Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy

The phosphoinositide 3-kinase (PI3K) signaling pathway is frequently up-regulated in human cancer and is a promising target for the treatment of cancer. Wortmannin and its analogues are potent inhibitors of PI3K but suffer from inherent defects such as instability, insolubility, and toxicity. Opening of the reactive furan ring of 17-hydroxywortmannin with amines gives compounds with improved properties such as greater stability and aqueous solubility and a larger therapeutic index. Ring-opened analogues such as compound 13 containing basic amine groups have significantly increased PI3K inhibitory potency and greater efficacy in nude mouse xenograft assays.     

Resorbable fixation techniques for genioplasty.

PURPOSE: This study evaluated the capability and effectiveness of resorbable bone fixation devices in genioplasty surgery. MATERIALS AND METHODS: Twenty patients underwent different genial movements that were stabilized with either 2.5-mm polylactic-polyglycolic acid lag screws or 2.0-mm polylactic-polyglycolic acid plates and screws. RESULTS: Twenty-one anterior mandibular osteotomies were performed in 20 patients. Sixteen patients had advancement (80%), 2 had horizontal setback (10%), and 2 had vertical reduction (10%). The average advancement was 7.6 mm (range, 4 to 14 mm), the average horizontal setback was 6.0 mm (range, 4 to 8 mm), and the average vertical reduction was 7.0 mm (range, 5 to 9 mm). Fixation was done using the lag screw technique in 13 patients (65%) and plate and screw fixation in 7 patients. (35%) Intraoperative stability was satisfactory in all cases. There were no postoperative infections or segmental instability up to 6 months after surgery. CONCLUSION: Resorbable polylactic-polyglycolic acid lag screw and plate and screw fixation is a viable alternative for fixation of anterior horizontal osteotomies of the mandible.     

3,4‐methylenedioxymethamphetamine (MDMA; Ecstasy) administration produces dose‐dependent neurochemical,endocrine and immune changes in the rat

3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely abused drug that is structurally related to both amphetamines and hallucinogens. In addition to the behavioural and neurochemical effects of MDMA, we recently reported that an acute administration of this drug produces a profound suppression of mitogen‐stimulated lymphocyte proliferation and reduction in the number of circulating white blood cells, which was accompanied by elevated circulating corticosterone concentrations. In the present study, the effect of acute MDMA administration on PHA‐induced lymphocyte proliferation, leucocyte subpopulations, HPA‐axis activity and cortical serotonin utilization were examined in a dose‐dependent manner in female Sprague‐Dawley rats. The results of this study demonstrate that MDMA induces a suppression of lymphocyte function even at doses that fail to provoke any significant alteration in central 5‐HT utilization and plasma corticosterone concentrations, thereby suggesting that the reduced functional responsiveness of lymphocytes to mitogenic stimulation after MDMA administration may be mediated by glucocorticoid independent mechanisms. In contrast, the MDMA‐induced reduction in the number of circulating blood lymphocytes was evident only at doses of MDMA which elevated circulating corticosterone concentrations, suggesting that the observed reduction in circulating lymphocytes may be at least partly a glucocorticoid‐mediated event. Copyright © 1999 John Wiley & Sons, Ltd.     

Laparoscopic Single-port Subtotal Hysterectomy: Technique and Advantages

Single-port laparoscopy aims to extend the benefits of minimally invasive surgery by reducing surgical trauma and enhancing patient recovery. Current evidence suggests that single-port hysterectomy is feasible, safe, and equally effective as compared with conventional laparoscopic hysterectomy, although global uptake of this approach has been geographically limited. To our knowledge, this is the first report of a single-port subtotal hysterectomy described in Canada.This online video discusses the technique and perioperative outcomes of a laparoscopic subtotal hysterectomy performed on a 47-year-old woman with severe dysmenorrhea refractory to medical management. In this case, the cervix was conserved in accordance with the patient's preference. The set-up for single-port entry consisted of widely available materials, and total equipment cost for the procedure was $230. The duration of the procedure was 2 hours. The patient was discharged the same day as surgery without the need for postoperative narcotics, and she endorsed a high level of satisfaction with wound cosmesis 6 weeks after surgery. Although the results of this single case cannot be generalized, they are consistent with prior studies underlining the feasibility and effectiveness of a single-port approach for laparoscopic hysterectomy.     

Neutrophil–lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival

Elevated neutrophil–lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan–Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18–70), 369 patients were included. Median follow up was 15.1 month (range 1.6–134.6). The OS was 66.1% (95% CI 61.2–70.6) and 31.4 (95% CI 26.8–36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p?<?0.0001) and baseline NLR?<?7.5 (HR 0.628, p?<?0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578–0.915), age (HR 1.025, 95% CI 1.012–1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532–0.891), total TMZ cycles (HR 0.89, 95% CI 0.867–0.913) and PS (HR 0.476, 95% CI 0.332–0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.     

Resveratrol rescues cAMP-dependent anionic transport in the cystic fibrosis pancreatic cell line CFPAC1

BACKGROUND AND PURPOSE

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride channel in the plasma membrane of epithelia whose mutation is the cause of the genetic disease cystic fibrosis (CF). The most frequent CFTR mutation is deletion of Phe⁵⁰⁸ and this mutant protein (delF508CFTR) does not readily translocate to the plasma membrane and is rapidly degraded within the cell. We hypothesized that treating epithelial cells with resveratrol, a natural polyphenolic, phyto-ooestrogenic compound from grapes, could modulate both the expression and localization of CFTR.

EXPERIMENTAL APPROACH

Cells endogenously expressing CFTR (MDCK1 and CAPAN1 cells) or delF508CFTR (CFPAC1 and airway epithelial cells, deriving from human bronchial biopsies) were treated with resveratrol for 2 or 18 h. The effect of this treatment on CFTR and delF508CFTR expression and localization was evaluated using RT-PCR, Western blot and immunocytochemistry. Halide efflux was measured with a fluorescent dye and with halide-sensitive electrodes. Production of interleukin-8 by these cells was assayed by ELISA.

KEY RESULTS

Resveratrol treatment increased CFTR expression or maturation in immunoblotting experiments in MDCK1 cells or in CFPAC1 cells. Indirect immunofluorescence experiments showed a shift of delF508CFTR localization towards the (peri)-membrane area in CFPAC1 cells and in human airway epithelial cells. A cAMP-dependent increase in membrane permeability to halide was detected in resveratrol-treated CFPAC1 cells, and was inhibited by a selective inhibitor of CFTR.

CONCLUSION AND IMPLICATIONS

These results show that resveratrol modulated CFTR expression and localization and could rescue cAMP-dependent chloride transport in delF508CFTR cells.