John Rediske - Academia.edu (original) (raw)

Papers by John Rediske

Blood, 2007

LBH589 is a novel cinnamic acid hydroxamate DACi which induces apoptosis in multiple hematologic ... more LBH589 is a novel cinnamic acid hydroxamate DACi which induces apoptosis in multiple hematologic tumor cell lines in vitro at nanomolar levels. LBH589 has been administered orally, once-a-day, on Monday/Wednesday/Friday, every week (Arm 1) or every other week (Arm 2), in cycles of 28 days, to adult pts with advanced hematologic malignancies. A 3-parameter Bayesian logistic regression model guided dose escalation. To date, 61 pts, median age 67 yrs (range 16–87), 40 male, 21 female, have been enrolled: 33 pts in Arm 1 at dose levels (mg/dose) of 20 (9 pts), 30 (12 pts), 40 (10 pts), and 60 (2 pts); 28 pts in Arm 2 at dose levels (mg/dose) of 30 (7 pts), 45 (12 pts), and 60 (9 pts). Diseases treated have included AML (36 pts), MDS (7 pts), MM (3 pts), NHL (3 pts), HL (3 pts), CML-BP (2 pts), CML-CP (1 pt), CMML (2 pts), Ph+ ALL (2 pts), CLL (1 pt), and chronic idiopathic myelofibrosis (CIMF) (1 pt). The MTD has not yet been determined for either schedule. In Arm 1, at the 40 mg dose l...

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1996

A differentiated human colonic epithelial cell has undergone relatively stable molecular, biochem... more A differentiated human colonic epithelial cell has undergone relatively stable molecular, biochemical, and cellular alterations resulting in the acquisition of structures, activities, and functions that characterize it as one of at least three mature phenotypes: a columnar absorptive, secretory, or enteroendocrine cell. We have shown previously that induction of HT29 cells with the short-chain fatty acid sodium butyrate elevates alkaline phosphatase activity, a marker of the absorptive cell phenotype, and increases mitochondrial gene expression. Furthermore, this induction is accompanied by subsequent apoptosis and cell shedding. In this report, we have investigated the effects of forskolin, a potent inducer of the MUC2 gene in HT29 cells, a marker of the secretory phenotype, and have shown that neither apoptosis nor mitochondrial gene expression are significantly stimulated. Thus, differentiation along the secretory cell lineage may not play a major role in apoptosis of colonic epi...

Cancer Research, 2011

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The prolactin receptor (... more Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The prolactin receptor (PRLR) is a class I cytokine receptor frequently expressed in breast and prostate cancer. The polypeptide hormone prolactin (PRL) has been demonstrated to induce PRLR signaling through the Jak/Stat, PI3-kinase/AKT and MAPK pathways, leading to cell proliferation and survival. Breast- and prostate-specific overexpression of PRL in transgenic mice leads to a higher incidence of mammary and prostate tumors, respectively. In addition, the PRLR locus is the site of frequent viral integrations in MMTV-derived mammary tumors. Elevated serum PRL levels in humans have been correlated with an increased risk for breast cancer, and an analysis of more than 3000 breast tumor specimens indicates that PRLR is expressed with high prevalence (60-70% of tumors) across all breast cancer subtypes. In prostate cancer specimens, the presence of prolactin and phosphorylated Stat5 have been reported to be associated with high-grade tumors and poor clinical outcomes, suggesting a role of the PRL/PRLR signaling pathway in the pathology of this disease as well. All of these lines of evidence support the hypothesis that targeting the PRL/PRLR axis may be a new approach for addressing unmet medical need in these tumor types. LFA102 is a Human Engineered™ anti-PRLR antibody of the IgG1 isotype that neutralizes the function of PRLR through a nonligand competitive binding interaction. LFA102 blocks PRL-induced signaling and proliferation in T47D and MCF7 human breast cancer cells in vitro, and abolishes PRL-induced phospho-Stat5 signaling in T47D xenograft tumors in vivo. This antibody also cross-reacts with and neutralizes rat PRLR and is capable of potently regressing PRL-dependent Nb2-C11 pre-T cell lymphoma tumors in vivo. In vitro studies have shown that LFA102 can mediate antibody-dependent cellular cytotoxicity (ADCC) and inhibit the PRL-dependent release of the proangiogenic factor VEGF from breast cancer cells. Thus, there are multiple potential mechanisms through which LFA102 could show antitumor activity in vivo. Preclinical toxicological studies of LFA102 indicate that this therapeutic is well tolerated and exhibits a normal pharmacokinetic profile in relevant animal species. The safety and pharmacokinetics of LFA102 in humans are currently being evaluated in a phase I healthy volunteer trial. A phase 1b trial in breast and prostate cancer is planned to evaluate the efficacy of this antibody in patient populations predicted to have the highest probability of benefiting from an anti-PRLR therapeutic. This presentation will provide a summary of the preclinical data supporting the clinical development of LFA102. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2011-DDT02-02

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1994

Human articular chondrocytes can be induced by IL-1/3, TNF-a or LPS to release high levels of nit... more Human articular chondrocytes can be induced by IL-1/3, TNF-a or LPS to release high levels of nitric oxide. Using degenerate PCR primers based on homologous regions from previously cloned NOS enzymes, a 1.9 kb eDNA fragment was amplified from IL-lfl stimulated but not from resting chondrocytes. Screening of a h gtll cDNA library, which was prepared from RNA of IL-lfl activated chondrocytes, resulted in the isolation of the complete eDNA, encoding a protein of 1153 amino acids. Comparison of the eDNA sequence identified human chondrocyte iNOS to be almost identical to the sequence recently reported for the hepatocyte enzyme, differing in 12 amino acids. Northern blot analysis revealed, that stimulated chondrocytes express a single 4.5 kb iNOS mRNA species. IL-lfl induction of iNOS mRNA was detectable by 6 h and continued to be elevated throughout a 72 h culture period. Screening of a human bone cDNA library identified this inducible NOS to be also expressed by bone cells.

Inflammation Research, 2004

The American Chemical Society (ACS) is a nonprofit organization with a membership of approximatel... more The American Chemical Society (ACS) is a nonprofit organization with a membership of approximately 160,000 chemists and chemical engineers. The ACS publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry.(http://www.chemistry.org).

Stimulation of human neutnophils with plate- let activating factor (PAF) resulted in a transient ... more Stimulation of human neutnophils with plate- let activating factor (PAF) resulted in a transient eleva- tion of free cytosolic calcium. Neutrophils exhibited a two-component calcium response observed as a double peak when stimulated with > 5 nM PAF. In contrast, leukotriene B4 (LTB4), C5a, on formylmethionyl-leucyl- phenylalanine stimulated only a single-peak calcium response. The double-peak calcium response was not elicited in human monocytes or differentiated U937 cells, which demonstrated a single peak. Pretreatment of neu- trophils with a 5-lipoxygenase inhibitor or a specific LTB4-receptor antagonist selectively blocked the second calcium peak. These results suggest that PAF-mediated activation of human neutrophils results in the activation of the 5-lipoxygenase and the subsequent generation of LTB4. This LTB4 in turn elicits a secondary rise in cal- cium, which contributes to the overall response of neu- tnophils to PAF. These results demonstrate how LTB4 par- ticipates in...

Journal of Cellular Physiology, 1993

umDus, Ohio 4320 1 Articular chondrocytes from rheumatoid joints have been shown to express class... more umDus, Ohio 4320 1 Articular chondrocytes from rheumatoid joints have been shown to express class II major histocompatibility (MHC) antigens that were correlated with the presence of interferon-gamma (IFN-y) in the inflamed joint. Chondrocytes expressing MHC antigen5 function as antigen presenting cells and thus stimulate lymphocyte proliferation. These responses suggest a powerful role for the IFN-y stimulation of chondrocytes. The present studies were designed to examine the functional role of chondrocytes exposed to IFN-y during cartilage degradation that occurs in synovial disease. Destruction of cartilage in arthritis is partially attributable to metalloproteinases released by the chondrocytes in response to interleukin-I (IL-I 1.

Cellular Immunology, 1993

Arthritis and Rheumatism, Dec 1, 1998

ABSTRACT To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matri... more ABSTRACT To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matrix protein (COMP) to produce fragments similar to those found in synovial fluid (SF) from patients with arthritis. COMP fragments were generated in vitro by treating (a) bovine articular cartilage with interleukin-1alpha (IL-1alpha), (b) purified bovine COMP with MMPs, and (c) articular cartilage with MMPs. The fragments generated in each case were analyzed by Western blot, using an antibody to the C-terminal heptadecapeptide of COMP. IL-1alpha stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BB-94. Isolated, recombinant MMPs rapidly degraded purified COMP, as well as COMP residing in cartilage. Several COMP fragments produced in vitro had similar electrophoretic mobility to those in SF of patients with arthritis. MMPs may contribute to the COMP fragments found in vivo. Quantitation of MMP-specific fragments may be useful in the evaluation of MMP inhibitors in patients with arthritis.

The Journal of clinical investigation, 1997

Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of... more Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of both rheumatoid and osteoarthritis. In this study, we examined intracellular events which follow ligation of Fn to its receptor, the integrin alpha5beta1. In addition, we examined the regulatory influence of nitric oxide on these events, since this free radical has been implicated in cartilage degradation. Exposure of chondrocytes to Fn-coated beads resulted in the circumferential clustering of the alpha5beta1 integrin receptor, which was accompanied by the subplasmalemmal assembly of a focal activation complex comprised of F-actin, the tyrosine kinase, focal adhesion kinase (FAK), the ras related G protein rho A, as well as tyrosine-phosphorylated proteins. Treatment with exogenous nitric oxide (NO) or catabolic cytokines which induce nitric oxide synthase blocked the assembly of F-actin, FAK, rho A and tyrosine-phosphorylated proteins while not affecting the total number of beads boun...

Journal of leukocyte biology, 1985

Tissue macrophages produce several proteins of the complement system. The mechanisms that regulat... more Tissue macrophages produce several proteins of the complement system. The mechanisms that regulate this process are poorly understood. The established ability of certain prostaglandins to influence macrophage secretory activity suggests that these lipid mediators may also modulate complement production (CP). Using the guinea pig peritoneal macrophages, we determined the effects of selected prostaglandins on in vitro CP and found that PGE2 inhibited production of complement proteins but not lysozyme; the response of elicited and resident peritoneal cells to PGE2 was identical; and PGE1, PGF2 alpha, and PGI2 had no detectable effect. PGE2 may contribute to regulation of CP in vivo.

Journal of biological standardization, 1985

Normal diploid human fibroblasts and first passage monkey kidney epithelial cells were examined f... more Normal diploid human fibroblasts and first passage monkey kidney epithelial cells were examined for growth and metabolic activity on microcarriers made from glass and on microcarriers made from DEAE-dextran. The cells grew to a higher density (cells cm2 of surface area) on the glass microcarriers made from glass and on microcarriers made from DEAE-dextran. The cells grew to a higher density (cells/cm2 of surface area) on the glass microcarriers than they did on the DEAE-dextran microcarriers and morphological differences were observed between the cells growing on the two substrates. On the DEAE-dextran microcarriers, the cells were much more resistant to protease-mediated detachment than were the cells on the glass microcarriers. In these respects, the cells grown on the glass microcarriers were similar to cells grown in conventional monolayer culture. Interestingly, the cells grown on the DEAE-dextran microcarriers expressed higher levels of proteolytic enzyme activity than the cel...

Arthritis research & therapy, 2005

The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics was held in Boston... more The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics was held in Boston, Massachusetts, USA in May 2004. Keystone lectures delivered by Drs Joseph Glorioso and Inder Verma provided comprehensive, up-to-date information on all major virus vectors. Other invited speakers covered the application of gene therapy to treatment of arthritis, including the latest clinical trial in rheumatoid arthritis, as well as lupus and Sjögren's syndrome. Applications in mesenchymal stem cell biology, tissue repair, and regenerative medicine were also addressed. The field has advanced considerably since the previous meeting in this series, and further clinical trials seem likely.

Pain, 2004

Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predomin... more Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.

Arthritis and Rheumatism, 1998

Molecular Medicine Today, 1999

1. Mol Med Today. 1999 Apr;5(4):148-51. Joint efforts: tackling arthritis using gene therapy. Fir... more 1. Mol Med Today. 1999 Apr;5(4):148-51. Joint efforts: tackling arthritis using gene therapy. First International Meeting on the Gene Therapy of Arthritis and Related Disorders. Bethesda, MD, USA, 2-3 December 1998. Evans CH, Rediske JJ, Abramson SB, Robbins PD. ...

Osteoarthritis and Cartilage, 1994

Nitric oxide (NO) may play a role in tissue remodeling associate4 with arthritis. The articular c... more Nitric oxide (NO) may play a role in tissue remodeling associate4 with arthritis. The articular cell sources of human inducible NO synthesis, however, have not been defined. This study demonstrates that human articular chondrocytes in primary or organ culture, but not synovial fibroblasts, produce NO in response to catabolic cytokines such as interleukin-1 (IL-1). As measured by the accumulation of NO~ in culture medium, NO production by IL-l-stimulated chondrocytes was inhibited by the NO synthase inhibitor Ng-monomethyl-L-arginine (NMA) and dependent on the presence of exogenous L-arginine. Other inflammatory cytokines such as tumor necrosis factor, but not transforming growth factor-/?, induced chondrocyte NO synthesis. The stimulation of NO synthesis required both RNA and protein synthesis. Chondrocytes isolated from cartilage derived from osteoarthritic patients also produced large amounts of NO in response to IL-1. In beginning to define potential effects of NO on chondrocyte function, it is shown that IL-1 induced an increase in cyclic guanosine monophosphate (cGMP) which was inhibited by NMA. In summary, these results demonstrate that cytokine-induced production of NO is a response of human articular chondrocytes but not of synovial fibroblasts. A potential role of NO in cytokine-induced tissue remodeling in the joint is provided by the induction of cGMP.

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Molecular Immunology, 1992

The fifth component of the complement cascade, C5a, was iodinated using the Bolton-Hunter reagent... more The fifth component of the complement cascade, C5a, was iodinated using the Bolton-Hunter reagent. Results from the present study, using the high affinity ligand, [125I]Bolton-Hunter-labeled C5a ([125I]BH-C5a), revealed a single binding site on membranes prepared from human neutrophils, U-937 cells and human monocytes. Saturation studies demonstrated Bmax values in these cells of 11.5, 47.3 and 16.6 fmol/10(6) cells, respectively. The C5a receptor demonstrated a very high affinity for [125I]BH-C5a of approximately 4 pM in each cell type. Competition studies using analogs of C5a generated a similar order of potency in each of the cell types of C5a > or = C5a(1-74), Ser66Ala > C5a(1-73) > C5a(1-69). These studies indicate that [125I]BH-C5a labels a similar receptor in neutrophil, U-937 cell and monocyte membranes. Furthermore, C5a(1-73) produced shallow inhibition curves in competition experiments in each cell type. Computer analysis of the binding data revealed two components of binding. When 10 nM unlabeled C5a was used to initiate dissociation of [125I]BH-C5a binding in neutrophil membranes, two binding components were observed. In addition, dissociation of [125I]BH-C5a binding by 10 nM unlabeled C5a in the presence of 1 mM GppNHp decreased the percentage of binding to the slowly dissociating, high affinity binding component from 84 to 58%. These results suggest that multiple states of the C5a receptor exist.