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BACKGROUND: Anti-CD20 B-cell depletion has not shown superior efficacy to standard immunosuppression in patients with systemic lupus erythematosus (SLE). Besides trial design, potential explanations are incomplete B-cell depletion in relation to substantial surges in B-cell-activating factor (BAFF). To improve B-cell targeting strategies, we conducted the first study in SLE patients aimed at investigating immunological effects and feasibility of combining rituximab (RTX; anti-CD20) and belimumab (BLM; anti-BAFF). METHODS: Reported is the long-term follow-up of a Phase 2 proof-of-concept study in 15 patients with SLE including 12 (80%) with lupus nephritis (LN). RESULTS: In 10/15 (67%) patients, a clinical response was observed by achievement of lupus low disease activity state, of which 8 (53%) continued treatment (BLM + ≤7.5 mg prednisolone) for the complete 2 years of follow-up. Five patients (33%) were referred to as 'non-responders' due to persistent LN, major flare or repetitive minor flares. Out of 12 LN patients, 9 (75%) showed a renal response including 8 (67%) complete renal responders. All anti-dsDNA+ patients converted to negative, and both anti-C1q and extractable nuclear antigen autoantibodies showed significant reductions. CD19+ B cells showed a median decrease from baseline of 97% at 24 weeks, with a persistent reduction of 84% up to 104 weeks. When comparing responders with non-responders, CD20+ B cells were depleted significantly less in non-responders and double-negative (DN) B cells repopulated significantly earlier. CONCLUSIONS: Combined B-cell targeted therapy with RTX and BLM prevented full B-cell repopulation including DN B cells, with concomitant specific reduction of SLE-relevant autoantibodies. The observed immunological and clinical benefits in a therapy-refractory SLE population prompt further studies on RTX + BLM.
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Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais Humanizados , Linfócitos B , Humanos , Imunomodulação , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Rituximab/uso terapêuticoRESUMO
BACKGROUND: The primary challenge of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patient care is the early detection of relapses to prevent organ damage and increase survival. Potential biomarkers for relapses are ANCA and B cells, but their predictive value is a matter of debate. Therefore this study investigated how ANCA and B-cell status related to relapses in AAV patients treated with rituximab (RTX) as remission induction (RI). METHODS: This single-centre cohort study identified 110 ANCA-positive AAV patients treated with RTX between 2006 and 2018. Serial ANCA, CD19+ B-cell status and relapses were assessed >2 years. RESULTS: Patients (31/110) relapsed within 2 years after RTX RI treatment. Patients who achieved and maintained PR3-ANCA negativity (n = 29) had few relapses (3%), while persistent proteinase 3 (PR3)-ANCA positivity (n = 49) and reappearance of PR3-ANCAs (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002). Patients with incomplete B-cell depletion (n = 11) had significantly more relapses (54%) as compared with patients with B-cell depletion [n = 76 (26%), P = 0.02]. Also, patients with repopulation of B cells (n = 58) had significantly more relapses (41%) as compared with patients without B-cell repopulation [n = 27 (15%), P = 0.03]. Overall, the absence of PR3- or myeloperoxidase (MPO)-ANCA positivity was highly predictive for remaining relapse-free. In PR3-ANCA-positive patients, 96% of the relapses occurred with persistent or reappearance of PR3-ANCAs and 81% with B-cell repopulation. In MPO-ANCA-positive patients, all relapses were restricted to patients with persistent MPO-ANCAs and B-cell repopulation. CONCLUSIONS: Upon RI treatment with RTX in AAV patients, ANCA and B-cell status were predictive of the majority of relapses and specifically their absence strongly predicted a relapse-free status. Therefore the implementation of ANCA and B-cell monitoring could guide therapeutic decision-making to prevent relapses in AAV patients treated with RTX.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Estudos de Coortes , Humanos , Mieloblastina , Peroxidase , Recidiva , Rituximab/uso terapêuticoRESUMO
OBJECTIVES: SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell-targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation. METHODS: Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation. RESULTS: Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ. CONCLUSION: This study demonstrated the impact of different B cell-targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.
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Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Imunidade Humoral/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Complexo Antígeno-Anticorpo/imunologia , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Rituximab/farmacologia , Rituximab/uso terapêuticoRESUMO
Background: B-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX. Methods: EuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA. Results: By employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138- plasmablasts (PBs) were rapidly and strongly reduced, while CD20-CD138- PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20- PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27- (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients. Conclusion: We demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Linfócitos B/imunologia , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Outcomes for mother and child following a diagnosis of Hodgkin lymphoma during pregnancy are underinvestigated, and antenatal management of the disease has not been reported on widely. The aim of this study was to assess obstetric outcomes, antenatal management, and maternal survival in patients with Hodgkin lymphoma diagnosed during pregnancy who were registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. METHODS: We did a multicentre, retrospective cohort study including oncological and obstetric data from 134 pregnant patients diagnosed with Hodgkin lymphoma between Jan 1, 1969, and Aug 1, 2018. Data collected from the INCIP database were obtained from 17 academic centres in Belgium, Czech Republic, Denmark, Greece, Israel, Italy, Mexico, the Netherlands, Russia, the UK, and the USA. We analysed patients' management over three epochs (before 1995, 1995-2004, and 2005-18). Obstetric outcomes (birthweight, obstetric or neonatal complications, and admission to a neonatal intensive care unit [NICU]) of patients who received antenatal chemotherapy were compared to those of patients who did not receive antenatal treatment. Maternal progression-free and overall survival was assessed by disease stage at diagnosis in pregnant patients and compared with outcomes of non-pregnant patients with Hodgkin lymphoma selected from databases of three tertiary centres, matched for stage and prognostic score. All patients included in survival analyses received standard doxorubicin, bleomycin, vinblastine and dacarbazone (ABVD) therapy since Jan 1, 1997. FINDINGS: Of the 134 pregnant patients diagnosed with Hodgkin lymphoma during pregnancy. 72 (54%) patients initiated antenatal chemotherapy, 56 (42%) did not receive treatment during pregnancy, and 6 (4%) received only radiotherapy. Over the years, chemotherapy was increasingly commenced during pregnancy. The incidence of neonates who were small for gestational age did not differ between chemotherapy-exposed neonates (15 [22%] of 69) and non-exposed neonates (six [16%] of 42; p=0·455). Admission to NICU also did not differ between groups (19 [29%] exposed to antenatal chemotherapy vs 12 [35%] unexposed to antenatal chemotherapy). Birthweight percentiles were lower in neonates prenatally exposed to chemotherapy compared with non-exposed neonates (p=0·035). Patients receiving antenatal therapy had more obstetric complications than those without antenatal therapy (p=0·005), the most common complications being preterm contractions (nine [12%] vs three [7%]) and preterm rupture of membranes (four [5%] vs 0). For the maternal survival analyses, we compared 77 pregnant patients and 211 non-pregnant, matched controls. 5-year progression-free survival for patients with early-stage Hodgkin lymphoma was 82·6% (95% CI 67·4-91·1) for 62 pregnant patients and 88·3% (81·6-92·7) for 142 controls (hazard ratio [HR] 1·80, 95% CI 0·84-3·87; p=0·130; 5-year overall survival was 97·3% (82·3-99·6) and 98·4% (93·6-99·6; HR 1·63, 0·35-7·65; p=0·534). In patients with advanced-stage disease (15 pregnant patients and 69 non-pregnant controls), 5-year progression-free survival was 90·9% (95% CI 50·8-98·7) versus 74·0% (60·9-83·3); HR 0·36, 95% CI 0·04-2·90; p=0·334. 5-year overall survival was 100% (no events occurred) and 96·2% (95% CI 85·5-99·1; HR cannot be estimated; p=0·146). INTERPRETATION: Occurrence of preterm contractions or preterm rupture of membranes was higher in patients with Hodgkin lymphoma receiving antenatal treatment compared with those who did not initiate treatment during pregnancy. Maternal survival did not differ between pregnant and non-pregnant patients with Hodgkin lymphoma, suggesting that antenatal chemotherapy or deferral of treatment until postpartum in selected patients can be considered, with regular obstetric follow-up to safeguard foetal growth. FUNDING: European Research Council, Research foundation Flanders, and Charles University Ministry of Health of the Czech Republic.
Assuntos
Doença de Hodgkin/diagnóstico , Adulto , Antineoplásicos/uso terapêutico , Parto Obstétrico , Intervalo Livre de Doença , Feminino , Idade Gestacional , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Doença de Hodgkin/radioterapia , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Nascido Vivo , Gravidez , Cuidado Pré-Natal , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies. However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs. This study aimed to examine whether the mechanisms of NET formation and the composition of NETs are distinct between AAV and SLE. METHODS: To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared. RESULTS: Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01). Lytic NET formation over several hours was observed in patients with AAV, as compared to rapid (within minutes), non-lytic NET formation coinciding with clustering of neutrophils in patients with SLE. AAV-induced NET formation was triggered independent of IgG ANCAs, whereas SLE immune complexes (ICx) induced NET formation through Fcγ receptor signaling. AAV-induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV-induced NETs were enriched for citrullinated histones (mean ± SEM 23 ± 2%). In contrast, SLE-induced NETs had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA, and were involved in ICx formation. CONCLUSION: The morphologic features, kinetics, induction pathways, and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE. Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiologic role of NETs in these different autoimmune diseases.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Formação de Anticorpos/fisiologia , Armadilhas Extracelulares/fisiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Neutrófilos/imunologia , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , MasculinoRESUMO
Neutrophil extracellular traps (NETs) are immunogenic extracellular DNA structures that can be released by neutrophils upon a wide variety of triggers. NETs have been demonstrated to serve as an important host defense mechanism that traps and kills microorganisms. On the other hand, they have been implicated in diverse systemic autoimmune diseases. NETs are immunogenic and toxic structures that contain a pool of relevant autoantigens including anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). Different forms of NETs can be induced depending on the stimulus. The amount of NETs can be quantified using different techniques including measuring DNA release in supernatants, measuring DNA-complexed with NET-molecules like myeloperoxidase (MPO) or neutrophil elastase (NE), measuring the presence of citrullinated histones by fluorescence microscopy, or flow cytometric detection of NET-components which all have different features regarding their specificity, sensitivity, objectivity, and quantity. Here is a protocol to quantify ex vivo NET formation in a highly-sensitive, high-throughput manner by using three-dimensional immunofluorescence confocal microscopy. This protocol can be applied to address various research questions about NET formation and degradation in health and disease.
Assuntos
Armadilhas Extracelulares/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Neutrófilos/imunologia , HumanosRESUMO
Neutrophil extracellular traps (NETs) are extracellular DNA structures covered with antimicrobial peptides, danger molecules, and autoantigens that can be released by neutrophils. NETs are an important first-line defense mechanism against bacterial, viral, fungal, and parasitic infections, but they can also play a role in autoimmune diseases. NETs are immunogenic and toxic structures that are recognized by the autoantibodies of patients with antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) (i.e., against myeloperoxidase or proteinase-3) and systemic lupus erythematosus (SLE) (i.e., against double-stranded DNA, histones, or nucleosomes). There is cumulating preclinical and clinical evidence that both excessive formation and impaired degradation of NETs are involved in the pathophysiology of AAV and SLE. These autoimmune diseases give rise to 2 clinically and pathologically distinct forms of glomerulonephritis (GN), respectively, crescentic pauci-immune GN and immune complex-mediated GN. Therefore, it is relevant to understand the different roles NET formation can play in the pathophysiology of these most prevalent renal autoimmune diseases. This review summarizes the current concepts on the role of NET formation in the pathophysiology of AAV and SLE, and provides a translational perspective on the clinical implications of NETs, such as potential therapeutic approaches that target NET formation in these renal autoimmune diseases.
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BACKGROUND: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. METHODS: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3 cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3 cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). DISCUSSION: If thermal ablation proves to be non-inferior in treating lesions ≤3 cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. TRIAL REGISTRATION: NCT03088150 , January 11th 2017.
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Neoplasias Colorretais/cirurgia , Neoplasias Hepáticas/cirurgia , Fígado/cirurgia , Adulto , Idoso , Ablação por Cateter/efeitos adversos , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Resultado do TratamentoRESUMO
Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA-associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA-independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Autoimunidade , Armadilhas Extracelulares/imunologia , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.
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INTRODUCTION: Female sex workers (FSWs) are at risk for human papillomavirus (HPV)-induced diseases but are currently not targeted by the HPV vaccination program in the Netherlands. We explored determinants of their intention to get vaccinated against HPV in case vaccination would be offered to them. METHODS: In 2016, FSWs 18 years and older having a sexually transmitted infection consultation with the Prostitution & Health Center (P&G292) in Amsterdam, either at the clinic or at their working location, were invited to complete a questionnaire assessing sociopsychological determinants of HPV vaccination intention (scale ranging from -3 to +3). Determinants of HPV vaccination intention were assessed with univariable and multivariable linear regression. In addition, we explored the effect of out-of-pocket payment on intention. RESULTS: Between May and September 2016, 294 FSWs participated. The median age was 29 years (interquartile range, 25-37 years). Human papillomavirus vaccination intention was high (mean, 2.0; 95% confidence interval [CI], 1.8-2.2). In multivariable analysis, attitude (ß = 0.6; 95% CI, 0.5-0.7), descriptive norm (ß = 0.2; 95% CI, 0.1-0.3), self-efficacy (ß = 0.2; 95% CI, 0.1-0.3), beliefs (ß = 0.1; 95% CI, 0.0-0.2), and subjective norm (ß = 0.1; 95% CI, 0.0-0.2) seemed to be the strongest predictors of HPV vaccination intention (R = 0.54). Human papillomavirus vaccination intention decreased significantly to a mean of 0.2 when vaccination would require out-of-pocket payment of &OV0556;350. CONCLUSIONS: The HPV vaccination intention among FSWs seems relatively high and is most strongly constituted in attitudinal, normative, and self-efficacy beliefs. Out-of-pocket payment will probably have a negative impact on their HPV vaccination acceptability.
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Gastos em Saúde , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/economia , Profissionais do Sexo/psicologia , Vacinação/economia , Adulto , Feminino , Humanos , Intenção , Modelos Lineares , Países Baixos , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Profissionais do Sexo/estatística & dados numéricos , Inquéritos e Questionários , Vacinação/estatística & dados numéricosRESUMO
Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.
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Colite Ulcerativa/metabolismo , Colite/metabolismo , Doença de Crohn/metabolismo , Macrófagos/metabolismo , NF-kappa B/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/imunologia , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Doença de Crohn/patologia , Citocinas/biossíntese , Citocinas/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Células RAW 264.7 , Ácido Trinitrobenzenossulfônico/toxicidadeRESUMO
Programmed cell death-1 (PD-1) and its ligands, PD-L1 and PD-L2 maintain self-tolerance and modulate physiological immune responses. Recently, targeting the PD-1/PD-L1 pathway with blocking antibodies has emerged as a potentially promising approach to treat advanced cancers in adult patients. Since tumor PD-L1 expression is currently considered the most important predictive biomarker for successful checkpoint blockade, we summarize expression data for the most common tumors of childhood. Additionally, we give an introduction into PD-1 function in the immune system to then focus on PD-1 mediated tumor immune escape. Pediatr Blood Cancer 2015;62:190-197. © 2014 Wiley Periodicals, Inc.