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1.
Leukemia ; 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131584

RESUMO

TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.

2.
Int J Cancer ; 143(11): 2943-2954, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29987839

RESUMO

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin-6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis-regulatory sequences by co-binding of GLI and STAT3 to common HH-IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI-driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH-IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

3.
J Child Fam Stud ; 27(7): 2315-2327, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29937680

RESUMO

In the present study, we investigated whether fathers' and mothers' parenting behavior is differentially related to parental factors (such as age and employment), child factors (age and gender) as well as social support. Parents reported on their use of a broad range of parenting behaviors, including affection, responsivity, explaining, autonomy, support, rewarding, and punishing. We used survey data from the Netherlands for 1197 mothers and 903 fathers of children aged 2 to 17. Seemingly unrelated regression analyses were conducted to combine the regression results on the separate subsamples (fathers and mothers) and to test for differences in the coefficients between those subsamples. Our expectation that the parenting behavior of fathers is more dependent on parents' characteristics, children's characteristics, and social support than that of mothers was only partly confirmed by the results of our analysis. In general, our results suggest that fathers' parenting behaviors seem to be associated with parental and child characteristics and contextual factors in ways that are similar to how these factors are associated with mothers' parenting behaviors. Results are discussed in relation to the roles and expectations associated with motherhood and fatherhood.

4.
Blood ; 131(12): 1337-1349, 2018 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-29352038

RESUMO

Chronic lymphocytic leukemia (CLL) outgrowth depends on signals from the microenvironment. We have previously found that in vitro reconstitution of this microenvironment induces specific variant isoforms of the adhesion molecule CD44, which confer human CLL with high affinity to hyaluronan (HA). Here, we determined the in vivo contribution of standard CD44 and its variants to leukemic B-cell homing and proliferation in Tcl1 transgenic mice with a B-cell-specific CD44 deficiency. In these mice, leukemia onset was delayed and leukemic infiltration of spleen, liver, and lungs, but not of bone marrow, was decreased. Competitive transplantation revealed that CLL homing to spleen and bone marrow required functional CD44. Notably, enrichment of CD44v6 variants particularly in spleen enhanced CLL engraftment and proliferation, along with increased HA binding. We recapitulated CD44v6 induction in the human disease and revealed the involvement of MAPK and NF-κB signaling upon CD40 ligand and B-cell receptor stimulation by in vitro inhibition experiments and chromatin immunoprecipitation assays. The investigation of downstream signaling after CD44v6-HA engagement uncovered the activation of extracellular signal-regulated kinase and p65. Consequently, anti-CD44v6 treatment reduced leukemic cell proliferation in vitro in human and mouse, confirming the general nature of the findings. In summary, we propose a CD44-NF-κB-CD44v6 circuit in CLL, allowing tumor cells to gain HA binding capacity and supporting their proliferation.

5.
Prev Vet Med ; 145: 78-82, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903879

RESUMO

Salmonella (S.) enterica subspecies diarizonae (IIIb) serovar 61:(k):1,5,(7) (S. IIIb 61:(k):1,5,(7)) is considered to be host adapted to sheep and is found regularly in feces of healthy carriers and of sheep with salmonellosis. A few cases of chronic proliferative rhinitis (CPR) in sheep have been described as a new disease in association with S. IIIb 61:k:1,5,(7) in the USA, in Spain and now for the first time in Switzerland. Three animals of a flock of Texel sheep suffering from chronic nasal discharge and dyspnea with subsequent death were necropsied. The pathological lesions are consistent with a severe proliferation of the nasal mucosae of the turbinates in association with severe chronic inflammation. S. IIIb 61:(k):1,5,(7) was isolated from the lesions by direct bacteriological culture and the presence of Salmonella spp. was confirmed by immunohistochemistry. The affected flock was systematically tested after the first occurrence of the disease. Clinical examination of the flock revealed approx. 20% of the adult sheep to show nasal discharge, approx. 5% having severe dyspnea and approx. 5% having chronic intermittent diarrhea. Lambs (n=28) showed no clinical signs at all. High positivity of nasal mucosa (46%), but low prevalence in feces (6%) for S. IIIb 61:k:1,5,(7) was found. The results lead to the assumption of a direct animal to animal transmission by nasal discharge followed by a chronic disease leading to death after several months to years. Animals tested positive for S. IIIb 61:k:1,5,(7) were all >1year old. CPR represents a chronic disease in adult sheep posing a risk for spreading S. IIIb 61:k:1,5,(7) between flocks and with a zoonotic potential.


Assuntos
Rinite/veterinária , Salmonelose Animal/microbiologia , Salmonella enterica/classificação , Doenças dos Ovinos/microbiologia , Animais , Doença Crônica , Rinite/microbiologia , Rinite/patologia , Salmonelose Animal/patologia , Salmonella enterica/crescimento & desenvolvimento , Sorogrupo , Ovinos , Doenças dos Ovinos/patologia , Suíça
6.
Blood ; 129(3): 371-382, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-27856463

RESUMO

Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. As found in other myeloproliferative neoplasms, increased production of profibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the proangiogenic cytokine CCL2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNA interference-mediated knockdown of KIT reduced expression of CCL2. We also found that nuclear factor κB contributes to KIT-dependent upregulation of CCL2 in mast cells. In addition, CCL2 secreted by KIT D816V+ mast cells was found to promote the migration of human endothelial cells in vitro. Furthermore, knockdown of CCL2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in vivo compared with CCL2-expressing cells. Finally, we measured CCL2 serum concentrations in patients with SM and found that CCL2 levels were significantly increased in mastocytosis patients compared with controls. CCL2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migration and angiogenesis in SM. CCL2 expression correlates with disease severity and prognosis. Whether CCL2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.


Assuntos
Medula Óssea/patologia , Quimiocina CCL2/sangue , Mastocitose Sistêmica/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Movimento Celular , Microambiente Celular , Quimiocina CCL2/fisiologia , Células Endoteliais/citologia , Fibrose , Humanos , Mastócitos/metabolismo , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/metabolismo , Mutação de Sentido Incorreto , Neovascularização Patológica , Prognóstico
7.
J Adolesc Health ; 59(3): 276-282, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27423901

RESUMO

PURPOSE: To assess the well-being and substance use of sexual minority adolescents growing up in a tolerant society, we examined differences among same-sex attracted (SSA), those who do not know their attraction yet (not yet attracted [NYA]), and heterosexual Dutch adolescents. METHODS: Unadjusted and adjusted logistic and linear multilevel analyses were performed using representative data of the 2013 Health Behaviour in School-Aged Children study (N = 5,995; 11-16 years old). The adjusted analyses controlled for sociodemographics (gender, age, education type, ethnicity, urbanicity, and religion). RESULTS: Adjusted results showed that SSA adolescents substantially more often reported alcohol use (adjusted odds ratio [AOR] = 2.01), tobacco smoking (AOR = 2.37), and cannabis smoking (AOR = 3.52) than their heterosexual peers, while NYA participants less often reported alcohol use (AOR = .57) and equal levels of tobacco (AOR = .71) and cannabis smoking (AOR = .87) compared with heterosexual adolescents. SSA adolescents reported lower levels of life satisfaction (b = -1.25) and higher levels of psychosomatic complaints (b = .61) and emotional problems (b = 1.57) than heterosexual adolescents. NYA adolescents reported equal levels of life satisfaction (b = -.18) and psychosomatic complaints (b = .06) as heterosexual adolescents, but higher levels of emotional problems (b = .51). CONCLUSIONS: In Dutch society, with over 20 years of inclusive policies for sexual minorities and generally tolerant population attitudes toward sexual minorities, SSA adolescents are still at increased risk of substance use and have lower levels of well-being compared with peers.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Fumar Cigarros/epidemiologia , Heterossexualidade/psicologia , Fumar Maconha/epidemiologia , Qualidade de Vida , Minorias Sexuais e de Gênero/estatística & dados numéricos , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Casamento/legislação & jurisprudência , Países Baixos/epidemiologia , Razão de Chances , Prevalência , Fatores de Risco , Autorrelato , Minorias Sexuais e de Gênero/psicologia
8.
Toxins (Basel) ; 7(4): 1235-52, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25860161

RESUMO

Beta-toxin (CPB) is the essential virulence factor of C. perfringens type C causing necrotizing enteritis (NE) in different hosts. Using a pig infection model, we showed that CPB targets small intestinal endothelial cells. Its effect on the porcine intestinal epithelium, however, could not be adequately investigated by this approach. Using porcine neonatal jejunal explants and cryosections, we performed in situ binding studies with CPB. We confirmed binding of CPB to endothelial but could not detect binding to epithelial cells. In contrast, the intact epithelial layer inhibited CPB penetration into deeper intestinal layers. CPB failed to induce cytopathic effects in cultured polarized porcine intestinal epithelial cells (IPEC-J2) and primary jejunal epithelial cells. C. perfringens type C culture supernatants were toxic for cell cultures. This, however, was not inhibited by CPB neutralization. Our results show that, in the porcine small intestine, CPB primarily targets endothelial cells and does not bind to epithelial cells. An intact intestinal epithelial layer prevents CPB diffusion into underlying tissue and CPB alone does not cause direct damage to intestinal epithelial cells. Additional factors might be involved in the early epithelial damage which is needed for CPB diffusion towards its endothelial targets in the small intestine.


Assuntos
Toxinas Bacterianas/toxicidade , Células Endoteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Animais , Linhagem Celular , Células Cultivadas , Células Endoteliais/patologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/citologia , Intestino Delgado , Suínos
9.
Eur J Public Health ; 25 Suppl 2: 46-50, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25805787

RESUMO

BACKGROUND: The quality of communication with parents is a determinant of health and well-being during adolescence, being predictive of self-esteem, self-rated health and the ability to navigate health risk behaviours. METHODS: This article describes trends in adolescent's (aged 11, 13 and 15 years) perception of communication with mothers and fathers by gender across 32 European and North American countries from 2002 to 2010. Analyses were performed on 425 699 records employing a General Linear Model (MANOVA). RESULTS: In most countries, significant increases in the prevalence of ease of communication with both mothers and fathers were observed, with the greatest positive changes over time in Estonia, Denmark and Wales. In some countries, the opposite trend was found with the greatest negative changes occurring in France, Slovenia and Poland. Across the pooled dataset, a significant positive trend was observed for ease of communication with father, for both boys and girls and for ease of communication with mother for boys only. CONCLUSION: The temporal trends demonstrated an increase in a positive health asset for many young people, that of family communication. Positive trends may be a feature of the economic boom over the past decade coupled with cultural changes in attitudes to parenting, especially fathering.


Assuntos
Comportamento do Adolescente , Relações Pais-Filho , Adolescente , Criança , Europa (Continente) , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , América do Norte
10.
Biomed Res Int ; 2014: 715841, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24689051

RESUMO

Mycobacterium avium subsp. avium (Maa) is an intracellular pathogen belonging to the Mycobacterium avium-intracellulare complex (MAC). Reservoirs of MAC are the natural environment, wildlife and domestic animals. In adult bovine, MAC infections are typically caused by Mycobacterium avium subsp. paratuberculosis (Map). Maa infections in bovine are rarely reported but may cause clinical disease and pathological lesions similar to those observed in paratuberculosis or those induced by members of the Mycobacterium tuberculosis complex (MTBC). Therefore, differentiation of MAC from MTBC infection should be attempted, especially if unusual mycobacterial lesions are encountered. Four veal calves from a fattening farm dying with clinical signs of otitis media, fever, and weight loss were submitted for necropsy. Samples from affected organs were taken for histologic investigation, bacteriologic culture, and bacterial specification using PCR. Macroscopic thickening of the intestinal mucosa was induced by granulomatous enteritis and colitis. Intracytoplasmic acid-fast bacteria were detected by Ziehl-Neelsen stains and PCR revealed positive results for Mycobacterium avium subsp. avium. Clinical and pathological changes of Maa infection in veal calves had features of Mycobacterium avium subsp. paratuberculosis and the MTBC. Therefore, Mycobacterium tuberculosis complex infection should be considered in cases of granulomatous enteritis in calves.


Assuntos
Mycobacterium avium/fisiologia , Tuberculose Gastrointestinal/diagnóstico , Tuberculose Gastrointestinal/veterinária , Animais , Bovinos , Diagnóstico Diferencial , Intestinos/microbiologia , Intestinos/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Reação em Cadeia da Polimerase , Tuberculose Gastrointestinal/microbiologia
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