Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3)

Abstract Background Signal transducer and activator of transcription 3 (STAT3) is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, to date the exact mechanism by which DIM induces growth suppressive effects has not been clear. In this report the mode of action of DIM is investigated. Methods Six human ovarian cancer cell lines and an ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination with cisplatin. Results Diindolylmethane treatment induced apoptosis in all six ovarian cancer cell lines. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. Interleukin (IL)-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, DIM treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. DIM treatment also inhibited cell invasion and angiogenesis by suppressing hypoxia-inducible factor 1α (HIF-1α) and vascular epithelial growth factor (VEGF). Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation. Conclusions These findings provide a rationale for further clinical investigation of DIM alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer.</p

Inhibition of EGFR-AKT axis results in the suppression of ovarian tumors in vitro and in preclinical mouse model

Ovarian cancer is the leading cause of cancer related deaths in women. Genetic alterations including overexpression of EGFR play a crucial role in ovarian carcinogenesis. Here we evaluated the effect of phenethyl isothiocyanate (PEITC) in ovarian tumor cells in vitro and in vivo. Oral administration of 12 μmol PEITC resulted in drastically suppressing ovarian tumor growth in a preclinical mouse model. Our in vitro studies demonstrated that PEITC suppress the growth of SKOV-3, OVCAR-3 and TOV-21G human ovarian cancer cells by inducing apoptosis in a concentration-dependent manner. Growth inhibitory effects of PEITC were mediated by inhibition of EGFR and AKT, which are known to be overexpressed in ovarian tumors. PEITC treatment caused significant down regulation of constitutive protein levels as well as phosphorylation of EGFR at Tyr1068 in various ovarian cancer cells. In addition, PEITC treatment drastically reduced the phosphorylation of AKT which is downstream to EGFR and disrupted mTOR signaling. PEITC treatment also inhibited the kinase activity of AKT as observed by the down regulation of p-GSK in OVCAR-3 and TOV-21G cells. AKT overexpression or TGF treatment blocked PEITC induced apoptosis in ovarian cancer cells. These results suggest that PEITC targets EGFR/AKT pathway in our model. In conclusion, our study suggests that PEITC could be used alone or in combination with other therapeutic agents to treat ovarian cancer. © 2012 Loganathan et al

Stability Analysis of Integrated Pest Management with Impulsive Biological Control

The aim of the present work is to study the dynamics of stage-structured pest control model including biological control, i.e. by releasing of natural enemies and infected pests periodically. It is assumed that only immature susceptible pests are attacked by natural enemies admitting Beddington DeAngelis functional response and mature susceptible pests are contacted by infected pests with bilinear incidence rate and become exposed. The sufficient condition for local stability of pest extinction periodic solution is derived by making use of Floquet’s theory and small amplitude perturbation technique. The global attractivity of pest extinction periodic solution is also established by applying comparison principle of impulsive differential equations

Benzyl Isothiocyanate Suppresses Pancreatic Tumor Angiogenesis and Invasion by Inhibiting HIF-α/VEGF/Rho-GTPases: Pivotal Role of STAT-3

Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cells in a dose dependant manner. Moreover, secretion of VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both VEGF and MMP-2 play a critical role in angiogenesis and metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of VEGFR-2 (Tyr-1175), and expression of HIF-α. Rho-GTPases, which are regulated by VEGF play a crucial role in pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB. STAT-3 over-expression or IL-6 treatment significantly induced HIF-1α and VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1α and VEGF expression. Finally, in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC, indicating reduced tumor angiogenesis. Immunoblotting of BITC treated tumors show reduced expression of STAT-3 phosphorylation (Tyr-705), HIF-α, VEGFR-2, VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through STAT-3-dependant pathway

An investigation of a deep learning based malware detection system

We investigate a Deep Learning based system for malware detection. In the investigation, we experiment with different combination of Deep Learning architectures including Auto-Encoders, and Deep Neural Networks with varying layers over Malicia malware dataset on which earlier studies have obtained an accuracy of (98%) with an acceptable False Positive Rates (1.07%). But these results were done using extensive man-made custom domain features and investing corresponding feature engineering and design efforts. In our proposed approach, besides improving the previous best results (99.21% accuracy and a False Positive Rate of 0.19%) indicates that Deep Learning based systems could deliver an effective defense against malware. Since it is good in automatically extracting higher conceptual features from the data, Deep Learning based systems could provide an effective, general and scalable mechanism for detection of existing and unknown malware.Comment: 13 Pages, 4 figure

On Stability of Differential Systems with Noninstantaneous Impulses

A new class of impulsive differential equations with noninstantaneous fixed time impulses is considered. Uniform stability and uniform asymptotic stability of solutions of the system have been established by employing piecewise Lyapunov functions. An example is also given to illustrate the theoretical results

Models for crop parameters due to normal load of tractor and number of passes

Multiple passage of power machinery system particularly heavy machines with high wheel loads creates sub-soil compaction which results into increasing in soil bulk density &amp; penetration resistance and reduction in water infiltration, crop germination, growth as well as yield. This study was conducted to determine the different crop growth and crop yield models could be developed to predict growth as well as yield of crop considering normal load and number of passes of tractor. A 36-plot experiment consisting of 12 treatments with three replications were set up using a randomized block design in a uniform field of Division of Agricultural Engineering, IARI, New Delhi during the period of 2007-08. Prediction models were developed between compaction parameters (normal loads and number of passes) and crop parameters like (a) plant height, (b) number of plants per meter, and (c) yield. In, other models a relation between crop yield and sub-soil bulk density and penetration resistance were established and their sensitivity analysis was done for developed models. The best fit model for plant height and number of plants per meter row was quadratic. However, the best fit model between yield vs soil bulk density and yield vs penetration resistance was exponential and quadratic, respectively. The developed model is not more sensitive for number of plants per meter row and yield vs soil bulk density. However, model was more sensitive to plant height model and yield vs soil penetration resistance is more sensitive

BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-Induced Apoptosis

Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways