Interleukin-21 expanded NKDC in vitro reduces the B16F10 tumor growth in vivo

AbstractInnate immunity to tumors is mediated mainly by natural killer cells (NKs) and dendritic cells (DCs). The function of these cells is coordinated by cytokines produced during the inflammatory process. NK cells are highly active against tumors, being an important source of IFN-γ. Natural killer dendritic cells (NKDCs) were recently identified as a group of hybrid cells; some studies claim that they have lytic activity, produce IFN-γ and can also stimulate antigen-specific T cells. Interleukin 21 (IL-21) regulates the proliferation capacity and cytotoxicity of NK and T cells. The main objective of this study was to investigate if IL-21 influences the frequency of NKDCs in vitro as well as IFN-γ production and also to verify if these cells could enhance the antitumor activity against B16F10 tumor model in vivo. Splenocytes from C57BL/6 mice were isolated and the DC were enriched by immunomagnetic beads and cultured for four days with recombinant IL-21 (10, 20, 40 or 100ng/ml). NKDC population was characterized as CD11clow/medB220+NK1.1+. Expanded cells were used to treat B16F10 tumor bearing mice and tumor growth was compared between the doses of IL-21 10ng/ml and 20ng/ml. The results indicate that IL-21 increases the expansion of splenic NKDCs in vitro in doses of 10ng/ml and 20ng/ml and these cells produce IFN-γ. In vivo, cells expanded with IL-21 and injected directly into the growing tumor efficiently reduced the tumor size. Together, these results showed for the first time that IL-21 influences the biology and the effector activity of NKDCs

Significance of K-Ar dating of very low-grade metamorphism in Triassic-Jurassic pelites from the Coastal Range of central Chile

El artículo original ha sido publicado por la Mineralogical Society disponible en: http://www.minersoc.org/pages/e_journals/clay.htmlK-Ar isotopic dating of very low-grade metamorphism affecting Triassic-Jurassic rocks in the Coastal Range of central Chile was carried out on whole rocks and their <2 mm size fractions. In the study area, a regional-burial low-grade metamorphism at anchizone conditions (T ≤ 190ºC) and low-pressure conditions (P ≥1.3 kbar) has been described. Observed temperatures are related to a contact metamorphism produced by nearby Jurassic intrusions, with a P-T estimate at the immediate contact zone of ~650-690ºC and 4 kbar. The whole-rock K-Ar age of 174?5 Ma is interpreted as belonging to the contact metamorphism due to the intrusion of Jurassic plutons (165±5 Ma to 175±5 Ma). A time-interval of ~20 Ma between the diagenesis (206 Ma) and the anchizonal very low-grade metamorphism (181-184 Ma) is obtained, and a rate of subsidence of ~120 m/Ma is proposed for these Triassic-Jurassic basins. A thermal influence on the burial, very low-grade, regional metamorphism is invoked.Departamento de Mineralogía y Petrologí

The anti-inflammatory mechanisms of Hsp70

Immune responses to heat shock proteins (Hsp) develop in virtually all inflammatory diseases; however, the significance of such responses is only now becoming clear. In experimental disease models, Hsp administration can prevent or arrest inflammatory damage, and in initial clinical trials in patients with chronic inflammatory diseases, Hsp peptides have been shown to promote the production of anti-inflammatory cytokines, indicating immunoregulatory potential of Hsp. Therefore, the presence of immune responses to Hsp in inflammatory diseases can be seen as an attempt of the immune system to correct the inflammatory condition. Hsp70 can modulate inflammatory responses in models of arthritis, colitis and graft rejection, and the mechanisms underlying this effect are now being elucidated. Incubation with microbial Hsp70 was seen to induce tolerogenic dendritic cells (DCs) and to promote a suppressive phenotype in myeloid-derived suppressor cells and monocytes. These DC could induce regulatory T cells (Tregs), independently of the antigens they presented. Some Hsp70 family members are associated with autophagy, leading to a preferential uploading of Hsp70 peptides in MHC class II molecules of stressed cells. Henceforth, conserved Hsp70 peptides may be presented in these situations and constitute targets of Tregs, contributing to downregulation of inflammation. Finally, an interfering effect in multiple intracellular inflammatory signaling pathways is also known for Hsp70. Altogether it seems attractive to use Hsp70, or its derivative peptides, for modulation of inflammation. This is a physiological immunotherapy approach, without the immediate necessity of defining disease-specific auto-antigens. In this article, we present the evidence on anti-inflammatory effects of Hsp70 and discuss the need for experiments that will be crucial for the further exploration of the immunosuppressive potential of this protein

O teste do anti-HSP70 na investigação da etiologia auto-imune da Doença de Ménière

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Distribution of Temperature and Strength in the Central Andean Lithosphere and Its Relationship to Seismicity and Active Deformation

We present three-dimensional (3D) models of the present-day steady-state conductive thermal field and strength distribution in the lithosphere beneath the Central Andes. Our primary objective was to investigate the influence that the structure of the Central Andean lithosphere has on its thermal and rheological state, and the relationship between the latter and the active deformation in the region. We used our previous data-driven and gravity-constrained 3D density model as starting point for the calculations. We first assigned lithology-derived thermal and rheological properties to the different divisions of the density model and defined temperature boundary conditions. We then calculated the 3D steady-state conductive thermal field and the maximum differential stresses for both brittle and ductile behaviors. We find that the thickness and composition of the crust are the main factors affecting the modeled thermal field, and consequently also the strength distribution. The orogen is characterized by a thick felsic crust with elevated temperatures and a low integrated strength, whereas the foreland and forearc are underlain by a more mafic and thinner crust with lower temperatures and a higher integrated strength. We find that most of the intraplate deformation coincides spatially with the steepest strength gradients and suggest that the high potential energy of the orogen together with the presence of rheological lateral heterogeneities produce high compressional stresses and strong strain localization along the margins of the orogen. We interpret earthquakes within the modeled ductile field to be related to the weakening effect of long-lived faults and/or the presence of seismic asperities.Fil: Ibarra, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Prezzi, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Bott, Judith. German Research Centre for Geosciences; AlemaniaFil: Scheck Wenderoth, Magdalena. German Research Centre for Geosciences; AlemaniaFil: Strecker, Manfred. Universitat Potsdam; Alemani

A Color-Coded Tape for Uterine Height Measurement: A Tool to Identify Preterm Pregnancies in Low Resource Settings

Introduction Neonatal mortality associated with preterm birth can be reduced with antenatal corticosteroids (ACS), yet <10% of eligible pregnant women in low-middle income countries. The inability to accurately determine gestational age (GA) leads to under-identification of high-risk women who could receive ACS or other interventions. To facilitate better identification in low-resource settings, we developed a color-coded tape for uterine height (UH) measurement and estimated its accuracy identifying preterm pregnancies. Methods We designed a series of colored-coded tapes with segments corresponding to UH measurements for 20–23.6 weeks, 24.0–35.6 weeks, and >36.0 weeks GA. In phase 1, UH measurements were collected prospectively in the Democratic Republic of Congo, India and Pakistan, using distinct tapes to address variation across regions and ethnicities. In phase 2, we tested accuracy in 250 pregnant women with known GA from early ultrasound enrolled at prenatal clinics in Argentina, India, Pakistan and Zambia. Providers masked to the ultrasound GA measured UH. Receiver operating characteristics (ROC) analysis was conducted. Results 1,029 pregnant women were enrolled. In all countries the tapes were most effective identifying pregnancies between 20.0–35.6 weeks, compared to the other GAs. The ROC areas under the curves and 95% confidence intervals were: Argentina 0.69 (0.63, 0.74); Zambia 0.72 (0.66, 0.78), India 0.84 (0.80, 0.89), and Pakistan 0.83 (0.78, 0.87). The sensitivity and specificity (and 95% confidence intervals) for identifying pregnancies between 20.0–35.6 weeks, respectively, were: Argentina 87% (82%–92%) and 51% (42%–61%); Zambia 91% (86%–95%) and 50% (40%–60%); India 78% (71%–85%) and 89% (83%–94%); Pakistan 63% (55%–70%) and 94% (89%–99%). Conclusions We observed moderate-good accuracy identifying pregnancies ≤35.6 weeks gestation, with potential usefulness at the community level in low-middle income countries to facilitate the preterm identification and interventions to reduce preterm neonatal mortality. Further research is needed to validate these findings on a population basis

Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention

Etiological factors in primary hepatic B-cell lymphoma

Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (p < 0.01 for both). Two hepatic DLBCL cases (16.7%) had rheumatoid arthritis treated with methotrexate, and four MALT lymphoma cases (50%) had Sjögren’s syndrome, primary biliary cirrhosis, or autoimmune hepatitis; one case in each of these two groups was complicated by chronic HCV-seropositive hepatitis. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play independent roles in the lymphomagenesis of hepatic B cells