The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Airway exposure to Staphylococcal enterotoxin type B (SEB) enhances the number and activity of bone marrow neutrophils via the release of multiple cytokines

The lung infections by Staphylococcus aureus are strongly associated with its ability to produce enterotoxins. However, little is known about the mechanisms underlying trafficking of bone marrow (BM) neutrophils during airway inflammation induced by Staphylococcal enterotoxin B (SEB). We therefore aimed to investigate the effects of mouse airways SEB exposure on BM neutrophil counts and its adhesive properties as well as on the release of cytokines/chemokines that orchestrate BM neutrophils trafficking to lung tissue. Male BALB/c mice were intranasally exposed to SEB (1 µg), and at 4, 16 and 24 h thereafter, BM, circulating blood, bronchoalveolar lavage (BAL) fluid and lung tissue were collected. BM neutrophils adhesion, MAC-1 and LFA1-α expressions (by flow cytometry) as well as measurement of cytokine and/or chemokines levels were assayed after SEB-airway exposure.Prior exposure to SEB promoted a marked influx of neutrophils to BAL and lung tissue, which was accompanied by increased counts of BM immature neutrophils and blood neutrophilia. BM neutrophil expressions of LFA1-α and MAC-1 were unchanged by SEB exposure whereas a significant enhancement of adhesion properties to VCAM-1 was observed. The early phase of airway SEB exposure was accompanied by high levels of GM-CSF, G-CSF, IFN-γ, TNF-α and KC/CXCL1, while the latter phase by the equilibrated actions of SDF1-α and MIP-2.Mouse airways exposure to SEB induces BM cytokines/chemokines release and their integrated actions enhance the adhesion of BM neutrophils leading to acute lung injury7

Mechanisms involved in the rat peritoneal leukocyte migration induced by a Kunitz-type inhibitor isolated from dimorphandra mollis seeds

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICODMTI-II is a Kunitz-type inhibitor isolated from Dimorphandra mollis seeds that causes rat inflammatory edema by mechanisms involving activation of mast cells and sensory C-fibers. The present study aimed to further explore the inflammatory mechanisms involved in DMTI-II-induced inflammation, focusing to the leukocyte migration in vivo. Male Wistar rats (250-280 g) were injected with DMTI-II (1-100 mu g/cavity), and at 4-24 h thereafter the leukocyte counts in peritoneal lavage were evaluated. DMTI-II caused dose- and time-dependent accumulation of neutrophils and eosinophils. The peritoneal neutrophil influx initiated at 4 h, achieving maximal responses at 16 h after DMTI-II injection (16- and 22-fold increase, respectively). The DMTI-II-induced eosinophil recruitment was observed as early as 4 h achieving the maximal responses at 16 h (12- and 17-fold increase, respectively). The mononuclear cell number increased at 4 h and 16 h (1.5-fold and 1.6-increase, respectively). Prior treatments with dexamethasone, the cyclooxygenase (COX) inhibitors indomethacin and celecoxib, as well as the PAF receptor antagonist PCA4248 largely reduced the neutrophil and eosinophil accumulation. The selective lypoxygenase inhibitor AA861, the tachykinin NK(1) antagonist SR-140333 and the nitric oxide inhibitor L-NAME reduced only the eosinophil number. The eotaxin levels were significantly higher in DMTI-II-injected rats compared with control animals. In conclusion, DMTI-II causes an early migration of eosinophils and neutrophils by mechanisms involving COX-2- and lipoxygenase-derived metabolites, PAF, substance P and NO. The capacity of DMTI-II to recruit eosinophils at early times is likely to reflect the allergen properties of proteinase inhibitors belonging to Kunitz family533323329FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã

Inflammatory mechanisms underlying the rat pulmonary neutrophil influx induced by airway exposure to staphylococcal enterotoxin type A

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOAssociation between staphylococcal infection and pathogenesis of upper airways disease has been reported. This study aimed to investigate the mechanisms underlying the rat pulmonary inflammation induced by airway exposure to staphylococcal enterotoxin A( SEA). 2 SEA( 0.3 - 10 ng trachea(-1)) caused dose-dependent neutrophil accumulation in BAL fluid, reaching maximal responses at 4 h ( 25-fold increase for 3 ng trachea(-1)). Significant accumulation of both lymphocytes and macrophages in BAL fluid was also observed at 4 h ( 2.1- and 1.9-fold increase, respectively, for 3 ng trachea(-1)). At later times ( 16 h), neutrophil counts in bone marrow ( immature forms) and peripheral blood increased by 63 and 81%, respectively. SEA failed to directly induce chemotaxis and adhesion of isolated neutrophils. 3 Analysis of mRNA expression for iNOS, COX-2 and CINC-2 in lung tissue showed an upregulation of these enzymes, which paralleled elevated levels of LTB4, PGE(2), TNF-alpha, IL-6 and NO2- in BAL fluid. Expression of CINC-1 was unchanged, whereas CINC-3 was reduced in SEA-treated rats. Incubation of isolated alveolar macrophages with SEA( 3 mu g ml(-1)) resulted in significant elevations of TNF-alpha and NO2- levels in the cell supernatants. 4 Dexamethasone ( 0.5 mg kg(-1)), celecoxib ( 3 mg kg(-1)) and compound 1400W ( 5 mg kg(-1)) markedly reduced SEA-induced lung neutrophil influx and NO2- levels in BAL fluid. The lipoxygenase inhibitor AA-861 ( 100 mu g kg(-1)) partly inhibited the neutrophil influx in SEA-treated rats without modifying the NO2- levels. None of these treatments reduced the number of mononuclear cells in BAL fluid ( except of dexamethasone, which abolished the increased lymphocyte counts). 5 Our study shows that airways exposure to SEA results in marked neutrophil influx through mechanisms involving increased expressions of CINC-2, iNOS and COX-2, as well as enhanced production of NO, PGE(2), LTB4, TNF-alpha and IL-61466781791FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

The public repository of xenografts enables discovery and randomized phase II-like trials in mice.

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease