Hepoxilins in cancer and inflammation��use of hepoxilin antagonists

Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author's laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists.     

Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms—Workshop Report

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.     

Levels of lactoferrin, secretory IgA and serum albumin in the tear film of people with keratoconus

Keratoconus is a degenerating disease of the eye which causes an irregularly shaped cornea leading to severe impairment of vision. Tear proteomics in keratoconus has been a topic of substantial discussion and speculation over many years. This study was designed to examine the levels of total protein, lactoferrin, secretory IgA and serum albumin in the tear film of people with keratoconus. Basal tears were collected using a capillary tube and corneal curvature was mapped using a topographer. Total protein in tears was estimated. The amount of regulated protein lactoferrin, constitutive protein sIgA and serum protein albumin was measured using specific ELISAs. The changes in protein concentrations in tears were correlated to the degree of corneal asphericity. There was a two-fold (p<0.0001) decrease in total protein levels between keratoconus (3.86 ± 1.62 mg/ml) and normal (7.00 ± 1.58 mg/ml) tears. The amount of lactoferrin (0.67 ± 0.28 vs. 1.13 ± 0.29 mg/ml) and secretory IgA (0.78 ± 0.36 vs. 1.70 ± 0.66 mg/ml) were significantly (p<0.0001) reduced in keratoconus tears. Variation in serum albumin levels between keratoconus (8.18 ± 4.72 μg/ml) and normal tears (11.66 ± 8.20 μg/ml) were not significant. The differences in total protein, lactoferrin and secretory IgA were not associated with contact lens wear, age, gender or atopy of subjects. The keratometry reading was negatively correlated to tear levels of total protein (r?=?-0.59, p?相似文献   

Metabolic syndrome and salivary cortisol: Is there dysregulation among a group of active duty urban police officers?

ObjectiveExamine metabolic syndrome risk and cortisol patterns in an actively employed group of urban police officers.MethodsA total of 102 actively employed Upstate New York police officers were randomly selected. Metabolic syndrome risk factor determinations were obtained during a scheduled clinic visit and salivary cortisol measures were subsequently obtained over the next 24 h.Results24% of male police offers demonstrated metabolic syndrome as defined by the National Cholesterol Education Program guidelines. Only one female officer met the criteria for metabolic syndrome; however, she declined to participate in the cortisol portion of the study. Among male officers were the most prevalent risk factors, while female officers most often exhibited as the most commonly identified risk factors. The various cortisol measures produced mixed results. Area under the curve cortisol did demonstrate moderate dysregulation.ConclusionCortisol dysregulation is evident among the male officers with metabolic syndrome who participated in the study. Of interest among those officers with only two syndrome characteristics, dysregulation of awakening area under the curve cortisol measures was also apparent. Continued monitoring of the officer population for manifest diabetic and cardiovascular disease should be undertaken.     

Technical Exhibits

Some important but little-emphasized nutritional aspects of gastrointestinal physiology are discussed. Experimental studies which form the basis for present understanding of fluid and electrolyte problems are reviewed briefly. Other topics include harmful and beneficial effects of gastrointestinal bacteria, protein-losing enteropathies, and nutritional problems associated with gastrointestinal resection.     

Adenovirus-mediated FLT1-targeted proapoptotic gene therapy of human prostate cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is of particular interest in the development of prostate carcinoma therapeutics as it preferentially induces apoptosis of tumor cells. To employ adenoviral vectors for highly efficient and specific TRAIL gene transfer into cancer cells could overcome some potential problems for recombinant TRAIL. The vascular endothelial growth factor receptor FLT-1 is involved in regulation of angiogenesis and tumor growth, invasion, and metastasis of prostate carcinoma. FLT-1 expression is observed in both tumor endothelial cells and prostate cancer cells. We developed an adenoviral vector encoding the TRAIL gene under control of the FLT1 promoter (AdFlt-TRAIL), which produced endothelial and prostate cancer cell death. The combination of ionizing radiation and adenovirus-driven TRAIL expression overcame human prostate cancer cell resistance to TRAIL. Furthermore, in vivo administration of AdFlt-TRAIL at the site of tumor growth in combination with radiation treatment produced significant suppression of the growth of DU145 human prostate tumor xenografts in athymic nude mice. Our results suggest that specific TRAIL delivery employing the FLT1 promoter can effectively inhibit tumor growth and demonstrate the advantage of combination radiotherapy and gene therapy for the treatment of prostate cancer.