Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

Emergency department documentation templates: variability in template selection and association with physical examination and test ordering in dizziness presentations

Abstract Background Clinical documentation systems, such as templates, have been associated with process utilization. The T-System emergency department (ED) templates are widely used but lacking are analyses of the templates association with processes. This system is also unique because of the many different template options available, and thus the selection of the template may also be important. We aimed to describe the selection of templates in ED dizziness presentations and to investigate the association between items on templates and process utilization. Methods Dizziness visits were captured from a population-based study of EDs that use documentation templates. Two relevant process outcomes were assessed: head computerized tomography (CT) scan and nystagmus examination. Multivariable logistic regression was used to estimate the probability of each outcome for patients who did or did not receive a relevant-item template. Propensity scores were also used to adjust for selection effects. Results The final cohort was 1,485 visits. Thirty-one different templates were used. Use of a template with a head CT item was associated with an increase in the adjusted probability of head CT utilization from 12.2% (95% CI, 8.9%-16.6%) to 29.3% (95% CI, 26.0%-32.9%). The adjusted probability of documentation of a nystagmus assessment increased from 12.0% (95%CI, 8.8%-16.2%) when a nystagmus-item template was not used to 95.0% (95% CI, 92.8%-96.6%) when a nystagmus-item template was used. The associations remained significant after propensity score adjustments. Conclusions Providers use many different templates in dizziness presentations. Important differences exist in the various templates and the template that is used likely impacts process utilization, even though selection may be arbitrary. The optimal design and selection of templates may offer a feasible and effective opportunity to improve care delivery.http://deepblue.lib.umich.edu/bitstream/2027.42/112490/1/12913_2010_Article_1586.pd

Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given

Wnt/β-catenin Signalling Is Active in a Highly Dynamic Pattern during Development of the Mouse Cerebellum

The adult cerebellum is composed of several distinct cell types with well defined developmental origins. However, the molecular mechanisms that govern the generation of these cell types are only partially resolved. Wnt/β-catenin signalling has a wide variety of roles in generation of the central nervous system, though the specific activity of this pathway during cerebellum development is not well understood. Here, we present data that delineate the spatio-temporal specific pattern of Wnt/β-catenin signaling during mouse cerebellum development between E12.5 and P21. Using the BAT-gal Wnt/β-catenin reporter mouse, we found that Wnt/β-catenin activity is present transiently at the embryonic rhombic lip but not at later stages during the expansion of cell populations that arise from there. At late embryonic and early postnatal stages, Wnt/β-catenin activity shifts to the cerebellar ventricular zone and to cells arising from this germinal centre. Subsequently, the expression pattern becomes progressively restricted to Bergmann glial cells, which show expression of the reporter at P21. These results indicate a variety of potential functions for Wnt/β-catenin activity during cerebellum development

Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity – a common inflammatory phenotype?

Chronic Obstructive Pulmonary Disease (COPD) is and will remain a major cause of morbidity and mortality worldwide. The severity of airflow obstruction is known to relate to overall health status and mortality. However, even allowing for common aetiological factors, a link has been identified between COPD and other systemic diseases such as cardiovascular disease, diabetes and osteoporosis. COPD is known to be an inflammatory condition and neutrophil elastase has long been considered a significant mediator of the disease. Pro-inflammatory cytokines, in particular TNF-α (Tumour Necrosis Factor alpha), may be the driving force behind the disease process. However, the roles of inflammation and these pro-inflammatory cytokines may extend beyond the lungs and play a part in the systemic effects of the disease and associated co-morbidities. This article describes the mechanisms involved and proposes a common inflammatory TNF-α phenotype that may, in part, account for the associations

Early Treatment with Basal Insulin Glargine in People with Type 2 Diabetes: Lessons from ORIGIN and Other Cardiovascular Trials

Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing beta cells to chronic hyperglycemia and excessive glycemic variability. Initiation of intensive insulin therapy at diagnosis of type 2 diabetes mellitus (T2DM) to achieve normoglycemia has been shown to reverse glucotoxicity, resulting in recovery of residual beta-cell function. The United Kingdom Prospective Diabetes Study (UKPDS) 10-year post-trial follow-up reported reductions in cardiovascular outcomes and all-cause mortality in persons with T2DM who initially received intensive glucose control compared with standard therapy. In the cardiovascular outcome trial, outcome reduction with an initial glargine intervention (ORIGIN), a neutral effect on cardiovascular disease was observed in the population comprising prediabetes and T2DM. Worsening of glycemic control was prevented over the 6.7 year treatment period, with few serious hypoglycemic episodes and only moderate weight gain, with a lesser need for dual or triple oral treatment versus standard care. Several other studies have also highlighted the benefits of early insulin initiation as first-line or add-on therapy to metformin. The decision to introduce basal insulin to metformin must, however be individualized based on a risk-benefit analysis. The landmark ORIGIN trial provides many lessons relating to the concept and application of early insulin therapy for the prevention and safe and effective induction and maintenance of glycemic control in type 2 diabetes

Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies

Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM

Recommendations for the diagnosis of pediatric tuberculosis

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease

Structure of photosynthetic LH1-RC supercomplex at 1.9 Å resolution

Light-harvesting complex 1 (LH1) and the reaction centre (RC) form a membrane-protein supercomplex that performs the primary reactions of photosynthesis in purple photosynthetic bacteria. The structure of the LH1-RC complex can provide information on the arrangement of protein subunits and cofactors; however, so far it has been resolved only at a relatively low resolution. Here we report the crystal structure of the calcium-ion-bound LH1-RC supercomplex of Thermochromatium tepidum at a resolution of 1.9 Å. This atomic-resolution structure revealed several new features about the organization of protein subunits and cofactors. We describe the loop regions of RC in their intact states, the interaction of these loop regions with the LH1 subunits, the exchange route for the bound quinone QB with free quinone molecules, the transport of free quinones between the inside and outside of the LH1 ring structure, and the detailed calcium-ion-binding environment. This structure provides a solid basis for the detailed examination of the light reactions that occur during bacterial photosynthesis