Exploiting biological and physical determinants of radiotherapy toxicity to individualise treatment.

This is the final version of the article. It first appeared from the British Institute of Radiology via http://dx.doi.org/10.1259/bjr.20150172The recent advances in radiation delivery can improve tumour control probability and reduce treatment related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day-to-day. Daily image guidance scans can be used to identify the position of normal tissue structures, and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues which limits radiotherapy dose and therefore tumour control. However, the dose response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of radiotherapy. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be due to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In prostate cancer patients receiving curative radiotherapy, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses (EUDs) was -2.7 Gy (5%), and a dose reduction was seen in 7/10 cases. If dose escalation were performed to take rectal dose back to the planned level, this should increase the mean tumour control probability (TCP) (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical radiotherapy who might benefit from either dose escalation, suggesting improved tumour cure, or reduced toxicity, or both.JS is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. The VoxTox Research Programme is funded by Cancer Research UK

Chronic thromboembolic pulmonary hypertension following long-term peripherally inserted central venous catheter use

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication

Scheme for generating entangled states of two field modes in a cavity

This paper considers a two-level atom interacting with two cavity modes with equal frequencies. Applying a unitary transformation, the system reduces to the analytically solvable Jaynes-Cummings model. For some particular field states, coherent and squeezed states, the transformation between the two bare basis's, related by the unitary transformation, becomes particularly simple. It is shown how to generate, the highly non-classical, entangled coherent states of the two modes, both in the zero and large detuning cases. An advantage with the zero detuning case is that the preparation is deterministic and no atomic measurement is needed. For the large detuning situation a measurement is required, leaving the field in either of two orthogonal entangled coherent states.Comment: Accepted in J. Mod. Opt.; 12 pages; Replaced with revised version. Extended discussion of experimental realizations, earlier studies in the field and on the frequency dependence in the adiabatic eliminatio

Rationale and design of the ADDITION-Leicester study, a systematic screening programme and randomised controlled trial of multi-factorial cardiovascular risk intervention in people with type 2 diabetes mellitus detected by screening.

BACKGROUND: Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in type 2 diabetes mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester). DESIGN: A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care. METHODS: ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-oral glucose tolerance tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments. DISCUSSION: ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians. TRIAL REGISTRATION: Clinicaltrial.gov (NCT00318032).RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Nanomechanical Detection of Itinerant Electron Spin Flip

Spin is an intrinsically quantum property, characterized by angular momentum. A change in the spin state is equivalent to a change in the angular momentum or mechanical torque. This spin-induced torque has been invoked as the intrinsic mechanism in experiments ranging from the measurements of angular momentum of photons g-factor of metals and magnetic resonance to the magnetization reversal in magnetic multi-layers A spin-polarized current introduced into a nonmagnetic nanowire produces a torque associated with the itinerant electron spin flip. Here, we report direct measurement of this mechanical torque and itinerant electron spin polarization in an integrated nanoscale torsion oscillator, which could yield new information on the itinerancy of the d-band electrons. The unprecedented torque sensitivity of 10^{-22} N m/ \sqrt{Hz} may enable applications for spintronics, precision measurements of CP-violating forces, untwisting of DNA and torque generating molecules.Comment: 14 pages, 4 figures. visit http://nano.bu.edu/ for related paper

Convergence and divergence in the evolution of cat skulls: temporal and spatial patterns of morphological diversity

Background: Studies of biological shape evolution are greatly enhanced when framed in a phylogenetic perspective. Inclusion of fossils amplifies the scope of macroevolutionary research, offers a deep-time perspective on tempo and mode of radiations, and elucidates life-trait changes. We explore the evolution of skull shape in felids (cats) through morphometric analyses of linear variables, phylogenetic comparative methods, and a new cladistic study of saber-toothed cats. Methodology/Principal Findings: A new phylogenetic analysis supports the monophyly of saber-toothed cats (Machairodontinae) exclusive of Felinae and some basal felids, but does not support the monophyly of various sabertoothed tribes and genera. We quantified skull shape variation in 34 extant and 18 extinct species using size-adjusted linear variables. These distinguish taxonomic group membership with high accuracy. Patterns of morphospace occupation are consistent with previous analyses, for example, in showing a size gradient along the primary axis of shape variation and a separation between large and small-medium cats. By combining the new phylogeny with a molecular tree of extant Felinae, we built a chronophylomorphospace (a phylogeny superimposed onto a two-dimensional morphospace through time). The evolutionary history of cats was characterized by two major episodes of morphological divergence, one marking the separation between saber-toothed and modern cats, the other marking the split between large and small-medium cats. Conclusions/Significance: Ancestors of large cats in the ‘Panthera’ lineage tend to occupy, at a much later stage, morphospace regions previously occupied by saber-toothed cats. The latter radiated out into new morphospace regions peripheral to those of extant large cats. The separation between large and small-medium cats was marked by considerable morphologically divergent trajectories early in feline evolution. A chronophylomorphospace has wider applications in reconstructing temporal transitions across two-dimensional trait spaces, can be used in ecophenotypical and functional diversity studies, and may reveal novel patterns of morphospace occupation

A review of acoustic telemetry in Europe and the need for a regional aquatic telemetry network

Background Globally, there are a large and growing number of researchers using biotelemetry as a tool to study aquatic animals. In Europe, this community lacks a formal network structure. The aim of this study is to review the use of acoustic telemetry in Europe and document the contribution of cross-boundary studies and inter-research group collaborations. Based on this, we explore the potential benefits and challenges of a network approach to identify future priorities and best practices for aquatic biotelemetry research in Europe. Results Over the past decade, there was an approximately sevenfold increase in the number of acoustic telemetry studies published on marine and diadromous species in Europe compared to a sixfold increase globally. Over 90% of these studies were conducted on fishes and undertaken in coastal areas, estuaries, or rivers. 75% of these studies were conducted by researchers based in one of five nations (Norway, UK, France, Portugal, and Spain) and, even though 34% were based on collaborations between scientists from several countries, there was only one study with an acoustic receiver array that extended beyond the borders of a single country. In recent years, acoustic telemetry in European waters has evolved from studying behavioural aspects of animals (82.2%), into more holistic approaches addressing management-related issues (10%), tagging methods and effects (5%), and technology and data analysis development (2.8%). Conclusions Despite the increasing number of publications and species tracked, there is a prominent lack of planned and structured acoustic telemetry collaborations in Europe. A formal pan-European network structure would promote the development of (1) a research platform that could benefit the acoustic telemetry community through capacity building, (2) a centralized database, and (3) key deployment sites and studies on priority species requiring research in Europe. A network may increase efficiency, expand the scope of research that can be undertaken, promote European science integration, enhance the opportunities and success of acquiring research funding and, ultimately, foster regional and transatlantic collaborations. It may also help address research priorities such as the large-scale societal challenges arising from climate change impacts and assist the EU’s Marine Strategy Framework Directive via identification of good environmental status of endangered or commercially important species.info:eu-repo/semantics/publishedVersio

Demonstration of a Melanoma-Specific CD44 Alternative Splicing Pattern That Remains Qualitatively Stable, but Shows Quantitative Changes during Tumour Progression

The role of CD44 in the progression of human melanoma has mostly been characterised by qualitative changes in expression of its individual variable exons. These exons however, may be expressed to form a number of molecules, the alternative splice variants of CD44, which may be structurally and functionally different. Using real-time PCR measurements with variable exon specific primers we have determined that all are expressed in human melanoma. To permit comparison between different tumours we identified a stable CD44 variable exon (CD44v) expression pattern, or CD44 ‘fingerprint’. This was found to remain unchanged in melanoma cell lines cultured in different matrix environments. To evaluate evolution of this fingerprint during tumour progression we established a scid mouse model, in which the pure expression pattern of metastatic primary tumours, circulating cells and metastases, non-metastatic primary tumours and lung colonies could be studied. Our analyses demonstrated, that although the melanoma CD44 fingerprint is qualitatively stable, quantitative changes are observed suggesting a possible role in tumour progression

Quantum nature of laser light

All compositions of a mixed-state density operator are equivalent for the prediction of the probabilities of future outcomes of measurements. For retrodiction, however, this is not the case. The retrodictive formalism of quantum mechanics provides a criterion for deciding that some compositions are fictional. Fictional compositions do not contain preparation device operators, that is operators corresponding to states that could have been prepared. We apply this to Molmer's controversial conjecture that optical coherences in laser light are a fiction and find agreement with his conjecture. We generalise Molmer's derivation of the interference between two lasers to avoid the use of any fictional states. We also examine another possible method for discriminating between conerent states and photon number states in laser light and find that it does not work, with the equivalence for prediction saved by entanglement