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1.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34795055

RESUMO

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength-sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength-sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.


Assuntos
Oftalmoscopia/métodos , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Retinose Pigmentar/metabolismo , Eletrorretinografia , Proteínas do Olho/metabolismo , Humanos
2.
Invest Ophthalmol Vis Sci ; 62(2): 8, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33544131

RESUMO

Purpose: Psychophysical and genetic testing provide substantial information about color vision phenotype and genotype. However, neither reveals how color vision phenotypes and genotypes manifest themselves in individual cones, where color vision and its anomalies are thought to originate. Here, we use adaptive-optics phase-sensitive optical coherence tomography (AO-PSOCT) to investigate these relationships. Methods: We used AO-PSOCT to measure cone function-optical response to light stimulation-in each of 16 human subjects with different phenotypes and genotypes of color vision (five color-normal, three deuteranopic, two protanopic, and six deuteranomalous trichromatic subjects). We classified three spectral types of cones (S, M, and L), and we measured cone structure-namely cone density, cone mosaic arrangement, and spatial arrangement of cone types. Results: For the different phenotypes, our cone function results show that (1) color normals possess S, M, and L cones; (2) deuteranopes are missing M cones but are normal otherwise; (3) protanopes are missing L cones but are normal otherwise; and (4) deuteranomalous trichromats are missing M cones but contain evidence of at least two subtypes of L cones. Cone function was consistent with the subjects' genotype in which only the first two M and L genes in the gene array are expressed and was correlated with the estimated spectral separation between photopigments, including in the deuteranomalous trichromats. The L/M cone ratio was highly variable in the color normals. No association was found between cone density and the genotypes and phenotypes investigated, and the cone mosaic arrangement was altered in the dichromats. Conclusions: AO-PSOCT is a novel method for assessing color vision phenotype and genotype in single cone cells.


Assuntos
Defeitos da Visão Cromática/genética , Visão de Cores/genética , Células Fotorreceptoras Retinianas Cones/metabolismo , Pigmentos da Retina/metabolismo , Adulto , Percepção de Cores/fisiologia , Defeitos da Visão Cromática/metabolismo , Defeitos da Visão Cromática/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Células Fotorreceptoras Retinianas Cones/patologia , Tomografia de Coerência Óptica/métodos , Adulto Jovem
3.
J Biomed Opt ; 26(1)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33496094

RESUMO

The note corrects an error that appeared in Equation 14 of the originally published article.

4.
J Biomed Opt ; 26(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33410310

RESUMO

SIGNIFICANCE: Adaptive optics optical coherence tomography (AO-OCT) technology enables non-invasive, high-resolution three-dimensional (3D) imaging of the retina and promises earlier detection of ocular disease. However, AO-OCT data are corrupted by eye-movement artifacts that must be removed in post-processing, a process rendered time-consuming by the immense quantity of data. AIM: To efficiently remove eye-movement artifacts at the level of individual A-lines, including those present in any individual reference volume. APPROACH: We developed a registration method that cascades (1) a 3D B-scan registration algorithm with (2) a global A-line registration algorithm for correcting torsional eye movements and image scaling and generating global motion-free coordinates. The first algorithm corrects 3D translational eye movements to a single reference volume, accelerated using parallel computing. The second algorithm combines outputs of multiple runs of the first algorithm using different reference volumes followed by an affine transformation, permitting registration of all images to a global coordinate system at the level of individual A-lines. RESULTS: The 3D B-scan algorithm estimates and corrects 3D translational motions with high registration accuracy and robustness, even for volumes containing microsaccades. Averaging registered volumes improves our image quality metrics up to 22 dB. Implementation in CUDA™ on a graphics processing unit registers a 512 × 512 × 512 volume in only 10.6 s, 150 times faster than MATLAB™ on a central processing unit. The global A-line algorithm minimizes image distortion, improves regularity of the cone photoreceptor mosaic, and supports enhanced visualization of low-contrast retinal cellular features. Averaging registered volumes improves our image quality up to 9.4 dB. It also permits extending the imaging field of view (∼2.1 × ) and depth of focus (∼5.6 × ) beyond what is attainable with single-reference registration. CONCLUSIONS: We can efficiently correct eye motion in all 3D at the level of individual A-lines using a global coordinate system.


Assuntos
Imageamento Tridimensional , Tomografia de Coerência Óptica , Artefatos , Óptica e Fotônica , Retina/diagnóstico por imagem
5.
Neurophotonics ; 7(1): 015013, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32206680

RESUMO

Significance: There are no label-free imaging descriptors related to physiological activity of inner retinal cells in the living human eye. A major reason is that inner retinal neurons are highly transparent and reflect little light, making them extremely difficult to visualize and quantify. Aim: To measure physiologically-induced optical changes of inner retinal cells despite their challenging optical properties. Approach: We developed an imaging method based on adaptive optics and optical coherence tomography (AO-OCT) and a suite of postprocessing algorithms, most notably a new temporal correlation method. Results: We captured the temporal dynamics of entire inner retinal layers, of specific tissue types, and of individual cells across three different timescales from fast (seconds) to extremely slow (one year). Time correlation analysis revealed significant differences in time constant (up to 0.4 s) between the principal layers of the inner retina with the ganglion cell layer (GCL) being the most dynamic. At the cellular level, significant differences were found between individual GCL somas. The mean time constant of the GCL somas ( 0.69 ± 0.17 s ) was ∼ 30 % smaller than that of nerve fiber bundles and inner plexiform layer synapses and processes. Across longer durations, temporal speckle contrast and time-lapse imaging revealed motion of macrophage-like cells (over minutes) and GCL neuron loss and remodeling (over one year). Conclusions: Physiological activity of inner retinal cells is now measurable in the living human eye.

6.
JAMA Ophthalmol ; 137(6): 652-659, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998818

RESUMO

Importance: Astronauts on International Space Station missions demonstrate adverse neuro-ocular changes. Reversing a negative translaminar pressure gradient (TLPG) by modulating cerebral blood flow, decreasing intracranial pressure, or increasing intraocular pressure (IOP) has been proposed as potential intervention for spaceflight-associated neuro-ocular syndrome (SANS). Objective: To examine whether exercise (resistance, moderate-intensity aerobic, and high-intensity aerobic) or artificially increasing IOP is associated with modulated cerebro-ocular hemodynamic and pressure changes during head-down tilt (HDT), an analogue of spaceflight, in healthy adults. Design, Setting, and Participants: A single-center investigation was conducted at Johnson Space Center, Houston, Texas, from January 1, 2014, to December 31, 2016, in 20 healthy men. Exposure: On 3 separate days, participants rested supine, were tilted to -15° HDT, and then completed 1 of 3 experimental exercise conditions (moderate-intensity aerobic, resistance, or high-intensity interval aerobic). A subset of 10 participants wore swimming goggles on all days. Main Outcomes and Measures: Applanation rebound tonometry was used to noninvasively assess IOP, and compression sonography was used to assess internal jugular venous pressure (IJVP). Estimated TLPG was calculated as the difference between IOP and IJVP. Cerebral inflow and outflow were measured in extracranial arteries using color-coded duplex ultrasonography. Results: Twenty men participated in the study (mean [SD] age, 36 [9] years). Compared with supine IOP (mean [SD], 19.3 [3.7] mm Hg), IJVP (mean [SD], 21.4 [6.0] mm Hg), and estimated TLPG (mean [SD], -2.1 [7.0] mm Hg), -15° HDT was associated with increased IOP (mean difference, 2.3 mm Hg; 95% CI, 1.4-3.3 mm Hg; P < .001) and IJVP (mean difference, 10.5 mm Hg; 95% CI, 8.9-12.2 mm Hg; P < .001) and with decreased TLPG (mean difference, -8.2 mm Hg; 95% CI, -10.1 to -6.3 mm Hg; P < .001). Exercise (regardless of modality) at -15° HDT was associated with decreased IOP (mean difference, -1.6 mm Hg; 95% CI, -2.6 to -0.6 mm Hg; P = .002) and TLPG (mean difference, -3.5 mm Hg; 95% CI, -6.2 to -0.7 mm Hg; P = .01) compared with rest. Both IOP (mean difference, 2.9 mm Hg; 95% CI, 0.7-5.1 mm Hg; P = .01) and TLPG (mean difference, 5.1 mm Hg; 95% CI, 0.8-9.4 mm Hg; P = .02) were higher in participants who wore swimming goggles compared with those not wearing goggles. Conclusions and Relevance: In this study, exercise was associated with decreased IOP and estimated translaminar pressure gradient in a spaceflight analogue of HDT. The addition of swimming goggles was associated with increased IOP and TLPG in HDT. Further evaluation in spaceflight may be warranted to determine whether modestly increasing IOP is an effective SANS countermeasure.


Assuntos
Circulação Cerebrovascular/fisiologia , Exercício Físico/fisiologia , Oftalmopatias/fisiopatologia , Dispositivos de Proteção dos Olhos , Olho/irrigação sanguínea , Hipertensão Intracraniana/fisiopatologia , Pressão Intraocular/fisiologia , Adulto , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Hemodinâmica/fisiologia , Humanos , Masculino , Modelos Biológicos , Voo Espacial , Tonometria Ocular , Ultrassonografia Doppler em Cores
7.
Proc Natl Acad Sci U S A ; 116(16): 7951-7956, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30944223

RESUMO

Human color vision is achieved by mixing neural signals from cone photoreceptors sensitive to different wavelengths of light. The spatial arrangement and proportion of these spectral types in the retina set fundamental limits on color perception, and abnormal or missing types are responsible for color vision loss. Imaging provides the most direct and quantitative means to study these photoreceptor properties at the cellular scale in the living human retina, but remains challenging. Current methods rely on retinal densitometry to distinguish cone types, a prohibitively slow process. Here, we show that photostimulation-induced optical phase changes occur in cone cells and carry substantial information about spectral type, enabling cones to be differentiated with unprecedented accuracy and efficiency. Moreover, these phase dynamics arise from physiological activity occurring on dramatically different timescales (from milliseconds to seconds) inside the cone outer segment, thus exposing the phototransduction cascade and subsequent downstream effects. We captured these dynamics in cones of subjects with normal color vision and a deuteranope, and at different macular locations by: (i) marrying adaptive optics to phase-sensitive optical coherence tomography to avoid optical blurring of the eye, (ii) acquiring images at high speed that samples phase dynamics at up to 3 KHz, and (iii) localizing phase changes to the cone outer segment, where photoactivation occurs. Our method should have broad appeal for color vision applications in which the underlying neural processing of photoreceptors is sought and for investigations of retinal diseases that affect cone function.


Assuntos
Visão de Cores/fisiologia , Estimulação Luminosa/métodos , Células Fotorreceptoras Retinianas Cones/classificação , Células Fotorreceptoras Retinianas Cones/fisiologia , Adulto , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/fisiologia , Tomografia de Coerência Óptica , Adulto Jovem
8.
Oncotarget ; 10(14): 1360-1387, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30858923

RESUMO

Studies of dominantly heritable cancers enabled insights about tumor progression. BCNS is a dominantly inherited disorder that is characterized by developmental abnormalities and postnatal neoplasms, principally BCCs. We performed an exploratory gene expression profiling of primary cell cultures derived from clinically unaffected skin biopsies of BCNS gene-carriers (PTCH1 +/-) and normal individuals. PCA and HC of untreated keratinocytes or fibroblasts failed to clearly distinguish BCNS samples from controls. These results are presumably due to the common suppression of canonical HH signaling in vitro. We then used a relaxed threshold (p-value <0.05, no FDR cut-off; FC 1.3) that identified a total of 585 and 857 genes differentially expressed in BCNS keratinocytes and fibroblasts samples, respectively. A GSEA identified pancreatic ß cell hallmark and mTOR signaling genes in BCNS keratinocytes, whereas analyses of BCNS fibroblasts identified gene signatures regulating pluripotency of stem cells, including WNT pathway. Significantly, rapamycin treatment (FDR<0.05), affected a total of 1411 and 4959 genes in BCNS keratinocytes and BCNS fibroblasts, respectively. In contrast, rapamycin treatment affected a total of 3214 and 4797 genes in normal keratinocytes and normal fibroblasts, respectively. The differential response of BCNS cells to rapamycin involved 599 and 1463 unique probe sets in keratinocytes and fibroblasts, respectively. An IPA of these genes in the presence of rapamycin pointed to hepatic fibrosis/stellate cell activation, and HIPPO signaling in BCNS keratinocytes, whereas mitochondrial dysfunction and AGRN expression were uniquely enriched in BCNS fibroblasts. The gene expression changes seen here are likely involved in the etiology of BCCs and they may represent biomarkers/targets for early intervention.

9.
Hum Factors ; 60(2): 236-247, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241017

RESUMO

Objective We implemented a gaze-contingent useful field of view paradigm to examine older adult multitasking performance in a simulated driving environment. Background Multitasking refers to the ability to manage multiple simultaneous streams of information. Recent work suggests that multitasking declines with age, yet the mechanisms supporting these declines are still debated. One possible framework to better understand this phenomenon is the useful field of view, or the area in the visual field where information can be attended and processed. In particular, the useful field of view allows for the discrimination of two competing theories of real-time multitasking, a general interference account and a tunneling account. Methods Twenty-five older adult subjects completed a useful field of view task that involved discriminating the orientation of lines in gaze-contingent Gabor patches appearing at varying eccentricities (based on distance from the fovea) as they operated a vehicle in a driving simulator. In half of the driving scenarios, subjects also completed an auditory two-back task to manipulate cognitive workload, and during some trials, wind was introduced as a means to alter general driving difficulty. Results Consistent with prior work, indices of driving performance were sensitive to both wind and workload. Interestingly, we also observed a decline in Gabor patch discrimination accuracy under high cognitive workload regardless of eccentricity, which provides support for a general interference account of multitasking. Conclusion The results showed that our gaze-contingent useful field of view paradigm was able to successfully examine older adult multitasking performance in a simulated driving environment. Application This study represents the first attempt to successfully measure dynamic changes in the useful field of view for older adults completing a multitasking scenario involving driving.


Assuntos
Envelhecimento/fisiologia , Percepção Auditiva/fisiologia , Função Executiva/fisiologia , Movimentos Oculares/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Desempenho Psicomotor/fisiologia , Campos Visuais/fisiologia , Idoso , Condução de Veículo , Humanos
10.
Cancer Res ; 77(13): 3564-3576, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28446463

RESUMO

To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI-ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at https://dtp.cancer.gov/ncialmanac Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials. Cancer Res; 77(13); 3564-76. ©2017 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , National Cancer Institute (U.S.) , Estados Unidos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 8(11): 17628-17642, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-27682873

RESUMO

Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the "Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Predisposição Genética para Doença/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Haploinsuficiência , Heterozigoto , Humanos , Immunoblotting , Neoplasias Renais/genética , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
12.
Hum Factors ; 58(4): 630-41, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27091370

RESUMO

OBJECTIVE: We aimed to develop and test a new dynamic measure of transient changes to the useful field of view (UFOV), utilizing a gaze-contingent paradigm for use in realistic simulated environments. BACKGROUND: The UFOV, the area from which an observer can extract visual information during a single fixation, has been correlated with driving performance and crash risk. However, some existing measures of the UFOV cannot be used dynamically in realistic simulators, and other UFOV measures involve constant stimuli at fixed locations. We propose a gaze-contingent UFOV measure (the GC-UFOV) that solves the above problems. METHODS: Twenty-five participants completed four simulated drives while they concurrently performed an occasional gaze-contingent Gabor orientation discrimination task. Gabors appeared randomly at one of three retinal eccentricities (5°, 10°, or 15°). Cognitive workload was manipulated both with a concurrent auditory working memory task and with driving task difficulty (via presence/absence of lateral wind). RESULTS: Cognitive workload had a detrimental effect on Gabor discrimination accuracy at all three retinal eccentricities. Interestingly, this accuracy cost was equivalent across eccentricities, consistent with previous findings of "general interference" rather than "tunnel vision." CONCLUSION: The results showed that the GC-UFOV method was able to measure transient changes in UFOV due to cognitive load in a realistic simulated environment. APPLICATION: The GC-UFOV paradigm developed and tested in this study is a novel and effective tool for studying transient changes in the UFOV due to cognitive load in the context of complex real-world tasks such as simulated driving.


Assuntos
Condução de Veículo , Fixação Ocular/fisiologia , Desempenho Psicomotor/fisiologia , Campos Visuais/fisiologia , Adulto , Humanos
13.
Hum Factors ; 58(1): 150-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26490442

RESUMO

OBJECTIVE: A fully immersive, high-fidelity street-crossing simulator was used to examine the effects of texting on pedestrian street-crossing performance. BACKGROUND: Research suggests that street-crossing performance is impaired when pedestrians engage in cell phone conversations. Less is known about the impact of texting on street-crossing performance. METHOD: Thirty-two young adults completed three distraction conditions in a simulated street-crossing task: no distraction, phone conversation, and texting. A hands-free headset and a mounted tablet were used to conduct the phone and texting conversations, respectively. Participants moved through the virtual environment via a manual treadmill, allowing them to select crossing gaps and change their gait. RESULTS: During the phone conversation and texting conditions, participants had fewer successful crossings and took longer to initiate crossing. Furthermore, in the texting condition, smaller percentage of time with head orientation toward the tablet, fewer number of head orientations toward the tablet, and greater percentage of total characters typed before initiating crossing predicted greater crossing success. CONCLUSION: Our results suggest that (a) texting is as unsafe as phone conversations for street-crossing performance and (b) when subjects completed most of the texting task before initiating crossing, they were more likely to make it safely across the street. APPLICATION: Sending and receiving text messages negatively impact a range of real-world behaviors. These results may inform personal and policy decisions.


Assuntos
Telefone Celular , Pedestres , Segurança , Envio de Mensagens de Texto/estatística & dados numéricos , Adolescente , Adulto , Atenção/fisiologia , Cabeça/fisiologia , Humanos , Interface Usuário-Computador , Adulto Jovem
14.
Hum Factors ; 56(3): 443-52, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24930167

RESUMO

OBJECTIVE: A high-fidelity street crossing simulator was used to test the hypothesis that experienced action video game players are less vulnerable than non-gamers to dual task costs in complex tasks. BACKGROUND: Previous research has shown that action video game players outperform nonplayers on many single task measures of perception and attention. It is unclear, however, whether action video game players outperform nonplayers in complex, divided attention tasks. METHOD: Experienced action video game players and nongamers completed a street crossing task in a high-fidelity simulator. Participants walked on a manual treadmill to cross the street. During some crossings, a cognitively demanding working memory task was added. RESULTS: Dividing attention resulted in more collisions and increased decision making time. Of importance, these dual task costs were equivalent for the action video game players and the nongamers. CONCLUSION: These results suggest that action video game players are equally susceptible to the costs of dividing attention in a complex task. APPLICATION: Perceptual and attentional benefits associated with action video game experience may not translate to performance benefits in complex, real-world tasks.


Assuntos
Atenção , Memória de Curto Prazo , Análise e Desempenho de Tarefas , Jogos de Vídeo , Caminhada , Adolescente , Adulto , Tomada de Decisões , Feminino , Humanos , Masculino , Desempenho Psicomotor , Adulto Jovem
15.
Acta Psychol (Amst) ; 140(1): 7-12, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22426426

RESUMO

The effect of landmarks in human path integration was investigated using virtual hallway-mazes. Participants traveled along random 5-segment paths either with or without distinctive landmarks at some segment intersections. They were required to directly return to the origin or to one of the landmark locations from the end of the path. Results showed that knowledge of the return targets prior to the outbound trip significantly reduced RTs to both the origin and the landmarks. Moreover, RTs in the return-to-origin trials were longer with landmarks present than without landmarks. This effect was eliminated when the return target was given prior to the trip. These results suggest that processing of the origin and the landmarks interfere with each other. However this interference is not obligatory and can be eliminated or reduced by prior knowledge about the target. The influences of landmarks on path integration and spatial updating were discussed.


Assuntos
Percepção Espacial/fisiologia , Comportamento Espacial/fisiologia , Adulto , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia
16.
Bioorg Med Chem Lett ; 21(23): 7146-50, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22001089

RESUMO

Several acetyl-protected hydroxybenzyl diethyl phosphates (EHBPs) that are capable of forming quinone methide intermediates were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. Compounds 1, 1a, and 1b, corresponding to (4-acetyloxybenzyl diethylphosphate), (3-methyl-4-acetyloxybenzyl diethylphosphate), and (3-chloro-4-acetyloxybenzyl diethylphosphate), were significantly more potent than compounds 2 and 3, (2-acetyloxybenzyl diethylphosphate) and (3-acetyloxybenzyl diethylphosphate), respectively. Using HT-29 human colon cancer cells, compounds 1 and 3 increased apoptosis, inhibited proliferation, and caused a G(2)/M block in the cell cycle. Our data suggest that these compounds merit further investigation as potential anti-cancer agents.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Organofosfatos/síntese química , Organofosfatos/farmacologia , Acetilação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neoplasias/tratamento farmacológico , Organofosfatos/química
17.
Cancer Prev Res (Phila) ; 4(11): 1938-44, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21846796

RESUMO

The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200 µg per day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This seems to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Because SELECT did not test the NPC agent, it is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, and selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine.


Assuntos
Cisteína/análogos & derivados , Compostos Organosselênicos/farmacocinética , Adulto , Estudos de Coortes , Cisteína/administração & dosagem , Cisteína/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Dose Máxima Tolerável , Compostos Organosselênicos/administração & dosagem , Selenocisteína/análogos & derivados , Resultado do Tratamento
18.
Oncol Rep ; 26(3): 731-6, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21617870

RESUMO

The abilities of 5,6-benzoflavone (5,6-BF, a synthetic flavonoid), indole-3-carbinol (I3C, a plant derived product) or diindolylmethane (DIM, a condensation product of I3C) to alter the induction of mammary cancers induced by the carcinogens 7,12-dimethylbenzanthracene (DMBA) or N-methyl-N-nitrosourea (MNU) were evaluated. Interestingly, the first two agents act as aryl hydrocarbon receptor (AhR) agonists, while DIM does not. The agents were initially examined for their ability to inhibit DMBA-induced mammary carcinogenesis. Agents were administered for 14 days starting 7 days prior to a single dose of the carcinogen. Evaluated over an extensive range of doses (165, 550 and 1650 ppm in the diet), 5,6-BF caused a dose-dependent decrease of mammary cancers. In addition, 5,6-BF at doses of 1650 and 165 ppm in the diet blocked the induction of DMBA-induced DNA adducts in the mammary gland by approximately 85% and 45%, respectively. In contrast, DIM (180 or 20 mg/kg BW/day) failed to block induction of DMBA tumors. The effect of these agents on the promotion/progression phase of carcinogenesis using the MNU mammary cancer model was also determined. 5,6-BF (1650 or 165 ppm in the diet), I3C (180 or 60 mg/kg BW/day administered by gavage), or DIM (180 or 60 mg/kg BW/day by gavage) were initiated 5 days after the administration of MNU, and continually thereafter. 5,6-BF decreased MNU- induced mammary tumor multiplicity by 40-60%. I3C reduced tumor multiplicity at the high dose, while DIM at either dose had minimal effects on tumor multiplicity. Thus, 5,6-BF and I3C were highly effective against initiation of DMBA-induced mammary carcinogenesis, and were also effective against MNU-induced tumors during the promotion/progression phase of carcinogenesis. In contrast, DIM had minimal effects in either model; arguing that administration of DIM is not analogous to administration of I3C.


Assuntos
Anticarcinógenos/farmacologia , Indóis/farmacologia , Neoplasias Mamárias Experimentais/prevenção & controle , beta-Naftoflavona/farmacologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Metilnitrosoureia , Ratos , Ratos Sprague-Dawley , Transcrição Gênica , Carga Tumoral
19.
Cancer Prev Res (Phila) ; 4(3): 347-53, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21372034

RESUMO

SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC(0-∞)) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC(0-∞) values were highest in the fed state (range = 122-439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.


Assuntos
Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Carbazóis/farmacologia , Quimioprevenção/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Resultado do Tratamento
20.
Oncotarget ; 2(3): 197-208, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21411865

RESUMO

Here we compared the proteomes of primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis (FAP) patients with those obtained from unaffected controls. The expression signature of about 19% of total fibroblast proteins separates FAP mutation carriers from unaffected controls (P < 0.01). More than 4,000 protein spots were quantified by 2D PAGE analysis, identifying 368 non-redundant proteins and 400 of their isoforms. Specifically, all three classes of cytoskeletal filaments and their regulatory proteins were altered as were oxidative stress response proteins. Given that FAP fibroblasts showed heightened sensitivity to transformation by KiMSV and SV40 including elevated levels of the p53 protein, events controlled in large measure by the Ras suppressor protein-1 (RSU-1) and oncogenic DJ-1, here we show decreased RSU1 and augmented DJ-1 expression in both fibroblasts and crypt-derived epithelial cells from morphologically normal colonic mucosa of FAP gene-carriers. The results indicate that heterozygosity for a mutant APC tumor suppressor gene alters the proteomes of both colon-derived normal fibroblasts in a gene-specific manner, consistent with a "one-hit" effect.


Assuntos
Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/metabolismo , Genes APC , Proteínas de Neoplasias/biossíntese , Proteoma/biossíntese , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Estudos de Casos e Controles , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , Estresse Oxidativo/genética , Proteína Desglicase DJ-1 , Proteoma/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Adulto Jovem
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