|Targeting Inflammatory Cytokines Using Adenoviruses: gene delivery of biological therapies in ovarian cancer|
Michael A. Salako, Hagen Kulbe, Iain A. McNeish, Frances R. Balkwill
Constitutive TNF-alpha expression is characteristic of the malignant ovarian surface epithelium. Adenoviral mutants hold great promise as gene therapy vectors but their efficacy is hindered by an inflammatory cascade orchestrated by TNF-alpha. We found that delivering TNF-alpha shRNA to ovarian cancer cells using oncolytic adenoviruses could reduce the inflammatory cascade generated by adenoviruses and also had direct anti-tumour activity on the cancer cells.
|Use of gamma scinitigraphy to understand inhaled device/formulation variables on delivery efficiency and|
Peter Scholes and Karen Jones
Systemic delivery of both small molecules and macromolecules via inhaled therapies is an area of significant ongoing research1. The pulmonary route offers the physiological benefits of a highly vascularised, large surface area for absorption which can promote high bioavailability and a rapid onset of action. For biomolecules such as peptides, proteins and nucleic acid derivatives, inhaled drug delivery can also provide a viable alterative to intravenous administration.
|Quantifying the Impact of a Drug on Gastric Emptying: Measuring the Pharmacodynamic Effect in Clinical Trials|
A Rankin, M Paterson, A Connor
Many drug classes are known to alter the rate of gastric emptying. Whilst there is no specific regulatory guidance requiring the impact of drugs on GE to be measured, it is important to fully understand the mode of action and the relationship between the pharmacokinetic profile and the pharmacodynamic response.
|Building Flexibility ino Phase I Protocols and Early Clinical Development Programs|
Lloyd Stevens and Gareth King
The transition of a drug candidate into Phase I and other early drug development programs is undergoing considerable examination and change. This has largely been brought about by commercial and scientific drivers to reduce attrition rates coupled with an evolving regulatory environment, all of which encourage the pharmaceutical industry to build both scientific focus and flexibility into the drug development program.
|Evaluation of Human Regional Bioavailability to Assess Whether Modified Release Development is Feasible|
A Connor, G King and K Jones
Many modified release (MR) oral formulations rely on bioavailability from the distal regions of the gastrointestinal (GI) tract (i.e. the ileum and colon). Therefore, by assessing the bioavailability of a drug following delivery to the distal intestines, it is possible to determine whether MR formulation development is achievable.
|THE OSTEOPROTECTIVE ACTION OF 6-OXA-8a-ANALOGUES OF STEROID ESTROGENS|
A.G. Shavva, V.N. Belov, A.Yu. Solovyev, S.N. Morozkina
We synthesized fourteen 6-oxa-8a-estrogens analogues and investigated osteoprotective and uterotropic actions. We demonstrated correlation: every modification in structure of 6-oxa-8-analogues leading to strong (>30%) reduction of uterotropic action induces slump of osteoprotective activity. This allows to make conclusion: main biotarget, responsible for appearance of osteoprotective action is a-estrogen receptor. We found steroid estrogen analogues with cholesterol-lowering properties without u
|Expression of stress response protein GRP78 is associated with the development of castration-resistant prostate cancer|
Llana Pootrakul, Anirban P. Mitra, Ram H. Datar, Shan-Rong Shi, Jie Cai, Debra Hawes, Susan G. Groshen, Amy S. Lee, Richard J. Cote
This study investigated the role of the GRP78 in prostate cancer progression and the development of castration-resistant prostate cancer, where cancer cells continue to survive despite the stress of an androgen-starved environment.
|Application of genetic programming in analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer|
Anirban P. Mitra, Arpit A. Almal, Ben George, David W. Fry, Peter F. Lenehan, Vincenzo Pagliarulo, Richard J. Cote, Ram H. Datar, William P. Worzel
Nodal involvement in bladder cancer is an independent indicator of prognosis. This study employed an iterative machine learning process called genetic programming on quantitative expression values of 70 genes to classify primary urothelial carcinoma samples into those associated with or without nodal metastasis. The generated rules showed a strong predilection for ICAM1, MAP2K6 and KDR resulting in gene expression motifs that cumulatively suggested a pattern ICAM1>MAP2K6>KDR for node positive ca
|Whole Body Endogenous Nitric Oxide Production in Patients with Decompensated Liver Disease|
Demoncheaux E., Elphick D.A., Dürner M.B., Higgins G.E., Crowther D., Williams E.J., Higenbottam T.W and Gleeson D
Increased nitric oxide (NO) production has been implicated in the pathogenesis of the hyperdynamic circulation found in patients with advanced liver disease. There were no differences between patients with liver disease and controls with regard whole body NO production. Our results, in a well characterised set of patients, argue against greater basal NOS-dependent whole body NO production in patients with decompensated liver disease.
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