Addition of Bevacizumab to Temsirolimus in Kidney Cancer Patients

Treatment of metastatic kidney cancer has changed dramatically in the past years with the use of VEGF-targeted therapies and mTOR inhibitors. However, resistance occurs. We report here two cases of patients who benefited, both on disease control and side effects, from the addition of bevacizumab to temsirolimus, after progression on the mTOR inhibitor alone

Micro-mechanical properties of the tendon-to-bone attachment

The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue that connects stiff bone to compliant tendon. The attachment site at the micrometer scale exhibits gradients in mineral content and collagen orientation, which likely act to minimize stress concentrations. The physiological micromechanics of the attachment thus define resultant performance, but difficulties in sample preparation and mechanical testing at this scale have restricted understanding of structure-mechanical function. Here, microscale beams from entheses of wild type mice and mice with mineral defects were prepared using cryo-focused ion beam milling and pulled to failure using a modified atomic force microscopy system. Micromechanical behavior of tendon-to-bone structures, including elastic modulus, strength, resilience, and toughness, were obtained. Results demonstrated considerably higher mechanical performance at the micrometer length scale compared to the millimeter tissue length scale, describing enthesis material properties without the influence of higher order structural effects such as defects. Micromechanical investigation revealed a decrease in strength in entheses with mineral defects. To further examine structure-mechanical function relationships, local deformation behavior along the tendon-to-bone attachment was determined using local image correlation. A high compliance zone near the mineralized gradient of the attachment was clearly identified and highlighted the lack of correlation between mineral distribution and strain on the low-mineral end of the attachment. This compliant region is proposed to act as an energy absorbing component, limiting catastrophic failure within the tendon-to-bone attachment through higher local deformation. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Gastroesophageal reflux disease in 2006: The imperfect diagnosis

There continues to be significant controversy related to diagnostic testing for gastroesophageal reflux disease (GERD). Clearly, barium contrast fluoroscopy is superior to any other test in defining the anatomy of the upper gastrointestinal (UGI) tract. Although fluoroscopy can demonstrate gastroesophageal reflux (GER), this observation does not equate to GERD. Fluoroscopy time should not be prolonged to attempt to demonstrate GER during barium contrast radiography. There are no data to justify prolonging fluoroscopy time to perform provocative maneuvers to demonstrate reflux during barium contrast UGI series. Symptoms of GERD may be associated with physiologic esophageal acid exposure measured by intraesophageal pH monitoring, and a significant percentage of patients with abnormal esophageal acid exposure have no or minimal clinical symptoms of reflux. Abnormal acid exposure defined by pH monitoring over a 24-h period does not equate to GERD. In clinical practice presumptive diagnosis of GERD is reasonably assumed by substantial reduction or elimination of suspected reflux symptoms during therapeutic trial of acid reduction therapy

Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence

<p>Abstract</p> <p>Background</p> <p>People with diabetes can suffer from diverse complications that seriously erode quality of life. Diabetes, costing the United States more than $174 billion per year in 2007, is expected to take an increasingly large financial toll in subsequent years. Accurate projections of diabetes burden are essential to policymakers planning for future health care needs and costs.</p> <p>Methods</p> <p>Using data on prediabetes and diabetes prevalence in the United States, forecasted incidence, and current US Census projections of mortality and migration, the authors constructed a series of dynamic models employing systems of difference equations to project the future burden of diabetes among US adults. A three-state model partitions the US population into no diabetes, undiagnosed diabetes, and diagnosed diabetes. A four-state model divides the state of "no diabetes" into high-risk (prediabetes) and low-risk (normal glucose) states. A five-state model incorporates an intervention designed to prevent or delay diabetes in adults at high risk.</p> <p>Results</p> <p>The authors project that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. Assuming low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in diabetes incidence continue and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle-ground scenario projects a prevalence of 25% to 28% by 2050. Intervention can reduce, but not eliminate, increases in diabetes prevalence.</p> <p>Conclusions</p> <p>These projected increases are largely attributable to the aging of the US population, increasing numbers of members of higher-risk minority groups in the population, and people with diabetes living longer. Effective strategies will need to be undertaken to moderate the impact of these factors on national diabetes burden. Our analysis suggests that widespread implementation of reasonably effective preventive interventions focused on high-risk subgroups of the population can considerably reduce, but not eliminate, future increases in diabetes prevalence.</p

Healthy Living after Cancer: A dissemination and implementation study evaluating a telephone-delivered healthy lifestyle program for cancer survivors

© 2015 Eakin et al. Background: Given evidence shows physical activity, a healthful diet and weight management can improve cancer outcomes and reduce chronic disease risk, the major cancer organisations and health authorities have endorsed related guidelines for cancer survivors. Despite these, and a growing evidence base on effective lifestyle interventions, there is limited uptake into survivorship care. Methods/Design: Healthy Living after Cancer (HLaC) is a national dissemination and implementation study that will evaluate the integration of an evidence-based lifestyle intervention for cancer survivors into an existing telephone cancer information and support service delivered by Australian state-based Cancer Councils. Eligible participants (adults having completed cancer treatment with curative intent) will receive 12 health coaching calls over 6 months from Cancer Council nurses/allied health professionals targeting national guidelines for physical activity, healthy eating and weight control. Using the RE-AIM evaluation framework, primary outcomes are service-level indicators of program reach, adoption, implementation/costs and maintenance, with secondary (effectiveness) outcomes of patient-reported anthropometric, behavioural and psychosocial variables collected at pre- and post-program completion. The total participant accrual target across four participating Cancer Councils is 900 over 3 years. Discussion: The national scope of the project and broad inclusion of cancer survivors, alongside evaluation of service-level indicators, associated costs and patient-reported outcomes, will provide the necessary practice-based evidence needed to inform future allocation of resources to support healthy living among cancer survivors. Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12615000882527(registered on 24/08/2015

Intensified surveillance after surgery for colorectal cancer significantly improves survival

<p>Abstract</p> <p>Background</p> <p>Postoperative surveillance after curative resection for colorectal cancer has been demostrated to improve survival. It remains unknown however, whether intensified surveillance provides a significant benefit regarding outcome and survival. This study was aimed at comparing different surveillance strategies regarding their effect on long-term outcome.</p> <p>Methods</p> <p>Between 1990 and 2006, all curative resections for colorectal cancer were selected from our prospective colorectal cancer database. All patients were offered to follow our institution's surveillance programm according to the ASCO guidelines. We defined surveillance as "intensive" in cases where > 70% appointments were attended and the program was completed. As "minimal" we defined surveillance with < 70% of the appointments attended and an incomplete program. As "none" we defined the group which did not take part in any surveillance.</p> <p>Results</p> <p>Out of 1469 patients 858 patients underwent "intensive", 297 "minimal" and 314 "none" surveillance. The three groups were well balanced regarding biographical data and tumor characteristics. The 5-year survival rates were 79% (intensive), 76% (minimal) and 54% (none) (OR 1.480, (95% CI 1.135-1.929); <it>p </it>< 0.0001), respectively. The 10-year survival rates were 65% (intensive), 50% (minimal) and 31% (none) (<it>p </it>< 0.0001), respectively. With a median follow-up of 70 months the median time of survival was 191 months (intensive), 116 months (minimal) and 66 months (none) (<it>p </it>< 0.0001). After recurrence, the 5-year survival rates were 32% (intensive, <it>p </it>= 0.034), 13% (minimal, <it>p </it>= 0.001) and 19% (none, <it>p </it>= 0.614). The median time of survival after recurrence was 31 months (intensive, <it>p </it>< 0.0001), 21 months (minimal, <it>p </it>< 0.0001) and 16 month (none, <it>p </it>< 0.0001) respectively.</p> <p>Conclusion</p> <p>Intensive surveillance after curative resection of colorectal cancer improves survival. In cases of recurrent disease, intensive surveillance has a positive impact on patients' prognosis. Large randomized, multicenter trials are needed to substantiate these results.</p

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

Cortactin Phosphorylated by ERK1/2 Localizes to Sites of Dynamic Actin Regulation and Is Required for Carcinoma Lamellipodia Persistence

Tumor cell motility and invasion is governed by dynamic regulation of the cortical actin cytoskeleton. The actin-binding protein cortactin is commonly upregulated in multiple cancer types and is associated with increased cell migration. Cortactin regulates actin nucleation through the actin related protein (Arp)2/3 complex and stabilizes the cortical actin cytoskeleton. Cortactin is regulated by multiple phosphorylation events, including phosphorylation of S405 and S418 by extracellular regulated kinases (ERK)1/2. ERK1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the Arp2/3 regulator neuronal Wiskott-Aldrich syndrome protein (N-WASp), promoting actin polymerization and enhancing tumor cell movement.In this report we have developed phosphorylation-specific antibodies against phosphorylated cortactin S405 and S418 to analyze the subcellular localization of this cortactin form in tumor cells and patient samples by microscopy. We evaluated the interplay between cortactin S405 and S418 phosphorylation with cortactin tyrosine phosphorylation in regulating cortactin conformational forms by Western blotting. Cortactin is simultaneously phosphorylated at S405/418 and Y421 in tumor cells, and through the use of point mutant constructs we determined that serine and tyrosine phosphorylation events lack any co-dependency. Expression of S405/418 phosphorylation-null constructs impaired carcinoma motility and adhesion, and also inhibited lamellipodia persistence monitored by live cell imaging.Cortactin phosphorylated at S405/418 is localized to sites of dynamic actin assembly in tumor cells. Concurrent phosphorylation of cortactin by ERK1/2 and tyrosine kinases enables cells with the ability to regulate actin dynamics through N-WASp and other effector proteins by synchronizing upstream regulatory pathways, confirming cortactin as an important integration point in actin-based signal transduction. Reduced lamellipodia persistence in cells with S405/418A expression identifies an essential motility-based process reliant on ERK1/2 signaling, providing additional understanding as to how this pathway impacts tumor cell migration

Stable Photosymbiotic Relationship under CO2-Induced Acidification in the Acoel Worm Symsagittifera Roscoffensis

As a consequence of anthropogenic CO2 emissions, oceans are becoming more acidic, a phenomenon known as ocean acidification. Many marine species predicted to be sensitive to this stressor are photosymbiotic, including corals and foraminifera. However, the direct impact of ocean acidification on the relationship between the photosynthetic and nonphotosynthetic organism remains unclear and is complicated by other physiological processes known to be sensitive to ocean acidification (e.g. calcification and feeding). We have studied the impact of extreme pH decrease/pCO2 increase on the complete life cycle of the photosymbiotic, non-calcifying and pure autotrophic acoel worm, Symsagittifera roscoffensis. Our results show that this species is resistant to high pCO2 with no negative or even positive effects on fitness (survival, growth, fertility) and/or photosymbiotic relationship till pCO2 up to 54 K µatm. Some sub-lethal bleaching is only observed at pCO2 up to 270 K µatm when seawater is saturated by CO2. This indicates that photosymbiosis can be resistant to high pCO2. If such a finding would be confirmed in other photosymbiotic species, we could then hypothesize that negative impact of high pCO2 observed on other photosymbiotic species such as corals and foraminifera could occur through indirect impacts at other levels (calcification, feeding)