The antiproliferative and antimetastatic compound L651582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release.

L651582, a carboxyamide-amino-imidazole, was shown previously to have antiproliferative and antimetastatic properties at low micromolar concentrations; yet little is known about its cellular mechanism(s) of action. L651582 was tested for its ability to block receptor-stimulated calcium influx, arachidonic acid release, inositol phosphate and cyclic AMP (cAMP) generation. These signal transduction pathways are activated by muscarinic receptors transfected and expressed in Chinese hamster ovary cells. L651582 blocked muscarinic m5 receptor-stimulated 45Ca++ influx and release of arachidonic acid at low micromolar concentrations. Muscarinic receptor-stimulated release of arachidonic acid was shown previously to be dependent on calcium influx and not intracellular calcium release suggesting L651582 may be useful as calcium channel blocker. At low micromolar concentrations, L651582 had little effect on muscarinic m5 receptor-stimulated release of inositol phosphates or cAMP accumulation. Moreover, L651582 had little effect on muscarinic m2 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation. Above 10 microM, L651582 inhibited all second messenger pathways tested and inhibited cell growth, suggesting its action may be less specific and toxic at these concentrations.     

A review of Aston Patterning

Judith Aston is a somatic pioneer. She began as a dancer and physical education teacher. Severe accidents prompted her to seek out Ida Rolf who not only worked on her but also entrusted her with developing the Rolf movement curriculum. She next followed her instincts and refined her concepts for helping people problem solve. For the past 28 years she has continued to improve the Aston Paradigm^® combining bodywork, ergonomic supports, exercises and movement therapy.     

Clinical and radiographic evaluation of bone tumors

Timely diagnosis of osseous tumors is essential in providing proper management. Appropriate imaging studies are essential to this process, however, if inconclusive, they can be superceded by information obtained through the patient history and physical examination. Disclaimer: Dr. Bhandari's salary was provided, in part, by a scholarship from the R.K Frasier Research Foundation     

Analysis of albumin-associated peptides and proteins from ovarian cancer patients

BACKGROUND: Albumin binds low-molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low-molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n = 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method. METHODS: Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition. RESULTS: In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin. CONCLUSION: Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.     

Creutzfeldt--Jakob Disease in Recipients of Human Growth Hormone in the United Kingdom: A Clinical and Radiographic Study

In the past 3 years there have been five further cases, in additionto one case reported in 1985, of Creutzfeldt-Jakob disease inrecipients of human growth hormone in the United Kingdom. Theclinical findings of two of these cases are described, demonstratinga typical presentation with a predominantly cerebellar syndromeat onset which is not commonly a presenting feature of sporadicCreutzfeldt-Jakob disease. In one case a ^99mTc hexamethylpropylenaminesingle photon emission tomographic scan showed marked impairmentof tracer uptake in the basal ganglia and cerebral cortex ata time when the clinical picture was predominantly cerebellar.This technique may be useful in early diagnosis. In the othercase post mortem examination of the brain showed prominent amyloiddeposition in the cerebellum, which has not been described previouslyin pituitary-hormone related Creutzfeldt-Jakob disease. Thepreviously published cases of growth hormone-related Creutzfeldt-Jakobdisease are reviewed and reasons for the particular clinicalpattern seen are discussed.     

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen(-/-) mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and beta-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIalpha3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.     

番茄红素与成骨细胞、破骨细胞及骨质疏松症

学术背景:骨质疏松症是较易发生的疾病,研究骨质疏松的发病机制寻找治疗骨质疏松的药物是预防老年性骨质疏松症的理想选择。目的:综述近几年来国内外关于氧化应激及番茄红素在骨质疏松发病中的作用的相关研究,为开发预防和治疗骨质骨质疏松的药物提供理论依据。检索策略:应用计算机检索Medline和Science Direct Online数据库1989-01/2007-04期间的相关文章,检索词为"oxidative stress,osteoclast,osteoblast,lycopene,osteoporosis",限定文章语言种类为English。同时计算机检索中国期刊全文数据库2000-01/2007-04期间的相关文章,检索词为"氧化应激,骨质疏松,成骨细胞,破骨细胞,番茄红素",限定文章语言种类为中文。对资料进行初审,选择有关人体内氧化应激形成机制、氧化应激与成骨细胞、氧化应激与破骨细胞、氧化应激与抗氧化剂、番茄红素与成骨细胞及破骨细胞和番茄红素与骨质疏松症关系的最新进展文献,共收集到121篇,排除综述类及重复研究。文献评价:符合纳入标准的31篇文献中,5篇涉及骨质疏松症的概述,20篇涉及氧化应激和抗氧化剂在骨质疏松症发病中作用的相关研究,6篇涉及番茄红素与氧化应激、成骨细胞、破骨细胞及绝经后骨质疏松关系的相关研究。资料综合:氧化应激是骨质疏松发病的一个危险因素。氧化应激不但作用于成骨细胞还作用于破骨细胞。国内外学者对于番茄红素的抗氧化性能研究取得了很大进展,已通过细胞培养观察到其对成骨细胞和破骨细胞均有作用,通过临床研究发现,番茄红素通过其抗氧化功能而影响成骨细胞和破骨细胞的功能,从而能够对骨质疏松症发生发展的病理过程进行有效干预,最终阻止和减缓骨质疏松症的发生。结论:番茄红素具有的抗氧化功能使其在骨质疏松的预防及治疗方面起着重要的作用。