BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop ...RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.
BACKGROUND. We conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies. METHODS. The aim of trial was to ...develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Д32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response. RESULTS. Infusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Д32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses. CONCLUSION. These findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses. REGISTRATION. ClinicalTrials.gov NCT02388594. FUNDING. NIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.
Tumor cells can engage in a process called collective invasion, in which cohesive groups of cells invade through interstitial tissue. Here, we identified an epigenetically distinct subpopulation of ...breast tumor cells that have an enhanced capacity to collectively invade. Analysis of spheroid invasion in an organotypic culture system revealed that these "trailblazer" cells are capable of initiating collective invasion and promote non-trailblazer cell invasion, indicating a commensal relationship among subpopulations within heterogenous tumors. Canonical mesenchymal markers were not sufficient to distinguish trailblazer cells from non-trailblazer cells, suggesting that defining the molecular underpinnings of the trailblazer phenotype could reveal collective invasion-specific mechanisms. Functional analysis determined that DOCK10, ITGA11, DAB2, PDFGRA, VASN, PPAP2B, and LPAR1 are highly expressed in trailblazer cells and required to initiate collective invasion, with DOCK10 essential for metastasis. In patients with triple-negative breast cancer, expression of these 7 genes correlated with poor outcome. Together, our results indicate that spontaneous conversion of the epigenetic state in a subpopulation of cells can promote a transition from in situ to invasive growth through induction of a cooperative form of collective invasion and suggest that therapeutic inhibition of trailblazer cell invasion may help prevent metastasis.
Cell identity signals influence the invasive capability of tumor cells, as demonstrated by the selection for programs of epithelial-to-mesenchymal transition (EMT) during malignant progression. ...Breast cancer cells retain canonical epithelial traits and invade collectively as cohesive groups of cells, but the signaling pathways critical to their invasive capabilities are still incompletely understood. Here we report that the transcription factor ΔNp63α drives the migration of basal-like breast cancer (BLBC) cells by inducing a hybrid mesenchymal/epithelial state. Through a combination of expression analysis and functional testing across multiple BLBC cell populations, we determined that ΔNp63α induces migration by elevating the expression of the EMT program components Slug and Axl. Interestingly, ΔNp63α also increased the expression of miR-205, which can silence ZEB1/2 to prevent the loss of epithelial character caused by EMT induction. In clinical specimens, co-expression of various elements of the ΔNp63α pathway confirmed its implication in motility signaling in BLBC. We observed that activation of the ΔNp63α pathway occurred during the transition from noninvasive ductal carcinoma in situ to invasive breast cancer. Notably, in an orthotopic tumor model, Slug expression was sufficient to induce collective invasion of E-cadherin-expressing BLBC cells. Together, our results illustrate how ΔNp63α can drive breast cancer cell invasion by selectively engaging promigratory components of the EMT program while, in parallel, still promoting the retention of epithelial character.
Introduction‘Task-shifting’ or ‘task-sharing’ is an effective strategy for delivering behavioural healthcare in lower resource communities. However, little is known regarding the actual steps ...(methods) in carrying out a task-shifting project. This paper presents a protocol for a systematic review that will identify steps in adapting an evidence-based psychological treatment for delivery by lay/non-licenced personnel.Methods and analysisA systematic review of peer-reviewed, published studies involving a non-licenced, non-specialist (eg, community health worker, promotor/a, peer and lay person) delivering an evidence-based psychological treatment for adults will be conducted. Study design of selected articles must include a statistical comparison (eg, randomised controlled trials, quasiexperimental trials, pre–post designs and pragmatic trials). Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Databases including PubMed, the Cochrane Library, Cochrane Central Register of Controlled Trials, SCOPUS, Cumulative Index to Nursing and Allied Health Literature, APA PsycInfo and Google Scholar will be searched from 2000 to 2020. Risk of bias will be assessed using the Cochrane Collaboration’s Risk of Bias (RoB 2) tool, and publication bias will be evaluated with the Cochrane GRADE approach. A narrative synthesis will be conducted for all included studies, and a summary table following Proctor’s framework for operationalising implementation strategies will be included. This protocol was developed following the 2015 guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.Ethics and disseminationThis review will analyse data from published studies only; thus, it will not require institutional board review. Findings will be presented at conferences, to the broader community via the Community Health Worker Translational Advisory Board and social media, and the final systematic review will be published in a peer-reviewed journal.
Several methods are available to estimate leg lengths at maturity to facilitate the determination of timing of epiphysiodesis. We compared the Paley multiplier, Sanders multiplier, and White-Menelaus ...methods in an epiphysiodesis-aged cohort. We assessed intra- and interrater reliability for Sanders skeletal stages and Greulich and Pyle atlas skeletal age.
Actual growth was recorded in healthy, unoperated femoral and tibial segments from an epiphysiodesis database. The predicted and actual lengths were compared with use of the Paley multiplier and White-Menelaus methods, Greulich and Pyle skeletal age, and the Sanders multiplier using Sanders stages. Intra- and interrater reliability were assessed in a separate group of 76 skeletal age films.
The cohort included 148 femora and 195 tibiae in 197 patients. Femoral length at maturity was slightly underestimated by the Sanders multiplier and staging, was overestimated by the Paley multiplier and skeletal age, and was most accurately predicted with use of the White-Menelaus formula and skeletal age. All methods overestimated tibial length at maturity. The whole-leg prediction accuracy of the Sanders multiplier and White-Menelaus formula were comparable and were more accurate than that of the Paley multiplier. For Sanders skeletal staging, the interrater reliability varied from 0.86 to 0.88 and the intrarater reliability varied from 0.87 to 0.96. For Greulich and Pyle skeletal age, the interrater reliability varied from 0.87 to 0.89 and the intrarater reliability varied from 0.91 to 0.95.
Use of the Sanders multiplier and skeletal stages was more accurate than the Paley multiplier and skeletal age in this cohort. Use of the White-Menelaus formula and skeletal age was slightly more accurate in predicting femoral length and slightly less accurate in predicting tibial length compared with the Sanders multiplier. Intra- and interrater reliability were similar between Sanders skeletal stages and Greulich and Pyle atlas skeletal age. The White-Menelaus formula and skeletal age was the recommended method for predicting lower-extremity segment lengths at maturity and epiphysiodesis effect. Although easier to recall without referencing an atlas and not sex-specific, Sanders skeletal staging does not correspond directly to years of growth remaining, and thus cannot be used with the White-Menelaus formula.
The Greulich and Pyle atlas to determine skeletal age and the White-Menelaus formula to determine growth remaining are reliable predictors of epiphysiodesis effect in the lower extremities.
Undergraduate research experiences in science, technology, engineering, and mathematics fields are championed for promoting students' personal and professional development. Mentorship is an integral ...part of undergraduate research, as effective mentorship maximizes the benefits undergraduates realize from participating in research. Yet almost no research examines instances in which mentoring is less effective or even problematic, even though prior research on mentoring in workplace settings suggests negative mentoring experiences are common. Here, we report the results of a qualitative study to define and characterize negative mentoring experiences of undergraduate life science researchers. Undergraduate researchers in our study reported seven major ways they experienced negative mentoring: absenteeism, abuse of power, interpersonal mismatch, lack of career support, lack of psychosocial support, misaligned expectations, and unequal treatment. They described some of these experiences as the result of absence of positive mentoring behavior and others as actively harmful behavior, both of which they perceive as detrimental to their psychosocial and career development. Our results are useful to mentors for reflecting on ways their behaviors might be perceived as harmful or unhelpful. These findings can also serve as a foundation for future research aimed at examining the prevalence and impact of negative mentoring experiences in undergraduate research.
Abstract
Objectives
Previous reports established the feasibility of a telehealth model for delivering speech–language therapy via Internet videoconferencing, which connects individuals with primary ...progressive aphasia (PPA) to an expert speech and language pathologist for treatment. This study reports feasibility of the same telehealth intervention in a larger set of progressive aphasia participants and explores factors potentially influencing functional intervention outcomes.
Methods
Participants with PPA or progressive aphasia in the context of a neurodegenerative dementia syndrome and their communication partners were enrolled into an 8-session intervention, with 3 evaluations (baseline, 2 months, and 6 months postenrollment). Half of the participants were randomized into a “check-in” group and received 3-monthly half-hour sessions postintervention. Mixed linear models with post hoc testing and percent change in area under the curve were used to examine communication confidence over time, as well as the influence of check-in sessions and the role of communication partner engagement on communication confidence.
Results
Communication confidence improved at the 2-month evaluation and showed no significant decline at the 6-month evaluation. Item-level analysis revealed gains in communication confidence across multiple communication contexts. Gains and maintenance of communication confidence were only present for the engaged communication partner group and were not bolstered by randomization to the check-in group.
Discussion
Internet-based, person-centered interventions demonstrate promise as a model for delivering speech–language therapy to individuals living with PPA. Maintenance is possible for at least 6 months postenrollment and is better for those with engaged communication partners, which supports the use of dyadic interventions.
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