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OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.
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Antirreumáticos , Artritis Reumatoide , Biosimilares Farmacéuticos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adalimumab/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/efectos adversos , Etanercept/uso terapéutico , Etanercept/efectos adversos , Necrosis/inducido químicamente , Necrosis/tratamiento farmacológico , Resultado del Tratamiento , AdultoRESUMEN
Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células Madre Neoplásicas/citología , Neovascularización Patológica , Factor de Crecimiento Transformador beta1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adolescente , Encéfalo , Niño , Preescolar , Células Endoteliales , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Lactante , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Infectious sacroiliitis is an infection of the sacroiliac joint, not easy to diagnose because of its non-specific signs, symptoms and laboratory abnormalities. We describe a case of a 16 year-old male with 5 days' history of fever, abdominal pain, constipation, low-back and left hip pain extended to the left knee associated with sudden inability to walk. In the first place, magnetic resonance imaging (MRI) examination of his sacroiliac joint revealed an enlarged corpuscolated fluid collection near the left iliopsoas muscle, extended to homolateral paravertebral muscles and a little fluid at the left sacroiliac joint. Drainage by aspiration of the iliopsoas abscess was applied; Staphylococcus aureus was found in the aspirated fluid and isolated from the blood too. Therefore intravenous antibiotic therapy was begun. Follow-up MRI exams confirmed the muscle abscess and revealed also a spongy bone edema of the left sacroiliac joint, persisting despite the disappearance of symptoms and the normalization of inflammatory values. It is important to make an early diagnosis of infectious sacroiliitis in order to begin antibiotic therapy as soon as possible, because of the increasing morbidity of infection of sacroiliac joint. In our case MR findings have provided significant orientation towards the final diagnosis of infectious sacroiliitis.
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Imagen por Resonancia Magnética , Absceso del Psoas/diagnóstico por imagen , Absceso del Psoas/microbiología , Sacroileítis/diagnóstico por imagen , Sacroileítis/microbiología , Infecciones Estafilocócicas , Adolescente , Humanos , Masculino , Absceso del Psoas/complicaciones , Sacroileítis/complicaciones , Infecciones Estafilocócicas/complicacionesRESUMEN
Small Ubiquitinlike MOdifier (SUMO) proteins are small protein modifiers capable of regulating cellular localization and function of target proteins. Over the last few years, a relevant role has been demonstrated for sumoylation in the modulation of important cellular processes, including gene transcription, DNA repair, cell-cycle regulation and apoptosis. Components of the sumoylation machinery have been found deregulated in different human cancers, and are thought to significantly affect cancer cell progression. In the present study we sought to analyze the expression of all the components of the sumoylation machinery in a case study comprising 77 papillary thyroid cancers (PTC) and normal matched tissues. In particular, we evaluated the expression of the SENP1 to SENP8 (SENtrin-specific proteases), SAE1 (SUMO1 activating enzyme subunit 1), UBA2 (UBiquitin-like modifier activating enzyme 2), UBC9 (UBiquitin conjugating enzyme 9), RanBP2 (RAN binding protein 2), MSMCE2 (Non- SMC element 2), CBX4 (ChromoBoX homolog 4), PIAS1 to PIAS4 (protein inhibitor of activated STAT), ZMIZ1 (zinc finger, MIZ-type containing 1) and ZMIZ2 (Zinc finger, MIZ-type containing 2) by means of quantitative RT-PCR. In most of the PTC examined we observed a significant alteration in the mRNAs of SENP8, ZMIZ1, SAE1, PIAS1 and PIAS2. These tended to be reduced in about 50 to 66% of cases, and unchanged or increased in the remaining ones. Univariate and Kaplan-Mayer analyses documented the lack of association between the expression of the above 5 genes and clinicopathological parameters. Only SAE1 was significantly higher in female PTC tissues, in respect to male PTC tissues (p=0.021), and SENP8 was significantly lower in TNM stages III-V, with respect to stages I-II (p=0.047). In conclusion, we demonstrated that the expression of SENP8, SAE1, PIAS1, PIAS2 and ZMIZ1 is deregulated in the majority of PTC tissues, likely contributing to the PTC phenotype. However, differently from other human cancers, their mRNA level does not represent a prognostic biomarker in PTC patients.
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Biomarcadores de Tumor/biosíntesis , Carcinoma/metabolismo , Carcinoma/mortalidad , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Sumoilación , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Carcinoma/terapia , Carcinoma Papilar , Niño , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapiaRESUMEN
PURPOSE: Down-regulation of thyroid hormone receptor beta (THRß) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRß mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical-biological features. METHODS: Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRß gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRß. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. RESULTS: THRß transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRß expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. CONCLUSIONS: Our results demonstrate that down-regulation of THRß is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis.
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Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Expresión Génica , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Receptores beta de Hormona Tiroidea/metabolismo , Neoplasias de la Tiroides/metabolismo , Adulto , Anciano , Carcinoma/genética , Carcinoma Papilar , Regulación hacia Abajo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Cáncer Papilar Tiroideo , Receptores beta de Hormona Tiroidea/genética , Neoplasias de la Tiroides/genética , Adulto JovenRESUMEN
Antiretroviral therapy allows a restoration of immune cell homeostasis associated with a normal immune competence. Our goal was to analyze the modulation of polyfunctional HIV-specific CD8+ T-cell responses during antiretroviral therapy. HIV-infected individuals were divided into four groups according to CD4+ cell count and viral load at the moment of recruitment. Whole blood was stimulated with a pool of CD8-specific HIV-antigens to assess cytokine/chemokine production and cytotoxicity activity by using flow cytometry. The groups show different modulation in HIV-specific CD8+ T-cell responses. In particular, immunological failure showed different distributions of polyfunctional HIVspecific CD8+ responses, mainly due to an increase of cells producing CD107alpha/IFNgamma/IL-2/MIP-1beta. Our results indicate that this particular 4+ functional subset is a possible correlate of immunological failure. Considering the complexity of interactions among HAART, immune system and HIV, work is in progress to find correlates of therapy efficacy.
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Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Antígenos VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Citocinas/metabolismo , Citomegalovirus/inmunología , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Herpesvirus Humano 4/inmunología , Humanos , Masculino , Persona de Mediana Edad , Orthomyxoviridae/inmunología , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND AND AIM: Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis. METHOD: Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5). RESULTS: Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril. CONCLUSION: Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores de Crecimiento/uso terapéutico , Nefroesclerosis/prevención & control , Oligopéptidos/uso terapéutico , Albuminuria/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Nefropatías Diabéticas/complicaciones , Evaluación Preclínica de Medicamentos , Tasa de Filtración Glomerular/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Nefroesclerosis/etiología , Oligopéptidos/farmacología , Ramipril/farmacología , Ramipril/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: In our study we used immunohistochemical technique to demonstrate the presence of the cytokines tumour necrosis factor alpha (TNF-α), interleukin 1beta (IL-1ß), transforming growth factor beta1 (TGF-ß1) and intercellular adhesion molecule-1 (ICAM-1) in porcine coronaries even in physiological conditions. MATERIALS AND METHODS: Inflammatory cytokines are polypeptide mediators which act as a communication signal between immune system cells and other types of cellsin different organs and tissues, both in human and pig coronary circulation. RESULTS: Our results show that pro-inflammatory cytokines TNF-α, IL-1ß, TGF-ß1 and ICAM-1 are also present in the medium tunica of the coronary arteries under physiological conditions. These results may be compared with those found in coronary atherosclerosis, where the increase in TNF-α has a dramatic effect on the function of the left ventricle, and the high value of IL-1 correlates directly with the extent of myocardial necrosis. In our study we observe the damage and activation of endothelial cells; this induces endothelial dysfunction by accumulation and oxidation of low density lipoproteins (LDL). The formation of oxidized LDL could play a central role in the amplification of the inflammatory response causing an increased expression of pro-inflammatory cytokines which promotes leukocyte recruitment in the intimal layer. These leukocytes, after the adhesion to the endothelium, penetrate the intimate tunic. CONCLUSIONS: Therefore inflammatory processes promote the onset and evolution of atheroma and the development of thrombotic complications.
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Factor de Crecimiento Transformador beta1 , Factor de Necrosis Tumoral alfa , Humanos , Porcinos , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Células Endoteliales/metabolismo , Vasos Coronarios , CitocinasRESUMEN
Multicolor flow cytometry allows to study the markers differentially expressed during maturation, activation, function and senescence on immune cells. Despite the availability of reagents and technology, scarce agreement has been gained regarding phenotypic markers of HIV disease progression other than CD4 T-cell count. In this work, we present a novel high-throughput global analysis of CD4 and CD8 T-lymphocyte profiles by standardized 8-color combinations of antibodies aimed at analyzing HIV disease course progression. For this purpose, two tubes with lyophilized reagent cocktails (CD4- and CD8-specific tubes) were designed to compare the immunological characteristics of HIV-infected persons (37 "high CD4" HAART-treated and 32 "low CD4" naïve or failed-treatment patients) with healthy donors (HD). In particular, T-cell activation (CD25, CD38, CD69), differentiation (CD45RA, CCR7), apoptosis (CD95) and immune suppression profiles (CD25(high)CD127-) in HIV+ patients were compared with HD. Statistical analysis was performed by identifying the parameters associated with disease progression, namely markers that were found to be significantly different between groups with high CD4 counts (including HD) and low CD4 counts (restricted to HIV patients) but not between the HD and the "high CD4" group. This set of markers, including those identifying different maturation and senescence subtypes of CD4 and CD8 T cells, was found to be associated with therapy failure, and it is in fact evaluated in an ongoing study aimed to verify its prognostic value. This robust assay was found feasible on a semi-routine scale for HIV-infected persons, and allows for broader clinical studies aimed at defining markers associated with treatment outcome, possibly having a high impact on the clinical management of HIV disease.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Senescencia Celular , Citometría de Flujo , Infecciones por VIH/diagnóstico , Ensayos Analíticos de Alto Rendimiento/métodos , Inmunofenotipificación/métodos , Activación de Linfocitos , Adulto , Terapia Antirretroviral Altamente Activa , Biomarcadores/sangre , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Estudios de Casos y Controles , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Italia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Adulto JovenRESUMEN
Urban waste can be valorized within a biorefinery approach, producing platform chemicals, biopolymers and energy. In this framework, hydrodynamic cavitation (HC) is a promising pre-treatment for improving biodegradability due to its high effectiveness and low cost. This paper deals with the effect of HC pre-treatment on the acidogenic co-fermentation process of thickened sewage sludge from a WWTP and seasonal vegetable waste from a wholesale market. Specifically, HC was assessed by testing two sets of parameters (i.e., treatment time of 30 and 50 min; vacuum pressure 1.4 and 2.0 bar; applied power 8 and 17 kW) to determine its effectiveness as a pre-treatment of the mixture. The highest increase in sCOD (+83%) and VFAs (from 1.93 to 17.29 gCODVFA L-1) was gained after 50 min of cavitation. Fermentations were conducted with not cavitated and cavitated mixtures at 37 °C on 4 L reactors in batch mode, then switched to semi-continuous with OLR of 8 kgTVS m-3 d-1 and HRT of 5-6.6 d. Good VFAs concentrations (12.94-18.27 gCODVFA L-1) and yields (0.44-0.53 gCODVFA gVS(0)-1) were obtained, which could be enhanced by pre-treatment optimization and pH control. The organic acid rich broth obtained was then assessed as a substrate for PHAs storage by C. necator. It yielded 0.37 g g-1 of polyhydroxybutyrate, such biopolymer resulted to have analogous physicochemical characteristics of commercial equivalent. The only generated side-stream would be the solid-rich fraction of the fermented effluent, which valorization was assessed through BMP tests, showing a higher SGP of 0.42 Nm3 kgTVS-1 for the cavitated.
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Reactores Biológicos , Hidrodinámica , Ácidos , Anaerobiosis , Fermentación , Aguas del AlcantarilladoRESUMEN
Representative models are needed to screen new therapies for patients with cancer. Cancer organoids are a leap forward as a culture model that faithfully represents the disease. Mouse-derived cancer organoids (MDCOs) are becoming increasingly popular, however there has yet to be a standardized method to assess therapeutic response and identify subpopulation heterogeneity. There are multiple factors unique to organoid culture that could affect how therapeutic response and MDCO heterogeneity are assessed. Here we describe an analysis of nearly 3500 individual MDCOs where individual organoid morphologic tracking was performed. Change in MDCO diameter was assessed in the presence of control media or targeted therapies. Individual organoid tracking was identified to be more sensitive to treatment response than well-level assessment. The impact of different generations of mice of the same genotype, different regions of the colon, and organoid specific characteristics including baseline size, passage number, plating density, and location within the matrix were examined. Only the starting size of the MDCO altered the subsequent growth. These results were corroborated using ~ 1700 patient-derived cancer organoids (PDCOs) isolated from 19 patients. Here we establish organoid culture parameters for individual organoid morphologic tracking to determine therapeutic response and growth/response heterogeneity for translational studies.
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Neoplasias , Organoides , Animales , Colon , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Organoides/patologíaRESUMEN
Glioblastoma multiforme (GBM), the most frequent and aggressive primary brain tumor in humans, responds modestly to treatment: most patients survive less than one year after diagnosis, despite both classical and innovative treatment approaches. A recent paper focused on γδ T-cell response in GBM patients, suggesting the application of an immunomodulating strategy based on γδ T-cells which is already in clinical trials for other tumors. Human Vγ2 T-cells recognize changes in the mevalonate metabolic pathway of transformed cells by activating cytotoxic response, and by cytokine and chemokine release. Interestingly, this activation may also be induced in vivo by drugs, such as zoledronic acid, that induce the accumulation of Vγ2 T-cell ligand Isopentenyl-pyrophosphate by blocking the farnesyl pyrophosphate synthase enzyme. The aim of our work is to confirm whether bisphosphonate treatment would make glioma cell lines more susceptible to lysis by in vitro expanded γδ T-cells, improving their antitumor activity. We expanded in vitro human Vγ2 T-cells by phosphoantigen stimulation and tested their activity against glioma cell lines. Co-culture with glioma cells induced Vγ2 T-cell differentiation in effector/memory cells, killing glioma cells by the release of perforin. Interestingly, glioma cells were directly affected by zoledronic acid; moreover, treatment increased their activating ability on Vγ2 T-cells, inducing an effective antitumor cytotoxic response. Taken together, our results show that aminobisphosphonate drugs may play a dual role against GBM, by directly affecting tumor cells, and by enhancing the antitumor response of Vγ2 T-cells. Our results confirm the practicability of this approach as a new immunotherapeutic strategy for GBM treatment.
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Conservadores de la Densidad Ósea/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Citotoxicidad Inmunológica/efectos de los fármacos , Difosfonatos/farmacología , Glioma/tratamiento farmacológico , Imidazoles/farmacología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/efectos de los fármacos , Neoplasias Encefálicas/inmunología , Línea Celular Tumoral , Glioma/inmunología , Humanos , Memoria Inmunológica , Subfamilia K de Receptores Similares a Lectina de Células NK/fisiología , Perforina/metabolismo , Linfocitos T/inmunología , Ácido ZoledrónicoRESUMEN
The aim of the study was to test 1) whether chronic and stable coronary artery disease (CAD) could downregulate epicardial fat adrenomedullin synthesis and secretion, and decrease intracoronary plasma adrenomedullin levels, and 2) whether intracoronary plasma adrenomedullin levels could be related to epicardial adipose tissue adrenomedullin gene and protein expression in subjects with CAD. We examined 12 patients with CAD who required coronary artery bypass graft (CABG) and 10 patients with non-CAD who underwent cardiac surgery for valve replacement. Plasma levels of adrenomedullin were measured in peripheral vein circulation, in left coronary artery (LCA) and coronary sinus (CS) during coronary angiography. Epicardial adipose tissue biopsy for Reverse Transcription and Real-Time PCR (RT-PCR) adrenomedullin mRNA analysis and Western Blotting (WB) protein expression was performed during cardiac surgery in all subjects. Peripheral, LCA, and CS plasma adrenomedullin levels were significantly lower in CAD patients than in those with non-CAD (3.0+/-0.9 vs. 4.4+/-0.9 pg/ml p<0.01; 2.9+/-1 vs. 4.05+/-0.8 pg/ml, p<0.01, 3.1+/-0.9 vs. 3.98+/-0.9 pg/ml p=0.04, respectively). However, CS adrenomedullin levels were not statistically different than those in LCA suggesting that adrenomedullin was not secreted from epicardial fat into the coronary artery lumen. Epicardial fat adrenomedullin mRNA levels and protein expression were lower in patients with CAD than in those with non-CAD (p<0.01 for both). We conclude that 1) epicardial fat adrenomedullin gene and protein expression can be downregulated in CAD subjects, and 2) intracoronary adrenomedullin levels are lower in CAD. No evidence that epicardial adipose tissue really contributes intracoronary adrenomedullin can be provided at this time.
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Tejido Adiposo/metabolismo , Adrenomedulina/análisis , Adrenomedulina/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/metabolismo , Pericardio/metabolismo , Tejido Adiposo/patología , Adrenomedulina/genética , Anciano , Enfermedad de la Arteria Coronaria/fisiopatología , Circulación Coronaria , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Pericardio/patología , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The role of adiponectin and epicardial adipose tissue in coronary artery disease (CAD) is a subject of debate. Whether plasma adiponectin concentration in the coronary circulation is locally modulated by the epicardial fat is still unexplored. We evaluated the hypothesis whether intracoronary plasma adiponectin levels are related to adiponectin expression in epicardial adipose tissue in vivo in patients with CAD and without CAD (non-CAD). We examined 12 patients with CAD who required CABG and 10 patients with non-CAD who underwent cardiac surgery for valve replacement. Plasma levels of adiponectin were measured in peripheral vein circulation and in left coronary artery (LCA) during coronary angiography. Epicardial adipose tissue biopsy for adiponectin protein extraction was performed during cardiac surgery in both CAD and non-CAD subjects. Adiponectin protein expression in epicardial adipose tissue was lower in patients with CAD than in those with non-CAD (0.45+/-0.4 vs. 1.1+/-1.0, p<0.05). LCA plasma adiponectin levels significantly correlated with epicardial adipose tissue adiponectin protein expression (r=0.68, p=0.02) in all subjects. Peripheral adiponectin levels and epicardial fat adiponectin protein expression were the best correlates of LCA adiponectin, r (2)=0.49, p<0.01, p<0.05, respectively). Our study showed that intracoronary adiponectin levels reflect systemic adiponectin levels. Epicardial adipose tissue could partially contribute to adiponectin levels in the coronary circulation.
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Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Enfermedad Coronaria/metabolismo , Vasos Coronarios/metabolismo , Adiponectina/sangre , Anciano , Angiografía Coronaria , Puente de Arteria Coronaria , Enfermedad Coronaria/sangre , Enfermedad Coronaria/cirugía , Estudios Transversales , Femenino , Enfermedades de las Válvulas Cardíacas/sangre , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Masculino , Persona de Mediana Edad , Válvula Mitral/cirugíaRESUMEN
Dilated cardiomyopathy due to thrombotic microangiopathy has been rarely reported as a clinical manifestation of antiphospholipid syndrome (APS). We describe the case of a 39-year-old woman affected by systemic lupus erythematosus (SLE) and positive antiphospholipid antibodies (aPL) who presented with orthopnea and peripheral oedema. Diagnosis of dilated cardiomyopathy due to myocardial thrombotic microangiopathy was made and treatment with anticoagulants prevented the worsening of the clinical condition. Interestingly, at variance with other cases, our patient showed no extracardiac signs of APS. The review of the current literature has confirmed that dilated cardiomyopathy due to thrombotic microangiopathy is a rare manifestation of APS.
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Síndrome Antifosfolípido/complicaciones , Cardiomiopatía Dilatada/etiología , Lupus Eritematoso Sistémico/complicaciones , Trombosis/complicaciones , Adulto , Circulación Coronaria , Femenino , Humanos , MicrocirculaciónRESUMEN
PURPOSE: To assess the diagnostic effectiveness of Multiparametric ultrasound (MPUS), which includes color Doppler ultrasound (CDUS), CEUS and Shear wave elastography (SWE), for evaluating carotid plaque as compared with CT-angiography (CTA) and histology. MATERIALS AND METHODS: Forty-three consecutive patients scheduled to undergo carotid endarterectomy underwent MPUS. Then, after periods ranging from 2 days to 2 weeks, all underwent CTA. Each plaque was classified by means of dedicated scores for CEUS and SWE as compared with CTA features. At surgery, each plaque was removed in a single fragment to facilitate histological analysis, which evaluated 4 features: extension of the lipid core, thickness of the fibrous cap, inflammatory infiltrate (CD68 + and CD3 + markers) and the presence of intraplaque microvessels. For the CEUS, SWE and CTA, the following values for identifying plaque vulnerability were evaluated: sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV) and Area under the curve (AUC). Cohen's kappa was used to evaluate the concordance between measurements in the different imaging methods. A p < 0.05 was considered statistically significant. RESULTS: At histology, 31 out of 43 plaques were identified as vulnerable because of the presence of at least one of the following criteria: fibrous cap < 200 µm, lipid core, intraplaque hemorrhage, inflammatory infiltrate or intraplaque neovascularization. CTA showed a sensitivity of 87.1%, a specificity of 100%, a PPV of 100%, an NPV of 75% and an AUC of 93.5%. SWE showed a sensitivity of 87.1%, a specificity of 66.7%, a PPV of 87.1%, an NPV of 66.7% and an AUC of 76.9%. CEUS showed a sensitivity of 87.1%, a specificity of 58.3%, a PPV of 84.4%, an NPV of 63.6% and an AUC of 72.7%. CONCLUSIONS: Multiparametric ultrasound is an effective modality to obtain comprehensive information on carotid plaques. Further studies are needed to determine whether it can be considered a diagnostic standard.
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Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad , Placa Aterosclerótica/diagnóstico por imagen , Ultrasonografía Doppler en Color , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/cirugía , Angiografía por Tomografía Computarizada , Medios de Contraste , Endarterectomía Carotidea , Humanos , Placa Aterosclerótica/patología , Placa Aterosclerótica/cirugía , Riesgo , Sensibilidad y Especificidad , Ultrasonografía Doppler en Color/métodosRESUMEN
In some early-treated HIV-positive patients, Structured Treatment Interruption (STI) is associated to spontaneous control of viral rebound. Thus, in this clinical setting, we analyzed the immunological parameters associated to viral control. Two groups of early treated patients who underwent STI were retrospectively defined, according to the ability to spontaneously control HIV replication (Controller and Non-controller). Plasma cytokine levels were analyzed by multiplex analysis. CD8 T cell differentiation was determined by polychromatic flow cytometry. Antigen-specific IFN-gamma production was analyzed by ELISpot and intracellular staining after stimulation with HIV-peptides. Long-term Elispot assays were performed in the presence or absence of IL-15. Plasma IL-15 was found decreased over a period of time in Non-Controller patients, whereas a restricted response to Gag (aa.167-202 and 265-279) and Nef (aa.86-100 and 111-138) immunodominant epitopes was more frequently observed in Controller patients. Interestingly, in two Non-Controller patients the CD8-mediated T cells response to immunodominant epitopes could be restored in vitro by IL-15, suggesting a major role of cytokine homeostasis on the generation of protective immunity. In early-treated HIV+ patients undergoing STI, HIV replication control was associated to CD8 T cell maturation and sustained IL-15 levels, leading to HIV-specific CD8 T cell responses against selected Gag and Nef epitopes.
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Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Epítopos/inmunología , Antígenos VIH/inmunología , Infecciones por VIH , Interleucina-15/inmunología , Adulto , Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa , Linfocitos T CD8-positivos/inmunología , Epítopos/farmacología , Antígenos VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/fisiología , Humanos , Memoria Inmunológica/efectos de los fármacos , Interferón gamma/inmunología , Interleucina-15/sangre , Interleucina-15/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Replicación Viral/efectos de los fármacos , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/farmacología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/farmacologíaRESUMEN
Meningococcus serogroup B (MenB), clonal complex 32 (cc 32), was the Brazilian epidemic strain of meningococcal disease (MD) in the 1990's. Currently, meningococcus serogroup C (MenC), cc 103, is responsible for most of the cases of the disease in Brazil. The aim of this study was to investigate the seroprevalence of bactericidal antibody (SBA) against representative epidemic strains of MenC, (N753/00 strain, C:23:P1.22,14-6, cc103) and MenB, (Cu385/83 strain, B:4,7:P1.15,19, cc32) in students and employees of a university hospital in the State of Rio Grande do Sul (RS, Brazil). A second MenC strain (N79/96, C:2b:P1.5-2,10, cc 8) was used as a prototype strain of Rio de Janeiro's outbreak that occurred in the 1990's. Our previous study showed a 9% rate of asymptomatic carriers in these same individuals. A second goal was to compare the SBA prevalence in meningococcal carriers and non-carriers. Fifty-nine percent of the studied population showed protective levels of SBA titers (log2≥2) against at least one of the three strains. About 40% of the individuals had protective levels of SBA against N753/00 and Cu385/83 strains. Nonetheless, only 22% of the individuals showed protective levels against N79/96 strain. Significantly higher antibody levels were seen in carriers compared to non-carriers (P≤0.009). This study showed that, similar to other States in Brazil, a MenC (23:P1.22,14-6, cc103) strain with epidemic potential is circulating in this hospital. Close control by the Epidemiological Surveillance Agency of RS of the number of cases of MD caused by MenC strains in the State is recommended to prevent a new disease outbreak.
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Anticuerpos Antibacterianos/sangre , Neisseria meningitidis Serogrupo B/inmunología , Neisseria meningitidis Serogrupo C/inmunología , Adulto , Brasil , Femenino , Hospitales Universitarios , Humanos , Immunoblotting/métodos , Masculino , Infecciones Meningocócicas/inmunología , Persona de Mediana Edad , Neisseria meningitidis Serogrupo B/aislamiento & purificación , Neisseria meningitidis Serogrupo C/aislamiento & purificación , Estudios Seroepidemiológicos , Serogrupo , Determinación de Anticuerpos Séricos Bactericidas , Estadísticas no Paramétricas , Adulto JovenRESUMEN
The model of monozygotic twins has been repeatedly studied to control the genetic and age-specific effects on HIV disease. Focusing on this natural model, the expression of CD27/CD45RA differentiation markers and the distribution of the Vbeta TCR repertoire was analyzed on CD4+ and CD8+ T cells. In our HIV-discordant monozygotic twins, a significant reduction of naive T cells and a parallel accumulation of effector/memory T cells was induced by HIV infection, as well as a skewing of T cell repertoire evidenced by VbetaTCR analysis. The block of HIV replication by highly active antiretroviral therapy (HAART) restored most of the T cell maturation and selection process, with some exception among CTL differentiation and repertoire. Altogether, the model of HIV-discordant monozygotic twins is a valuable tool showing that HAART is not able to completely restore the CTL profile.
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Síndrome de Inmunodeficiencia Adquirida/inmunología , Diferenciación Celular/inmunología , Linfocitos T/inmunología , Gemelos Monocigóticos/inmunología , Síndrome de Inmunodeficiencia Adquirida/patología , Células Cultivadas , Humanos , Modelos Biológicos , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/patologíaRESUMEN
BACKGROUND: Circumferential radiofrequency ablation around pulmonary vein (PV) ostia has recently been described as a new anatomic approach for atrial fibrillation (AF). METHODS AND RESULTS: We treated 251 consecutive patients with paroxysmal (n=179) or permanent (n=72) AF. Circular PV lesions were deployed transseptally during sinus rhythm (n=124) or AF (n=127) using 3D electroanatomic guidance. Procedures lasted 148+/-26 minutes. Among 980 lesions surrounding individual PVs (n=956) or 2 ipsilateral veins with close openings or common ostium (n=24), 75% were defined as complete by a bipolar electrogram amplitude <0.1 mV inside the lesion and a delay >30 ms across the line. The amount of low-voltage encircled area was 3594+/-449 mm(2), which accounted for 23+/-9% of the total left atrial (LA) map surface. Major complications (cardiac tamponade) occurred in 2 patients (0.8%). No PV stenoses were detected by transesophageal echocardiography. After 10.4+/-4.5 months, 152 patients with paroxysmal AF (85%) and 49 with permanent AF (68%) were AF-free. Patients with and without AF recurrence did not differ in age, AF duration, prevalence of heart disease, or ejection fraction, but the LA diameter was significantly higher (P<0.001) in permanent AF patients with recurrence. The proportion of PVs with complete lesions was similar between patients with and without recurrence, but the latter had larger low-voltage encircled areas after radiofrequency (expressed as percent of LA surface area; P<0.001). CONCLUSIONS: Circumferential PV ablation is a safe and effective treatment for AF. Its success is likely due to both PV trigger isolation and electroanatomic remodeling of the area encompassing the PV ostia.