Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They ...are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4
and CD8
T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
Given predicted increases in urbanization in tropical and subtropical regions, understanding the processes shaping urban coral reefs may be essential for anticipating future conservation challenges. ...We used a case study approach to identify unifying patterns of urban coral reefs and clarify the effects of urbanization on hard coral assemblages. Data were compiled from 11 cities throughout East and Southeast Asia, with particular focus on Singapore, Jakarta, Hong Kong, and Naha (Okinawa). Our review highlights several key characteristics of urban coral reefs, including “reef compression” (a decline in bathymetric range with increasing turbidity and decreasing water clarity over time and relative to shore), dominance by domed coral growth forms and low reef complexity, variable city-specific inshore-offshore gradients, early declines in coral cover with recent fluctuating periods of acute impacts and rapid recovery, and colonization of urban infrastructure by hard corals. We present hypotheses for urban reef community dynamics and discuss potential of ecological engineering for corals in urban areas.
Display omitted
•Corals and coral reefs near coastal cities are subject to a suite of intense stressors.•Sediment pollution constrains urban reefs to shallow depths and limits complexity.•Reefs in major cities declined early, and coral cover now fluctuates frequently.•Artificial structures near cities provide novel habitats that are colonized by coral.•Whether urban coral reefs constitute a unique ecosystem type needs to be tested.
Behavior-specific praise (BSP) is a core component of many positive behavioral interventions and supports at each level of prevention, often used to increase student academic outcomes and/or reduce ...inappropriate behavior. We conducted a systematic literature review to explore this low-intensity, teacher-delivered strategy, applying Council for Exceptional Children (CEC) quality indicators and standards to determine whether BSP can be considered an evidence-based practice (EBP). Included articles (N = 6) investigated BSP delivered by a classroom teacher in K–12 traditional school-based settings with academic and/or behavioral student outcome measures. Findings indicated using BSP increased student time on task, decreased inappropriate behaviors, and reduced student tardiness. All studies met our 80% weighted coding criterion. We concluded BSP can be categorized as a potentially EBP based on CEC guidelines. Limitations and directions for future inquiry are presented.
Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently ...(Meikle et al., 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001 40-O-(2-hydroxyethyl)-rapamycin, both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7-30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms.
The purpose of this in vivo exploratory study was to investigate human stratum corneum (SC) lipid conformational order and chain packing in healthy face (cheek) skin as a function of stratum corneum ...depth using a combination of tape-stripping and horizontal attenuated total reflection Fourier transform infrared (HATR-FTIR) spectroscopy. Equivalent data were also collected from volar forearm skin as we, and others, have previously characterized forearm SC lipid order as a function of depth, therefore these data served as a comparison site and an experimental internal standard for the previously unmeasured in vivo face skin data. An SC depth profile was achieved by using tape strips to sequentially remove “layers” of SC. Trans epidermal water loss (TEWL) measurements were recorded following each sequential tape strip. In vivo HATR-FTIR spectra were collected after each tape strip, providing a depth profile of spectral data through the SC of both faces and arms. Spectral data were analyzed at five discrete SC depths corresponding to baseline and SC depths at which the increase in TEWL was 25, 50, 75, and 100 percent (%) from the baseline measurement. Analysis of the SC in vivo HATR-FTIR spectroscopic data utilized mean spectra generated by averaging the spectra from all panelists (n = 10) at the five specific SC depths corresponding to when TEWL had increased by 25, 50, 75 and 100 % from baseline for each subject, respectively. While this is an exploratory study, and the data could be collated and processed in many ways, the average spectral data reveal clear trends in the face and arm SC. Increasing SC lipid order with depth is observed for face skin, as with arm skin, albeit with significant differences at all relative depths in the absolute lipid order between faces and arms. In vivo SC lipids are significantly more ordered at all depths in arms versus cheeks. The less ordered SC lipids of face skin can be in part attributed to the presence of a high amount of fluid sebaceous lipid species observed deep into the face SC. Interestingly, no evidence of orthorhombic packing is observed at any depth in face SC. This is consistent with the high degree of disorder indicated from the chain fluidity measurements. These in vivo HATR-FTIR depth studies of face skin highlight how different SC barrier organization is in the face compared to the more widely studied body sites such as arms and legs. Further studies of the SC lipid barrier in faces are needed to understand the significant differences in lipid organization and its implication for the penetration of drug and cosmetic actives through face skin.
The use of circulating cell-free DNA (cfDNA) as a biomarker in transplant recipients offers advantages over invasive tissue biopsy as a quantitative measure for detection of transplant rejection and ...immunosuppression optimization. However, the fraction of donor-derived cfDNA (dd-cfDNA) in transplant recipient plasma is low and challenging to quantify. Previously reported methods to measure dd-cfDNA require donor and recipient genotyping, which is impractical in clinical settings and adds cost. We developed a targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping. Analytical performance of the assay was characterized and validated using 1117 samples comprising the National Institute for Standards and Technology Genome in a Bottle human reference genome, independently validated reference materials, and clinical samples. The assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs. The dd-cfDNA assay can reliably measure dd-cfDNA (limit of blank, 0.10%; limit of detection, 0.16%; limit of quantification, 0.20%) across the linear quantifiable range (0.2% to 16%) with across-run CVs of 6.8%. Precision was also evaluated for independently processed clinical sample replicates and is similar to across-run precision. Application of the assay to clinical samples from heart transplant recipients demonstrated increased levels of dd-cfDNA in patients with biopsy-confirmed rejection and decreased levels of dd-cfDNA after successful rejection treatment. This noninvasive clinical-grade sequencing assay can be completed within 3 days, providing the practical turnaround time preferred for transplanted organ surveillance.
Studies of nighttime intensivist staffing have yielded mixed results.
To review the association of nighttime intensivist staffing with outcomes of intensive care unit (ICU) patients.
We searched five ...databases (2000-2016) for studies comparing in-hospital nighttime intensivist staffing with other nighttime staffing models in adult ICUs and reporting mortality or length of stay. We abstracted data on staffing models, outcomes, and study characteristics and assessed study quality, using standardized tools. Meta-analyses used random effects models.
Eighteen studies met inclusion criteria: one randomized controlled trial and 17 observational studies. Overall methodologic quality was high. Studies included academic hospitals (n = 10), community hospitals (n = 2), or both (n = 6). Baseline clinician staffing included residents (n = 9), fellows (n = 4), and nurse practitioners or physician assistants (n = 2). Studies included both general and specialty ICUs and were geographically diverse. Meta-analysis (one randomized controlled trial; three nonrandomized studies with exposure limited to nighttime intensivist staffing with adjusted estimates of effect) demonstrated no association with mortality (odds ratio, 0.99; 95% confidence interval, 0.75-1.29). Secondary analyses including studies without risk adjustment, with a composite exposure of organizational factors, stratified by intensity of daytime staffing and by ICU type, yielded similar results. Minimal or no differences were observed in ICU and hospital length of stay and several other secondary outcomes.
Notwithstanding limitations of the predominantly observational evidence, our systematic review and meta-analysis suggests nighttime intensivist staffing is not associated with reduced ICU patient mortality. Other outcomes and alternative staffing models should be evaluated to further guide staffing decisions.
Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. ...We established and validated dynamical connections between viral loads, infected cells, CD8
+
T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8
+
T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8
+
T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8
+
T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8
+
T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.
PDF
