Merkel cell carcinoma (MCC) is an extremely aggressive skin cancer that must be distinguished from other basaloid cutaneous neoplasms that have different treatments and prognoses. This is sometimes ...challenging in small shave specimens, crushed samples, lymph nodes, and core needle biopsies. Insulinoma-associated protein 1 (INSM1) immunohistochemistry is a sensitive nuclear marker of neuroendocrine differentiation. INSM1 staining was performed on 56 MCC (47 primary tumors, 9 nodal metastases), 50 skin control cases that included basal cell carcinomas, basaloid squamous cell carcinomas, Bowen disease, sebaceous neoplasms, melanoma, and B-cell lymphomas, and 28 lymph node control cases that included metastatic neuroendocrine neoplasms, melanomas, squamous cell carcinomas, lymphomas, and adenocarcinomas. Percent of staining nuclei (0, <25%, 25% to 50%, 50% to 75%, >75%) and intensity (weak, moderate, strong) were recorded for each sample. All 56 MCC expressed INSM1. By comparison, synaptophysin, CK20, and chromogranin were expressed in 96%, 92%, and 32% of MCC, respectively. While the 3 conventional markers showed significant variability in staining intensity and distribution, INSM1 stained >75% tumor nuclei in 89% of MCC and 50% to 75% of tumor nuclei in 11%. Staining intensity was strong in 85% and moderate in 15%. None of the 50 cutaneous basaloid non-MCC neoplasms in the control group stained with INSM1, and among the lymph node controls 5 of 5 neuroendocrine neoplasms expressed INSM1, confirming that INSM1 staining cannot distinguish MCC from metastatic extracutaneous neuroendocrine carcinoma. INSM1 holds promise as a neuroendocrine marker that can distinguish MCC from its mimickers in the skin and improve detection of sentinel lymph node metastases.
To test the hypothesis that lower 25-hydroxyvitamin D 25(OH)D levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline.
We measured 25(OH)D and assessed ...cognitive function using the Modified Mini-Mental State Examination (3MS) and Trail Making Test Part B (Trails B) in a cohort of 1,604 men enrolled in the Osteoporotic Fractures in Men Study and followed them for an average of 4.6 years for changes in cognitive function.
In a model adjusted for age, season, and site, men with lower 25(OH)D levels seemed to have a higher odds of cognitive impairment, but the test for trend did not reach significance (impairment by 3MS: odds ratio OR 1.84, 95% confidence interval CI 0.81-4.19 for quartile Q 1; 1.41, 0.61-3.28 for Q2; and 1.18, 0.50-2.81 for Q3, compared with Q4 referent group; p trend = 0.12; and impairment by Trails B: OR 1.66, 95% CI 0.98-2.82 for Q1; 0.96, 0.54-1.69 for Q2; and 1.30, 0.76-2.22 for Q3, compared with Q4 p trend = 0.12). Adjustment for age and education further attenuated the relationships. There was a trend for an independent association between lower 25(OH)D levels and odds of cognitive decline by 3MS performance (multivariable OR 1.41, 95% CI 0.89-2.23 for Q1; 1.28, 0.84-1.95 for Q2; and 1.06, 0.70-1.62 for Q3, compared with Q4 p = 0.10), but no association with cognitive decline by Trails B.
We found little evidence of independent associations between lower 25-hydroxyvitamin D level and baseline global and executive cognitive function or incident cognitive decline.
Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via
Multimechanisms
Yiying Zhang 1 2 ,
Kaiying Guo 1 ,
Robert E. LeBlanc 1 ,
...Daniella Loh 1 ,
Gary J. Schwartz 3 and
Yi-Hao Yu 4
1 Department of Pediatrics, Division of Molecular Genetics, Columbia University, New York, New York
2 Naomi Berrie Diabetes Center, Columbia University, New York, New York
3 Department of Medicine and Neuroscience, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx,
New York
4 Department of Medicine, Division of Preventive Medicine, Columbia University, New York, New York
Address correspondence and reprint requests to Yiying Zhang, PhD, Division of Molecular Genetics, Department of Pediatrics,
Columbia University, Russ Berrie Pavilion, Rm. 620, 1150 St. Nicholas Ave., New York, NY 10032. E-mail: yz84{at}columbia.edu . Or Yi-Hao Yu, MD, PhD, Division of Preventive Medicine, Department of Medicine, Columbia University, 630 W. 168th St., PH
10-305J, New York, NY 10032. E-mail: yy102{at}columbia.edu
Abstract
Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and
suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and
whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled
dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat
diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32%
reduction of weight gain ( P < 0.05) and a 25% decrease in adiposity ( P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased
expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased.
Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity,
decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase.
Additionally, plasma levels of total and LDL cholesterol were decreased by 27% ( P < 0.001) and 53% ( P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction
in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary
leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum
consumption of HFD likely via multiple mechanisms.
BAT, brown adipose tissue
G6P, glucose-6-phosphatase
HFD, high-fat diet
HOMA-IR, homeostasis model assessment of insulin resistance
mTOR, mammalian target of rapamycin
UCP, uncoupling protein
WAT, white adipose tissue
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db07-0123.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 19, 2007.
Received January 27, 2007.
DIABETES
Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional ...role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen-induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as “selective angiogenesis blockers” for targeted therapy.
This study explores the relationship between parental over involvement and the career development of emerging adults. Specifically, it investigates how emerging adults’ career meta competencies of ...vocational identity formation and career adaptability relate to perceived helicopter parenting. Participants included 491 emerging adults studying in a Canadian University (74.1% female, average age = 20.4 years old). We begin by reviewing the commonalities between helicopter parenting and other parenting constructs and styles. Next, using structural equation modeling, we explore the relationships between perceived helicopter parenting and the components of vocational identity (exploration: in depth exploration, in breadth; commitment: career commitment, identification with commitment; and reconsideration: career self doubt, career flexibility) and career adaptability, as well as the relationships between identity components and career adaptability. Third, we explore the association between perceived helicopter parenting and identity status progress (i.e., achievement, foreclosure, moratorium, undifferentiated, and searching moratorium). Results indicate that individuals reporting higher levels of perceived helicopter parenting experience significantly lower levels of career adaptability and in-depth exploration. Furthermore, these individuals report higher levels of career self doubt and are more likely to be in the vocational identity status of searching moratorium. Limitations and future research directions are discussed.
Hyperspectral reflectance data representing a wide range of canopies were simulated using the combined PROSPECT+SAIL model. The simulations were used to study the stability of recently proposed ...vegetation indices (VIs) derived from adjacent narrowband spectral reflectance data across the visible (VIS) and near infrared (NIR) region of the electromagnetic spectrum. The prediction power of these indices with respect to green leaf area index (LAI) and canopy chlorophyll density (CCD) was compared, and their sensitivity to canopy architecture, illumination geometry, soil background reflectance, and atmospheric conditions were analyzed. The second soil-adjusted vegetation index (SAVI2) proved to be the best overall choice as a greenness measure. However, it is also shown that the dynamics of the VIs are very different in terms of their sensitivity to the different external factors that affects the spectral reflectance signatures of the various modeled canopies. It is concluded that hyperspectral indices are not necessarily better at predicting LAI and CCD, but that selection of a VI should depend upon (1) which parameter that needs to be estimated (LAI or CCD), (2) the expected range of this parameter, and (3) a priori knowledge of the variation of external parameters affecting the spectral reflectance of the canopy.
Pelvic lymph node dissection has been the standard of care for patients with early cervical cancer. Sentinel node (SN) mapping is safe and feasible and may increase the detection of metastatic ...disease, but benefits of omitting pelvic lymph node dissection in terms of decreased morbidity have not been demonstrated.
In an open-label study, patients with early cervical carcinoma (FIGO 2009 stage IA2 to IIA1) were randomly assigned to SN resection alone (SN arm) or SN and pelvic lymph node dissection (SN + PLND arm). SN resection was followed by radical surgery of the tumour (radical hysterectomy or radical trachelectomy). The primary end-point was morbidity related to the lymph node dissection; 3-year recurrence-free survival was a secondary end-point.
A total of 206 patients were eligible and randomly assigned to the SN arm (105 patients) or SN + PLND arm (101 patients). Most patients had stage IB1 lesion (87.4%). No false-negative case was observed in SN + PLND arm. Lymphatic morbidity was significantly lower in the SN arm (31.4%) than in the SN + PLND arm (51.5%; p = 0.0046), as was the rate of postoperative neurological symptoms (7.8% vs. 20.6%, p = 0.01, respectively). However, there was no significant difference in the proportion of patients with significant lymphoedema between the two groups. During the 6-month postoperative period, the difference in morbidity decreased over time. The 3-year recurrence-free survival was not significantly different (92.0% in SN arm and 94.4% in SN + PLND arm).
SN resection alone is associated with early decreased lymphatic morbidity when compared with SN + PLND in early cervical cancer.
•Randomised study comparing sentinel node biopsy and pelvic lymph node dissection.•Sentinel node biopsy alone is associated with decreased minor lymphatic morbidity.•No increased risk of recurrence while omitting pelvic lymph node dissection.
Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for ...patients and to identify any preferable therapeutic approaches for subgroup populations.
We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic.
Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years IQR 7·3–10·4; CHORUS, 5·9 years IQR 4·3–7·4). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months IQR 14·1–51·3 and 26·9 months 12·7–50·1, respectively; hazard ratio HR 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months IQR 14·1–47·6 and 21·2 months 10·0–36·4, respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months 7·9–15·0 and 9·7 months 5·2–13·2, respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049).
Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.
National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).
Diabetic retinopathy (DR) is a leading cause of vision loss with retinal vascular leakage and/or neovascularization. Current antiangiogenic therapy against vascular endothelial growth factor (VEGF) ...has limited efficacy. In this study, we applied a new technology of comparative ligandomics to diabetic and control mice for the differential mapping of disease-related endothelial ligands. Secretogranin III (Scg3) was discovered as a novel disease-associated ligand with selective binding and angiogenic activity in diabetic but not healthy vessels. In contrast, VEGF bound to and induced angiogenesis in both diabetic and normal vasculature. Scg3 and VEGF signal through distinct receptor pathways. Importantly, Scg3-neutralizing antibodies alleviated retinal vascular leakage in diabetic mice with high efficacy. Furthermore, anti-Scg3 prevented retinal neovascularization in oxygen-induced retinopathy mice, a surrogate model for retinopathy of prematurity (ROP). ROP is the most common cause of vision impairment in children, with no approved drug therapy. These results suggest that Scg3 is a promising target for novel antiangiogenic therapy of DR and ROP.
Summary
The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus ...400 IU of vitamin D
3
daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer.
Introduction
This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality.
Methods
WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS).
Results
Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio HR for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38–1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44–0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive.
Conclusion
Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.
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