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Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells
The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8
T cells, leading to enhanced antitumor CD8
T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8
T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8
T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8
T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8
T cell responses.
Journal Article
Bidirectional signals of PD-L1 in T cells that fraternize with cancer cells
PD-L1 expressed by T cells provides backward and forward signals to restrain both innate and adaptive immune responses in tumor tissues.
Journal Article
Enhancing reproducibility in stable isotope analysis (SIA) of fish eye lenses: A comparison between lamina number and diameter
Analyzing stable isotopes in archival tissues, such as fish eye lenses, is used to document shifts in feeding ecology, diet, habitat use, and to reconstruct life history. Fish eye lenses grow throughout their ontogeny, forming multiple sequential layers, or laminae. These laminae represent the chronology of the fish’s life, much like tree rings, which record environmental conditions over time. Lenses are protein-rich, which makes them an ideal structure for analyzing light isotopes such as δ¹³C, δ¹⁵N, and δ 34 S. These light isotopes are primarily integrated into the lens tissue through the fish’s diet, where they are bound to amino acid structures during protein synthesis. As research begins to emerge using eye lenses to reconstruct the life histories of fishes, the need for a reproducible method of delamination grows. For this study, each researcher independently delaminated one lens from each of the 10 adult Chinook Salmon ( Oncorhynchus tshawytscha ). Lens lamina number, diameter (mm), and mass (mg) of each lamina were recorded. Laminae were then submitted for stable isotope analysis of both δ¹³C and δ¹⁵N. Isotope values were used as a validation to compare delamination patterns between researchers. δ¹³C and δ¹⁵N values from the lenses were then plotted using both the assigned lamina number and lens diameter to compare the difference between researchers. Analysis based on lamina number showed significant shifts in isotope values and variability in lamina counts between researchers. However, when lens diameter was used instead of lamina number, isotope patterns throughout the lenses of the same fish were nearly identical. Using lens diameter removes subjectivity between researchers, thereby increasing the reproducibility of the technique and providing a more robust interpretation of the data.
Journal Article
Kidney donation after circulatory death (DCD): state of the art
The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation.
Journal Article
Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study
Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death.
We used the UK transplant registry to select a cohort of first-time recipients (aged ≥18 years) of deceased-donor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with χ2 tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors.
6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1·14, 95% CI 0·95–1·36, p=0·16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceased-donor kidneys (2·35, 1·85–3·00, p<0·0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0·30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2·36, 1·39–4·02, p for interaction=0·004).
Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy.
UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.
Journal Article
Nonnutritive Sweeteners: Current Use and Health Perspectives: A Scientific Statement from the American Heart Association and the American Diabetes Association
Regarding stevia, at this time, the U.S. Food and Drug Administration has not made a determination as to the Generally Recognized As Safe status, but has issued no objection letters for a number of Generally Recognized As Safe notifications for stevia sweeteners (http://www. fda.gov/Food/FoodlngrethentsPackaging/ GenerallyRecognizedasSafeGRAS/ GRASNotificationProgram/default.htm). Because all 6 of these NNS have current U.S. Food and Drug Administration approval, issues related to safety of these compounds are not addressed. [...]the review that follows is notably limited by the lack of an extensive evidence base.
Journal Article
Update on Preservice Training in Augmentative and Alternative Communication for Speech-Language Pathologists
Purpose This is a report of the data from a current survey of academic programs in the United States, which provide preservice training in augmentative and alternative communication (AAC) for speech-language pathologists in the United States. A comparison of these findings to the last reported survey was made to identify changes and areas in need of further improvement following implementation of the recent changes to the American Speech-Language-Hearing Association Certification Standards of Clinical Practice. Method A survey was distributed to 279 speech-language pathology graduate training programs in the United States identified from the Council on Academic Accreditation program list. Results A total of 79 survey responses were received for a 28.4% response rate. There was a statistically significant increase in the percentage of programs reported to provide at least 1 course with primary content in AAC compared to the last survey performed. The reported inclusion of AAC content in other courses has also increased, and several programs report multiple AAC courses are now offered for specialized training. The majority of the programs report that less than half of the students graduate with clinical hours in AAC. The number of training grants and doctoral training remains limited to a few programs. Conclusion Academic programs have increased the preservice training in AAC over the past decade. Data indicate a critical need for clinical experience and doctoral training to meet the growing demands of speech-language pathologists.
Journal Article
Use of a blinded hypnotic tapering strategy to promote hypnotic discontinuation
Abstract
Study Objectives
Cognitive behavioral insomnia therapy (CBT-I) combined with supervised open-label tapering is effective for helping hypnotic-dependent patients discontinue their hypnotics. This study tested whether slowing the tapering pace and blinding the tapering process enhance outcomes.
Methods
Seventy-eight benzodiazepines (BZD) or benzodiazepine receptor agonists (BZRA) users completed 4 CBT-I sessions, followed by a randomly assigned blinded tapering protocol wherein hypnotic dosage was: held constant, reduced by 10% every two weeks, or reduced by 25% every two weeks. After 20 weeks those who did not have their medications reduced were offered an open-label tapering protocol. Participants completed assessments 3 months after completing their respective tapering protocols. Outcomes included discontinuation rates, hypnotic withdrawal effects, and responder and remission rates determined by Insomnia Severity Index (ISI) scores.
Results
No differences were observed between the two tapering paces (10% vs. 25%). Blinded tapering had a consistent association with better outcomes that did not reach statistical significance. At 3-month follow-up the number of patients needed to be treated with blinded taper instead of open-label tapering in order for one additional individual to achieve desired endpoints was 7.7 for BZD/BZRA discontinuation, 3.4 for hypnotic withdrawal effects, 4.4 for ISI responder status, and 5.0 for insomnia remission. One-third (32.3%) of the sample was using benzo-related hypnotics at 3-month follow-up. Twice as many individuals (64.6%) were using some type of medication or substance for sleep at this time point.
Conclusions
Blinding tapering may enhance hypnotic discontinuation rates and insomnia treatment response and remission rates.
Trial Registration: Clinicaltrials.gov Identifier: NCT02831894, “The Role of Tapering Pace and Selected Traits on Hypnotic Discontinuation;” URL:https://clinicaltrials.gov/ct2/show/NCT02831894?term=hypnotics&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&draw=2&rank=2
Journal Article
A large-scale analysis of bioinformatics code on GitHub
In recent years, the explosion of genomic data and bioinformatic tools has been accompanied by a growing conversation around reproducibility of results and usability of software. However, the actual state of the body of bioinformatics software remains largely unknown. The purpose of this paper is to investigate the state of source code in the bioinformatics community, specifically looking at relationships between code properties, development activity, developer communities, and software impact. To investigate these issues, we curated a list of 1,720 bioinformatics repositories on GitHub through their mention in peer-reviewed bioinformatics articles. Additionally, we included 23 high-profile repositories identified by their popularity in an online bioinformatics forum. We analyzed repository metadata, source code, development activity, and team dynamics using data made available publicly through the GitHub API, as well as article metadata. We found key relationships within our dataset, including: certain scientific topics are associated with more active code development and higher community interest in the repository; most of the code in the main dataset is written in dynamically typed languages, while most of the code in the high-profile set is statically typed; developer team size is associated with community engagement and high-profile repositories have larger teams; the proportion of female contributors decreases for high-profile repositories and with seniority level in author lists; and, multiple measures of project impact are associated with the simple variable of whether the code was modified at all after paper publication. In addition to providing the first large-scale analysis of bioinformatics code to our knowledge, our work will enable future analysis through publicly available data, code, and methods. Code to generate the dataset and reproduce the analysis is provided under the MIT license at https://github.com/pamelarussell/github-bioinformatics. Data are available at https://doi.org/10.17605/OSF.IO/UWHX8.
Journal Article