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OBJECTIVES: The congenital lung malformation volume ratio (CVR) is a prenatal ultrasound measurement that parameterizes congenital lung malformation (CLM) size. The aims of this study were to use serial measurements to create estimated growth curves of fetal CVR for asymptomatic and symptomatic neonates with CLM and to investigate whether a discriminant prognostic model based on these measurements could predict accurately which fetuses with CLM will require invasive respiratory support at delivery and should therefore be delivered at a tertiary-care facility. METHODS: This was a retrospective study of fetuses diagnosed prenatally with CLM at three tertiary-care children's hospitals between 2009 and 2016. Those with two or more sonographic measurements of CVR were included. Serial fetal CVR measurements were used to create estimated growth curves for neonates with and those without respiratory symptoms at delivery, defined as requiring invasive respiratory support for the first 24 h after delivery. A discriminant model based on serial CVR measurements was used to calculate the dynamic probability of the need for invasive respiratory support. The performance of this model overall and in preterm and term neonates was compared with those using maximum CVR thresholds of 1.0 and 1.6. RESULTS: Of the 147 neonates meeting the inclusion criteria, 16 (10.9%) required postnatal invasive respiratory support. The estimated CVR growth curve models showed different growth trajectories for asymptomatic and symptomatic neonates, with significantly higher CVR in symptomatic neonates, and values peaking late in the second trimester at around 25 weeks' gestation in asymptomatic neonates. All prognostic methods had high accuracy for the prediction of the need for invasive respiratory support in term neonates, but the discriminant model had the best performance overall (area under the receiver-operating characteristics curve (AUC) = 0.88) and in the preterm population (AUC = 0.85). CONCLUSIONS: The estimated CVR growth curves showed different growth patterns in asymptomatic and symptomatic neonates with CLM. The dynamic discriminant model performed well overall and particularly in neonates that were carried to term. Development of an externally validated clinical tool based on this analysis could be useful in determining the site of delivery for fetuses with CLM. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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Pneumopatias/congênito , Pneumopatias/diagnóstico por imagem , Pulmão/anormalidades , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Feminino , Feto , Idade Gestacional , Gráficos de Crescimento , Humanos , Recém-Nascido , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/patologia , Medidas de Volume Pulmonar/métodos , Valor Preditivo dos Testes , Gravidez , Segundo Trimestre da Gravidez , Cuidado Pré-Natal/normas , Prognóstico , Respiração Artificial/tendências , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Estudos RetrospectivosRESUMO
Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.
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Anticorpos Monoclonais/administração & dosagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Idoso , Anticorpos Monoclonais/efeitos adversos , Estudos de Coortes , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/patologia , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidoresRESUMO
BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. RESULTS: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. CONCLUSIONS: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. CLINICAL TRIAL NUMBER: NCT01068769.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Proteínas Proto-Oncogênicas c-kit/genética , Piridinas/administração & dosagem , Adulto , Idoso , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Genótipo , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , SunitinibeRESUMO
BACKGROUND: Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-ß) in patients with advanced GIST following failure of at least imatinib and sunitinib. METHODS: Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. RESULTS: Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR). CONCLUSIONS: Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.
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Inibidores da Angiogênese/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Benzamidas/farmacologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Indazóis , Indóis/farmacologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piperazinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/efeitos adversos , Sunitinibe , Falha de Tratamento , Carga Tumoral , Adulto JovemRESUMO
BACKGROUND: Congenital diaphragmatic hernia (CDH) accounts for 8% of all major congenital anomalies. Neonates who are small for gestational age (SGA) generally have a poorer prognosis. We sought to identify risk factors and variables associated with outcomes in neonates with CDH who are SGA in comparison to neonates who are appropriate for gestational age (AGA). METHODS: We used the multicenter Diaphragmatic Hernia Research & Exploration Advancing Molecular Science (DHREAMS) study to include neonates enrolled from 2005 to 2019. Chi-squared or Fisher's exact tests were used to compare categorical variables and t tests or Wilcoxon rank sum for continuous variables. Cox model analyzed time to event outcomes and logistic regression analyzed binary outcomes. RESULTS: 589 neonates were examined. Ninety were SGA (15.3%). SGA patients were more likely to be female (p = 0.003), have a left sided CDH (p = 0.05), have additional congenital anomalies and be diagnosed with a genetic syndrome (p < 0.001). On initial single-variable analysis, SGA correlated with higher frequency of death prior to discharge (p < 0.001) and supplemental oxygen requirement at 28 days (p = 0.005). Twice as many SGA patients died before repair (12.2% vs 6.4%, p = 0.04). Using unadjusted Cox model, the risk of death prior to discharge among SGA patients was 1.57 times the risk for AGA patients (p = 0.029). There was no correlation between SGA and need for ECMO, pulmonary hypertensive medication at discharge or oxygen at discharge. After adjusting for confounding variables, SGA no longer correlated with mortality prior to discharge or incidence of unrepaired defects but remained significant for oxygen requirement at 28 days (p = 0.03). CONCLUSION: Infants with CDH who are SGA have worse survival and poorer lung function than AGA infants. However, the outcome of SGA neonates is impacted by other factors including gestational age, genetic syndromes, and particularly congenital anomalies that contribute heavily to their poorer prognosis.
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Oxigenação por Membrana Extracorpórea , Hérnias Diafragmáticas Congênitas , Feminino , Idade Gestacional , Hérnias Diafragmáticas Congênitas/complicações , Humanos , Lactente , Recém-Nascido , Masculino , Oxigênio , Estudos Retrospectivos , Fatores de RiscoRESUMO
Phase-separation fronts leave in their wakes morphologies that are substantially different from the morphologies formed in homogeneous phase separation. In this paper we focus on fronts in binary mixtures that are enslaved phase-separation fronts, i.e., fronts that follow in the wake of a control-parameter front. In the one-dimensional case, which is the focus of this paper, the formed morphology is deceptively simple: alternating domains of a regular size. However, determining the size of these domains as a function of the front speed and other system parameters is a nontrivial problem. We present an analytical solution for the case where no material is deposited ahead of the front and numerical solutions and scaling arguments for more general cases. Through these enslaved phase-separation fronts large domains can be formed that are practically unattainable in homogeneous one-dimensional phase separation.
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The c-Myc oncoprotein, which is required for cellular proliferation, resembles in its structure a growing number of transcription factors. However, the mechanism of its action in vivo is not yet clear. The discovery of the specific cognate DNA-binding site for Myc and its specific heterodimerization partner, Max, enabled the use of direct experiments to elucidate how Myc functions in vivo and how this function is modulated by Max. Here we demonstrate that exogenously expressed Myc is capable of activating transcription in vivo through its specific DNA-binding site. Moreover, transcriptional activation by Myc is dependent on the basic region, the integrity of the helix-loop-helix and leucine zipper dimerization motifs located in the carboxy-terminal portion of the protein, and the regions in the amino terminus conserved among Myc family proteins. In contrast to Myc, exogenously expressed Max elicited transcriptional repression and blocked transcriptional activation by Myc through the same DNA-binding site. Our results suggest a functional antagonism between Myc and Max which is mediated by their relative levels in the cells. A model for the activity of Myc and Max in vivo is presented.
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Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Fatores de Transcrição , Transcrição Gênica , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica , Células Cultivadas , Técnicas In Vitro , Substâncias Macromoleculares , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/química , Relação Estrutura-AtividadeRESUMO
The product of the c-myc proto-oncogene is an important positive regulator of cell growth and proliferation. Recently, c-Myc has also been demonstrated to be a potent inducer of apoptosis when expressed in the absence of serum or growth factors. To further examine Myc-induced apoptosis, we coexpressed the proto-oncogene bcl2, which has been shown to block apoptosis in other systems, with c-myc in serum-deprived Rat 1a fibroblasts. Here we report that ectopic expression of bcl2 specifically blocks apoptosis induced by constitutive c-myc expression. Constitutive c-myc expression in serum-deprived Rat 1a cells caused a > 15-fold increase in the number of dead cells, accompanied by DNA fragmentation. However, coexpression of bcl2 with c-myc in these cells led to a 10-fold increase in the number of live cells and a significant decrease in DNA fragmentation. Thus, Bcl-2 effectively inhibits Myc-induced apoptosis in serum-deprived Rat 1a fibroblasts without blocking entry into the cell cycle. These results imply that apoptosis serves as a protective mechanism to prevent tumorigenicity elicited by deregulated Myc expression. This protective mechanism is abrogated, however, by Bcl-2 and therefore may explain the synergism between Myc and Bcl-2 observed in certain tumor cells.
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Apoptose , Genes myc , Proteínas Proto-Oncogênicas c-myc/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Animais , Ciclo Celular , Células Cultivadas , Meios de Cultura , Dano ao DNA , Expressão Gênica , Vetores Genéticos , Técnicas In Vitro , Proteínas Proto-Oncogênicas c-bcl-2 , RNA Mensageiro/genética , Ratos , Retroviridae , TransfecçãoRESUMO
Analysis of amino-terminus mutants of c-Myc has allowed a systematic study of the interrelationship between Myc's ability to regulate transcription and its apoptotic, proliferative, and transforming functions. First, we have found that c-Myc-accelerated apoptosis does not directly correlate with its ability to transactivate transcription using the endogenous ornithine decarboxylase (ODC) gene as readout for transactivation. Furthermore, deletion of the conserved c-Myc box I domain implicated in transactivation does not inhibit apoptosis. Second, the ability of c-Myc to repress transcription, using the gadd45 gene as a readout, correlates with its ability to accelerate apoptosis. A conserved region of c-Myc implicated in mediating transrepression is absolutely required for c-Myc-accelerated apoptosis. Third, a lymphoma-derived Thr58Ala mutation diminishes c-Myc-accelerated apoptosis through a decreased ability to induce the release of cytochrome c from mitochondria. This mutation in a potential phosphorylation site does not affect cell cycle progression, providing genetic evidence that induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc. Finally, we show that the increased ability of Thr58Ala mutant to elicit cellular transformation correlates with its diminished ability to accelerate apoptosis. Bcl-2 overexpression blocked and the lymphoma-associated Thr58Ala mutation decreased c-Myc-accelerated apoptosis, and both led to a significant increase in the ability of Rat1a cells to form colonies in soft agar. This enhanced transformation was greater in soft agar containing a low concentration of serum, suggesting that protection from apoptosis is a mechanism contributing to the increased ability of these cells to proliferate in suspension. Thus, we show here for the first time that, in addition to mutations in complementary antiapoptotic genes, c-Myc itself can acquire mutations that potentiate neoplastic transformation by affecting apoptosis independently of cell cycle progression.
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Apoptose/genética , Ciclo Celular/genética , Regulação da Expressão Gênica , Genes myc , Animais , Linhagem Celular , Fibroblastos , Mutação , RatosRESUMO
We present a lattice Boltzmann algorithm based on an underlying free energy that allows the simulation of the dynamics of a multicomponent system with an arbitrary number of components. The thermodynamic properties, such as the chemical potential of each component and the pressure of the overall system, are incorporated in the model. We derived a symmetrical convection diffusion equation for each component as well as the Navier Stokes equation and continuity equation for the overall system. The algorithm was verified through simulations of binary and ternary systems. The equilibrium concentrations of components of binary and ternary systems simulated with our algorithm agree well with theoretical expectations.
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Simulations of liquid-gas systems with interface terms evaluated by central difference discretizations are observed to fail to give accurate results for two reasons: the interface can get "stuck" on the lattice or a density overshoot develops around the interface. In the first case, the bulk densities can take a range of values, dependent on the initial conditions. In the second case, inaccurate bulk densities are found. We derived the minimum interface width required for the accurate simulation of liquid-gas systems with a diffuse interface. This criterion is demonstrated for lattice Boltzmann simulations of a van der Waals gas. Combining this criterion with predictions for the bulk stability defines the parameter range for stable and accurate simulation results even for high density ratios of over 1000.
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SETTING: A suburban area of Bissau, the capital of Guinea-Bissau; the study was conducted among presumptive pulmonary tuberculosis (prePTB) patients seeking medical care for signs and symptoms suggestive of PTB. OBJECTIVE: To determine if a clinical TB score and a biomarker suPAR (soluble urokinase plasminogen activator receptor) have separate and composite ability to predict PTB diagnosis and mortality in prePTB patients. DESIGN: Observational prospective follow-up study conducted from August 2010 to August 2012. RESULTS: We included 1011 prePTB patients (mean age 34 years, 95%CI 33-35); 55% (n = 559) were female and 161 (16%) had human immunodeficiency virus (HIV) infection. Of all included patients, 10% (n = 101) were diagnosed with PTB. Mortality during follow-up was 5% (n = 48), with a mean survival time of 158 days (95%CI 27-289) in prePTB patients diagnosed with PTB vs. 144 days (95%CI 109-178) in those not diagnosed with PTB (P = 0.774). After adjusting for HIV status and age, the best separate predictor was suPAR î¶5 ng/ml, with a hazard ratio (HR) of 4.6 (95%CI 2.1-9.9) for mortality and 6.7 (95%CI 4.0-11.2) for TB diagnosis. All patients who died had a TBscore II + suPAR î¶7; the HR of the composite score for subsequent PTB diagnosis was 33.0 (95%CI 4.6-236.6). CONCLUSION: The proposed composite score of suPAR + TBscore II î¶7 can improve TB case finding and clinical monitoring.
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Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/mortalidade , Adolescente , Adulto , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Feminino , Seguimentos , Guiné-Bissau/epidemiologia , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Lattice Boltzmann simulations have been very successful in simulating liquid-gas and other multiphase fluid systems. However, the underlying second-order analysis of the equation of motion has long been known to be insufficient to consistently derive the fourth-order terms that are necessary to represent an extended interface. These same terms are also responsible for thermodynamic consistency--i.e., to obtain a true equilibrium solution with both a constant chemical potential and a constant pressure. In this article we present an equilibrium analysis of nonideal lattice Boltzmann methods of sufficient order to identify those higher-order terms that lead to a lack of thermodynamic consistency. We then introduce a thermodynamically consistent forcing method.
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The Bcl-2 protein coded by the proto-oncogene bcl-2 is expressed in a variety of embryonic and postnatal tissues and is overproduced in several types of tumours. Bcl-2 expression suppresses apoptosis induced by a multitude of stimuli in diverse cell types without exerting significant effects on cell proliferation, and is believed to contribute to oncogenesis by extending cell survival. In certain B-cell lymphomas, chromosomal translocations result in a gain of function of Bcl-2 by overexpression. Here, we report that a deletion of a nonconserved region of human Bcl-2 (residues 51-85) confers a novel gain of function that not only suppresses apoptosis induced by the tumor suppressor protein p53 and the Myc oncoprotein but also permits continued cell proliferation. Our result raises the possibility that mutations within the bcl-2 gene may contribute to oncogenesis by both suppressing apoptosis and facilitating cell proliferation.
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Apoptose , Divisão Celular , Proteínas Proto-Oncogênicas/genética , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Primers do DNA/química , Humanos , Dados de Sequência Molecular , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-myc/fisiologia , Deleção de Sequência , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/fisiologiaRESUMO
The tumor suppressor p53 is an inducer of cell cycle arrest and programmed cell death (apoptosis). The ability of p53 to induce cell cycle arrest is linked to its ability to induce transcription of genes such as the cyclin-dependent kinase inhibitor p21. However, the dependence of p53-mediated apoptosis on transcriptional activation remains controversial. Ectopic expression of a temperature-sensitive (ts) p53 allele induced expression of p53 target genes and elicited both G1 and G2/M cell cycle arrest upon shift to the permissive temperature. Ectopic expression of the same ts p53 allele with two additional point mutations (Gln22, Ser23) that abolish p53-transcriptional activation did not induce p53 target genes and G1 nor G2/M cell cycle arrest. In HCT116 colon carcinoma cells ectopic expression of wild type p53 does not elicit apoptosis whereas p53 mutant deficient in trans-activation induces apoptosis. The ability of wild type p53 to induce apoptosis is restored in HCT116 cells that are null for p21. However, the trans-activation deficient mutant of p53 is still more potent mediator of apoptosis than wild type p53 in the p21 null cells. Although the ability of Gln22,Ser23 to trans-activate p53 target genes is diminished, it retains the ability to repress Bcl-2 expression. Thus, we conclude that while ectopic expression of wild type p53 can induce both G1 and G2/M arrest, in a p21 dependent manner, without apoptosis, a p53 mutant defective in trans-activation elicits apoptosis without inducing cell cycle arrest. Further, the anti-apoptotic function of p53 is dependent on trans-activation and is linked to cell cycle arrest. The results strongly suggest that the trans-activation deficient mutant is a more potent inducer of apoptosis because it lost its anti-apoptotic function and retains its ability to repress pro-apoptotic genes such as Bcl-2. Taken together, the results imply that employing a trans-activation deficient p53 in gene therapy approaches or the use of drugs that convert mutant p53 to a trans-activation-independent mediator of apoptosis may be much more efficient therapeutic approaches than current approaches that employ wild type p53.
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Apoptose/genética , Ciclo Celular/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Transativadores/genética , Proteína Supressora de Tumor p53/genética , Carcinoma/genética , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/genética , Regulação Neoplásica da Expressão Gênica , Genes bcl-2 , Humanos , Masculino , Mutação , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas/genética , Proteína X Associada a bcl-2RESUMO
OBJECTIVE: To describe the pattern of dedifferentiated liposarcoma (DDLPS) metastases and to analyze their predictors and outcome. MATERIALS AND METHODS: In this retrospective study, we reviewed the imaging and clinical records of all consenting patients with histopathology-confirmed DDLPS seen from 2000 through 2012. The predictive value of clinical and histopathologic parameters for metastasis later in the disease course was analyzed using univariate and multivariate analyses. Survival of patients with and without metastasis was compared using Log-rank test. RESULTS: Records of 148 patients (57 women, 91 men; mean age 59 years, range 30-87 years) were reviewed. Distant metastases were observed in 44/148 patients (29.7%), 9/44 (20.5%) at presentation and 35/44 (79.5%) developing them later at a median interval of 8 months (IQR = 0.80-26 months). Median duration of follow-up was 38 months (IQR = 18-74 months) with 77/148 patients (31 with metastases) deceased at the time of analysis. Median survival was 28 months (IQR = 10-56 months) for patients with metastases and 38 months (IQR, 17-65 months) for patients without metastases (p = 0.0123, Log-Rank test; Hazard ratio 1.79 [95% confidence interval 1.11-2.84]). Lung was the most common site of metastases (33 patients, 22.3%). On univariate analysis, grade and local recurrence were associated with subsequent risk of metastasis where as age, tumor size, site, de novo dedifferentiation, number of previous surgical resections, margin positivity and chemoradiation were not. On multivariate analysis, high tumor grade (p-value = 0.0005, OR 5.05; 95% CI 2.01-13.48) and local recurrence (p-value = 0.0025, OR 4.46; 95% CI 1.67-13.40) predicted metastasis. CONCLUSION: Lung was most frequent site of DDLPS metastases. Risk of developing metastatic disease was statistically associated with tumor grade and local recurrence. Metastatic disease was associated with decreased survival.
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Lipossarcoma/epidemiologia , Lipossarcoma/secundário , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Boston/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Lipossarcoma/mortalidade , Neoplasias Pulmonares/mortalidade , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/epidemiologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Prognóstico , Encaminhamento e Consulta , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Pharmacokinetics, immunogenicity, and biodistribution of a 131I-labeled mouse/human chimeric monoclonal antibody (C-17-1A) was studied in six metastatic colon cancer patients. Pharmacokinetics obtained from serum radioactivity or chimera concentration were identical after 5 mCi of 131I-C-17-1A with mean alpha half-lives of 17.6 +/- 2.3 and 19.7 +/- 2.9 and mean beta half-lives of 100.9 +/- 16.1 and 106.4 +/- 14.1 hr, respectively. HPLC analysis documented the monomeric chimeric 17-1A without evidence of immune complexes or free 131I. None of the patients developed antibody after 131I-chimeric 17-1A exposure. Radiolocalization occurred in known areas of disease greater than 4 cm in all patients. The half-life of total-body radioactivity was 58 +/- 7 hr by whole-body counts and 64 +/- 13 hr by urine measurements. Whole-body and bone marrow dose estimates ranged from 0.75-1.03 and 0.76-1.05 rad/mCi, respectively. These studies confirm the prolonged circulation and reduced immunogenicity of chimeric 17-1A versus murine 17-1A. Marrow radiation exposure using antibodies with prolonged circulation is a critical factor in planning for radioimmunotherapeutic applications.
Assuntos
Adenocarcinoma/metabolismo , Anticorpos Monoclonais/farmacocinética , Neoplasias do Colo/metabolismo , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Feminino , Humanos , Radioisótopos do Iodo , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Cintilografia , Distribuição TecidualRESUMO
Two separate components could be resolved in tests of the dynamic autoregulation of renal blood flow. The slow component corresponds to the frequency at which spontaneous proximal tubular pressure oscillations are found, and are most likely due to the operation of the TGF. The high frequency component most likely represents an intrinsic vascular, myogenic, mechanism. The gain maximum of the admittance in the frequency range corresponding to the autonomous tubular oscillations indicates that the dynamic characteristics responsible for the occurrence of the spontaneous tubular oscillations must be common to a significant fraction of the total nephron population.
Assuntos
Circulação Renal/fisiologia , Animais , Pressão Sanguínea/fisiologia , Homeostase/fisiologia , Masculino , Pressão , Ratos , Ratos EndogâmicosRESUMO
Mammographic contrast is commonly evaluated by visualizing small objects of varying size or mass divided by projected area. These qualitative contrast determinations are commonly performed by imaging a phantom like the American College of Radiology accreditation phantom at clinical mammographic settings. However, this contrast assessment does not take into account the kVp of the machine. This work describes a quantitative mammography contrast threshold test tool which examines light object contrast on a uniform background for a contrast range of 0.32% to 1.38% at 25 kVp. For this mammography contrast threshold test tool, contrast is defined by delta I/I = loge (psi O/ psi b), where psi O is the target energy flux, and psi b is the background energy flux. Contrast threshold is defined as the lowest contrast value for which the objects are visible. Unlike traditional assessments of mammographic contrast, this measurement of contrast threshold is kVp corrected. The mammography contrast threshold test tool is constructed out of common plastics and provides a quantitative means of assessing contrast threshold for individual mammographic units and total mammographic systems.
Assuntos
Mamografia/métodos , Imagens de Fantasmas , Acreditação , Meios de Contraste , Feminino , Humanos , Mamografia/normas , Matemática , Sensibilidade e Especificidade , Sociedades Médicas , Estados UnidosRESUMO
Fluoroscopic contrast resolution is commonly determined at a specified kVp by imaging a test object comprised of targets where contrast decreases gradually and sequentially. Threshold contrast or contrast resolution is the contrast of the lowest contrast target that can be perceived. This approach suffers from two problems. First, test object contrast is specified at a x-ray tube voltage that is not always obtainable in practice. Second, the small change in contrast between adjacent targets contributes to observer variability making consistent and reproducible contrast threshold determinations difficult. Described is a contrast resolution test tool that eliminates or reduces these problems. The novel target arrangement allows one to quickly and easily specify the contrast resolution of a fluoroscopic imaging chain to a precision approximately equal to 0.5%. Tables of target contrast versus x-ray tube potential are developed that permit one to employ the test object for contrast resolution determination over the normal range of tube potentials encountered on clinical units.