Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway

Prostaglandin (PG) E2 promotes tumor growth via interaction with its G protein-coupled receptors and activation of intracellular signaling. Tuberous sclerosis 2 (tuberin) is a tumor suppressor, which negatively regulates cell growth. Its phosphorylation results in its inactivation and targeted down- regulation, thus lifting the growth inhibition effects. This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Quantitative RT-PCR and Western blot analysis demonstrated reduced expression of tuberin in neoplastic tissue, compared with normal endometrial tissue. Tuberin expression was localized by immunohistochemistry to the glandular epithelial compartment in neoplastic and normal endometrium. We investigated the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Treatment of neoplastic and normal endometrium with 100 nm PGE2 enhanced phosphorylated tuberin immunoreactivity in the glandular epithelium. PGE2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein. Cotreatment of cells with wortmannin or LY294002 inhibited the PGE2-induced phosphorylation of Akt and tuberin. These data suggest that PGE2 signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway.     

Immunomagnetic purging of breast cancer from bone marrow for autologous transplantation

Intensive chemotherapy with autologous bone marrow transplantation is a promising approach for the treatment of breast cancer, provided that clonogenic tumor cells do not contaminate the patient's bone marrow. We have previously demonstrated that a combination of 4-hydroperoxycyclophosphamide (4-HC) and immunomagnetic purging (IMP) with monoclonal antibodies and microspheres could remove 4-5 logs of clonogenic breast cancer cells from a 10-fold excess of human bone marrow cells. In the present report we have evaluated an apparatus for separating tumor cells from a large volume of human marrow. This apparatus will permit preparation of large volumes of purged marrow for use in studies of intensive therapy with autologous marrow support. Bone marrow progenitor cell (CFU-GM) recovery following this IMP technique was 85% of the unpurged control, and suggests that marrow recovery following high dose systemic chemotherapy will not be adversely affected. A phase I study to evaluate marrow reconstitution following IMP is underway. Preliminary data suggest that this IMP method will not delay engraftment in breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support, but further study is required.     

Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy

OBJECTIVES: The purpose of this study was to evaluate the effect of chelation therapy with ethylenediamine tetraacetic acid (EDTA) on endothelium-dependent vasomotor responses in patients with documented coronary artery disease (CAD). BACKGROUND: Oxidative stress plays an important role in the dysfunction of endothelium and development of atherosclerosis. Modification of cardiac risk factors and employment of antioxidants have been shown to improve endothelial function. Ethylenediamine tetraacetic acid chelation therapy is considered to be a complementary therapy for patients with CAD and is proposed to have antioxidant properties. METHODS: A total of 47 patients enrolled in the Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health (PATCH) participated in this substudy and had complete data. High-resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with CAD in a randomized, double-blind, and placebo-controlled fashion. Patients were randomized to chelation therapy or placebo. The primary end point was the absolute difference in FMD after the first and 33rd treatments (6 months) of study groups compared with their baselines. RESULTS: At the baseline, the study population had mild impairment of FMD (7.2 +/- 3.4%). The first chelation treatment did not change FMD as compared with placebo (chelation 6.5 +/- 3.5% vs. placebo 7.4 +/- 2.9%; p value = 0.371). The brachial artery studies at six months did not demonstrate significant differences in FMD between study groups (placebo 7.3 +/- 3.4% vs. chelation 7.3 +/- 3.2%; p value = 0.961). CONCLUSIONS: Our results suggest that EDTA chelation therapy in combination with vitamins and minerals does not provide additional benefits on abnormal vasomotor responses in patients with CAD optimally treated with proven therapies for atherosclerotic risk factors.     

Significant ethnic variation in total and free testosterone concentration

OBJECTIVE: Measurement of serum testosterone is an integral part of the assessment of men presenting to endocrine clinics. Little is known about the variation of total bound or bioavailable testosterone by ethnic group. The principal determinant of testosterone bioavailability is SHBG, which itself is a marker for insulin sensitivity. Our aim was to examine variations in testosterone and SHBG levels across three ethnic groups in relation to ethnic differences in insulin sensitivity. DESIGN: Men of three ethnic groups living in Manchester, UK, were sampled randomly from population registers being of white European (n = 55), Pakistani (n = 50) and African-Caribbean (AfC) origin (n = 75). Circulating serum testosterone and SHBG concentrations were measured and free testosterone calculated. Insulin sensitivity (HOMA-S) and insulin secretory capacity (HOMA-B) were determined from fasting plasma intact insulin and glucose values. RESULTS: Testosterone levels were lower in Pakistani men (mean 14.6 nmol/l, 95% confidence interval 12.6-16.6 nmol/l) than in Europeans (18.7, 16.8-20.6 nmol/l) or AfCs (18.0, 16.4-19.6 nmol/l) (F = 4.8, P = 0.009). Despite SHBG levels also being lower in Pakistani men (22.9, 19.4-26.5 nmol/l) compared with Europeans (28.7, 25.7-31.8 nmol/l) and AfCs (26.9, 23.9-30.0 nmol/l) (F = 3.0, P < 0.05), circulating free testosterone was significantly lower in the Pakistani group (367, 326-408 pmol/l) than in Europeans (455, 416-494 pmol/l) or AfCs (458, 424-492 pmol/l) (F = 6.8, P = 0.001). Pakistani men were on average 4 cm shorter than other groups. However, the lower free testosterone persisted even when adjusted for height or waist-hip ratio. The lower SHBG in the Pakistani men was paralleled by a lower HOMA-S (0.40, 0.25-0.56) compared with Europeans (0.77, 0.61-0.93) and AfCs (0.80, 0.66-0.93) (F = 8.2, P < 0.0001). SHBG correlated positively with HOMA-S (rho = 0.28, P < 0.001) and strongly with total testosterone (rho = 0.54, P < 0.001). There was no difference in insulin secretory capacity (HOMA-B) in Pakistani men compared with Europeans and AfCs. Multiple linear regression analysis showed that total testosterone was independently and negatively related to ln fasting insulin (beta = -0.28, P < 0.001) and age (beta = -0.17, P = 0.02) and positively to ln SHBG (beta = 0.23, P < 0.001) and height (beta = 0.22, P = 0.001). There was no relationship with ethnicity or waist-hip ratio. CONCLUSION: Both total bound and calculated free testosterone were lower in Pakistani men. SHBG levels were also lower in Pakistani men, in keeping with poorer insulin sensitivity. We propose that further work is necessary to establish ethnic-specific ranges for the interpretation of total circulating and free testosterone levels in men.     

Design and results of the antiarrhythmics vs implantable defibrillators (AVID) registry. The AVID Investigators

BACKGROUND: The Antiarrhythmics Versus Implantable Defibrillators (AVID) Study compared treatment with implantable cardioverter-defibrillators versus antiarrhythmic drugs in patients with life-threatening ventricular arrhythmias (VAs). AVID maintained a Registry on all patients, randomized or not, with any VA or unexplained syncope who could be considered for either of the treatment strategies. Trial-eligible arrhythmias were the categories of VF cardiac arrest, Syncopal VT, and Symptomatic VT, below. METHODS AND RESULTS: Of 5989 patients screened, 4595 were registered and 1016 were randomized. Mortality follow-up through 1996 was obtained on the 4219 Registry patients enrolled before 1997 through the National Death Index. Crude mortality rates (mean+/-SD, follow-up, 16.9+/-11.5 months) were: VF cardiac arrest, 17.0% (n=1399, 238 deaths); Syncopal VT, 21.2% (n=598, 127 deaths); Symptomatic VT, 15.8% (n=1065, 168 deaths); Stable (asymptomatic) VT, 19.7% (n=497, 98 deaths); VT/VF with transient/correctable cause, 17.8% (n=270, 48 deaths); and Unexplained syncope, 12.3% (n=390, 48 deaths). CONCLUSIONS: Patients with seemingly lower-risk or unknown-risk VAs (asymptomatic VT, and VT/VF associated with a transient factor) have a (high) mortality similar to that of higher-risk, AVID-eligible VAs. The similar (and poor) prognosis of most patients with VT/VF suggests the need for reevaluation of a priori risk grouping and raises the question of the appropriate arrhythmia therapy for a broad range of patients.     

The influence of balloon inflation duration on the acute angiographic result of percutaneous transluminal coronary angioplasty

This study was performed to evaluate the importance of the duration of balloon inflation during PTCA, by comparing two common inflation durations. Patients were randomized to a 30-second inflation protocol (group I, 83 procedures, 109 lesions), or a 60-second protocol (group II, 83 procedures, 115 lesions). There were no differences in baseline characteristics between the two groups, and no subsequent differences in mean inflation number (3.4 +/- 1.6 vs 3.1 +/- 1.6), residual stenosis (34% +/- 17% vs 33% +/- 16%), presence of dissection (29% vs 34%), or clinical success (89% vs 84%), group I versus group II, respectively. The 30-second inflations caused significantly less chest pain score (147 +/- 239 vs 399 +/- 516, P less than 0.001), and ST segment alteration (75 +/- 94 seconds vs 136 +/- 163, P less than 0.05). These results indicate that 60-second inflations do not produce a superior result to 30-second inflations. Furthermore, shorter inflations are much better tolerated.     

Feasibility of an interprofessional collaborative osteoporosis screening programme in Malaysia

Background Population screening for osteoporosis using bone mineral density scan is not feasible in Malaysia as this test is costly. Hence, there is a need to develop a more efficient method to screen for osteoporosis.Objectives To determine the feasibility of an interprofessional collaborative osteoporosis screening programme (IPC-OSP). Methods Postmenopausal women aged?≥?50 years, who had not been diagnosed with osteoporosis were recruited from a primary care clinic from June to August 2014. Patients were assessed for their osteoporosis risk and were counselled on prevention methods. Patients at risk were referred to the doctor with a recommendation for a bone mineral density (BMD) scan. Results Fifty out of 55 patients were recruited (response rate?=?90.9%). A total 26/50 (52.0%) went for a bone mineral density scan, none were osteoporotic, 17/50 (34%) were osteopenic, 2/50 (4.0%), were started on osteoporosis medications and 14/50 (28%) modified their lifestyle to improve bone health or started on calcium supplements. Osteoporosis knowledge significantly increased from baseline to month two (46.3?±?21.4 vs. 79.1?±?14.3, p?<?0.001). Patients had a satisfaction score of 89.8?±?12.4. Follow-up rates were 83.9% and 100% at months 1 (BMD appointment) and 2 (phone follow up), respectively. The intervention was successfully coordinated. Data entry was determined to be viable based on the researchers’ experience. Conclusion The interprofessional collaborative osteoporosis screening programme was found to be feasible in Malaysia.

     

Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

We utilized synthetic photochemistry to generate novel sp³-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1–5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.