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1.
J Geophys Res Planets ; 128(1): e2022JE007480, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37034458

RESUMO

The pressure sensors on Mars rover Perseverance measure the pressure field in the Jezero crater on regular hourly basis starting in sol 15 after landing. The present study extends up to sol 460 encompassing the range of solar longitudes from L s  âˆ¼ 13°-241° (Martian Year (MY) 36). The data show the changing daily pressure cycle, the sol-to-sol seasonal evolution of the mean pressure field driven by the CO2 sublimation and deposition cycle at the poles, the characterization of up to six components of the atmospheric tides and their relationship to dust content in the atmosphere. They also show the presence of wave disturbances with periods 2-5 sols, exploring their baroclinic nature, short period oscillations (mainly at night-time) in the range 8-24 min that we interpret as internal gravity waves, transient pressure drops with duration ∼1-150 s produced by vortices, and rapid turbulent fluctuations. We also analyze the effects on pressure measurements produced by a regional dust storm over Jezero at L s  âˆ¼ 155°.

2.
Nat Commun ; 13(1): 7505, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513637

RESUMO

Dust devils (convective vortices loaded with dust) are common at the surface of Mars, particularly at Jezero crater, the landing site of the Perseverance rover. They are indicators of atmospheric turbulence and are an important lifting mechanism for the Martian dust cycle. Improving our understanding of dust lifting and atmospheric transport is key for accurate simulation of the dust cycle and for the prediction of dust storms, in addition to being important for future space exploration as grain impacts are implicated in the degradation of hardware on the surface of Mars. Here we describe the sound of a Martian dust devil as recorded by the SuperCam instrument on the Perseverance rover. The dust devil encounter was also simultaneously imaged by the Perseverance rover's Navigation Camera and observed by several sensors in the Mars Environmental Dynamics Analyzer instrument. Combining these unique multi-sensorial data with modelling, we show that the dust devil was around 25 m large, at least 118 m tall, and passed directly over the rover travelling at approximately 5 m s-1. Acoustic signals of grain impacts recorded during the vortex encounter provide quantitative information about the number density of particles in the vortex. The sound of a Martian dust devil was inaccessible until SuperCam microphone recordings. This chance dust devil encounter demonstrates the potential of acoustic data for resolving the rapid wind structure of the Martian atmosphere and for directly quantifying wind-blown grain fluxes on Mars.


Assuntos
Meio Ambiente Extraterreno , Marte , Poeira/análise , Vento , Atmosfera
3.
Geophys Res Lett ; 49(17): e2022GL100126, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36245893

RESUMO

Rovers and landers on Mars have experienced local, regional, and planetary-scale dust storms. However, in situ documentation of active lifting within storms has remained elusive. Over 5-11 January 2022 (LS 153°-156°), a dust storm passed over the Perseverance rover site. Peak visible optical depth was ∼2, and visibility across the crater was briefly reduced. Pressure amplitudes and temperatures responded to the storm. Winds up to 20 m s-1 rotated around the site before the wind sensor was damaged. The rover imaged 21 dust-lifting events-gusts and dust devils-in one 25-min period, and at least three events mobilized sediment near the rover. Rover tracks and drill cuttings were extensively modified, and debris was moved onto the rover deck. Migration of small ripples was seen, but there was no large-scale change in undisturbed areas. This work presents an overview of observations and initial results from the study of the storm.

4.
Geophys Res Lett ; 49(17): e2022GL099776, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36245894

RESUMO

Observations by several cameras on the Perseverance rover showed a 22° scattering halo around the Sun over several hours during northern midsummer (solar longitude 142°). Such a halo has not previously been seen beyond Earth. The halo occurred during the aphelion cloud belt season and the cloudiest time yet observed from the Perseverance site. The halo required crystalline water-ice cloud particles in the form of hexagonal columns large enough for refraction to be significant, at least 11 µm in diameter and length. From a possible 40-50 km altitude, and over the 3.3 hr duration of the halo, particles could have fallen 3-12 km, causing downward transport of water and dust. Halo-forming clouds are likely rare due to the high supersaturation of water that is required but may be more common in northern subtropical regions during northern midsummer.

5.
J Proteome Res ; 21(8): 2055-2062, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35787094

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here we report a novel strategy for the rapid detection of SARS-CoV-2 based on an enrichment approach exploiting the affinity between the virus and cellulose sulfate ester functional groups, hot acid hydrolysis, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Virus samples were enriched using cellulose sulfate ester microcolumns. Virus peptides were prepared using the hot acid aspartate-selective hydrolysis and characterized by MALDI-TOF MS. Collected spectra were processed with a peptide fingerprint algorithm, and searching parameters were optimized for the detection of SARS-CoV-2. These peptides provide high sequence coverage for nucleocapsid (N protein) and allow confident identification of SARS-CoV-2. Peptide markers contributing to the detection were rigorously identified using bottom-up proteomics. The approach demonstrated in this study holds the potential for developing a rapid assay for COVID-19 diagnosis and detecting virus variants from a variety of sources, such as sewage and nasal swabs.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Teste para COVID-19 , Celulose/análogos & derivados , Ésteres , Humanos , Peptídeos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
6.
J Geophys Res Planets ; 127(12): e2022JE007523, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37033152

RESUMO

Wind speeds measured by the Mars 2020 Perseverance rover in Jezero crater were fitted as a Weibull distribution. InSight wind data acquired in Elysium Planitia were also used to contextualize observations. Jezero winds were found to be much calmer on average than in previous landing sites, despite the intense aeolian activity observed. However, a great influence of turbulence and wave activity was observed in the wind speed variations, thus driving the probability of reaching the highest wind speeds at Jezero, instead of sustained winds driven by local, regional, or large-scale circulation. The power spectral density of wind speed fluctuations follows a power-law, whose slope deviates depending on the time of day from that predicted considering homogeneous and isotropic turbulence. Daytime wave activity is related to convection cells and smaller eddies in the boundary layer, advected over the crater. The signature of convection cells was also found during dust storm conditions, when prevailing winds were consistent with a tidal drive. Nighttime fluctuations were also intense, suggesting strong mechanical turbulence. Convective vortices were usually involved in rapid wind fluctuations and extreme winds, with variations peaking at 9.2 times the background winds. Transient high wind events by vortex-passages, turbulence, and wave activity could be driving aeolian activity at Jezero. We report the detection of a strong dust cloud of 0.75-1.5 km in length passing over the rover. The observed aeolian activity had major implications for instrumentation, with the wind sensor suffering damage throughout the mission, probably due to flying debris advected by winds.

7.
J Geophys Res Planets ; 127(12): e2022JE007605, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37033154

RESUMO

Martian atmospheric dust is a major driver of weather, with feedback between atmospheric dust distribution, circulation changes from radiative heating and cooling driven by this dust, and winds that mobilize surface dust and distribute it in the atmosphere. Wind-driven mobilization of surface dust is a poorly understood process due to significant uncertainty about minimum wind stress and whether the saltation of sand particles is required. This study utilizes video of six Ingenuity helicopter flights to measure dust lifting during helicopter ascents, traverses, and descents. Dust mobilization persisted on takeoff until the helicopter exceeded 3 m altitude, with dust advecting at 4-6 m/s. During landing, dust mobilization initiated at 2.3-3.6 m altitude. Extensive dust mobilization occurred during traverses at 5.1-5.7 m altitude. Dust mobilization threshold friction velocity of rotor-induced winds during landing is modeled at 0.4-0.6 m/s (factor of two uncertainty in this estimate), with higher winds required when the helicopter was over undisturbed terrain. Modeling dust mobilization from >5 m cruising altitude indicates mobilization by 0.3 m/s winds, suggesting nonsaltation mechanisms such as mobilization and destruction of dust aggregates. No dependence on background winds was seen for the initiation of dust lifting but one case of takeoff in 7 m/s winds created a track of darkened terrain downwind of the helicopter, which may have been a saltation cluster. When the helicopter was cruising at 5-6 m altitude, recirculation was seen in the dust clouds.

8.
Space Sci Rev ; 217(3): 48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776548

RESUMO

NASA's Mars 2020 (M2020) rover mission includes a suite of sensors to monitor current environmental conditions near the surface of Mars and to constrain bulk aerosol properties from changes in atmospheric radiation at the surface. The Mars Environmental Dynamics Analyzer (MEDA) consists of a set of meteorological sensors including wind sensor, a barometer, a relative humidity sensor, a set of 5 thermocouples to measure atmospheric temperature at ∼1.5 m and ∼0.5 m above the surface, a set of thermopiles to characterize the thermal IR brightness temperatures of the surface and the lower atmosphere. MEDA adds a radiation and dust sensor to monitor the optical atmospheric properties that can be used to infer bulk aerosol physical properties such as particle size distribution, non-sphericity, and concentration. The MEDA package and its scientific purpose are described in this document as well as how it responded to the calibration tests and how it helps prepare for the human exploration of Mars. A comparison is also presented to previous environmental monitoring payloads landed on Mars on the Viking, Pathfinder, Phoenix, MSL, and InSight spacecraft.

9.
J Clin Microbiol ; 59(12): e0077821, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34586893

RESUMO

The SARS-CoV-2 pandemic has strained manufacturing capacity worldwide, resulting in significant shortages of laboratory supplies both directly and indirectly. Such shortages include probe-based kits for detection of the Mycobacterium tuberculosis complex from positive liquid broth cultures. These shortages and possible loss of this particular assay have consequences for laboratory testing algorithms and public health in the United States. As there are no FDA-approved, commercially available options that currently exist which could immediately fill this gap, laboratories must identify alternatives and plan for modifying current testing algorithms to accommodate this change.


Assuntos
COVID-19 , Mycobacterium , Tuberculose , Humanos , Pandemias , SARS-CoV-2 , Tuberculose/diagnóstico , Estados Unidos
10.
Space Sci Rev ; 217(2): 29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678912

RESUMO

The NASA Perseverance rover Mast Camera Zoom (Mastcam-Z) system is a pair of zoomable, focusable, multi-spectral, and color charge-coupled device (CCD) cameras mounted on top of a 1.7 m Remote Sensing Mast, along with associated electronics and two calibration targets. The cameras contain identical optical assemblies that can range in focal length from 26 mm ( 25.5 ∘ × 19.1 ∘ FOV ) to 110 mm ( 6.2 ∘ × 4.2 ∘ FOV ) and will acquire data at pixel scales of 148-540 µm at a range of 2 m and 7.4-27 cm at 1 km. The cameras are mounted on the rover's mast with a stereo baseline of 24.3 ± 0.1  cm and a toe-in angle of 1.17 ± 0.03 ∘ (per camera). Each camera uses a Kodak KAI-2020 CCD with 1600 × 1200 active pixels and an 8 position filter wheel that contains an IR-cutoff filter for color imaging through the detectors' Bayer-pattern filters, a neutral density (ND) solar filter for imaging the sun, and 6 narrow-band geology filters (16 total filters). An associated Digital Electronics Assembly provides command data interfaces to the rover, 11-to-8 bit companding, and JPEG compression capabilities. Herein, we describe pre-flight calibration of the Mastcam-Z instrument and characterize its radiometric and geometric behavior. Between April 26 t h and May 9 t h , 2019, ∼45,000 images were acquired during stand-alone calibration at Malin Space Science Systems (MSSS) in San Diego, CA. Additional data were acquired during Assembly Test and Launch Operations (ATLO) at the Jet Propulsion Laboratory and Kennedy Space Center. Results of the radiometric calibration validate a 5% absolute radiometric accuracy when using camera state parameters investigated during testing. When observing using camera state parameters not interrogated during calibration (e.g., non-canonical zoom positions), we conservatively estimate the absolute uncertainty to be < 10 % . Image quality, measured via the amplitude of the Modulation Transfer Function (MTF) at Nyquist sampling (0.35 line pairs per pixel), shows MTF Nyquist = 0.26 - 0.50 across all zoom, focus, and filter positions, exceeding the > 0.2 design requirement. We discuss lessons learned from calibration and suggest tactical strategies that will optimize the quality of science data acquired during operation at Mars. While most results matched expectations, some surprises were discovered, such as a strong wavelength and temperature dependence on the radiometric coefficients and a scene-dependent dynamic component to the zero-exposure bias frames. Calibration results and derived accuracies were validated using a Geoboard target consisting of well-characterized geologic samples. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11214-021-00795-x.

11.
Space Sci Rev ; 217(1): 24, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33612866

RESUMO

Mastcam-Z is a multispectral, stereoscopic imaging investigation on the Mars 2020 mission's Perseverance rover. Mastcam-Z consists of a pair of focusable, 4:1 zoomable cameras that provide broadband red/green/blue and narrowband 400-1000 nm color imaging with fields of view from 25.6° × 19.2° (26 mm focal length at 283 µrad/pixel) to 6.2° × 4.6° (110 mm focal length at 67.4 µrad/pixel). The cameras can resolve (≥ 5 pixels) ∼0.7 mm features at 2 m and ∼3.3 cm features at 100 m distance. Mastcam-Z shares significant heritage with the Mastcam instruments on the Mars Science Laboratory Curiosity rover. Each Mastcam-Z camera consists of zoom, focus, and filter wheel mechanisms and a 1648 × 1214 pixel charge-coupled device detector and electronics. The two Mastcam-Z cameras are mounted with a 24.4 cm stereo baseline and 2.3° total toe-in on a camera plate ∼2 m above the surface on the rover's Remote Sensing Mast, which provides azimuth and elevation actuation. A separate digital electronics assembly inside the rover provides power, data processing and storage, and the interface to the rover computer. Primary and secondary Mastcam-Z calibration targets mounted on the rover top deck enable tactical reflectance calibration. Mastcam-Z multispectral, stereo, and panoramic images will be used to provide detailed morphology, topography, and geologic context along the rover's traverse; constrain mineralogic, photometric, and physical properties of surface materials; monitor and characterize atmospheric and astronomical phenomena; and document the rover's sample extraction and caching locations. Mastcam-Z images will also provide key engineering information to support sample selection and other rover driving and tool/instrument operations decisions.

12.
J Geophys Res Planets ; 124(7): 1899-1912, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31534881

RESUMO

The Rover Environmental Monitoring Station (REMS) instrument that is onboard NASA's Mars Science Laboratory (MSL) Curiosity rover. REMS has been measuring surface pressure, air and ground brightness temperature, relative humidity, and UV irradiance since MSL's landing in 2012. In Mars Year (MY) 34 (2018) a global dust storm reached Gale Crater at Ls ~190°. REMS offers a unique opportunity to better understand the impact of a global dust storm on local environmental conditions, which complements previous observations by the Viking landers and Mars Exploration Rovers. All atmospheric variables measured by REMS are strongly affected albeit at different times. During the onset phase, the daily maximum UV radiation decreased by 90% between sols 2075 (opacity ~1) and 2085 (opacity ~8.5). The diurnal range in ground and air temperatures decreased by 35K and 56K, respectively, with also a diurnal-average decrease of ~2K and 4K respectively. The maximum relative humidity, which occurs right before sunrise, decreased to below 5%, compared with pre-storm values of up to 29%, due to the warmer air temperatures at night while the inferred water vapor abundance suggests an increase during the storm. Between sols 2085 and 2130, the typical nighttime stable inversion layer was absent near the surface as ground temperatures remained warmer than near-surface air temperatures. Finally, the frequency-domain behavior of the diurnal pressure cycle shows a strong increase in the strength of the semidiurnal and terdiurnal modes peaking after the local opacity maximum, also suggesting differences in the dust abundance inside and outside Gale.

13.
Sci Rep ; 8(1): 17576, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514860

RESUMO

In situ measurements by the Curiosity rover provide a unique opportunity for studying the effects of dust on assets placed at the surface of Mars. Here we use in situ measurements of solar UV radiation to quantify the seasonal and interannual variability of dust accumulation on the sensor on the rover deck. We show that the amount of dust accumulated on the sensor follows a seasonal cycle, with net dust removal during the perihelion season until Ls ~ 300°, and net dust deposition until the end of the aphelion season (Ls ~ 300°-180°). We use independent in situ measurements of atmospheric opacity and pressure perturbations in combination with numerical modeling, showing that daytime convective vortices and nighttime winds are likely responsible for the seasonal dust cleaning, with the role of nighttime wind being more important in Martian Year (MY) 32 than in MY 33 and that of daytime convective vortices being more important in MY 33 than in MY 32. The fact that the UV sensor is cleaner in MY 33 than in MY 32 indicates that natural cleaning events make solar energy an excellent candidate to power extended (multiannual) Mars missions at similar latitudes as the Curiosity rover.

14.
J Perinatol ; 37(11): 1224-1229, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28749479

RESUMO

OBJECTIVE: Delivering prognostic information to families requires clinicians to forecast an infant's illness course and future. We lack robust empirical data about how prognosis is shared and how that affects clinician-family concordance regarding infant outcomes. STUDY DESIGN: Prospective audiorecording of neonatal intensive care unit family conferences, immediately followed by parent/clinician surveys. Existing qualitative analysis frameworks were applied. RESULTS: We analyzed 19 conferences. Most prognostic discussion targeted predicted infant functional needs, for example, medications or feeding. There was little discussion of how infant prognosis would affect infant/family quality of life. Prognostic framing was typically optimistic. Most parents left the conference believing their infant's prognosis to be more optimistic than did clinicians. CONCLUSIONS: Clinician approach to prognostic disclosure in these audiotaped family conferences tended to be broad and optimistic, without detail regarding implications of infant health for infant/family quality of life. Families and clinicians left these conversations with little consensus about infant prognosis.


Assuntos
Pais/psicologia , Relações Profissional-Família , Prognóstico , Revelação da Verdade , Comunicação , Aconselhamento/normas , Estado Terminal/psicologia , Estado Terminal/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Percepção , Pesquisa Qualitativa , Qualidade de Vida , Gravação em Vídeo
15.
J Perinatol ; 36(5): 331-7, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26658120

RESUMO

Infants with neurological injury and their families face unique challenges in the neonatal intensive care unit. As specialty palliative care support becomes increasingly available, we must consider how to intentionally incorporate palliative care principles into the care of infants with neurological injury. Here, we review data regarding neonatal symptom management, prognostic uncertainty, decision making, communication and parental support for neonatal neurology patients and their families.


Assuntos
Doenças do Recém-Nascido , Doenças do Sistema Nervoso , Cuidados Paliativos , Pais/psicologia , Tomada de Decisão Clínica/ética , Humanos , Recém-Nascido , Doenças do Recém-Nascido/psicologia , Doenças do Recém-Nascido/terapia , Unidades de Terapia Intensiva Neonatal/organização & administração , Doenças do Sistema Nervoso/psicologia , Doenças do Sistema Nervoso/terapia , Neurologia/métodos , Cuidados Paliativos/ética , Cuidados Paliativos/métodos , Cuidados Paliativos/psicologia , Apoio Social
16.
J Perinatol ; 35(6): 460-2, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26012477

RESUMO

We report the case of a 1-month old, 28-week gestational age infant who presented with acute paraplegia after cardiopulmonary arrest. Later imaging confirms cerebral sinovenous thrombosis (CSVT) and a suspected infarction in the conus medullaris of the spinal cord. A prothrombotic state may explain the numerous areas of infarction visualized on neuroimaging. To our knowledge this is the first case report of acute and persistent paraplegia in an infant with CSVT and conus medullaris injury, which may be due to venous infarction of the spinal cord.


Assuntos
Paraplegia/etiologia , Trombose dos Seios Intracranianos/complicações , Parada Cardíaca , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro , Infarto/complicações , Imageamento por Ressonância Magnética , Medula Espinal/irrigação sanguínea
17.
J Med Chem ; 57(9): 3845-55, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24694215

RESUMO

Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and ß-lactam core structures. Results from drug sensitivity studies with ß-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.


Assuntos
Bactérias Gram-Negativas/metabolismo , Peptídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Sideróforos/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Testes de Sensibilidade Microbiana , Peptídeos/efeitos dos fármacos , Peptídeos Cíclicos , beta-Lactamases/metabolismo
18.
J Med Chem ; 56(13): 5541-52, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23755848

RESUMO

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/farmacologia , Piridonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Concentração Inibidora 50 , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efeitos dos fármacos , Piridonas/química , Piridonas/farmacocinética , Ratos , Ratos Wistar
19.
Bioorg Med Chem Lett ; 22(18): 5989-94, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22892121
20.
Oncogene ; 31(46): 4859-67, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22266870

RESUMO

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in neuroblastoma, a devastating pediatric cancer of the sympathetic nervous system. Germline and somatically acquired ALK aberrations induce increased autophosphorylation, constitutive ALK activation and increased downstream signaling. Thus, ALK is a tractable therapeutic target in neuroblastoma, likely to be susceptible to both small-molecule tyrosine kinase inhibitors and therapeutic antibodies-as has been shown for other receptor tyrosine kinases in malignancies such as breast and lung cancer. Small-molecule inhibitors of ALK are currently being studied in the clinic, but common ALK mutations in neuroblastoma appear to show de novo insensitivity, arguing that complementary therapeutic approaches must be developed. We therefore hypothesized that antibody targeting of ALK may be a relevant strategy for the majority of neuroblastoma patients likely to have ALK-positive tumors. We show here that an antagonistic ALK antibody inhibits cell growth and induces in vitro antibody-dependent cellular cytotoxicity of human neuroblastoma-derived cell lines. Cytotoxicity was induced in cell lines harboring either wild type or mutated forms of ALK. Treatment of neuroblastoma cells with the dual Met/ALK inhibitor crizotinib sensitized cells to antibody-induced growth inhibition by promoting cell surface accumulation of ALK and thus increasing the accessibility of antigen for antibody binding. These data support the concept of ALK-targeted immunotherapy as a highly promising therapeutic strategy for neuroblastomas with mutated or wild-type ALK.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Neuroblastoma/imunologia , Neuroblastoma/terapia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/imunologia , Quinase do Linfoma Anaplásico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Morte Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe , Humanos , Mutação/imunologia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
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