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1.
Artigo em Inglês | MEDLINE | ID: mdl-32187499

RESUMO

We assessed energy compensation, appetite and reward value of foods during a 14-day military expedition in Greenland realized by 12 male French soldiers during which energy compensation was optimized by providing them with easy-to-eat palatable foods in excess. Although daily energy expenditure (estimated by accelerometry) stayed relatively constant throughout the expedition (15 ± 9 MJ.d-1), energy intake (EI estimated by self-reported diaries) was 17% higher during the D8-D14 than D1-D7 period, leading to a neutral energy balance (EB). Body fat mass (BFM) significantly decreased (-1.0 ± 0.7 kg, p<0.001) but not body mass (BM). Neither hunger scores (assessed by visual analog scales), nor components of the reward value of food (explicit liking [EL] and food preference) were significantly altered. However, changes in EL at D10 positively correlated with changes in BM (r=0.600, p<0.05) and BFM (r = 0.680, p < 0.05) and changes in hunger with the EI of the relevant period (r=0.743, p<0.01 for D1-D7, r=0.652, p<0.05 for D8-14). This study shows that the negative EB and BM loss can be attenuated by an appropriate food supply and that subjective components of eating behaviour, such as hunger and EL, may be useful to predict the magnitude of energy compensation.

2.
Neurology ; 94(10): e1027-e1039, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31907289

RESUMO

OBJECTIVE: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL. METHODS: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed. RESULTS: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis. CONCLUSIONS: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

3.
J Virol ; 94(1)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619555

RESUMO

Soluble recombinant native-like (NL) envelope glycoprotein (Env) trimers of various human immunodeficiency virus type 1 (HIV-1) genotypes are being developed as vaccine candidates aimed at the induction of broadly neutralizing antibodies (bNAbs). The prototypic design, designated BG505 SOSIP.664, incorporates an intersubunit disulfide bond (SOS) to covalently link the gp120 and gp41 ectodomain (gp41ECTO) subunits and a point substitution, I559P (IP), to further stabilize the gp41ECTO components. Without the SOS and IP changes, proteolytically cleaved trimers tend to disintegrate into their constituent gp120 and gp41ECTO subunits. We show, however, that NL trimers lacking the SOS and/or IP change can be affinity purified in amounts sufficient for analyses of their antigenicity and thermal stability. In general, these trimer variants have properties highly comparable to those of the fully stabilized SOSIP.664 version. We conclude that the major effect of the SOS and IP changes is to substantially increase trimer stability during and after the expression process, thereby allowing useful amounts to be produced. However, once the trimers have been purified, the SOS and IP changes have only subtle impacts on thermostability and the antigenicity of bNAb and other epitopes.IMPORTANCE Recombinant trimeric proteins based on HIV-1 env genes are being developed for vaccine trials in humans. A feature of these proteins is their mimicry of the envelope glycoprotein structure on virus particles that is targeted by neutralizing antibodies, i.e., antibodies that prevent cells from becoming infected. One vaccine concept under exploration is that recombinant trimers may be able to elicit virus-neutralizing antibodies when delivered as immunogens. A commonly used design is designated SOSIP.664, a term reflecting the sequence changes that are used to stabilize the trimers and allow their production in practically useful amounts. Here, we show that these stabilizing changes act to increase trimer yield during the biosynthesis process within the producer cell but have little impact on the properties of purified trimers.

4.
PLoS Pathog ; 14(12): e1007432, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30521629

RESUMO

CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs.


Assuntos
Infecções por HIV/metabolismo , HIV-1/fisiologia , Receptores CCR5/química , Receptores CCR5/metabolismo , Internalização do Vírus , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Fenótipo , Ligação Proteica
5.
J Appl Clin Med Phys ; 19(6): 88-98, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30216702

RESUMO

The purpose of this work is to assess eight detectors performance for output factor (OF), percent depth dose (PDD), and beam profiles in a 6-MV Clinac stereotactic radiosurgery mode for cone irradiation using Monte Carlo simulation as reference. Cones with diameters comprised between 30 and 4 mm have been studied. The evaluated detectors were ionization chambers: pinpoint and pinpoint 3D, diodes: SRS, P and E, Edge, MicroDiamond and EBT3 radiochromic films. The results showed that pinpoints underestimate OF up to -2.3% for cone diameters ≥10 mm and down to -12% for smaller cones. Both nonshielded (SRS and E) and shielded diodes (P and Edge) overestimate the OF respectively up to 3.3% and 5.2% for cone diameters ≥10 mm and in both cases more than 7% for smaller cones. MicroDiamond slightly overestimates the OF, 3.7% for all the cones and EBT3 film is the closest to Monte Carlo with maximum difference of ±1% whatever the cone size is. For the profiles and the PDD, particularly for the small cones, the size of the detector predominates. All diodes and EBT3 agree with the simulation within ±0.2 mm for beam profiles determination. For PDD curve all the active detectors response agree with simulation up to 1% for all the cones. EBT3 is the more accurate detector for beam profiles and OF determinations of stereotactic cones but it is restrictive to use. Due to respectively inappropriate size of the sensitive volume and composition, pinpoints and diodes do not seem appropriate without OF corrective factors below 10 mm diameter cone. MicroDiamond appears to be the best detector for OF determination regardless all cones. For off-axis measurements, the size of the detector predominates and for PDD all detectors give promising results.


Assuntos
Método de Monte Carlo , Neoplasias/cirurgia , Aceleradores de Partículas/instrumentação , Imagens de Fantasmas , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Algoritmos , Simulação por Computador , Humanos , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos
6.
J Neurosurg ; 128(1): 3-13, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28298039

RESUMO

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.


Assuntos
Neoplasias Encefálicas/epidemiologia , Glioma/epidemiologia , Complicações Neoplásicas na Gravidez/epidemiologia , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Progressão da Doença , Feminino , Seguimentos , Glioma/diagnóstico , Glioma/terapia , Humanos , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/terapia , Resultado da Gravidez , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
7.
Nat Commun ; 8(1): 1239, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093476

RESUMO

Direct collection of extracellular fluid (ECF) plays a central role in the monitoring of neurological disorders. Current approaches using microdialysis catheters are however drastically limited in term of temporal resolution. Here we show a functional in vivo validation of a droplet collection system included at the tip of a neural probe. The system comprises an advanced droplet formation mechanism which enables the collection of neurochemicals present in the brain ECF at high-temporal resolution. The probe was implanted in a rat brain and could successfully collect fluid samples organized in a train of droplets. A microfabricated target plate compatible with most of the surface-based detection methods was specifically developed for sample analysis. The time-resolved brain-fluid samples are analyzed using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The results provide a time evolution picture of the cerebral tissues neurochemical composition for selected elements known for their involvement in neurodegenerative diseases.


Assuntos
Cérebro/química , Líquido Extracelular/química , Microdiálise/métodos , Animais , Encéfalo , Química Encefálica , Cálcio/análise , Feminino , Magnésio/análise , Espectrometria de Massas , Mercúrio/análise , Potássio/análise , Ratos , Ratos Sprague-Dawley , Sódio/análise , Fatores de Tempo
8.
Mol Cell Neurosci ; 85: 1-11, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28811225

RESUMO

The normal cellular role of α-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of α-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that α-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be measured in vivo. Experiments with rats overexpressing human α-synuclein in nigral dopaminergic neurons demonstrated a correlation between α-synuclein expression and ferrireductase activity. Furthermore, studies on tissue from Parkinson's disease patient brains showed a significant decrease in ferrireductase activity, possibly due to deposition of large amounts of inactive protein. Cellular studies suggest that increase ferrireductase activity results in increased levels of dopamine metabolites and increased sensitivity to the toxicity of DOPAL. These findings demonstrate that α-synuclein ferrireductase activity is present in vivo and its alteration may play a role in neuron loss in disease.


Assuntos
Encéfalo/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , FMN Redutase/metabolismo , Feminino , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
9.
Retrovirology ; 13(1): 50, 2016 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-27473399

RESUMO

BACKGROUND: Covariation is an essential process that leads to coevolution of parts of proteins and genomes. In organisms subject to strong selective pressure, coevolution is central to keep the balance between the opposite requirements of antigenic variation and retention of functionality. Being the viral component most exposed to the external environment, the HIV-1 glycoprotein gp120 constitutes the main target of the immune response. Accordingly its more external portions are characterised by extensive sequence heterogeneity fostering constant antigenic variation. RESULTS: We report that a single polymorphism, present at the level of the viral population in the conserved internal region C2, was sufficient to totally abolish Env functionality when introduced in an exogenous genetic context. The prominent defect of the non-functional protein is a block occurring after recognition of the co-receptor CCR5, likely due to an interference with the subsequent conformational changes that lead to membrane fusion. We also report that the presence of compensatory polymorphisms at the level of the external and hypervariable region V3 fully restored the functionality of the protein. The functional revertant presents different antigenic profiles and sensitivity to the entry inhibitor TAK 779. CONCLUSIONS: Our data suggest that variable regions, besides harbouring intrinsic extensive antigenic diversity, can also contribute to sequence diversification in more structurally constrained parts of the gp120 by buffering the deleterious effect of polymorphisms, further increasing the genetic flexibility of the protein and the antigenic repertoire of the viral population.


Assuntos
Proteína gp120 do Envelope de HIV/genética , HIV-1/genética , Polimorfismo Genético , Amidas/farmacologia , Variação Antigênica , Antígenos CD4/metabolismo , Evolução Molecular , Variação Genética , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/imunologia , Inibidores da Fusão de HIV/farmacologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Estabilidade Proteica , Compostos de Amônio Quaternário/farmacologia , Receptores CCR5/metabolismo , Alinhamento de Sequência , Internalização do Vírus
10.
J Virol Methods ; 236: 184-195, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27451265

RESUMO

The trimeric HIV-1 envelope (Env) glycoproteins gp120 and gp41 mediate virus entry into target cells by engaging CD4 and the coreceptors CCR5 or CXCR4 at the cell surface and driving membrane fusion. Receptor/gp120 interactions regulate the virus life cycle, HIV infection transmission and pathogenesis. Env is also the target of neutralizing antibodies. Efforts have thus been made to produce soluble HIV-1 glycoproteins to develop vaccines and study the role and mechanisms of HIV/receptor interactions. However, production and purification of Env glycoproteins and their functional assessment has to cope with multiple obstacles. These include difficulties in amplifying and cloning env sequences and setting up receptor binding assays that are suitable for studies on large collections of glycoproteins, flexible enough to adapt to Env and receptor structural heterogeneities, and allow recapitulating the receptor binding properties of virion-associated Env trimers. Here we identify these difficulties and present protocols to produce primary gp120 and determination of their binding properties to receptors. The receptor binding assays confirmed that the produced glycoproteins are competent for binding CD4 and undergo proper CD4-induced conformational changes required for interaction with CCR5. These assays may help elucidate the role of gp120/receptor interactions in the pathophysiology of HIV infection and develop HIV-1 entry inhibitors.


Assuntos
Clonagem Molecular , Expressão Gênica , Biologia Molecular/métodos , Proteínas Recombinantes/isolamento & purificação , Produtos do Gene env do Vírus da Imunodeficiência Humana/isolamento & purificação , Guias como Assunto , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
11.
Neuro Oncol ; 18(9): 1297-303, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26951382

RESUMO

BACKGROUND: Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS: We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS: Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS: About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Resistencia a Medicamentos Antineoplásicos , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/patologia , Terapia Combinada , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Transplante Autólogo
12.
Neurology ; 85(15): 1325-31, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26385879

RESUMO

OBJECTIVES: We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs). METHODS: This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset. RESULTS: The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively). CONCLUSION: Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Variações do Número de Cópias de DNA/genética , Glioma/diagnóstico , Glioma/epidemiologia , Perda de Heterozigosidade/genética , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
13.
Retrovirology ; 12: 50, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26081316

RESUMO

BACKGROUND: Maraviroc (MVC) is an allosteric CCR5 inhibitor used against HIV-1 infection. While MVC-resistant viruses have been identified in patients, it still remains incompletely known how they adjust their CD4 and CCR5 binding properties to resist MVC inhibition while preserving their replicative capacity. It is thought that they maintain high efficiency of receptor binding. To date however, information about the binding affinities to receptors for inhibitor-resistant HIV-1 remains limited. RESULTS: Here, we show by means of viral envelope (gp120) binding experiments and virus-cell fusion kinetics that a MVC-resistant virus (MVC-Res) that had emerged as a dominant viral quasispecies in a patient displays reduced affinities for CD4 and CCR5 either free or bound to MVC, as compared to its MVC-sensitive counterpart isolated before MVC therapy. An alanine insertion within the GPG motif (G310_P311insA) of the MVC-resistant gp120 V3 loop is responsible for the decreased CCR5 binding affinity, while impaired binding to CD4 is due to sequence changes outside V3. Molecular dynamics simulations of gp120 binding to CCR5 further emphasize that the Ala insertion alters the structure of the V3 tip and weakens interaction with CCR5 ECL2. Paradoxically, infection experiments on cells expressing high levels of CCR5 also showed that Ala allows MVC-Res to use CCR5 efficiently, thereby improving viral fusion and replication efficiencies. Actually, although we found that the V3 loop of MVC-Res is required for high levels of MVC resistance, other regions outside V3 are sufficient to confer a moderate level of resistance. These sequence changes outside V3, however, come with a replication cost, which is compensated for by the Ala insertion in V3. CONCLUSION: These results indicate that changes in the V3 loop of MVC-resistant viruses can augment the efficiency of CCR5-dependent steps of viral entry other than gp120 binding, thereby compensating for their decreased affinity for entry receptors and improving their fusion and replication efficiencies. This study thus sheds light on unsuspected mechanisms whereby MVC-resistant HIV-1 could emerge and grow in treated patients.


Assuntos
Fármacos Anti-HIV/farmacologia , Cicloexanos/farmacologia , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/efeitos dos fármacos , Mutação de Sentido Incorreto , Receptores CCR5/metabolismo , Triazóis/farmacologia , Proteína gp120 do Envelope de HIV/genética , HIV-1/genética , Humanos , Maraviroc , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Ligação Proteica , Receptores de HIV/metabolismo , Internalização do Vírus , Replicação Viral
14.
Endocrine ; 50(3): 741-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25956280

RESUMO

The treatment of acromegaly is based on surgery, drugs, and radiotherapy as a third-line option. Fractionated stereotactic radiotherapy (FSRT) is a new technique with a need for long-term evaluation. The purpose of the study was to evaluate long-term results of FSRT in acromegaly. Overall, 34 patients [sex ratio 1.12, age 45 (5-65) years] with a pituitary adenoma of 24.5 (9-76) mm including 20 invasive tumors were treated by radiotherapy in fractionated stereotactic conditions delivering 50 gy in 27 sessions. Baseline growth hormone (GH) and IGF1 levels were 18 (±14.5) and 632.6 (±339) µg/L, respectively. Indications of FSRT were failure of surgery and drug treatments (n = 30) or contraindication/refusal of surgery (n = 4). Hormonal control was defined by normal age- and sex-adjusted IGF1. Remission was defined by hormonal control after withdrawal of drugs for a minimum of three consecutive months. Data were analyzed in SPSS software with a significance level at p < 0.05. After a mean follow-up of 152 months, hormonal control was achieved in 33 patients (97 %) with withdrawal of drugs in 13 patients (38.2 %) without any recurrence. Factors found to be significantly associated to remission in a multivariate Cox regression were lower baseline hormone levels (GH and IGF1) and smaller tumor size. Tumor control was achieved in all patients. Acquired hypopituitarism after radiotherapy was the main side effect reported with a rate of 39 %. FSRT seems to be an effective and well tolerated third-line treatment of acromegaly, particularly adapted to macro adenomas treatment.


Assuntos
Adenoma/radioterapia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/radioterapia , Adenoma/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radioterapia/efeitos adversos , Terapia de Salvação , Técnicas Estereotáxicas , Resultado do Tratamento , Adulto Jovem
15.
Neurobiol Dis ; 77: 49-61, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25731749

RESUMO

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 contains functional GTPase and kinase domains. The most common G2019S mutation enhances the kinase activity of LRRK2 in vitro whereas G2019S LRRK2 expression in cultured neurons induces toxicity in a kinase-dependent manner. These observations suggest a potential role for kinase activity in LRRK2-associated PD. We have recently developed a novel rodent model of PD with progressive neurodegeneration induced by the adenoviral-mediated expression of G2019S LRRK2. In the present study, we further characterize this LRRK2 model and determine the contribution of kinase activity to LRRK2-mediated neurodegeneration. Recombinant human adenoviral vectors were employed to deliver human wild-type, G2019S or kinase-inactive G2019S/D1994N LRRK2 to the rat striatum. LRRK2-dependent pathology was assessed in the striatum, a region where LRRK2 protein is normally enriched in the mammalian brain. Human LRRK2 variants are robustly expressed throughout the rat striatum. Expression of G2019S LRRK2 selectively induces the accumulation of neuronal ubiquitin-positive inclusions accompanied by neurite degeneration and the altered distribution of axonal phosphorylated neurofilaments. Importantly, the introduction of a kinase-inactive mutation (G2019S/D1994N) completely ameliorates the pathological effects of G2019S LRRK2 in the striatum supporting a kinase activity-dependent mechanism for this PD-associated mutation. Collectively, our study further elucidates the pathological effects of the G2019S mutation in the mammalian brain and supports the development of kinase inhibitors as a potential therapeutic approach for treating LRRK2-associated PD. This adenoviral rodent model provides an important tool for elucidating the molecular basis of LRRK2-mediated neurodegeneration.


Assuntos
Adenoviridae/fisiologia , Corpo Estriado/patologia , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas Serina-Treonina Quinases/genética , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Feminino , Membro Anterior/fisiopatologia , Regulação da Expressão Gênica/genética , Glicina/genética , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/fisiopatologia , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Serina/genética , Fatores de Tempo , Transdução Genética , Tubulina (Proteína)/metabolismo , alfa-Sinucleína/metabolismo
16.
J Biol Chem ; 289(27): 19042-52, 2014 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-24855645

RESUMO

CCR5 binds the chemokines CCL3, CCL4, and CCL5 and is the major coreceptor for HIV-1 entry into target cells. Chemokines are supposed to form a natural barrier against human immunodeficiency virus, type 1 (HIV-1) infection. However, we showed that their antiviral activity is limited by CCR5 adopting low-chemokine affinity conformations at the cell surface. Here, we investigated whether a pool of CCR5 that is not stabilized by chemokines could represent a target for inhibiting HIV infection. We exploited the characteristics of the chemokine analog PSC-RANTES (N-α-(n-nonanoyl)-des-Ser(1)-[l-thioprolyl(2), l-cyclohexylglycyl(3)]-RANTES(4-68)), which displays potent anti-HIV-1 activity. We show that native chemokines fail to prevent high-affinity binding of PSC-RANTES, analog-mediated calcium release (in desensitization assays), and analog-mediated CCR5 internalization. These results indicate that a pool of spare CCR5 may bind PSC-RANTES but not native chemokines. Improved recognition of CCR5 by PSC-RANTES may explain why the analog promotes higher amounts of ß-arrestin 2·CCR5 complexes, thereby increasing CCR5 down-regulation and HIV-1 inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade.


Assuntos
Fármacos Anti-HIV/farmacologia , Quimiocina CCL5/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Receptores CCR5/metabolismo , Internalização do Vírus/efeitos dos fármacos , Arrestinas/metabolismo , Células HEK293 , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , beta-Arrestina 2 , beta-Arrestinas
17.
Proc Natl Acad Sci U S A ; 110(23): 9475-80, 2013 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-23696662

RESUMO

CC chemokine receptor 5 (CCR5) is a receptor for chemokines and the coreceptor for R5 HIV-1 entry into CD4(+) T lymphocytes. Chemokines exert anti-HIV-1 activity in vitro, both by displacing the viral envelope glycoprotein gp120 from binding to CCR5 and by promoting CCR5 endocytosis, suggesting that they play a protective role in HIV infection. However, we showed here that different CCR5 conformations at the cell surface are differentially engaged by chemokines and gp120, making chemokines weaker inhibitors of HIV infection than would be expected from their binding affinity constants for CCR5. These distinct CCR5 conformations rely on CCR5 coupling to nucleotide-free G proteins ((NF)G proteins). Whereas native CCR5 chemokines bind with subnanomolar affinity to (NF)G protein-coupled CCR5, gp120/HIV-1 does not discriminate between (NF)G protein-coupled and uncoupled CCR5. Interestingly, the antiviral activity of chemokines is G protein independent, suggesting that "low-chemokine affinity" (NF)G protein-uncoupled conformations of CCR5 represent a portal for viral entry. Furthermore, chemokines are weak inducers of CCR5 endocytosis, as is revealed by EC50 values for chemokine-mediated endocytosis reflecting their low-affinity constant value for (NF)G protein-uncoupled CCR5. Abolishing CCR5 interaction with (NF)G proteins eliminates high-affinity binding of CCR5 chemokines but preserves receptor endocytosis, indicating that chemokines preferentially endocytose low-affinity receptors. Finally, we evidenced that chemokine analogs achieve highly potent HIV-1 inhibition due to high-affinity interactions with internalizing and/or gp120-binding receptors. These data are consistent with HIV-1 evading chemokine inhibition by exploiting CCR5 conformational heterogeneity, shed light into the inhibitory mechanisms of anti-HIV-1 chemokine analogs, and provide insights for the development of unique anti-HIV molecules.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/fisiopatologia , HIV-1/fisiologia , Conformação Proteica , Receptores CCR5/química , Internalização do Vírus , Linhagem Celular , Quimiocinas/metabolismo , Endocitose/fisiologia , Infecções por HIV/metabolismo , HIV-1/metabolismo , Humanos , Ensaio Radioligante , Receptores CCR5/metabolismo
18.
Radiother Oncol ; 108(1): 114-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23714654

RESUMO

Our previous studies showed that intrafraction motion needs to be corrected for in frameless radiosurgery. This study was designed to evaluate if verification images can correct for mechanical inaccuracy and intrafraction motion. With proper immobilization and verification images on a regular basis during treatment, mechanical (table-) inaccuracies and intrafraction motion can be corrected for and the absence of PTV-margins warranted.


Assuntos
Posicionamento do Paciente , Radiocirurgia/métodos , Humanos , Imobilização , Erros de Configuração em Radioterapia
19.
J Neurosurg ; 118(6): 1157-68, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23495881

RESUMO

OBJECT: The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed. METHODS: Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age ≥ 18 years at diagnosis, histological diagnosis of WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value ≤ 0.1) were included in the multivariate Cox proportional hazard regression model analysis. RESULTS: At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were an age ≥ 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a greater extent of resection. CONCLUSIONS: This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico , Glioma/cirurgia , Organização Mundial da Saúde , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Adulto Jovem
20.
Neuro Oncol ; 15(5): 595-606, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23393207

RESUMO

BACKGROUND: Supratentorial diffuse low-grade gliomas present a slow macroscopic tumor growth that can be quantified through the measurement of their velocity of diametric expansion. We assessed whether spontaneous velocity of diametric expansion can predict long-term outcomes as a categorical variable and as a continuous predictor. METHODS: A total of 407 adult patients with newly diagnosed supratentorial diffuse low-grade gliomas in adults were studied. RESULTS: The mean spontaneous velocity of diametric expansion before first-line treatment was 5.8 ± 6.3 mm/year. During the follow-up (mean, 86.5 ± 59.4 months), 209 patients presented a malignant transformation, and 87 died. The malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (median, 103 and 249 months, respectively) than in cases of fast velocity of diametric expansion (median, 35 and 91 months, respectively; P < .001). In multivariate analyses, spontaneous velocity of diametric expansion as a categorical variable (<4, ≥4 and <8, ≥8 and <12, ≥12 mm/year) was an independent prognostic factor for malignant progression-free survival (P < .001; hazard ratio, 3.87; 95% confidence interval [CI], 2.67-5.52) and for overall survival (P < .001; hazard ratio, 4.62; 95% CI, 2.58-7.97). Velocity of diametric expansion was also an independent prognostic factor for overall survival as a continuous predictor, showing a linear relationship between overall survival and spontaneous velocity of diametric expansion (hazard ratio, 1.09 per one unit increase; 95% CI, 1.06-1.12; P < .001). CONCLUSIONS: Independent of the molecular status, the spontaneous velocity of diametric expansion allows the identification of rapidly growing diffuse low-grade gliomas (at higher risk of worsened evolution) during the pretherapeutic period and without delaying treatment.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Recidiva Local de Neoplasia/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Taxa de Sobrevida , Carga Tumoral , Adulto Jovem
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