Blood pressure, blood flow, and oxygenation in the clipped kidney of chronic 2-kidney, 1-clip rats: effects of tempol and Angiotensin blockade.

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls.

A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform.

The anticancer agent docetaxel shows significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also shows wide pharmacological variation. Past pharmacogenetic research has not explained this variation.

Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor.

The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) and its ligand, the growth factor pleiotrophin (PTN), are highly expressed during the development of the nervous system and have been implicated in the malignant progression of different tumor types. Here, we describe human single-chain variable fragment (scFv) antibodies that target the ligand-binding domain (LBD) in ALK and show the effect in vitro and in vivo. The ALK LBD was used as a bait in a yeast two-hybdrid system to select human scFv from a library with randomized complementarity-determining region 3 domains.

Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers.

Objective: BRCA1 mutation carriers have a high rate of both breast and ovarian cancer. Tamoxifen is a selective estrogen receptor modulator (SERM), which is used for the treatment of primary breast cancer and for the prevention of contralateral breast cancer. Our objective is to assess if tamoxifen treatment is associated with an increase in the subsequent risk of ovarian cancer among women with a BRCA1 mutation.

A distinct role for secreted fibroblast growth factor-binding proteins in development.

FGFs modulate diverse biological processes including embryonic development. Secreted FGF-binding proteins (BPs) can release FGFs from their local extracellular matrix storage, chaperone them to their cognate receptors, and thus modulate FGF signaling. Here we describe 2 chicken BP homologs (chBP) that show distinct expression peaks at embryonic days E7.

The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer.

AIB1 (amplified in breast cancer 1), also called SRC-3 and NCoA-3, is a member of the p160 nuclear receptor co-activator family and is considered an important oncogene in breast cancer. Increased AIB1 levels in human breast cancer have been correlated with poor clinical prognosis. Overexpression of AIB1 in conjunction with members of the epidermal growth factor receptor (EGF/HER) tyrosine kinase family, such as HER2, is associated with resistance to tamoxifen therapy and decreased disease-free survival.

Results from four rounds of ovarian cancer screening in a randomized trial.

Objective: To test whether annual screening with transvaginal ultrasonography and CA 125 reduces ovarian cancer mortality.

Methods: Data from the first four annual screens, denoted T0-T3, are reported. A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasonography was considered a positive screen.

Viral and non-viral risk factors for non-Hodgkin's lymphoma in Egypt: heterogeneity by histological and immunological subtypes.

Objective: Non-Hodgkin's lymphomas (NHL) are etiologically heterogeneous malignancies. In Egypt, we previously reported an association of increased NHL risk with chronic hepatitis C virus (HCV) infection. Our present aim is to assess the association between HCV infection and histological subtypes of NHL.

Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies.

Background: Few risk factors have been implicated in pancreatic cancer etiology. Alcohol has been theorized to promote carcinogenesis. However, epidemiologic studies have reported inconsistent results relating alcohol intake to pancreatic cancer risk.

Serum concentrations of cytokines and lung cancer survival in African Americans and Caucasians.

Accumulating evidence suggests a role for inflammation in the development and progression of cancer. Our group recently identified a cytokine gene signature in lung tissue associated with lung cancer prognosis. Therefore, we hypothesized that concentrations of circulating cytokines in serum may be associated with lung cancer survival.

Involvement of P-glycoprotein and multidrug resistance associated protein 1 on the transepithelial transport of a mercaptoacetamide-based histone-deacetylase inhibitor in Caco-2 cells.

Oral bioavailability is one of the important criteria for development of a drug-lead candidate. In this study, the absorptive characteristics and the efflux mechanism of a mercaptoacetamide-based histone deacetyalse (HDAC) inhibitor, coded as W2, were investigated using Caco-2 cells. The transport of W2 was asymmetric as indicated by 1.

Epigenetic targets in cancer epidemiology.

Recently, it has been shown that epigenetic changes are involved in early stages of tumorigenesis, and they may trigger the genetic events leading to tumor development. In cancer epidemiology, there are several epigenetic alterations involved, such as DNA hypermethylation, DNA hypomethylation, and chromatin modifications with critical roles in the initiation and progression of human neoplasms. This chapter discusses the hypermethylation profiles of several tumor types, including bladder, brain, breast, colorectal, ovarian, prostate, and other cancers as well as DNA hypomethylation phenomena together with the chromatin modifications and their role in the complex mechanism of epigenetic silencing.

Dramatically reduced surface expression of NK cell receptor KIR2DS3 is attributed to multiple residues throughout the molecule.

Using flow cytometry, fluorescent microscopy and examination of receptor glycosylation status, we demonstrate that an entire killer cell immunoglobulin-like receptor (KIR) locus (KIR2DS3)--assumed earlier to be surface expressed--appears to have little appreciable surface expression in transfected cells. This phenotype was noted for receptors encoded by three allelic variants including the common KIR2DS3*001 allele. Comparing the surface expression of KIR2DS3 with that of the better-studied KIR2DS1 molecule in two different cell lines, mutational analysis identified multiple polymorphic amino-acid residues that significantly alter the proportion of molecules present on the cell surface.

Co-expression of EGFRvIII with ErbB-2 enhances tumorigenesis: EGFRvIII mediated constitutively activated and sustained signaling pathways, whereas EGF-induced a transient effect on EGFR-mediated signaling pathways.

Elevated levels of epidermal growth factor receptor (EGFR) have been detected in a variety of human cancers. Several reports have demonstrated that the Type III EGF receptor deletion-mutant (EGFRvIII) is frequently detected in various human cancers, including breast cancer. We generated and characterized monoclonal antibody against EGFRvIII.

Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells.

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells.

Biologic therapies for advanced pancreatic cancer.

Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers.

Extracellular domain alterations impact surface expression of stimulatory natural killer cell receptor KIR2DS5.

In the human killer cell immunoglobulin-like receptors, KIR2DL2, and KIR2DL3, a triad of amino acids in the D1 domain interact to stabilize protein structure. Substitution of any one of these residues caused significant loss of cell surface expression. Although KIR2DS4 and KIR2DS5, two homologous receptors, differ for this triad, flow cytometry analysis of NK and T cell lines transfected with stimulatory KIR genes KIR2DS4 (allele *001) and KIR2DS5 (allele *002) demonstrated cell surface expression.

Effect of FGF-binding protein 3 on vascular permeability.

Fibroblast growth factor-binding protein 1 (FGF-BP1 is BP1) is involved in the regulation of embryonic development, tumor growth, and angiogenesis by mobilizing endogenous FGFs from their extracellular matrix storage. Here we describe a new member of the FGF-BP family, human BP3. We show that the hBP3 protein is secreted from cells, binds to FGF2 in vitro and in intact cells, and inhibits FGF2 binding to heparin.

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDACIs) are emerging as a new class of therapeutic agents with potent antitumor activities in a broad spectrum of human cancers. In this study, the in vitro plasma stability, permeability, solubility, and lipophilicity (log D) of two mercaptoacetamide-based HDACIs (coded as W2 and S2) were evaluated and compared to Vorinostat (SAHA). The results demonstrated that the compounds manifested high solubility in HCl (pH 1.

TGF-beta signaling in neuronal stem cells.

Transforming growth factor beta (TGF-beta) signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-beta signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-beta in stem/progenitor cell biology.

Transforming growth factor-beta signaling and ubiquitinators in cancer.

Transforming growth factor-beta (TGF-beta) represents a large family of growth and differentiation factors that mobilize complex signaling networks to regulate cellular differentiation, proliferation, motility, adhesion, and apoptosis. TGF-beta signaling is tightly regulated by multiple complex mechanisms, and its deregulation plays a key role in the progression of many forms of cancer. Upon ligand binding, TGF-beta signals are transduced by Smad proteins, which in turn are tightly dependent on modulation by adaptor proteins such as embryonic liver fodrin, Smad anchor for receptor activation, filamin, and crkl.

Co-overexpression of Janus kinase 2 and signal transducer and activator of transcription 5a promotes differentiation of mammary cancer cells through reversal of epithelial-mesenchymal transition.

Signal transducer and activator of transcription (Stat) 5 appears to play a vital role in prolactin (PRL)-induced cell differentiation and normal mammary gland development. We previously showed that PRL-activated Stat5a induced expression of E-cadherin-beta-catenin complex in vitro and in xenotransplant tumors in vivo led to inhibition of breast cancer invasion. In the present study, we show that human breast cancer cells co-overexpressing Stat5a and its tyrosine kinase (Jak) 2 cultured in three-dimensional (3D) Matrigel culture demonstrate changes consistent with induction of mesenchymal-epithelial redifferentiation.