Here, the dynamics of phosphorus (P) in the environment is important for regulating nutrient cycles in natural and managed ecosystems and an integral part in assessing biological resilience against ...environmental change. Organic P (Po) compounds play key roles in biological and ecosystems function in the terrestrial environment being critical to cell function, growth and reproduction. We asked a group of experts to consider the global issues associated with Po in the terrestrial environment, methodological strengths and weaknesses, benefits to be gained from understanding the Po cycle, and to set priorities for Po research. In conclusion, we identified seven key opportunities for Po research including: the need for integrated, quality controlled and functionally based methodologies; assessment of stoichiometry with other elements in organic matter; understanding the dynamics of Po in natural and managed systems; the role of microorganisms in controlling Po cycles; the implications of nanoparticles in the environment and the need for better modelling and communication of the research. Each priority is discussed and a statement of intent for the Po research community is made that highlights there are key contributions to be made toward understanding biogeochemical cycles, dynamics and function of natural ecosystems and the management of agricultural systems.
Abstract 2707
We hypothesized that immunotherapy with autologous tumor-derived idiotype (Id)-vaccine may improve the outcome of mantle cell lymphoma (MCL). Some murine lymphoma models have shown that ...Id-vaccine can induce an anti-tumor humoral response but others indicate that eradication of tumor requires a CD4+ and/or a CD8+ T-cell response. Antitumor T-cells may produce one or many cytokines. The Th1/Tc1 cytokines (IFNγ, IL-2, TNFα, GM-CSF) are commonly believed to mediate antitumor effects. However, a recent paper (Codarri et al. Nat Immunol 2011) proposes that production of GM-CSF by helper T-cells relies on activation of RORγt and that GM-CSF secretion is required for induction of autoimmune inflammation irrespective of helper T-cell polarization. We reported the results of Id-vaccine following DA-EPOCH-R in 26 untreated MCL patients (Neelapu et al Nat Med 2005) and found no association between PFS (19%) or OS (89%) and immune responses at the median of 46 months potential follow-up. We now present an 11-year follow-up and association between OS and antitumor immune responses. Study Design: DA-EPOCH-R was administered q3 weeks × 6, followed by 5 cycles of Id-vaccine beginning at least 12 weeks later to untreated MCL patients. Id protein was produced using hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH), and administered together with GM-CSF × 5 over 6 months. Pre- and post-vaccine samples were tested in parallel to assess humoral and cellular immune responses. Anti-Id and anti-KLH antibody responses were determined by ELISA. KLH-specific cellular responses were determined by intracellular cytokine assay and cellular responses against autologous tumor cells were determined by cytokine induction and IFNγ ELISPOT assays. For cytokine induction assay, PBMCs were cultured with and without autologous tumor cells. After 6 days TNFα, IFNγ and GM-CSF were assessed in culture supernatants by ELISA. Normalized post-vaccine responses were calculated for each patient. Results: Characteristics of all 26 patients: median age 57 (r 22–73), PS 1 (0–2), male sex 73%, blastoid variant 15%, and MIPI (low-65%; intermediate-16%; high-19%). Responses to DA-EPOCH-R: CR-92%, PR-8%. Immune analyses were performed in 24 patients; vaccine could not be made in one patient and one patient progressed and did not have immune analyses. The associations between OS and MIPI scores and normalized immune responses (KLH and anti-Id antibody responses, frequency of KLH-specific CD4+ T-cell responses in PBMC (intracellular IL-2 and TNFα), antitumor cytokine responses and IFNγ ELISPOT) were determined. With 122 mos median potential follow-up (r 111–132), the median PFS is 24 mos and OS is 104 mos. MIPI was significantly associated with OS (Fig 1; p=0.01); median OS: low (not reached), intermediate (84 mos) and high (44 mos). There was no association between OS and KLH humoral response or KLH-specific CD4+ T cells. There was also no association between OS and Id-specific humoral response, IFNγ ELISPOT, or antitumor TNFα, or IFNγ cytokine responses. However, there was a significant association between antitumor GM-CSF production and OS (Fig 2). The median OS at the median GM-CSF normalized value (<4.3 versus >4.3) was 79 mos versus not reached, respectively (p=0.015 (unadjusted) and p=0.045 (bonferroni adjusted)). MIPI and GM-CSF were jointly assessed in a Cox model and showed a trend toward improved OS for higher GM-CSF (p=0.10) after adjusting for MIPI (p=0.20). Conclusions: With 10-year median potential follow-up, GM-CSF cytokine response mediated by antitumor T-cells was significantly associated with OS. Recent studies support the hypothesis that antitumor T-cells that produce significant amounts of GM-CSF are uniquely polarized and that non-GM-CSF producing T-cells do not induce antitumor effects even if they produce TNFα or IFNγ. This may explain why we did not observe an association between OS and TNFα or IFNγ cytokine responses or an anti-Id-antibody response. These results provide the first evidence that Id-vaccines may improve the survival of MCL following induction with immuno-chemotherapy and need to be confirmed in future trials. Display omitted Display omitted
Neelapu:Biovest International, Inc.: Research Funding. Kwak:Biovest International, Antigenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biovest International: Other remuneration; Antigenics, Xeme Biopharma: Equity Ownership.
Mutagenized populations have become indispensable resources for introducing variation and studying gene function in plant genomics research. In this study, fast neutron (FN) radiation was used to ...induce deletion mutations in the soybean (Glycine max) genome. Approximately 120,000 soybean seeds were exposed to FN radiation doses of up to 32 Gray units to develop over 23,000 independent M2 lines. Here, we demonstrate the utility of this population for phenotypic screening and associated genomic characterization of striking and agronomically important traits. Plant variation was cataloged for seed composition, maturity, morphology, pigmentation, and nodulation traits. Mutants that showed significant increases or decreases in seed protein and oil content across multiple generations and environments were identified. The application of comparative genomic hybridization (CGH) to lesion-induced mutants for deletion mapping was validated on a midoleate x-ray mutant, M23, with a known FAD2-1A (for fatty acid desaturase) gene deletion. Using CGH, a subset of mutants was characterized, revealing deletion regions and candidate genes associated with phenotypes of interest. Exome resequencing and sequencing of PCR products confirmed FN-induced deletions detected by CGH. Beyond characterization of soybean FN mutants, this study demonstrates the utility of CGH, exome sequence capture, and next-generation sequencing approaches for analyses of mutant plant genomes. We present this FN mutant soybean population as a valuable public resource for future genetic screens and functional genomics research.
To describe a case of mucous membrane pemphigoid (MMP) with ocular manifestations in a patient subsequently diagnosed with B-cell chronic lymphocytic leukemia (CLL).
Case report and literature ...review.
A 64-year-old man presented with redness and irritation of both eyes. The patient also had blistering lesions on the roof of his mouth, trunk, and buttocks as well as bilateral conjunctival ulceration and symblepharon formation. A complete blood count performed before initiating treatment of presumed mucous membrane pemphigoid revealed a markedly increased white blood cell count (83,920) with a predominance of lymphocytes. Hematologic evaluation including immunophenotyping flow cytometry resulted in the diagnosis of B-cell chronic lymphocytic leukemia. Cyclophosphamide treatment improved his MMP and decreased the white blood cell count.
Mucous membrane pemphigoid has been reported in association with a variety of nonhematologic malignancies. This case suggests that mucous membrane pemphigoid may also occur in B-cell CLL and supports the concept that autoantibodies play a role in the pathogenesis of this cicatricial conjunctival disease.
Combat experiences early in adulthood may have lifelong ramifications. In the Vietnam Era Twin Study of Aging (VETSA), the authors studied lifetime educational attainment (LEA) in 236 male twins from ...the Vietnam Era Twin Registry. Twins who served in Vietnam had completed significantly fewer years of education by their 50s. Level of combat exposure was negatively correlated with LEA. To control for variables that might confound the relationship between combat and LEA, the authors compared twin pairs discordant for Vietnam service (n = 44 pairs); the twins who served in Vietnam had significantly lower LEA than their cotwins. Greater cognitive ability at military induction and older age at induction both predicted higher LEA, but after statistically controlling for these variables, the relationship between combat exposure and LEA remained significant. The VETSA results demonstrate that combat experience and entering military service at a younger age may reduce lifelong educational prospects, even after cognitive ability is controlled.
Transgenic mouse lineages were established that carry the normal (M) or mutant (Z) alleles of the human alpha 1-antitrypsin (alpha 1-Pi) gene. All of the alpha 1-Pi transgenic mice expressed the ...human protein in the liver, cartilage, gut, kidneys, lymphoid macrophages, and thymus. The human M-allele protein was secreted normally into the serum. However, the human Z-allele protein accumulated in several cell types, but particularly in hepatocytes, and was found in serum in tenfold lower concentrations than the M-allele protein. Mice in one lineage carrying the mutant Z allele expressed high levels of human alpha 1-Pi RNA and displayed significant runting (50% of normal weight) in the neonatal period. This lineage was found to have alpha 1-Pi-induced liver pathology in the neonatal period, concomitant with the accumulation of human Z protein in diastase-resistant cytoplasmic globules that could be revealed in the Periodic acid-Schiff reaction (PAS). The phenotype of mice in the strain expressing high levels of the Z allele is remarkably similar to human neonatal hepatitis, and this strain may prove to be a useful animal model for studying this disease.
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