Cancer immunology and canine malignant melanoma: a comparative review

Oral canine malignant melanoma (CMM) is a spontaneously occurring aggressive tumour with relatively few medical treatment options, which provides a suitable model for the disease in humans. Historically, multiple immunotherapeutic strategies aimed at provoking both innate and adaptive anti-tumour immune responses have been published with varying levels of activity against CMM. Recently, a plasmid DNA vaccine expressing human tyrosinase has been licensed for the adjunct treatment of oral CMM. This article reviews the immunological similarities between CMM and the human counterpart; mechanisms by which tumours evade the immune system; reasons why melanoma is an attractive target for immunotherapy; the premise of whole cell, dendritic cell (DC), viral and DNA vaccination strategies alongside preliminary clinical results in dogs. Current “gold standard” treatments for advanced human malignant melanoma are evolving quickly with remarkable results being achieved following the introduction of immune checkpoint blockade and adoptively transferred cell therapies. The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of this disease in both species should enhance treatment outcomes in veterinary and human clinics

Turning off the Lights: How Dark is Dark Matter?

We consider current observational constraints on the electromagnetic charge of dark matter. The velocity dependence of the scattering cross-section through the photon gives rise to qualitatively different constraints than standard dark matter scattering through massive force carriers. In particular, recombination epoch observations of dark matter density perturbations require that $\epsilon$, the ratio of the dark matter to electronic charge, is less than $10^{-6}$ for $m_X = 1 GeV$, rising to $\epsilon < 10^{-4}$ for $m_X = 10 TeV$. Though naively one would expect that dark matter carrying a charge well below this constraint could still give rise to large scattering in current direct detection experiments, we show that charged dark matter particles that could be detected with upcoming experiments are expected to be evacuated from the Galactic disk by the Galactic magnetic fields and supernova shock waves, and hence will not give rise to a signal. Thus dark matter with a small charge is likely not a source of a signal in current or upcoming dark matter direct detection experiments.Comment: 19 pages, 2 figures; v2 - figures fixed, references adde

Magnetism in SQUIDs at Millikelvin Temperatures

We have characterized the temperature dependence of the flux threading dc SQUIDs cooled to millikelvin temperatures. The flux increases as 1/T as temperature is lowered; moreover, the flux change is proportional to the density of trapped vortices. The data is compatible with the thermal polarization of surface spins in the trapped fields of the vortices. In the absence of trapped flux, we observe evidence of spin-glass freezing at low temperature. These results suggest an explanation for the "universal" 1/f flux noise in SQUIDs and superconducting qubits.Comment: 4 pages, 4 figure

The burgeoning field of innate immune-mediated disease and autoinflammation.

Immune-mediated autoinflammatory diseases are occupying an increasingly prominent position among the pantheon of debilitating conditions that afflict mankind. This review focuses on some of the key developments which have occurred since the original description of autoinflammatory disease in 1999, and focuses on underlying mechanisms that trigger autoinflammation. The monogenic autoinflammatory disease range has expanded considerably during that time, and now includes a broad spectrum of disorders, including relatively common conditions such as cystic fibrosis and subsets of systemic lupus erythematosus. The innate immune system also plays a key role in the pathogenesis of complex inflammatory disorders. We have proposed a new nomenclature to accommodate the rapidly increasing number of monogenic disorders, which predispose to either autoinflammation or autoimmunity or, indeed, combinations of both. This new terminology also encompasses a wide spectrum of genetically determined autoinflammatory diseases, with variable clinical manifestations of immunodeficiency and immune dysregulation/autoimmunity. We also explore some of the ramifications of the breakthrough discovery of the physiologic role of pyrin and the search for identifiable factors that may serve to trigger attacks of autoinflammation. The evidence that pyrin, as part of the pyrin inflammasome, acts as a sensor of different inactivating bacterial modification Rho GTPases, rather than interacting directly with these microbial products, sets the stage for a better understanding of the role of micro-organisms and infections in the autoinflammatory disorders. Finally, we discuss some of the triggers of autoinflammation as well as potential therapeutic interventions aimed at enhancing autophagy and proteasome degradation pathways

Learning physics in context: a study of student learning about electricity and magnetism

This paper re-centres the discussion of student learning in physics to focus on context. In order to do so, a theoretically-motivated understanding of context is developed. Given a well-defined notion of context, data from a novel university class in electricity and magnetism are analyzed to demonstrate the central and inextricable role of context in student learning. This work sits within a broader effort to create and analyze environments which support student learning in the sciencesComment: 36 pages, 4 Figure

Costs and cost effectiveness of cardiovascular screening and intervention: The British family heart study

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright @ 1996 BMJ Publishing Group.Objective-To measure costs and cost effectiveness of the British family heart study cardiovascular screening and intervention programme.Design-Cost effectiveness analysis of randomised controlled trial. Clinical and resource use data taken from trial and unit cost data from external estimates.Setting-13 general practices across Britain.Subjects-4185 men aged 40-59 and their 2827 partners.Intervention-Nurse led programme using a family centred approach, with follow up according to degree of risk.Main outcome measures-Cost of the programme itself; overall short term cost to NHS; cost per 1% reduction in coronary risk at one year.Results-Estimated cost of putting the programme into practice for one year was pound 63 per person (95% confidence interval pound 60 to pound 65). The overall short term cost to the health service was pound 77 per man (pound 29 to pound 124) but only pound 13 per woman (-pound 48 to pound 74), owing to differences in utilisation of other health service resources. The cost per 1% reduction in risk was pound 5.08 per man (pound 5.92 including broader health service costs) and pound 5.78 per woman (pound 1.28 taking into account wider health service savings).Conclusions-The direct cost of the programme to a four partner practice of 7500 patients would be approximately pound 58 000. Annually, pound 8300 would currently be paid to a practice of this size working to the ma target on the health promotion bands, plus any additional reimbursement of practice staff salaries for which the practice qualified. The broader short term costs to the NHS may augment these costs for men but offset them considerably for women

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered