Fuzapladib in a randomized controlled multicenter masked study in dogs with presumptive acute onset pancreatitis.

Background: Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib is a novel leukocyte function-associated antigen type-1 (LFA-1) activation inhibitor, blocking activation and subsequent adhesion and migration of neutrophils, potentially decreasing the risk of pancreatitis progression and systemic inflammation.

Objective: Evaluate the safety and clinical response of dogs with AP after 3 days of administration of fuzapladib.

Do radiation oncologists and urologists endorse decision aids for active surveillance of low-risk prostate cancer: Results from a national survey.

Objective: The degree decision aids (DAs) can promote active surveillance (AS) for prostate cancer (PCa) remains poorly understood. Herein, we surveyed radiation oncologists (RO) and urologists (URO) about their attitudes towards DAs in counselling patients about AS for low-risk PCa.

Methods: We conducted a national survey of RO (n = 915) and URO (n = 940) to assess their attitudes about DAs for AS for patients with low-risk PCa.

The comparative effectiveness of decision aids in diverse populations with early stage prostate cancer: a study protocol for a cluster-randomized controlled trial in the NCI Community Oncology Research Program (NCORP), Alliance A191402CD.

Background: Treatments for localized prostate cancer present challenging tradeoffs in the face of uncertain treatment benefits. These options are best weighed in a process of shared decision-making with the patient's healthcare team. Minority men experience disparities in prostate cancer outcomes, possibly due in part to a lack of optimal communication during treatment selection.

Association of race and margin status among patients undergoing robotic partial nephrectomy for T1 renal cell carcinoma: Results from a population-based cohort.

Objective: To assess the relationship of race and margin status among patients undergoing robotic partial nephrectomy (RPN) for T1 renal tumors from a contemporary population-based cohort.

Methods: Using the National Cancer Database, we identified patients with localized renal cell carcinoma (RCC) (clinical T1N0M0) who underwent RPN from 2010 to 2013. The primary outcome was positive surgical margins (PSM).

Comparative Effectiveness of Surgical Treatments for Small Renal Masses.

In the management of small renal masses (SRMs), treatment options include partial nephrectomy (PN), radical nephrectomy (RN), ablation, renal biopsy, and active surveillance. Large series retrospective and meta-analyses demonstrate PN may confer greater preservation of renal function, overall survival, and equivalent cancer control when compared with RN. As newer therapies emerge, we should critically evaluate the risks and benefits associated with the surgical management of SRMs among patients with competing comorbidities, complex tumors, and high-risk disease.

Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs.

Maropitant (Cerenia; a novel, selective neurokinin(1) receptor antagonist), chlorpromazine, metoclopramide and ondansetron were compared in two randomized, placebo-controlled studies for efficacy in preventing emesis induced by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were treated in a five-treatment, five-period crossover design. The five treatments were 0.

Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs.

Maropitant (Cerenia), a selective neurokinin(1) receptor antagonist, was evaluated for efficacy and safety in prevention of vomiting due to motion sickness in dogs in two randomized clinical trials. One-hundred eighty-nine dogs with a history of motion sickness were enrolled at 26 veterinary clinics (across 12 US states) across the two trials; of these, 163 were fully evaluable, 19 were evaluable only for safety, and seven were not evaluable. Each trial used a two-period crossover design.

NK cell depletion diminish tumour-specific B cell responses.

Natural killer (NK) cells can exercise immediate cytotoxicity against malignant cells and thus far modulate the development of tumour directed T cell immunity. To investigate the impact of NK cells on the development of tumour directed B cell immunity mice were immunised with IMR5-75 human neuroblastoma cells with or without prior in vivo NK cell depletion. Flow cytometry analyses gave evidence for an impaired IgG response against the cells immunised with.

Mechanisms of action of flavopiridol.

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells.

Pharmacological aspects of targeting cancer gene therapy to endothelial cells.

Targeting cancer gene therapy to endothelial cells seems to be a rational approach, because (a) a clear correlation exists between proliferation of tumor vessels and tumor growth and malignancy, (b) differences of cell membrane structures between tumor endothelial cells and normal endothelial cells exist which could be used for targeting of vectors and (c) tumor endothelial cells are accessible to vector vehicles in spite of the peculiarities of the transvascular and interstitial blood flow in tumors. Based on the knowledge on the pharmacokinetics of macromolecules it can be concluded that vectors targeting tumor endothelial cells should own a long blood residence time after intravascular application. This precondition seems to be fulfilled best by vectors exhibiting a slight anionic charge.

Kinase inhibitors in cancer therapy: a look ahead.

The most essential kinases involved in cell membrane receptor activation, signal transduction and cell cycle control or programmed cell death and their interconnections are reviewed. In tumours, the genes of many of those kinases are mutated or amplified or the proteins are overexpressed. The use of key kinases offers the possibility to screen in vitro for synthetic small molecule kinase inhibitors.

Secreted human beta-glucuronidase: a novel tool for gene-directed enzyme prodrug therapy.

A major problem of tumor gene therapy is the low transduction efficiency of the currently available vectors. One way to circumvent this problem is the delivery of therapeutic genes encoding intracellular enzymes for the conversion of a prodrug to a cytotoxic drug which can then spread to neighboring non-transduced cells (bystander effect). One possibility to improve the bystander effect could be the extracellular conversion of a hydrophilic prodrug to a lipophilic, cell-permeable cytotoxic drug.

Elevated expression of endoglin, a component of the TGF-beta-receptor complex, correlates with proliferation of tumor endothelial cells.

Endoglin/CD105 is a membrane protein involved in the TGF-beta receptor signalling pathway. Endoglin expression has been reported to be selective for a few cell types, in particular endothelial cells, although a number of conflicting reports have been published. In this study, we performed a detailed analysis of endoglin expression in human lung tumors and different tumor and endothelial cell lines, employing reverse-transcriptase-polymerase-chain reaction as well as immunoblotting and immunohistochemistry using verified antibodies to endoglin.

Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells.

The anti-tumor drug Flavopiridol is a potent inhibitor of cyclin-dependent kinases (cdks). As a consequence, Flavopiridol-treated cells arrest in both G1 and G2, but Flavopiridol has also been shown to be cytotoxic for some tumor cell lines. The underlying molecular events are, however, unclear.

Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver.

Flavopiridol (FLAP) is a promising novel chemotherapeutic agent currently undergoing clinical phase I trials. To examine hepatic metabolism and biliary disposition of FLAP we applied the isolated perfused rat liver system. Besides FLAP two metabolites were detected by high performance liquid chromatography in bile and perfusate.

Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy.

Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally purified from Dysoxylum binectariferum, a plant indigenous to India and used in Indian folk medicine. Flavopiridol was detected by a tandem screening system consisting in inhibition of the EGF-receptor Tyrosine phosphokinase and cytotoxicity. As a cytostatic mechanism, however, Flavopiridol strongly inhibits the cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk7), with the potential to cause inhibition of cell cycle progression in G(1) and G(2) by multiple mechanisms relatable to cdk inhibition.

Antitumoral activity of flavone L-86-8275.

L 86-8275, a flavone of novel structure, was shown to be a kinase inhibitor and to possess surprising potent antiproliferative potency (IC50=0.1-0.15 mu M) on various tumor cell lines after long period of incubation.

Biochemical properties of recombinant human beta-glucuronidase synthesized in baby hamster kidney cells.

The cDNA sequence encoding human beta-glucuronidase [Oshima, Kyle, Miller, Hoffmann, Powell, Grubb, Sly, Troplak, Guise and Gravel (1987) Proc. Natl. Acad.

Vaccination for treatment of tumors: a critical comment.

Tumors are resistant to the immune response as evidenced by both their progressive growth in patients despite specific humoral and cellular immune responses to tumor antigens and by the moderate clinical effect of active specific immunotherapy with tumor vaccines tested to date. This "immune resistance" may be due to various reasons, among which the most important ones are: (1) in the afferent pathway of the immune response, (a) expression of major histocompatibility complex (MHC)-class II molecules without coexpression of costimulatory B7 molecules on tumor cells, which impairs activation of T- and B-cells and, (b) release of prostaglandins and other factors from tumor cells, that may inhibit proliferation and function of helper T-cells; and (2) in the efferent pathway; (c) release of tumor antigens, which blocks cytotoxic cells and antibodies and release of proteolytic enzymes, which degrades specific antibodies; (d) reduced expression of MHC-class I molecules by tumor cells, which inhibits their recognition by cytotoxic T-lymphocytes (CTL); and (e) cell membrane-associated inhibitors of complement factors that block complement-mediated lysis. Altogether, the chance for a successful tumor therapy by tumor vaccines has to be estimated to be low.

Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275.

Background: Previous studies have shown that polyhydroxylated flavonoids such as quercetin and genistein can inhibit tumor cell growth in vitro, and preliminary in vivo studies of the flavone L86-8275 have shown growth inhibition of LX529 and A549 lung carcinomas. L86-8275 [(-)cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1-methyl)- piperidinyl]-4H-1-benzopyran-4-one] is a flavone of novel structure.

Purpose: The purpose of this study was to determine in vitro whether L86-8275 is a more potent inhibitor of growth in breast carcinoma and lung carcinoma cells than quercetin or genistein.

Expression of GD2-epitopes in human intracranial tumors and normal brain.

Two monoclonal antibodies (mabs) were raised against ganglioside GD2 (Gtri2) and tested on human intracranial tumors and normal brain by immunohistochemical methods both in frozen and paraffin embedded sections. In normal brain structures, astrocytes were visualized with both mabs (BW 625 and BW 704) almost exclusively in the subventricular and subpial layer. A minor amount of myelin sheaths in well defined localisation was only recognized in frozen sections.

Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activation.

A fusion protein consisting of the humanised Fab fragment of the anti CEA MAb BW 431 and the human beta-glucuronidase was expressed in BHK cells. Functional testing revealed that the specificity and avidity of the humanised V region was similar to the original murine MAb BW 431. Furthermore, the enzymatic activity, pH sensitivity and stability of the human beta-glucuronidase in the fusion protein was comparable to the activity of recombinant human beta-glucuronidase.

Generation of bispecific monoclonal antibodies for two phase radioimmunotherapy.

A two phase radioimmunotherapy based on bispecific MAbs in which one arm recognises a tumour antigen and the other a radiolabelled chelate, may prove more effective in the treatment of carcinomas than currently available immunotherapies. To establish this system we first showed that penetration into human carcinoma xenografts as well as long term retention of intact MAb outside the carcinoma cells can be obtained. Epitope saturation was not obtained however, despite the large MAb doses injected i.