741-4. ©2017 AACR.

Leptin receptor expression and cell signaling in breast cancer.

Obesity is considered a risk factor for many cancers, including breast cancer. Our laboratory has previously shown that leptin is mitogenic in many cancer cell lines, including breast. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. In addition, SOCS-3 expression (a leptin inducible inhibitor of leptin signaling), plus MAPK and PI3K signaling, were examined to determine their role in leptin-induced cell proliferation. Breast cancer cell lines, ZR75-1 and HTB-26, were treated with 0, 4, 40 or 80 ng/ml of leptin. Multiplex RT-PCR was performed to determine relative mRNA expression levels of the human short (huOB-Ra) or long (huOB-Rb) leptin receptor isoforms, or SOCS-3. MAPK and PI3K signaling was analyzed by phosphorylation of ERK and Akt, respectively, via Western blotting. Cell proliferation and inhibitor studies were analyzed by MTT assay. HTB-26 and ZR75-1 both expressed huOB-Ra, huOB-Rb and SOCS-3 mRNA; however, mRNA expression levels generally remained unchanged over time with leptin treatment. MAPK and PI3K pathways were activated in the presence of leptin over time. MAPK and PI3K inhibitors significantly blocked leptin-induced proliferation. Higher levels of circulating leptin contribute to breast cancer proliferation by activation of the MAPK and PI3K signaling pathways involved in cell growth and survival. The mitogenic effects of leptin are not a consequence of altered leptin receptor or SOCS-3 mRNA expression.

Peptide YY attenuates STAT1 and STAT3 activation induced by TNF-alpha in acinar cell line AR42J.

BACKGROUND: STAT1 and STAT3, members of the cytoplasmic family of signal transducers and activators of transcription factors (STAT), have been associated with numerous inflammatory pathologies, including inflammatory bowel disease, hepatitis, and acute lung injury. But little is known about their role in the pancreas. Peptide YY (PYY), an inhibitory gastrointestinal hormone, ameliorates pancreatitis in vivo and in vitro. In addition, we have shown that PYY attenuates transcription factors, such as nuclear transcription factor (NF)-kappaB and Smad3/4, which mediate inflammation. We hypothesized that tumor necrosis factor (TNF)-alpha would induce STAT1 and STAT3, and PYY would attenuate their transcription factor binding. STUDY DESIGN: Rat pancreatic acinar cells were treated with recombinant TNF-alpha (200 ng/mL); PYY (3-36; 500 pM) was added 30 minutes post-TNF-alpha treatment. Cells were harvested at 2 hours, and nuclear protein and conditioned media were extracted. Levels of amylase secretion and cytokine production were measured using commercially available kits. STAT transcription factor binding was determined by protein/DNA array analysis and densitometry; results were verified again by electrophoretic mobility shift assay (EMSA) and ELISA-based assay. RESULTS: Amylase production was considerably increased (p < 0.05) as early as 5 minutes after addition of exogenous TNF-alpha and remained elevated for 24 hours. PYY decreased amylase production to control levels. A notable increase (p < 0.05) in the production of cytokines interleukin (IL)-1beta, IL-4, IL-6, IL-10, and TNF-alpha was observed with TNF-alpha treatment; production was reduced with PYY. TNF-alpha substantially upregulated STAT1 and STAT3 (two-fold or greater); PYY downregulated their binding activity to control levels. Results from both the electrophoretic mobility shift assay- and the ELISA-based assays verified STAT1 and STAT3 responses to TNF-alpha and PYY. CONCLUSIONS: In pancreatic acinar cells, TNF-alpha activated STAT1 and STAT3, known mediators of inflammatory cytokines. Interestingly, PYY attenuated their protein/DNA binding, which may have an impact on development of the disease. Additional investigation of STAT proteins and PYY could provide new therapeutic strategies for pancreatitis.

Inferior vena cava filter placement in late-stage cancer.

Inferior vena cava (IVC) filters are increasingly used in patients with advanced-stage cancer for prophylaxis of pulmonary embolus. We evaluated the survival benefit of placing IVC filters in patients with late-stage malignancy and assessed their effectiveness in preventing pulmonary embolism. Between 1998 and 2003, 5,970 patients were treated with a primary diagnosis of malignancy at a tertiary care facility. Retrospective analysis identified 55 consecutive patients with stage III or IV malignant disease and venous thromboembolism (VTE) who received IVC filters. Retrospective review of electronic hospital charts identified subsequent pulmonary emboli, procedure-related complications, and survival. In a case control study, 16 patients with VTE but without IVC filter were matched for age, sex, type of malignancy, and stage of disease. IVC filter placement effectively prevented computed tomography (CT) scan or ventilation/perfusion ratio (V/Q) scan-proven pulmonary embolus in 52/55 (94.5%) patients. Complications developed in 4/55 or 7.3% of patients; 13/55 (23.6%) patients with late-stage cancer survived less than 30 days following placement of the filter. Another 23.6% of this group survived longer than 1 year. Ambulatory status differed significantly (p = 0.01) between these 2 subgroups. In the case control study, IVC filter placement conferred no survival benefit compared to the control group. One recurrent pulmonary embolism was observed in both the filter group and the control group. No deaths due to thromboembolic complications were observed in either group. In late-stage cancer, patient survival is limited primarily by the malignant process. While IVC filter placement is effective in preventing pulmonary emboli, there may be limited survival benefit in this particular patient population. However, there exists a subset of this population whose functional status predicts longer survival times after filter placement.

In vitro effects of keyhole limpet hemocyanin in breast and pancreatic cancer in regards to cell growth, cytokine production, and apoptosis.

BACKGROUND: We have previously shown the inhibitory effects of keyhole limpet hemocyanin (KLH) against breast and pancreatic cancer in vitro. We hypothesize that its actions in breast and pancreas cancer cells are via apoptotic or cytokine pathways. METHODS: Two breast cancer cell lines, ZR75-1 and MCF-7, and one pancreas cancer cell line, PANC-1, were treated with KLH at 500 mug, 250 mug, and 250 ng/mL. Cell viability, cytokine production, and apoptosis were measured. RESULTS: Significant growth inhibition was observed in all cell lines at all KLH concentrations tested. Significant changes in cytokine production were observed in all cell lines. An increase in early and late apoptotic activity was observed in the MCF-7, whereas a reduction in late apoptotic activity was observed in the ZR75-1 cells. CONCLUSIONS: KLH directly inhibits the growth of human breast and pancreas cancer in vitro by apoptotic and nonapoptotic mechanisms.

The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer.

Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index-defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin.

High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer.

Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

Loss of Adipocyte VEGF Impairs Endurance Exercise Capacity in Mice.

PURPOSE: Reducing vascular endothelial growth factor (VEGF) in adipose tissue alters adipose vascularity and metabolic homeostasis. We hypothesized that this would also affect metabolic responses during exercise-induced stress and that adipocyte-specific VEGF-deficient (adipoVEGF-/-) mice would have impaired endurance capacity. METHODS: Endurance exercise capacity in adipoVEGF-/- (n = 10) and littermate control (n = 11) mice was evaluated every 4 wk between 6 and 24 wk of age using a submaximal endurance run to exhaustion at 20 m·min(-1) at 10° incline. Maximal running speed, using incremental increases in speed at 30-s intervals, was tested at 25 and 37 wk of age. RESULTS: White and brown adipose tissue capillarity were reduced by 40% in adipoVEGF-/-, and no difference in skeletal muscle capillarity was observed. Endurance run time to exhaustion was 30% lower in adipoVEGF-/- compared with that in controls at all time points (P < 0.001), but no difference in maximal running speed was observed between the groups. After exercise (1 h at 50% maximum running speed), adipoVEGF-/- mice displayed lower circulating insulin (P < 0.001), lower glycerol (P < 0.05), and tendency for lower blood glucose (P = 0.06) compared with controls. There was no evidence of altered oxidative damage or changes in carnitine palmitoyltransferase-1ß expression in skeletal muscle of adipoVEGF-/- mice. CONCLUSIONS: These data suggest that VEGF-mediated deficits in adipose tissue blunt the availability of lipid substrates during endurance exercise, which likely reduced endurance performance. Surprisingly, we also found an unchanged basal blood glucose despite lower circulating insulin in adipoVEGF-/- mice, suggesting that loss of adipocyte VEGF can blunt insulin release and/or increase basal insulin sensitivity.

Essential Components of Cancer Education.

Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine.

Cardiac response to nitric oxide synthase inhibition using aminoguanidine in a rat model of endotoxemia.

This study evaluates the effect of aminoguanidine, a preferential inhibitor of inducible nitric oxide synthase (iNOS), on the prevention of cardiac depression in acute endotoxemia. Cardiac performance was evaluated after 4 h of exposure to endotoxin. Rats (n = 5) were selected randomly to receive, by intraperitoneal injection, one of four treatments: saline, LPS (lipopolysaccharide, E. coli, 4 mg/kg, AG (aminoguanidine 100 mg/kg), and LPS + AG at various times. AG and saline treatments were administered 30 min before LPS and at 1 and 3 h after LPS injection. Hearts were perfused using the Langendorff isolated perfusion system and a balloon-tipped catheter was placed into the left ventricle to measure left ventricular developed pressure (LVDP). Myocyte contractile function was assessed with electrical field stimulation and video microscopy. Tissue was immunostained for the expression of iNOS and for nitrotyrosine, a byproduct of protein nitration by peroxynitrite. Perfused hearts from LPS-treated rats exhibited a 57% decrease (P < 0.05) in LVDP compared to saline-treated animals. No improvement in ventricular function was observed with the administration of AG. Similarly, cardiac myocytes prepared from LPS-treated animals demonstrated a significant (P < 0.05) reduction in percent and velocity of shortening and this effect was unaltered with the same dose of AG. AG administration significantly reduced serum nitrite/nitrate levels (P < 0.05) in endotoxemic rats to control levels. Localized expression of iNOS in the myocardium was lessened with AG treatment and was not associated with peroxynitrite formation in this model of endotoxemia. The results indicate that AG given in vivo before and after endotoxin (at a concentration sufficient to decrease NO production) did not reduce cardiac depression. We conclude that selective inhibition of iNOS and the reduction of NO production do not prevent cardiac dysfunction at an early stage in an acute model of endotoxemia.