Search

Supplementary figure 1-3 Supplementary tables 1 and 2 Supplementary data showing responses induced in mice from double and triple citrullinated vimentin aa28-49 peptides, murine aa415-433 peptide and evidence responses are not CD8 mediated as well as vimentin peptide sequences and cytokine data from human patient.

Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4+ T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8+ T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy. Cancer Res; 76(3); 548–60. ©2015 AACR.

figure legends

Molecular links between breast cancer risk factors and pro-oncogenic tissue alterations are poorly understood. The goal of this study was to characterize the impact of overweight and obesity on tissue markers of risk, using normal breast biopsies, a mouse model of obesity, and cultured breast acini. Proliferation and disruption of epithelial polarity, both necessary for tumor initiation, were quantified by immunostaining. High BMI and elevated leptin were associated with compromised epithelial polarity whereas overweight was associated with proliferation in human and mice mammary glands. Human serum with unfavorable adipokine levels altered epithelial polarization of cultured acini, recapitulating the effect of leptin. Weight loss in mice led to metabolic improvements and restored epithelial polarity. In acini cultures, epithelial polarity loss was prevented by antioxidants and could be reverted by normalizing culture conditions. This study provides a framework to set target values for metabolic improvements and to assess the efficacy of interventional studies aimed at reducing breast cancer risk.

Currently, no dressings utilized in burn clinics provide adhesion, hydration or mechanical strength on the same order as human skin as well as the ability to be atraumatically removed. We report the synthesis, characterization, and in vivo evaluation of in situ polymerized and subsequent dissolvable hydrogels as burn wound dressings. Hydrogel dressings, from a small library of synthesized materials form in situ, exhibit storage moduli between 100-40,000 Pa, dissolve on-demand within 10 minutes to 90 minutes, swell up to 350%, and adhere to both burned and healthy human skin at 0.2-0.3N/cm(2). Further, results from an in vivo porcine second degree burn model demonstrate functional performance with healing equivalent to conventional treatments with the added benefit of facile, in situ application and subsequent removal via dissolution.

International audience; Immobilization of biosensors in or on a functional material is critical for subsequent device development and translation to wearable technology. Here we present the development and assessment of an immobilized quantum dot - transcription factor - nucleic acid complex for progesterone detection as a first step toward such device integration. The sensor is composed of a polyhistidine-tagged transcription factor linked to a quantum dot and a fluorophore-modified cognate DNA, and embedded within a hydrogel as an immobilization matrix. The hydrogel is optically transparent, soft, and flexible as well as traps the quantum dot - transcription factor DNA assembly but allows free passage of the analyte, progesterone. Upon progesterone exposure, DNA dissociates from the quantum dot - transcription factor DNA assembly resulting in an attenuated ratiometric fluorescent output via Förster resonance energy transfer. The sensor performs in a dose-dependent manner with a limit of detection of 55 nM. Repeat analyte measurements are also similarly successful. Our approach combines a systematically characterized hydrogel as an immobilization matrix and a transcription factor - DNA binding as a recognition/ transduction element, offering a promising framework for future biosensor devices based upon allosteric transcription factor.

Currently, no dressings are utilized after removal of polyps during a colonoscopy rendering these tissue sites susceptible to bleeding, sepsis, and perfusion. We report the design specifications, synthesis, and ex vivo evaluation of in situ polymerized hydrogels as colon wound dressings post polypectomy. The hydrogels exhibited varied properties to include moduli between 100 and 16 000 Pa, dissolution times between 4 h to 7 days or longer, swelling up to 200%, and adhesion to colon tissue from 0.1 to 0.4 N/cm(2). The hydrogels displayed minimal cytotoxicity, prevented the migration/spread of bacteria, and exhibited rapid gelation, a requirement for application to the lumen of the colon via an endoscope. This work highlights the structure–property relationship of hydrogels prepared from N-hydroxysuccinimide functionalized PEG cross-linkers and hyperbranched polyethylenimines or 4-arm PEG-NH(2) star polymers, and their potential as colon wound dressings.

We investigated if infants with a Barlow positive hip(s) have natural hip stabilization and can thus avoid Pavlik Harness (PH) treatment. We conducted a chart review for infants who presented within two weeks of life, had a Barlow positive hip, and were deferred treatment. Of the thirty infants, eighteen were treated with PH at 4-6 weeks or 12 weeks due to persistent dysplasia. Twelve infants avoided PH entirely. There were zero cases of PH failure. Parents can be counseled that deferring treatment until at least 4-6 weeks of age might avoid treatment altogether without an increased risk of harness failure.

Inclusive approaches to archaeology (including queer, feminist, black, indigenous, etc. perspectives) have increasingly intersected with coding, maker, and hacker cultures to develop a uniquely ‘Do-It-Yourself’ style of disruption and activism. Digital technology provides opportunities to challenge conventional representations of people past and present in creative ways, but at what cost? As a critical appraisal of transhumanism and the era of digital scholarship, this article outlines compelling applications in inclusive digital practice but also the pervasive structures of privilege, inequity, inaccessibility, and abuse that are facilitated by open, web-based heritage projects. In particular, it evaluates possible means of creating a balance between individual-focused translational storytelling and public profiles, and the personal and professional risks that accompany these approaches, with efforts to foster, support, and protect traditionally marginalized archaeologists and communities.

Introduction It is predicted that erectile dysfunction will affect around 322 million men worldwide by 2025. Because of the large volume of literature on the topic, physicians often turn to systematic reviews and meta-analyses—and particularly abstracts of such articles—for clinical guidance. Thus, it is crucial that findings are not misrepresented in abstracts. In this study, we evaluated the use of spin (ie, the misreporting of study findings by overstating or selectively reporting efficacy results, minimizing harms, or making unwarranted clinical recommendations) in the abstracts of systematic reviews on erectile dysfunction. Methods A search strategy was developed using the MEDLINE and Embase databases to retrieve systematic reviews focused on treatments for erectile dysfunction. 2 investigators independently screened the titles and abstracts from the reviews for study inclusion. Investigators analyzed the included systematic reviews for 9 of the most severe types of spin using a previously developed classification scheme and rated them for methodological quality using the revised A MeaSurement Tool to Assess systematic Reviews (AMSTAR) in a masked, duplicate manner. Study characteristics for each review were also extracted in duplicate. Results Our search returned 2,224 articles, of which 102 systematic reviews and meta-analyses were included in the final analysis. A total of 31.4% (32/102) of systematic reviews contained spin. 8 types of spin were identified in our sample. Type 3 (selective reporting of or overemphasis on efficacy outcomes) and type 5 (conclusion claims beneficial effect despite high risk of bias) were the most common types of spin, each occurring in 10.8% (11/102) of abstracts. There was no significant association between the presence of spin and the extracted study characteristics or methodological quality. Conclusion Spin was present in systematic reviews and meta-analyses covering erectile dysfunction treatments. Steps should be taken to improve the reporting quality of abstracts on erectile dysfunction treatment.

Background Physical activity (PA) is important for both the prevention and management of long-term conditions (1). Previous research has identified a beneficial impact of PA on pain, function and overall health (2, 3, 4). However, levels of PA are often lower in people with a long-term condition (LTC) and decline further for those with multiple conditions (5, 6). Digital tools, such as websites, apps or wearables, show some potential for supporting engagement with PA in the short term (7, 8), but lack data on maintaining PA behaviours longer term. A search of existing reviews in this area identified only a small number of systematic reviews that included digital interventions with a focus on maintaining PA for people with a LTC (9, 10, 11). Of these, only Grimmett et al (2019) reported effective maintenance at >3 months post-intervention (9). Consequently, a scoping review methodology has been chosen to explore digital PA maintenance for people with a LTC more widely. The aims of this review are to: Identify the range and variety of digital tools and their associated theoretical foundations for supporting people with a LTC/s to maintain physical activity. Uncover the components considered to be necessary for engagement with digital tools to support maintenance of physical activity Review objectives: What is the “extent (size), range (variety) and nature (characteristics) of the evidence” (12) on digital tools to support the maintenance of physical activity for people with a LTC/s? What theoretical underpinnings are used in digital tools to promote the maintenance of physical activity? What are the experiences of people using digital tools to maintain physical activity? What are the barriers and facilitators to maintaining physical activity for people with a LTC/s using digital tools? Design This scoping review will be undertaken in accordance with PRISMA-ScR guidelines (12) and the frameworks developed by Arksey and O’Malley (13) and Levac et al., (14). Preliminary searches will be undertaken in consultation with an academic librarian to create a comprehensive search strategy. Screening of titles and abstracts will be undertaken by two independent reviewers, with conflicts resolved by an independent verifier, using Covidence software (15). Full-text screening will subsequently be undertaken following this same approach. A charting form will be developed based on the objectives of the review and refined by the research team. Data will be collated and summarised, with quantitative sources described descriptively and qualitative data analysed thematically (16). Results will be presented using summary tables and/or using pictorial/flow charts, if appropriate.

What does it mean to decolonise archaeology in teaching and learning today? What role can (or should) digital technology and approaches play in transforming training and practice? This chapter will use case studies developing hybrid interventions in museum exhibits through collaborations between the University of Victoria, the Royal BC Museum (RBCM), descendant communities and diverse publics in Victoria, BC, to examine how digital media and platforms can be used to extend and reshape existing archaeology and decolonisation measures and spark relevant and much needed dialogues about heritage, education and practice in an increasingly digital era.

Digital literacy has been cited as one of the primary challenges to ensuring data reuse and increasing the value placed on open science. Incorporating published data into classrooms and training is at the core of tackling this issue. This article presents case studies in teaching with different published data platforms, in three different countries (the Netherlands, Canada, and the United States), to students at different levels and with differing skill levels. In outlining their approaches, successes, and failures in teaching with open data, it is argued that collaboration with data publishers is critical to improving data reuse and education. Moreover, increased opportunities for digital skills training and scaffolding across program curriculum are necessary for managing the learning curve and teaching students the values of open science.

The value of open data is transforming archaeological practice while also introducing new concerns relating to the ethics of studying the dead. This paper uses the Monumental Archive Project, recently launched as a public database of cemetery records from Barbados, as a case study to critically examine the realities of platforms created to bring together academic and general audiences in open mortuary archaeology. Digital literacy and support structures are significant barriers to digital data within the discipline, while the impact of open data on the public(s) that archaeologists seek to engage and collaborate with is rarely considered let alone measured. Is it possible to serve diverse audiences with a single platform? What are the implications (social, ethical, emotional) for sharing cemetery data? When digitizing the dead, strategies in platform design, marketing and communication for public interest and use becomes even more complex and necessitates further attention.

To build a theoretical and empirical foundation for interpretation of the absence, segregation or simplicity of infant burials in archaeological contexts, we review social theories of emotion, inter-disciplinary views on the relationship between mortality rates and emotional investment, and archaeological interpretations of infant burial patterns. The results indicate a lack of explicit theory in most archaeological accounts and a general lack of consideration for individual variation and the process of change in mortuary practice. We outline the tenets of Bowlby's attachment theory and Stroebe and Schut's dual process model of bereavement to account theoretically for pattern, variation and change in modes of infant burial. We illustrate the value of this psychology-based perspective in an analysis of Victorian gravestone commemorations of infant burials in 35 villages in rural south Cambridgeshire, England, where individual and class-based variation, relative to falling mortality rates, is best explained as a function of coping strategies and contextually based social constraint on the overt representation of grief and loss.

Concussions carry devastating potential for cognitive, neurologic, and socio-emotional disease, but no objective test reliably identifies a concussion and its severity. A variety of neurological insults compromise sound processing, particularly in complex listening environments that place high demands on brain processing. The frequency-following response captures the high computational demands of sound processing with extreme granularity and reliably reveals individual differences. We hypothesize that concussions disrupt these auditory processes, and that the frequency-following response indicates concussion occurrence and severity. Specifically, we hypothesize that concussions disrupt the processing of the fundamental frequency, a key acoustic cue for identifying and tracking sounds and talkers, and, consequently, understanding speech in noise. Here we show that children who sustained a concussion exhibit a signature neural profile. They have worse representation of the fundamental frequency, and smaller and more sluggish neural responses. Neurophysiological responses to the fundamental frequency partially recover to control levels as concussion symptoms abate, suggesting a gain in biological processing following partial recovery. Neural processing of sound correctly identifies 90% of concussion cases and clears 95% of control cases, suggesting this approach has practical potential as a scalable biological marker for sports-related concussion and other types of mild traumatic brain injuries.

We applied the concept of source–sink dynamics to investigate a recent (1999–2013) increase in the occurrence of the siphonophore Muggiaea atlantica in Scottish coastal waters. Our aim was to determine whether this change represented the establishment of resident populations (i.e. “sources”), or transient populations reliant on immigration (i.e. “sinks”). First, we show that local production was not always sufficient to account for recruitment (a “source” prerequisite), suggesting reliance on immigration (a “sink” prerequisite). Using variation partitioning, we then discriminated between the exclusive effects of immigration [indexed by the European Slope Current (ESC)] and local production (indexed by local sea temperature and food availability). On the west coast (Loch Ewe), interannual variability in the species’ abundance was determined by, in order of increasing importance: (i) suitable local environmental conditions (13%); (ii) the role of the ESC in modulating these conditions (20%); and (iii) immigration via the ESC (29%). These results provided a strong indication that Loch Ewe represents a sink habitat for M. atlantica. However, on the east coast (Stonehaven) our results were less conclusive, probably due to the less direct influence of the ESC. For both locations, we suggest that low winter temperatures prevented overwintering, necessitating annual re-colonization via immigration.

We measured egg hatching times and stage specific naupliar development times of the key calanoid copepods Calanus helgolandicus and C. finmarchicus in response to temperature, food quantity and food type. Calanus helgolandicus development times decreased with increasing temperature and when fed Isochrysis galbana (4.4 μm ESD) rather than Prorocentrum micans (29.5 μm ESD). Nauplii needed higher food carbon concentration to develop past the first feeding stage (N3) when fed I. galbana compared with P. micans. At low food carbon concentrations nauplii developed more slowly past N3 than at more saturated levels. The survival of nauplii fed P. micans increased with temperature, but starved nauplii survival decreased at higher temperatures. We parameterized a temperature-dependent model of development for both species which fitted the observed stage durations under non-limiting food extremely well and demonstrated that C. finmarchicus develops faster than C. helgolandicus. Further data are needed to clarify the effect of food-temperature interactions on development rates.

Background Prolonged QT interval may lead to ventricular arrhythmias, torsade de pointes and sudden death. Triazole antifungals are often administered to inpatients with cardiac disease and with other QT prolonging drugs. Amiodarone is a commonly used antiarrhythmic that can prolong QT and be proarrhythmic but safety of co-administering these agents in the clinical setting is not known. Methods We conducted a retrospective, observational cohort study of adult inpatients at Duke University Medical Center who received concomitant systemic azoles and amiodarone from 2007 to 2013. Included subjects had ≥1 electrocardiogram (EKG) performed while receiving either agent alone within 1 month of starting concomitant therapy (baseline, BL) and ≥1 follow-up (FU) EKG after ≥2 days of concomitant therapy. A paired t-test was used to assess the maximum change in corrected QT interval (QTc, Bazett’s correction) from BL to FU. Logistic regression was used to evaluate predictors of FU QTc ≥500 ms (age, race, gender, and BL QTc ≥500 ms). Patient discharge diagnoses of ventricular arrhythmias or other cardiac events were reviewed to assess clinical outcome. Results Of 816 subjects identified, 252 had EKG results eligible for analysis. Azoles received were fluconazole (86.5%), voriconazole (11.5%), posaconazole (1.6%) or itraconazole (0.4%). Subjects were a median of 65 (IQR 25–88) years of age, 64.3% male and 78.6% Caucasian. Median duration of concomitant therapy was 7 days (IQR 4–11 days). Mean maximal change in QTc was +32 ms from BL (95% CI 26.2–38.6, P < 0.0001). 25.4 and 48.8% of subjects had a BL and FU QTc ≥500 ms, respectively. BL QTc ≥500 ms but not age, race, or gender was associated with FU QTc ≥500 ms (OR 6.32 95% CI 3.21–12.43). Thirty-day all-cause mortality was 26.2%. No cardiac events were apparent in relation to concomitant azole-amiodarone therapy. Conclusion Prolongation of the QTc interval was frequently observed in this cohort of patients receiving azoles and amiodarone. Clinical impact is challenging to assess in this critically ill, complex patient population but appears to be limited. Additional analyses are needed to further evaluate safety of azoles in the setting of other QTc prolonging agents. Disclosures All authors: No reported disclosures.

Cell-free transmission of the herpes-type virus of Marek's disease was obtained by demineralized water treatment of infected chick embryo fibroblasts.

The effect of adenine and its derivatives on mitotic division in plant cells has been known for a number of years (Huskins, 1948). There is also information on the effects of these compounds against at least one parasitic protozoon, Trichomonas vaginalis, (Sprince et al, 1953). The effect of adenine against the poliomyelitis virus has been described (Brown, 1952), but as far as the author is aware, the effects of this and related compounds against other obligate intracellular parasites have not been recorded.