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1.
World Allergy Organ J ; 17(8): 100928, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39156600

RESUMO

Hypereosinophilic syndromes (HES) represent a group of rare dis-immune conditions characterized by blood hyper-eosinophilia and eosinophilic related burden. Especially the idiopathic subtype (I-HES) is particularly difficult to diagnose because of its heterogeneous clinical presentation, the lack of specific findings on physical exam, lab tools, and imaging informative enough to unequivocally confirm the diagnosis and the overlap with other entities, including eosinophilic organ-diseases or systemic dis-immune conditions other than I-HES (from atopy to eosinophilic granulomatosis with polyangiitis [EGPA], the last often extremely difficult to distinguish from HES). Taken together, all the features mentioned above account for an extremely difficult early recognition HES and on-time referral to a specialized centre. The referral itself is challenging due to a not univocal specialist identification, because of the variability of physicians managing HES in different settings (including allergist/clinical immunologist, haematologist, internal medicine doctors, pulmonologist, rheumatologist). Furthermore, the approach in terms of personalized treatment identification and follow-up plan (timing, organ assessment), is poorly standardized. Further translational and clinical research is needed to address the mentioned unmet needs, but on practical grounds increasing the overall clinicians' awareness on HES and implementing healthcare pathways for HES patients represent a roadmap that every clinician might try to realize in his specific setting. The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model.

2.
Life Sci Alliance ; 7(11)2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39191488

RESUMO

Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment.


Assuntos
Imunofenotipagem , Leucemia Mieloide Aguda , Análise de Célula Única , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/genética , Criança , Análise de Célula Única/métodos , Feminino , Masculino , Pré-Escolar , Adolescente , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Citometria de Fluxo/métodos , Lactente , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Biologia Computacional/métodos , Prognóstico
3.
J Clin Med ; 13(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731034

RESUMO

Background: Petrous apex cholesterol granulomas (PACGs) are benign inflammatory cystic lesions of the temporal bone. Usually, asymptomatic patients may develop symptoms as the lesions expand. The diagnosis is based on both CT and MRI scans and the management relies on "wait and scan" or surgery. This paper aims at evaluating surgical outcomes and proposing a CT-based classification and a management algorithm. Methods: Patients with PACGs who were surgically treated between 2014 and 2024 were included. Symptoms, imaging, approach type and complications were considered. CT scans were classified as Type A (preserved apex cellularity), Type B (erosion of the apex cellularity), and Type C (involvement of the noble structures bone boundaries). The possible connection of the lesion with the infracochlear, perilabyrinthine and sphenoidal cellularity was assessed. Results: Nineteen patients with symptoms like diplopia, headache and sensorineural hearing loss were included. According to our classification, 1/19 patients was Type A, 4/19 were Type B and 14/19 were Type C. Five patients underwent a total resection, seven a subtotal and seven a surgical drainage. Only two complications were recorded, and 17/19 patients showed symptom regression and stability during follow-up. Conclusions: While the management of PACGs is still controversial, according to our classification and surgical outcomes, Type A, being mostly asymptomatic, should be managed with "wait and scan", Type B should undergo surgery when symptoms are present, while Type C should always undergo surgery because of their invasiveness and potential complications. When possible, a drainage should be attempted; otherwise, a surgical resection is chosen, and its completeness depends on the preoperative general and hearing status.

4.
Br J Haematol ; 203(2): 264-281, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37539479

RESUMO

Acute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo-HCT) is often driven by immune-related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft-versus-leukaemia effect. Still, data about using this combination regimen after allo-HCT are limited. We conducted a prospective, phase II, open-label, single-arm study in which we treated patients with haematological AML relapse after allo-HCT with HMA plus the anti-PD-1 antibody nivolumab. The response was correlated with DNA-, RNA- and protein-based single-cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1-7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High-parametric cytometry documented a higher frequency of activated (ICOS+ , HLA-DR+ ), low senescence (KLRG1- , CD57- ) CD8+ effector T cells in responders. We confirmed these findings in a preclinical model. Single-cell transcriptomics revealed a pro-inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post-allo-HCT HMA/nivolumab combination induces anti-AML immune responses in selected patients and could be considered as a bridging approach to a second allo-HCT. Trial-registration: EudraCT-No. 2017-002194-18.

5.
Nat Immunol ; 24(6): 941-954, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37095378

RESUMO

The range of vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) provides a unique opportunity to study immunization across different platforms. In a single-center cohort, we analyzed the humoral and cellular immune compartments following five coronavirus disease 2019 (COVID-19) vaccines spanning three technologies (adenoviral, mRNA and inactivated virus) administered in 16 combinations. For adenoviral and inactivated-virus vaccines, heterologous combinations were generally more immunogenic compared to homologous regimens. The mRNA vaccine as the second dose resulted in the strongest antibody response and induced the highest frequency of spike-binding memory B cells irrespective of the priming vaccine. Priming with the inactivated-virus vaccine increased the SARS-CoV-2-specific T cell response, whereas boosting did not. Distinct immune signatures were elicited by the different vaccine combinations, demonstrating that the immune response is shaped by the type of vaccines applied and the order in which they are delivered. These data provide a framework for improving future vaccine strategies against pathogens and cancer.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , SARS-CoV-2 , Linfócitos T , Imunogenicidade da Vacina
6.
Sci Immunol ; 6(61)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301800

RESUMO

The transcription factor Pax5 controls B cell development, but its role in mature B cells is largely enigmatic. Here, we demonstrated that the loss of Pax5 by conditional mutagenesis in peripheral B lymphocytes led to the strong reduction of B-1a, marginal zone (MZ), and germinal center (GC) B cells as well as plasma cells. Follicular (FO) B cells tolerated the loss of Pax5 but had a shortened half-life. The Pax5-deficient FO B cells failed to proliferate upon B cell receptor or Toll-like receptor stimulation due to impaired PI3K-AKT signaling, which was caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrained PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescued FO B cell numbers and the development of MZ B cells but did not restore GC B cell formation. Hence, the posttranscriptional down-regulation of PTEN expression is an important function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.


Assuntos
Linfócitos B/imunologia , Fator de Transcrição PAX5/imunologia , PTEN Fosfo-Hidrolase/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Animais , Diferenciação Celular , Regulação para Baixo , Feminino , Masculino , Camundongos Transgênicos , Fator de Transcrição PAX5/genética , PTEN Fosfo-Hidrolase/genética , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais , Receptores Toll-Like/imunologia
7.
Open Biol ; 11(2): 200339, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33622105

RESUMO

The hippocampus is a brain area central for cognition. Mutations in the human SOX2 transcription factor cause neurodevelopmental defects, leading to intellectual disability and seizures, together with hippocampal dysplasia. We generated an allelic series of Sox2 conditional mutations in mouse, deleting Sox2 at different developmental stages. Late Sox2 deletion (from E11.5, via Nestin-Cre) affects only postnatal hippocampal development; earlier deletion (from E10.5, Emx1-Cre) significantly reduces the dentate gyrus (DG), and the earliest deletion (from E9.5, FoxG1-Cre) causes drastic abnormalities, with almost complete absence of the DG. We identify a set of functionally interconnected genes (Gli3, Wnt3a, Cxcr4, p73 and Tbr2), known to play essential roles in hippocampal embryogenesis, which are downregulated in early Sox2 mutants, and (Gli3 and Cxcr4) directly controlled by SOX2; their downregulation provides plausible molecular mechanisms contributing to the defect. Electrophysiological studies of the Emx1-Cre mouse model reveal altered excitatory transmission in CA1 and CA3 regions.


Assuntos
Giro Denteado/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição SOXB1/metabolismo , Potenciais de Ação , Animais , Linhagem Celular Tumoral , Giro Denteado/citologia , Giro Denteado/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Fatores de Transcrição SOXB1/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo
8.
Org Biomol Chem ; 13(9): 2570-3, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25614037
9.
BMC Genomics ; 14: 508, 2013 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-23889749

RESUMO

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers; the majority of EOC is the serous histotype and diagnosed at advanced stage. IL6 is the cytokine that has been found most frequently associated with carcinogenesis and progression of serous EOCs. IL6 is a growth-promoting and anti-apoptotic factor, and high plasma levels of IL6 in advanced stage EOCs correlate with poor prognosis. The objective of the present study was to identify IL6 co-regulated genes and gene network/s in EOCs. RESULTS: We applied bioinformatics tools on 7 publicly available data sets containing the gene expression profiles of 1262 EOC samples. By Pearson's correlation analysis we identified, in EOCs, an IL6-correlated gene signature containing 40 genes mainly associated with proliferation. 33 of 40 genes were also significantly correlated in low malignant potential (LMP) EOCs, while 7 genes, named C5AR1, FPR1, G0S2, IL8, KLF2, MMP19, and THBD were IL6-correlated only in advanced stage EOCs. Among the 40-gene signature EGFR ligand HBEGF, genes of the EGR family members and genes encoding for negative feedback regulators of growth factor signaling were included. The results obtained by Gene Set Enrichment and Ingenuity Pathway Analyses enabled the identification, respectively, of gene sets associated with 'early growth factor response' for the 40-gene signature, and a biological network related to 'thrombosis and cardiovascular disease' for the 7-gene signature. In agreement with these results, selected genes from the identified signatures were validated in vitro by real time RT-PCR in serous EOC cell lines upon stimulation with EGF. CONCLUSIONS: Serous EOCs, independently of their aggressiveness, co-regulate IL6 expression together with that of genes associated to growth factor signaling, arguing for the hypothesis that common mechanism/s driven by EGFR ligands characterize both advanced-stage and LMP EOCs. Only advanced-stage EOCs appeared to be characterized by a scenario that involves genes which are so far associated with thrombosis and cardiovascular disease, thus suggesting that this pathway is implicated in the growth and/or spread of more aggressive tumors. We have discovered novel activated signaling pathways that drive the expression of IL6 and of co-regulated genes and are possibly involved in the pathobiology of EOCs.


Assuntos
Genômica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-1/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transcriptoma , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/complicações , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/metabolismo , Transdução de Sinais , Trombose/complicações
10.
PLoS One ; 5(9): e12701, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20877637

RESUMO

BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel therapeutic approaches against these tumors. The aim of this study is to identify signaling pathways activated in PTCs. METHODOLOGY/PRINCIPAL FINDINGS: We examined coordinated gene expression patterns of ligand/receptor (L/R) pairs using the L/R database DRLP-rev1 and five publicly available thyroid cancer datasets of gene expression on a total of 41 paired PTC/normal thyroid tissues. We identified 26 (up) and 13 (down) L/R pairs coordinately and differentially expressed. The relevance of these L/R pairs was confirmed by performing the same analysis on REarranged during Transfection (RET)/PTC1-infected thyrocytes with respect to normal thyrocytes. TGFA/EGFR emerged as one of the most tightly regulated L/R pair. Furthermore, PTC clinical samples analyzed by real-time RT-PCR expressed EGFR transcript levels similar to those of 5 normal thyroid tissues from patients with pathologies other than thyroid cancer, whereas significantly elevated levels of TGFA transcripts were only present in PTCs. Biochemical analysis of PTC cell lines demonstrated the presence of EGFR on the cell membrane and TGFA in conditioned media. Moreover, conditioned medium of the PTC cell line NIM-1 activated EGFR expressed on HeLa cells, culminating in both ERK and AKT phosphorylation. In NIM-1 cells harboring BRAF mutation, TGFA stimulated proliferation, contributing to PI3K/AKT activation independent of MEK/ERK signaling. CONCLUSIONS/SIGNIFICANCE: We compiled a reliable list of L/R pairs associated with PTC and validated the biological role of one of the emerged L/R pair, the TGFA/EGFR, in this cancer, in vitro. These data provide a better understanding of the factors involved in the biology of PTCs and would be useful in developing combination therapeutic approaches against these cancers.


Assuntos
Carcinoma Papilar/metabolismo , Biologia Computacional , Receptores ErbB/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Carcinoma Papilar/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Ligação Proteica , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/fisiopatologia , Fator de Crescimento Transformador alfa/genética
11.
J Cell Mol Med ; 11(6): 1384-94, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18205708

RESUMO

We previously found that neurons are able to affect the ability of brain capillary endothelial cells to form in vitro a monolayer with properties resembling the blood-brain barrier. We then looked, by immunofluorescence and western analysis, for factors, produced by neurons, with the potential to influence growth and differentiation of endothelial cells. In the present paper, we report that neurons produce both vascular endothelial growth factor and fibroblast growth factor 2, two well-known angiogenic factors. More interestingly, we gained evidence that both factors are released by neurons, at least in part, by shedding of extracellular vesicles, that contain beta1 integrin, a membrane protein already known to be part of extracellular vesicles released by tumour cells. Shedding of extracellular vesicles by neurons was also confirmed by scanner electron microscopy.


Assuntos
Espaço Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neurônios/metabolismo , Vesículas Secretórias/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Camptotecina/farmacologia , Células Cultivadas , Espaço Extracelular/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Integrina beta1/metabolismo , Proteínas de Neurofilamentos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Vesículas Secretórias/efeitos dos fármacos
12.
AIDS ; 21(1): 13-22, 2007 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-17148963

RESUMO

OBJECTIVE: The genital mucosa represents the major site for initial host-HIV-1 contact. HIV-1-protective mucosal immunity has been identified either in subjects who despite repeated sexual exposure, remain seronegative (ESN) or in long-term non-progressor HIV-1-seropositive individuals (LTNP). As a subset of ESN and LTNP produce anti-CCR5 antibodies both at systemic and mucosal level, we studied the role of anti-CCR5 antibodies in blocking HIV transfer through human epithelial cells. DESIGN AND METHODS: To evaluate HIV-1-inhibitory activity by anti-CCR5 antibodies, a two-chambers system was established to model HIV-1 infection across the human mucosal epithelium. Moreover, peripheral blood mononuclear cells (PBMC) and a CCR5 transfected cell line were also used in a classical HIV-infectivity assay. CCR5-specific IgG and IgA were used to inhibit HIV replication. RESULTS: Either serum or mucosal IgA to CCR5 were able to specifically block transcytosis of CCR5- but not CXCR4-HIV strains across a tight epithelial cell layer by interacting with the first extracellular loop of the receptor (amino acids YAAAQWDFGNTMCQ). Monoclonal antibodies against other regions of CCR5 had no effect on HIV transcytosis. Moreover, mucosal CCR5-specific IgA neutralized CCR5-tropic strains and SOS-JRFL pseudovirus replication in PBMC and CCR5 transfected cell lines respectively, with a mechanism different than that observed for transcytosis. CONCLUSIONS: Anti-CCR5 Abs shed light on the immunological mechanisms involved in the control of HIV-1 infection in a model that can be considered an experimentum naturae for resistance to HIV. They could be useful in the design of new strategies against HIV infection at mucosal sites.


Assuntos
Anticorpos/imunologia , Células Epiteliais/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Mucosa Intestinal/imunologia , Receptores CCR5/metabolismo , Adulto , Bioensaio , Transporte Biológico , Colo , Células Epiteliais/virologia , Epitopos , Feminino , Soronegatividade para HIV/imunologia , Humanos , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Mucosa Intestinal/virologia , Masculino , Ligação Proteica , Reto
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