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1.
Invest New Drugs ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35015172

RESUMO

BACKGROUND:  Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2V617F pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients. AIMS: We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2V617F-knockin MPN mice. RESULTS: In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2V67F cells. Long-term treatment with 40 mg/kg phenformin in Jak2V617F knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2V617F knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice. CONCLUSIONS: Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2V617F-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.

2.
Orbit ; : 1-4, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34974797

RESUMO

We report the case of a 64-year-old male patient with a 5 month history of proptosis, motility limitation and vision loss in OD. Visual acuity (VA) was 20/200 in OD and 20/20 in OS. CT showed a large, round, intraconal lesion, with bony density and no apparent connection to adjacent orbital walls. MRI showed a T1-weighted hypointense lesion surrounded by a contrast enhancing capsule. The orbital tumor was excised through a lateral orbitotomy revealing a nodular, round, osseous structure. Histological examination disclosed well-formed lamellar bone trabeculae, with no necrosis or mitosis figures. Immunohistochemical staining was negative for MDM2 and CDK4. After 3 years, there was no evidence of tumor recurrence and VA had improved to 20/30. Intraconal osteomas with no clear attachment to orbital walls are extremely rare. We are aware of a few reported cases in the lid, hand, thigh, tongue, pterygopalatine fossa and brain. To the authors' knowledge, this is the first report in English literature of an orbital intraconal osteoma without any visible relation to the orbital walls.

3.
BMC Ophthalmol ; 21(1): 404, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814862

RESUMO

BACKGROUND: To provide basic demographic information and clinicopathologic features of ophthalmic Rosai-Dorfman disease (RDD) with a literature review. METHODS: A multi-centre retrospective case series reviewing all patients with histopathologically confirmed ophthalmic RDD at three tertiary eye care centres between January 1993 and December 2018. RESULTS: Eleven eyes of eight patients with histopathologically confirmed ophthalmic RDD were included, with equal numbers of males and females. The median age was 40.25 years (range: 26.6-72.4). Two patients had familial RDD. The orbit was the most commonly involved site (90.9% eyes). One patient (one eye) presented with a scleral nodule, anterior uveitis and cystoid macular oedema. Visual acuity ranged from 20/25 to light perception. Six patients had an extra-nodal ophthalmic disease, and the remaining two had an associated submandibular lymphadenopathy (nodal RDD). CONCLUSIONS: Ophthalmic RDD can be the only manifestation of this systemic disease, with the orbit being the most commonly involved site, exhibiting bone destruction, intracranial and/or sinus involvement and variable degree of visual loss. Ophthalmic familial RDD represent a severe form with a malignant course. Steroid monotherapy may be inadequate to control orbital RDD; thus, combined treatment is usually necessary. A comprehensive approach to assessment and management is recommended.


Assuntos
Histiocitose Sinusal , Edema Macular , Adulto , Feminino , Histiocitose Sinusal/diagnóstico , Humanos , Masculino , Estudos Retrospectivos , Transtornos da Visão , Acuidade Visual
4.
Int J Pharm ; 610: 121217, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34688848

RESUMO

In acne management, oral isotretinoin (IST) is associated with various untoward systemic effects, while its topical formulation has irritation side effects. Delonix (DLX) is a natural galactomannan derived from Delonix regia seed that can fabricate nanoparticles for topical skin delivery. This study aims to develop IST-DLX nanoparticles and assess their prospects for acne treatment. Fluorescent-DLX nanoparticles (made with a lipophilic BODIPY dye) or IST-DLX nanoparticles were prepared and characterized. BODIPY-DLX nanoparticles' skin distribution and IST-DLX nanoparticles' in-vitro targeting were assessed in pig ear skin, inflammatory modulation was assessed in AMJ-2 macrophage cells, while skin penetration and irritation were assessed in Wistar rats. IST-DLX nanoparticles had ≈230 nm, negative zeta potential, and ≈30% encapsulation efficiency. Confocal showed BODIPY in DLX nanoparticles accumulated in hair follicles as compared to BODIPY solution. IST-DLX nanoparticles released ≈37% IST over 48 h and increased IST 3-fold in hair follicles compared to IST solution. IST-DLX nanoparticles suppressed IL-6 expression in cells and reduced photo-irritation in Wistar rats compared to IST solution. In conclusion, IST-DLX nanoparticles may target and deliver adequate IST to skin layers associated with acne, avoid systemic penetration, modulate inflammatory pathogenic acne stage and prevent IST topical photo-irritation.

5.
Ophthalmic Plast Reconstr Surg ; 37(6): e206-e208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366384

RESUMO

The association of C-antineutrophil cytoplasmic antibody (ANCA) vasculitis and IgG4 positivity is a new condition not well described in clinical terms. The authors examined a 28-year-old man with a previous diagnosis of eosinophilic granulomatosis with polyangiitis, formerly known as Churg-Strauss disease, who presented with bilateral orbital inflammation. Magnetic resonance imaging revealed diffuse orbital infiltration and enlargement of the major divisions of the trigeminal nerve. Biopsy of the orbital contents showed necrotizing granulomatous vasculitis and a high number of IgG4-positive plasma cells (IgG4/IgG = 60%).


Assuntos
Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Adulto , Anticorpos Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/diagnóstico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Humanos , Imunoglobulina G , Masculino , Plasmócitos
6.
J Med Virol ; 93(11): 6132-6139, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34050944

RESUMO

Cholesteatomas are frequent middle ear benign tumors of unknown etiology. Infectious agents have been considered as possible contributing factors in the pathogenesis of cholesteatomas. Aiming to investigate the presence of respiratory viruses in primary cholesteatoma tissues, 26 formalin-fixed paraffin-embedded primary cholesteatoma tissues obtained from patients seen at the of the Clinical Hospital of the University of São Paulo School of Medicine, in Ribeirão Preto, Brazil were tested by real-time polymerase chain reaction (PCR). Considering the PCR results, 35% of the tissues were positive for human rhinovirus (HRV), 15.3% for human enterovirus (EV), 3.8% for human metapneumovirus (HMPV), and 3.8% for human bocavirus (HBoV). Serial immunohistochemistry for virus antigens and cell surface markers evidenced that the viruses were associated with fibroblasts, dendritic cells, macrophages, B lymphocytes, CD4+ , and CD8+ T lymphocytes. These findings indicate for the first time the presence of active respiratory virus infection in primary cholesteatoma tissues, suggesting that persisting virus infection in the middle could play a role in the pathogenesis and evolution of cholesteatomas.

8.
Ophthalmic Plast Reconstr Surg ; 37(3): e109-e111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33229952

RESUMO

Congenital optic nerve cystic-like malformations associated with normally developed globes are extremely rare. We describe 3 children who presented since birth with proptosis, and eye motility limitation. MRI showed in all cases that the intraorbital segment of the optic nerves was malformed with large cystic-like lesions in the intraconal segment of the orbit. In all cases, biopsies of the wall of the lesions were positive for glial fibrillary acidic protein. Since this protein is a neurobiomarker that exists only in astrocytes in the central nervous system, nonmyelinating Schwann cells of peripheral nerves, and enteric glial cells, we believe that these lesions represent true opticmeningoceles.


Assuntos
Exoftalmia , Meningocele/diagnóstico , Nervo Óptico/patologia , Astrócitos , Criança , Proteína Glial Fibrilar Ácida , Humanos , Neuroglia , Células de Schwann
9.
Ophthalmic Plast Reconstr Surg ; 37(2): 176-178, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32501880

RESUMO

PURPOSE: To describe the occurrence of multiple trigeminal nerves (TGNs) enlargement in patients with orbital IgG4-related disease. METHODS: Retrospective review of MRI findings and medical records of 6 patients (10 orbits) with orbital IgG4-related disease and enlargement of more than 1 TGN. Orbital biopsies were performed in all cases revealing the typical lymphoplasmacytic infiltrate with significant plasma cell positivity for IgG4 (IgG4+/IgG ratio ≥ 40%). Three experienced neuroradiologists reviewed the MRI sequences using a digital imaging viewer system (Horos, https://horosproject.org/). RESULTS: Bilateral involvement of at least 2 TGNs divisions was detected in all 6 patients. Enlargement of both V1 and V2 nerves was diagnosed in 5 patients, and in 3 cases, all TGN divisions were involved. V2 nerves were the most affected. In this division, all 12 infraorbital nerves were enlarged, followed by lesser palatines (10/83.3%), superior alveolar (10/83.3%), and zygomatic (6/50%). V1 and V3 nerves were less affected albeit 9 (75%) frontal branches (V1), and 50% of the inferior alveolar (V3) nerves were also enlarged. CONCLUSIONS: Widespread involvement of the TGN is an important feature of IgG4-related disease.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Doenças Orbitárias , Humanos , Imunoglobulina G , Doenças Orbitárias/diagnóstico , Estudos Retrospectivos , Nervo Trigêmeo
12.
Genet Mol Biol ; 43(4): e20200100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33001133

RESUMO

Endometrial cancer (EC) harboring heterozygous POLE proofreading inactivating mutations (POLE-exo*) is associated with an increased number of somatic mutations that result in a distinctive anti-tumor immune response. However, the consequences of such POLE mutations in the context of the missing wild-type allele have not yet been described in endometrial tumors. A 72-year-old woman harboring a germline monoallelic frameshift mutation (p.Pro269fsTer26) in POLE was diagnosed with an EC having a somatic heterozygous mutation in the exonuclease domain of POLE (S459F). Targeted gene sequencing revealed an ultramutated phenotype (381 mutations/Mb) in the tumor and a 2-fold excess of mutations on the DNA leading strand. Additionally, we observed a mutational signature similar to the COSMIC signature 10, a higher mutation rate in this tumor than in endometrial tumors with heterozygous POLE-exo*, and an increased number of T lymphocytes. This is the first report of an ultramutated EC harboring a somatic POLE-exo* mutation in association with a germline loss-of-function mutation in this gene. The absence of a wild type POLE allele led to a particularly high mutational burden.

13.
Int Arch Allergy Immunol ; 181(12): 941-946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894844

RESUMO

BACKGROUND: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. OBJECTIVES: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. METHODS: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. RESULTS: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. CONCLUSIONS: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.


Assuntos
Angioedema/diagnóstico , Angioedemas Hereditários/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Baço/patologia , Neoplasias Esplênicas/diagnóstico , Angioedema/terapia , Angioedemas Hereditários/terapia , Detecção Precoce de Câncer , Serviços Médicos de Emergência , Epinefrina/uso terapêutico , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/terapia , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Neoplasias Esplênicas/terapia
15.
Scand J Immunol ; 92(6): e12950, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32738155

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia commonly affecting children with frequent somatic mutations in MAPK pathway genes including BRAFV600E and MAP2K1. Some studies suggest that LCH cells can recruit and modulate inflammatory cells, which could provide reciprocal survival signals. To characterize the immune profile of infiltrating inflammatory cells, and to clarify their participation in LCH pathogenesis, a detailed immunohistochemical analysis was performed. Fifteen (10 children, 5 adults) LCH cases were assessed through macrophage (CD68 and CD163), mature dendritic cell (mDC; CD83 and CD208), regulatory T cell (Treg; CD4, CD25 and FOXP3) and cytotoxic lymphocyte (CL; CD56, CD57, perforin and granzyme B) immunomarkers. Moreover, lymphocytic and LCH markers were also analysed. All cases were S100, CD1a, CD207 and CD4-positive. Bcl-2 and cyclin D1 expression was observed in 13 of 15 cases. In the immune microenvironment, M2-polarized macrophages and Tregs were the predominant cell populations, followed by significantly (P < .005) smaller levels of mDCs and CLs. Additionally, the number of CD3 + cells was significantly higher than that of CD20 + cells. In the CD3 + cell population, there were a significantly higher number of CD4 + cells than CD8 + cells. While there were no differences when comparing the paediatric and adult populations, FOXP3 + cells were significantly higher in patients with multisystem involvement and treated with chemotherapy, than single-site cases and those without chemotherapy. Our results suggest that M2-polarized macrophages and Treg infiltration can promote LCH development and survival, probably through pro-tumoral, immunosuppressive and/or cytokine-mediated mechanisms. This work highlights the need for further exploration of immune-targeted therapy for LCH.


Assuntos
Histiocitose de Células de Langerhans/metabolismo , Células de Langerhans/fisiologia , Macrófagos/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Antígenos CD/metabolismo , Diferenciação Celular , Microambiente Celular , Criança , Pré-Escolar , Citocinas/metabolismo , Células Dendríticas/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica/métodos , Lactente , Macrófagos/imunologia , Masculino , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-32760596

RESUMO

The authors developed a retinoblastoma model using fresh harvested cells from an enucleated eye that were transplanted in chick embryos (chorioallantoic membrane model). The transplanted embryos were treated with escalating doses of Melphalan. This exploratory model was developed with the goal of testing drug sensitivity. Our findings suggest this tumor model could be employed to personalize treatment for patients with retinoblastoma, especially those with bilateral and more refractory disease.

17.
Gynecol Oncol ; 159(1): 229-238, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32694065

RESUMO

OBJECTIVE: To report the frequency of Lynch syndrome (LS) in a cohort of patients from Southeast Brazil bearing endometrial cancer (EC), using a tumor screening universal approach. METHODS: A total of 242 endometrial carcinomas were screened by immunohistochemistry (IHC) and microsatellite instability (MSI) for detection of DNA mismatch repair deficiency (dMMR). MLH1 methylation was assessed to identify sporadic cases. Patients with dMMR tumors were recruited for germline variant analysis by next-generation sequencing of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. RESULTS: Ninety-three out of 242 tumors (38.5%) were classified as dMMR based on MSI and IHC results. Of these, 54 cases were selected for germline analysis, and 37/54 (68.5%) were available for sequencing. Ten patients (10/37, 27%) harbored germline pathogenic or likely pathogenic variants, most of them in the MSH6 gene (4/10, 40%). Seven variants of uncertain significance were found. Eight novel germline variants were identified. The LS prevalence in our cohort was of at least 4.1%. LS patients presented lower mean age at cancer diagnosis compared with patients diagnosed with sporadic EC. Individuals with dMMR tumors, without germline pathogenic variants detected in LS-genes ("Lynch-like" syndrome), had an intermediate mean age at cancer diagnosis between LS and sporadic cases. CONCLUSION: This is the first report of the LS prevalence in EC screened by a universal approach in Brazil. Our findings contribute to a better understanding of the mutational landscape of this syndrome in Brazil, which is relevant for improved identification, genetic counseling, prevention and control of cancer in LS.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias do Endométrio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Brasil/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/prevenção & controle , Endométrio/patologia , Feminino , Aconselhamento Genético/organização & administração , Aconselhamento Genético/estatística & dados numéricos , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Estudos Retrospectivos
19.
Br J Radiol ; 93(1108): 20190975, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31971819

RESUMO

OBJECTIVES: To assess the diagnostic accuracy of signal loss on in-phase (IP) gradient-echo (GRE) images for differentiation between renal cell carcinomas (RCCs) and lipid-poor angiomyolipomas (lpAMLs). METHODS: We retrospectively searched our institutional database for histologically proven small RCCs (<5.0 cm) and AMLs without visible macroscopic fat (lpAMLs). Two experienced radiologists assessed MRIs qualitatively, to depict signal loss foci on IP GRE images. A third radiologist drew regions of interest (ROIs) on the same lesions, on IP and out-of-phase (OP) images to calculate the ratio of signal loss. Diagnostic accuracy parameters were calculated for both techniques and the inter-reader agreement for the qualitative analysis was evaluated using the κ test. RESULTS: 15 (38.4%) RCCs lost their signal on IP images, with a sensitivity of 38.5% (95% CI = 23.4-55.4), a specificity of 100% (71.1-100), a positive predictive value (PPV) of 100% (73.4-100), a negative predictive value (NPV) of 31.4% (26.3-37.0), and an overall accuracy of 52% (37.4-66.3%). In terms of the quantitative analysis, the signal intensity index (SII= [(SIIP - SIOP) / SIOP] x 100) for RCCs was -0.132 ± 0.05, while for AMLs it was -0.031 ± 0.02, p = 0.26. The AUC was 0.414 ± -0.09 (0.237-0.592). Using 19% of signal loss as the threshold, sensitivity was 16% and specificity was 100%. The κappa value for subjective analysis was 0.63. CONCLUSION: Signal loss in "IP" images, assessed subjectively, was highly specific for distinction between RCCs and lpAMLs, although with low sensitivity. The findings can be used to improve the preoperative diagnostic accuracy of MRI for renal masses. ADVANCES IN KNOWLEDGE: Signal loss on "IP" GRE images is a reliable sign for differentiation between RCC and lpAMLs.


Assuntos
Angiomiolipoma/diagnóstico por imagem , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Pequenas/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiomiolipoma/patologia , Área Sob a Curva , Carcinoma de Células Renais/patologia , Carcinoma de Células Pequenas/patologia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
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