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1.
J Immunother Cancer ; 9(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34353848

RESUMO

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. METHODS: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. RESULTS: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. CONCLUSIONS: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Antineoplásicos Imunológicos/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino
2.
Tissue Cell ; 73: 101627, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34425516

RESUMO

The requirement to achieve natural looking restorations is one of the most challenging aspects in dentistry. Although zirconia has provided new opportunities for achieving superior aesthetics and physicochemical outcomes, very little has been achieved for its cellular and molecular performance, especially considering angiogenesis and osteogenesis. As angiogenesis is a secondary event and concomitant to osteogenesis, an indirect effect of dental implant on endothelial cells could be the release of active molecules such as those already reported affecting osteoblasts. To better address this issue, we challenged human endothelial cells (HUVECs) with zirconia-conditioned medium up to 72 h to allow analysis specific gene expression and protein pattern of mediators of epigenetic machinery in full. Our data shows involvement of zirconia in triggering intracellular signaling through MAPK-ERK activation, leading the signal to activate histone deacetylase HDAC6 likely with concomitant well-modulated DNA methylation profile by DNMTs and TETs. These signaling pathways seem to culminate in cytoskeleton rearrangement of endothelial cells, an important prerequisite to cell migration expected in angiogenesis. Collectively, this study demonstrates for the first time epigenetic-related molecular mechanism involved in endothelial cells responding to zirconia, revealing a repertoire of signaling molecules capable of executing the reprogramming process of gene expression, which are necessary to drive cell proliferation, migration, and consequently angiogenesis. This set of data can further studies using gene editing approaches to better elucidate functional roles.


Assuntos
Epigênese Genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Transdução de Sinais , Zircônio/farmacologia , Meios de Cultura/química , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
J Periodontol ; 92(12): 1697-1718, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33851728

RESUMO

BACKGROUND: The social diversity, heterogeneous culture, and inherent economic inequality factors in Latin America (LA) justify conducting a comprehensive analysis on the current status and future trends of peri-implant diseases and conditions. Thus, the aim of this Delphi study was to predict the future trends in the diagnosis and treatment of peri-implant diseases and conditions in LA countries for the year 2030. METHODS: A Latin American steering committee and group of experts in implant dentistry validated a questionnaire including 64 questions divided into eight sections. The questionnaire was run twice with an interval of 45 days, with the results from the first round made available to all the participants in the second round. The results were expressed in percentages and data was analyzed describing the consensus level reached in each question. RESULTS: A total of 221 experts were invited to participate in the study and a total 214 (96.8%) completed the two rounds. Moderate (65%-85%) to high consensus (≥ 85%) was reached in 51 questions (79.69%), except in the questions dealing with "prevalence", where no consensus was reached. High and moderate consensus was attained for all the questions in three fields (risk factors and indicators, diagnosis and treatment of peri-implant conditions and deficiencies, and prevention and maintenance). CONCLUSIONS: The present study has provided relevant and useful information on the predictions in the diagnosis and treatment of peri-implant diseases with a high level of consensus among experts. Nevertheless, there is still a lack of agreement in certain domains.


Assuntos
Implantes Dentários , Peri-Implantite , Consenso , Técnica Delfos , Humanos , América Latina/epidemiologia , Peri-Implantite/diagnóstico , Peri-Implantite/epidemiologia , Peri-Implantite/terapia , Periodontia
4.
Blood Adv ; 5(2): 593-601, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33496754

RESUMO

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events. These trials were registered at www.clinicaltrials.gov as #NCT02435849 and #NCT02228096.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Criança , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T
5.
Biomed Res Int ; 2020: 3026893, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005686

RESUMO

There is an increased effort on developing novel and active surfaces in order to accelerate their osteointegration, such as nanosized crystalline hydroxyapatite coating (HAnano®). To better understand the biological behavior of osteoblasts grown on HAnano® surface, the set of data was compared with SLActive®, a hydrophilic sandblasted titanium surface. Methodologically, osteoblasts were seeded on both surfaces up to 72 hours, to allow evaluating cell adhesion, viability, and set of genes encoding proteins related with adhesion, proliferation, and differentiation. Our data shows HAnano® displays an interesting substrate to support cell adhesion with typical spread morphologic cells, while SLActive®-adhering cells presented fusiform morphology. Our data shows that the cellular adhesion mechanism was accompanied with upexpression of integrin ß1, Fak, and Src, favoring the assembling of focal adhesion platforms and coupling cell cycle progression (upmodulating of Cdk2, Cdk4, and Cdk6 genes) in response to HAnano®. Additionally, both bioactive surfaces promoted osteoblast differentiation stimulus, by activating Runx2, Osterix, and Alp genes. Although both surfaces promoted Rankl gene expression, Opg gene expression was higher in SLActive® and this difference reflected on the Rankl/Opg ratio. Finally, Caspase1 gene was significantly upmodulated in response to HAnano® and it suggests an involvement of the inflammasome complex. Collectively, this study provides enough evidences to support that the nanohydroxyapatite-coated surface provides the necessary microenvironment to drive osteoblast performance on dental implants and these stages of osteogenesis are expected during the early stages of osseointegration.


Assuntos
Durapatita/farmacologia , Nanopartículas/administração & dosagem , Osseointegração/efeitos dos fármacos , Propriedades de Superfície/efeitos dos fármacos , Titânio/farmacologia , Células 3T3 , Animais , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos
6.
Int J Public Health ; 65(1): 17-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31932856

RESUMO

OBJECTIVES: To assess the policy utility of national cause of death (COD) data of six high-income countries with highly developed health information systems. METHODS: National COD data sets from Australia, Canada, Denmark, Germany, Japan and Switzerland for 2015 or 2016 were assessed by applying the ANACONDA software tool. Levels, patterns and distributions of unusable and insufficiently specified "garbage" codes were analysed. RESULTS: The average proportion of unusable COD was 18% across the six countries, ranging from 14% in Australia and Canada to 25% in Japan. Insufficiently specified codes accounted for a further 8% of deaths, on average, varying from 6% in Switzerland to 11% in Japan. The most commonly used garbage codes were Other ill-defined and unspecified deaths (R99), Heart failure (I50.9) and Senility (R54). CONCLUSIONS: COD certification errors are common, even in countries with very advanced health information systems, greatly reducing the policy value of mortality data. All countries should routinely provide certification training for hospital interns and raise awareness among doctors of their public health responsibility to certify deaths correctly and usefully for public health policy.


Assuntos
Causas de Morte , Confiabilidade dos Dados , Coleta de Dados/estatística & dados numéricos , Países Desenvolvidos/estatística & dados numéricos , Mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Canadá , Dinamarca , Feminino , Alemanha , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Suíça
7.
CPT Pharmacometrics Syst Pharmacol ; 8(5): 285-295, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30848084

RESUMO

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed-effect model-based analysis of chimeric antigen receptor-T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric antigen receptor-T cell expansion.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Feminino , Meia-Vida , Humanos , Imunoterapia Adotiva , Masculino , Modelos Teóricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Adulto Jovem
8.
Nat Med ; 24(10): 1504-1506, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30275569

RESUMO

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Antígenos CD19/genética , Antígenos CD19/imunologia , Humanos , Imunoterapia Adotiva , Perda de Heterozigosidade/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia
9.
Clin Cancer Res ; 24(24): 6175-6184, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30190371

RESUMO

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. CONCLUSIONS: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Terapia Genética , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfócitos T , Adolescente , Adulto , Animais , Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Criança , Pré-Escolar , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Humanos , Imunidade Humoral , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Contagem de Linfócitos , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Transgenes/genética , Resultado do Tratamento , Adulto Jovem
11.
J Hematol Oncol ; 11(1): 35, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29499750

RESUMO

BACKGROUND: Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. DISCUSSION: The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. CONCLUSION: We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.


Assuntos
Citocinas/imunologia , Imunoterapia Adotiva/efeitos adversos , Inflamação/etiologia , Leucemia de Células B/terapia , Leucemia Linfocítica Crônica de Células B/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Animais , Humanos , Imunoterapia Adotiva/métodos , Inflamação/diagnóstico , Inflamação/imunologia , Leucemia de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia
12.
N Engl J Med ; 378(5): 439-448, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29385370

RESUMO

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19 , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Análise de Sobrevida , Adulto Jovem
13.
Blood ; 130(21): 2317-2325, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-28935694

RESUMO

Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Citocinas/sangue , Humanos , Lactente , Cinética , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva , Transgenes , Carga Tumoral/efeitos dos fármacos , Adulto Jovem
15.
Periodontia ; 26(3): 57-64, 2016. ilus
Artigo em Português | LILACS, BBO - Odontologia | ID: biblio-837022

RESUMO

Os enxertos ósseos utilizados em reconstruções são chamados de autógenos quando são retirados da própria pessoa que recebe o implante. Os enxertos autógenos ainda são utilizados pela maioria dos cirurgiões na Odontologia, mas sabe-se que essa opção apresenta algumas desvantagens, como necessidade de segunda área cirúrgica para coletar o osso, maior tempo cirúrgico, maior incidência de complicações e quantidade limitada de tecido. Devido a essas restrições, alternativas têm sido propostas e uma delas é o uso da proteina óssea morfogenética. Esta é capaz de induzir células tronco do local que foi aplicada, a diferenciarem-se em osteoblastos, promovendo assim a formação de tecido ósseo. Este trabalho demonstrou um caso clinico de reconstrucção da região anterior de uma maxilla extremamente atrófica com uso apenas de BMP e tela de titânio como arcabouço. Clínica, histológica e radiograficamente foi demonstrado um grande crescimento ósseo, possibilitando a instalação de implantes dentários.(AU)


Bone grafts used in reconstructions can be taken from the same person, when called autogenous. Autografts are still used by most surgeons in dentistry, but it is known that this option has some disadvantages, such as requiring a second surgical area to collect the bone, surgery time, higher incidence of complications and limited amount of tissue. Because of these constraints, alternatives have been proposed, one of which is the use of bone morphogenetic protein. This protein is capable of inducing stem cells has been applied, to differentiate in osteoblasts thereby promoting the formation of bone tissue. This report demonstrated a clinical case of reconstruction of extremely atrophic maxilla using only the BMP and titanium mesh scaffold. Clinically, histological and radiographically demonstrated a great bone growth, enabling the installation of dental implants. (AU)


Assuntos
Humanos , Feminino , Adulto , Osso e Ossos , Transplante Ósseo , Implantação Dentária Endóssea
16.
School Ment Health ; 7(3): 161-173, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26442131

RESUMO

Researchers have consistently documented a gap between the large number of US youth meeting criteria for a mental health disorder with significant associated impairment, and the comparatively few youth receiving services. School-based mental health care may address the need-services gap by offering services more equitably to youth in need, irrespective of family economic resources, availability of transportation, and other factors that can impede access to community clinics. However, diagnoses alone do not fully capture the severity of an individual's mental health status and need for services. Studying service use only in relation to diagnoses may restrict our understanding of the degree to which service use is reflective of service need, and inhibit our ability to compare school and non-school-based outpatient settings on their responsiveness to service need. The present study evaluated predictors of mental health service use in school- and community-based settings for youth who had had an active case in one of two public sectors of care, comparing empirically-derived dimensional measurements of youth mental health service need and impairment ratings against non-need variables (e.g., ethnicity, income). Three dimensions of youth mental health service need were identified. Mental health service need and non-need variables each played a significant predictive role. Parent-rated impairment was the strongest need-based predictor of service use across settings. The impact of non-need variables varied by service setting, with parental income having a particularly noticeable effect on school-based services. Across time, preceding service use and impairment each significantly predicted future service use.

17.
ImplantNews ; 11(6a): 153-159, 2014. ilus, tab
Artigo em Português | LILACS, BBO - Odontologia | ID: lil-733631

RESUMO

Objetivo: reportar a relação do fumo com a perfuração da mucosa paranasal de ratos submetidos à ação intermitente da fumaça de cigarro. Material e métodos: foram utilizados nesta pesquisa 32 ratos machos e adultos Wistar (Rattus norvegicus, peso médio 400 g), divididos aleatoriamente em dois grupos (n=16), sendo: controle (não expostos à fumaça) e experimental (expostos). O grupo experimental era exposto à fumaça produzida por dez cigarros durante dez minutos, duas vezes ao dia. O nível de carboxihemoglobina (HbCO) no sangue arterial de cada rato foi coletado e analisado no espectrofotômetro. Depois, as mucosas sinusais foram retiradas cirurgicamente, embutidas em parafina, seccionadas no sentido anteroposterior, coradas e analisadas sob microscopia óptica nos períodos de 45 e 60 dias. O teste t pareado de Student foi usado para comparar os níveis de HbCO, e o teste exato de Fischer para possíveis correlações entre os achados histológicos e a exposição à fumaça (nível de significância 5%). Resultados: os níveis de HbCO no sangue dos ratos expostos foi significativamente maior (faixa de 1% - 20%, p < 0,0001) logo aos 45 dias. Os resultados histológicos demonstraram alterações significativas nas células caliciformes (60 dias, p=0,01) e na integridade ciliar (60 dias, p=0,001). Entretanto, metaplasias foram significativamente expressas nos períodos de 45 e 60 dias (p=0,03). Conclusão: nos períodos de 45 e 60 dias, alterações histológicas de grande relevância foram vistas nas mucosas sinusais expostas à fumaça do cigarro.


Assuntos
Animais , Ratos , Implantes Dentários , Seio Maxilar , Fumar
18.
Stat Med ; 32(3): 393-405, 2013 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-22991275

RESUMO

Development of biosimilars to innovative therapeutic biologics promises reduction of healthcare cost and therefore will provide patients worldwide greater access to effective treatments. Because of the differences in raw materials or manufacturing processes, 'equivalence' of bioavailability between a biosimilar and the reference biologic is generally regarded as insufficient, and thus, clinical trials providing efficacy and safety data are often required by regulatory agencies. The traditional non-inferiority trial design may not be accepted for establishing biosimilarity in order to avoid superior efficacy with additional safety (e.g., immunogenicity) risks. On the other hand, the bioequivalence trial design, which is used in the generic paradigm for the evaluation of bioavailability of generic chemical drugs, is not appropriate for evaluating clinical efficacy because the equivalence margins are generally too wide and not justified on statistical or clinical grounds. Motivated by the World Health Organization guideline and the newly released Food and Drug Administration draft guideline on biosimilars, we propose a biosimilarity trial design for evaluating clinical efficacy. The design uses a non-inferiority margin and an asymmetrical non-superiority margin for statistical inference. The independent choice of both margins provides the scientific foundation for drawing clinical efficacy conclusions while maintaining the logical consistency of the inference. The design also has a higher statistical power than a naïve equivalence trial design.


Assuntos
Algoritmos , Medicamentos Biossimilares , Ensaios Clínicos como Assunto , Avaliação de Medicamentos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Aprovação de Drogas , Avaliação de Medicamentos/estatística & dados numéricos , Estados Unidos , United States Food and Drug Administration , Organização Mundial da Saúde
19.
Contraception ; 85(4): 398-401, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22036045

RESUMO

BACKGROUND: Although induced abortion is one of the most commonly performed gynecological procedures in Great Britain and medical termination of pregnancy is being used more frequently, very little is known about the role of ambulation during the procedure. We sought to compare ambulatory and non-ambulatory groups of patients undergoing medical termination in the hospital setting and determine whether ambulation impacted clinical outcomes. STUDY DESIGN: This was a prospective patient-preference study carried out among 130 women with pregnancies up to 63 days of gestation fulfilling the requirements of the 1967 Abortion Act and undergoing medical termination of pregnancy. The objective was to evaluate the effect of ambulation during medical termination of pregnancy. The women were given the choice to be ambulatory or non-ambulatory throughout the process of medical termination of pregnancy. They received 200 mg oral mifepristone and 800 mcg vaginal misoprostol for the termination procedure. Outcomes measured included time taken to pass the products of conception, first feeling of abdominal cramps, estimated blood loss, time to discharge from the hospital, pain scores and need for analgesia. RESULTS: In both ambulatory and non-ambulatory groups, the mean time taken to pass the products of conception was similar: 230.7 min (118-343.4) and 233.0 min (134.5-331.5) for ambulatory and non-ambulatory patients, respectively. Time to onset of cramps was 75.6 min (29.4-121.8) for ambulatory and 91.7 min (22.2-161.2) for non-ambulatory patients, from administration of misoprostol. Mean estimated blood loss (assessed by weighing the pads as well as blood in bed pan) was less than 100 mL in both groups, and overall, approximately 85% of patients ranked their pain score as 3 or less (on a scale of 0-5). There were no statistically significant differences in the ambulatory versus non-ambulatory groups with regard to clinical outcomes. CONCLUSION: Ambulation during medical termination of pregnancy neither appears to influence the amount of bleeding or pain nor hasten the process of medical termination of pregnancy.


Assuntos
Abortivos/uso terapêutico , Aborto Induzido/métodos , Mifepristona/uso terapêutico , Misoprostol/uso terapêutico , Preferência do Paciente , Caminhada , Adulto , Feminino , Humanos , Gravidez , Estudos Prospectivos , Resultado do Tratamento , Reino Unido
20.
Child Dev ; 83(1): 351-66, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22188462

RESUMO

This study tests a model of reciprocal influences between absenteeism and youth psychopathology using 3 longitudinal datasets (Ns = 20,745, 2,311, and 671). Participants in 1st through 12th grades were interviewed annually or biannually. Measures of psychopathology include self-, parent-, and teacher-report questionnaires. Structural cross-lagged regression models were tested. In a nationally representative data set (Add Health), middle school students with relatively greater absenteeism at Study Year 1 tended toward increased depression and conduct problems in Study Year 2, over and above the effects of autoregressive associations and demographic covariates. The opposite direction of effects was found for both middle and high school students. Analyses with 2 regionally representative data sets were also partially supportive. Longitudinal links were more evident in adolescence than in childhood.


Assuntos
Absenteísmo , Transtornos de Ansiedade/epidemiologia , Transtorno da Conduta/epidemiologia , Transtorno Depressivo/epidemiologia , Transtornos Fóbicos/epidemiologia , Adolescente , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/psicologia , Criança , Comorbidade , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/psicologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Programas de Rastreamento , Determinação da Personalidade/estatística & dados numéricos , Inventário de Personalidade/estatística & dados numéricos , Transtornos Fóbicos/diagnóstico , Transtornos Fóbicos/psicologia , Psicometria , Psicopatologia , Análise de Regressão , Medição de Risco/estatística & dados numéricos , Estatística como Assunto
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