The Auto Schottische

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Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

INTRODUCTION: Predictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A copy number can be used to predict benefit from epirubicin (E) containing chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil (CMF) treatment. METHODS: For the purpose of this study, formalin fixed paraffin embedded tumor tissue from women recruited into the BR9601 clinical trial, which randomized patients to E-CMF versus CMF, were analyzed for TIMP-1 immunoreactivity. Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1 immunoreactive and HER2 negative) and anthracycline responsive (all other cases). RESULTS: In total, 288 tumors were available for TIMP-1 analysis with (183/274) 66.8%, and (181/274) 66.0% being classed as 2T and HT responsive, respectively. TIMP-1 was neither associated with patient prognosis (relapse free survival or overall survival) nor with a differential effect of E-CMF and CMF. Also, TIMP-1 did not add to the predictive value of HER2, TOP2A gene aberrations, or to Ki67 immunoreactivity. CONCLUSION: This study could not confirm the predictive value of TIMP-1 immunoreactivity in patients randomized to receive E-CMF versus CMF as adjuvant treatment for primary breast cancer

A novel micronutrient blend mimics calorie restriction transcriptomics in multiple tissues of mice and increases lifespan and mobility in C. elegans.

We previously described a novel micronutrient blend that behaves like a putative calorie restriction mimetic. The aim of this paper was to analyze the beneficial effects of our micronutrient blend in mice and C. elegans, and compare them with calorie restriction. Methods: Whole transcriptomic analysis was performed in the brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. Longevity and vitality were tested in C. elegans. Results: The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and different from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to aging, were the most affected. Furthermore, a functional analysis in C. elegans was used. We found that feeding C. elegans the micronutrient blend increased longevity as well as vitality. Conclusions: We describe a micronutrient supplement that causes similar changes (transcriptomic and promoting longevity and vitality) as a calorie restriction in mice and C. elegans, respectively, but further studies are required to confirm these effects in human

Controlling crystallization and its absence: Proteins, colloids and patchy models

The ability to control the crystallization behaviour (including its absence) of particles, be they biomolecules such as globular proteins, inorganic colloids, nanoparticles, or metal atoms in an alloy, is of both fundamental and technological importance. Much can be learnt from the exquisite control that biological systems exert over the behaviour of proteins, where protein crystallization and aggregation are generally suppressed, but where in particular instances complex crystalline assemblies can be formed that have a functional purpose. We also explore the insights that can be obtained from computational modelling, focussing on the subtle interplay between the interparticle interactions, the preferred local order and the resulting crystallization kinetics. In particular, we highlight the role played by ``frustration'', where there is an incompatibility between the preferred local order and the global crystalline order, using examples from atomic glass formers and model anisotropic particles.Comment: 11 pages, 7 figure

Comparison of the within-reader and inter-vendor agreement of left ventricular circumferential strains and volume indices derived from cardiovascular magnetic resonance imaging

PurposeVolume indices and left ventricular ejection fraction (LVEF) are routinely used to assess cardiac function. Ventricular strain values may provide additional diagnostic information, but their reproducibility is unclear. This study therefore compares the repeatability and reproducibility of volumes, volume fraction, and regional ventricular strains, derived from cardiovascular magnetic resonance (CMR) imaging, across three software packages and between readers.MethodsSeven readers analysed 16 short-axis CMR stacks of a porcine heart. Endocardial contours were manually drawn using OsiriX and Simpleware ScanIP and repeated in both softwares. The images were also contoured automatically in Circle CVI42. Endocardial global, apical, mid-ventricular, and basal circumferential strains, as well as end-diastolic and end-systolic volume and LVEF were compared.ResultsBland-Altman analysis found systematic biases in contour length between software packages. Compared to OsiriX, contour lengths were shorter in both ScanIP (-1.9 cm) and CVI42 (-0.6 cm), causing statistically significant differences in end-diastolic and end-systolic volumes, and apical circumferential strain (all pConclusionOsiriX and CVI42 gave consistent results for all strain and volume metrics, with no statistical differences found between OsiriX and ScanIP for mid-ventricular, global or basal strains, or left ventricular ejection fraction. However, volumes were influenced by the choice of contouring software, suggesting care should be taken when comparing volumes across different software

Optimization of Naked DNA Delivery for Interferon Subtype Immunotherapy in Cytomegalovirus Infection

Type I interferon (IFN) gene therapy modulates the immune response leading to inflammatory heart disease following cytomegalovirus (CMV) infection in a murine model of post-viral myocarditis. Efficacy of different immunisation protocols for the IFN constructs was influenced by the dose of DNA, subtype choice, combination use, pre-medication, and timing of DNA administration. Optimal efficacy was found with bupivacaine treatment prior to DNA inoculation of 200mg IFN DNA 14 days prior to virus challenge. Maximal antiviral and antimyocarditic effects were achieved with this vaccination schedule. Furthermore, inoculation of synergistic IFN subtypes demonstrated enhanced efficacy when delivered either alone or with CMV gB DNA vaccination in the CMV model. Thus naked DNA delivery of IFN provides an avenue of immunotherapy for regulating herpesvirus-induced diseases

Beginning to explore the experience of managing a direct payment for someone with dementia: The perspectives of suitable people and adult social care practitioners

Following legal improvements made around mental capacity together with the Health and Social Care Act, it is now possible for a direct payment to be paid to a 'Suitable Person' to manage on someone's behalf to purchase directly care and support services. People with dementia are a key group affected by this change in England of adult social care. We interviewed nine social care practitioners and seven Suitable People for people with dementia across five English local authorities to begin to examine their experiences of this new method of social care provision. Findings from thematic analyses suggest positive outcomes and multiple beneficiaries, but some challenges: potentially inappropriate processes, support planning, divergence in attitudes towards care and support outcomes. Implications for practice include obfuscation of recipients' and Suitable People's best interests and supporting practitioners to explore fully clients' aspirations for care and support

A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/RHL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation

Spatiotemporal Electrochemistry on Flexible Microelectrode Arrays: Progress Towards Smart Contact Lens Integration

We demonstrate a real-speed spatiotemporal electrochemical map showing both time- and position-varying concentration of an analyte in contact with a flexible microelectrode array. A polymer-based device of 11 μm in thickness comprising patterned gold metallisation on a polyimide substrate was fabricated, with eight in- dividually addressable working electrodes (diameter 30 μm) and an integrated counter electrode. We performed a repeated sequence of high-speed chronoamperometric measurements at each electrode and processed the data to generate a spatiotemporal concentration map, in which a number of fluid effects, including bulk flow, dif- fusive mixing and homogenisation of two miscible fluids of different concentration were observed. This device was fabricated using processes compatible with an existing smart contact lens platform, with a view to develop integrated sensors in future work. We believe this technique has significant potential in the field of electro- chemical smart contact lenses, both in introducing new functionality and in improving our ability to draw accurate and clinically-relevant conclusions from measurements made in the tear film

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed