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Stenstrom M.,Lund University | Stenstrom M.,Active Biotech Research AB | Anderson P.,Lund University | Anderson P.,Institute Parasitologia y Biomedicina | And 3 more authors.
International Immunopharmacology | Year: 2010

The quinoline-3-carboxamide ABR-215757 (5757) is in clinical development for the treatment of human SLE and has shown efficacy in several mouse models of T cell-mediated inflammatory autoimmune disease. The goal of this study was to determine the impact of 5757 on steady state immune cells. We show that the number of splenic CD4 dendritic cells (DCs) was reduced in 5757-treated mice, while there was no effect on other splenic DC populations, on DCs in lymph nodes or on lymphocytes. This reduction was fully reversible and the kinetics of CD4 DC loss during exposure and recovery after withdrawal of treatment was identical. The loss of CD4 DCs was neither caused by reduced proliferation nor by increased apoptosis. CD4 DCs reside in the splenic marginal zone, but the loss of these cells did not influence other cell populations at this site. The similar kinetics of the decay and repopulation of the splenic CD4 DC compartment suggests that the reduced number of CD4 DC in 5757 treated mice may be a result of blockade of CD4 DC precursor development in the spleen and not of toxicity. Alternatively, induced emigration of CD4 DC to the periphery, or an interference with adherence of these cells in the spleen marginal zone, may also explain our data. © 2010 Elsevier B.V. Source


Zurita M.,Radiation Oncology | Lara P.C.,Instituto Canario Of Investigacion Del Cancer | del Moral R.,Radiation Oncology | Torres B.,CIBER ISCIII | And 6 more authors.
BMC Cancer | Year: 2010

Background: Numerous hypermethylated genes have been reported in breast cancer, and the silencing of these genes plays an important role in carcinogenesis, tumor progression and diagnosis. These hypermethylated promoters are very rarely found in normal breast. It has been suggested that aberrant hypermethylation may be useful as a biomarker, with implications for breast cancer etiology, diagnosis, and management. The relationship between primary neoplasm and metastasis remains largely unknown. There has been no comprehensive comparative study on the clinical usefulness of tumor-associated methylated DNA biomarkers in primary breast carcinoma and metastatic breast carcinoma. The objective of the present study was to investigate the association between clinical extension of breast cancer and methylation status of Estrogen Receptor1 (ESR1) and Stratifin (14-3-3-σ) gene promoters in disease-free and metastatic breast cancer patients.Methods: We studied two cohorts of patients: 77 patients treated for breast cancer with no signs of disease, and 34 patients with metastatic breast cancer. DNA was obtained from serum samples, and promoter methylation status was determined by using DNA bisulfite modification and quantitative methylation-specific PCR.Results: Serum levels of methylated gene promoter 14-3-3-σ significantly differed between Control and Metastatic Breast Cancer groups (P < 0.001), and between Disease-Free and Metastatic Breast Cancer groups (P < 0.001). The ratio of the 14-3-3-σ level before the first chemotherapy cycle to the level just before administration of the second chemotherapy cycle was defined as the Biomarker Response Ratio [BRR]. We calculated BRR values for the "continuous decline" and "rise-and-fall" groups. Subsequent ROC analysis showed a sensitivity of 75% (95% CI: 47.6 - 86.7) and a specificity of 66.7% (95% CI: 41.0 - 86.7) to discriminate between the groups for a cut-off level of BRR = 2.39. The area under the ROC curve (Z = 0.804 ± 0.074) indicates that this test is a good approach to post-treatment prognosis.Conclusions: The relationship of 14-3-3-σ with breast cancer metastasis and progression found in this study suggests a possible application of 14-3-3-σ as a biomarker to screen for metastasis and to follow up patients treated for metastatic breast cancer, monitoring their disease status and treatment response. © 2010 Zurita et al; licensee BioMed Central Ltd. Source


Munoz-Fernandez R.,Institute Parasitologia y Biomedicina | Prados A.,University of Granada | Leno-Duran E.,University of Granada | Blazquez A.,Hospital Universitario San Cecilio | And 4 more authors.
Human Reproduction | Year: 2012

BACKGROUND Decidual stromal cells (DSCs) have classically been considered fibroblastic cells, although their function, cell lineage and origin are not fully understood. We previously demonstrated that human DSCs showed similarities with follicular dendritic cells (FDCs): DSCs expressed FDC-associated antigens, both types of cells are contractile and both are related to mesenchymal stem cells (MSCs). To further characterize DSCs, we investigated whether DSCs and FDCs share any distinctive phenotypical and functional characteristics. METHODS Human FDC lines were obtained from tonsillectomy samples, human DSC lines from elective termination of pregnancy samples and human MSC lines from bone marrow aspirates. We isolated DSC, FDC and MSC lines and compared their characteristics with flow cytometry and enzyme-linked immunosorbent assay. Cell lines were cultured with tumour necrosis factor (TNF) and lymphotoxin (LT)α1β2, cytokines involved in FDC differentiation. Cell lines were also differentiated in culture after exposure to progesterone and cAMP, factors involved in the differentiation (decidualization) of DSC. RESULTS Like MSCs, DSCs and FDCs expressed MSC-associated antigens (CD10, CD29, CD54, CD73, CD106, α-smooth muscle actin and STRO-1) and lacked CD45 expression, and all three types of cell line showed increased expression of CD54 (ICAM-1) and CD106 (VCAM-1) when cultured TNF and LTα1β2. DSCs and FDCs, however, exhibited characteristics not observed in MSCs: DSCs expressed FDC-associated antigens CD14, CD21 and CD23, B cell-activating factor and secreted C-X-C motif chemokine 13. Moreover, DSC lines but not MSC lines inhibited the spontaneous apoptosis of B lymphocytes, a typical functional attribute of FDC. During culture with progesterone and cAMP, FDCs, like DSCs but in contrast to MSCs, changed their morphology from a fibroblastic to a rounder shape, and cells secreted prolactin. CONCLUSIONS Our results suggest that DSCs and FDCs share a common precursor in MSCs but this precursor acquires new capacities when it homes to peripheral tissues. We discuss these shared properties in the context of immuneendocrine regulation during pregnancy. © The Author 2012. Source


Delgado M.,Institute Parasitologia y Biomedicina | Ganea D.,Temple University
Amino Acids | Year: 2013

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/ neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions. © 2011 Springer-Verlag. Source


Ienne S.,University of Sao Paulo | Pappas G.,Catholic University of Brasilia | Benabdellah K.,Institute Parasitologia y Biomedicina | Benabdellah K.,University of Granada | And 2 more authors.
Infection, Genetics and Evolution | Year: 2012

Among trypanosomatids, the genus . Phytomonas is the only one specifically adapted to infect plants. These hosts provide a particular habitat with a plentiful supply of carbohydrates. . Phytomonas sp. lacks a cytochrome-mediated respiratory chain and Krebs cycle, and ATP production relies predominantly on glycolysis. We have characterised the complete gene encoding a putative pyruvate/indolepyruvate decarboxylase (PDC/IPDC) (548 amino acids) of . P. serpens, that displays high amino acid sequence similarity with phytobacteria and . Leishmania enzymes. No orthologous . PDC/IPDC genes were found in . Trypanosoma cruzi or . T. brucei. Conservation of the . PDC/IPDC gene sequence was verified in 14 . Phytomonas isolates. A phylogenetic analysis shows that . Phytomonas protein is robustly monophyletic with . Leishmania spp. and . C. fasciculata enzymes. In the trees this clade appears as a sister group of indolepyruvate decarboxylases of γ-proteobacteria. This supports the proposition that a horizontal gene transfer event from a donor phytobacteria to a recipient ancestral trypanosome has occurred prior to the separation between . Phytomonas, . Leishmania and . Crithidia. We have measured the PDC activity in . P. serpens cell extracts. The enzyme has a Km value for pyruvate of 1.4. mM. The acquisition of a PDC, a key enzyme in alcoholic fermentation, explains earlier observations that ethanol is one of the major end-products of glucose catabolism under aerobic and anaerobic conditions. This represents an alternative and necessary route to reoxidise part of the NADH produced in the highly demanding glycolytic pathway and highlights the importance of this type of event in metabolic adaptation. © 2012 Elsevier B.V.. Source

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