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At least 469 records · Page 26Linked to original sources
PubMed2004

Essential role of PDGFRalpha-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo: role of PDGFRalpha during angiogenesis.

Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-alpha (PDGFRalpha)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFRalpha-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFRalpha-p70S6K pathway is an essential regulator for FGF-2-mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.

Animals↗
PubMed2001

Role of Ca(2+) in excitation-contraction coupling in echinoderm muscle: comparison with role in other tissues.

The longitudinal muscle of the body wall of Isostichopus badionotus may be considered a model for excitation-contraction coupling in echinoderm muscle. Other echinoderm muscles are reviewed by comparison with the model. Echinoderm muscle is also of interest as a model for 'mutable collagenous tissue'; however, in that tissue, Ca(2+) has been proposed to function both in living control systems and in regulation of non-living interstitial substance.

Animals↗
PubMed1999

[The role of general pharmacological studies and pharmacokinetics in the evaluation of drugs (1): The role of general/safety pharmacology studies in the development of pharmaceuticals: international harmonization of guidelines].

The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of "General pharmacology" to "Safety pharmacology", because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available.

Animals↗
PubMed2005

The role of the dental team in preventing and diagnosing cancer: 5. Alcohol and the role of the dentist in alcohol cessation.

Alcohol use contributes to many health disorders and social problems which may affect both the individual and the community, and is a major risk factor for oral cancer and potentially malignant lesions - leukoplakia and erythroplakia. Counselling by doctors and dentists can increase users' motivation to stop alcohol use but is not often applied in a systematic or frequent manner to people presenting with potentially malignant oral lesions. This paper makes recommendations for interventions by health professionals to encourage and aid cessation of alcohol use as a part of prevention of oral cancer.

Alcohol Drinking↗
PubMed2004

Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax).

Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.

Antineoplastic Agents↗
PubMed2003

A role for two-stage pharmacoeconomic appraisal? Is there a role for interim approval of a drug for reimbursement based on modelling studies with subsequent full approval using phase III data?

Healthcare decision makers and pharmaceutical companies are increasingly using techniques of economic evaluation, particularly modelling, to assist them in their decisions about drug purchasing and drug development. The use of models in other types of policy decisions is also well established. One option, to shorten the time to a purchasing decision, would be for an interim decision for approval for reimbursement to be based on an economic model. Such a system would mainly benefit the drug development process and thus the pharmaceutical industry; however the approach could also lead to poor decision making, unethical marketing and withdrawal of drugs from the consumer. In this article, we consider the option of a two-stage economic appraisal process from the point of view of the seller, the purchaser and the patient and public. Although a two-stage process may offer some advantages in terms of early return on investment and access, there are significant disadvantages in terms of certainty about effects and public policy and expenditure. Until there are better methods of predicting the effectiveness of a new product, it is unlikely that interim decisions can be seen as a reasonable health policy alternative, although it seems likely that industry may continue to lobby for such an approach.

Australia↗
PubMed1992

Role of lipoprotein lipase and apolipoprotein E secretion by macrophages in modulating lipoprotein uptake. Possible role in acceleration of atherosclerosis in diabetes.

Because the accumulation of lipid in macrophages is a characteristic feature of atherosclerosis, the mechanisms by which this lipid accumulation occurs have been intensively studied. This paper reviews the receptor- and non-receptor-mediated pathways that promote lipid accumulation in macrophages. Particular emphasis is placed on the contributions of two secretory products of macrophages, lipoprotein lipase and apolipoprotein E, to both receptor- and non-receptor-mediated uptake of triglyceride-rich lipoproteins by macrophages. The hormonal, lipid, and immunological factors that regulate the secretion of LpL and apoE by macrophages are discussed, as are how changes in the secretion of apoE and LpL that can modulate the uptake of triglyceride-rich lipoproteins by macrophages might influence the atherosclerotic process in people with diabetes.

Apolipoproteins E↗
PubMed2003

Role of ovarian progesterone and potential role of prostaglandin F2alpha and prostaglandin E2 in modulating the uterine response to infectious bacteria in postpartum ewes.

In sheep and cattle, the postpartum uterus is resistant to bacterial challenge until after corpora lutea develop. A 2 x 2 factorial arrangement of treatments was used to determine whether prostaglandins may mediate the effects of progesterone in transforming the postpartum uterus from resistant to susceptible. On d 14 postpartum, ewes (n = 6/group) were ovariectomized or sham ovariectomized, and the vena cava was catheterized for daily collection of uteroovarian-enriched blood. From d 15 to 20, ewes received twice daily intramuscular injections of progesterone in sesame oil or plain sesame oil. On d 20, each uterus received 75 x 10(7) cfu of Arcanobacterium pyogenes and 35 x 10(7) cfu of Escherichia coli. Uteri were collected on d 25 and examined for signs of infection. For each blood sample, unstimulated and mitogen-stimulated lymphocyte proliferation was measured as [3H]thymidine incorporation, smears were prepared for differential white blood cell (WBC) counts, and progesterone, prostaglandin F2alpha, (PGF2alpha), and prostaglandin E2 (PGE2) were quantified. All 12 progesterone-treated, but only two of the 12 oil-treated, ewes developed uterine infections (P < 0.001). Progesterone treatment increased (P < 0.001; 3.1 vs 1.5 ng/mL) and ovariectomy decreased (P < 0.001; 3.7 vs 0.9 ng/mL) vena caval progesterone. Progesterone treatment reduced (P < 0.01) PGF2alpha, (303.9 vs 801.3 pg/mL), and PGF2alpha was greater (P < 0.05) before than after inoculation (626.4 vs 478.8 pg/mL). The PGE2 concentration was greater in progesterone-treated, ovary-intact ewes than in ewes in the other groups (ovariectomy x progesterone treatment; P < 0.01). Ovariectomy increased (P < 0.005; 4.4 vs 2.9 pmol) and progesterone treatment decreased (P < 0.05; 3.2 vs 4.1 pmol) concanavalin A-stimulated lymphocyte proliferation. Ovariectomy increased lipopolysaccharides-stimulated proliferation (P < 0.05; 2.4 vs 1.9 pmol). For neutrophils per 100 WBC, the ovariectomy x progesterone and progesterone x period interactions were significant (P < 0.01). The ovariectomy x progesterone interaction was significant (P < 0.01) for lymphocytes per 100 WBC. Ovariectomy decreased monocytes (P < 0.001; 10 vs 13) and increased eosinophils (P < 0.001; 10 vs 5) per 100 WBC. Progesterone makes the postpartum uterus in ewes susceptible to infection, but ovariectomy allows ewes to remain resistant; uterine prostaglandins may mediate this change. This model creates opportunities to determine the mechanisms responsible for the shift from resistance to susceptible.

Actinomycetales Infections↗