Switching off malignant mesothelioma : exploiting the hypoxic microenvironment

Malignant mesotheliomas are aggressive, asbestos-related cancers with poor patient prognosis, typically arising in the mesothelial surfaces of tissues in pleural and peritoneal cavity. The relative unspecific symptoms of mesotheliomas, misdiagnoses, and lack of precise targeted therapies call for a more critical assessment of this disease. In the present review, we categorize commonly identified genomic aberrations of mesotheliomas into their canonical pathways and discuss targeting these pathways in the context of tumor hypoxia, a hallmark of cancer known to render solid tumors more resistant to radiation and most chemo-therapy. We then explore the concept that the intrinsic hypoxic microenvironment of mesotheliomas can be Achilles’ heel for targeted, multimodal therapeutic intervention

Healthcare professionals' preferences for surgery or primary endocrine therapy to treat older women with operable breast cancer

Introduction : Primary endocrine therapy (PET) is an alternative treatment to surgery for oestrogen receptor (ER) positive operable breast cancer in older women. However, there is variable use of PET in the UK, with up to 40% of patients aged over 70 receiving PET instead of surgery in some regions. Treatment options offered to patients rely heavily on healthcare professional (HCP) assessment and opinion on which treatments are appropriate. Materials and methods : This was a mixed methods study combining semi-structured interviews with HCPs working in high and low PET regions in the UK, followed by a postal questionnaire survey distributed via the Association of Breast Surgery (ABS). Results : Thirty-four HCPs (20 breast surgeons; 13 nurse specialists; 1 geriatrician) were interviewed from 14 sites across the UK and 252/641 questionnaires returned (39%). There was an overriding view that PET is not suitable for patients under the age of 80 unless there are significant comorbidities. Opinion was split regarding the best way to treat patients with dementia. Patient preference was generally stated to be the most important factor when considering treatment, however only around a quarter 65/244 (26.6%) felt that all patients over the age of 70 should be offered PET as an alternative treatment option. Conclusions : Opinions differ on the best way to treat women over 70 with operable breast cancer, especially if they have co-existing dementia, as well as whether they should be offered PET as a treatment option. This may be a significant cause of treatment variation in the UK. Keywords : Breast cancer; Primary endocrine therapy; Surgery; Elderly; Older; Mixed methods.</p

A Survey of Satisfiability Modulo Theory

Satisfiability modulo theory (SMT) consists in testing the satisfiability of first-order formulas over linear integer or real arithmetic, or other theories. In this survey, we explain the combination of propositional satisfiability and decision procedures for conjunctions known as DPLL(T), and the alternative "natural domain" approaches. We also cover quantifiers, Craig interpolants, polynomial arithmetic, and how SMT solvers are used in automated software analysis.Comment: Computer Algebra in Scientific Computing, Sep 2016, Bucharest, Romania. 201

A CDCL-style calculus for solving non-linear constraints

In this paper we propose a novel approach for checking satisfiability of non-linear constraints over the reals, called ksmt. The procedure is based on conflict resolution in CDCL style calculus, using a composition of symbolical and numerical methods. To deal with the non-linear components in case of conflicts we use numerically constructed restricted linearisations. This approach covers a large number of computable non-linear real functions such as polynomials, rational or trigonometrical functions and beyond. A prototypical implementation has been evaluated on several non-linear SMT-LIB examples and the results have been compared with state-of-the-art SMT solvers.Comment: 17 pages, 3 figures; accepted at FroCoS 2019; software available at <http://informatik.uni-trier.de/~brausse/ksmt/

Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness.

In the fourth article of a five-part series providing a global perspective on integrating mental health, Sylvia Kaaya and colleagues discuss the importance of integrating mental health interventions into HIV prevention and treatment platforms. Please see later in the article for the Editors' Summary

Reducing Constraints in a Higher Dimensional Extension of the Randall and Sundrum Model

In order to investigate the phenomenological implications of warped spaces in more than five dimensions, we consider a $4+1+\delta$ dimensional extension to the Randall and Sundrum model in which the space is warped with respect to a single direction by the presence of an anisotropic bulk cosmological constant. The Einstein equations are solved, giving rise to a range of possible spaces in which the $\delta$ additional spaces are warped. Here we consider models in which the gauge fields are free to propagate into such spaces. After carrying out the Kaluza Klein (KK) decomposition of such fields it is found that the KK mass spectrum changes significantly depending on how the $\delta$ additional dimensions are warped. We proceed to compute the lower bound on the KK mass scale from electroweak observables for models with a bulk $SU(2)\times U(1)$ gauge symmetry and models with a bulk $SU(2)_R\times SU(2)_L\times U(1)$ gauge symmetry. It is found that in both cases the most favourable bounds are approximately $M_{KK}\gtrsim 2$ TeV, corresponding to a mass of the first gauge boson excitation of about 4-6 TeV. Hence additional warped dimensions offer a new way of reducing the constraints on the KK scale.Comment: 27 pages, 15 figures, v3: Additional comments in sections 1, 2 and 4. New appendix added. Five additional figures. References adde

Trends in BRCA testing over time and socioeconomic deprivation

OBJECTIVES: BRCA1&2 (BRCA) testing received much publicity following Angelina Jolie’s editorial ‘My Medical Choice’ in the New York Times on the 14th May 2013. In addition, in the UK, guidelines were updated by NICE (clinical guidance CG164) on the 25th June 2013. We analysed the effects of these two events on uptake of BRCA1 and BRCA2 testing in the area covered by Cheshire and Merseyside Regional Genetic Service, and whether this was affected by socioeconomic deprivation. METHODS: A database was collated using routinely collected hospital data for patients who received hereditary breast and ovarian cancer (HBOC) BRCA testing. A total of 1393 patients received BRCA testing. A natural experimental approach was undertaken using segmented linear regression to estimate changes in the level and trend of BRCA testing following the publication of both the Jolie’s editorial and NICE CG164. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend. The Index of Multiple Deprivation (IMD) of patients from areas who received BRCA testing to those of the catchment population were compared. RESULTS: The month following the publication of Jolie’s editorial and NICE CG164, BRCA testing increased by approximately 84% (P=0.006). Between April 2010 and March 2017, testing rates increased 11-fold from 0.14 to 1.52 tests/100,000 per month. The odds of receiving BRCA testing were higher for patients from socioeconomically advantaged areas pre-publication (OR 1.21 95% CI 0.99-1.48, P=0.06) although this was not significant. After publication the odds were significantly higher for patients from advantaged areas compared with disadvantaged areas (OR 1.18 95% CI 1.08-1.29, P=0.0002). CONCLUSIONS: Our study found that BRCA testing uptake increased following the publication of Jolie’s editorial and NICE CG164. However, uptake was lower in more deprived areas. This inequity should be further investigated, and consideration given to targeted care within areas of greater socioeconomic deprivation

Engaging with community researchers for exposure science: lessons learned from a pesticide biomonitoring study

A major challenge in biomonitoring studies with members of the general public is ensuring their continued involvement throughout the necessary length of the research. The paper presents evidence on the use of community researchers, recruited from local study areas, as a mechanism for ensuring effective recruitment and retention of farmer and resident participants for a pesticides biomonitoring study. The evidence presented suggests that community researchers' abilities to build and sustain trusting relationships with participants enhanced the rigour of the study as a result of their on-the-ground responsiveness and flexibility resulting in data collection beyond targets expected

Demography and disorders of German Shepherd Dogs under primary veterinarycare in the UK

The German Shepherd Dog (GSD) has been widely used for a variety of working roles. However, concerns for the health and welfare of the GSD have been widely aired and there is evidence that breed numbers are now in decline in the UK. Accurate demographic and disorder data could assist with breeding and clinical prioritisation. The VetCompassTM Programme collects clinical data on dogs under primary veterinary care in the UK. This study included all VetCompassTM dogs under veterinary care during 2013. Demographic, mortality and clinical diagnosis data on GSDs were extracted and reported