Cancer testis antigen and interleukin expression correlates with survival in small bowel neuroendocrine tumors

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Movement and Fluctuations of the Vacuum

Quantum fields possess zero-point or vacuum fluctuations which induce mechanical effects, namely generalised Casimir forces, on any scatterer. Symmetries of vacuum therefore raise fundamental questions when confronted with the principle of relativity of motion in vacuum. The specific case of uniformly accelerated motion is particularly interesting, in connection with the much debated question of the appearance of vacuum in accelerated frames. The choice of Rindler representation, commonly used in General Relativity, transforms vacuum fluctuations into thermal fluctuations, raising difficulties of interpretation. In contrast, the conformal representation of uniformly accelerated frames fits the symmetry properties of field propagation and quantum vacuum and thus leads to extend the principle of relativity of motion to uniform accelerations. Mirrors moving in vacuum with a non uniform acceleration are known to radiate. The associated radiation reaction force is directly connected to fluctuating forces felt by motionless mirrors through fluctuation-dissipation relations. Scatterers in vacuum undergo a quantum Brownian motion which describes irreducible quantum fluctuations. Vacuum fluctuations impose ultimate limitations on measurements of position in space-time, and thus challenge the very concept of space-time localisation within a quantum framework. For test masses greater than Planck mass, the ultimate limit in localisation is determined by gravitational vacuum fluctuations. Not only positions in space-time, but also geodesic distances, behave as quantum variables, reflecting the necessary quantum nature of an underlying geometry.Comment: 17 pages, to appear in Reports on Progress in Physic

The AFHSC-Division of GEIS Operations Predictive Surveillance Program: a multidisciplinary approach for the early detection and response to disease outbreaks

The Armed Forces Health Surveillance Center, Division of Global Emerging Infections Surveillance and Response System Operations (AFHSC-GEIS) initiated a coordinated, multidisciplinary program to link data sets and information derived from eco-climatic remote sensing activities, ecologic niche modeling, arthropod vector, animal disease-host/reservoir, and human disease surveillance for febrile illnesses, into a predictive surveillance program that generates advisories and alerts on emerging infectious disease outbreaks. The program’s ultimate goal is pro-active public health practice through pre-event preparedness, prevention and control, and response decision-making and prioritization. This multidisciplinary program is rooted in over 10 years experience in predictive surveillance for Rift Valley fever outbreaks in Eastern Africa. The AFHSC-GEIS Rift Valley fever project is based on the identification and use of disease-emergence critical detection points as reliable signals for increased outbreak risk. The AFHSC-GEIS predictive surveillance program has formalized the Rift Valley fever project into a structured template for extending predictive surveillance capability to other Department of Defense (DoD)-priority vector- and water-borne, and zoonotic diseases and geographic areas. These include leishmaniasis, malaria, and Crimea-Congo and other viral hemorrhagic fevers in Central Asia and Africa, dengue fever in Asia and the Americas, Japanese encephalitis (JE) and chikungunya fever in Asia, and rickettsial and other tick-borne infections in the U.S., Africa and Asia

Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells

In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12 The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further investigations identified multiple barriers to successful engraftment, including lack of space within the hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment, differentiation, and systemic repopulation after IUHCT

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

Malaria and other vector-borne infection surveillance in the U.S. Department of Defense Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance program: review of 2009 accomplishments

Vector-borne infections (VBI) are defined as infectious diseases transmitted by the bite or mechanical transfer of arthropod vectors. They constitute a significant proportion of the global infectious disease burden. United States (U.S.) Department of Defense (DoD) personnel are especially vulnerable to VBIs due to occupational contact with arthropod vectors, immunological naiveté to previously unencountered pathogens, and limited diagnostic and treatment options available in the austere and unstable environments sometimes associated with military operations. In addition to the risk uniquely encountered by military populations, other factors have driven the worldwide emergence of VBIs. Unprecedented levels of global travel, tourism and trade, and blurred lines of demarcation between zoonotic VBI reservoirs and human populations increase vector exposure. Urban growth in previously undeveloped regions and perturbations in global weather patterns also contribute to the rise of VBIs. The Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) and its partners at DoD overseas laboratories form a network to better characterize the nature, emergence and growth of VBIs globally. In 2009 the network tested 19,730 specimens from 25 sites for Plasmodium species and malaria drug resistance phenotypes and nearly another 10,000 samples to determine the etiologies of non-Plasmodium species VBIs from regions spanning from Oceania to Africa, South America, and northeast, south and Southeast Asia. This review describes recent VBI-related epidemiological studies conducted by AFHSC-GEIS partner laboratories within the OCONUS DoD laboratory network emphasizing their impact on human populations

Interstellar Grains -- The 75th Anniversary

The year of 2005 marks the 75th anniversary since Trumpler (1930) provided the first definitive proof of interstellar grains by demonstrating the existence of general absorption and reddening of starlight in the galactic plane. This article reviews our progressive understanding of the nature of interstellar dust.Comment: invited review article for the "Light, Dust and Chemical Evolution" conference (Gerace, Italy, 26--30 September 2004), edited by F. Borghese and R. Saija, 2005, in pres

Bayesian Action–Perception Computational Model: Interaction of Production and Recognition of Cursive Letters

In this paper, we study the collaboration of perception and action representations involved in cursive letter recognition and production. We propose a mathematical formulation for the whole perception–action loop, based on probabilistic modeling and Bayesian inference, which we call the Bayesian Action–Perception (BAP) model. Being a model of both perception and action processes, the purpose of this model is to study the interaction of these processes. More precisely, the model includes a feedback loop from motor production, which implements an internal simulation of movement. Motor knowledge can therefore be involved during perception tasks. In this paper, we formally define the BAP model and show how it solves the following six varied cognitive tasks using Bayesian inference: i) letter recognition (purely sensory), ii) writer recognition, iii) letter production (with different effectors), iv) copying of trajectories, v) copying of letters, and vi) letter recognition (with internal simulation of movements). We present computer simulations of each of these cognitive tasks, and discuss experimental predictions and theoretical developments

Current assessment of the Red Rectangle band problem

In this paper we discuss our insights into several key problems in the identification of the Red Rectangle Bands (RRBs). We have combined three independent sets of observations in order to try to define the constraints guiding the bands. We provide a summary of the general behavior of the bands and review the evidence for a molecular origin of the bands. The extent, composition, and possible absorption effects of the bands are discussed. Comparison spectra of the strongest band obtained at three different spectral resolutions suggests that an intrinsic line width of individual rotational lines can be deduced. Spectroscopic models of several relatively simple molecules were examined in order to investigate where the current data are weak. Suggestions are made for future studies to enhance our understanding of these enigmatic bands

What works for whom in the management of diabetes in people living with dementia: a realist review

Background Dementia and diabetes mellitus are common long-term conditions and co-exist in a large number of older people. People living with dementia (PLWD) may be less able to manage their diabetes, putting them at increased risk of complications such as hypoglycaemia. The aim of this review was to identify key mechanisms within different interventions that are likely to improve diabetes outcomes in PLWD. Methods This is a realist review involving scoping of the literature and stakeholder interviews to develop theoretical explanations of how interventions might work, systematic searches of the evidence to test and develop the theories and their validation with a purposive sample of stakeholders. Twenty-six stakeholders — user/patient representatives, dementia care providers, clinicians specialising in diabetes or dementia and researchers — took part in interviews, and 24 participated in a consensus conference. Results We included 89 papers. Ten focused on PLWD and diabetes, and the remainder related to people with either dementia, diabetes or other long-term conditions. We identified six context-mechanism-outcome configurations which provide an explanatory account of how interventions might work to improve the management of diabetes in PLWD. This includes embedding positive attitudes towards PLWD, person-centred approaches to care planning, developing skills to provide tailored and flexible care, regular contact, family engagement and usability of assistive devices. An overarching contingency emerged concerning the synergy between an intervention strategy, the dementia trajectory and social and environmental factors, especially family involvement. Conclusions Evidence highlighted the need for personalised care, continuity and family-centred approaches, although there was limited evidence that this happens routinely. This review suggests there is a need for a flexible service model that prioritises quality of life, independence and patient and carer priorities. Future research on the management of diabetes in older people with complex health needs, including those with dementia, needs to look at how organisational structures and workforce development can be better aligned to their needs. Trial registration PROSPERO, CRD42015020625. Registered on 18 May 2015