Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA–chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg−1 i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg−1 i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy

Effects of sex, age, and visits on receipt of preventive healthcare services: a secondary analysis of national data

BACKGROUND: Sex and age may exert a combined influence on receipt of preventive services with differences due to number of ambulatory care visits. METHODS: We used nationally representative data to determine weighted percentages and adjusted odds ratios of men and women stratified by age group who received selected preventive services. The presence of interaction between sex and age group was tested using adjusted models and retested after adding number of visits. RESULTS: Men were less likely than women to have received blood pressure screening (aOR 0.44;0.40–0.50), cholesterol screening (aOR 0.72;0.65–0.79), tobacco cessation counseling (aOR 0.66;0.55–0.78), and checkups (aOR 0.53;0.49–0.57). In younger age groups, men were particularly less likely than women to have received these services. In adjusted models, this observed interaction between sex and age group persisted only for blood pressure measurement (p = .016) and routine checkups (p < .001). When adjusting for number of visits, the interaction of age on receipt of blood pressure checks was mitigated but men were still overall less likely to receive the service. CONCLUSION: Men are significantly less likely than women to receive certain preventive services, and younger men even more so. Some of this discrepancy is secondary to a difference in number of ambulatory care visits

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change &#8805;2) and significantly altered in GBM (p &#8804; 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

Quantifying vertical mixing in estuaries

© 2008 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Environmental Fluid Mechanics 8 (2008): 495-509, doi:10.1007/s10652-008-9107-2.Estuarine turbulence is notable in that both the dissipation rate and the buoyancy frequency extend to much higher values than in other natural environments. The high dissipation rates lead to a distinct inertial subrange in the velocity and scalar spectra, which can be exploited for quantifying the turbulence quantities. However, high buoyancy frequencies lead to small Ozmidov scales, which require high sampling rates and small spatial aperture to resolve the turbulent fluxes. A set of observations in a highly stratified estuary demonstrate the effectiveness of a vessel-mounted turbulence array for resolving turbulent processes, and for relating the turbulence to the forcing by the Reynolds-averaged flow. The observations focus on the ebb, when most of the buoyancy flux occurs. Three stages of mixing are observed: (1) intermittent and localized but intense shear instability during the early ebb; (2) continuous and relatively homogeneous shear-induced mixing during the mid-ebb, and weakly stratified, boundary-layer mixing during the late ebb. The mixing efficiency as quantified by the flux Richardson number Rf was frequently observed to be higher than the canonical value of 0.15 from Osborn (J Phys Oceanogr 10:83–89, 1980). The high efficiency may be linked to the temporal–spatial evolution of shear instabilities.The funding for this research was obtained from ONR Grant N00014-06-1-0292 and NSF Grant OCE-0729547

Patterns of perceived barriers to medical care in older adults: a latent class analysis

<p>Abstract</p> <p>Background</p> <p>This study examined multiple dimensions of healthcare access in order to develop a typology of perceived barriers to healthcare access in community-dwelling elderly. Secondary aims were to define distinct classes of older adults with similar perceived healthcare access barriers and to examine predictors of class membership to identify risk factors for poor healthcare access.</p> <p>Methods</p> <p>A sample of 5,465 community-dwelling elderly was drawn from the 2004 wave of the Wisconsin Longitudinal Study. Perceived barriers to healthcare access were measured using items from the Group Health Association of America Consumer Satisfaction Survey. We used latent class analysis to assess the constellation of items measuring perceived barriers in access and multinomial logistic regression to estimate how risk factors affected the probability of membership in the latent barrier classes.</p> <p>Results</p> <p>Latent class analysis identified four classes of older adults. Class 1 (75% of sample) consisted of individuals with an overall low level of risk for perceived access problems (No Barriers). Class 2 (5%) perceived problems with the availability/accessibility of healthcare providers such as specialists or mental health providers (Availability/Accessibility Barriers). Class 3 (18%) perceived problems with how well their providers' operations arise organized to accommodate their needs and preferences (Accommodation Barriers). Class 4 (2%) perceived problems with all dimension of access (Severe Barriers). Results also revealed that healthcare affordability is a problem shared by members of all three barrier groups, suggesting that older adults with perceived barriers tend to face multiple, co-occurring problems. Compared to those classified into the No Barriers group, those in the Severe Barrier class were more likely to live in a rural county, have no health insurance, have depressive symptomatology, and speech limitations. Those classified into the Availability/Accessibility Barriers group were more likely to live in rural and micropolitan counties, have depressive symptomatology, more chronic conditions, and hearing limitations. Those in the Accommodation group were more likely to have depressive symptomatology and cognitive limitations.</p> <p>Conclusions</p> <p>The current study identified a typology of perceived barriers in healthcare access in older adults. The identified risk factors for membership in perceived barrier classes could potentially assist healthcare organizations and providers with targeting polices and interventions designed to improve access in their most vulnerable older adult populations, particularly those in rural areas, with functional disabilities, or in poor mental health.</p

Comparison of immunohistochemistry with immunoassay (ELISA) for the detection of components of the plasminogen activation system in human tumour tissue

Enzyme-linked immunosorbent assay (ELISA) methods and immunohistochemistry (IHC) are techniques that provide information on protein expression in tissue samples. Both methods have been used to investigate the impact of the plasminogen activation (PA) system in cancer. In the present paper we first compared the expression levels of uPA, tPA, PAI-1 and uPAR in a compound group consisting of 33 cancer lesions of various origin (breast, lung, colon, cervix and melanoma) as quantitated by ELISA and semi-quantitated by IHC. Secondly, the same kind of comparison was performed on a group of 23 melanoma lesions and a group of 28 breast carcinoma lesions. The two techniques were applied to adjacent parts of the same frozen tissue sample, enabling the comparison of results obtained on material of almost identical composition. Spearman correlation coefficients between IHC results and ELISA results for uPA, tPA, PAI-1 and uPAR varied between 0.41 and 0.78, and were higher for the compound group and the breast cancer group than for the melanoma group. Although a higher IHC score category was always associated with an increased median ELISA value, there was an overlap of ELISA values from different scoring classes. Hence, for the individual tumour cases the relation between ELISA and IHC is ambiguous. This indicates that the two techniques are not directly interchangeable and that their value for clinical purposes may be different. © 1999 Cancer Research Campaig

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Literacy and blood pressure – do healthcare systems influence this relationship? A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Limited literacy is common among patients with chronic conditions and is associated with poor health outcomes. We sought to determine the association between literacy and blood pressure in primary care patients with hypertension and to determine if this relationship was consistent across distinct systems of healthcare delivery.</p> <p>Methods</p> <p>We conducted a cross-sectional study of 1224 patients with hypertension utilizing baseline data from two separate, but similar randomized controlled trials. Patients were enrolled from primary care clinics in the Veterans Affairs healthcare system (VAHS) and a university healthcare system (UHS) in Durham, North Carolina. We compared the association between literacy and the primary outcome systolic blood pressure (SBP) and secondary outcomes of diastolic blood pressure (DBP) and blood pressure (BP) control across the two different healthcare systems.</p> <p>Results</p> <p>Patients who read below a 9^thgrade level comprised 38.4% of patients in the VAHS and 27.5% of the patients in the UHS. There was a significant interaction between literacy and healthcare system for SBP. In adjusted analyses, SBP for patients with limited literacy was 1.2 mmHg lower than patients with adequate literacy in the VAHS (95% CI, -4.8 to 2.3), but 6.1 mmHg higher than patients with adequate literacy in the UHS (95% CI, 2.1 to 10.1); (p = 0.003 for test of interaction). This literacy by healthcare system interaction was not statistically significant for DBP or BP control.</p> <p>Conclusion</p> <p>The relationship between patient literacy and systolic blood pressure varied significantly across different models of healthcare delivery. The attributes of the healthcare delivery system may influence the relationship between literacy and health outcomes.</p

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination