Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer

The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evofosfamide alone showed no effects in an in vivo syngeneic model of colorectal cancer. However, the mechanisms behind the interaction between the tumor microenvironment in the context of oxygenation (hypoxic, normoxic), immunotherapy, and tumor cells are not fully understood. To begin to understand this issue, we develop a system of ordinary differential equations to simulate the growth and decline of tumors and their vascularization (oxygenation) in response to treatment with evofosfamide and immunotherapy (6 combinations of scenarios). The model is calibrated to data from in vivo experiments on mice implanted with colon adenocarcinoma cells and longitudinally imaged with [18F]-fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) to quantify hypoxia. The results show that evofosfamide is able to rescue the immune response and sensitize hypoxic tumors to immunotherapy. In the hypoxic scenario, evofosfamide reduces tumor burden by $45.07 \pm 2.55$%, compared to immunotherapy alone, as measured by tumor volume. The model accurately predicts the temporal evolution of five different treatment scenarios, including control, hypoxic tumors that received immunotherapy, normoxic tumors that received immunotherapy, evofosfamide alone, and hypoxic tumors that received combination immunotherapy and evofosfamide. The average concordance correlation coefficient (CCC) between predicted and observed tumor volume is $0.86 \pm 0.05$. Interestingly, the model values to fit those five treatment arms was unable to accurately predict the response of normoxic tumors to combination evofosfamide and immunotherapy (CCC = $-0.064 \pm 0.003$). However, guided by the sensitivity analysis to rank the most influential parameters on the tumor volume, we found that increasing the tumor death rate due to immunotherapy by a factor of $18.6 \pm 9.3$ increases CCC of $0.981 \pm 0.001$. To the best of our knowledge, this is the first study to mathematically predict and describe the increased efficacy of immunotherapy following evofosfamide

A coaching program to improve dietary intake of patients with CKD: ENTICE-CKD

The dietary self-management of CKD is challenging. Telehealth interventions may provide an effective delivery method to facilitate sustained dietary change.This pilot, randomized, controlled trial evaluated secondary and exploratory outcomes after a dietitian-led telehealth coaching intervention to improve diet quality in people with stage 3-4 CKD. The intervention group received phone calls every 2 weeks for 3 months (with concurrent, tailored text messages for 3 months), followed by 3 months of tailored text messages without telephone coaching, to encourage a diet consistent with CKD guidelines. The control group received usual care for 3 months, followed by nontailored, educational text messages for 3 months.Eighty participants (64% male), aged 62±12 years, were randomized to the intervention or control group. Telehealth coaching was safe, with no adverse events or changes to serum biochemistry at any time point. At 3 months, the telehealth intervention, compared with the control, had no detectable effect on overall diet quality on the Alternative Health Eating Index (3.2 points, 95% confidence interval, -1.3 to 7.7), nor at 6 months (0.5 points, 95% confidence interval, -4.6 to 5.5). There was no change in clinic BP at any time point in any group. There were significant improvements in several exploratory diet and clinical outcomes, including core food group consumption, vegetable servings, fiber intake, and body weight.Telehealth coaching was safe, but appeared to have no effect on the Alternative Healthy Eating Index or clinic BP. There were clinically significant changes in several exploratory diet and clinical outcomes, which require further investigation.Evaluation of Individualized Telehealth Intensive Coaching to Promote Healthy Eating and Lifestyle in CKD (ENTICE-CKD), ACTRN12616001212448

The blood transfer conductance for nitric oxide: infinite vs. finite θNO

Whether the specific blood transfer conductance for nitric oxide (NO) with hemoglobin (θNO) is finite or infinite is controversial but important in the calculation of alveolar capillary membrane conductance (DmCO) and pulmonary capillary blood volume (VC) from values of lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). In this review, we discuss the background associated with θNO, explore the resulting values of DmCO and VC when applying either assumption, and investigate the mathematical underpinnings of DmCO and VC calculations. In general, both assumptions yield reasonable rest and exercise DmCO and VC values. However, the finite θNO assumption demonstrates increasing VC, but not DmCO, with submaximal exercise. At relatively high, but physiologic, DLNO/DLCO ratios both assumptions can result in asymptotic behavior for VC values, and under the finite θNO assumption, DmCO values. In conclusion, we feel that the assumptions associated with a finite θNO require further in vivo validation against an established method before widespread research and clinical use

Improving the effectiveness of psychological interventions for depression and anxiety in the cardiac rehabilitation pathway using group-based metacognitive therapy (PATHWAY Group MCT) : study protocol for a randomised controlled trial

BACKGROUND: Anxiety and depression are prevalent among cardiac rehabilitation patients but pharmacological and psychological treatments have limited effectiveness in this group. Furthermore, psychological interventions have not been systematically integrated into cardiac rehabilitation services despite being a strategic priority for the UK National Health Service. A promising new treatment, metacognitive therapy, may be well-suited to the needs of cardiac rehabilitation patients and has the potential to improve outcomes. It is based on the metacognitive model, which proposes that a thinking style dominated by rumination, worry and threat monitoring maintains emotional distress. Metacognitive therapy is highly effective at reducing this thinking style and alleviating anxiety and depression in mental health settings. This trial aims to evaluate the effectiveness and cost-effectiveness of group-based metacognitive therapy for cardiac rehabilitation patients with elevated anxiety and/or depressive symptoms. METHODS/DESIGN: The PATHWAY Group-MCT trial is a multicentre, two-arm, single-blind, randomised controlled trial comparing the clinical- and cost-effectiveness of group-based metacognitive therapy plus usual cardiac rehabilitation to usual cardiac rehabilitation alone. Cardiac rehabilitation patients (target sample n = 332) with elevated anxiety and/or depressive symptoms will be recruited across five UK National Health Service Trusts. Participants randomised to the intervention arm will receive six weekly sessions of group-based metacognitive therapy delivered by either cardiac rehabilitation professionals or research nurses. The intervention and control groups will both be offered the usual cardiac rehabilitation programme within their Trust. The primary outcome is severity of anxiety and depressive symptoms at 4-month follow-up measured by the Hospital Anxiety and Depression Scale total score. Secondary outcomes are severity of anxiety/depression at 12-month follow-up, health-related quality of life, severity of post-traumatic stress symptoms and strength of metacognitive beliefs at 4- and 12-month follow-up. Qualitative interviews will help to develop an account of barriers and enablers to the effectiveness of the intervention. DISCUSSION: This trial will evaluate the effectiveness and cost-effectiveness of group-based metacognitive therapy in alleviating anxiety and depression in cardiac rehabilitation patients. The therapy, if effective, offers the potential to improve psychological wellbeing and quality of life in this large group of patients. TRIAL REGISTRATION: UK Clinical Trials Gateway, ISRCTN74643496 , Registered on 8 April 2015

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Metacognitive therapy home-based self-help for cardiac rehabilitation patients experiencing anxiety and depressive symptoms : study protocol for a feasibility randomised controlled trial (PATHWAY Home-MCT)

BACKGROUND: Anxiety and depression are common among patients attending cardiac rehabilitation services. Currently available pharmacological and psychological interventions have limited effectiveness in this population. There are presently no psychological interventions for anxiety and depression integrated into cardiac rehabilitation services despite emphasis in key UK National Health Service policy. A new treatment, metacognitive therapy, is highly effective at reducing anxiety and depression in mental health settings. The principal aims of the current study are (1) to evaluate the acceptability of delivering metacognitive therapy in a home-based self-help format (Home-MCT) to cardiac rehabilitation patients experiencing anxiety and depressive symptoms and conduct a feasibility trial of Home-MCT plus usual cardiac rehabilitation compared to usual cardiac rehabilitation; and (2) to inform the design and sample size for a full-scale trial. METHODS: The PATHWAY Home-MCT trial is a single-blind feasibility randomised controlled trial comparing usual cardiac rehabilitation (control) versus usual cardiac rehabilitation plus home-based self-help metacognitive therapy (intervention). Economic and qualitative evaluations will be embedded within the trial. Participants will be assessed at baseline and followed-up at 4 and 12 months. Patients who have been referred to cardiac rehabilitation programmes and have a score of ≥ 8 on the anxiety and/or depression subscales of the Hospital Anxiety and Depression Scale will be invited to take part in the study and written informed consent will be obtained. Participants will be recruited from the National Health Service in the UK. A minimum of 108 participants will be randomised to the intervention and control arms in a 1:1 ratio. DISCUSSION: The Home-MCT feasibility randomised controlled trial will provide evidence on the acceptability of delivering metacognitive therapy in a home-based self-help format for cardiac rehabilitation patients experiencing symptoms of anxiety and/or depression and on the feasibility and design of a full-scale trial. In addition, it will provide provisional point estimates, with appropriately wide measures of uncertainty, relating to the effectiveness and cost-effectiveness of the intervention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03129282 , Submitted to Registry: 11 April 2017

The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages

The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tailanchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction

Annotated Bibliography of Evaluating the Educational Impact of Digital Libraries

This annotated bibliography was commissioned to support the NSDL Evaluation Workshop (planned for October 2003) that will 1) explore the issues around evaluating the impact of digital libraries on education and that will 2) begin developing a strategy to evaluate the impact of the National Science Digital Library (NSDL) on STEM education. The bibliographyâ s purpose, then, is to identify research to date on evaluating the impact of digital libraries on learning and teaching. It contains a Summary & Analysis section, which defines terms, makes observations about the literature, reviews the resources included, highlights issues, and suggests areas for further consideration. The Annotated Bibliography is organized alphabetically. Details about each resource include: a citation; the abstract provided with each resource; a summary, if necessary, to highlight relevant ideas not expressed in the abstract; and, a comment section with a short analysis of the resource. The annotations are followed by a description of the Methodology used to compile this document