TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis

A number of receptor tyrosine kinases (RTKs) are involved in angiogenesis. TSU-68 (SU-6668) was developed as an inhibitor of RTKs involved in VEGF, bFGF and PDGF signaling, which then inhibits endothelial cell proliferation. We investigated the antitumor effects of TSU-68 against human colon cancer xenografts in male SCID mice and its anti-angiogenic activity using a dorsal air-sac (DAS) assay. TSU-68 was administered orally at a dose of 200 mg/kg twice daily. Mice bearing human colon carcinoma, HT-29, or WiDr xenografts were treated for 16 days. To determine the effect on hepatic metastasis, cell suspensions of HT-29 or WAV-I were injected into the spleen of mice on day 0, and mice treated for 28 days starting from day 1. For the DAS assay, HT-29, WiDr or WAV-I cells suspended in PBS at 2 x 10(7) cells/Millipore chamber were implanted subcutaneously into SCID mice, which were then treated from day 0 to 5, On day 6, the anti-angiogenic effects were assessed. Results indicated that TSU-68 significantly inhibited the growth of subcutaneous tumors. In the hepatic metastasis model, liver weights of the TSU-68-treated group were significantly reduced, compared to those of control mice. In the DAS assay, the angiogenic indices of the treated groups were significantly decreased for HT-29, WiDr and WAV-I tumors, with T/C ratios of 13.4, 50 and 35.3%, respectively. As TSU-68 significantly inhibited tumor growth and liver metastasis formation of human colon cancer xenografts, probably through anti-angiogenic activity, this agent may be useful for the treatment of colon cancer.     

Estimation of increased concentration of intracellular Cd(2+) by fluo-3 in rat thymocytes exposed to CdCl(2)

Cadmium, an environmental pollutant, has been reported to induce apoptosis in murine lymphocytes. To reveal the mechanism of cadmium-induced apoptosis, one of important questions is whether cadmium increases intracellular concentration of Ca(2+) ([Ca(2+)](i)), Cd(2+) ([Cd(2+)](i)) or both. It is difficult to detect the increase in [Ca(2+)](i) using Ca(2+)-chelator-based fluorescent Ca(2+) indicators in the presence of Cd(2+) because of their sensitivity to Cd(2+). Therefore, the study on membrane response such as Ca(2+)-dependent hyperpolarization gives a clue to reveal whether the [Ca(2+)](i) or [Cd(2+)](i) is increased. Cadmium at concentrations of 3 μM or more dose-dependently augmented fluo-3 fluorescence in rat thymocytes, presumably suggesting an increased [Ca(2+)](i). However, the membranes were not hyperpolarized although the cells possess Ca(2+)-dependent K(+) channels. One may argue that cadmium inhibits Ca(2+)-dependent K(+) channels so that cadmium fails to hyperpolarize the membranes. It is unlikely because the [Ca(2+)](i) increased by A23187, a calcium ionophore, elicited the hyperpolarization in the presence of Cd(2+). Furthermore, the profile of cytotoxicity induced by cadmium, examined by ethidium bromide and annexin V-FITC, was different from that induced by A23187. Taken together, it is concluded that the application of cadmium increases the [Cd(2+)](i) rather than the [Ca(2+)](i) in rat thymocytes, resulting in the induction of cytotoxicity.     

Identifying best practices of community participation in providing services to refugee survivors of torture: a case description

There is an increased interest in best practices in the design and implementation of specialized programs for refugee survivors of torture. The processes taking place in the development of such a program also warrant assessment. In particular, this paper addresses the importance of community participation. Using the Host Support Program for Survivors of Torture as a case study, we identify the community participation practices that emerged during stages of program development and describe how these practices have made possible a collaborative service delivery model and facilitated community capacity building that addresses the complex needs of refugee survivors of torture. The process of community collaboration is discussed as central to the process of effective community participation and organizing. The illustrated benefits of community participation position this model as a best practice.     

Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1

A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.     

Vitamin K Supplementation for Prevention of Vascular Calcification in Chronic Kidney Disease Patients: Are We There Yet?

Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization. Matrix Gla Protein (MGP), one the most powerful naturally occurring inhibitors of arterial calcification, requires vitamin K as a co-factor in order to undergo post-translational γ-carboxylation and phosphrorylation and become biologically active. The inactive form of MGP (dephosphorylated, uncarboxylated dp-ucMGP) reflects vitamin K deficiency and has been repeatedly associated with surrogate markers of VC, stiffness, and cardiovascular outcomes in CKD populations. As CKD is a state of progressive vitamin K depletion and VC, research has focused on clinical trials aiming to investigate the possible beneficial effects of vitamin K in CKD and dialysis patients. In this study, we aim to review the current evidence regarding vitamin K supplementation in uremic patients.     

Therapeutic options for management of endometrial hyperplasia

Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.     

Giant lipomas of the upper extremity: Case reports and a literature review

Giant fibrolipomas involving the upper extremities are rare tumours. These large masses grow slowly and produce symptoms due to their size, location and compression of adjacent structures. Surgical excision usually leads to complete recovery from symptoms.     

The Opioid Receptor Antagonist Nalmefene Reduces Responding Maintained by Ethanol Presentation: Preclinical Studies in Ethanol-Preferring and Outbred Wistar Rats

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.     

Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests

The term aspirin-resistance describes the failure of aspirin to inhibit thromboxane A₂ production. Many new tests have become available for potentially measuring aspirin responses but some are non-specific and do not isolate COX-1 activity. We previously demonstrated that agreement between two tests (PFA-100® and VerifyNow®-ASA) and light transmission aggregation (LTA) was no greater than would be expected by chance. In this study we re-tested the same patients using identical methods after 1 year to determine whether poor agreement might have been due to assessment in the acute phase and whether the results of the individual tests are consistent over time. Platelet function by all three tests was re-tested in the 72 patients who were alive and still receiving low dose ASA therapy one year after the first tests were performed. On re-testing the prevalence of ASA non-responsiveness compared with baseline was 10% vs 17% by the VerifyNow®-ASA test, 25% vs 22% by the PFA-100®, and 1% vs 5% by LTA. Agreement between the tests at 1 year remained poor (kappas: 0.02–0.17) and only one patient was identified as a non-responder by all three tests, in keeping with the theoretical differences between the tests. Within test comparisons of baseline vs 1 year showed moderate agreement for the PFA-100® (kappa = 0.44, 95% CI 0.19–0.68, p = 0.0006), a fair agreement for VerifyNow®-ASA (kappa = 0.34, 0.04–0.64, p = 0.12) and poor agreement for LTA (kappa = 0.14, ?0.11 ?0.39, p = 0.24 for ADP; kappa = 0.09, ?0.21–0.39, p = 0.41 for arachidonic acid). Agreement between the three tests in identifying aspirin non-responsiveness remained poor in patients who had been taking aspirin for at least 1 year follow-up. Reproducibility over time was no greater than chance for LTA and only moderate for VerifyNow®-ASA and PFA-100®. Lack of consistency over time in identification of apparently non-responsiveness individuals is likely to substantially undermine any ability of these tests to predict risk of recurrent vascular events.