Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (P(heterogeneity) = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.     

An economic evaluation of telehealth data collection with rural populations

OBJECTIVE: This study compared direct costs of conducting structured clinical interviews via real-time interactive videoconferencing (known as telehealth) versus standard in-person methods with American Indians in rural locations. METHODS: Psychiatrists administered in person and via telehealth on two occasions the Structured Clinical Interview for DSM-III-R to 53 non-VA male, American-Indian veterans. Telehealth interviews were conducted by an integrated services digital network (ISDN) connection at 384 kbps. Direct costs were compared for the two interview modalities. Models for starting telehealth in new clinics and established clinics were created, and the models were further subdivided to examine 2003 and 2005 differences in transmission fees. Direct costs included transmission, personnel, travel, and equipment (where applicable). RESULTS: The model of conducting interviews via telehealth in new clinics cost about $6,000 more than in-person interviews in 2003. However, reduced transmission fees and a different videoconferencing setup resulted in telehealth interviews' costing $8,000 less than in-person interviews in 2005. The same pattern held true for the model for established clinics. Telehealth interviews cost $1,700 more than in-person interviews in 2003 but $12,000 less in 2005. Scenarios using nonphysician interviewers and current, rather than historical, transmission costs favored telehealth as a cost-effective means for clinical research. CONCLUSIONS: On the basis of current transmission costs, telehealth proved less expensive than in-person interviews. Telehealth may therefore increase the efficiency and decrease the cost of research with rural, remote, and underserved populations, facilitating the ease with which one can investigate health disparities in these otherwise neglected settings.     

Adventitial endothelial implants reduce matrix metalloproteinase-2 expression and increase luminal diameter in porcine arteriovenous grafts

OBJECTIVE: Vascular access dysfunction is a major problem in hemodialysis patients. Only 50% of arteriovenous grafts (AVGs) will remain patent 1 year after surgery. AVGs frequently develop stenoses and occlusions at the venous anastomoses in the venous outflow tract. Lumen diameter is not only determined by intimal thickening but is also influenced by remodeling of the vessel wall. Vascular remodeling requires degradation and reorganization of the extracellular matrix by the degradation enzymes, matrix metalloproteinases (MMPs). In this study, we aimed to provide further insight into the mechanism of endothelial regulation of vascular remodeling and luminal narrowing in AVGs. METHODS: End-to-side carotid artery-jugular vein polytetrafluoroethylene grafts were created in 20 domestic swine. The anastomoses and outflow vein were treated with Gelfoam matrices (Pfizer, New York, NY) containing allogeneic porcine aortic endothelial (PAE, n = 10) cells or control matrices without cells (n = 10), and the biologic responses to PAE implants were investigated 3 and 28 days postoperatively. Angiograms before euthanasia were compared with baseline angiograms. Tissue sections were stained with hematoxylin and eosin, Verhoeff elastin, and antibodies specific to MMP-9 and MMP-2 and underwent histopathologic, morphometric and immunohistochemical analysis. RESULTS: Veins treated with PAE cell implants had a 2.8-fold increase in venous lumen diameter compared with baseline (P < .05), a 2.3-fold increase in lumen diameter compared with control, and an 81% decrease in stenosis (P < .05) compared with control at 28 days. The increase in lumen diameter by angiographic analysis correlated with morphometric analysis of tissue sections. PAE implants increased the venous lumen area 2.3-fold (P < .05), decreased venous luminal occlusion 66%, and increased positive venous remodeling 1.9-fold (P < .05) compared with control at 28 days. PAE cell implants reduced MMP-2 expression and neovascularization at 3 and 28 days and adventitial fibrosis at 28 days, suggesting a role of the implants in controlling the affects of medial and adventitial cells in the response to vascular injury. CONCLUSIONS: These results demonstrate that the adventitial application of endothelial implants significantly reduced MMP-2 expression within the venous wall, and increased venous lumen diameter and positive remodeling in a porcine arteriovenous graft model. Adventitial endothelial implants may be useful in decreasing luminal narrowing in a clinical setting.     

Plasma dehydroepiandrosterone and risk of myocardial infarction in women

BACKGROUND: In this study we prospectively evaluated the relationships between plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) and subsequent myocardial infarction in women. METHODS: Using case-control sampling, we selected participants from the Nurses' Health Study cohort. Blood samples were collected from 1989 to 1990 when the women were 43 to 69 years old. During follow-up through June 1998, 239 women were diagnosed with myocardial infarction (fatal and nonfatal). We matched cases 1:2 by age, cigarette smoking status, fasting status, and month of blood collection and used conditional logistic regression to adjust for potential confounders, including anthropometric factors and dietary intake. RESULTS: Baseline median (10th, 90th percentiles) concentrations of DHEA were 17.1 (4.3, 46.7) nmol/L among women who subsequently developed myocardial infarction and 16.6 (6.1, 37.9) among controls. The risk of myocardial infarction increased with plasma concentrations of DHEA and its sulfate. Women in the highest DHEA quartile had a rate ratio (RR) of 1.27 (95% CI 0.92-1.74, P for trend = 0.008) for myocardial infarction compared with those in the lowest quartile, after adjusting for covariates. The results did not vary significantly by menopausal status, postmenopausal estrogen therapy, fasting status, or age at time of blood collection. Similar relationships between concentrations of DHEA-S and risk were observed, with an RR of 1.58 (95% CI 1.13-2.21; P for trend = 0.06) for myocardial infarction in the highest vs lowest quartile. CONCLUSIONS: We observed a modest positive relationship between plasma concentrations of DHEA and its sulfate and the risk of subsequent myocardial infarction among predominantly postmenopausal women.     

Antibodies to apolipoprotein A‐I,high‐density lipoprotein,and C‐reactive protein are associated with disease activity in patients with systemic lupus erythematosus

Objective

Inflammatory disease activity in patients with systemic lupus erythematosus (SLE) may affect the development of atherosclerosis, contributing to their increased risk of cardiovascular disease (CVD). This process may be mediated by anti–apolipoprotein A‐I (anti–Apo A‐I), anti–high‐density lipoprotein (anti‐HDL), and anti–C‐reactive protein (anti‐CRP) autoantibodies. We undertook this study to examine whether levels of these antibodies rise in association with increased SLE disease activity.

Methods

IgG anti–Apo A‐I, anti‐HDL, and anti‐CRP levels were measured in serum from the following groups: 39 patients with persistently high disease activity (British Isles Lupus Assessment Group [BILAG] A or B score) over the previous 2 years, 42 patients with persistently low disease activity (no BILAG A or B scores) over the previous 2 years, 34 healthy controls, 25 individual patients from whom paired samples (at time of disease flare and quiescence) were obtained and compared, 16 patients with newly diagnosed lupus nephritis from whom multiple samples were obtained and who were followed up prospectively for up to 2 years, and 24 patients with SLE who had experienced CVD events.

Results

Serum levels of IgG anti–Apo A‐I, anti‐HDL, and anti‐CRP were higher in patients with SLE than in controls. Anti–Apo A‐I and anti‐HDL levels, but not anti‐CRP levels, were higher in patients with persistently high disease activity than in those with low disease activity. Mean levels of the 3 autoantibodies in patients who had experienced CVD events lay between the mean levels in the high and low disease activity groups. Only levels of anti–Apo A‐I were significantly higher in samples obtained from individual patients during disease flares than in samples obtained during disease quiescence. In the lupus nephritis patients, anti–Apo A‐I and anti‐HDL levels correlated with serum levels of high avidity IgG anti–double‐stranded DNA.

Conclusion

Persistent disease activity is associated with a significant increase in IgG anti–Apo A‐I and anti‐HDL in patients with SLE.

     

The balance of thrombosis and hemorrhage in surgery

Postoperative hemorrhage and thrombosis is a significant problem during the perioperative period. Understanding the complex and dynamic interplay of factors, proteins, and enzymes during coagulation is imperative to maintain balance between hemostasis and thrombosis. To improve patient outcome, each patient should be risk stratified for bleeding or thrombosis during the preoperative examination. Additional research focused on improvement in screening tools, monitoring, and therapeutic regimens for surgical patients with a coagulopathy are warranted.     

Comparison of oxaliplatin- and curcumin-mediated antiproliferative effects in colorectal cell lines

Colorectal cancer remains a leading cause of cancer death worldwide, despite markedly improved response rates to current systemic therapies. Oxaliplatin either alone or incorporated into 5-fluorouracil/leucovorin regimes has resulted in increased survival rates, particularly with regards to metastatic colorectal carcinoma. The chemopreventive polyphenol curcumin, which is currently in clinical trial, has been advocated for use in colorectal cancer either singly or in combination with chemotherapeutic drugs. In this study, the antiproliferative capacity of both compounds was compared in HCEC (normal-derived), HT29 (p53 mutant adenocarcinoma) and HCT116 (p53wt adenocarcinoma) colorectal cell lines to determine whether effects were cell-type specific at pharmacologically achievable doses, and whether the combination resulted in enhanced efficacy. Both oxaliplatin and curcumin displayed marked antiproliferative capacity at therapeutic concentrations in the two tumor cell lines. Order of sensitivity to oxaliplatin was HCT116>HT29>HCEC, whereas order of sensitivity to curcumin was HT29>HCT116>HCEC. HCT116 cells underwent induction of G2/M arrest in response to both oxaliplatin (irreversible) and curcumin (reversible). Apoptosis was induced by both agents, and up to 16-fold induction of p53 protein was observed in response to the combination. Antiproliferative effects in HT29 cells were largely cell cycle independent, and were mediated by induction of apoptosis. Effects were greatly enhanced in both cell lines when agents were combined. This study provides further evidence that curcumin may be of use in therapeutic regimes directed against colorectal cancer, and suggests that in combination with oxaliplatin it may enhance efficacy of the latter in both p53wt and p53 mutant colorectal tumors.