RESUMO
Mycoplasma pneumoniae and Streptococcus pneumoniae are the most common bacterial causes of pneumonia in children. The clinical characteristics of pneumonia differ significantly between the two bacteria. We aimed to elucidate the differences in pathogenesis between M. pneumoniae and S. pneumoniae by characterizing the respiratory epithelial cell immune response to both pathogens. Using primary human bronchial epithelial cells in air-liquid interface cultures, we observed lower production of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in response to M. pneumoniae than to S. pneumoniae. In contrast to the differences in proinflammatory cytokine production, Toll-like receptor 2 (TLR2)-mediated signaling in response to M. pneumoniae was stronger than to S. pneumoniae. This difference largely depended on TLR1 and not TLR6. We found that M. pneumoniae, but not S. pneumoniae, also induced signaling of TLR10, a coreceptor of TLR2 that has inhibitory properties. M. pneumoniae-induced TLR10 signaling on airway epithelial cells was partially responsible for low IL-8 production, as blocking TLR10 by specific antibodies increased cytokine production. M. pneumoniae maintained Th2-associated cytokine production by epithelial cells, which concurs with the known association of M. pneumoniae infection with asthma. M. pneumoniae left IL-33 levels unchanged, whereas S. pneumoniae downregulated IL-33 production both under homeostatic and Th2-promoting conditions. By directly comparing M. pneumoniae and S. pneumoniae, we demonstrate that M. pneumoniae avoids induction of proinflammatory cytokine response despite its ability to induce robust TLR2 signaling. Our new findings suggest that this apparent paradox may be partially explained by M. pneumoniae-induced signaling of TLR2/TLR10.
Assuntos
Mycoplasma pneumoniae , Streptococcus pneumoniae , Criança , Citocinas , Células Epiteliais , Humanos , Interleucina-33 , Interleucina-8 , Receptor 2 Toll-Like/genéticaRESUMO
BACKGROUND: Recent studies have provided evidence for an important contribution of the immune system in the pathophysiology of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In this report, we investigated whether the inflammatory profile of pulmonary hypertension patients changes over time and correlates with patient WHO subgroups or survival. METHODS: 50 PAH patients (16 idiopathic (I)PAH, 24 Connective Tissue Disease (CTD)-PAH and 10 Congenital Heart Disease (CHD)-PAH), 37 CTEPH patients and 18 healthy controls (HCs) were included in the study. Plasma inflammatory markers at baseline and after 1-year follow-up were measured using ELISAs. Subsequently, correlations with hemodynamic parameters and survival were explored and data sets were subjected to unbiased multivariate analyses. RESULTS: At diagnosis, we found that plasma levels of interleukin-6 (IL-6) and the chemokines (C-X3-C) motif legend CXCL9 and CXCL13 in CTD-PAH patients were significantly increased, compared with HCs. In idiopathic PAH patients the levels of tumor growth factor-ß (TGFß), IL-10 and CXCL9 were elevated, compared with HCs. The increased CXCL9 and IL-8 concentrations in CETPH patients correlated significantly with decreased survival, suggesting that CXCL9 and IL-8 may be prognostic markers. After one year of treatment, IL-10, CXCL13 and TGFß levels changed significantly in the PAH subgroups and CTEPH patients. Unbiased multivariate analysis revealed clustering of PH patients based on inflammatory mediators and clinical parameters, but did not separate the WHO subgroups. Importantly, these multivariate analyses separated patients with < 3 years and > 3 years survival, in particular when inflammatory mediators were combined with clinical parameters. DISCUSSION: Our study revealed elevated plasma levels of inflammatory mediators in different PAH subgroups and CTEPH at baseline and at 1-year follow-up, whereby CXCL9 and IL-8 may prove to be prognostic markers for CTEPH patients. While this study is exploratory and hypothesis generating, our data indicate an important role for IL-8 and CXCL9 in CHD and CTEPH patients considering the increased plasma levels and the observed correlation with survival. CONCLUSION: In conclusion, our studies identified an inflammatory signature that clustered PH patients into WHO classification-independent subgroups that correlated with patient survival.
Assuntos
Citocinas/sangue , Mediadores da Inflamação/sangue , Hipertensão Arterial Pulmonar/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Cromossomos Humanos Par 14/genética , Glioma/genética , Glioma/patologia , Metilação de DNA , Feminino , Humanos , Masculino , Monossomia , Neurocitoma/genética , Neurocitoma/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologiaRESUMO
AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores/métodos , Adulto JovemRESUMO
BACKGROUND: Fibrocytes are implicated in Idiopathic Pulmonary Fibrosis (IPF) pathogenesis and increased proportions in the circulation are associated with poor prognosis. Upon tissue injury, fibrocytes migrate to the affected organ. In IPF patients, circulating fibrocytes are increased especially during exacerbations, however fibrocytes in the lungs have not been examined. Therefore, we sought to evaluate if fibrocytes can be detected in IPF lungs and we compare percentages and phenotypic characteristics of lung fibrocytes with circulating fibrocytes in IPF. METHODS: First we optimized flow cytometric detection circulating fibrocytes using a unique combination of intra- and extra-cellular markers to establish a solid gating strategy. Next we analyzed lung fibrocytes in single cell suspensions of explanted IPF and control lungs and compared characteristics and numbers with circulating fibrocytes of IPF. RESULTS: Using a gating strategy for both circulating and lung fibrocytes, which excludes potentially contaminating cell populations (e.g. neutrophils and different leukocyte subsets), we show that patients with IPF have increased proportions of fibrocytes, not only in the circulation, but also in explanted end-stage IPF lungs. These lung fibrocytes have increased surface expression of HLA-DR, increased intracellular collagen-1 expression, and also altered forward and side scatter characteristics compared with their circulating counterparts. CONCLUSIONS: These findings demonstrate that lung fibrocytes in IPF patients can be quantified and characterized by flow cytometry. Lung fibrocytes have different characteristics than circulating fibrocytes and represent an intermediate cell population between circulating fibrocytes and lung fibroblast. Therefore, more insight in their phenotype might lead to specific therapeutic targeting in fibrotic lung diseases.
Assuntos
Fibroblastos/patologia , Fibrose Pulmonar Idiopática/patologia , Leucócitos Mononucleares/patologia , Pulmão/patologia , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Citometria de Fluxo/métodos , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Leucócitos Mononucleares/metabolismo , Pulmão/metabolismo , MasculinoRESUMO
BACKGROUND: Chronic exposure to environmental triggers, such as house dust mite (HDM), drives T helper 2 (Th2) cell-mediated asthma. Recent evidence has shown that B-T cell interaction, and in particular germinal centre reactions and follicular T helper (Tfh) cells are required for the development of eosinophilic airway inflammation in HDM-driven models containing a sensitization and challenge phase. Whether B-T cell interactions are essential for pulmonary eosinophilic inflammation following chronic allergen provocation remains unknown. AIMS: In this study, we investigated the importance of B-T cell interaction in the development of eosinophilic airway inflammation and pulmonary remodelling in a chronic HDM-driven asthma model. METHODS: We exposed C57BL/6, Cd40l-/- , and Mb1-/- mice to HDM three times a week for five consecutive weeks. RESULTS: Chronic HDM exposure induced a pronounced eosinophilic allergic airway inflammation in broncho-alveolar lavage fluid (BALf) and lung tissue, associated with the formation of immunologically active inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. The absence of B cells or lack of CD40L signalling did not hamper eosinophilic inflammation in the airways, although the number of Tfh and Th2 cells was substantially reduced in the lungs. Importantly, type 2 innate lymphoid cell (ILC2) numbers in BALf and lung were not affected by the absence of B cells or B-T cell interaction. Furthermore, eosinophilic airway inflammation is not sufficient to induce pulmonary remodelling and airway hyperresponsiveness. CONCLUSION AND CLINICAL RELEVANCE: From these findings, we conclude that B-T cell interaction is required for robust Tfh and Th2 cell induction, but not essential for eosinophilic airway inflammation during a chronic HDM-driven asthma model.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Asma/patologia , Linfócitos B/imunologia , Comunicação Celular/imunologia , Eosinófilos/patologia , Pyroglyphidae/imunologia , Linfócitos T/imunologia , Remodelação das Vias Aéreas , Animais , Asma/metabolismo , Linfócitos B/metabolismo , Biomarcadores , Ligante de CD40/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais , Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismoAssuntos
Monofenol Mono-Oxigenase/análise , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Pré-Escolar , Metilação de DNA , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Monofenol Mono-Oxigenase/metabolismo , Tumor Rabdoide/metabolismo , Sensibilidade e Especificidade , Teratoma/metabolismoAssuntos
Carcinoma Papilar/patologia , Proteína SMARCB1/genética , Neoplasias da Medula Espinal/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/cirurgia , Humanos , Laminectomia , Masculino , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/cirurgia , Vértebras Torácicas , Resultado do TratamentoRESUMO
Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação/genética , Pseudoxantoma Elástico/genética , Transportadores de Cassetes de Ligação de ATP/química , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 16/genética , Análise Mutacional de DNA , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Genes Dominantes/genética , Genes Recessivos/genética , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Linhagem , Pseudoxantoma Elástico/patologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Deleção de Sequência/genéticaRESUMO
BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. RESULTS: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 µM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). CONCLUSION: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Cerebelares/genética , Reparo de Erro de Pareamento de DNA/genética , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Meduloblastoma/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Linhagem Celular Tumoral , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Criança , Pré-Escolar , Metilases de Modificação do DNA/biossíntese , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/biossíntese , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Proteína 1 Homóloga a MutL , Proteínas Nucleares/biossíntese , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Temozolomida , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genéticaRESUMO
INTRODUCTION: The management of complex cysts of the breast is an ongoing topic of discussion. The aim of this study was to determine the prevalence of underlying malignancy in radiologically diagnosed complex cysts, and to assess whether watchful waiting could be the preferred method to safely manage complex cysts of the breast. SUBJECTS AND METHODS: A single-center retrospective study was performed between May 2003 and November 2019 in the VieCuri Medical Centre. Women with a radiologically diagnosed complex cyst of the breast were included. Prevalence of underlying malignancy was calculated, as were absolute risk reduction and number needed to treat in order to diagnose malignancy. In addition, patient characteristics were compared to determine characteristics associated with malignancy. RESULTS: Of 78 radiologically diagnosed complex cysts of the breast, five (6,4%) were found to be malignant. The number needed to treat was calculated at 12,8 (absolute riks reduction 0,078). Age (P = 0,003) was associated with malignancy. CONCLUSION: Complex cysts of the breast could be managed more conservatively. Patient characteristics can be used to assess the eligibility for radiological follow-up. This, in turn, would lead to a lower NNT and possibly a decrease in disease burden and healthcare costs.
Assuntos
Cisto Mamário/patologia , Mama/patologia , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha/métodos , Líquido Cístico , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND AND PURPOSE: The 5th edition of the World Health Organization Classification of CNS tumors defines the CNS neuroblastoma FOXR2 in the group of embryonal tumors. Published clinical outcomes tend to suggest a favorable outcome after resection, craniospinal irradiation, and chemotherapy. This multicenter study aimed to describe imaging features of CNS neuroblastoma-FOXR2, which have been poorly characterized thus far. MATERIALS AND METHODS: On the basis of a previously published cohort of tumors molecularly classified as CNS neuroblastoma-FOXR2, patients with available imaging data were identified. The imaging features on preoperative MR imaging and CT data were recorded by 8 experienced pediatric neuroradiologists in consensus review meetings. RESULTS: Twenty-five patients were evaluated (13 girls; median age, 4.5 years). The tumors were often large (mean, 115 [ SD, 83] mL), showed no (24%) or limited (60%) perilesional edema, demonstrated heterogeneous enhancement, were often calcified and/or hemorrhagic (52%), were always T2WI-hyperintense to GM, and commonly had cystic and/or necrotic components (96%). The mean ADC values were low (687.8 [SD 136.3] × 10-6 mm2/s). The tumors were always supratentorial. Metastases were infrequent (20%) and, when present, were of nodular appearance and leptomeningeal. CONCLUSIONS: In our cohort, CNS neuroblastoma FOXR2 tumors showed imaging features suggesting high-grade malignancy and, at the same time, showed characteristics of less aggressive behavior. There are important differential diagnoses, but the results of this study may assist in considering this diagnosis preoperatively.
Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Embrionárias de Células Germinativas , Neuroblastoma , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Fatores de Transcrição Forkhead , Imageamento por Ressonância Magnética , Estudos Retrospectivos , MasculinoRESUMO
OBJECTIVES: The health problems of patients with rheumatoid arthritis and fibromyalgia are mostly invisible to others, which can lead to a discrepancy between patients' and spouses' appraisals of the severity of the health problems. As a consequence, some patients may feel 'invalidation' from their spouse, such as not being understood and believed. Aim of this study was to compare patients' and spouses' appraisals of the health status of patients with rheumatoid arthritis and patients with fibromyalgia, and to examine whether discrepancies in these appraisals are associated with invalidation experiences of the patient. METHODS: Eighty-four patients with rheumatoid arthritis and 95 patients with fibromyalgia filled out a health status questionnaire (MOS short-form general health survey, SF-20) and a questionnaire on invalidation by the spouse (Illness Invalidation Inventory, 3*I). The spouses appraised the patients' health status independently from the patients using a spouse version of the SF-20. RESULTS: Patients with fibromyalgia and their spouses appraised the patients' health status significantly worse than patients with rheumatoid arthritis and their spouses. The agreement between patients and spouses was generally fair with somewhat more agreement in rheumatoid arthritis than in fibromyalgia. Patient-spouse discrepancies in health status appraisals were not associated with invalidation experiences. CONCLUSIONS: The invisibility of health problems in fibromyalgia and rheumatoid arthritis is not accompanied by large patient-spouse discrepancies of health status appraisals, which suggests that invalidation by spouses is not dependent on observable evidence such as clinical signs of damage or pathology.
Assuntos
Artrite Reumatoide/psicologia , Dor Crônica/psicologia , Fibromialgia/psicologia , Nível de Saúde , Satisfação do Paciente , Cônjuges/psicologia , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Dor Crônica/fisiopatologia , Feminino , Fibromialgia/fisiopatologia , Fibromialgia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor , Avaliação de Processos em Cuidados de Saúde , Inquéritos e Questionários , SíndromeRESUMO
BACKGROUND: Patients with rheumatic diseases may face 'discounting' (denying and patronising) or 'lack of understanding' because of having symptoms without external clinical signs, but instruments to assess such invalidation experiences are lacking. OBJECTIVES: To develop and evaluate the Illness Invalidation Inventory (3*I), to compare invalidation experiences of two groups of patients who differ in visual signs and laboratory findings-rheumatoid arthritis (RA) and fibromyalgia-and to examine the association of invalidation with health status. METHODS: A questionnaire (eight items with respect to five sources: spouse, family, medical professionals, work environment and social services) was constructed. It was completed by 142 patients with RA and 167 patients with fibromyalgia. RESULTS: Principal axis factoring with oblimin rotation yielded two factors with high internal consistency (α>0.70): 'discounting' (five items) and 'lack of understanding' (three items). Patients with fibromyalgia experienced significantly more discounting and lack of understanding from their family, medical professionals, colleagues and social services than did patients with RA. Both patient groups experienced more invalidation from social services, colleagues and family than from medical professionals and spouses. More discounting and lack of understanding correlated with poorer mental well-being and social functioning in both patient groups. Discounting correlated with more physical disability and pain in patients with RA. CONCLUSIONS: The 3*I is a brief, reliable instrument for assessing patients' perceptions of invalidation from different sources, which differ between patient groups and are associated with health status. Future validation research should clarify the clinical impact of invalidation on treatment adherence and outcome.
Assuntos
Artrite Reumatoide/psicologia , Atitude Frente a Saúde , Compreensão , Fibromialgia/psicologia , Adulto , Idoso , Empatia , Feminino , Indicadores Básicos de Saúde , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Relações Profissional-Paciente , Psicometria , Serviço SocialRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive, and ultimately fatal, chronic interstitial lung disease characterized by enhanced extracellular matrix deposition. Repetitive alveolar epithelial injury triggers the early development of fibrosis. These injuries, in combination with dysregulated wound repair and fibroblast dysfunction, lead to ongoing tissue remodelling and fibrosis seen in end-stage pulmonary fibrosis. Although the exact etiology in IPF is unknown and probably diverse, all stages of fibrosis are accompanied by innate and adaptive immune responses. The role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. This view is partly the result of negative multicenter trials of anti-inflammatory drugs for IPF treatment. However, new insights on the role of macrophages, the loss of T-cell and B-cell tolerance leading auto-immune responses in IPF, and the interaction of immune cells with (myo)fibroblasts have led to a slow change of this opinion. Clearly, more insight is needed to integrate basic immune mechanisms into translational research and finally new IPF therapies. In this concise review, we will focus on the role of our innate and adaptive immune system in the initiation and perpetuation of IPF pathobiology. Next, we will discuss how immune responses are influenced by current anti-fibrotic treatments, such as pirfenidone and nintedanib and end with an overview of recent and upcoming therapeutic trials that target and modulate our immune system in patients with IPF.
Assuntos
Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Inflamação/imunologia , Imunidade Adaptativa/imunologia , Anti-Inflamatórios/uso terapêutico , Ensaios Clínicos como Assunto , Matriz Extracelular/patologia , Fibroblastos/patologia , Fibrose/classificação , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/etiologia , Imunidade Inata/imunologia , Indóis/uso terapêutico , Inflamação/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes. MATERIALS AND METHODS: Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival. RESULTS: Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas (n = 27), high-grade gliomas (n = 17), embryonal tumors (n = 7), atypical teratoid/rhabdoid tumors (n = 3), and ependymomas (n = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not. CONCLUSIONS: In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.
Assuntos
Tumores Neuroectodérmicos Primitivos/diagnóstico por imagem , Tumores Neuroectodérmicos Primitivos/genética , Pinealoma/diagnóstico por imagem , Pinealoma/genética , Neoplasias Supratentoriais/diagnóstico por imagem , Neoplasias Supratentoriais/genética , Adolescente , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Tumores Neuroectodérmicos Primitivos/classificação , Tumores Neuroectodérmicos Primitivos/patologia , Glândula Pineal/diagnóstico por imagem , Glândula Pineal/patologia , Pinealoma/patologia , Estudos Retrospectivos , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Neoplasias Supratentoriais/patologia , Teratoma/diagnóstico por imagem , Teratoma/genética , Teratoma/patologia , Adulto JovemRESUMO
The canalicular (apical) membrane of the hepatocyte contains an ATP-dependent transport system for organic anions, known as the multispecific organic anion transporter (cMOAT). The deduced amino acid sequence of cMOAT is 49% identical to that of the human multidrug resistance- associated protein (MRP) MRP1, and cMOAT and MRP1 are members of the same sub-family of adenine nucleotide binding cassette transporters. In contrast to MRP1, cMOAT was predominantly found intracellularly in nonpolarized cells, suggesting that cMOAT requires a polarized cell for plasma membrane routing. Therefore, we expressed cMOAT cDNA in polarized kidney epithelial MDCK cell lines. When these cells are grown in a monolayer, cMOAT localizes to the apical plasma membrane. We demonstrate that cMOAT causes transport of the organic anions S-(2,4-dinitrophenyl)-glutathione, the glutathione conjugate of ethacrynic acid, and S-(PGA1)-glutathione, a substrate not shown to be transported by organic anion transporters previously. Transport is inhibited only inefficiently by compounds known to block MRP1. We also show that cMOAT causes transport of the anticancer drug vinblastine to the apical side of a cell monolayer. We conclude that cMOAT is a 5'-adenosine triphosphate binding cassette transporter that potentially might be involved in drug resistance in mammalian cells.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Transporte/metabolismo , Células Epiteliais/metabolismo , Proteínas de Transporte de Ânions , Transporte Biológico Ativo , Compartimento Celular , Linhagem Celular , Membrana Celular/metabolismo , Polaridade Celular , Técnica Indireta de Fluorescência para Anticorpo , Glutationa/análogos & derivados , Glutationa/metabolismo , Humanos , Imuno-Histoquímica , Rim/citologia , Rim/metabolismo , Transfecção , Vimblastina/metabolismoRESUMO
Medulloblastoma is a malignant, invasive embryonal tumor of the cerebellum with preferential manifestation in children, predominantly neuronal differentiation and an inherent tendency to metastasize via CSF pathways. In this review we present an overview of the clinicopathological aspects of medulloblastoma and the recent developments in the biology and genetics of these embryonal brain tumors. Increased knowledge of the signaling pathways that play a role in normal cerebellum development and tumor formation may lead to new therapeutic approaches resulting in a higher cure rate and a better quality of life of medulloblastoma patients.
Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Animais , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Transdução de SinaisRESUMO
A healthy 1-year old girl visits her general practitioner with a solitary dome-shaped tumour on her thorax. The lesion is about one cm in diameter and is present since several months. Pathological research reveals a solitary giant molluscum contagiosum. This is a common viral disease of the childhood. In contrast to this case, mollusca contagiosa typically present as several small papules.
Assuntos
Molusco Contagioso/diagnóstico , Feminino , Humanos , LactenteRESUMO
Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.