PYGO2 (pygopus family PHD finger 2)

PYGO2 is member of a conserved family of plant homeo domain (PHD)-containing proteins and takes part in a wide range of developmental and transcriptional processes. The most relevant role played by PYGO2 is in Wnt signaling pathway, where it is required for β-catenin/TCF-dependent transcription, even if it has showed to have a crucial role also in absence of β-catenin in tissues such as eye and testis. PYGO2 is also known as a chromatin effector because of its implication in chromatin remodelling processes through regulation of histones methylation

FZD4 (frizzled class receptor 4)

Fzd4 is a receptor for Wnt proteins, belonging to the frizzled receptors family. Its stimulation can activate both Wnt/β-catenin canonical and Wnt/Ca2+ non canonical pathways. This receptor plays an important role in the development processes, in particular in the retinal vascularization: it binds the Norrin ligand, a Wnt-unrelated growth factor, and activates β-catenin signalling pathway. Mutations of FZD4 gene are associated with Familial Exudative Vitreoretinopathy (FEVR

Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions

Mesenchymal stromal cells (MSCs) are multipotent cells, immunomodulatory stem cells that are currently used for regenerative medicine and treatment of a number of inflammatory diseases, thanks to their ability to significantly influence tissue microenvironments through the secretion of large variety of soluble factors. Recently, several groups have reported the presence of extracellular vesicles (EVs) within MSC secretoma, showing their beneficial effect in different animal models of disease. Here, we used a standardized methodological approach to dissect the immunomodulatory effects exerted by MSC-derived EVs on unfractionated peripheral blood mononuclear cells and purified T, B and NK cells. We describe here for the first time: i. direct correlation between the degree of EV-mediated immunosuppression and EV uptake by immune effector cells, a phenomenon further amplified following MSC priming with inflammatory cytokines; ii. induction in resting MSCs of immunosuppressive properties towards T cell proliferation through EVs obtained from primed MSCs, without any direct inhibitory effect towards T cell division. Our conclusion is that the use of reproducible and validated assays is not only useful to characterize the mechanisms of action of MSC-derived EVs, but is also capable of justifying EV potential use as alternative cell-free therapy for the treatment of human inflammatory diseases

Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma.

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasmacells (PCs) represent attractive new therapeutic targets. The endothelin-1(EDN1) axis, consisting of EDN1 acting through EDN-receptor A(EDNRA) and B (EDNRB), was previously shown to be overexpressed inseveral tumours, including MM. However, there is incomplete understand-ing of how EDN1 axis regulates MM growth and response to therapy.Besides EDNRA, the majority of MM cell lines and primary malignant PCsexpress high levels of EDNRB and release EDN1. Similarly, bone-marrowmicroenvironment cells also secrete EDN1. Investigating the extent of epi-genetic dysregulation of EDNRB gene in MM, we found that hypermethyla-tion of EDNRB promoter and subsequent down-regulation of EDNRB genewas observed in PCs or B lymphocytes from healthy donors compared toEDNRB-expressing malignant PCs. Pharm acological blockade with the dualEDN1 receptor antagonist bosentan decreased cell viability and MAPK acti-vation of U266 and RPMI-8226 cells. Interestingly, the combination ofbosentan and the proteasome inhibitor bortezomib, currently approved forMM treatment, resulted in synergistic cytotoxic effects. Overall, our datahas uncovered EDN1-mediated autocrine and paracrine mechanisms thatregulate malignant PCs growth and drug response, and support EDN1receptors as new therapeutic targets in MM

Ocorrência de enfermidades virais em asininos (Equus asinus) no estado de São Paulo, Brasil

Among the diseases that affect equines, viral diseases play an important role from a health and economic point of view, especially influenza, viral arteritis, herpes infections and vesicular stomatitis. In the Brazilian literature, there is little or no account of the occurrence of infectious diseases in donkeys. Given the importance of donkeys in different activities and the lack of information on infections that may occur in these animals, the aim of this study was to determine the frequency of anti-equine herpesvirus (EHV), anti-equine arteritis virus (EAV), anti-vesicular stomatitis, and anti-equine influenza (H3N8) antibodies in the serum of 85 donkeys bred in some regions of the state of Sao Paulo. We found the following antibody frequencies: 50.6% (43/85) antibodies against influenza virus subtype H3N8, 47% (40/85) anti-EHV, and 20% (17/85) anti-EAV. The donkeys were not seropositive for vesicular stomatitis. The results suggested that the agents EHV, EAV, and equine influenza subtype H3N8 circulate among donkeys in some regions of the state of Sao Paulo, Brazil, reinforcing the importance of establishing a routine diagnosis and epidemiological study of this species.Dentre as doenças que acometem os equídeos, as enfermidades virais assumem um papel importante do ponto de vista sanitário e econômico, especialmente a influenza, arterite viral, as infecções herpéticas e a estomatite vesicular. Na literatura nacional, existe pouco ou nenhum relato sobre a ocorrência de enfermidades infecciosas nos asininos. Tendo em vista a importância dos asininos para diferentes atividades e a falta de informações sobre as doenças que acometem esses animais, este trabalho teve como objetivo estudar a frequência de anticorpos anti-EHV, antivírus da arterite equina, anti-estomatite vesicular e anti-influenza equina (H3N8) em 85 soros de jumentos criados no estado de São Paulo. Estimou-se que 50,6% apresentavam anticorpos contra o subtipo H3N8 do vírus da influenza; 47% (40/85) apresentavam anticorpos contra o EHV e 20% apresentavam anticorpos contra o vírus da arterite. Os jumentos não foram soro reagentes contra a estomatite vesicular. Os resultados obtidos sugerem que os agentes EHV, vírus da arterite equina e influenza equina subtipo H3N8, circulam entre os jumentos do estado de São Paulo, caracterizando a importância do estabelecimento de uma rotina diagnostica e estudos epidemiológicos na espécie

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML

Inquérito sorológico de lentiviroses de pequenos ruminantes (Maedi-Visna e artrite-encefalite caprina) no estado de São Paulo

The aim of this study was to carry out the serological occurrence of Maedi-Visna virus (MVV) and CAE virus (CAEV) in ovines and caprines breeding in São Paulo state. The test to detect MVV and CAEV antibodies was agar gel immunodiffusion (AGID). The detection of antibodies against MVV was 0,3% (4/1235) and against CAEV was 15,1% (30/199). Was carried analysis of risk factors associated with the presence of positive property for CAEV and Maedi-Visna. Variables were selected for both diseases, however, when these variables were used in multivariate logistic regression model were not identified risk factors for the infections. The CAEV infection in the São Paulo state has a wide spread and a high prevalence while MVV has low prevalence. It emphasizes the importance of prevention and control measures to reduce CAEV occurrence and prevent the spread of Maedi-Visna.O objetivo deste estudo foi determinar a frequência de animais soropositivos ao vírus da Maedi-Visna (MVV) em ovinos e ao vírus da CAE (CAEV) em caprinos criados no estado de São Paulo. Na pesquisa dos anticorpos séricos anti- MVV e anti-CAEV foi utilizada a técnica de imunodifusão em gel de ágar (IDGA). Dentre os ovinos estudados, 0,3% (4/1235) eram sororreagentes ao MVV e 15,1% caprinos (30/199) ao CAEV. Foi realizada a análise de fatores de risco associados à condição de propriedade positiva para CAEV e Maedi-Visna. Foram selecionadas variáveis para as duas enfermidades, no entanto, quando essas variáveis foram usadas na regressão logística múltipla, não foram identificados fatores de risco para as infecções. A infecção pelo CAEV no estado de São Paulo tem uma ampla disseminação e com uma alta prevalência enquanto que o MVV apresenta baixa prevalência. Ressalta-se a importância de medidas de prevenção e controle para diminuir a ocorrência da CAE e evitar a disseminação da Maedi-Visna

Assessment of the contribution of Wnt pathway modulators to acute myeloid leukemia chemosensitivity

La leucemia mieloide acuta (LAM) \ue8 la forma di leucemia mieloide pi\uf9 frequente e solo parzialmente curabile nell\u2019adulto, la recidiva dopo trattamento chemioterapico rimane ancora Il principale problema riscontrato nella cura di questa malattia. Recenti studi hanno dimostrato una disregolazione della via del segnale Wnt / \u3b2-catenina e il suol coinvolgimento nella crescita e nella ricorrenza di vari tumori, ma il suo ruolo nella LAM rimane controverso e poco chiaro. In questo studio, abbiamo studiato il ruolo del signaling Wnt / \u3b2-catenina nella proliferazione, sopravvivenza e chemioresistenza delle cellule LAM sia coltivate da sole o in co-coltura con cellule mesenchimali stromali del midollo osseo umano (HBM-MSCs). L'espressione di componenti della via Wnt \ue8 stata analizzata in linee cellulari LAM, blasti primari e HBM-MSCs da donatori sani e pazienti con LAM. Inoltre, abbiamo valutato se l'inibizione farmacologica della via Wnt potrebbe influenzare la vitalit\ue0 delle cellule LAM e la sensibilit\ue0 agli agenti chemioterapici, tra cui Ara-C e Idarubicina. Abbiamo scoperto che gli inibitori di Wnt riducono la proliferazione cellulare e la vitalit\ue0 delle cellule LAM sia in coltura che in co-coltura con HBM-MSCs, l'inibizione farmacologica della via Wnt ha inoltre notevolmente migliorato gli effetti di agenti chemioterapici in linee cellulari di LAM e in blasti leucemici primari in assenza o presenza di HBM-MSC. I nostri dati suggeriscono che il targeting della via Wnt pu\uf2 essere una nuova strategia terapeutica per migliorare l'efficacia degli agenti chemioterapici per il trattamento della LAMAcute myeloid leukemia (AML) is the most common and only partially curable malignant disorder in adults, as drug resistance leading to relapse or refractoriness still remains the major problem in the treatment of patients. Recent studies have demonstrated a dysregulation of Wnt/\u3b2-catenin signaling and involvement in the growth and recurrence of various tumors, but its role in AML remains controversial and unclear. In this study, we investigated the role of Wnt/\u3b2-catenin signaling in the proliferation, survival and chemoresistance of AML cells either cultured alone or in co-culture with human bone marrow mesenchymal stromal cells (hBM-MSCs). The expression of Wnt pathway components were analyzed in AML cell lines, primary blast cells and hBM-MSCs from healthy donors and AML patients. Moreover, we evaluated whether pharmacologic inhibition of Wnt signaling could affect AML cell viability and sensitivity to chemotherapeutic agents, including Ara-C and Idarubucin. We found that Wnt inhibitors reduced cell proliferation and viability of AML cells both cultured alone and in co-culture with hBM-MSCs , pharmacological inhibition of Wnt signaling significantly enhanced the effects of chemotherapeutic agents AML cell lines and primary blast cells in absence or presence of hBM-MSCs. Our data suggest that targeting Wnt pathway may be a new therapeutic strategy to enhance the effectiveness of chemotherapeutic agents for the treatment of AML

TNIK (TRAF2 and NCK interacting kinase)

The serine/threonine kinase Traf2- and Nck interacting kinase (TNIK), is a member of the germinal center kinase (GCK) family that has been reported to have an important role in the regulation of Jun N-terminal kinase pathway (JNK) activation and actin cytoskeleton. It has also been demonstrated that TNIK is an important activator of Wnt pathway, where it interacts with β-catenin/TCF4 complex, phosphorylates Tcf4 inducing the transcription of Wnt target genes. In several studies, the expression of TNIK has been established to be involved in different human cancers