Silva F.,Mayo Medical School |
Silva F.,University of Michigan |
Seo P.,Johns Hopkins University |
Schroeder D.R.,Mayo Medical School |
And 12 more authors.
Arthritis and Rheumatism | Year: 2011
Objective An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. Methods The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Results Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup. Conclusion The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients. Copyright © 2011 by the American College of Rheumatology.
Gupta S.K.,Thoracic Disease Research Unit |
Oommen S.,Thoracic Disease Research Unit |
Aubry M.-C.,Mayo Medical School |
Williams B.P.,Thoracic Disease Research Unit |
Vlahakis N.E.,Thoracic Disease Research Unit
Oncogene | Year: 2013
The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed. Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression. These findings highlight a novel mechanism of integrin α9β1 function in human cancer. © 2013 Macmillan Publishers Limited All rights reserved.
Plataki M.,Thoracic Disease Research Unit |
Hubmayr R.D.,Thoracic Disease Research Unit
Expert Review of Respiratory Medicine | Year: 2010
Although mechanical ventilation (MV) is a life-saving intervention for patients with acute respiratory distress syndrome (ARDS), it can aggravate or cause lung injury, known as ventilator-induced lung injury (VILI). The biophysical characteristics of heterogeneously injured ARDS lungs increase the parenchymal stress associated with breathing, which is further aggravated by MV. Cells, in particular those lining the capillaries, airways and alveoli, transform this strain into chemical signals (mechanotransduction). The interaction of reparative and injurious mechanotransductive pathways leads to VILI. Several attempts have been made to identify clinical surrogate measures of lung stress/strain (e.g., density changes in chest computed tomography, lower and upper inflection points of the pressure-volume curve, plateau pressure and inflammatory cytokine levels) that could be used to titrate MV. However, uncertainty about the topographical distribution of stress relative to that of the susceptibility of the cells and tissues to injury makes the existence of a single 'global stress/strain injury threshold doubtful. © 2010 Expert Reviews Ltd.
Silva F.,University of Santiago de Chile |
Cisternas M.,University of Santiago de Chile |
Specks U.,Thoracic Disease Research Unit
Current Rheumatology Reports | Year: 2012
ANCA-associated vasculitides (AAV) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality. This group includes granulomatosis with polyangiitis (Wegener's, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs. These have broad mechanisms of action as well as important adverse effects. Efforts have been made to investigate novel agents with better-defined and narrower mechanisms of action, such as biologics, including TNF-α blockers. Etanercept, a well-known TNF-α blocker evaluated for GPA in the Wegener's Granulomatosis Etanercept Trial (WGET), was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period. A 5-year follow-up after the WGET trial showed a sustained increase in incidence of solid malignancies, but this could no longer be solely attributed to etanercept exposure. These studies raised concerns about the use of the family of TNF-α blockers in AAV. Here, we review the evidence about the association between therapeutic inhibition of tumor necrosis factor (TNF-α) by etanercept and other TNF-α blockers with the development of solid malignancies in GPA and other AAV. © Springer Science+Business Media, LLC 2012.
Yin X.,Thoracic Disease Research Unit |
Murphy S.J.,Rochester College |
Wilkes M.C.,Thoracic Disease Research Unit |
Ji Y.,Thoracic Disease Research Unit |
Leof E.B.,Thoracic Disease Research Unit
Molecular Biology of the Cell | Year: 2013
Transforming growth factor β (TGF-β) is critical for the development and maintenance of epithelial structures. Because receptor localization and trafficking affect the cellular and organismal response to TGF-β, the present study was designed to address how such homeostatic control is regulated. To that end, we identify a new role for the mammalian retromer complex in maintaining basolateral plasma membrane expression of the type II TGF-β receptor (TβRII). Retromer and TβRII associate in the presence or absence of TGF-β ligand. After retromer knockdown, although TβRII internalization and trafficking to a Rab5-positive compartment occur as in wild-type cells, receptor recycling is inhibited. This results in TβRII mislocalization from the basolateral to both the basolateral and apical plasma membranes independent of Golgi transit and the Rab11-positive apical recycling endosome. The data support a model in which, after initial basolateral TβRII delivery, steady-state polarized TβRII expression is maintained by retromer/TβRII binding and delivery to the common recycling endosome. © 2013 Yin et al.
Bhattacharyya S.,Rochester College |
Singh R.D.,Rochester College |
Singh R.D.,Thoracic Disease Research Unit |
Pagano R.,Thoracic Disease Research Unit |
And 4 more authors.
Angewandte Chemie - International Edition | Year: 2012
On the right path: The mechanisms of endocytosis of cetuximab (C225) and its nanoconjugates have been elucidated in a pancreatic cancer cell line. By using gold nanoparticles as a scaffold, it is possible to switch the pathway for endocytosis from a Dyn-2-dependent caveolar mechanism to Cdc42-dependent pinocytosis/phagocytosis. Tailoring endocytotic mechanisms may enable specific intracellular pathways to be targeted. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Oommen S.,Thoracic Disease Research Unit |
Gupta S.K.,Thoracic Disease Research Unit |
Vlahakis N.E.,Thoracic Disease Research Unit
Journal of Biological Chemistry | Year: 2011
Integrin α9β1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the α9β1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin α9β1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for α9β1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin α9β1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
PubMed | Thoracic Disease Research Unit, University of North Carolina at Chapel Hill and State University of New York at Buffalo
Type: Journal Article | Journal: Lung | Year: 2016
A series of bracts from Deltapine 41 variety cotton were harvested weekly from October 16 through November 25, 1982, and examined for changes in biologically active components accompanying senescence. Aqueous extracts of cotton bracts (CBE) were tested for their ability to cause 5-hydroxytryptamine (5-HT) release from human platelets and contraction of isolated canine tracheal smooth muscle (TSM). In addition, the amounts of soluble tannins (the platelet-activating factor found in CBE) and endotoxin were determined for each CBE. The amount of CBE decreased significantly from October 16 through November 25, whereas endotoxin levels rose dramatically from October 23 to November 6 and declined thereafter. The amount of soluble tannin and platelet 5-HT release both decreased from highs on October 23 to unmeasurable levels on November 25. Smooth muscle contraction was attributed to two primary factors contained in CBE. The major constrictor was a 5-HT receptor agonist and its levels remained stable from October 16 through October 30, but then decreased to unmeasurable levels by November 13. In contrast, CBE also contained lesser amounts of an acetylcholine receptor agonist whose levels paralleled the changes in endotoxin levels. We conclude that several important biochemical changes occur in cotton bracts during senescence and that these changes profoundly influence their biological activity in various assays.
PubMed | Thoracic Disease Research Unit and European University of Brittany
Type: | Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2017
The prognosis of the antineutrophil cytoplasmic antibody associated vasculitides (AAV), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), has been fundamentally improved over the last five decades by the use of glucocorticoids and immunosuppressants, turning them from consistently fatal diseases into chronic conditions. The long-term course is now largely determined by the frequency of disease flares and by accruing damage caused by disease activity and treatment-related comorbidities. This review summarizes the evidence derived from clinical trials performed during the last 30 years and the remaining clinical unmet needs that new studies aim to address. In MPA and GPA, ongoing studies assess (i) different strategies to reduce cumulative glucocorticoid doses currently used for induction and maintenance of remission, (ii) the efficacy of new drugs and (iii) the optimal duration of immunosuppression and the use of biomarkers to individualize therapy. Prospective randomized trials also target disease-associated cardiovascular risk and infections. The first prospective controlled trials specifically designed for EGPA have recently been launched and could lead to new therapeutic options for patients diagnosed with this rare disease. This is an exciting time for researchers in the field of AAV, and for patients as collaborative efforts raise the hope of developing new therapies and more individualized approaches to the management of the diseases, maximizing efficacy while minimizing treatment toxicities.
Pupaibool J.,Mayo Medical School |
Kottom T.J.,Thoracic Disease Research Unit |
Bouchonville K.,Thoracic Disease Research Unit |
Limper A.H.,Thoracic Disease Research Unit |
Limper A.H.,Rochester College
Infection and Immunity | Year: 2013
Rtt109 is a lysine acetyltransferase that acetylates histone H3 at lysine 56 (H3K56) in fungi. This acetylation event is important for proper DNA replication and repair to occur. Efficient Rtt109 acetyltransferase activity also requires a histone chaperone, vacuolar protein sorting 75 (Vps75), as well as the major chaperone of the H3-H4 dimer, anti-silencing factor 1 (Asf1). Little is known about the role of these proteins in the opportunistic fungal pathogen Pneumocystis carinii. To investigate the functions of Asf1 and Vps75 in Pneumocystis carinii, we cloned and characterized both of these genes. Here, we demonstrate that both genes, P. carinii asf1 (Pcasf1) and Pcvps75, function in a fashion analogous to their Saccharomyces cerevisiae counterparts. We demonstrate that both P. carinii Asf1 (PcAsf1) and PcVps75 can bind histones. Furthermore, when Pcasf1 is expressed heterologously in S. cerevisiae asf1δ cells, PcAsf1 can restore full H3 lysine acetylation. We further demonstrated that the Pcasf1 cDNA expressed in asf1δ S. cerevisiae cells can restore growth to wild-type levels in the presence of genotoxic agents that block DNA replication. Lastly, we observed that purified PcAsf1 and PcVps75 proteins enhance the ability of PcRtt109 to acetylate histone H3-H4 tetramers. Together, our results indicate that the functions of the Rtt109-Asf1-Vps75 complex in the acetylation of histone H3 lysine 56 and in DNA damage response are present in P. carinii DNA and cell cycle progression. © 2013, American Society for Microbiology.