Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Absorbable and nonabsorbable packing after functional endoscopic sinus surgery: systematic review and meta-analysis of outcomes

The purpose of the study was to perform a systematic review and meta-analysis of the literature to compare the efficacy (and other postoperative outcomes) of nonabsorbable versus absorbable nasal packing after functional endoscopic sinus surgery (FESS) for the treatment of chronic rhinosinusitis. Studies were considered for inclusion if they were published in English language, were randomized clinical trials, and reported on outcomes following postoperative synechia. The primary outcome for meta-analysis was the incidence of postoperative synechia; pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using fixed-effects models. Five studies, involving 241 nasal cavities in each treatment group, were included in the systematic review. The prevalence of synechia ranged from 4.6 to 8.0 % in the absorbable groups and from 8.0 to 35.7 % in the nonabsorbable groups. Postoperative bleeding was lower in the absorbable groups, whereas there was no clear finding regarding postoperative pain. Postoperative edema was generally similar between groups. There were no consistent findings regarding bleeding and pain on packing removal. Two studies using the same type of packing material were included in the meta-analysis. The combined OR (0.33, 95 % CI 0.04–2.78) for postoperative synechia did not significantly favor (P = 0.308) absorbable packing over nonabsorbable packing. Although there is some evidence in the available literature that absorbable nasal packing may provide superior outcomes to nonabsorbable packing after FESS, the lack of homogeneity between studies makes definitive conclusions impossible. Further randomized clinical trials are needed to compare the efficacy of different types of absorbable nasal packing for preventing synechia after FESS

Development of a New HPLC Method for the Simultaneous Determination of Ticarcillin and Clavulanic Acid in Pharmaceutical Formulations

Abstract A new HPLC method has been developed and validated for the simultaneous determination of ticarcillin (TIC) and clavulanic acid (CA) in pharmaceutical formulations. The HPLC separation was achieved on a -cyclodextrin column (Cyclobond I, 250 4.6 mm, 5 mm) with methanol16 mM pH 6.0 ammonium acetate buffer (50 + 50, v/v) mobile phase at a flow rate of 0.8 mL/min. Detection was at 220 nm. Validation of the method was performed by evaluating specificity, robustness, accuracy, and precision. The calibration curves were linear in the range of 1100 g/mL for CA and 2200 g/mL for TIC. The LOQs based on the standard regression lines were 0.42 and 1.42 g/mL for CA and TIC, respectively, and the LOD were 0.14 and 0.47 g/mL, respectively. Total recoveries of synthetic mixtures (CA:TIC = 1:10, 1:15, and 1:30) were 99.25100.99 for CA and 99.54100.82 for TIC. Compared with the U.S. Pharmacopeia method, the proposed method has the advantage of a relatively low flow rate and short analysis time. The proposed method was successfully applied for the simultaneous determination of these two drugs in sterilized H2O and 5 dextrose injection solutions.</jats:p