Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

The Evolution of Expressing and Exchanging Cyber-Investigation Information in a Standardized Form

The growing number of investigations involving digital traces from various data sources is driving the demand for a standard way to represent and exchange pertinent information. Enabling automated combination and correlation of cyber-investigation information from multiple systems or organizations enables more efficient and comprehensive analysis, reducing the risk of mistakes and missed opportunities. These needs are being met by the evolving open-source, community-developed specification language called CASE, the Cyber-investigation Analysis Standard Expression. CASE leverages the Unified Cyber Ontology (UCO), which abstracts and expresses concepts that are common across multiple domains. This paper introduces CASE and UCO, explaining how they improve upon prior related work. The value of fully-structured data, representing provenance, and action lifecycles are discussed. The guiding principles of CASE and UCO are presented, and illustrative examples of CASE are provided using the default JSON-LD serialization

Floral temperature and optimal foraging: is heat a feasible floral reward for pollinators?

As well as nutritional rewards, some plants also reward ectothermic pollinators with warmth. Bumble bees have some control over their temperature, but have been shown to forage at warmer flowers when given a choice, suggesting that there is some advantage to them of foraging at warm flowers (such as reducing the energy required to raise their body to flight temperature before leaving the flower). We describe a model that considers how a heat reward affects the foraging behaviour in a thermogenic central-place forager (such as a bumble bee). We show that although the pollinator should spend a longer time on individual flowers if they are warm, the increase in total visit time is likely to be small. The pollinator's net rate of energy gain will be increased by landing on warmer flowers. Therefore, if a plant provides a heat reward, it could reduce the amount of nectar it produces, whilst still providing its pollinator with the same net rate of gain. We suggest how heat rewards may link with plant life history strategies

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients with Varicella Infection: a Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Patients <18 years old diagnosed with varicella during 2014-2018 with 3-month follow-up available were included. We described varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3-month post-diagnosis. RESULTS: We identified 114,578 children with a primary varicella diagnosis. 7.7% (n = 8,814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1%, n = 3,271). In all, 25.9% (n = 29,706/114,578) were prescribed antibiotics. A higher proportion of patients with complications than those without complications were prescribed antibiotics (64.3%, n = 5,668/8,814 vs. 22.7%, n = 24,038/105,764). Mean annualized varicella-related costs were £2,231,481 for the study cohort. Overall, antibiotic prescriptions cost ∼£262,007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

Intrathoracic fire during preparation of the left internal thoracic artery for coronary artery bypass grafting

A surgical fire is a serious complication not previously described in the literature with regard to the thoracic cavity. We report a case in which an intrathoracic fire developed following an air leak combined with high pressure oxygen ventilation in a patient with severe chronic obstructive pulmonary disease. The patient presented to our institution with diffuse coronary artery disease and angina pectoris. He was treated with coronary artery bypass graft surgery, including left internal thoracic artery harvesting. Additionally to this rare presentation of an intrathoracic fire, a brief review of surgical fires is included to this paper

The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation

\ua9 2024 The AuthorsThe time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD

The association of health literacy with adherence in older 2 adults, and its role in interventions: a systematic meta-review

Background: Low health literacy is a common problem among older adults. It is often suggested to be associated with poor adherence. This suggested association implies a need for effective adherence interventions in low health literate people. However, previous reviews show mixed results on the association between low health literacy and poor adherence. A systematic meta-review of systematic reviews was conducted to study the association between health literacy and adherence in adults above the age of 50. Evidence for the effectiveness of adherence interventions among adults in this older age group with low health literacy was also explored. Methods: Eight electronic databases (MEDLINE, ERIC, EMBASE, PsycINFO, CINAHL, DARE, the Cochrane Library, and Web of Knowledge) were searched using a variety of keywords regarding health literacy and adherence. Additionally, references of identified articles were checked. Systematic reviews were included if they assessed the association between health literacy and adherence or evaluated the effectiveness of interventions to improve adherence in adults with low health literacy. The AMSTAR tool was used to assess the quality of the included reviews. The selection procedure, data-extraction, and quality assessment were performed by two independent reviewers. Seventeen reviews were selected for inclusion. Results: Reviews varied widely in quality. Both reviews of high and low quality found only weak or mixed associations between health literacy and adherence among older adults. Reviews report on seven studies that assess the effectiveness of adherence interventions among low health literate older adults. The results suggest that some adherence interventions are effective for this group. The interventions described in the reviews focused mainly on education and on lowering the health literacy demands of adherence instructions. No conclusions could be drawn about which type of intervention could be most beneficial for this population. Conclusions: Evidence on the association between health literacy and adherence in older adults is relatively weak. Adherence interventions are potentially effective for the vulnerable population of older adults with low levels of health literacy, but the evidence on this topic is limited. Further research is needed on the association between health literacy and general health behavior, and on the effectiveness of interventions

Managing contested spaces: Public managers, obscured mechanisms and the legacy of the past in Northern Ireland

Societies emerging from ethno-political and inter-communal conflict face a range of complex problems that stem directly from the recent lived experience of bloodshed and injury, militarisation, securitisation and segregation. As institutional agents in such an environment, public managers perform the dual role of both interpreting public policy and implementing it within a politically contested space and place. In this article we address how managers cope with the outworking of ethno-nationalist conflict and peace building within government processes and policy implementation and contend this is a subject of emerging concern within the wider public administration, urban studies and conflict literature. Using data from a witness seminar initiative on the Northern Ireland conflict transformation experience, we explain how public sector managers make sense of their role in post-agreement public management and highlight the importance of three identified mechanisms; ‘bricolage’, ‘diffusion’ and ‘translation’ in the management of public sector organisations and urban spaces in a context of entrenched conflict and an uncertain path to peace

Photodisintegration of 4^4He into p+t

The two-body photodisintegration of $^4$He into a proton and a triton has been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at Jefferson Laboratory. Real photons produced with the Hall-B bremsstrahlung-tagging system in the energy range from 0.35 to 1.55 GeV were incident on a liquid $^4$He target. This is the first measurement of the photodisintegration of $^4$He above 0.4 GeV. The differential cross sections for the $\gamma$$^4$He$\to pt$ reaction have been measured as a function of photon-beam energy and proton-scattering angle, and are compared with the latest model calculations by J.-M. Laget. At 0.6-1.2 GeV, our data are in good agreement only with the calculations that include three-body mechanisms, thus confirming their importance. These results reinforce the conclusion of our previous study of the three-body breakup of $^3$He that demonstrated the great importance of three-body mechanisms in the energy region 0.5-0.8 GeV .Comment: 13 pages submitted in one tgz file containing 2 tex file and 22 postscrip figure