VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer.

We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated.

In silico predicative studies for cytotoxic potential of NSAIDs using self-organizing molecular field analysis.

Antiproliferative potential of nonsteroidal anti-inflammatory drugs (NSAIDs) has generated an immense interest among the scientific fraternity to assess its broader role in the chemoprevention of colon cancer. Due to serious adverse events associated with the chemotherapy, NSAIDs have been exploited as adjuvants to synergize the cytotoxic potential of conventional chemotherapeutic agents at low-dose regimens. The present investigation has been focused on in silico model generation for in vitro cytotoxicity activity of the clinically active NSAIDs using self-organizing molecular field analysis (SOMFA) studies.

Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling.

The neuropilins (NRPs) contribute to the function of cancer cells in their capacity as VEGF receptors. Given that NRP2 is induced in breast cancer and correlates with aggressive disease, we examined the role of NRP2 in regulating the interaction of breast cancer cells with the ECM. Using epithelial cells from breast tumors, we defined NRP2(high) and NRP2(low) populations that differed in integrin expression and adhesion to laminin.

Oral leiomyoma extending in retromolar region.

Leiomyoma is a benign smooth muscle tumor that rarely affects children and occurs most frequently in the uterine myometrium and gastrointestinal tract. Its occurrence in the oral cavity is considered rare probably because of the scarcity of smooth muscle tissue in the oral cavity. The most common intraoral sites for leiomyoma are lips, palate and tongue.

Molecular simulation of hydroxypropyl-beta-cyclodextrin with hydrophobic selective Cox-II chemopreventive agent using host-guest phenomena.

The present investigation outlays the host-guest penetration of hydrophobic selective Cox-II chemopreventive agent, celecoxib (CXB), with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) using inclusion complexation phenomena. Phase solubility studies conducted at 37 degrees C and 25 degrees C revealed typical A(L)-type curve for the HP-beta-CD indicating the formation of soluble complexes. The inclusion complexes in the molar ratio of 1:1 and 2:1 (CXB-HP-beta-CD) were prepared by kneading technique.

Fabrication and optimization of fast disintegrating tablets employing interpolymeric chitosan-alginate complex and chitin as novel superdisintegrants.

The objective of the present work was to optimize the formulation of fast disintegrating tablets (FDTs) of ondansetron HCl containing novel superdisintegrants, possessing sufficient mechanical strength and disintegration time comparable to those containing crospovidone or croscarmellose sodium. The FDTs were formulated using a novel superdisintegrant (chitosan-alginate (1:1) interpolymer complex and chitin) to achieve a sweet tasting disintegrating system. The results revealed that chitin (5-20%) increased the porosity and decreased the DT of tablets.

Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland.

Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2.

Assessment of biological half life using in silico QSPkR approach: a self organizing molecular field analysis (SOMFA) on a series of antimicrobial quinolone drugs.

The quinolones belong to a family of synthetic potent broad-spectrum antibiotics and particularly active against gram-negative organisms, especially Pseudomonas aeruginosa. A 3D-QSPkR approach has been used to obtain the quantitative structure pharmacokinetic relationship for a series of quinolone drugs using SOMFA. The series consisting of 28 molecules have been investigated for their pharmacokinetic performance using biological half life (t(1/2)).

Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease.

Background: The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.

Methods: We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry.

Reciprocal balanced translocation: infertility and recurrent spontaneous abortions in a family.

In this case report we present a family with infertile, azoospermic but otherwise apparently healthy males with history of recurrent spontaneous abortions (RSA) in females. Karyotype of the infertile man revealed a reciprocal balanced translocation t(8; 13) with breakpoints at 8q22 and 13p11.2.

In vivo bioavailability and therapeutic assessment of host-guest inclusion phenomena for the hydrophobic molecule etodolac: pharmacodynamic and pharmacokinetic evaluation.

The aim of present investigation was 1) to evaluate the in vivo bioavailability of an Etodolac (ETD)-Î-cyclodextrin (Î-CD) inclusion complex system prepared by kneading and spray drying techniques in rats, 2) to study the pharmacodynamic parameters in various animal models for analyzing the therapeutic response and, 3) to evaluate the pharmacokinetic profile of the drug administered. Inclusion complexation with Î-CD enhanced the solubility of the drug, improved bioavailability and reduced ulcerogenicity of ETD in rats. Pharmacodynamic studies were carried out in normal LACA mice and pharmacokinetic evaluation was done in male Wistar rats.

Formulation development of stronger and quick disintegrating tablets: a crucial effect of chitin.

A well known superdisintegrant like croscarmellose sodium or crospovidone loses their quick disintegration property when compressed at more than 4 kg tablet crushing strength (TCS). Therefore, the objective of the present work was to develop a disintegrating system that could be used for preparing fast disintegrating tablets (FDTs) of highly water soluble drug, metoclopramide, without compromising on the mechanical strength, irrespective of the TCS used for compressing the granules. For this purpose disintegrating system consisting of chitosan-alginate (CTN-ALG) complex (1:1): glycine and chitin was developed.

CD133, Trop-2 and alpha2beta1 integrin surface receptors as markers of putative human prostate cancer stem cells.

Cancer stem cells (CSCs) play a key role in initiation and development of cancer and are attractive targets for therapy. The identification of CSC surface receptors to be used as therapeutic targets in vivo remains a difficult task. In this study, we assessed the expression pattern of three surface receptors: CD133, Trop-2 and alpha2beta1 integrin in human prostate cancer in order to identify CSC-niches.

Beta1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1.

The beta1 integrins play an important role in the modulation of cancer cell proliferation and tumor growth. We have previously shown that beta1 integrins associate with insulin-like growth factor type 1 receptor (IGF-IR) and regulate IGF-stimulated prostate cancer cell proliferation. In the present study, we find that downregulation of beta1 in prostate cancer cells inhibits IGF-IR and AKT activation.

Development and evaluation of mathematical model to predict disintegration time of fast disintegrating tablets using powder characteristics.

The objective of the study was to develop a mathematical model for predicting the disintegration time of fast disintegrating tablets (FDTs) by estimating the powder characteristics of powder blend prior to compression. A combination of chitosan-alginate complex and glycine in the ratio of 50:50 was used for preparing FDTs. The developed mathematical model allowed water sorption time (WST), effective pore radius (R(eff.

Integrin signaling aberrations in prostate cancer.

Integrins are cell surface receptors for extracellular matrix proteins and play a key role in cell survival, proliferation, migration and gene expression. Integrin signaling has been shown to be deregulated in several types of cancer, including prostate cancer. This review is focused on integrin signaling pathways known to be deregulated in prostate cancer and known to promote prostate cancer progression.

Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer.

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1.

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels.

T-helper (Th) type 1/Th2 cytokines are key mediators in induction/effecter phases of all immune and inflammatory responses playing role in acute/chronic renal allograft rejection. Association studies lead to identification of patient risk profiles enabling individualization of level of immunosuppressions. We investigated the association of allograft rejection with interleukin-2 (IL-2), IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha) -308, transforming growth factor-beta (TGF-beta) (C-del, codon 10 and 25) gene variants in 184 renal transplant recipients and 180 controls.

Beta1 integrin cytoplasmic variants differentially regulate expression of the antiangiogenic extracellular matrix protein thrombospondin 1.

Beta(1) integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to beta(1), we show here that, in vivo, beta(1) integrins are essential for prostate cancer growth. Among the five known beta(1) integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions.

Formulation of orodispersible tablets of ondansetron HCl: investigations using glycine-chitosan mixture as superdisintegrant.

The objective of this investigation was to prepare orodispersible tablets (ODTs) of ondansetron HCl using a direct compression method. A combination of glycine and chitosan was used as a disintegrating system and these tablets were compared for mechanical strength and disintegration time with those containing superdisintegrants. The Plackett-Burman screening design was used to screen the independent variables [concentration of glycine (X(1)), concentration of chitosan (X(2)), concentration of ondansetron HCl (X(3)) and tablet crushing strength (X(4))] which were found to actively influence the dependent variables [disintegration time in the oral cavity (DT), wetting time (WT), and water absorption ratio (WAR)].

Organic anion transporter protein (OATP1B1) encoded by SLCO1B1 gene polymorphism (388A>G) & susceptibility in gallstone disease.

Background & Objectives: Organic anion transport protein 1B1 (OATP1B1) is a major transporter protein for bile salt uptake in the enterohepatic circulation of bile salts. As the role of SLCO1B1 gene (encodes OATP1B1 or liver specific transporter-1) 388 A>G polymorphism in susceptibility towards gallstone disease is unclear the prevalence of this polymorphism in healthy north Indian population was investigated.

Methods: Peripheral venous blood of 270 unrelated northern Indian patients with symptomatic gallstone disease and 270 unrelated healthy control subjects was screened for SLCO1B1 gene 388 A>G polymorphism by PCR-RFLP method and genotyping was done on 12 per cent polyacrylamide gel.

Understanding the mechanism for paradoxical effect of ionized and unionized chitosan: Orodispersible tablets of Ondansetron Hydrochloride.

The objective of the present investigation was to formulate and evaluate orodispersible tablets (ODTs) of ondansetron HCl possessing sufficient mechanical strength by wet granulation or direct compression method. A combination of glycine and chitosan was employed for providing a sweet tasting disintegrating system. The evaluation of ODTs prepared by a wet granulation method revealed that in vitro disintegration time (DT) as well as wetting time (WT) increased and water absorption ratio (WAR) decreased with an increase in concentration of chitosan (as binder).