Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by ...Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.
Abstract Background Elevated COX-2 expression has been correlated with inferior outcome in NSCLC. COX-2 catalyzes the transformation of arachidonate to PGE2 . We and others have demonstrated that ...PGE2 induces proliferation and metastatic spread and immunosuppression through the G protein-coupled EP4 receptor. We hypothesized that EP4 expression on malignant cells would correlate with outcome and patterns of relapse after treatment of LANSCLC stage IIIA (7th edition, N2+). Methods Tissue specimens from 41 pts treated for LANSC at UMGCC were obtained. A tissue microarray was prepared and examined for EP4 expression. Intensity of staining was scored semi-quantitatively as 0–4 in both the nuclear and cytoplasmic compartments by a pathologist blinded to the clinical data. Results EP4 nuclear staining 0–1 vs. 2+ was associated with overall survival, (OS) (44.3 vs. 18 mo; HR = 0.41, p = 0.024) and numerically superior progression free survival (PFS) (16.4 vs. 10.2 mo, p =0.16). EP4 cytoplasmic staining did not correlate with OS (0–1 vs. 2+, 23.8 vs. 28.8 mo; HR = 1.2, p = 0.81). Relapse pattern (no relapse or local vs. systemic) did not correlate with EP nuclear staining (p = 1.0, X2 ). Conclusions This is the first clinical study of EP4 expression in lung cancer. There was a significant correlation between OS and nuclear EP4 expression, indicating that this is a potential therapeutic target. Studies with AT-007, a specific inhibitor of EP4, are planned to commence this year.
Reaction of bauxite residue with seawater results in neutralization of alkalinity through precipitation of Mg-, Ca-, and Al-hydroxide and carbonate minerals. In batch studies, the initial pH ...neutralization reaction was rapid (<5 min), with further reaction continuing to reduce pH for several weeks. Reaction with seawater produced a residue pH of 8 to 8.5. Laboratory leaching column studies were undertaken to provide information on seawater neutralization of the coarse-textured fraction of the waste, residue sand (RS), under conditions comparable with those that might be applied in the field. An 0.80-m-deep column of RS was neutralized by the application of the equivalent of 2-m depth of seawater. In addition to lowering the pH and Na content of the residue, seawater neutralization resulted in the addition of substantial amounts of the plant nutrients Ca, Mg, and K to the profile. Similar results were also obtained from a field-scale assessment of neutralization. However, the accumulation of precipitate, consisting of hydrotalcite, aragonite, and pyroaurite, in the drainage system may preclude the use of in situ seawater neutralization as a routine rehabilitation practice. Following seawater neutralization, RS remains too saline to support plant growth and would require fresh water leaching before revegetation.
Abstract
In Smith et al. we published estimates of the volumetric rate of supernovae within 100 Mpc. These were incorrect and we present the correct values in this corrigendum.
High salinities and high temperatures at the seafloor record the upward flow of water and hydrocarbons from depth at natural vents in the deepwater Gulf of Mexico. We present a multiphase heat- and ...solute-transport model, in which water supplied from depth transports heat and salt, and hydrocarbon transports heat. We show that there is a unique water and hydrocarbon flux that simulates the observed salinity and temperature. We estimate the hydrocarbon flux to be 3.2–15×104 tyr−1 and 1.8–8.0×104 tyr−1 from two vents at lease blocks MC852/853 and GB425. These fluxes are 1–4 orders of magnitude greater than previous estimates from individual deepwater vents. If these results are extrapolated to the entire Gulf of Mexico, then we estimate the regional hydrocarbon flux to be at least 100× greater than previous estimates and 14–120% of the hydrocarbon flux from the Macondo oil spill. Large natural seepage may inoculate marine basins such as the Gulf of Mexico from oil spills like the 2010 Deepwater Horizon blowout by sustaining populations of hydrocarbon-degrading bacteria.
•High salinities and temperatures are present at deepwater Gulf of Mexico vents.•The upward flow of water and hydrocarbon from depth can explain these observations.•New method for estimating hydrocarbon flux from deepwater vents.•Hydrocarbon flux into the Gulf of Mexico may be significantly underestimated.
Hydrogeologic properties of fault zones are critical to faulting processes; however, they are not well understood and difficult to measure in situ, particularly in low‐permeability fractured bedrock ...formations. Analysis of continuous water level response to Earth tides in monitoring wells provides a method to measure the in situ hydrogeologic properties. We utilize four monitoring wells within the San Andreas Fault zone near Logan Quarry to study the fault zone hydrogeologic architecture by measuring the water level tidal response. The specific storage and permeability inferred from the tidal response suggest that there is a difference in properties at different distances from the fault. The sites closer to the fault have higher specific storage and higher permeability than farther from the fault. This difference of properties might be related to the fault zone fracture distribution decreasing away from the fault. Although permeability channels near faults have been documented before, the difference in specific storage near the fault is a new observation. The inferred compliance contrast is consistent with prior estimates of elastic moduli in the near‐fault environment, but the direct measurements are new. The combination of measured permeability and storage yields a diffusivity of about 10−2 m2/s at all the sites both near and far from the fault as a result of the competing effects of permeability and specific storage. This uniform diffusivity structure suggests that the permeability contrast might not efficiently trap fluids during the interseismic period.
Key Points:
The sites near the fault have larger hydraulic storage and larger permeability
The observed fault zone has localized permeability and storage but uniform diffusivity
The diffusivity of the San Andreas Fault near Logan Quarry is about 10−2 m2/s
Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate ...into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A–metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARα (dnRARα) showed markedly diminished lethality. The dnRARα transgenic T cells showed reduced Th1 differentiation and α4β7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4+ T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.
•Expression and function of vitamin A metabolizing enzymes are increased in the intestine and mesenteric lymph nodes during GVHD.•Inhibiting donor T-cell RAR signaling reduces Th1 differentiation, gut homing, and GVHD while preserving graft-versus-lymphoma effects.
Cyclooxygenase-2 is frequently overexpressed and associated with poor prognosis in breast cancer. The cyclooxygenase-2 product prostaglandin E(2) elicits cellular responses through four ...G-protein-coupled receptors, designated EP1 to EP4, coupled to distinct intracellular signaling pathways. EP4, expressed on malignant breast cells, promotes metastasis; however, a role for EP1 in metastasis has not been investigated. Using a murine model of metastatic breast cancer, we now show that pharmacologic antagonism of EP1 with SC19220 or AH6809 promoted lung colonization of mammary tumor cells by 3.7- to 5.4-fold. Likewise, reducing EP1 gene expression by shRNA also increased metastatic capacity relative to cells transfected with nonsilencing vector but did not affect the size of transplanted tumors. Examination of invasive ductal carcinomas by immunohistochemistry shows that EP1 was detected in both the cytoplasm and nucleus of benign ducts as well as malignant cells in some samples, but was absent or limited to either the nucleus or cytoplasm in other malignant samples. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression (P = 0.008). There was no difference in survival for women with differences in cytoplasmic EP1 expression (P = 0.46). Comparing EP1 mRNA in breast tumors from African American and European American women revealed that many more African American breast tumors lacked detectable EP1 mRNA (P = 0.04). These studies support the hypothesis that EP1 functions as a metastasis suppressor and that loss of nuclear EP1 is associated with poorer overall survival and may contribute to disparities in outcome in different populations.
is the etiologic agent of tularemia, and subspecies
(type A) is the most virulent subspecies. The live vaccine strain (LVS) of subspecies
produces a capsule-like complex (CLC) that consists of a ...large variety of glycoproteins. Expression of the CLC is greatly enhanced when the bacteria are subcultured in and grown on chemically defined medium. Deletion of two genes responsible for CLC glycosylation in LVS results in an attenuated mutant that is protective against respiratory tularemia in a mouse model. We sought to further characterize the CLC composition and to determine if a type A CLC glycosylation mutant would be attenuated in mice. The CLCs isolated from LVS extracted with 0.5% phenol or 1 M urea were similar, as determined by gel electrophoresis and Western blotting, but the CLC extracted with urea was more water-soluble. The CLC extracted with either 0.5% phenol or 1 M urea from type A strains was also similar to the CLC of LVS in antigenic properties, electrophoretic profile, and by transmission electron microscopy (TEM). The solubility of the CLC could be further enhanced by fractionation with Triton X-114 followed by N-Lauroylsarcosine detergents; the largest (>250 kDa) molecular size component appeared to be an aggregate of smaller components. Outer membrane vesicles/tubules (OMV/T) isolated by differential centrifugation and micro-filtration appeared similar to the CLC by TEM, and many of the proteins present in the OMV/T were also identified in soluble and insoluble fractions of the CLC. Further investigation is warranted to assess the relationship between OMV/T and the CLC. The CLC conjugated to keyhole limpet hemocyanin or flagellin was highly protective against high-dose LVS intradermal challenge and partially protective against intranasal challenge. A protective response was associated with a significant rise in cytokines IL-12, IL-10, and IFN-γ. However, a type A CLC glycosylation mutant remained virulent in BALB/c mice, and immunization with the CLC did not protect mice against high dose respiratory challenge with type A strain SCHU S4.
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