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81.
The aim of this study was to evaluate protein expression of Karyopherin alpha 2 (KPNA2) in invasive breast cancer and matched ductal carcinoma in situ (DCIS) and to correlate it with clinicopathological data, including patient survival. KPNA2 protein expression was assessed by immunohistochemistry in breast tissue samples, containing invasive carcinomas, DCIS, and adjacent histologically benign breast tissues. A polyclonal goat KPNA2 antibody was used for immunostaining of 83 clinicopathologically characterized cases. For statistical analysis, staining of at least 10% of nuclei was considered KPNA2 positive. Immunohistochemical detection of KPNA2 in invasive carcinoma showed a significant correlation with higher tumor stage, positive lymph node status, higher tumor grade, and negative ER status. Concordantly, KPNA2-positive tumors (31.3%) showed significantly shorter disease-free survival times (69 months vs 118 months; p = 0.007). KPNA2 protein expression was also detected in DCIS (21.3%) adjacent to invasive tumor and correlated with nuclear grade (p = 0.013). Expression of KPNA2 in invasive breast cancer correlates with conventional prognostic parameters and shorter disease-free survival. Additionally, KPNA2 is overexpressed in DCIS, particularly high grade lesions, which emphasizes its potential role in carcinogenesis of invasive breast carcinomas.  相似文献   
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A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K(i) = 9.1 microM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K(i) = 0.074 microM and K(i) = 0.049 microM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC(50) = 0.37 microM and IC(50) = 0.02 microM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC(50) = 0.24 microM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED(50) = 0.024 micromol/kg) and 7s (ED(50) = 0.21 micromol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.  相似文献   
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5-hydroxytryptamine (5-HT; serotonin) is a neurotransmitter essential for a large number of physiological processes including the regulation of vascular and non-vascular smooth muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety, wakefulness and perception. To mediate this astonishing array of functions, no fewer than 15 separate receptors have evolved, of which all but two (5-HT(3A) and 5-HT(3B)) are G-protein coupled receptors. This review will summarize our current understanding of the structure and function of the G-protein coupled 5-HT receptors. In particular, a systematic review of the available mutagenesis studies of 5-HT receptors will be presented. This information will be synthesized to provide a working model of agonist and antagonist actions at a prototypic 5-HT receptor the 5-HT(2A) receptor. Finally, examples will be given to demonstrate that a detailed knowledge of the predicted structure of one receptor can be useful for structure-based drug design.  相似文献   
86.

Aims/hypothesis

Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production.

Methods

We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal.

Results

After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in the systemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB.

Conclusions/interpretation

A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged.

Trial registration

ClinicalTrials.gov NCT01559792.

Funding

The study was part of the UNIK program: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). Funding was received from the Novo Nordisk foundation and the Strategic Research Counsel for the Capital Area and Danish Research Agency. The primary investigator received a PhD scholarship from the University of Copenhagen, which was one-third funded by Novo Nordisk.  相似文献   
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Pharmacological interventions for osteoporosis may reduce morbidity and mortality, but they incur additional health care costs. The aim was to quantify the additional costs and health benefits of prescribing alendronate 10 mg and calcium/vitamin D daily for 71-year-old women with a fracture risk twice that of the population average in stead of calcium/vitamin D alone. A state transition model based primarily on Scandinavian data was developed. Women were followed from age of 71 years until 100. Alendronate was assumed to reduce the fracture risk by 50%. Health benefits from the interventions were expressed in terms of life years, quality adjusted life years, and fractures avoided. Societal costs were estimated using literature estimates and Danish tariffs. All costs were measured in 2002 Danish Kroner (DKK). Future costs and benefits were discounted at 5% per year. The incremental cost per QALY gained was DKK125,000 while the cost per life year gained was DKK 374,000. The use of alendronate was cost-saving when 1) the treatment was extended to five years, 2) the risk of fracture was four times the population average, 3) the effect of alendronate was assumed to persist for three years after discontinuation of treatment, 4) a greater proportion had severe sequelae after a hip fracture, or 5) the start of therapy was delayed until age of 77 years. In conclusion, the use of alendronate compares well with other well established therapies in terms of cost-effectiveness in older women with high risk of fracture.  相似文献   
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