Treatment of wild-type gastrointestinal stromal tumor (WT-GIST) with imatinib and sunitinib

We report a rare case of advanced, metastatic gastrointestinal stromal tumor (GIST) in a young female. Molecular analysis of the tumor revealed wild-type (WT) KIT and platelet derived growth factor receptor alpha (PDGFRA) gene status with no mutations characteristic of adult GIST. Despite this she had clinical benefit and evidence of radiological response to sequential treatment with the tyrosine kinase inhibitors imatinib and sunitinib.     

Neem Seed Oil Induces Apoptosis in MCF-7 and MDA MB-231Human Breast Cancer Cells

Background: In traditional Indian medicine, azadirachta indica (neem) is known for its wide range of medicinal properties. Various parts of neem tree including its fruit, seed, bark, leaves, and root have been shown to possess antiseptic, antiviral, antipyretic, anti-inflammatory, antiulcer, antimalarial, antifungal and anticancer activity. Materials and Methods: MCF-7 and MDA MB-231 cells were exposed to various concentrations of 2% ethanolic solution of NSO (1-30 μl/ml) and further processed for cell viability, cell cycle and apoptosis analysis. In addition, cells were analyzed for alteration in Mitochondrial Membrane Potential (MMP) and generation of Reactive Oxygen Species (ROS) using JC-1 and DCFDA staining respectively. Results: NSO give 50% inhibition at 10 μl/ml and 20 μl/ml concentration in MCF-7 and MDA MB-231 cells respectively and, arrests cells at G0/G1 phase in both the cell types. There was a significant alteration in mitochondrial membrane potential that leads to the generation of ROS and induction of apoptosis in NSO treated MCF-7 and MDA MB-231 cells. Conclusion: The results showed that NSO inhibits the growth of human breast cancer cells via induction of apoptosis and G1 phase arrest. Collectively these results suggest that NSO could potentially be used in the management of breast cancer.     

Post-transplant dyslipidemia: Mechanisms,diagnosis and management

Post-transplant dyslipidemia is highly prevalent and presents unique management challenges to the clinician. The two major outcomes to consider with post-transplant therapies for dyslipidemia are preserving or improving allograft function, and reducing cardiovascular risk. Although there are other cardiovascular risk factors such as graft dysfunction, hypertension, and diabetes, attention to dyslipidemia is warranted because interventions for dyslipidemia have an impact on reducing cardiac events in clinical trials specific to the transplant population. Dyslipidemia is not synonymous with hyperlipidemia. Numerous mechanisms exist for the occurrence of post-transplant dyslipidemia, including those mediated by immunosuppressive drug therapy. Statin therapy has received the most attention in all solid organ transplant recipient populations, although the effect of proper dietary advice and adjuvant pharmacological and non-pharmacological agents should not be dismissed. At all stages of treatment appropriate monitoring strategies for side effects should be implemented so that the benefits from these therapies can be achieved. Clinicians have a choice when there is a conflict between various transplant society and lipid society guidelines for therapy and targets.     

Mitral valve repair in chronic severe mitral regurgitation: short-term results and analysis of mortality predictors

IntroductionMitral valve repair is the accepted treatment for mitral regurgitation (MR) but lack of resources and socioeconomic concerns delay surgical referral and intervention in developing countries. We evaluated immediate and short-term results of mitral valve repair for non-ischemic MR at our centre and aimed to identify the predictors of in-hospital and follow-up mortality.Materials and methodsThe study was conducted at a tertiary-level hospital in South India. All patients >18 years with severe non-ischemic MR who underwent mitral valve repair over a period of 6 years were included. Perioperative data was collected from hospital records and follow-up data was obtained by prospective methods.ResultsThere were 244 patients (170 males). Most of the patients were in the age group 31–60 years (76.6%). Aetiology of MR was degenerative (n = 159; 65.2%), rheumatic (n = 34; 13.9%), structural (n = 42; 17.2%), or miscellaneous (n = 9; 3.7%). All patients underwent ring annuloplasty with various valve repair techniques. One hundred patients (44.7%) underwent additional cardiac procedures. At discharge, MR was moderate in 4 patients; the rest had no or mild MR. The mean hospital stay of survivors was 7.1 days (SD 2.52, range 5–25 days). There were 9 in-hospital deaths (3.68%) and 10 deaths during follow-up (4.2%). The mean follow-up period was 1.39 years, complete for 87.6%. Pre-operative left ventricle ejection fraction (LVEF) <60% (p = 0.04) was found to be significantly associated with immediate mortality. Logistic regression analysis detected age (p = 0.019), female sex (p = 0.015), and left ventricular (LV) dysfunction at discharge (p = 0.025) to be significantly associated with follow-up mortality.ConclusionPre-operative LV dysfunction was identified as a significant risk factor for in-hospital mortality. Female sex, age greater than 45 years, and LV dysfunction at discharge were found to be significantly associated with follow-up mortality. Hence, it is important to perform mitral valve repair in severe regurgitation patients before significant LV dysfunction sets in for a better outcome.     

The Attenuation of Early Benzo(a)Pyrene-Induced Carcinogenic Insults by Diallyl Disulfide (DADS) in MCF-10A Cells

Diallyl disulfide (DADS), a garlic organosulfur compound, has been researched as a cancer prevention agent; however, the role of DADS in the suppression of cancer initiation in nonneoplastic cells has not been elucidated. To evaluate DADS inhibition of early carcinogenic events, MCF-10A cells were pretreated (PreTx) with DADS followed by the ubiquitous carcinogen benzo(a)pyrene (BaP), or cotreated (CoTx) with DADS and BaP for up to 24 h. The cells were evaluated for changes in cell viability/proliferation, cell cycle, induction of peroxide formation, and DNA damage. BaP induced a statistically significant increase in cell proliferation at 6 h, which was attenuated with DADS CoTx. PreTx with 6 and 60 μM of DADS inhibited BaP-induced G2/M arrest by 68% and 78%, respectively. DADS, regardless of concentration or method, inhibited BaP-induced extracellular aqueous peroxide formation within 24 h. DADS attenuated BaP-induced DNA single-strand breaks at all time points through both DADS Pre- and CoTx, with significant inhibition for all treatments sustained after 6 h. DADS was effective in inhibiting BaP-induced cell proliferation, cell cycle transitions, reactive oxygen species, and DNA damage in a normal cell line, and thus may inhibit environmentally induced breast cancer initiation.     

Cucurbitacin B potently suppresses non-small-cell lung cancer growth: Identification of intracellular thiols as critical targets

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB’s cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB’s cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.