Effect of acute exercise on postprandial lipemia and biomarkers of endothelial dysfunction and inflammation in normal weight and overweight adolescents

Elevated postprandial lipemia (PPL) is associated with impaired endothelial function, an increase in adhesion molecule expression and inflammation. Acute exercise reduces PPL in adults. No studies have examined the effect of acute exercise on PPL in normal weight (NW) and overweight (OW) adolescents. PURPOSE: To investigate the effect of an acute bout of exercise (600 kcal) on postprandial changes in triglycerides (TG), glucose, insulin, adhesion molecules (sICAM-1, sVCAM-1) and inflammatory markers (CRP, IL-6, TNF-α, WBC) following a high-fat meal in NW and OW adolescents. METHODS: 10 NW (BMI: 20.9 ± 1.7 kg.m-2, 15.6 ± 0.7 y) and 8 OW (BMI: 28.3 ± 3.6 kg.m-2, 15.9 ± 0.4 y) adolescent boys underwent two 6h oral fat tolerance tests (OFTT) separated by 7 d. On the evening prior to each OFTT, subjects rested (CTL) or completed a treadmill walk/run at 70% VO2max until 600 kcal had been expended (EX). Blood samples were obtained at baseline and at 30 min, 1, 2, 4 and 6 h after eating. RESULTS: Exercise reduced (p<0.01) the postprandial TG area under the curve by ~25% in both the NW and OW groups. The postprandial glucose and insulin response did not differ between the control and exercise trials or between the NW and OW groups. Circulating leukocytes and plasma IL-6 levels increased (p<0.01) in the NW and OW groups 6 h following the OFTT in both experimental conditions. Plasma concentrations of TNF-α were higher (p<0.05) in the OW than the NW group at rest and 6 h following the OFTT in both the control and exercise experimental condition. There were no changes in CRP, sVCAM-1 or sICAM-1 following the OFTT and there were no differences between experimental condition or BMI group. CONCLUSION: Acute exercise attenuates the postprandial TG response to a high-fat meal similarly in NW and OW adolescents but does not reduce inflammation or alter adhesion molecule expression in the postprandial period

Aging and Endothelial Progenitor Cell Telomere Length in Healthy Men

BACKGROUND: Telomere length declines with age in mature endothelial cells and is thought to contribute to endothelial dysfunction and atherogenesis. Bone marrow-derived circulating endothelial progenitor cells (EPCs) are critical to vascular health as they contribute to both reendothelialization and neovascularization. We tested the hypothesis that EPC telomere length decreases with age in healthy adult humans. METHODS: Peripheral blood samples were collected from 40 healthy, non-obese, sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and 16 older (57-68 years). Putative EPCs were isolated from peripheral blood mononuclear cells and telomere length was determined using genomic DNA preparation and Southern hybridization techniques. RESULTS: EPC telomere length (base pairs) was approximately 20% (p=0.01) lower in the older (8492+523 bp) compared to the middle-aged (10,565+572 bp) and young (10,205+501 bp) men. Of note, there was no difference in EPC telomere length between the middle-aged and young men. CONCLUSIONS: These results demonstrate that EPC telomere length declines with age in healthy, sedentary men. Interestingly, telomere length was well preserved in the middle-aged compared to young men, suggesting that EPC telomere shortening occurs after the age of 55 years

Aging and Endothelial Progenitor Cell Telomere Length in Healthy Men

BACKGROUND: Telomere length declines with age in mature endothelial cells and is thought to contribute to endothelial dysfunction and atherogenesis. Bone marrow-derived circulating endothelial progenitor cells (EPCs) are critical to vascular health as they contribute to both reendothelialization and neovascularization. We tested the hypothesis that EPC telomere length decreases with age in healthy adult humans.METHODS: Peripheral blood samples were collected from 40 healthy, non-obese, sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and 16 older (57-68 years). Putative EPCs were isolated from peripheral blood mononuclear cells and telomere length was determined using genomic DNA preparation and Southern hybridization techniques.RESULTS: EPC telomere length (base pairs) was approximately 20% (p=0.01) lower in the older (8492+523 bp) compared to the middle-aged (10,565+572 bp) and young (10,205+501 bp) men. Of note, there was no difference in EPC telomere length between the middle-aged and young men.CONCLUSIONS: These results demonstrate that EPC telomere length declines with age in healthy, sedentary men. Interestingly, telomere length was well preserved in the middle-aged compared to young men, suggesting that EPC telomere shortening occurs after the age of 55 years

CD31+ T Cells Represent a Functionally Distinct Vascular T Cell Phenotype

In contrast to CD3(+)/CD31(-) cells, CD3(+)/CD31(+) cells aid in endothelial repair and revascularization. There are limited data regarding the functional differences between circulating CD3(+)/CD31(+) and CD3(+)/CD31(-) cells that may contribute to their divergent cardiovascular effects. The aim of the present study was to characterize functional differences between CD3(+)/CD31(+) and CD3(+)/CD31(-) cells. To address this aim, migratory capacity, proangiogenic cytokine release and apoptotic susceptibility of CD3(+)/CD31(+) and CD3(+)/CD31(-) cells were determined. Human CD3(+)/CD31(+) and CD3(+)/CD31(-)cells from peripheral blood were isolated using magnetic-activated cell sorting. CD3(+)/CD31(+) cells demonstrated significantly higher ( approximately 60%) migratory capacity to the chemokines SDF-1alpha (655+/-99 vs. 273+/-54 AU) and VEGF (618+/-99 vs. 259+/-57 AU) vs. CD3(+)/CD31(-) cells. Release of angiogenic cytokines G-CSF, interleukin-8 and matrix metallopeptidase-9 were all approximately 100% higher (P\u3c0.05) in CD3(+)/CD31(+) than CD3(+)/CD31(-) cells. CD3(+)/CD31(+) cells exhibited significantly higher intracellular concentrations of active caspase-3 (2.61+/-0.60 vs. 0.34+/-0.09 ng/mL) and cytochrome-c (21.8+/-1.4 vs. 13.7+/-1.0 ng/mL). In summary, CD3(+)/CD31(+) cells have greater migratory and angiogenic cytokine release capacity, but are more susceptible to apoptosis compared with CD3(+)/CD31(-) cells. Enhanced migratory capacity and angiogenic cytokine release may contribute to the vasculogenic properties of this unique T cell subpopulation

Marked hyperandrogenicity in a 60-year-old woman

Markedly elevated androgen levels can lead to clinical virilization in females. Clinical features of virilization in a female patient, in association with biochemical hyperandrogenism, should prompt a search for an androgen-producing tumor, especially of ovarian or adrenal origin. We herein report the case of a 60-year-old woman of Pakistani origin who presented with the incidental finding of male pattern baldness and hirsutism. Her serum testosterone level was markedly elevated at 21 nmol/L (normal range: 0.4–1.7 nmol/L), while her DHEAS level was normal, indicating a likely ovarian source of her elevated testosterone. Subsequently, a CT abdomen-pelvis was performed, which revealed a bulky right ovary, confirmed on MRI of the pelvis as an enlarged right ovary, measuring 2.9 × 2.2 cm transaxially. A laparoscopic bilateral salpingo-oophorectomy was performed, and histopathological examination and immunohistochemistry confirmed the diagnosis of a Leydig cell tumor, a rare tumor accounting for 0.1% of ovarian tumors. Surgical resection led to normalization of testosterone levels

Human aging and CD31+ T-cell number, migration, apoptotic susceptibility, and telomere length

CD31+ T cells, or so-called “angiogenic T cells,” have been shown to demonstrate vasculoprotective and neovasculogenic qualities. The influence of age on CD31+ T-cell number and function is unclear. We tested the hypothesis that circulating CD31+ T-cell number and migratory capacity are reduced, apoptotic susceptibility is heightened, and telomere length is shortened with advancing age in adult humans. Thirty-six healthy, sedentary men were studied: 12 young (25 ± 1 yr), 12 middle aged (46 ± 1 yr), and 12 older (64 ± 2 yr). CD31+ T cells were isolated from peripheral blood samples by magnetic-activated cell sorting. The number of circulating CD31+ T cells (fluorescence-activated cell sorting analysis) was lower (P < 0.01) in older (24% of CD3+ cells) compared with middle-aged (38% of CD3+ cells) and young (40% of CD3+ cells) men. Migration (Boyden chamber) to both VEGF and stromal cell-derived factor-1α was markedly blunted (P < 0.05) in cells harvested from middle-aged [306.1 ± 45 and 305.6 ± 46 arbitrary units (AU), respectively] and older (231 ± 65 and 235 ± 62 AU, respectively) compared with young (525 ± 60 and 570 ± 62 AU, respectively) men. CD31+ T cells from middle-aged and older men demonstrated greater apoptotic susceptibility, as staurosporine-stimulated intracellular caspase-3 activation was ∼40% higher (P < 0.05) than young. There was a progressive age-related decline in CD31+ T-cell telomere length (young: 10,706 ± 220 bp; middle-aged: 10,179 ± 251 bp; and older: 9,324 ± 192 bp). Numerical and functional impairments in this unique T-cell subpopulation may contribute to diminished angiogenic potential and greater cardiovascular risk with advancing age

Functional antagonism of junctional adhesion molecule-A (JAM-A), overexpressed in breast ductal carcinoma in situ (DCIS), reduces HER2-Positive tumor progression

Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS

High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients

Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n = 94) and Belgium (n = 60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is - BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P &lt;0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P = 0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)-mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease