Education-related variation in coronary procedure rates and the contribution of private health care in Australia: a prospective cohort study.

BACKGROUND: Contemporary Australian evidence on socioeconomic variation in secondary cardiovascular disease (CVD) care, a possible contributor to inequalities in cardiovascular disease outcomes, is lacking. This study examined the relationship between education, an individual-level indicator of socioeconomic position, and receipt of angiography and revascularisation procedures following incident hospitalisation for acute myocardial infarction (AMI) or angina, and the role of private care in this relationship. METHODS: Participants aged ≥45 from the New South Wales population-based 45 and Up Study with no history of prior ischaemic heart disease hospitalised for AMI or angina were followed for receipt of angiography or revascularisation within 30 days of hospital admission, ascertained through linked hospital records. Education attainment, measured on baseline survey, was categorised as low (no school certificate/qualifications), intermediate (school certificate/trade/apprenticeship/diploma) and high (university degree). Cox regression estimated the association (hazard ratios [HRs]) between education and coronary procedure receipt, adjusting for demographic and health-related factors, and testing for linear trend. Private health insurance was investigated as a mediating variable. RESULTS: Among 4454 patients with AMI, 68.3% received angiography within 30 days of admission (crude rate: 25.8/person-year) and 48.8% received revascularisation (rate: 11.7/person-year); corresponding figures among 4348 angina patients were 59.7% (rate: 17.4/person-year) and 30.8% (rate: 5.3/person-year). Procedure rates decreased with decreasing levels of education. Comparing low to high education, angiography rates were 29% lower among AMI patients (adjusted HR = 0.71, 95% CI: 0.56-0.90) and 40% lower among angina patients (0.60, 0.47-0.76). Patterns were similar for revascularisation among those with angina (0.78, 0.61-0.99) but not AMI (0.93, 0.69-1.25). After adjustment for private health insurance status, the HRs were attenuated and there was little evidence of an association between education and angiography among those admitted for AMI. CONCLUSIONS: There is a socioeconomic gradient in coronary procedures with the most disadvantaged patients being less likely to receive angiography following hospital admission for AMI or angina, and revascularisation procedures for angina. Unequal access to private health care contributes to these differences. The extent to which the remaining variation is clinically appropriate, or whether angiography is being underused among people with low socioeconomic position or overused among those with higher socioeconomic position, is unclear.

Failures in preclinical and clinical trials of c-Met inhibitors: evaluation of pathway activity as a promising selection criterion.

C-Met is a frequently overexpressed or amplified receptor tyrosine kinase involved in metastatic-related functions, including migration, invasion, cell survival, and angiogenesis. Because of its role in cancer progression and metastasis, many inhibitors have been developed to target this pathway. Unfortunately, most c-Met inhibitor clinical trials have failed to show significant improvement in survival of cancer patients. In these trials tumor type, protein overexpression, or gene amplification are the primary selection criteria for patient inclusion. Our data show that none of these criteria are associated with c-Met pathway activation. Hence, it is conceivable that the majority of c-Met inhibitor clinical trial failures are the consequence of a lack of appropriate patient selection. Further complicating matters, c-Met inhibitors are routinely tested in preclinical studies in the presence of high levels of exogenous Hepatocyte Growth Factor (HGF), its activating ligand. In our studies, several tumor cell lines showed sensitivity to a c-Met inhibitor at high HGF concentrations (50 ng/mL). However, when the tumor lines were tested at HGF levels typically detected in human serum (0.4 to 0.8 ng/mL), inhibitor activity was lost. Thus testing c-Met inhibitors at non-physiological concentrations of HGF may lead to incorrect predictions of drug efficacy in vivo.

Tumor oxygenation and cancer therapy-then and now.

In 2012, cancer affected 14.1 million people worldwide and was responsible for 8.2 million deaths. The disease predominantly affects aged populations and is one of the leading causes of death in most western countries. In tumors, the aggressive growth of the neoplastic cell population and associated overexpression of pro-angiogenic factors lead to the development of disorganized blood vessel networks that are structurally and functionally different from normal vasculature. A disorganized labyrinth of vessels that are immature, tortuous and hyperpermeable typifies tumor vasculature. Functionally, the ability of the tumor vasculature to deliver nutrients and remove waste products is severely diminished. A critical consequence of the inadequate vascular networks in solid tumors is the development of regions of hypoxia [low oxygen tensions typically defined as oxygen tensions (pO2 values) < 10 mm Hg]. Tumor cells existing in such hypoxic environments have long been known to be resistant to anticancer therapy, display an aggressive phenotype, and promote tumor progression and dissemination. This review discusses the physiological basis of hypoxia, methods of detection, and strategies to overcome the resulting therapy resistance.

Stromal cells in breast cancer as a potential therapeutic target.

Breast cancer in the United States is the second most commonly diagnosed cancer in women. About 1 in 8 women will develop invasive breast cancer over the course of her lifetime and breast cancer remains the second leading cause of cancer-related death. In pursuit of novel therapeutic strategies, researchers have examined the tumor microenvironment as a potential anti-cancer target. In addition to neoplastic cells, the tumor microenvironment is composed of several critical normal cell types, including fibroblasts, vascular and lymph endothelial cells, osteoclasts, adipocytes, and immune cells. These cells have important roles in healthy tissue stasis, which frequently are altered in tumors. Indeed, tumor-associated stromal cells often contribute to tumorigenesis, tumor progression, and metastasis. Consequently, these host cells may serve as a possible target in anti-tumor and anti-metastatic therapeutic strategies. Targeting the tumor associated host cells offers the benefit that such cells do not mutate and develop resistance in response to treatment, a major cause of failure in cancer therapeutics targeting neoplastic cells. This review discusses the role of host cells in the tumor microenvironment during tumorigenesis, progression, and metastasis, and provides an overview of recent developments in targeting these cell populations to enhance cancer therapy efficacy.

Treatment with Src inhibitor Dasatinib results in elevated metastatic potential in the 4T1 murine mammary carcinoma model.

INTRODUCTION: The src inhibitor Dasatinib has been widely studied as an anti-metastatic agent. The aims of this study were to examine the effect of Src inhibition on the metastatic potential of the 4T1 murine mammary carcinoma. CONTEXT: Src is a non-receptor tyrosine kinase well-known to contribute to the metastatic potential of tumour cells. It does so through alteration of signalling pathways important to metastasis. Elevated levels of Src are common in many cancer types, and have been correlated with tumour progression and poor patient prognosis. AIMS: This study examined whether disruption of the Src signalling pathway could inhibit metastases formation. SETTINGS AND DESIGN: The Src inhibitor Dasatinib was evaluated in vitro and in vivo using the highly metastatic 4T1 murine mammary adenocarcinoma cell line. METHODS AND MATERIAL: In vitro assays included growth curve, western blot, migration, and invasion assays. In vivo assays included intradermal and tail vein injection models. STATISTICAL ANALYSIS USED: In vitro data were analysed using one-way ANOVA with Dunnett's multiple comparisons in GraphPad Prism 6.0. In vivo data were analysed using GraphPad Prism 6.0, using the Wilcoxon matched pairs test. RESULTS: Dasatinib is effective at inhibiting in vitro phosphorylation of Src, migration and invasion in the 4T1 cell line, as well as angiogenesis in vivo. In vitro treatment with Dasatinib impaired the metastatic ability of tumour cells as assessed by a tail vein injection model. However, both the syngeneic BALB/c and the athymic nu/nu mice receiving oral doses of the drug developed significantly higher numbers of 4T1 lung metastases. This effect was not seen in a different breast carcinoma cell line, the MDA-MB-231-4175-LM2, nor was this effect seen in the murine fibrosarcoma KHT cell line. CONCLUSIONS: The 4T1 cell line is not an appropriate model to study Src inhibition.

Have Clinical Trials Properly Assessed c-Met Inhibitors?

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria.

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