Adaptive immunity in cancer immunology and therapeutics.

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune checkpoint proteins, by tumours, which induces a form of self-tolerance. The majority of monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity

Law-Based Arguments and Messages to Advocate for Later School Start Time Policies in the United States

The increasing scientific evidence that early school start times are harmful to the health and safety of teenagers has generated much recent debate about changing school start times policies for adolescent students. Although efforts to promote and implement such changes have proliferated in the United States in recent years, they have rarely been supported by law-based arguments and messages that leverage the existing legal infrastructure regulating public education and child welfare in the United States. Furthermore, the legal bases to support or resist such changes have not been explored in detail to date. This article provides an overview of how law-based arguments and messages can be constructed and applied to advocate for later school start time policies in U.S. public secondary schools. The legal infrastructure impacting school start time policies in the United States is briefly reviewed, including descriptions of how government regulates education, what legal obligations school officials have concerning their students\u27 welfare, and what laws and public policies currently exist that address adolescent sleep health and safety. On the basis of this legal infrastructure, some hypothetical examples of law-based arguments and messages that could be applied to various types of advocacy activities (e.g., litigation, legislative and administrative advocacy, media and public outreach) to promote later school start times are discussed. Particular consideration is given to hypothetical arguments and messages aimed at emphasizing the consistency of later school start time policies with existing child welfare law and practices, legal responsibilities of school officials and governmental authorities, and societal values and norms

Crossing the race divide : interracial sex in antebellum Savannah

This article explores the social significance of inter-racial sexual contact in an antebellum Southern city. How did inter-racial sex challenge the established social hierarchy in Savannah? Was it a controversial issue, viewed as a threat to the social order, or was it accepted as an inevitable evil resulting from a mixed population residing in close proximity

Digit-only sauropod pes trackways from China - evidence of swimming or a preservational phenomenon?

For more than 70 years unusual sauropod trackways have played a pivotal role in debates about the swimming ability of sauropods. Most claims that sauropods could swim have been based on manus-only or manus-dominated trackways. However none of these incomplete trackways has been entirely convincing, and most have proved to be taphonomic artifacts, either undertracks or the result of differential depth of penetration of manus and pes tracks, but otherwise showed the typical pattern of normal walking trackways. Here we report an assemblage of unusual sauropod tracks from the Lower Cretaceous Hekou Group of Gansu Province, northern China, characterized by the preservation of only the pes claw traces, that we interpret as having been left by walking, not buoyant or swimming, individuals. They are interpreted as the result of animals moving on a soft mud-silt substrate, projecting their claws deeply to register their traces on an underlying sand layer where they gained more grip during progression. Other sauropod walking trackways on the same surface with both pes and manus traces preserved, were probably left earlier on relatively firm substrates that predated the deposition of soft mud and silt . Presently, there is no convincing evidence of swimming sauropods from their trackways, which is not to say that sauropods did not swim at all

Communication practices of the Karen in Sheffield: Seeking to navigate their three zones of displacement

This study investigates communication practices of a newly arrived Karen refugee community in the UK who, as well as establishing themselves in a strange country, seek to keep in touch, campaign politically and maintain identity collectively through communication and contact with their global diaspora. We look at the technologies, motivations and inhibiting factors applying to the communication by adult members of this community and construct the idea of three zones of displacement which help to model the particular contexts, challenges and methods of their communication. We find that overall, they are using a wide range of internet-based technologies, with the aim to 'keep-in-touch' (personal contacts) and to 'spread the word' (political communication). This also includes archaic, traditional and hybrid methods to achieve extended communication with contacts in other 'zones'. We also identify the importance of the notion of ‘village’ as metaphor and entity in their conceptualisation of diasporic and local community cohesion. We identify the key inhibitors to their communication as cost, education, literacy and age. Finally, we speculate on the uncertain outcomes of their approach to digital media in achieving their political aims

Implementing a 48 h EWTD-compliant rota for junior doctors in the UK does not compromise patients’ safety : assessor-blind pilot comparison

Background: There are currently no field data about the effect of implementing European Working Time Directive (EWTD)-compliant rotas in a medical setting. Surveys of doctors’ subjective opinions on shift work have not provided reliable objective data with which to evaluate its efficacy. Aim: We therefore studied the effects on patient's safety and doctors’ work-sleep patterns of implementing an EWTD-compliant 48 h work week in a single-blind intervention study carried out over a 12-week period at the University Hospitals Coventry & Warwickshire NHS Trust. We hypothesized that medical error rates would be reduced following the new rota. Methods: Nineteen junior doctors, nine studied while working an intervention schedule of <48 h per week and 10 studied while working traditional weeks of <56 h scheduled hours in medical wards. Work hours and sleep duration were recorded daily. Rate of medical errors (per 1000 patient-days), identified using an established active surveillance methodology, were compared for the Intervention and Traditional wards. Two senior physicians blinded to rota independently rated all suspected errors. Results: Average scheduled work hours were significantly lower on the intervention schedule [43.2 (SD 7.7) (range 26.0–60.0) vs. 52.4 (11.2) (30.0–77.0) h/week; P < 0.001], and there was a non-significant trend for increased total sleep time per day [7.26 (0.36) vs. 6.75 (0.40) h; P = 0.095]. During a total of 4782 patient-days involving 481 admissions, 32.7% fewer total medical errors occurred during the intervention than during the traditional rota (27.6 vs. 41.0 per 1000 patient-days, P = 0.006), including 82.6% fewer intercepted potential adverse events (1.2 vs. 6.9 per 1000 patient-days, P = 0.002) and 31.4% fewer non-intercepted potential adverse events (16.6 vs. 24.2 per 1000 patient-days, P = 0.067). Doctors reported worse educational opportunities on the intervention rota. Conclusions: Whilst concerns remain regarding reduced educational opportunities, our study supports the hypothesis that a 48 h work week coupled with targeted efforts to improve sleep hygiene improves patient safety

Randomized trial of polychromatic blue-enriched light for circadian phase shifting, melatonin suppression, and alerting responses.

Wavelength comparisons have indicated that circadian phase-shifting and enhancement of subjective and EEG-correlates of alertness have a higher sensitivity to short wavelength visible light. The aim of the current study was to test whether polychromatic light enriched in the blue portion of the spectrum (17,000 K) has increased efficacy for melatonin suppression, circadian phase-shifting, and alertness as compared to an equal photon density exposure to a standard white polychromatic light (4000 K). Twenty healthy participants were studied in a time-free environment for 7 days. The protocol included two baseline days followed by a 26-h constant routine (CR1) to assess initial circadian phase. Following CR1, participants were exposed to a full-field fluorescent light (1 × 10 14 photons/cm 2 /s, 4000 K or 17,000 K, n = 10/condition) for 6.5 h during the biological night. Following an 8 h recovery sleep, a second 30-h CR was performed. Melatonin suppression was assessed from the difference during the light exposure and the corresponding clock time 24 h earlier during CR1. Phase-shifts were calculated from the clock time difference in dim light melatonin onset time (DLMO) between CR1 and CR2. Blue-enriched light caused significantly greater suppression of melatonin than standard light ((mean ± SD) 70.9 ± 19.6% and 42.8 ± 29.1%, respectively, p \u3c 0.05). There was no significant difference in the magnitude of phase delay shifts. Blue-enriched light significantly improved subjective alertness (p \u3c 0.05) but no differences were found for objective alertness. These data contribute to the optimization of the short wavelength-enriched spectra and intensities needed for circadian, neuroendocrine and neurobehavioral regulation

A Diverse Mammal-Dominated, Footprint Assemblage from Wetland Deposits in the Lower Cretaceous of Maryland

A newly discovered assemblage of predominantly small tracks from the Cretaceous Patuxent Formation at NASAs Goddard Space Flight Center, Maryland, reveals one of the highest track densities and diversities ever reported (~70 tracks, representing at least eight morphotypes from an area of only ~2m(exp 2)). The assemblage is dominated by small mammal tracks including the new ichnotxon Sederipes goddardensis, indicating sitting postures. Small crow-sized theropod trackways, the first from this unit, indicate social trackmakers and suggest slow-paced foraging behavior. Tracks of pterosaurs, and other small vertebrates suggest activity on an organic-rich substrate. Large well-preserved sauropod and nodosaurs tracks indicate the presence of large dinosaurs. The Patuxent Formation together with the recently reported Angolan assemblage comprise the worlds two largest Mesozoic mammal footprint assemblages. The high density of footprint registration at the NASA site indicates special preservational and taphonomic conditions. These include early, penecontemporaneous deposition of siderite in organic rich, reducing wetland settings where even the flesh of body fossils can be mummified. Thus, the track-rich ironstone substrates of the Patuxent Formation, appear to preserve a unique vertebrate ichnofacies, with associated, exceptionally-preserved body fossil remains for which there are currently no other similar examples preserved in the fossil record

The peritoneal tumour microenvironment of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3(+) T cells and CD68(+) macrophages, with occasional neutrophils. Alpha-smooth muscle actin(+) (α-SMA(+) ) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6-48 h) with an extensive CD45(+) leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3(+) T lymphocytes and CD68(+) macrophages with α-SMA(+) cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2-3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease

Interventions to reduce suicides at suicide hotspots: a systematic review

Background: 'Suicide hotspots' include tall structures (for example, bridges and cliffs), railway tracks, and isolated locations (for example, rural car parks) which offer direct means for suicide or seclusion that prevents intervention. Methods. We searched Medline for studies that could inform the following question: 'What interventions are available to reduce suicides at hotspots, and are they effective?'. Results: There are four main approaches: (a) restricting access to means (through installation of physical barriers); (b) encouraging help-seeking (by placement of signs and telephones); (c) increasing the likelihood of intervention by a third party (through surveillance and staff training); and (d) encouraging responsible media reporting of suicide (through guidelines for journalists). There is relatively strong evidence that reducing access to means can avert suicides at hotspots without substitution effects. The evidence is weaker for the other approaches, although they show promise. Conclusions: More well-designed intervention studies are needed to strengthen this evidence base. © 2013 Cox et al.; licensee BioMed Central Ltd.published_or_final_versio