Severe and Persistent Depletion of Circulating Plasmacytoid Dendritic Cells in Patients with 2009 Pandemic H1N1 Infection

Background: Dysregulation of host immune responses plays a critical role in the pathogenesis of severe 2009 pandemic H1N1 infection. Whether H1N1 virus could escape innate immune defense in vivo remains to be investigated. The aim of this study was to evaluate the pattern of innate immune response during human 2009 H1N1 infection. We performed the enumeration of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) in blood from patients with H1N1 pneumonia shortly after the onset of symptoms and during follow-up at different intervals of time. The analysis of CD4 and CD8 count, CD38 T-cell activation marker and serum cytokine/chemokine plasma levels was also done. Methodology/Principal Findings: Blood samples were collected from 13 hospitalized patients with confirmed H1N1-related pneumonia at time of admission and at weeks 1, 4, and 16 of follow-up. 13 healthy donors were enrolled as controls. In the acute phase of the disease, H1N1-infected patients exhibited a significant depletion in both circulating pDC and mDC in conjunction with a decrease of CD4 and CD8 T cell count. In addition, we found plasmatic hyperproduction of IP-10 and RANTES, whereas increase in T-cell immune activation was found at all time points. When we assessed the changes in DC count over time, we observed a progressive normalization of mDC number. On the contrary, H1N1-infected patients did not achieve a complete recovery of pDC count as values remained lower than healthy controls even after 16 weeks of follow-up. Conclusions: H1N1 disease is associated with a profound depletion of DC subsets. The persistence of pDC deficit for several weeks after disease recovery could be due to H1N1 virus itself or to a preexisting impairment of innate immunity

The insulin-like growth factor system is modulated by exercise in breast cancer survivors: a systematic review and meta-analysis

Abbreviations: CI, Confidence interval; ELISA, Enzyme-linked immunosorbent assay; IGF, Insulin-like growth factors; IGFBP, Insulin-like growth factor binding protein; MD, Mean difference; PEDro, Physiotherapy evidence database; RCT, Randomized controlled trials; SD, Standard deviation.Background: Insulin-like growth factors (IGF´s) play a crucial role in controlling cancer cell proliferation, differentiation and apoptosis. Exercise has been postulated as an effective intervention in improving cancerrelated outcomes and survival, although its effects on IGF´s are not well understood. This meta-analysis aimed to determine the effects of exercise in modulating IGF´s system in breast cancer survivors. Methods: Databases of PuMed, EMBASE, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials. gov, SPORTDiscus, LILACS and Scopus were systematically searched up to November 2014. Effect estimates were calculated through a random-effects model of meta-analysis according to the DerSimonian and Laird method. Heterogeneity was evaluated with the I2 test. Risk of bias and methodological quality were evaluated using the PEDro score. Results: Five randomized controlled trials (n = 235) were included. Most women were post-menopausal. Highquality and low risk of bias were found (mean PEDro score = 6.2 ± 1). Exercise resulted in significant improvements on IGF-I, IGF-II, IGFBP-I, IGFBP-3, Insulin and Insulin resistance (P < 0.05). Non-significant differences were found for Glucose. Aerobic exercise improved IGF-I, IGFBP-3 and Insulin. No evidence of publication bias was detected by Egger´s test (p = 0.12). Conclusions: Exercise improved IGF´s in breast cancer survivors. These findings provide novel insight regarding the molecular effects of exercise on tumoral microenvironment, apoptosis and survival in breast cancer survivors

Analysis of the effect of locally applied inhomogeneous static magnetic field-exposure on mouse ear edema - a double blind study

The effect static magnetic field (SMF)-exposure may exert on edema development has been investigated. A 6 h long whole-body (WBSMF) or local (LSMF), continuous, inhomogeneous SMF-exposure was applied on anesthetized mice in an in vivo model of mustard oil (MO)-induced ear edema. LSMF was applied below the treated ear, below the lumbar spine, or below the mandible. Ear thickness (v) was checked 8 times during the exposure period (at 0, 0.25, 1, 2, 3, 4, 5, and 6 h). The effect size of the applied treatment (eta) on ear thickness was calculated by the formula eta = 100% x (1-vj/vi), where group i is the control group and j is the treated group. Results showed that MO treatment in itself induced a significant ear edema with an effect of 9% (p11% in both cases compared to SMF-exposure alone (p<0.001). In these cases SMF-exposure alone without MO treatment reduced ear thickness significantly (p<0.05), but within estimated experimental error. In cases of LSMF-exposure on the head, a significant SMF-exposure induced ear thickness reduction was found (eta = 5%, p<0.05). LSMF-exposure on the spine affected ear thickness with and without MO treatment almost identically, which provides evidence that the place of local SMF action may be in the lower spinal region

Eficácia do exercício físico na fadiga dos pacientes com câncer durante o tratamento ativo: revisão sistemática e meta-análise

El objetivo del estudio fue determinar la efectividad del ejercicio físico en la fatiga de pacientes con cáncer durante el tratamiento activo. Las bases de datos de PubMed Central, EMBASE y OVID fueron consultadas hasta abril de 2014 para identificar ensayos clínicos aleatorizados, que evaluaran el efecto del ejercicio en la fatiga de pacientes con cáncer sometidos a tratamiento activo. Once estudios (n = 1.407) fueron incluidos. La quimioterapia fue el tratamiento más común (n = 1.028). Los estudios tuvieron bajo riesgo de sesgo y alta calidad metodológica. Las estimaciones de efecto mostraron que el ejercicio físico mejoró significativamente la fatiga (SMD = -3,0; IC95%: -5,21; -0,80), p < 0,0001. Se encontraron efectos similares para el entrenamiento de resistencia (SMD = -4,5; IC95%: -7,24; -1,82), p = 0,001. Se encontraron mejoras significativas en pacientes con cáncer de mama y de próstata (p < 0,05). El ejercicio es una intervención segura y eficaz en el control de la fatiga en pacientes sometidos a tratamiento activoThis study aimed to determine the effectiveness of physical exercise in decreasing fatigue in cancer patients during active treatment. The PubMed Central, EMBASE, and OVID databases were consulted up to April 2014 to identify randomized clinical trials that evaluated the effect of exercise on fatigue in cancer patients undergoing active treatment. Eleven studies (n = 1,407) were included. Chemotherapy was the most common form of treatment (n = 1,028). The studies showed a low risk of bias and high methodological quality. Effect estimates showed that physical exercise significantly improved fatigue (SMD = -3.0; 95%CI: -5.21; -0.80), p < 0.0001. Similar effects were found for resistance training (SMD = -4.5; 95%CI: -7.24; -1.82), p = 0.001. Significant improvements were found in breast and prostate cancer patients (p < 0.05). Exercise is a safe and effective intervention in the management fatigue in cancer patients undergoing active treatmentO objetivo foi determinar a efetividade do exercício físico sobre a fadiga em pacientes com câncer durante o tratamento ativo. As bases de dados PubMed Central, EMBASE e OVID foram consultadas até abril de 2014 para identificar ensaios clínicos randomizados que avaliaram o efeito do exercício sobre a fadiga em pacientes com câncer em tratamento ativo. Onze estudos (n = 1.407) foram incluídos. A quimioterapia foi o tratamento mais comum (n = 1.028). Os estudos tiveram baixo risco de viés e alta qualidade metodológica. As estimativas de efeito mostraram que o exercício melhorou significativamente a fadiga (DMP = -3,0; IC95%: -5,21; -0,80), p < 0,0001. Efeitos semelhantes sobre o treinamento de resistência (DMP = -4,5; IC95%: -7,24; -1,82), p = 0,001 foram encontrados. O exercício físico é uma intervenção segura e eficaz contra a fadiga em pacientes submetidos ao tratamento ativoEl presente trabajo forma parte del Proyecto Práctica del autoexamen de seno y los conocimientos, factores de riesgo y estilos de vida relacionados con el cáncer de mama en mujeres jóvenes de la Universidad Santo Tomás de Bogotá: un análisis transversal (9ª Convocatoria FODEIN- Código del proyecto 4110060001 - 008)

Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 channels

TRPA1 is a Ca2+-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca2+, with low Ca2+ potentiating and high Ca2+ inactivating TRPA1. However, it remains unknown how Ca2+ exerts such contrasting effects. Here, we show that Ca2+ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca2+-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca2+-evoked potentiation of TRPA1 at low Ca2+, but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca2+. Ca2+-dependent potentiation and inactivation of TRPA1 were selectively prevented by disrupting the interaction of the carboxy-lobe of calmodulin with a calmodulin-binding domain in the C-terminus of TRPA1. Calmodulin is thus a critical Ca2+ sensor enabling TRPA1 to respond to diverse Ca2+ signals distinctly

TRPA1 Is a Polyunsaturated Fatty Acid Sensor in Mammals

Fatty acids can act as important signaling molecules regulating diverse physiological processes. Our understanding, however, of fatty acid signaling mechanisms and receptor targets remains incomplete. Here we show that Transient Receptor Potential Ankyrin 1 (TRPA1), a cation channel expressed in sensory neurons and gut tissues, functions as a sensor of polyunsaturated fatty acids (PUFAs) in vitro and in vivo. PUFAs, containing at least 18 carbon atoms and three unsaturated bonds, activate TRPA1 to excite primary sensory neurons and enteroendocrine cells. Moreover, behavioral aversion to PUFAs is absent in TRPA1-null mice. Further, sustained or repeated agonism with PUFAs leads to TRPA1 desensitization. PUFAs activate TRPA1 non-covalently and independently of known ligand binding domains located in the N-terminus and 5th transmembrane region. PUFA sensitivity is restricted to mammalian (rodent and human) TRPA1 channels, as the drosophila and zebrafish TRPA1 orthologs do not respond to DHA. We propose that PUFA-sensing by mammalian TRPA1 may regulate pain and gastrointestinal functions

Hitting Hotspots: Spatial Targeting of Malaria for Control and Elimination

Teun Bousema and colleagues argue that targeting malaria “hotspots” is a highly efficient way to reduce malaria transmission at all levels of transmission intensity

Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza

<p>Abstract</p> <p>Background</p> <p>Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients.</p> <p>Methods</p> <p>Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient.</p> <p>Results</p> <p>Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1β, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus.</p> <p>Conclusions</p> <p>Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.</p

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC