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Butenolide is an environmentally friendly antifouling natural product, but its efficiency and mechanism in preventing biofilm formation have not been examined. Furthermore, controlling the release of butenolide from paints into seawater is technically challenging. A coating was developed by mixing butenolide with a biodegradable polymer, poly (e-caprolactone)-based polyurethane, and a one-month in situ anti-biofilm test was conducted in a subtidal area. The constant release of butenolide from the surface suggested that its release was well controlled. Direct observation and confocal microscope investigation indicated that the coating was effective against both biofilm formation and attachment of large fouling organisms. Metatranscriptomic analysis of biofilm samples implied that the coating selectively inhibited the adhesion of microbes from a variety of phyla and targeted particular functional pathways including energy metabolism, drug transport and toxin release. These integrated analyses demonstrated the potential application of this butenolide/polymer coating as an anti-biofilm material. [ABSTRACT FROM AUTHOR]

Furin, a proprotein-convertase, is distributed in the upper third layer and the lower quarter region of the rat gastric gland. We previously identified the upper furin-positive cells as parietal cells, and here, we identify the lower furin-positive cells as chief cells. Chief cells express three isoforms of transforming growth factor β (TGFβ), whose precursor requires cleavage by furin for its activation. When the chief cell mass was decreased in rats by adrenalectomy, pepsinogen-, furin-, and TGFβ-positive cells were also reduced. Stimulation of mouse chief cell primary-cultures with transforming growth factor a (TGFα) induced an increase in the expression of furin and TGFβ mRNAs and in the formation of mature TGFβ. Since parietal cells are known to express a high level of the epidermal growth factor (EGF) -family growth factors and chief cells strongly express EGF receptors (EGF-R), we suggest that chief cells receive the EGF-R signal from parietal cells in a paracrine fashion and regulate parietal cell mass by controlling the formation of mature TGFβ. [ABSTRACT FROM AUTHOR]

Mice genetically deficient in TGF-β1 or TGF-β signaling c apacity in T or B cells demonstrate profound immune dysregulation, as evidenced by increased lymph node size, expression of markers o f memory/activation on T cells, inflammation in a variety of tissues and development of autoantibodies. H owever, this constant and complete lack of TGF-β1 or TGF-βR signaling may not reflect effects of TGF-β neutralization using antibodies in mature animals. Thus, t he present studies were designed to determine if administration o f an anti-TGF-β monoclonal antibody (neutralizes TGF-β1, 2 and 3) to mature, normal mice results in evidence of immune dysregulation or immune-mediated pathology. An initial study examined daily administration of 0.25, 0 .75 and 2.5 mg/kg of anti-TGF-β to mice for three weeks, achieving blood levels of as high a s 9 mg/ml. Comprehensive hematological and histopathological evaluation showed no evidence of pathology. A second study was designed to extend the antibody treatment period and further examine t he functional status of the immune system. Mice were injected with 1 mg/mouse ( approximately 5 0 m g/kg) o f anti-TGF-β (1D11) three times per week achieving circulating blood levels of 1-2 mg/ml. Many parameters of immune status were assessed, including natural killer ( NK) c ell activity, lymphocyte proliferative responses, phagocytic activity, phenotypic assessment of leukocyte subsets, and serum measurements of proinflammatory cytokines, autoantibodies and immunoglobulin isotypes. In addition, histopathological assessment of heart, lungs, liver, kidney, salivary glands, skin, spleen and lymph nodes was also performed. Very few of the multiple immune parameters examined showed detectable changes in anti-TGF-β-treated mice. Changes that were observed were primarily restricted to the spleen and included increased spleen cell r ecoveries, increased percentages of macrophages, decreased... [ABSTRACT FROM AUTHOR]

The beneficial clinical effects of immunotherapy with GD2-specific monoclonal antibodies (mAbs) in melanoma and neuroblastoma patients have stimulated interest in characterizing the mechanisms underlying their antitumor effects. Previous studies have shown that GD2-specific mAbs mediate complement- and cell-dependent cytotoxicity and induce caspase-dependent apoptosis of tumor cells. In this study, we showed that GD2-specific mAb 3F8, which is undergoing clinical evaluation, inhibited thein vitrogrowth and induced apoptosis of melanoma cells. This effect was dose- and time-dependent, mediated by the interaction of mAb 3F8 combining site with GD2 ganglioside, associated with GD2 expression level on the cell surface, mAb internalization and increase of GD2 containing endosomes triggered by mAb 3F8. The induction of apoptosis by mAb 3F8 was mediated by caspase 3-, 7-, and 8-dependent pathways, downregulation of the anti-apoptotic molecules survivin and cytochrome c, and caspase 9 independent-AIF release from mitochondria. In addition, analyses of signaling pathway components demonstrated that mAb 3F8 strongly inhibited AKT and FAK activation and increased cleaved PARP expression. These results indicated that multiple mechanisms played a role in the antitumor activity of mAb 3F8 in melanoma cells. This information should provide a mechanistic basis for the optimization of the rational design of immunotherapeutic strategies in the mAb-based treatment of GD2 positive tumors. [ABSTRACT FROM PUBLISHER]

The graft-versus-leukemia (GVL) effect following allogeneic hematopoietic stem cell transplantation (allo-HCT) is critical for its curative potential. Hwever, GVL is tightly linked to graft-versus-host disease (GVHD). Among hematological malignancies, acute lymphoblastic leukemia (ALL) is the most resistant to GVL, although the reasons for this remain poorly understood. Clinical studies have identified alterations in Ikaros (Ik) transcription factor as the major marker associated with poor outcomes in ALL. We have shown that the absence of Ik in professional host-derived hematopoietic antigen-presenting cells (APCs) exacerbates GVHD. However, whetherIkexpression plays a role in resistance to GVL is not known. In this study we used multiple clinically relevant murine models of allo-HCT to explore whetherIkexpression in hematopoietic APCs and/or leukemic cells is critical for increasing resistance to GVL and thus inducing relapse. We found thatIkdeficiency in host APCs failed to enhance GVL despite increased GVHD severity. Mechanistic studies with bone marrow (BM) chimeras and tetramer analyses demonstrated reduced tumor-specific immunodominant (gag+) antigen responses in the [B6Ik−/−→B6] group. Loss of GVL was observed when both the leukemia cells and the host APCs were deficient inIk. We found that calreticulin (CRT) expression in host antigen-presenting dendritic cells (DCs) ofIk−/−animals was significantly lower than in wild-type animals. Rescuing CRT expression inIk−/−DCs improved leukemic-specific cytotoxic T cell function. Together, our data demonstrate that the absence of Ikaros in host hematopoietic cells promotes resistance to GVL despite increasing GVHD and thus provides a potential mechanism for the poor outcome ofIk−/−ALL patients. [ABSTRACT FROM PUBLISHER]

Background.Glioblastoma (GBM) is the most common malignant brain tumor in adults and is nearly always fatal. Emerging evidence suggests that humanCytomegalovirus(HCMV) is present in 90–100% of GBMs and that add-on antiviral treatment for HCMV show promise to improve survival. Methods.In a randomized, placebo-controlled trial of valganciclovir in 42 GBM patients, blood samples were collected for analyses of HCMV DNA, RNA, reactivity against HCMV peptides, IgG, and IgM at baseline and at 3, 12, and 24 weeks of treatment. Results.All 42 tumors were positive for HCMV protein. All patients examined had at least one blood sample positive for HCMV DNA, 63% were HCMV RNA positive, and 21% were IgM positive. However, 29% of GBM patients were IgG negative for HCMV. Five of these samples were positive in an enzyme-linked immunosorbent assay (ELISA) that used antigens derived from a clinical isolate. Blood T cells from 11 of 13 (85%) HCMV IgG-negative GBM patients reacted against HCMV peptides. Valganciclovir did not affect IgG titers, DNA, or RNA levels of theHCMV immediate early (HCMV IE)gene in blood. Conclusion.In GBM patients, HCMV activity is higher than in healthy controls and serology is a poor test to define previous or active HCMV infection in these patients. [ABSTRACT FROM PUBLISHER]