Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome

As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathologic parameter, the tumor's biological behavior, or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or nontumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63 of 74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104 of 202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33 of 50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including microluminal, basal-laminal, cytoplasmic, or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression, or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence, and bladder cancer-specific mortality (P = .042, P = .035, P = .023, and P = .022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27, and cyclin D1, thus excluding a functional link between these 2 groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and -negative carcinomas have different clonal origins or may be derived from different cancer stem cells.     

A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90?mg of brigatinib for 7?days and then 180?mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.     

Development and validation of UPLC-PDA method for concurrent analysis of bergenin and menisdaurin in aerial parts of Flueggea virosa (Roxb. ex Willd.)

Bergenin and menisdaurin are biologically active components which are found in plant Flueggea virosa (Phyllanthaceae). Bergenin has pharmacological actions such as chemopreventive and antihepatotoxic while menisdaurin has an anti-viral activity which needs its evaluation by an analytical method (UPLC-PDA method) that can be applied to the quality control of pharmaceutical preparations. The developed UPLC-PDA method was applied for identification and quantification of standards bergenin and menisdaurin in the methanol extract of F. virosa (FVME). The analysis was carried out using Eclipse C18 (4.6?×?100?mm, 3.5?µm) UPLC column. The optimized chromatographic condition was achieved at 0.16?mL/min flow rate using gradient system with acetonitrile and water as mobile phase. Both biomarkers were measured at λ_max 235?nm in PDA detector at ambient temperature. The developed method furnished sharp and intense peaks of menisdaurin and bergenin at Rt?=?2.723 and 3.068?min, respectively along with r2?>?0.99 for both. The recoveries of bergenin and menisdaurin were found in the range of 99.37–101.49% and 98.20–100.08%, respectively. With other validation data, including precision, specificity, accuracy, and robustness, this method demonstrated excellent reliability and sensitivity. The separation parameters i.e. retention, separation, and resolution factors for resolved standards (bergenin and menisdaurin) were >1, which showed good separation. The quantity of bergenin and menisdaurin in the FVME sample was found as 15.16 and 3.28% w/w, respectively. The developed UPLC-PDA method could be conveniently adopted for the routine quality control analysis.     

Closure of a nonhealing gastrocutaneous fistula using an endoscopic clip

Gastrocutaneous fistula after gastrostomy tube removal may persist for a prolonged period. We present a case of a 58-year-old woman with a GCF that had persisted for 5 months following the removal of an endoscopically-placed gastrostomy tube (PEG). Conservative therapy with anti-acid medications and administering motility agents was unsuccessful. For the closure of the GCF, the endoscopic metal clips were used to close the fistula.     

Substituted phenyl containing 1,3,4-oxadiazole-2-yl-but-2-enamides: synthesis and preliminary evaluation as promising anticonvulsants

A series of 3-(4-substitutedphenyl)-N-(5-(4-substitutedphenyl-1,3,4-oxadiazol-2-yl)but-2-enamide were synthesized using pharmacophoric elements for in vivo anticonvulsant activity yielding two potent candidates (4d and 4j) in the Phase I and Phase II screening employing maximal electroshock seizure and subcutaneous pentylenetetrazole test having minimal neurotoxicity. Their Phase II screen depicted an increment of nearly 2–10 times for MES and 7–67 folds for scPTZ in the therapeutic index and protective index—the two mainstays in the drug discovery.     

Low-fidelity simulation improves mastery of the aseptic technique for labour epidurals: an observational study

Purpose

The objective of this study was to determine the impact of a low-fidelity simulation model on mastering the sterile technique during placement of epidural catheters.

Methods

Trainees, including residents and fellows, were given conventional teaching consisting of a lecture and a video demonstration on the appropriate sterile technique to apply during the placement of epidural catheters. The trainees were then provided with a one-on-one demonstration session using a low-fidelity Styrofoam? epidural model, followed by a series of simulation sessions. After conventional teaching and following each simulation session, the trainees were assessed on their performance until competence was achieved based on a 15-point checklist. The retention of competence was subsequently evaluated bi-weekly in clinical practice for four assessments.

Results

Twenty-one trainees participated in the study. The average score for the residents following conventional teaching was 6.0 out of 15 points on the checklist. Following the initial one-on-one hands-on demonstration, the average score increased to 10.8 (difference = 4.8, 95% confidence interval (CI): 3.3 to 6.2; P < 0.001). The average score for the fellows following conventional teaching was 7.9 out of 15 points on the checklist. Following the initial one-on-one hands-on demonstration the average score increased to 11.2 (difference = 3.3, 95% CI: 0.05 to 6.6; P = 0.047). During the retention of competence phase, scores ranged from 13-15 for both residents and fellows.

Conclusion

This study describes a comprehensive teaching model for mastering the sterile technique during epidural catheter placement. It suggests that low-fidelity simulation improves the learning process when used in addition to conventional teaching.