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Diego Jose Laderach

Bio: Diego Jose Laderach is an academic researcher from National University of Luján. The author has contributed to research in topics: Galectin & Tumor microenvironment. The author has an hindex of 14, co-authored 21 publications receiving 591 citations. Previous affiliations of Diego Jose Laderach include National Scientific and Technical Research Council & French Institute of Health and Medical Research.

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Journal ArticleDOI
TL;DR: A dynamically regulated "galectin-specific signature" that accompanies disease evolution in prostate cancer is identified and highlighted, highlighting a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease.
Abstract: Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the "galectin signature" of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal-3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor-vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease.

138 citations

Journal ArticleDOI
TL;DR: RNA interference was used to assess the role of the p50 (NF-κB1) protein in the maturation and activation of cultured human monocyte-derived DC, revealing a pivotal requirement for p50 in MoDC for IL-12 production and induction of optimal type-1 immune responses.
Abstract: Specific NF-kappaB/Rel proteins regulate murine dendritic cell (DC) survival, differentiation, and activation, but little is known of their role in human cells because of limited loss-of-function analyses. RNA interference (RNAi) is a mechanism to effectively silence gene expression via sequence-specific double-stranded small interfering RNAs (siRNAs). RNAi was used to assess the role of the p50 (NF-kappaB1) protein in the maturation and activation of cultured human monocyte-derived DC (MoDC). Transfection of cultured MoDC with siRNAs reduced p50 mRNA and protein levels in a specific, dose-dependent, and time-dependent manner. Basal or maturation-induced expression of HLA-DR and costimulatory molecules were not affected, whereas transcription of the IL-12 p40 gene and the secretion of IL-12alphabeta were reduced. Such MoDC induced less IFN-gamma production by T cells in MLR. This is the first report of RNAi-induced phenotype in human primary DC with a method that caused no measurable toxicity or type-I IFN response. siRNAs appear useful for the study of signaling pathways in immune cells, revealing a pivotal requirement for p50 in MoDC for IL-12 production and induction of optimal type-1 immune responses.

77 citations

Journal ArticleDOI
TL;DR: Extensive Gal1 expression facilitated the transition from epithelial cell morphology towards a fibroblastoid phenotype and favored up‐regulation of the mesenchymal marker vimentin in HCC cells, with critical implications in H CC metastasis.
Abstract: Galectin-1 (Gal1), a β-galactoside-binding protein abundantly expressed in tumor microenvironments, is associated with the development of metastasis in hepatocellular carcinomas (HCC). However, the precise roles of Gal1 in HCC cell invasiveness and dissemination are uncertain. Here, we investigated whether Gal1 mediate epithelial-mesenchymal transition (EMT) in HCC cells, a key process during cancer progression. We used the well-differentiated and low invasive HepG2 cells and performed 'gain-of-function' and 'loss-function' experiments by transfecting cells with Gal1 cDNA constructs or by siRNA strategies, respectively. Epithelial and mesenchymal markers expression, changes in apico-basal polarity, independent-anchorage growth, and activation of specific signaling pathways were studied using Western blot, fluorescence microscopy, soft-agar assays, and FOP/TOP flash reporter system. Gal1 up-regulation in HepG2 cells induced down-regulation of the adherens junction protein E-cadherin and increased expression of the transcription factor Snail, one of the main inducers of EMT in HCC. Enhanced Gal1 expression facilitated the transition from epithelial cell morphology towards a fibroblastoid phenotype and favored up-regulation of the mesenchymal marker vimentin in HCC cells. Cells overexpressing Gal1 showed enhanced anchorage-independent growth and loss of apico-basal polarity. Remarkably, Gal1 promoted Akt activation, β-catenin nuclear translocation, TCF4/LEF1 transcriptional activity and increased cyclin D1 and c-Myc expression, suggesting activation of the Wnt pathway. Furthermore, Gal1 overexpression induced E-cadherin downregulation through a PI3K/Akt-dependent mechanism. Our results provide the first evidence of a role of Gal1 as an inducer of EMT in HCC cells, with critical implications in HCC metastasis.

59 citations

Journal ArticleDOI
TL;DR: A novel role for gal-8 is described in the regulation of vascular and lymphatic angiogenesis and evidence of its critical implications in tumor biology is provided, including cell adhesion and migration, which collectively demonstrate the multi-functionality of this complex lectin.
Abstract: Fil: Troncoso, Maria Fernanda. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Quimica y Fisico-Quimica Biologicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Quimica y Fisico-Quimica Biologicas; Argentina

53 citations

Journal ArticleDOI
TL;DR: Current knowledge on the intracellular signaling pathways triggered by this multifunctional family of β‐galactoside‐binding proteins in selected physiological and pathological settings are discussed.
Abstract: Summary Galectins are a family of evolutionarily conserved animal lectins with pleiotropic functions and widespread distribution. Fifteen members have been identified in a wide variety of cells and tissues. Through recognition of cell surface glycoproteins and glycolipids, these endogenous lectins can trigger a cascade of intracellular signaling pathways capable of modulating cell differentiation, proliferation, survival, and migration. These cellular events are critical in a variety of biological processes including embryogenesis, angiogenesis, neurogenesis, and immunity and are substantially altered during tumorigenesis, neurodegeneration, and inflammation. In addition, galectins can modulate intracellular functions and this effect involves direct interactions with distinct signaling pathways. In this review, we discuss current knowledge on the intracellular signaling pathways triggered by this multifunctional family of b-galactosidebinding proteins in selected physiological and pathological settings. Understanding the ‘‘galectin signalosome’’ will be essential to delineate rational therapeutic strategies based on the specific control of galectin expression and function. 2009 IUBMB IUBMB Life, 62(1): 1–13, 2010

51 citations


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TL;DR: The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks and NF-κB activation is a central event leading to the activation of these networks.
Abstract: The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-κB activation is a central event leading to the activation of these networks. The rol...

674 citations

Journal ArticleDOI
TL;DR: The observed increase of apoptotic PMNs and macrophages and the poor ability of macrophage from patients with SLE to phagocytose apoptotic bodies may indicate an impaired clearance mechanism, which may be mediated by factors in a patient's serum.
Abstract: Objective To evaluate whether patients with systemic lupus erythematosus (SLE) have a higher rate of apoptosis in and secondary necrosis of polymorphonuclear neutrophils (PMNs) and macrophages compared with controls; to compare the rate of macrophage phagocytic clearance of apoptotic PMNs in patients with SLE and healthy controls; to evaluate whether in vitro PMN and macrophage apoptosis and secondary necrosis, and the ability of macrophages to phagocytose apoptotic bodies, are correlated with lupus disease activity; and to determine whether macrophage clearance of apoptotic bodies in patients with SLE and normal controls is related to certain serum factors. Methods Thirty-six patients with SLE and 18 healthy, nonsmoking volunteers were studied. PMNs and monocytes were isolated from fresh blood and cultured in the presence of different sources of serum. Apoptotic PMNs and macrophages were examined by annexin V binding and morphology on May-Giemsa-stained cytopreparations, at different time points. The presence of secondary necrotic PMNs and macrophages was verified by staining with trypan blue. Macrophage phagocytosis of apoptotic PMNs was measured using a coded, observer-blinded, microscopically quantified phagocytosis assay. Cells were cultured in the presence of serum obtained from healthy subjects or from patients with SLE. Results At 5 and 24 hours, the percentage of apoptotic PMNs from patients with SLE was significantly higher than that of PMNs from healthy subjects. At 24 and 48 hours, the percentage of secondary necrotic PMNs from patients with SLE was also significantly higher than the percentage of necrotic PMNs from controls. Serum from patients with SLE accelerated the rate of apoptosis in and secondary necrosis of PMNs from healthy subjects. Macrophages from SLE patients were less capable of phagocytosing apoptotic PMNs compared with macrophages obtained from controls. Macrophages from patients with active SLE were less capable of phagocytosing apoptotic PMNs than were macrophages from patients with inactive SLE, but the difference was not statistically significant. The percentage of phagocytosis of apoptotic PMNs by macrophages from SLE patients correlated negatively with the SLE Disease Activity Index, serum levels of anti-double-stranded DNA, and the erythrocyte sedimentation rate, and correlated positively with serum levels of C3, C4, and albumin, the hemoglobin level, and the leukocyte count. Serum from SLE patients not only significantly increased macrophage apoptosis in cells from healthy subjects but also remarkably down-regulated the clearance of apoptotic PMNs by macrophages from healthy subjects. In contrast, serum from healthy subjects significantly increased phagocytosis of apoptotic PMNs by macrophages from SLE patients. Conclusion The observed increase of apoptotic PMNs and macrophages and the poor ability of macrophages from patients with SLE to phagocytose apoptotic bodies may indicate an impaired clearance mechanism, which may be mediated by factors in a patient's serum.

346 citations

Journal ArticleDOI
15 Nov 2004-Blood
TL;DR: The cross-talk between DCs and NK cells is dictated by functional synapses, and the synaptic delivery of IL-12 by DCs was required for IFN-gamma secretion by NK cells, as assessed using inhibitors of cytoskeleton rearrangements and transwell experiments.

331 citations

Journal ArticleDOI
Bali Pulendran1
TL;DR: The present review provides a summary of emerging themes in the biology DCs and TLRs, with a particular focus on relevance for vaccine development.
Abstract: The immune system is ignorant or even unresponsive to most foreign proteins that are injected in a soluble, deaggregated form, but when injected together with an immune-stimulating agent (i.e. an adjuvant, such as CpG-rich DNA), these foreign proteins can generate robust immunity and long-lived memory to the antigen. In fact, the nature of the adjuvant is what determines the particular type of immune response that follows, which may be biased towards cytotoxic T-cell responses, antibody responses, particular classes of T-helper responses, or antibody isotypes. Clearly, the ability of a vaccine to skew the response toward a particular type is of paramount importance, because different pathogens require distinct types of protective immunities. Therefore, the quest to manipulate the immune system to generate optimally effective immunity against different pathogens can justifiably be considered the 'grand challenge' of modern immunology. Central to this issue is a rare but widely distributed network of cells known as dendritic cells (DCs). DCs, which have been called 'Nature's adjuvants,' express pathogen recognition receptors, such as the Toll-like receptors (TLRs) and C-type lectins, which enable them to sense and respond to microbes or vaccines. Research in the last decade has demonstrated a fundamental role for DCs in initiating and controlling the quality and strength of the immune response. As such, DCs and TLRs represent attractive immune modulatory targets for vaccinologists. The present review provides a summary of emerging themes in the biology DCs and TLRs, with a particular focus on relevance for vaccine development.

322 citations