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1.
Ann Pathol ; 44(2): 130-136, 2024 Mar.
Artigo em Francês | MEDLINE | ID: mdl-37798152

RESUMO

BACKGROUND: Castleman's disease is a rare and benign lymphoproliferative disorder which can be unicentric (UCD) or multicentric (MCD). UCD usually involves a single lymph node or less frequently a group of lymph nodes. The most common sites of nodal UCD presentation are the mediastinum, neck, abdomen and retroperitoneum. Rarely extranodal involvement has been reported. The intramuscular location is very unusual with only about 10 cases described in medical literature so far. CASE REPORT: We present a case of atypical localization of Castleman's disease occurring in the right gluteal area in a 40-years-old female patient. The patient was asymptomatic and clinical examination was unremarkable except for a right gluteal palpable mass. The CT scanner-guided needle core biopsy was inconclusive. A surgical excision was then performed that revealed a hyaline-vascular type of Castleman's disease. The patient has an uneventful post-operative course. CONCLUSION: The present case is instructive in the work-up of primary soft tissue tumors, for which Castleman's disease is extremely rare and not considered in the differential diagnosis of clinicians. Pathologists must be aware of its existence so that it can be evoked in the presence of a lymphoid population on histological examination.


Assuntos
Hiperplasia do Linfonodo Gigante , Humanos , Feminino , Adulto , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/cirurgia , Hiperplasia do Linfonodo Gigante/patologia , Linfonodos/patologia , Biópsia , Mediastino/patologia , Diagnóstico Diferencial
2.
Dermatology ; 239(6): 860-867, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37611553

RESUMO

BACKGROUND: The advancing evolution toward a Th2 immune environment confers a progressive immunosuppression in patients with longstanding cutaneous T-cell lymphoma (CTCL). The conjunction of the disease-related immunosuppression as well as the immunosuppressive character of some CTCL treatments increase the risk of infectious and neoplastic diseases, sometimes with fatal outcomes. OBJECTIVES: The aim of the study was to prospectively study the causes of death in a cohort of CTCL patients, in a tertiary university skin cancer center. METHODS: All CTCL patients who died between 2008 and 2020 were included. The cause of the death was classified as directly or indirectly related or unrelated to CTCL. RESULTS: Over the study period, 31 (13F/18m) patients with CTCL died (mean age: 75.2 years), mean delay between diagnosis and death: 3.2 years (min: 1, max: 12 years), 58.1% of death causes were classified as indirect (infection), 12.9% directly related (blastic transformation), 22.5% unrelated, and 6.5% of unknown cause. 51.6% of mycosis fungoides (MF) patients who died had early-stage disease (1A-2A) or were on remission. 45.2% of dead patients had advanced-stage MF (2B-4B). Mean CRP level is increased in patients who died from infection whereas LDH level increased in patients with blastosis. A tertiary center is expected to manage of a higher proportion of CTCL patients with advanced-stage disease. CONCLUSIONS: As infection represented more than 50% of the causes of death in CTCL patients, particular attention should be given to preventive measures such as anti-infective vaccination. Regular surveillance of CRP and LDH levels could be helpful for follow-up of MF patients, respectively, with regards to infection and blastosis.


Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Idoso , Causas de Morte , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Neoplasias Cutâneas/patologia , Pele/patologia
3.
Blood ; 135(5): 360-370, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31774495

RESUMO

The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.


Assuntos
Implantes de Mama/efeitos adversos , Epigênese Genética , Janus Quinases/metabolismo , Linfoma Anaplásico de Células Grandes/etiologia , Linfoma Anaplásico de Células Grandes/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Feminino , Genoma Humano , Humanos , Linfoma Anaplásico de Células Grandes/patologia , Pessoa de Meia-Idade , Mutação/genética
4.
Br J Clin Pharmacol ; 87(12): 4848-4852, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33899928

RESUMO

A drug-induced sarcoidosis-like reaction is a systemic granulomatous reaction indistinguishable from sarcoidosis and occurring in temporal relationship with a drug initiation. In this article, we report a patient who developed lung and liver granulomatous lesions following tocilizumab initiation for a giant cell arteritis. Infectious, toxic, neoplastic and inflammatory differential diagnoses were ruled out and lesions regressed after treatment cessation, leading to the diagnosis of tocilizumab induced sarcoidosis-like reaction. We review the 6 cases reported so far and emphasize the value of a prompt diagnosis. Finally, we discuss the potential pathophysiological mechanisms underlying this rare reaction, which could help to better understand the pathophysiology of sarcoidosis.


Assuntos
Anticorpos Monoclonais Humanizados , Sarcoidose , Anticorpos Monoclonais Humanizados/efeitos adversos , Diagnóstico Diferencial , Humanos , Fígado , Pulmão , Sarcoidose/induzido quimicamente , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico
5.
Kidney Int ; 95(3): 693-707, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30528263

RESUMO

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs (∼2 × 106/kg) on day 3 ± 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m2, compared to 32.5 ml/min/1.73m2 in controls and 29.3 ml/min/1.73m2 in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.


Assuntos
Rejeição de Enxerto/prevenção & controle , Terapia de Imunossupressão/métodos , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Administração Intravenosa , Idoso , Aloenxertos/imunologia , Aloenxertos/fisiopatologia , Linfócitos B , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Humanos , Terapia de Imunossupressão/efeitos adversos , Rim/imunologia , Rim/fisiopatologia , Contagem de Linfócitos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T Reguladores/imunologia , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do Tratamento
6.
Biol Blood Marrow Transplant ; 25(2): 204-215, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30326279

RESUMO

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4+ T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rγ null (NSG) mice. Naive human CD4+ T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A+IFNγ+ profile in vivo. Importantly, cotransfer of Th17-polarized cells (1 × 106) with PBMCs (1 × 106) exacerbated xGVHD compared with transplantation of PBMCs alone (2 × 106). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4+ T cells stimulated in nonpolarizing conditions (Th0 cells, 1 × 106 + 1 × 106 PBMCs) or with Th1-polarized cells (1 × 106 + 1 × 106 PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Células Th17/imunologia , Células Th17/transplante , Doença Aguda , Adulto , Animais , Feminino , Doença Enxerto-Hospedeiro/patologia , Xenoenxertos , Humanos , Interferon gama/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Th17/patologia
7.
Br J Cancer ; 116(6): 742-751, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28196064

RESUMO

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. METHODS: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. RESULTS: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. CONCLUSIONS: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Receptores ErbB/metabolismo , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Epirubicina/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Hepatol ; 67(1): 47-55, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28284916

RESUMO

BACKGROUND & AIMS: Mesenchymal stromal cell (MSC) infusion could be a means to establish tolerance in solid organ recipients. The aim of this prospective, controlled, phase I study was to evaluate the feasibility, safety and tolerability of a single infusion of MSCs in liver transplant recipients. METHODS: Ten liver transplant recipients under standard immunosuppression received 1.5-3×106/kg third-party unrelated MSCs on postoperative day 3±2, and were prospectively compared to a control group of ten liver transplant recipients. As primary endpoints, MSC infusion toxicity was evaluated, and infectious and cancerous complications were prospectively recorded until month 12 in both groups. As secondary endpoints, rejection rate, month-6 graft biopsies, and peripheral blood lymphocyte phenotyping were compared. Progressive immunosuppression weaning was attempted from month 6 to 12 in MSC recipients. RESULTS: No variation in vital parameters or cytokine release syndrome could be detected during and after MSC infusion. No patient developed impairment of organ functions (including liver graft function) following MSC infusion. No increased rate of opportunistic infection or de novo cancer was detected. As secondary endpoints, there was no difference in overall rates of rejection or graft survival. Month-6 biopsies did not demonstrate a difference between groups in the evaluation of rejection according to the Banff criteria, in the fibrosis score or in immunohistochemistry (including Tregs). No difference in peripheral blood lymphocyte typing could be detected. The immunosuppression weaning in MSC recipients was not successful. CONCLUSIONS: No side effect of MSC infusion at day 3 after liver transplant could be detected, but this infusion did not promote tolerance. This study opens the way for further MSC or Treg-based trials in liver transplant recipients. LAY SUMMARY: Therapy with mesenchymal stromal cells (MSCs) has been proposed as a means to improve results of solid organ transplantation. One of the potential MSC role could be to induce tolerance after liver transplantation, i.e. allowing the cessation of several medications with severe side effects. This study is the first-in-man use of MSC therapy in ten liver transplant recipients. This study did not show toxicity after a single MSC infusion but it was not sufficient to allow withdrawal of immunosuppression. CLINICAL TRIAL REGISTRATION NUMBER: Eudract: # 2011-001822-81, ClinicalTrials.gov: # NCT 01429038.


Assuntos
Transplante de Fígado , Transplante de Células-Tronco Mesenquimais , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
9.
Clin Proteomics ; 14: 9, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344541

RESUMO

BACKGROUND: Despite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages remains challenging and is important for reducing CRC incidence and increasing patient's survival. METHODS: We analysed 76 colorectal tissue samples originated from early CRC stages, normal or inflamed mucosa by label-free proteomics. The characterisation of three selected biomarker candidates was performed by immunohistochemistry on an independent set of precancerous and cancerous lesions harbouring increasing CRC stages. RESULTS: Out of 5258 proteins identified, we obtained 561 proteins with a significant differential distribution among groups of patients and controls. KNG1, OLFM4 and Sec24C distributions were validated in tissues and showed different expression levels especially in the two early CRC stages compared to normal and preneoplastic tissues. CONCLUSION: We highlighted three proteins that require further investigations to better characterise their role in early CRC carcinogenesis and their potential as early CRC markers.

10.
Rev Med Suisse ; 13(571): 1431-1434, 2017 Aug 23.
Artigo em Francês | MEDLINE | ID: mdl-28837281

RESUMO

Inflammatory bowel diseases are chronic diseases whose long-term evolution depends on the depth of remission. Their clinical and endoscopic evaluation is imperfect. The development of confocal endomicroscopy allows microscopic images to be obtained in vivo. These microscopic data are correlated with the activity of the disease. They predict a possible relapse of the disease and also predict the response to treatment with a biological agent, which allows to modify the therapy before the relapse or to make a rational choice between the different biological agents before introducing a new treatment.


Les maladies inflammatoires intestinales sont des maladies chroniques dont l'évolution au long cours dépend de la profondeur de la rémission. Leur évaluation clinique et endoscopique est imparfaite. Le développement de l'endomicroscopie confocale permet d'obtenir des images microscopiques in vivo qui sont corrélées à l'activité de la maladie. Ces données microscopiques permettent de prédire une éventuelle rechute de la maladie et la réponse au traitement par un agent biologique, ce qui amène à modifier la thérapeutique avant la rechute ou de réaliser un choix rationnel entre les différents agents biologiques avant d'instaurer un nouveau traitement.


Assuntos
Doenças Inflamatórias Intestinais , Microscopia Confocal , Doença Crônica , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/terapia , Recidiva
11.
Int J Cancer ; 137(2): 345-58, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25492101

RESUMO

Acquisition of an impaired functionality by plasmacytoid dendritic cells (pDCs) contributing to cancer progression has been documented in different types of cancers. In the present study, we postulate that molecules secreted by (pre)neoplastic epithelial cells of the genital tract (cervix/vulva) might attract pDCs but also modify their proper functionality, allowing these cells to initiate a tolerogenic response interfering with antitumor immunity. We demonstrated that pDCs are recruited during the cervical metaplasia-dysplasia-cancer sequence, through the action of their chemoattractant, chemerin. We showed that stimulated-pDCs exposed to cervical/vulvar tumor microenvironment display an altered phenotype. We also demonstrated that cervical/vulvar neoplastic keratinocytes inhibit the proper function of pDCs by decreasing their IFNα secretion in response to CpG oligonucleotides. In parallel, we observed that (pre)neoplastic areas of the cervix are infiltrated by FoxP3(+) Treg cells which colocalize with pDCs. Accordingly, pDCs cocultured with cervical/vulvar neoplastic keratinocytes have the capacity to induce a Treg cell differentiation from naïve CD4(+) T cells, which is in agreement with the development of a tolerogenic response. We identified HMGB1 as a soluble factor produced by neoplastic keratinocytes from the genital tract involved in pDCs functional alteration. Indeed, this molecule inhibited pDC maturation, decreased IFNα secretion following TLR9 stimulation and forced these cells to become tolerogenic. In contrast, inhibition of HMGB1 restored pDC phenotype. Our findings indicate that the use of inhibitory molecules notably directed against HMGB1 in cervical/vulvar (pre)neoplastic lesions might prevent alterations of pDCs functionality and represent an attractive therapeutic strategy to overcome immune tolerance in cancers.


Assuntos
Carcinogênese/imunologia , Colo do Útero/imunologia , Células Dendríticas/imunologia , Proteína HMGB1/imunologia , Carcinogênese/patologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Colo do Útero/metabolismo , Colo do Útero/patologia , Quimiocinas/imunologia , Quimiocinas/metabolismo , Técnicas de Cocultura , Células Dendríticas/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteína HMGB1/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Microscopia Confocal , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo , Microambiente Tumoral/imunologia
12.
Int J Cancer ; 136(5): 1043-52, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24839092

RESUMO

Recent studies have identified a putative cell of origin for cervical intraepithelial neoplasia (CIN) and cervical cancer at the squamocolumnar junction (SCJ) and suggest that these cells may not regenerate after excision (loop electrosurgical excision procedure). Our study addressed the impact of SCJ excision on the temporal dynamics, histologic and viral (human papillomavirus, HPV) characteristics of recurrent CIN. One hundred and thirty-one consecutive patients treated by excision and attending follow-up visits were enrolled. We compared recurrent and initial CIN with attention to excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype and SCJ immunophenotype. During the follow-up period (up to 4 years), 16 (12.2%) recurrences were identified. Four (25%) were identified at the first follow-up visit, closely resembled the initial CIN 2/3 in grade and HPV type and were typically SCJ marker positive [SCJ(+)], suggesting nonexcised (residual) disease. Twelve (75%) manifested after the first postoperative visit and all were in the ectocervix or in mature metaplastic epithelium. All of the 12 delayed recurrences were classified as CIN 1 and were SCJ (-). In total, 9 out of 11 SCJ (-) recurrences (82%) followed regressed spontaneously. Taken together, these results show that new lesions developing from any HPV infection are delayed and occur within the ectocervix or metaplastic epithelium. This markedly lower risk of CIN 2/3 after successful SCJ excision suggests that the removal of the SCJ could be a critical variable in reducing the risk of subsequent CIN 2/3 and cervical cancer.


Assuntos
Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Neoplasias de Células Escamosas/patologia , Infecções por Papillomavirus/patologia , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Eletrocirurgia , Feminino , Seguimentos , Humanos , Histerectomia , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Neoplasia Residual/cirurgia , Neoplasia Residual/virologia , Neoplasias de Células Escamosas/cirurgia , Neoplasias de Células Escamosas/virologia , Papillomaviridae , Infecções por Papillomavirus/cirurgia , Infecções por Papillomavirus/virologia , Prognóstico , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/cirurgia , Displasia do Colo do Útero/virologia
13.
Hepatology ; 59(3): 924-34, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23832580

RESUMO

UNLABELLED: Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. CONCLUSION: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens.


Assuntos
Neoplasias Colorretais , Heterogeneidade Genética , Neoplasias Hepáticas , Proteômica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Regulação Neoplásica da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Metabolismo dos Lipídeos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Am J Pathol ; 182(6): 2168-79, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23619476

RESUMO

Barrett's esophagus corresponds to the replacement of the normal esophageal squamous epithelium by a columnar epithelium through a metaplastic process. This tissue remodeling is associated with chronic gastroesophageal reflux and constitutes a premalignant lesion leading to a 30- to 60-fold increase in the risk to evolve into esophageal adenocarcinoma. The present study aimed to investigate a possible immune evasion in Barrett's esophagus favoring esophageal adenocarcinoma development. We demonstrated that myeloid and plasmacytoid dendritic cells are recruited during the esophageal metaplasia-dysplasia-carcinoma sequence, through the action of their chemoattractants, macrophage inflammatory protein 3α and chemerin. Next, we showed that, in contrast to plasmacytoid dendritic cells, myeloid dendritic cells, co-cultured with Barrett's esophagus and esophageal adenocarcinoma cell lines, display a tolerogenic phenotype. Accordingly, myeloid dendritic cells co-cultured with esophageal adenocarcinoma cell lines stimulated regulatory T cell differentiation from naïve CD4(+) T cells. In agreement with those results, we observed that both metaplastic areas and (pre)malignant lesions of the esophagus are infiltrated by regulatory T cells. In conclusion, soluble factors secreted by epithelial cells during the esophageal metaplasia-dysplasia-carcinoma sequence influence dendritic cell distribution and promote tumor progression by rendering them tolerogenic.


Assuntos
Esôfago de Barrett/imunologia , Transformação Celular Neoplásica/imunologia , Células Dendríticas/imunologia , Neoplasias Esofágicas/imunologia , Lesões Pré-Cancerosas/imunologia , Adenocarcinoma/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Quimiocina CCL20/metabolismo , Quimiocinas/metabolismo , Quimiotaxia/imunologia , Técnicas de Cocultura , Progressão da Doença , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Ligante RANK/metabolismo , Linfócitos T Reguladores/imunologia , Células Tumorais Cultivadas , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
15.
Transfusion ; 54(2): 353-63, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23772685

RESUMO

BACKGROUND: We investigated the ability of clinical-grade enriched human regulatory T cells (Treg) to attenuate experimental xenogeneic graft-versus-host disease (GVHD) induced by peripheral blood mononuclear cells (PBMNCs; autologous to Treg) infusion in NSG mice, as well as verified their inability to induce xenogeneic GVHD when infused alone. STUDY DESIGN AND METHODS: Human Treg were isolated from peripheral blood apheresis products with a cell separation system (CliniMACS, Miltenyi Biotec GmbH) using a two-step procedure (simultaneous CD8 and CD19 depletion followed by CD25-positive selection) in six independent experiments with six different healthy volunteer donors. Sublethally (2.5 Gy) irradiated NSG mice were given 2 × 10(6) cytapheresis (PBMNC) product cells intravenously (IV) without (PBMNC group) or with 1 × 10(6) Treg (PBMNC + Treg group), while other NSG mice received 2 × 10(6) enriched Treg alone (also in IV; Treg group). RESULTS: The first five procedures were successful at obtaining a relatively pure Treg population (defined as >50%), while the sixth procedure, due to a technical problem, was not (Treg purity, 42%). Treg cotransfusion significantly delayed death from xenogeneic GVHD in the first five experiments, (p < 0.0001) but not in the sixth experiment. Importantly, none of the mice given enriched Treg alone (Treg group) experienced clinical signs of GVHD, while, interestingly, the CD4+ cells found in these mice 26 days after transplantation were mainly conventional T cells (median CD25+FoxP3+ cells among human CD4+ total cells were only 2.1, 3.1, and 12.2% in spleen, marrow, and blood, respectively). CONCLUSIONS: Infusion of clinical-grade enriched Treg delayed the occurrence of xenogeneic GVHD without inducing toxicity in this murine model.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Animais , Remoção de Componentes Sanguíneos/métodos , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fatores de Tempo , Transplante Heterólogo
16.
Inflamm Bowel Dis ; 30(2): 240-246, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37042951

RESUMO

BACKGROUND AND AIMS: Confocal endomicroscopy is a technique allowing the in vivo assessment of the superficial layers of the mucosa. Preliminary studies have already suggested its added value in the assessment of endoscopic remission in inflammatory bowel disease. However, most of these studies were performed on patients still having incomplete mucosal healing. Our aim was to disclose persisting endomicroscopic anomalies in patients with full endoscopic remission and to compare them between vedolizumab- and anti-tumor necrosis factor-treated patients. METHODS: We screened patients with Crohn's disease (CD) or ulcerative colitis (UC) treated for more than 6 months with biologic therapy, and being in steroid-free clinical and biological remission. White light endoscopy and probe-based confocal laser endomicroscopy (pCLE) analysis were performed in the ileum, right colon, transverse colon, left colon, and rectum. Full endoscopic remission was defined by a Mayo endoscopic score of 0 in UC and no remaining ulcer or erosion in CD. Patients were prospectively followed up and clinical relapses were recorded. RESULTS: Seventy-two CD and UC patients treated by biologic therapy and in clinical and biological remission were screened. A total of 37 were also in full endoscopic remission and were included in our study; 183 intestinal segments were analyzed. We found residual pCLE anomalies in most of the patients. These anomalies were not significantly associated with any demographic or clinical characteristic including the treatment received, nor were they associated with histological parameters, levels of C-reactive protein or fecal calprotectin. Among the 37 patients, 7 (18.9%) relapsed over a median follow-up of 33.7 months. The risk of relapse was not associated with any clinical, biological, histologic, or pCLE feature at baseline. CONCLUSION: Despite endoscopic, biological, and even histological remission, we found a high prevalence of endomicroscopic abnormalities, which were not different between anti-tumor necrosis factor- and vedolizumab-treated patients. The clinical significance of these anomalies remains to be clarified.


We studied the abnormalities found by confocal endomicroscopy in patients with chronic inflammatory disease in deep endoscopic remission under immunosuppressive treatment. Relapse was not associated with the abnormalities found, which, although numerous, remain of unknown significance.


Assuntos
Anticorpos Monoclonais Humanizados , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Doença de Crohn/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Endoscopia , Fator de Necrose Tumoral alfa/uso terapêutico , Necrose , Indução de Remissão
17.
J Biol Chem ; 287(35): 29213-26, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22700971

RESUMO

NOD2 is one of the best characterized members of the cytosolic NOD-like receptor family. NOD2 is able to sense muramyl dipeptide, a specific bacterial cell wall component, and to subsequently induce various signaling pathways leading to NF-κB activation and autophagy, both events contributing to an efficient innate and adaptive immune response. Interestingly, loss-of-function NOD2 variants were associated with a higher susceptibility for Crohn disease, which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-Jun N-terminal kinase-binding protein 1 (JNKBP1), a scaffold protein characterized by an N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following muramyl dipeptide activation. This interaction attenuates NOD2-mediated NF-κB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signaling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and in immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis.


Assuntos
Mucosa Intestinal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Multimerização Proteica/fisiologia , Transdução de Sinais/fisiologia , Células HEK293 , Humanos , Interleucina-8/imunologia , Interleucina-8/metabolismo , Mucosa Intestinal/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Jurkat , NF-kappa B/genética , NF-kappa B/imunologia , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/imunologia , Fosforilação/fisiologia , Estrutura Terciária de Proteína , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Células U937
18.
Cardiovasc Ultrasound ; 11: 4, 2013 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-23351880

RESUMO

BACKGROUND: Calcification is an independent predictor of mortality in calcific aortic valve disease (CAVD). The aim of this study was to evaluate the use of non-invasive, non-ionizing echocardiographic calibrated integrated backscatter (cIB) for monitoring progression and subsequent regression of aortic valvular calcifications in a rat model of reversible renal failure with CAVD, compared to histology. METHODS: 28 male Wistar rats were prospectively followed during 21 weeks. Group 1 (N=14) was fed with a 0.5% adenine diet for 9 weeks to induce renal failure and CAVD. Group 2 (N=14) received a standard diet. At week 9, six animals of each group were killed. The remaining animals of group 1 (N=8) and group 2 (N=8) were kept on a standard diet for an additional 12 weeks. cIB of the aortic valve was calculated at baseline, 9 and 21 weeks, followed by measurement of the calcified area (Ca Area) on histology. RESULTS: At week 9, cIB values and Ca Area of the aortic valve were significantly increased in the adenine-fed rats compared to baseline and controls. After 12 weeks of adenine diet cessation, cIB values and Ca Area of group 1 decreased compared to week 9, while there was no longer a significant difference compared to age-matched controls of group 2. CONCLUSIONS: cIB is a non-invasive tool allowing quantitative monitoring of CAVD progression and regression in a rat model of reversible renal failure, as validated by comparison with histology. This technique might become useful for assessing CAVD during targeted therapy.


Assuntos
Valva Aórtica/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia/métodos , Doenças das Valvas Cardíacas/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Progressão da Doença , Masculino , Ratos , Ratos Wistar
19.
Acta Cardiol ; 78(7): 763-772, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37171264

RESUMO

The data on constrictive pericarditis following heart transplantation are scarce. Herein, the authors present 2 patients who developed a constrictive pericarditis 19, and 55 months after heart transplantation. They underwent several diagnostic procedures and successfully recovered after a radical pericardiectomy. In addition, the authors review the literature and report the incidence, aetiology, diagnostic features, and management of this rare and challenging condition.


Assuntos
Transplante de Coração , Pericardite Constritiva , Humanos , Pericardite Constritiva/diagnóstico , Pericardite Constritiva/etiologia , Pericardite Constritiva/cirurgia , Transplante de Coração/efeitos adversos , Pericardiectomia/efeitos adversos , Pericardiectomia/métodos
20.
Acta Clin Belg ; 77(4): 778-781, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34515613

RESUMO

BACKGROUND: : Hereditary leiomyomatosis (HL) is an autosomal dominant condition due to a variety of fumarate hydratase (FH) mutations in which individuals tend to develop cutaneous leiomyomas, multiple uterine leiomyomas and are at risk for developing aggressive papillary renal cell carcinoma. CASE PRESENTATION: : A 26-year-old man with a past history of acute lymphoblastic leukemia (T-ALL) presented with numerous painful light brown papules and nodules spread all over his body except for the head, appearing since infancy. Similar lesions were present in his mother's family. A cutaneous biopsy revealed a cutaneous leiomyoma. His mother died from metastatic uterine neoplasia and his sister suffered from leiomyoma of the uterus. No renal cancer was reported in his family. A heterozygous pathogenic variant was detected in the FH gene. CONCLUSION: : To our knowledge, this is the first case possibly linking HL and T-ALL through FH deficiency.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Leiomiomatose , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Neoplasias Cutâneas , Neoplasias Uterinas , Adulto , Carcinoma de Células Renais/patologia , Feminino , Fumaratos , Predisposição Genética para Doença , Humanos , Neoplasias Renais/genética , Leiomiomatose/genética , Leiomiomatose/patologia , Masculino , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
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