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INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.
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Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Neoplasias Cardíacas/tratamiento farmacológico , Rabdomioma/tratamiento farmacológico , Esclerosis Tuberosa/complicaciones , Antineoplásicos/efectos adversos , Niño , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Everolimus/efectos adversos , Neoplasias Cardíacas/complicaciones , Humanos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Rabdomioma/complicaciones , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
A novel treatment approach to address the nasolabial fold is the insertion facial suspension threads. However, there is a paucity of data available to guide insertion techniques and material selection. Three female and two male cephalic specimens of Caucasian ethnicity (73.6 ± 6.5 years; 21.41 ± 2.2 kg/m2) were included into this experimental split-face study. One facial side was treated with polycaprolactone (PCL) thread: 180 mm, bidirectional, 18G 100 mm cannula, 20 degrees trajectory, preauricular approach whereas the contralateral side was treated with polydioxanone (PDO) thread: 100 mm, bidirectional, 19G, 60 mm cannula, 50 degrees trajectory, infraorbital approach. Three-dimensional imaging outcome measures included vertical and horizontal skin displacement and volume changes at the nasolabial sulcus, at the labiomandibular sulcus, and along the jawline. Comparing PCL 180 mm 20 degrees to PDO 100 mm 50 degrees: vertical lifting effect 1.42 ± 2.63 mm versus 1.24 ± 1.88 mm (p = 0.906); horizontal lifting effect 3.42 ± 1.44 mm versus -2.02 ± 1.84 mm (p = 0.001); nasolabial volume change -0.80 ± 0.65 mL versus -0.52 ± 0.17 mL (p = 0.367); labiomandibular volume change -0.45 ± 0.42 mL versus -0.16 ± 0.16 mL (p = 0.191); jawline volume change 0.02 ± 0.43 mL versus -0.01 ± 0.21 mL (p = 0.892). The study provides objective evidence for the short-term effectiveness of facial suspension threads in treating the nasolabial folds. The results point toward a better aesthetic outcome when utilizing long facial suspension threads that can effect full-face changes as compared with short facial suspension threads.
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Surco Nasolabial , Ritidoplastia , Cadáver , Estética Dental , Femenino , Humanos , Masculino , PolidioxanonaRESUMEN
SARS-CoV-2 serologic surveys estimate the proportion of the population with antibodies against historical variants, which nears 100% in many settings. New approaches are required to fully exploit serosurvey data. Using a SARS-CoV-2 anti-Spike (S) protein chemiluminescent microparticle assay, we attained a semi-quantitative measurement of population IgG titers in serial cross-sectional monthly samples of blood donations across seven Brazilian state capitals (March 2021−November 2021). Using an ecological analysis, we assessed the contributions of prior attack rate and vaccination to antibody titer. We compared anti-S titer across the seven cities during the growth phase of the Delta variant and used this to predict the resulting age-standardized incidence of severe COVID-19 cases. We tested ~780 samples per month, per location. Seroprevalence rose to >95% across all seven capitals by November 2021. Driven by vaccination, mean antibody titer increased 16-fold over the study, with the greatest increases occurring in cities with the highest prior attack rates. Mean anti-S IgG was strongly correlated (adjusted R2 = 0.89) with the number of severe cases caused by Delta. Semi-quantitative anti-S antibody titers are informative about prior exposure and vaccination coverage and may also indicate the potential impact of future SARS-CoV-2 variants.
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Background: The COVID-19 situation in Brazil is complex due to large differences in the shape and size of regional epidemics. Understanding these patterns is crucial to understand future outbreaks of SARS-CoV-2 or other respiratory pathogens in the country. Methods: We tested 97,950 blood donation samples for IgG antibodies from March 2020 to March 2021 in 8 of Brazil's most populous cities. Residential postal codes were used to obtain representative samples. Weekly age- and sex-specific seroprevalence were estimated by correcting the crude seroprevalence by test sensitivity, specificity, and antibody waning. Results: The inferred attack rate of SARS-CoV-2 in December 2020, before the Gamma variant of concern (VOC) was dominant, ranged from 19.3% (95% credible interval [CrI] 17.5-21.2%) in Curitiba to 75.0% (95% CrI 70.8-80.3%) in Manaus. Seroprevalence was consistently smaller in women and donors older than 55 years. The age-specific infection fatality rate (IFR) differed between cities and consistently increased with age. The infection hospitalisation rate increased significantly during the Gamma-dominated second wave in Manaus, suggesting increased morbidity of the Gamma VOC compared to previous variants circulating in Manaus. The higher disease penetrance associated with the health system's collapse increased the overall IFR by a minimum factor of 2.91 (95% CrI 2.43-3.53). Conclusions: These results highlight the utility of blood donor serosurveillance to track epidemic maturity and demonstrate demographic and spatial heterogeneity in SARS-CoV-2 spread. Funding: This work was supported by Itaú Unibanco 'Todos pela Saude' program; FAPESP (grants 18/14389-0, 2019/21585-0); Wellcome Trust and Royal Society Sir Henry Dale Fellowship 204311/Z/16/Z; the Gates Foundation (INV- 034540 and INV-034652); REDS-IV-P (grant HHSN268201100007I); the UK Medical Research Council (MR/S0195/1, MR/V038109/1); CAPES; CNPq (304714/2018-6); Fundação Faculdade de Medicina; Programa Inova Fiocruz-CE/Funcap - Edital 01/2020 Number: FIO-0167-00065.01.00/20 SPU N°06531047/2020; JBS - Fazer o bem faz bem.
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COVID-19 , Anticuerpos Antivirales , Donantes de Sangre , Brasil/epidemiología , COVID-19/epidemiología , Estudios Transversales , Femenino , Humanos , Inmunoglobulina G , Masculino , SARS-CoV-2 , Estudios SeroepidemiológicosRESUMEN
INTRODUCTION: Radiation resistance is a major cause of death in cancer patients. Cancer cells react during radiotherapy by re-programming specific cell functions that may confer resistance to radiation. The understanding of this complex process is hindered due to the lack of appropriate study models. We describe an experimental development of a radioresistant isogenic cancer cell line, and its molecular characterization. MATERIALS AND METHODS: A431-cultured cells were irradiated for 7 month until 85 Gy. Then, a selected single cell was left to grow as stable A431-R cell line. Clonogenic assay was used to determine cell survival, the α and ß parameters of the LQ model, and the mean inactivation dose. The DNA repair ability of cells was evaluated by pulsed-field electrophoresis method. Differential effect of fractionated radiation was ultimately tested in xenografts. Furthermore, we used a wound healing assay, Western blot for EGFR, AKT and ERK1/2 and ELISA test for vascular endothelial growth factor (VEGF) secretion. Finally we explored CD44 marker and cell cycle distribution. RESULTS: The established A431-R cell line showed radiation resistance in clonogenic assays, repair of radiation-induced DNA fragmentation and xenografted tumours. The radiation resistance was associated with in vitro higher cell growth and migration, increased levels of former oncoproteins, and secretion of VEGF. CONCLUSIONS: In this model, the emergence of radiation resistance was associated with the acquisition of biological traits that support more aggressive behaviour of cancer cells. We have generated a model that will be useful for mechanistic studies and development of rational treatments against radiation resistance in cancer.
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Carcinoma de Células Escamosas/patología , Tolerancia a Radiación , Animales , Apoptosis , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Ciclo Celular , Movimiento Celular , Proliferación Celular , Relación Dosis-Respuesta en la Radiación , Femenino , Citometría de Flujo , Rayos gamma , Humanos , Receptores de Hialuranos/metabolismo , Ratones , Ratones Desnudos , Fenotipo , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
COVID-19 , SARS-CoV-2 , Incidencia , Donantes de Sangre , Epidemiología , Salud Global , Mortalidad , VirusRESUMEN
Four novel polyketide-derived metabolites, myriaporones 1, 2, 3, and 4, have been isolated from the Mediterranean bryozoan Myriapora truncata. Their structures and stereochemistry have been assigned from the analysis of spectroscopic data. The inseparable equilibrium mixture of myriaporones 3 and 4 showed 88% inhibition of L1210 murine leukemia cells at 0.2 microg/mL.