Utility of tissue Doppler and strain echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy

Arrhythmogenic right ventricular dysplasia (ARVD) is a heritable cardiomyopathy characterized by the fibrofatty replacement of right ventricular (RV) myocardium leading to RV failure and arrhythmias. This study evaluated the potential utility of tissue Doppler echocardiography (TDE) and strain echocardiography (SE) to quantitatively assess RV function and their potential role in diagnosing ARVD. Images of 30 patients with ARVD (diagnosed by task force criteria) and 36 healthy controls were obtained. Peak systolic velocity, early diastolic velocity, displacement, strain rate, strain, outflow tract diameter, and fractional RV area change were measured in all subjects. Peak RV systolic velocity (6.4 +/- 2.2 vs 9 +/- 1.6 cm/s, p <0.0001), early diastolic velocity (-6.7 +/- 2.7 vs -9.4 +/- 2 cm/s, p <0.0001), displacement (13.7 +/- 5.8 vs 18.7 +/- 3.5 mm, p <0.0003), strain rate (-1 +/- 0.7 vs -2 +/- 1 s(-1), p = 0.002), and strain (-10 +/- 6% vs -28 +/- 11%, p = 0.001) were significantly lower in patients with ARVD compared with controls, respectively. Sensitivity and specificity, respectively, were 67% and 89% for systolic velocity, 77% and 71% for displacement, 73% and 87% for strain, 50% and 96% for strain rate, 53% and 93% for outflow tract diameter, and 47% and 83% for fractional area change. RV systolic velocity and displacement were significantly lower than in controls, even in the subset of patients with ARVD with apparently normal right ventricles by conventional echocardiography. Inter- and intraobserver agreement was high. In conclusion, TDE and SE enable the detection of ARVD via the quantification of RV function and may have potential clinical value in the assessment of patients with suspected ARVD. Peak RV systolic velocity <7.5 cm/s and peak RV strain <18% best identify patients with ARVD.     

Effect of celecoxib and novel agent LC-1 in a hamster model of lung cancer

BACKGROUND: Lung cancer is the leading cause of cancer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompanying inhibition of NF-kappaB, were investigated. MATERIALS AND METHODS: Syrian golden hamsters (n = 140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were randomized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treatments were given via orogastric lavage for 32 wk. Immunohistochemistry was used to determine COX-2 expression and NF-kappaB activity. Ki-67 labeling was used as an index of proliferation. COX activity was measured by prostaglandin E(2) enzyme-linked immunosorbent assay. RESULTS: BOP successfully induced lung adenocarcinoma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-kappaB. Prostaglandin E(2) levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activity, but no decrease in NF-kappaB was seen as measured by immunohistochemistry in the tumors. There was no significant difference in tumor size, tumor incidence, or tumor proliferation index between placebo and treatment groups. CONCLUSIONS: Carcinogen exposure results in increased COX-2 and NF-kappaB expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer development when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-kappaB activity will need to be explored to determine the viability of this approach to prevent lung cancer development.     

Development and validation of a stability-indicating RP-LC method for famciclovir

A novel stability-indicating gradient reverse phase liquid chromatographic (RP-LC) method was developed for the determination of purity of famciclovir (FCV) in presence of its impurities and degradation products. The method was developed using Inertsil ODS 3 V (250 × 4.6 mm, 5 μm) column with mobile phase containing a gradient mixture of solvent A and B. 0.01 M potassium dihydrogen orthophosphate buffer, pH adjusted to 6.0 with 1% potassium hydroxide was used as buffer. Buffer and methanol in 80:20 (v/v) ratio was used as solvent A and buffer and methanol in 20:80 (v/v) ratio was used as solvent B. The gradient program (T/%B) was set as 0/5, 15/30, 25/50, 45/60, 55/5 and 60/5. The eluted compounds were monitored at 215 nm. FCV was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. FCV was found to degrade significantly in oxidative, acid and base degradation conditions and mildly in hydrolytic degradation conditions and stable in thermal and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities thus proved the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantitation, precision, linearity, accuracy, robustness and system suitability. This method is also suitable for the assay of famciclovir which ranged from 99.9% to 100.2%.     

Breast-cancer stem cells-beyond semantics

Intratumoral heterogeneity in breast cancer is well documented. Although the mechanisms leading to this heterogeneity are not understood, a subpopulation of cancer cells, cancer stem cells (CSCs), that have some phenotypic similarities with adult tissue stem cells, has been suggested to contribute to tumour heterogeneity. It has been postulated that these CSCs are dormant, and by virtue of their low proliferative activity and ability to exclude intracellular toxins, are resistant to chemotherapy and radiation therapy. These cells were initially isolated based on the presence of markers such as CD44, CD24, and ALDH1, with further characterisation using mammosphere assay and transplantation into immunodeficient mice. The CSC hypothesis raises several theoretical and practical questions. Does cancer arise in normal mammary stem cells or do some malignant cells acquire a CSC phenotype through clonal evolution? Are CSCs in different molecular (intrinsic) subtypes of breast cancer similar, or do they have distinct properties based on the subtype? Does the CSC phenotype reflect plasticity or the dynamic nature of a few cancer cells? How do these cells acquire invasive behaviour, as they go through epithelial-to-mesenchymal transition and then revert to epithelial phenotype at sites of metastasis in response to tumour microenvironmental and metastasis site-specific cues? It is increasingly recognised that the methods and assays used for identifying CSCs have substantial limitations; does this negate the entire concept? In this Personal View, we argue that the CSC phenotype represents an aggressive clone that survives in an adverse environment through constant evolution and integration of various hallmarks of cancer. This evolution could involve acquiring mutations that permit asymmetric and symmetric division, converting the host immune attack to its own advantage, and plasticity to adapt to sites of metastasis through reversible change in adhesion molecules. We also argue that the cell-type origin of cancer could affect the rate at which CSCs develop in a tumour, with an eventual effect on disease outcome.     

Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer

The objective of this study was to overcome drug resistance upon systemic administration of combination paclitaxel (PTX) and the apoptotic signaling molecule C(6)-ceramide (CER) in biodegradable poly(ethylene oxide)-modified poly(epsilon-caprolactone (PEO-PCL) nanoparticles. Subcutaneous sensitive (wild-type) and multidrug resistant (MDR-1 positive) SKOV-3 human ovarian adenocarcinoma xenografts were established in female Nu/Nu mice. PTX and CER were administered intravenously either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles to the tumor-bearing mice. There was significant (p< 0.05) tumor growth suppression in both wild-type SKOV-3 and multidrug resistant SKOV-3(TR) models upon single dose co-administration of PTX (20 mg/kg) and CER (100 mg/kg) in nanoparticle formulations as compared to the individual agents and administration in aqueous solutions. For instance, in SKOV-3 wild-type model, more than 4.3-fold increase (p < 0.05) in tumor growth delay and 3.6-fold (p < 0.05) increase in tumor volume doubling time (DT) were observed with the combination treatment in nanoparticles as compared to untreated animals. Similarly, 3-fold increase (p < 0.05) in tumor growth delay and tumor volume DT was observed in SKOV-3(TR) model. Body weight changes and blood cells counts were used as measures of safety and, except for an increase in platelet counts (p < 0.05) in PTX + CER treated animals, there was no difference between various treatment strategies. The results of this study show that combination of PTX and CER in biodegradable polymeric nanoparticles can serve as a very effective therapeutic strategy to overcome drug resistance in ovarian cancer.