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1.
Sci Immunol ; 5(51)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943497

RESUMO

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Monócitos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologia
2.
Medicine (Baltimore) ; 99(25): e20738, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569215

RESUMO

There is a discordance in the immunohistochemical markers between primary breast cancer and recurrent or metastatic breast cancer. This study aimed to assess the recent trends and prognostic features in the treatment of recurrent or metastatic breast cancerOverall, 107 patients were identified from January 2001 to August 2018 at the Peking Union Medical College Hospital, Beijing, and People's Republic of China to obtain a cohort of breast carcinoma patients who were confirmed to have recurrent or metastatic breast cancer by histopathology. We evaluated patient and tumor characteristics and examined the relationships between these factors and prognosis.The estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) positivity, and Ki67 index in primary breast cancer were 63.6% (68/107), 58.9% (63/107), 19.8% (21/106) and 75.8% (75/99), respectively, while those in recurrent or metastatic lesions were 60.6% (65/107) (P = .672), 46.7% (50/107) (P = 0.013), 23.8% (25/105) (P = 0.482)and 83.5%(81/97)(P = 0.178), respectively. The discordance rate of HER2 expression was 10.6% (11/104), while that of PR expression was 23.3% (21/90). HER2 was the most stable biomarker. The discordance rates for luminal A and HER2 were as high as 100% and 25%, respectively, while the luminal B and triple negative values were as low as 8.3% and 5.3%, respectively.ER and PR positivity and the Ki-67 index tended to increase due to recurrence or metastases; however, the discordance for PR and Ki-67 was high. PR is more variable than ER in the expression of primary and recurrent or metastatic breast cancer. The expression of HER2 receptor was the most stable and the discordance rate of triple negative breast cancer was the lowest. Therefore, although changes in biomarkers are due to recurrence or metastasis, pathological confirmation and exploration of markers are very important.


Assuntos
Neoplasias da Mama/imunologia , Recidiva Local de Neoplasia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Humanos , Antígeno Ki-67/imunologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Receptor ErbB-2/imunologia , Receptores Estrogênicos/imunologia , Receptores de Progesterona/imunologia , Estudos Retrospectivos , Adulto Jovem
3.
Nat Commun ; 11(1): 2859, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503973

RESUMO

Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.


Assuntos
Autoantígenos/imunologia , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoantígenos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo
5.
Virol J ; 16(1): 143, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752941

RESUMO

BACKGROUND: We evaluated the prognostic and diagnostic ability of p16/Ki-67 immunocytochemistry, HPV E6/E7 mRNA testing and HPV DNA assay in triaging ASCUS to find a way to manage cervical lesions more effectively. METHODS: We conducted a prospective study through follow-up. The detection methods of the three factors: p16/Ki-67 immunocytochemistry conducted by using the CINtec® Plus Kit, E6/E7 mRNA testing by QuantiVirus®HPV E6/E7 mRNA assay and DNA by Hybrid Capture 2 assay. RESULTS: One hundred three women with ASCUS satisfied requirements and completed the entire follow-up process. All CIN2+ occurred in women who were mRNA positive at baseline, none in mRNA negative. 100% (6/6) patients with CIN2+ were HPV DNA assay positive, 100% (6/6) were HPV E6/E7 mRNA testing positive and 50.0% (3/6) were p16/Ki-67 immunocytochemistry positive. The risk ratio of E6/E7 mRNA test was 57.306 (95% CI 0.077-42,400.545). For endpoint of CIN2+, the sensitivity between HPV DNA assay and HPV E6/E7 mRNA testing is no statistical difference, but statistical difference exists between HPV E6/E7 mRNA testing vs. p16/Ki-67 immunocytochemistry (χ2 = 5.718, P = 0.023) and HPV DNA assay vs. p16/Ki-67 immunocytochemistry (χ2 = 5.718, P = 0.023). The specificity of E6/E7 mRNA testing, p16/Ki-67 and DNA assay in triaging ASCUS was 44.33, 75.26 and 11.34% respectively and is all statistical difference (χ2 = 26.277, P < 0.001(HPV DNA assay vs. HPV E6/E7 mRNA testing), χ2 = 19.297, P < 0.001(HPV E6/E7 mRNA testing vs. p16/Ki-67 immunocytochemistry), χ2 = 80.707, P < 0.001(HPV DNA assay vs. p16/Ki-67 immunocytochemistry). The expression level of 2097.09 copies/ml was the optimal cut-off value for HPV E6/E7 mRNA testing to diagnose CIN2+, the sensitivity and specificity was 61.1 and 68.2%. CONCLUSIONS: High expression of HPV E6/E7 mRNA could be a good candidate as a diagnostic biomarker to triage ASCUS superseding HPV DNA. p16/Ki-67 immunocytochemistry is suggested to be a good tool to triage ASCUS, but it reduced the sensitivity of diagnosis when improves the diagnostic specificity.


Assuntos
Células Escamosas Atípicas do Colo do Útero/citologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA Viral/análise , Testes Diagnósticos de Rotina/métodos , Antígeno Ki-67/análise , Proteínas Oncogênicas Virais/análise , RNA Mensageiro/análise , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , DNA Viral/genética , Feminino , Seguimentos , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/imunologia , Técnicas de Diagnóstico Molecular/métodos , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/patologia , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , Sensibilidade e Especificidade
6.
BMC Cancer ; 19(1): 978, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640622

RESUMO

BACKGROUND: An External Quality Assessment (EQA) program was developed to investigate the status of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 immunohistochemical (IHC) detection in breast cancer and to evaluate the reproducibility of staining and interpretation in 44 pathology laboratories in China. METHODS: This program was implemented through three specific steps. In study I, three revising centres defined the reference value for 11 sections. In study II, 41 participating centres (PC) stained and interpreted 11 sections by their own daily practice IHC protocols. In study III, all cases received second interpretation opinions. RESULTS: The stained slides of 44 laboratories were up to the interpretation standard. The overall interpretation concordance rate of this study was over 90%. A perfect agreement was reached among the PCs for the cases with ER+ and PR+ > 50% and Ki-67 > 30%, whereas a moderate agreement was observed for intermediate categories. After second interpretations, the misclassification rates for ER were reduced by 12.20%, for PR were reduced by 17.07%, and for Ki-67 were reduced by 4.88%. Up to 31 PCs observed a benefit from the second opinion strategy. CONCLUSIONS: This project is the first EQA study performed on a national scale for assessment of ER, PR and Ki-67 status by IHC in China. In the whole IHC evaluation process, the intermediate categories were less reproducible than those with high expression rates. Second opinions can significantly improve the diagnostic agreement of pathologists' interpretations.


Assuntos
Neoplasias da Mama/metabolismo , Imuno-Histoquímica/métodos , Antígeno Ki-67/metabolismo , Ensaio de Proficiência Laboratorial/métodos , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , China , Confiabilidade dos Dados , Testes Diagnósticos de Rotina , Feminino , Humanos , Antígeno Ki-67/imunologia , Patologistas/psicologia , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/imunologia , Receptores de Progesterona/imunologia , Reprodutibilidade dos Testes , Estudos Retrospectivos
7.
Front Immunol ; 10: 2085, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572357

RESUMO

Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.


Assuntos
Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Rituximab/imunologia , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antígenos CD57/imunologia , Granzimas/imunologia , Humanos , Interferon gama/imunologia , Antígeno Ki-67/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Perforina/imunologia , Receptores de IgG/imunologia , Receptores KIR/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
8.
Sci Rep ; 9(1): 13534, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537812

RESUMO

The assessment of Ki-67 in early-stage breast cancer has become an important diagnostic tool in planning adjuvant therapy, particularly for the administration of additional chemotherapy to hormone-responsive patients. An accurate determination of the Ki-67 index is of the utmost importance; however, the reproducibility is currently unsatisfactory. In this study, we addressed the predictive/prognostic value of Ki-67 index assessed by using the most reproducible methods, which were identified in the pilot phase. Paraffin blocks obtained from patients with moderately differentiated, estrogen receptor (ER)-positive early-stage breast cancer in Switzerland, who were originally randomized to the treatment arms with and without chemotherapy in the IBCSG VIII-IX trials, were retrieved. Of these 344 randomized patients, we identified 158 patients (82 treated with and 76 treated without chemotherapy) for whom sufficient tumour tissue was available. The presence of Ki-67 was assessed visually by counting 2000 cells at the periphery (A) and estimating the number of positive cells in five different peripheral regions (C), which was determined to be the most reproducible method identified the pilot phase. The prognostic and predictive value was assessed by calculating the breast cancer-free interval (BCFI) and overall survival (OS) rate. Ki-67 was considered a numerical and categorical variable when different cut-off values were used (10%, 14%, 20% and 30%). An mRNA-based subtyping by using the MammaTyper kit with the application of a 20% Ki-67 immunohistochemistry (IHC) cut-off equivalent was also performed. 158 of 344 randomized patients could be included in the Ki-67 analysis. The mean Ki-67 values obtained by using the two methods differed (A: 21.32% and C: 16.07%). Ki-67 assessed by using method A with a cut-off of 10% was a predictive marker for OS, as the hazard ratio (>10% vs. <=10%) in patients with chemotherapy was 0.48 with a 95% confidence interval of [0.19-1.19]. Further, the HR of patients treated without chemotherapy was 3.72 with a 95% confidence interval of [1.16-11.96] (pinteraction=0.007). Higher Ki-67 index was not associated with outcome and using the 10% Ki-67 cut-off there was an opposite association for patients with and without chemotherapy. Ki-67 assessments with IHC significantly correlated with MammaTyper results (p=0.002). The exact counting method (A) performed via a light-microscope revealed the predictive value of Ki-67 assessment with a 10% cut-off value. Further analyses employing image analyses and/or mRNA-based-assessments in larger populations are warranted.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Antígeno Ki-67/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/análise , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/imunologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Reprodutibilidade dos Testes , Suíça
9.
Cancer Cytopathol ; 127(10): 643-649, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398281

RESUMO

BACKGROUND: The Ki-67 proliferation marker has multiple diagnostic and prognostic applications. Although several clones to the Ki-67 antigen are commercially available, the MIB1 clone is widely recommended in the surgical pathology literature for neuroendocrine tumors. In our cytopathology practice, we have encountered unexpectedly low MIB1 immunoreactivity in CytoLyt-fixed cell blocks (CBs). The current study evaluated the impact of fixatives, CB processing, and immunocytochemical (ICC) procedures on Ki-67 immunoreactivity. METHODS: Test CBs were prepared from freshly resected tumors, and multiple variables in the MIB1 ICC procedure were tested, including CytoLyt versus formalin collection media, MIB1 versus other Ki-67 clones including 30-9, and other variables. MIB1 versus Ki-67 30-9 clones were tested in parallel on CytoLyt-fixed CBs from clinical samples of small cell lung carcinoma (SCLC). RESULTS: In the test CBs (n = 10), the mean MIB1 labeling index was 10% in CytoLyt versus 47% in formalin (P = .0116), with a mean loss of reactivity in matched CBs of 37% (up to 70%). None of the procedure modifications tested in 223 individual ICC reactions recovered MIB1 reactivity in CytoLyt except for switching to the Ki-67 30-9 antibody. In CytoLyt-fixed SCLC samples (n = 14), the Ki-67 30-9 antibody demonstrated expected ranges of reactivity (mean, 83%; range, 60%-100%), whereas MIB1 demonstrated markedly inhibited labeling (mean, 60%; range, 10%-95%) (P = .0058). CONCLUSIONS: CytoLyt fixation substantially inhibits MIB1 immunoreactivity, whereas the Ki-67 30-9 clone is not susceptible to inhibition. Markedly discrepant MIB1 reactivity may present a pitfall in the diagnosis of SCLC and may lead to the incorrect prognostic stratification of other tumor types. For laboratories using CytoLyt, we recommend using the Ki-67 30-9 antibody rather than the MIB1 antibody.


Assuntos
Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/imunologia , Formaldeído/efeitos adversos , Antígeno Ki-67/química , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Fixação de Tecidos/métodos , Anticorpos Antinucleares/química , Anticorpos Monoclonais/química , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/metabolismo
10.
Cell Oncol (Dordr) ; 42(5): 691-703, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201646

RESUMO

PURPOSE: Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration. METHODS: TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32ß and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR. RESULTS: We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32ß expression in TC cells. Overexpression of IL-32ß and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32ß overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected. CONCLUSIONS: From our data, we conclude that TAM-derived TNFα induces IL-32ß in TC cells. Although IL-32ß does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32ß isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.


Assuntos
Movimento Celular/imunologia , Interleucinas/metabolismo , Macrófagos/imunologia , Neoplasias da Glândula Tireoide/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Processamento Alternativo/genética , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Interleucinas/genética , Antígeno Ki-67/imunologia , Monócitos/metabolismo , Isoformas de Proteínas/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Cytopathology ; 30(5): 510-518, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30943322

RESUMO

OBJECTIVE: Immunocytochemistry has attained a marginal role in urology so far. Combining the morphological and immunophenotypical changes of the urothelial cells retrieved from urine is a logical approach. The study aimed to analyse the diagnostic potential of immunocytological staining in the detection of high-grade and low-grade urothelial carcinoma. METHODS: Freshly voided urine was collected from 152 consecutive individuals, cytology classes were determined and cell blocks produced. A total of 77 patients were diagnosed with urothelial carcinoma and 75 patients had various benign urological conditions. Immunocytochemistry was performed using four antibodies: p53, MCM2, MCM5 and Ki-67. A diagnostic power to detect low grade and high-grade urothelial carcinoma was analysed for each antibody and their combinations with cytology. RESULTS: There were no significant differences between patients with low-grade tumours and control group. Antibodies p53 and Ki-67 slightly improved the sensitivity of urinary cytology while maintaining its specificity. The best negative predictive value was demonstrated in combinations of cytology and MCM5 (88.9%) and cytology, p53 and MCM5 (90.6%). In the diagnosis of high-grade tumours, all antibodies apart from MCM2 yielded better sensitivity and specificity than cytology alone (receiver operating characteristic curves: p53 = 0.853, MCM5 = 0.931, and Ki-67 = 0.895). Combined with cytology, the sensitivities went even higher for the cost of lower specificity. The best diagnostic performance was observed in the combination of MCM5 and Ki-67 (sensitivity = 96.2%; specificity = 80%). CONCLUSIONS: Immunocytochemistry with p53, MCM5 and Ki-67 antibodies can improve the diagnostic power of urinary cytology in the detection and follow-up of urinary bladder urothelial carcinoma.


Assuntos
Anticorpos Antineoplásicos/imunologia , Proteínas de Ciclo Celular/imunologia , Citodiagnóstico , Antígeno Ki-67/imunologia , Componente 2 do Complexo de Manutenção de Minicromossomo/imunologia , Proteína Supressora de Tumor p53/imunologia , Neoplasias da Bexiga Urinária/diagnóstico , Urina/citologia , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Curva ROC , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/patologia
12.
Photodiagnosis Photodyn Ther ; 26: 270-276, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986538

RESUMO

INTRODUCTION: Ultraviolet light induced DNA damage, combined with immunosuppression and inflammation are involved in the pathogenesis of actinic keratosis. Photodynamic therapy not only destroys dysplastic cells via tissue destruction and vascular shutdown, but also induces an acute local inflammatory response and activates both the innate and adaptive immune system. In our current work we aimed to compare immunohistochemistry features of inflammatory infiltrate of actinic keratoses after 5-aminolevulinic acid photodynamic therapy with or without Er:YAG laser resurfacing. METHODS: Eleven patients with multiple actinic keratosis on the scalp, face, hands or forearms were treated by conventional and Er:YAG laser assisted 5-aminolevulinic acid PDT in split-site manner. Biopsies of AKs were taken before, 48 h and 3 months after the treatment. CD3, CD4, CD8, CD1a, Ki67 and p53 expressions were analyzed by immunohistochemical methods. RESULTS: The number of p53 and Ki67 positive cells decreased significantly 3 months after treatment, but the abnormal cells were not eliminated totally. The number of CD1a+ Langerhans cells significantly decreased 48 h after both treatments, while CD8+ T cell count was significantly lower 3 months after Er:YAG laser assisted photodynamic therapy. However, the number of CD3+ and CD4+ T cells were not changed significantly 48 h and 3 months later. CONCLUSIONS: One session of 5-aminolevulinic acid photodynamic therapy even with Er:YAG laser pretreatment could not terminate actinic damage totally. Photodynamic therapy induced immunological changes. However further investigations are needed to answer how the composition of actinic keratosis' immune infiltrate influence the effect of photodynamic therapy.


Assuntos
Ácido Aminolevulínico/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Ceratose Actínica/imunologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Feminino , Humanos , Antígeno Ki-67/imunologia , Lasers de Estado Sólido , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/imunologia
13.
ANZ J Surg ; 89(1-2): 48-52, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710432

RESUMO

BACKGROUND: Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21-year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt. METHODS: A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken. RESULTS: Thirty-five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki-67 index were strong prognostic indicators for survival. CONCLUSIONS: Early stage, complete resection and Ki-67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long-term survivors of patients with Stage 4 disease in our aggregate cohort.


Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Neoplasias das Glândulas Suprarrenais/cirurgia , Carcinoma Adrenocortical/cirurgia , Terapia Combinada/métodos , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Austrália/epidemiologia , Feminino , Humanos , Comunicação Interdisciplinar , Antígeno Ki-67/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
14.
J Invest Dermatol ; 139(8): 1753-1761.e4, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30779913

RESUMO

Staphylococcus aureus is a significant bacterial pathogen that may penetrate through the barrier into the epidermis and dermis of the skin. We hypothesized that the S. aureus cell wall product lipoteichoic acid (LTA) may contribute to the development of inflammation and skin barrier defects; however, the effects of LTA in vivo are not well understood. In this study, we examined the effects induced by intradermal S. aureus LTA. We found that keratinocytes in LTA-treated skin were highly proliferative, expressing 10-fold increased levels of Ki67. Furthermore, we observed that LTA caused damage to the skin barrier with substantial loss of filaggrin and loricrin expression. In addition, levels of the IL-1 family of inflammatory cytokines, as well as the neutrophil-attracting chemokines Cxcl1 and Cxcl2, were increased. Concomitantly, we observed significant numbers of neutrophils infiltrating into the epidermis. Finally, we determined that LTA-induced signals were mediated in part through IL-1, because an IL-1 receptor type 1 antagonist ameliorated the effects of LTA, blocking neutrophil recruitment and increasing the expression of skin barrier proteins. In summary, we show that S. aureus LTA alone is sufficient to promote keratinocyte proliferation, inhibit expression of epidermal barrier proteins, induce IL-1 signaling, and recruit cells involved in skin inflammation.


Assuntos
Epiderme/patologia , Interleucina-1/metabolismo , Lipopolissacarídeos/metabolismo , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/patogenicidade , Ácidos Teicoicos/metabolismo , Animais , Parede Celular/metabolismo , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/imunologia , Modelos Animais de Doenças , Epiderme/imunologia , Epiderme/microbiologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Interleucina-1/imunologia , Queratinócitos/imunologia , Queratinócitos/patologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Camundongos , Infiltração de Neutrófilos , Neutrófilos/imunologia , Cultura Primária de Células , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/imunologia , Receptores Tipo I de Interleucina-1/metabolismo , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Ácidos Teicoicos/administração & dosagem , Ácidos Teicoicos/imunologia
15.
Nat Immunol ; 20(3): 301-312, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664737

RESUMO

The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Feto/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD5/genética , Antígenos CD5/imunologia , Antígenos CD5/metabolismo , Células Cultivadas , Feto/citologia , Feto/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Memória Imunológica/genética , Imunofenotipagem , Intestinos/citologia , Intestinos/embriologia , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo
17.
Immunol Cell Biol ; 97(5): 470-484, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30582666

RESUMO

Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti-inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation-induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki-67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB-p65 nuclear translocation. The Ki-67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS-induced proliferative conditions, thereby blocking p53-dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation-dictated Ki-67high thymocytes possibly by modulating the hypothalamus-pituitary-adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation-biased immune cells, authenticating a novel antiproliferative role of an established drug.


Assuntos
Apoptose/efeitos dos fármacos , Fluoxetina/farmacologia , Antígeno Ki-67/imunologia , Timócitos/imunologia , Animais , Apoptose/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Timócitos/patologia , Fator de Transcrição RelA/imunologia
18.
Bull Exp Biol Med ; 166(2): 241-244, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30488197

RESUMO

In patients with primary resectable breast cancer, a positive correlation between the age and the count of CD16+ lymphocytes and a negative correlation of this parameter with the number of regulatory CD4+CD25+CD127- cells and proliferative activity of Ki-67 tumor cells were revealed. Higher level of Ki-67 was associated with reduced number of effector lymphocytes (CD8+ and CD16+) and elevated content of regulatory CD8+CD11b-CD28- T cells. The absence of expression of estrogen receptors was associated with reduced cytotoxic potential of CD8+ T cell in comparison with ER+ breast cancer. The percentage of CD8+ lymphocytes (CD3+CD8+ and CD8+CD11b+CD28+) among lymphocytes infiltrating the tumor was higher in PR+ breast cancer than in PR- tumors. With increasing the tumor load, the number of lymphocytes expressing CD16 marker and their cytotoxic potential decreased.


Assuntos
Antígenos CD/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/patologia , Linfócitos do Interstício Tumoral/patologia , Linfócitos T Reguladores/patologia , Antígenos CD/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunofenotipagem , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Laringite , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores Estrogênicos/imunologia , Receptores de Progesterona/genética , Receptores de Progesterona/imunologia , Linfócitos T Reguladores/imunologia , Carga Tumoral
19.
Bull Exp Biol Med ; 165(5): 702-706, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30225704

RESUMO

Changes in the structure and cell composition of carinal lymph nodes were studied in humans during aging. Replacement of node parenchyma with fibrous connective tissue progressing with age was demonstrated. The medullary matter significantly prevailed over the cortical substance. The lymph nodes in the cortical substance were small and had no light centers; the concentration of mature CD20+ B cells was high; the paracortical area was fragmented and thinned and contained no CD4+ T helpers. Ki-67+ cells were absent in all structural components of the lymph nodes reflecting exhaustion of lymphopoietic function, which was determined by the replacement of the reticular tissue of the microenvironment with the connective tissue and by the absence of CD4+ T cells regulating cellular and humoral immunity. The disintegration of the reticular stroma in the sinus system that acts as a biological filter impairs the function of lymph purification.


Assuntos
Envelhecimento/imunologia , Linfócitos B/imunologia , Tecido Conjuntivo/imunologia , Linfonodos/imunologia , Tecido Parenquimatoso/imunologia , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Antígenos CD20/genética , Antígenos CD20/imunologia , Autopsia , Linfócitos B/patologia , Biomarcadores/metabolismo , Tecido Conjuntivo/patologia , Tecido Conjuntivo/ultraestrutura , Feminino , Fibrose , Expressão Gênica , Granulócitos/imunologia , Granulócitos/patologia , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Linfonodos/patologia , Linfonodos/ultraestrutura , Contagem de Linfócitos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Tecido Parenquimatoso/patologia , Tecido Parenquimatoso/ultraestrutura , Células Estromais/imunologia , Células Estromais/patologia , Cavidade Torácica/imunologia , Cavidade Torácica/patologia
20.
Medicine (Baltimore) ; 97(26): e11109, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29952951

RESUMO

BACKGROUND: That breast carcinoma is the most common malignant lesion in women. This study aimed to differentiate benign from malignant breast lesions and to predict grading of the latter by comparing the diagnostic value of different parameters in intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). MATERIALS AND METHODS: Retrospective analysis was performed utilizing imaging and pathological data from 112 patients with 124 breast lesions that underwent IVIM-DWI examination with 3.0 T MRI. Out of 124, 47 benign and 77 malignant lesions were confirmed by pathological diagnosis. The diagnostic performance of f, D, and D* value to distinguish benign from malignant breast lesions, was evaluated using pathological results as the gold standard. Correlation between D value and Ki-67 index was evaluated to predict grading of malignant breast lesions. RESULTS: The D value (0.99 ±â€Š0.21) of patients with malignant lesions was significantly lower than that (1.34 ±â€Š0.18) of patients harboring benign lesions (P = .00). The D* value (7.60 ±â€Š2.10) in malignant lesion group was higher than that (6.83 ±â€Š2.13) of the benign lesion group (P = .113). The f value (8.50 ±â€Š2.13) in malignant lesion group was remarkably higher than that (7.68 ±â€Š1.98) of benign lesion group (P = .035). For differential diagnosis of benign from malignant breast lesions, optimal diagnostic threshold of D value and f value were 1.21 and 7.86, respectively. The areas of D and f values under the ROC curve were 0.883 and 0.601, respectively. The sensitivity, specificity, and accuracy of D value were 83.0%, 86.7%, and 85.5%, respectively. Accordingly, those indexes of f value were 64.9%, 57.4%, and 62.1%, respectively. Furthermore, the Ki-67 staining index of malignant lesions was robustly negatively correlated with D value (r = -0.395, P < .01). CONCLUSION: Concrete parameters of IVIM-DWI can help to improve the specificity and accuracy in differential diagnosis of breast benign and malignant lesions. D value is most relevant and valuable in predicting the grading of malignant breast lesions.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Adulto , Mama/patologia , Neoplasias da Mama/patologia , Diagnóstico Diferencial , Feminino , Humanos , Antígeno Ki-67/imunologia , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Valor Preditivo dos Testes , Estudos Retrospectivos
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