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1.
Virus Res ; 347: 199416, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38897236

RESUMO

Epizootic haemorrhagic disease (EHD), caused by the EHD virus (EHDV), is a vector-borne viral disease transmitted through Culicoides biting midges. EHDV comprises seven serotypes (1, 2, and 4-8), with EHDV-8 having recently emerged and spread in Europe over the last two years. Such event has raised concerns about the significant threat posed by EHDV-8 to livestock industry. In this study, an inactivated vaccine against EHDV-8 (vEHDV8-IZSAM) was developed. Safety and efficacy of the vaccine were evaluated in calves through clinical, serological, and virological monitoring following experimental challenge. The vaccine was proven safe, with only transient fever and localized reactions observed in a few animals, consistent with adjuvanted vaccine side effects. vEHDV8-IZSAM elicited a robust humoral response, as evidenced by the presence of neutralizing antibodies. After challenge with a virulent isolate, viraemia and clinical signs were evidenced in control animals but in none of the vaccinated animals. This study highlights the potential of vEHDV8-IZSAM as a safe and highly effective vaccine against EHDV-8 in cattle. It offers protection from clinical disease and effectively prevents viraemia. With the recent spread of EHDV-8 in European livestock, the use of an inactivated vaccine could be key in protecting animals from clinical disease and thus to mitigate the economic impact of the disease. Further investigations are warranted to assess the duration of the induced immunity and the applicability of this vaccine in real-world settings. Accordingly, joint efforts between public veterinary institutions and pharmaceutical companies are recommended to scale up vaccine production.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Doenças dos Bovinos , Vírus da Doença Hemorrágica Epizoótica , Vacinas de Produtos Inativados , Vacinas Virais , Viremia , Animais , Bovinos , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Viremia/prevenção & controle , Doenças dos Bovinos/prevenção & controle , Doenças dos Bovinos/virologia , Doenças dos Bovinos/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Vírus da Doença Hemorrágica Epizoótica/imunologia , Infecções por Reoviridae/prevenção & controle , Infecções por Reoviridae/veterinária , Infecções por Reoviridae/imunologia , Eficácia de Vacinas , Vacinação/veterinária
2.
J Immunol ; 187(11): 5941-51, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22048771

RESUMO

Diacylglycerol kinases (DGKs) metabolize diacylglycerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of TCR signaling by decreasing diacylglycerol levels and inducing anergy. In this study, we show that upon costimulation of the TCR with CD28 or signaling lymphocyte activation molecule (SLAM), DGKα, but not DGKζ, exits from the nucleus and undergoes rapid negative regulation of its enzymatic activity. Inhibition of DGKα is dependent on the expression of SAP, an adaptor protein mutated in X-linked lymphoproliferative disease, which is essential for SLAM-mediated signaling and contributes to TCR/CD28-induced signaling and T cell activation. Accordingly, overexpression of SAP is sufficient to inhibit DGKα, whereas SAP mutants unable to bind either phospho-tyrosine residues or SH3 domain are ineffective. Moreover, phospholipase C activity and calcium, but not Src-family tyrosine kinases, are also required for negative regulation of DGKα. Finally, inhibition of DGKα in SAP-deficient cells partially rescues defective TCR/CD28 signaling, including Ras and ERK1/2 activation, protein kinase C membrane recruitment, induction of NF-AT transcriptional activity, and IL-2 production. Thus SAP-mediated inhibition of DGKα sustains diacylglycerol signaling, thereby regulating T cell activation, and it may represent a novel pharmacological strategy for X-linked lymphoproliferative disease treatment.


Assuntos
Diacilglicerol Quinase/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Western Blotting , Diglicerídeos/metabolismo , Imunofluorescência , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Jurkat , Transporte Proteico/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transfecção
3.
Microbiol Resour Announc ; 12(4): e0103422, 2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-36920210

RESUMO

In this report, we describe eight complete genome sequences of African horse sickness virus (AHSV) strains belonging to four different serotypes, namely, AHSV-5, AHSV-6, AHSV-8, and AHSV-9. Samples were collected in Namibia and South Africa from infected horses between 2000 and 2011. As expected, phylogenetic analyses of the variable outer capsid protein VP2 genomic sequences of AHSV-6 and AHSV-8 show higher nucleotide identity between the isolated viruses than that of the relevant reference strains. The full-genome sequence of AHSV will provide useful information on its geographical origin, and it will also be instrumental for comparing the distribution of the Namibian isolate with that of global isolates.

4.
Liver Transpl ; 23(2): 257-261, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28006872
5.
Vet Res Commun ; 46(2): 329-351, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35195874

RESUMO

Mastitis is one of the most impacting diseases in dairy farming, and its sensitive and specific detection is therefore of the greatest importance. The clinical evaluation of udder and mammary secretions is typically combined with the milk Somatic Cell Count (SCC) and often accompanied by its bacteriological culture to identify the causative microorganism. In a constant search for improvement, several non-enzymatic milk proteins, including milk amyloid A (M-SAA), haptoglobin (HP), cathelicidin (CATH), and lactoferrin (LF), have been investigated as alternative biomarkers of mastitis for their relationship with mammary gland inflammation, and immunoassay techniques have been developed for detection with varying degrees of success. To provide a general overview of their implementation in the different dairy species, we carried out a systematic review of the scientific literature using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Our review question falls within the type "Diagnostic test accuracy questions" and aims at answering the diagnostic question: "Which are the diagnostic performances of mastitis protein biomarkers investigated by immunoassays in ruminant milk?". Based on 13 keywords combined into 42 searches, 523 manuscripts were extracted from three scientific databases. Of these, 33 passed the duplicate removal, title, abstract, and full-text screening for conformity to the review question and document type: 78.8% investigated cows, 12.1% sheep, 9.1% goats, and 6.1% buffaloes (some included more than one dairy species). The most frequently mentioned protein was M-SAA (48.5%), followed by HP (27.3%), CATH (24.2%) and LF (21.2%). However, the large amount of heterogeneity among studies in terms of animal selection criteria (45.5%), index test (87.9%), and standard reference test (27.3%) resulted in a collection of data not amenable to meta-analysis, a common finding illustrating how important it is for case definitions and other criteria to be standardized between studies. Therefore, results are presented according to the SWiM (Synthesis Without Meta-analysis) guidelines. We summarize the main findings reported in the 33 selected articles for the different markers and report their results in form of comparative tables including sample selection criteria, marker values, and diagnostic performances, where available. Finally, we report the study limitations and bias assessment findings.


Assuntos
Doenças dos Bovinos , Doenças das Cabras , Mastite Bovina , Doenças dos Ovinos , Animais , Biomarcadores/análise , Bovinos , Contagem de Células/veterinária , Feminino , Cabras , Haptoglobinas/análise , Glândulas Mamárias Animais , Mastite Bovina/diagnóstico , Leite/química , Proteínas do Leite , Proteína Amiloide A Sérica/análise , Ovinos
6.
United European Gastroenterol J ; 9(1): 102-109, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33203342

RESUMO

BACKGROUND: Few data exist regarding the long-term effectiveness of golimumab in ulcerative colitis. No data have been reported on real-world continuous clinical response. OBJECTIVE: This study aimed to describe the long-term outcomes in a large cohort of patients on golimumab who had ulcerative colitis. METHODS: Consecutive patients with active ulcerative colitis, started on golimumab, were enrolled and prospectively followed up. The primary end point was to evaluate the long-term persistence on golimumab therapy. RESULTS: A total of 173 patients with ulcerative colitis were studied. Of these, 79.2% were steroid dependent, and 46.3% were naïve to anti-tumour necrosis factor alpha agents. The median duration of golimumab therapy was 52 weeks (range: 4-142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively. Biological-naïve status (odds ratio [OR] = 3.02, 95% confidence interval [CI]: 1.44-6.29; p = 0.003) and being able to discontinue steroids at Week 8 (OR = 3.32, 95% CI: 1.34-8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.08-8.02; p = 0.036) were associated with longer persistence on therapy. At Week 54, 65/124 (52.4%) postinduction responders were in continuous clinical response. A continuous clinical response was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (p < 0.01). Overall, 40 (23.1%) patients were in clinical remission at the last follow-up visit. Twenty-six adverse events were recorded, leading to golimumab withdrawal in 9.2% of patients. CONCLUSIONS: Biological-naïve status and not requiring steroids at Weeks 8 and 14 seem to be associated with a longer persistence on golimumab therapy in ulcerative colitis.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
7.
Mol Biol Cell ; 18(12): 4859-71, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17898083

RESUMO

Diacylglycerol kinases (Dgk) phosphorylate diacylglycerol (DG) to phosphatidic acid (PA), thus turning off and on, respectively, DG-mediated and PA-mediated signaling pathways. We previously showed that hepatocyte growth factor (HGF), vascular endothelial growth factor, and anaplastic lymphoma kinase activate Dgkalpha in endothelial and leukemia cells through a Src-mediated mechanism and that activation of Dgkalpha is required for chemotactic, proliferative, and angiogenic signaling in vitro. Here, we investigate the downstream events and signaling pathways regulated by Dgkalpha, leading to cell scatter and migration upon HGF treatment and v-Src expression in epithelial cells. We report that specific inhibition of Dgkalpha, obtained either pharmacologically by R59949 treatment, or by expression of Dgkalpha dominant-negative mutant, or by small interfering RNA-mediated down-regulation of endogenous Dgkalpha, impairs 1) HGF- and v-Src-induced cell scatter and migration, without affecting the loss of intercellular adhesions; 2) HGF-induced cell spreading, lamellipodia formation, membrane ruffling, and focal adhesions remodeling; and 3) HGF-induced Rac activation and membrane targeting. In summary, we provide evidence that Dgkalpha, activated downstream of tyrosine kinase receptors and Src, regulates crucial steps directing Rac activation and Rac-dependent remodeling of actin cytoskeleton and focal contacts in migrating epithelial cells.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Diacilglicerol Quinase/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Fator de Crescimento de Hepatócito/farmacologia , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Caderinas/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Diacilglicerol Quinase/genética , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/citologia , Humanos , Ligação Proteica
8.
Mol Biol Cell ; 18(3): 986-94, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17202410

RESUMO

Ghrelin is an acylated peptidyl gastric hormone acting on the pituitary and hypothalamus to stimulate appetite, adiposity, and growth hormone release, through activation of growth hormone secretagogue receptor (GHSR)-1a receptor. Moreover, ghrelin features several activities such as inhibition of apoptosis, regulation of differentiation, and stimulation or inhibition of proliferation of several cell types. Ghrelin acylation is absolutely required for both GHSR-1a binding and its central endocrine activities. However, the unacylated ghrelin form, des-acyl ghrelin, which does not bind GHSR-1a and is devoid of any endocrine activity, is far more abundant than ghrelin in plasma, and it shares with ghrelin some of its cellular activities. In here we show that both ghrelin and des-acyl ghrelin stimulate proliferating C2C12 skeletal myoblasts to differentiate and to fuse into multinucleated myotubes in vitro through activation of p38. Consistently, both ghrelin and des-acyl ghrelin inhibit C2C12 proliferation in growth medium. Moreover, the ectopic expression of ghrelin in C2C12 enhances differentiation and fusion of these myoblasts in differentiation medium. Finally, we show that C2C12 cells do not express GHSR-1a, but they do contain a common high-affinity binding site recognized by both acylated and des-acylated ghrelin, suggesting that the described activities on C2C12 are likely mediated by this novel, yet unidentified receptor for both ghrelin forms.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Hormônios Peptídicos/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Biomarcadores , Fusão Celular , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , DNA/biossíntese , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Grelina , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Dig Liver Dis ; 48(11): 1340-1345, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27476463

RESUMO

BACKGROUND: Recent data showed an increasing number of "autochthonous" cases of hepatitis E in Italy. AIMS: Analysing cases of acute hepatitis E to define frequency, clinical features, prognosis and risk factors. METHODS: We considered all the patients admitted to our Regional Hospital between August 2011 and September 2014, with a diagnosis of acute hepatitis; serological screening for hepatitis B, C and A viruses was performed; in the event of negative results, sera were tested for cytomegalovirus, Epstein-Barr and hepatitis E viruses. RESULTS: Among 200 patients, 66 were affected by viral infection. IgM anti-HEV was detected in 14 patients with a predominance of males (79%) with a mean age of 55. Genotype 3 of HEV was found in 8 patients. Only one patient died of acute on chronic liver failure; all others evolved favourably towards clinical remission within two months from clinical onset. Thirteen patients had had local exposure to infection and 9 reported the consumption of raw or undercooked locally produced pork. CONCLUSION: The incidence of HEV in our cohort of patients with acute viral hepatitis is high (about 20% per year). In over 85% an autochthonous exposure to infection could be recognised, with a clear link with food habits.


Assuntos
Doenças Transmitidas por Alimentos/epidemiologia , Hepatite E/epidemiologia , Insuficiência Hepática Crônica Agudizada/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Genótipo , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/genética , Humanos , Imunoglobulina M/sangue , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carne Vermelha , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
10.
Mol Cancer Ther ; 13(4): 916-25, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24552775

RESUMO

Accumulating evidence indicates that serum and tissue levels of lectin, galactoside-binding soluble 3 binding protein (LGALS3BP), a secreted glycoprotein, are elevated in human cancers. Recently, we have identified LGALS3BP as a factor capable of stimulating angiogenesis of microvascular endothelial cells in vitro as well as in vivo. However, the potential therapeutic implications of LGALS3BP function blockade have not been explored yet. Here, we tested the ability of an anti-LGALS3BP mouse monoclonal antibody, SP-2, to antagonize LGALS3BP-induced angiogenesis and tumor growth. The antibody was found to inhibit endothelial cell tubulogenesis induced by either conditioned medium of breast cancer and melanoma cells or human recombinant LGALS3BP. In addition, SP-2 inhibited phosphorylation of FAK and its recruitment to membrane sites as well as AKT and ERK phosphorylation promoted by LGALS3BP. When used in vivo, the antibody restrained LGALS3BP-stimulated angiogenesis and growth of tumor xenografts. Furthermore, the combination of SP-2 and low-dose bevacizumab was more effective than either agent alone. Taken together, these results lead to consideration of SP-2 as a promising candidate for LGALS3BP-targeted therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Proteínas de Transporte/antagonistas & inibidores , Glicoproteínas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Mamárias Experimentais , Camundongos , Camundongos Nus , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Transl Oncol ; 6(6): 676-84, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24466370

RESUMO

ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development of specific inhibitors impairing the activity of ErbB-3 is an attractive tool for cancer therapeutics. MP-RM-1, a murine monoclonal antibody targeting human ErbB-3, has shown anticancer activity in preclinical models. With the aim to provide novel candidates for clinical use, we have successfully generated a humanized version of MP-RM-1. The humanized antibody, named EV20, abrogates both ligand-dependent and ligand-independent receptor signaling of several tumor cell types, strongly promotes ErbB-3 down-regulation, and efficiently and rapidly internalizes into tumor cells. Furthermore, treatment with EV20 significantly inhibits growth of xenografts originating from prostatic, ovarian, and pancreatic cancers as well as melanoma in nude mice. In conclusion, we provide a novel candidate for ErbB-3-targeted cancer therapy.

12.
J Mol Med (Berl) ; 91(1): 83-94, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22864925

RESUMO

Elevated serum or tissue levels of lectin galactoside-binding soluble 3 binding protein (LGALS3BP) have been associated with short survival and development of metastasis in a variety of human cancers. However, the role of LGALS3BP, particularly in the context of tumor-host relationships, is still missing. Here, we show that LGALS3BP knockdown in MDA-MB-231 human breast cancer cells leads to a decreased adhesion to fibronectin, a reduced transendothelial migration and, more importantly, a reduced expression of vascular endothelial growth factor (VEGF). Production of VEGF, that was restored by exposure of silenced cells to recombinant LGALS3BP, required an intact PI3k/Akt signaling. Furthermore, we show that LGALS3BP was able to directly stimulate HUVEC tubulogenesis in a VEGF-independent, galectin-3-dependent manner. Immunohistochemical analysis of human breast cancer tissues revealed a correlation among LGALS3BP expression, VEGF expression, and blood vessel density. We propose that in addition to its prometastatic role, LGALS3BP secreted by breast cancer cells functions critically as a pro-angiogenic factor through a dual mechanism, i.e by induction of tumor VEGF and stimulation of endothelial cell tubulogenesis.


Assuntos
Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/irrigação sanguínea , Carcinoma Ductal de Mama/irrigação sanguínea , Carcinoma Lobular/irrigação sanguínea , Proteínas de Transporte/genética , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Feminino , Galectina 3/metabolismo , Técnicas de Silenciamento de Genes , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neovascularização Patológica , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
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