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1.
J Mol Biol ; 435(15): 168181, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37468182

RESUMO

Identifying the common structural elements of functionally related RNA sequences (family) is usually based on an alignment of the sequences, which is often subject to human bias and may not be accurate. The resulting covariance model (CM) provides probabilities for each base to covary with another, which allows to support evolutionarily the formation of double helical regions and possibly pseudoknots. The coexistence of alternative folds in RNA, resulting from its dynamic nature, may lead to the potential omission of motifs by CM. To overcome this limitation, we present D-ORB, a system of algorithms that identifies overrepresented motifs in the secondary conformational landscapes of a family when compared to those of unrelated sequences. The algorithms are bundled into an easy-to-use website allowing users to submit a family, and optionally provide unrelated sequences. D-ORB produces a non-pseudoknotted secondary structure based on the overrepresented motifs, a deep neural network classifier and two decision trees. When used to model an Rfam family, D-ORB fits overrepresented motifs in the corresponding Rfam structure; more than a hundred Rfam families have been modeled. The statistical approach behind D-ORB derives the structural composition of an RNA family, making it a valuable tool for analyzing and modeling it. Its easy-to-use interface and advanced algorithms make it an essential resource for researchers studying RNA structure. D-ORB is available at https://d-orb.major.iric.ca/.


Assuntos
RNA , Humanos , Algoritmos , Sequência de Bases , Conformação de Ácido Nucleico , RNA/genética , RNA/química , Análise de Sequência de RNA/métodos , Software , Alinhamento de Sequência
2.
Sci Rep ; 13(1): 3609, 2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36869125

RESUMO

We recently proposed a new approach for the real-time monitoring of particle therapy treatments with the goal of achieving high sensitivities on the particle range measurement already at limited counting statistics. This method extends the Prompt Gamma (PG) timing technique to obtain the PG vertex distribution from the exclusive measurement of particle Time-Of-Flight (TOF). It was previously shown, through Monte Carlo simulation, that an original data reconstruction algorithm (Prompt Gamma Time Imaging) allows to combine the response of multiple detectors placed around the target. The sensitivity of this technique depends on both the system time resolution and the beam intensity. At reduced intensities (Single Proton Regime-SPR), a millimetric proton range sensitivity can be achieved, provided the overall PG plus proton TOF can be measured with a 235 ps (FWHM) time resolution. At nominal beam intensities, a sensitivity of a few mm can still be obtained by increasing the number of incident protons included in the monitoring procedure. In this work we focus on the experimental feasibility of PGTI in SPR through the development of a multi-channel, Cherenkov-based PG detector with a targeted time resolution of 235 ps (FWHM): the TOF Imaging ARrAy (TIARA). Since PG emission is a rare phenomenon, TIARA design is led by the concomitant optimisation of its detection efficiency and Signal to Noise Ratio (SNR). The PG module that we developed is composed of a small PbF[Formula: see text] crystal coupled to a silicon photoMultiplier to provide the time stamp of the PG. This module is currently read in time coincidence with a diamond-based beam monitor placed upstream the target/patient to measure the proton time of arrival. TIARA will be eventually composed of 30 identical modules uniformly arranged around the target. The absence of a collimation system and the use of Cherenkov radiators are both crucial to increase the detection efficiency and the SNR, respectively. A first prototype of the TIARA block detector was tested with 63 MeV protons delivered from a cyclotron: a time resolution of 276 ps (FWHM) was obtained, resulting in a proton range sensitivity of 4 mm at 2[Formula: see text] with the acquisition of only 600 PGs. A second prototype was also evaluated with 148 MeV protons delivered from a synchro-cyclotron obtaining a time resolution below 167 ps (FWHM) for the gamma detector. Moreover, using two identical PG modules, it was shown that a uniform sensitivity on the PG profiles would be achievable by combining the response of gamma detectors uniformly distributed around the target. This work provides the experimental proof-of-concept for the development of a high sensitivity detector that can be used to monitor particle therapy treatments and potentially act in real-time if the irradiation does not comply to treatment plan.

3.
Phys Med Biol ; 66(13)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34020438

RESUMO

We propose a novel prompt-gamma (PG) imaging modality for real-time monitoring in proton therapy: PG time imaging (PGTI). By measuring the time-of-flight (TOF) between a beam monitor and a PG detector, our goal is to reconstruct the PG vertex distribution in 3D. In this paper, a dedicated, non-iterative reconstruction strategy is proposed (PGTI reconstruction). Here, it was resolved under a 1D approximation to measure a proton range shift along the beam direction. In order to show the potential of PGTI in the transverse plane, a second method, based on the calculation of the centre of gravity (COG) of the TIARA pixel detectors' counts was also explored. The feasibility of PGTI was evaluated in two different scenarios. Under the assumption of a 100 ps (rms) time resolution (achievable in single proton regime), MC simulations showed that a millimetric proton range shift is detectable at 2σwith 108incident protons in simplified simulation settings. With the same proton statistics, a potential 2 mm sensitivity (at 2σwith 108incident protons) to beam displacements in the transverse plane was found using the COG method. This level of precision would allow to act in real-time if the treatment does not conform to the treatment plan. A worst case scenario of a 1 ns (rms) TOF resolution was also considered to demonstrate that a degraded timing information can be compensated by increasing the acquisition statistics: in this case, a 2 mm range shift would be detectable at 2σwith 109incident protons. By showing the feasibility of a time-based algorithm for the reconstruction of the PG vertex distribution for a simplified anatomy, this work poses a theoretical basis for the future development of a PG imaging detector based on the measurement of particle TOF.


Assuntos
Terapia com Prótons , Diagnóstico por Imagem , Raios gama , Método de Monte Carlo , Imagens de Fantasmas , Prótons
4.
Phys Med Biol ; 66(10)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33770774

RESUMO

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.


Assuntos
Inteligência Artificial , Software , Simulação por Computador , Método de Monte Carlo , Tomografia Computadorizada por Raios X
5.
iScience ; 21: 68-83, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31655257

RESUMO

Computed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26Met mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment.

6.
Blood ; 131(17): 1955-1959, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29437588

RESUMO

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.


Assuntos
Aspergilose/induzido quimicamente , Aspergilose/epidemiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/microbiologia , Masculino , Piperidinas , Fatores de Tempo
7.
Front Genet ; 6: 291, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26500677

RESUMO

We present a methodology which jointly infers haplotypes and the causal alleles at a gene influencing a given trait. Often in human genetic studies, the available data consists of genotypes (series of genetic markers along the chromosomes) and a phenotype. However, for many genetic analyses, one needs haplotypes instead of genotypes. Our methodology is not only able to estimate haplotypes conditionally on the disease status, but is also able to infer the alleles at the unknown disease locus. Some applications of our methodology are in genetic mapping and in genetic counseling.

9.
Epilepsy Behav ; 15(2): 98-105, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19258049

RESUMO

Approximately 1 year after rats were seized as young adults with lithium (3 mEq/kg) and pilocarpine (30 mg/kg) and given acepromazine or ketamine, 18 blood measures, wet tissue weights, and detailed damage scores for 107 brain structures were completed. Compared with normal and ketamine-treated rats, acepromazine-treated seized rats (total n=54) had lighter pancreata and spleens and elevated aspartate aminotransferase and alanine aminotransferase blood levels. Even though average damage did not differ, the mosaic of brain damage completely discriminated the two seized groups. Differential effects of postseizure treatment on functions of the thyroid, pancreas, and spleen were indicated. Ketamine-treated seized rats were healthier than acepromazine-treated seized rats or normal rats. This experiment demonstrates the importance of whole-organism assessment and that the single administration of a specific drug after onset of status epilepticus can produce marked differences in the evolution of brain damage and its influence on specific organs for the rest of the animal's life.


Assuntos
Acepromazina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Antagonistas de Dopamina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Convulsões/tratamento farmacológico , Convulsões/patologia , Convulsões/fisiopatologia , Acepromazina/farmacologia , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ketamina/farmacologia , Cloreto de Lítio , Estudos Longitudinais , Masculino , Exame Neurológico , Pilocarpina , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Estatística como Assunto , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia
10.
J Immunol ; 175(4): 2056-60, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16081770

RESUMO

PGs play key regulatory roles in inflammation and immunity. PGD2, released from mast cells and Th2 cells during allergic responses, has recently been shown to target a novel receptor, chemoattractant receptor-homologous molecule expressed TH2 cells (CRTH2), in addition to the classic PGD (DP) receptor. CRTH2 is expressed on Th2 cells and eosinophils and mediates chemotaxis of these cells to PGD2. Thus, CRTH2 is thought to be a key receptor mediating eosinophil and Th2 cell recruitment during allergic responses. To examine the role of CRTH2 in this context in vivo, we generated CRTH2 knockout mice. Surprisingly, in an allergic inflammatory model of asthma, CRTH2 knockout mice showed enhanced eosinophil recruitment into the lung compared with wild-type littermate mice. This is consistent with our observation that CRTH2 knockout cells produce significantly higher amounts of IL-5 and IL-3 in vitro. These results suggest a nonredundant role of CRTH2 in restricting eosinophilia and allergic response in vivo.


Assuntos
Quimiotaxia de Leucócito/imunologia , Eosinófilos/imunologia , Interleucina-5/biossíntese , Receptores Imunológicos/fisiologia , Receptores de Prostaglandina/fisiologia , Células Th2/imunologia , Células Th2/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Quimiotaxia de Leucócito/genética , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Eosinofilia/genética , Eosinofilia/imunologia , Eosinófilos/citologia , Feminino , Interleucina-5/antagonistas & inibidores , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandina D2/metabolismo , Prostaglandina D2/fisiologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/biossíntese , Receptores Imunológicos/deficiência , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/biossíntese , Receptores de Prostaglandina/deficiência , Regulação para Cima/genética , Regulação para Cima/imunologia
11.
J Acquir Immune Defic Syndr ; 37(4): 1477-88, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15602126

RESUMO

BACKGROUND: Lipodystrophy is now widely described in HIV infected patients under antiretroviral regimen with important psychological impact. But physiopathology of loss of fat mass is still debated and the role of mitochondrial impairment is not clearly defined. OBJECTIVE: To correlate clinical lipoatrophy (LA) in HIV patients with long-term treatment by nucleoside reverse transcriptase inhibitors (NRTIs) and muscular impairment related to mitochondrial dysfunction. METHODS: Ten consecutive patients with clinical LA and 10 nonlipodystrophic (NLD) individuals on antiretroviral therapy were included. Patients underwent the following investigations: dual-energy x-ray absorptiometry (DEXA) scanning and lactate kinetics during standardized exercise. The mitochondrial respiratory complex activity (III and IV) and histoenzymatic abnormalities (classified as none, mild, or severe) were evaluated on muscle tissue obtained by biopsy in deltoid muscle. RESULTS: Mean NRTI exposure was longer in the LA group than in the NLD group (81 +/- 30 months vs. 59 +/- 15 months), but mean protease inhibitor exposure was identical in both groups. Mean fat mass distribution for leg in the LA and NLD groups was 860 +/- 381 g versus 1895 +/- 999 g, respectively. The lactic acidosis threshold during exercise was reached in the LA group at lower workloads (mean: 45 +/- 17 W in the LA group vs. 68 +/- 11 W in the NLD group), and maximum power output exercise was restricted in LA patients (mean: 115 +/- 30 W vs. 153 +/- 28 W). Total complex activities in muscular tissue were lower in LA patients: the median (range) for complex III was 67 (1-128) versus 112 (28-143), and the median (range) for complex IV was 28 (1-70) versus 42 (1-75). Six patients had severe histoenzymatic abnormalities in the LA group versus none in the NLD group. CONCLUSION: Clinical LA, confirmed by DEXA, in long-term NRTI-treated patients was associated with muscular mitochondrial dysfunction as shown by rapid lactic acidemia increase, impairment of respiratory chain activity for complexes III and IV, and mitochondrial histoenzymatic abnormalities.


Assuntos
Acidose Láctica/induzido quimicamente , Antirretrovirais/efeitos adversos , Infecções por HIV/tratamento farmacológico , Lipodistrofia/induzido quimicamente , Doenças Mitocondriais/complicações , Inibidores da Transcriptase Reversa/efeitos adversos , Absorciometria de Fóton , Acidose Láctica/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirretrovirais/administração & dosagem , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Humanos , Pessoa de Meia-Idade , Mitocôndrias Musculares/efeitos dos fármacos , Inibidores da Transcriptase Reversa/administração & dosagem
12.
Chest ; 125(5): 1815-20, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15136395

RESUMO

STUDY OBJECTIVES: Respiratory failure (RF) is a frequent cause of death among patients with bilateral bronchiectasis. An ICU admission is commonly required, and neither short-term or long-term outcomes have been studied. DESIGN: We performed a retrospective study over a 10-year period (January 1990 to March 2000). All patients with bilateral bronchiectasis admitted for the first time in the medical ICU for RF were reviewed. Patients with cystic fibrosis were excluded. MEASUREMENTS AND RESULTS: Forty-eight patients (mean age +/- SD, 63 +/- 11 years; mean simplified acute physiology score [SAPS] II, 32 +/- 12) of whom 25% received long-term oxygen therapy (LTOT) were identified. All the patients were treated with intensive medical care, associated with noninvasive ventilation in 13 patients (27%), and 26 patients (54%) required intubation. Nine patients (19%) died in the ICU. The 1-year mortality rate was 40%. Among the variables recorded at ICU admission, age > 65 years (p = 0.002), SAPS II score > 32 (p = 0.012), use of LTOT (p = 0.047), and intubation (p = 0.027) were associated with reduced survival in univariate analysis by Cox regression. Multivariate analysis by Cox proportional hazard model showed that age > 65 years (relative risk [RR], 2.70; 95% confidence interval [CI], 1.15 to 6.29) and use of LTOT (RR, 2.52; 95% CI, 1.15 to 5.54) were independently associated with reduced survival. CONCLUSIONS: We performed the first study providing information related to the impact of the first ICU stay for RF on long-term outcomes for patients with bilateral bronchiectasis. Age > 65 years and prior use of LTOT were associated with reduced survival.


Assuntos
Bronquiectasia/complicações , Bronquiectasia/mortalidade , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/terapia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo
16.
HIV Clin Trials ; 3(2): 125-32, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11976990

RESUMO

OBJECTIVE: To evaluate the safety profile and efficacy of salvage regimens containing amprenavir (APV) 600 mg twice daily and ritonavir (RTV) 200 mg twice daily. DESIGN: Prospective, single-center study. METHOD: The patient database of the department of infectious diseases was screened for patients who had failed at least two successive three-drug combinations. These patients were proposed to take APV and RTV in association with two to four other drugs. They were followed monthly for 6 months. RESULTS: Seventeen patients were included. They had been previously treated for 70 +/- 23 months. At baseline, viral load (VL) was 4.86 +/- 0.98 log10 copies/mL and CD4 187 +/- 145 10(6)/L. On week 24, using intent-to-treat analysis, VL decreased to 2.95 +/- 1.59 log10 copies/mL and CD4 increased to 365 +/- 210 10(6)/L. Nine patients (53%) had a VL < 2.3 log10 copies/mL. The most common adverse events were grade 1 or 2 diarrhea and an increase of cholesterol and triglyceride levels. Mean APV trough concentration was 1727 +/- 1749 ng/mL on week 24. CONCLUSION: These data show that the combination of low-dose RTV and reduced doses of APV is safe. This combination can be added to nonnucleoside analogs.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Ritonavir/uso terapêutico , Terapia de Salvação , Sulfonamidas/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Carbamatos , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Furanos , Genótipo , Inibidores da Protease de HIV/efeitos adversos , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fenótipo , Estudos Prospectivos , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Carga Viral
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