Dread and latency impacts on a VSL for cancer risk reduction

We propose a structural relationship between the value of preventing a statistical cancer fatality and the value of statistical life (VSL) for risks of an instantaneous road accident fatality. This relationship incorporates a context effect reflecting both the illness or ‘morbidity’ associated with cancer fatality and the ‘dread’ or horror associated with the prospect of eventual death from cancer, as well as a latency effect that captures the discounting likely to arise because the onset of the symptoms of cancer typically occurs after some delay. We use a Risk-Risk trade-off study to validate this model by directly estimating the influence of context and latency effects upon the relative size of the VSL for cancer and for road accidents, confirming that both effects are significant and estimating their size using regression analysis. We show that morbidity accounts for the majority of the context premium. We use the elicited coefficients to reconstruct VSL estimates for a range of cancers characterised by their latency and morbidity periods

Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection.

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts

Study protocol for a randomised controlled trial of brief, habit-based, lifestyle advice for cancer survivors: exploring behavioural outcomes for the Advancing Survivorship Cancer Outcomes Trial (ASCOT)

Introduction Positive health behaviours such as regular physical activity and a healthy diet have significant effects on cancer outcomes. There is a need for simple but effective behaviour change interventions with the potential to be implemented within the cancer care pathway. Habit-based advice encourages repetition of a behaviour in a consistent context so that the behaviour becomes increasingly automatic in response to a specific contextual cue. This approach therefore encourages long-term behaviour change and can be delivered through printed materials. ‘Healthy Habits for Life’ is a brief intervention based on habit theory, and incorporating printed materials plus a personally tailored discussion, that has been designed specifically for patients with a diagnosis of cancer. The aim of this trial was to test the effect of ‘Healthy Habits for Life’ on a composite health behaviour risk index (CHBRI) over 3 months in patients with a diagnosis of breast, colorectal or prostate cancer. Method and analysis A 2-arm, individually randomised controlled trial in patients with breast, colorectal and prostate cancer. Patients will be recruited over 18 months from 7 National Health Service Trusts in London and Essex. Following baseline assessments and allocation to intervention or usual care, patients are followed up at 3 and 6 months. The primary outcome will be change in CHBRI at 3 months. Maintenance of any changes over 6 months, and changes in individual health behaviours (including dietary intake, physical activity, alcohol consumption and smoking status) will also be explored. Ethics and dissemination Ethical approval was obtained through the National Research Ethics Service Committee South Central—Oxford B via the Integrated Research Application System (reference number 14/SC/1369). Results of this study will be disseminated through peer-reviewed publications and scientific presentation

Fabrication and functionalisation of nanocarbon-based field-effect transistor biosensors

Nanocarbon-based field-effect transistor (NC-FET) biosensors are at the forefront of future diagnostic technology. By integrating biological molecules with electrically conducting carbon-based platforms, high sensitivity real-time multiplexed sensing is possible. Combined with their small footprint, portability, ease of use, and label-free sensing mechanisms, NC-FETs are prime candidates for the rapidly expanding areas of point-of-care testing, environmental monitoring and biosensing as a whole. In this review we provide an overview of the basic operational mechanisms behind NC-FETs, synthesis and fabrication of FET devices, and developments in functionalisation strategies for biosensing applications

Comparing web-based mindfulness with loving-kindness and compassion training for promoting well-being in pregnancy: Protocol for a three-arm pilot randomized controlled trial

© Amy Louise Finlay-Jones, Jacqueline Ann Davis, Amanda O\u27Donovan, Keerthi Kottampally, Rebecca Anne Ashley, Desiree Silva, Jeneva Lee Ohan, Susan L Prescott, Jenny Downs. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 14.10.2020. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included. Background: Promoting psychological well-being and preventing distress among pregnant women is an important public health goal. In addition to adversely impacting the mother’s health and well-being, psychological distress in pregnancy increases the risk of poor pregnancy outcomes, compromises infant socioemotional development and bonding, and heightens maternal and child vulnerability in the postpartum period. Mindfulness and compassion-based interventions show potential for prevention and early intervention for perinatal distress. As there is an established need for accessible, scalable, flexible, and low-cost interventions, there is increased interest in the delivery of these programs on the web. This project aims to pilot a three-arm randomized controlled trial (RCT) to determine the feasibility of a full-scale RCT comparing 2 web-based interventions (mindfulness vs loving-kindness and compassion) with a web-based active control condition (progressive muscle relaxation). Objective: The primary objective of this study is to assess the feasibility of an RCT protocol comparing the 3 conditions delivered on the web as a series of instructional materials and brief daily practices over a course of 8 weeks. The second objective is to explore the experiences of women in the different intervention conditions. The third objective is to estimate SD values for the outcome measures to inform the design of an adequately powered trial to determine the comparative efficacy of the different conditions. Methods: Pregnant women (n=75) participating in a longitudinal birth cohort study (the ORIGINS project) will be recruited to this study from 18 weeks of gestational age. We will assess the acceptability and feasibility of recruitment and retention strategies and the participants’ engagement and adherence to the interventions. We will also assess the experiences of women in each of the 3 intervention conditions by measuring weekly changes in their well-being and engagement with the program and by conducting a qualitative analysis of postprogram interviews. Results: This project was funded in September 2019 and received ethics approval on July 8, 2020. Enrollment to the study will commence in September 2020. Feasibility of a full-scale RCT will be assessed using ADePT (a process for decision making after pilot and feasibility trials) criteria. Conclusions: If the study is shown to be feasible, results will be used to inform future full-scale RCTs. Evidence for flexible, scalable, and low-cost interventions could inform population health strategies to promote well-being and reduce psychological distress among pregnant women

Microstructural differences in the thalamus and thalamic radiations in the congenitally deaf

There is evidence of both crossmodal and intermodal plasticity in the deaf brain. Here, we investigated whether sub-cortical plasticity, specifically of the thalamus, contributed to this reorganisation. We contrasted diffusion weighted magnetic resonance imaging data from 13 congenitally deaf and 13 hearing participants, all of whom had learnt British Sign Language after 10 years of age. Connectivity based segmentation of the thalamus revealed changes to mean and radial diffusivity in occipital and frontal regions, which may be linked to enhanced peripheral visual acuity, and differences in how visual attention is deployed in the deaf group. Using probabilistic tractography, tracts were traced between the thalamus and its cortical targets, and microstructural measurements were extracted from these tracts. Group differences were found in microstructural measurements of occipital, frontal, somatosensory, motor and parietal thalamo-cortical tracts. Our findings suggest there is sub-cortical plasticity in the deaf brain, and that white matter alterations can be found throughout the deaf brain, rather than being restricted to, or focussed in auditory cortex

Molecular evolution of human adenoviruses

The recent emergence of highly virulent human adenoviruses (HAdVs) with new tissue tropisms underscores the need to determine their ontogeny. Here we report complete high quality genome sequences and analyses for all the previously unsequenced HAdV serotypes (n = 20) within HAdV species D. Analysis of nucleotide sequence variability for these in conjunction with another 40 HAdV prototypes, comprising all seven HAdV species, confirmed the uniquely hypervariable regions within species. The mutation rate among HAdV-Ds was low when compared to other HAdV species. Homologous recombination was identified in at least two of five examined hypervariable regions for every virus, suggesting the evolution of HAdV-Ds has been highly dependent on homologous recombination. Patterns of alternating GC and AT rich motifs correlated well with hypervariable region recombination sites across the HAdV-D genomes, suggesting foci of DNA instability lead to formulaic patterns of homologous recombination and confer agility to adenovirus evolution

Therapeutic targeting of integrin αvβ6 in breast cancer

BACKGROUND: Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n &gt; 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P &lt; .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.<br/

Mre11 modulates the fidelity of fusion between short telomeres in human cells

The loss of telomere function can result in the fusion of telomeres with other telomeric loci, or non-telomeric double-stranded DNA breaks. Sequence analysis of fusion events between short dysfunctional telomeres in human cells has revealed that fusion is characterized by a distinct molecular signature consisting of extensive deletions and micro-homology at the fusion points. This signature is consistent with alternative error-prone end-joining processes. We have examined the role that Mre11 may play in the fusion of short telomeres in human cells; to do this, we have analysed telomere fusion events in cells derived from ataxia-telangiectasia-like disorder (ATLD) patients that exhibit hypomorphic mutations in MRE11. The telomere dynamics of ATLD fibroblasts were indistinguishable from wild-type fibroblasts and they were proficient in the fusion of short telomeres. However, we observed a high frequency of insertion of DNA sequences at the fusion points that created localized sequence duplications. These data indicate that Mre11 plays a role in the fusion of short dysfunctional telomeres in human cells and are consistent with the hypothesis that as part of the MRN complex it serves to stabilize the joining complex, thereby controlling the fidelity of the fusion reaction