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1.
Biomimetics (Basel) ; 8(6)2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37887602

RESUMEN

As human-robot interaction becomes more prevalent in industrial and clinical settings, detecting changes in human posture has become increasingly crucial. While recognizing human actions has been extensively studied, the transition between different postures or movements has been largely overlooked. This study explores using two deep-learning methods, the linear Feedforward Neural Network (FNN) and Long Short-Term Memory (LSTM), to detect changes in human posture among three different movements: standing, walking, and sitting. To explore the possibility of rapid posture-change detection upon human intention, the authors introduced transition stages as distinct features for the identification. During the experiment, the subject wore an inertial measurement unit (IMU) on their right leg to measure joint parameters. The measurement data were used to train the two machine learning networks, and their performances were tested. This study also examined the effect of the sampling rates on the LSTM network. The results indicate that both methods achieved high detection accuracies. Still, the LSTM model outperformed the FNN in terms of speed and accuracy, achieving 91% and 95% accuracy for data sampled at 25 Hz and 100 Hz, respectively. Additionally, the network trained for one test subject was able to detect posture changes in other subjects, demonstrating the feasibility of personalized or generalized deep learning models for detecting human intentions. The accuracies for posture transition time and identification at a sampling rate of 100 Hz were 0.17 s and 94.44%, respectively. In summary, this study achieved some good outcomes and laid a crucial foundation for the engineering application of digital twins, exoskeletons, and human intention control.

2.
Sensors (Basel) ; 23(16)2023 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-37631740

RESUMEN

The gait pattern of exoskeleton control conflicting with the human operator's (the pilot) intention may cause awkward maneuvering or even injury. Therefore, it has been the focus of many studies to help decide the proper gait operation. However, the timing for the recognization plays a crucial role in the operation. The delayed detection of the pilot's intent can be equally undesirable to the exoskeleton operation. Instead of recognizing the motion, this study examines the possibility of identifying the transition between gaits to achieve in-time detection. This study used the data from IMU sensors for future mobile applications. Furthermore, we tested using two machine learning networks: a linearfFeedforward neural network and a long short-term memory network. The gait data are from five subjects for training and testing. The study results show that: 1. The network can successfully separate the transition period from the motion periods. 2. The detection of gait change from walking to sitting can be as fast as 0.17 s, which is adequate for future control applications. However, detecting the transition from standing to walking can take as long as 1.2 s. 3. This study also find that the network trained for one person can also detect movement changes for different persons without deteriorating the performance.


Asunto(s)
Intención , Movimiento , Humanos , Movimiento (Física) , Marcha , Aprendizaje Automático
3.
Sleep Med ; 98: 127-138, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35834983

RESUMEN

OBJECTIVE/BACKGROUND: This study evaluated psychometric properties of the Pediatric Narcolepsy Screening Questionnaire (PNSQ), developed in response to the difficulty of identifying pediatric narcolepsy. PATIENTS/METHODS: The initial PNSQ was updated following debriefing interviews with parents of children with suspected/diagnosed narcolepsy. Subsequently, newly recruited caregivers were categorized into groups: clinician-confirmed narcolepsy, other sleep problems (OSP), and no sleep problems (controls). Caregivers completed the 11-item PNSQ assessing narcolepsy symptomatology. PNSQ psychometric properties were evaluated; mean PNSQ Total Score (TS) was compared inter-group using analysis of variance. RESULTS: The analysis population (N = 158) included patients with narcolepsy (n = 49), OSP (n = 55), and controls (n = 54); mean ± SD age was 13.8 ± 2.8, 10.2 ± 4.3, and 10.0 ± 3.8 years, respectively. Inter-item Pearson correlations (range, 0.22-0.75) indicated good construct validity. Principal component analysis confirmed unidimensionality. Item discriminative power was high for narcolepsy vs control (range, 0.693-0.936) and lower for narcolepsy vs OSP (range, 0.584-0.729). The latent trait was well covered (separation index = 0.868). Item 7 (vivid dreams/nightmares), having low discriminative power and specificity, was removed. Cronbach's alpha (final PNSQ) indicated high internal consistency reliability (raw alpha = 0.88). Mean ± SD PNSQ TS (range, 0-50) in the narcolepsy, OSP, and control groups were 34.98 ± 7.98, 25.20 ± 9.43, and 9.54 ± 9.38, respectively (nominal P < 0.0001). Classification by PNSQ TS was defined: PNSQ+ (likely narcolepsy, TS ≥ 29), PNSQ 0 (likely OSP, TS 19-28), and PNSQ- (narcolepsy unlikely, TS ≤ 18); patients with narcolepsy were classified as PNSQ+ (79.6%), PNSQ 0 (18.4%), and PNSQ- (2.0%). CONCLUSIONS: The PNSQ demonstrated good psychometric properties and excellent performance discriminating narcolepsy, OSP, and control groups.


Asunto(s)
Narcolepsia , Niño , Estudios Transversales , Humanos , Narcolepsia/diagnóstico , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios
4.
J Int Med Res ; 50(6): 3000605221108100, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35766023

RESUMEN

OBJECTIVE: To investigate the correlation between corneal biomechanical properties and topographic parameters using machine learning networks for automatic severity diagnosis and reference benchmark construction. METHODS: This was a retrospective study involving 31 eyes from 31 patients with keratonus. Two clustering approaches were used (i.e., shape-based and feature-based). The shape-based method used a keratoconus benchmark validated for indicating the severity of keratoconus. The feature-based method extracted imperative features for clustering analysis. RESULTS: There were strong correlations between the symmetric modes and the keratoconus severity and between the asymmetric modes and the location of the weak centroid. The Pearson product-moment correlation coefficient (PPMC) between the symmetric mode and normality was 0.92 and between the asymmetric mode and the weak centroid value was 0.75. CONCLUSION: This study confirmed that there is a relationship between the keratoconus signs obtained from topography and the corneal dynamic behaviour captured by the Corvis ST device. Further studies are required to gather more patient data to establish a more extensive database for validation.


Asunto(s)
Queratocono , Análisis por Conglomerados , Córnea , Topografía de la Córnea/métodos , Humanos , Queratocono/diagnóstico , Estudios Retrospectivos
5.
Future Oncol ; 17(4): 443-453, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33300811

RESUMEN

Background: Real-world data are lacking on patients with small-cell lung cancer (SCLC) with extensive-stage SCLC (eSCLC) and poor performance status (PS). Patients & methods: Eligible patients diagnosed with eSCLC between 1 January 2008 and 31 December 2017 were included in this retrospective, observational study. Results: The study included 406 patients, with 14.3% impaired PS. Progression-free survival and overall survival were not significantly different between impaired (Eastern Cooperative Oncology Group ≥2) and not impaired patients (median, 4.5 vs 5.3 months, and 7.2 vs 8.4 months, respectively). Impaired patients used more supportive care drugs (mean, 3.0 vs 2.0; p = 0.033). Conclusion: Effectiveness outcomes among patients with and without impaired PS did not differ in the real-world setting. Progression-free survival and overall survival were similar to data from clinical trials.


Asunto(s)
Recursos en Salud , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células Pequeñas/terapia , Anciano , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/mortalidad
6.
Future Oncol ; 17(9): 1001-1011, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33167685

RESUMEN

Background: Limited studies have evaluated palbociclib-based therapy use in patients with advanced/metastatic breast cancer in the real world. This retrospective study used medical records from US community oncology practices to address the gap. Materials & methods: Eligible patients receiving palbociclib-based therapy per label indication from 3 February 2015 to 31 December 2017 were included. Descriptive analyses were conducted for patient characteristics, treatment patterns and clinical outcomes. Results: The study included 233 patients who received palbociclib + aromatase inhibitor (P+AI) and 48 who received palbociclib + fulvestrant (P+F). Real-world progression-free rate for P+AI was 69.8% (46.8%) at 12 (24) months (P+F: 43.5% [39.9%]) months. Real-world survival rate was 89.8% (71.4%) at 12 (24) months (P+F: 76.3% [65.0%]). Conclusion: The study findings are consistent with previous studies of palbociclib-based therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Fulvestrant/uso terapéutico , Humanos , Persona de Mediana Edad , Supervivencia sin Progresión , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Estados Unidos
7.
J Oncol Pharm Pract ; 25(1): 16-24, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28814194

RESUMEN

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.


Asunto(s)
Anemia , Antineoplásicos/efectos adversos , Darbepoetina alfa , Neoplasias/tratamiento farmacológico , Anemia/tratamiento farmacológico , Anemia/genética , Antineoplásicos/clasificación , Darbepoetina alfa/administración & dosificación , Darbepoetina alfa/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas/métodos , Eritropoyesis/efectos de los fármacos , Femenino , Hematínicos/administración & dosificación , Hematínicos/farmacocinética , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/clasificación , Neoplasias/patología , Estudios Retrospectivos , Estados Unidos
8.
Am J Manag Care ; 24(8 Spec No.): SP294-SP302, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30020741

RESUMEN

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.


Asunto(s)
Benzoatos/economía , Análisis Costo-Beneficio , Árboles de Decisión , Costos de los Medicamentos , Hidrazinas/economía , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/economía , Proteínas Recombinantes de Fusión/economía , Trombopoyetina/economía , Adulto , Teorema de Bayes , Benzoatos/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Hidrazinas/uso terapéutico , Masculino , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/economía , Pirazoles/uso terapéutico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Insuficiencia del Tratamiento , Resultado del Tratamiento
9.
Clin Ther ; 39(3): 603-609.e1, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28190600

RESUMEN

PURPOSE: We estimated the real-world costs of bleeding-related episodes (BREs) in adults with primary immune thrombocytopenia (ITP). METHODS: This retrospective cohort study used the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. We identified adult patients diagnosed with primary ITP between 2007 and 2012, defined by at least 2 outpatient claims separated by ≥30 days or 1 inpatient claim (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for primary ITP [287.31]). BRE was defined according to a combination of diagnosis codes and/or procedure codes indicating bleeding or use of rescue therapies. Costs were estimated using total reimbursed amount received by providers (including out-of-pocket costs and reimbursement from insurance, adjusted to 2015 US dollars). FINDINGS: In 6551 patients, 14,115 BREs were identified, mean (SD) age was 55 (18) years, and 62% of patients were women. Mean total reimbursement per BRE was $6022, with significantly higher mean inpatient ($45,114) versus outpatient ($2150) reimbursements (P < 0.0001). Mean BRE reimbursements were higher in splenectomized patients compared with nonsplenectomized patients ($8365 vs $5858); however, the difference was not statistically significant. Mean reimbursement for BREs associated with bleeding alone was $10,396, and with rescue therapy alone it was $2787. Reimbursement for BREs that included both bleeding and rescue therapy was $11,065. IMPLICATIONS: The real-world reimbursement rates of BREs in adult patients with primary ITP can be substantial, with significantly higher values among patients requiring hospitalization and for those with bleeding events. Additionally, there is a trend toward higher reimbursement rates among splenectomized patients.


Asunto(s)
Hemorragia/economía , Hospitalización/economía , Púrpura Trombocitopénica Idiopática/economía , Adulto , Anciano , Costos y Análisis de Costo , Bases de Datos Factuales , Femenino , Gastos en Salud , Humanos , Clasificación Internacional de Enfermedades , Masculino , Medicare , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos
10.
Thromb Res ; 135(4): 636-42, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25666908

RESUMEN

BACKGROUND: There are limitations to using administrative data to identify postoperative venous thromboembolism (VTE). We used a novel approach to quantify postoperative VTE events among Department of Veterans Affairs (VA) surgical patients during 2005-2010. METHODS: We used VA administrative data to exclude patients with VTE during 12 months prior to surgery. We identified probable postoperative VTE events within 30 and 90 days post-surgery in three settings: 1) pre-discharge inpatient, using a VTE diagnosis code and a pharmacy record for anticoagulation; 2) post-discharge inpatient, using a VTE diagnosis code followed by a pharmacy record for anticoagulation within 7 days; and 3) outpatient, using a VTE diagnosis code and either anticoagulation or a therapeutic procedure code with natural language processing (NLP) to confirm acute VTE in clinical notes. RESULTS: Among 468,515 surgeries without prior VTE, probable VTEs were documented within 30 and 90 days in 3,931 (0.8%) and 5,904 (1.3%), respectively. Of probable VTEs within 30 or 90 days post-surgery, 47.8% and 62.9%, respectively, were diagnosed post-discharge. Among post-discharge VTE diagnoses, 86% resulted in a VA hospital readmission. Fewer than 25% of outpatient records with both VTE diagnoses and anticoagulation prescriptions were confirmed by NLP as acute VTE events. CONCLUSION: More than half of postoperative VTE events were diagnosed post-discharge; analyses of surgical discharge records are inadequate to identify postoperative VTE. The NLP results demonstrate that the combination of VTE diagnoses and anticoagulation prescriptions in outpatient administrative records cannot be used to validly identify postoperative VTE events.


Asunto(s)
Estadística como Asunto/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Historia del Siglo XXI , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Vigilancia en Salud Pública , Estudios Retrospectivos , Estados Unidos , Tromboembolia Venosa/epidemiología , Veteranos
11.
Clinicoecon Outcomes Res ; 6: 349-56, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25075195

RESUMEN

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for lung infections and other pathologies (eg, pneumonia); however, few studies have evaluated the impact of pneumonia on health care resource utilization and costs in this population. The purpose of this study was to estimate health care resource utilization and costs among COPD patients with newly acquired pneumonia compared to those without pneumonia. METHODS: A retrospective claims analysis using Truven MarketScan(®) Commercial and Medicare databases was conducted. COPD patients with and without newly acquired pneumonia diagnosed between January 1, 2004 and September 30, 2011 were identified. Propensity score matching was used to create a 1:1 matched cohort. Patient demographics, comorbidities (measured by Charlson Comorbidity Index), and medication use were evaluated before and after matching. Health care resource utilization (ie, hospitalizations, emergency room [ER] and outpatient visits), and associated health care costs were assessed during the 12-month follow-up. Logistic regression was conducted to evaluate the risk of hospitalization and ER visits, and gamma regression models and two-part models compared health care costs between groups after matching. RESULTS: In the baseline cohort (N=467,578), patients with newly acquired pneumonia were older (mean age: 70 versus [vs] 63 years) and had higher Charlson Comorbidity Index scores (3.3 vs 2.6) than patients without pneumonia. After propensity score matching, the pneumonia cohort was nine times more likely to have a hospitalization (odds ratio; 95% confidence intervals [CI] =9.2; 8.9, 9.4) and four times more likely to have an ER visit (odds ratio; 95% CI =4.4; 4.3, 4.5) over the 12-month follow-up period compared to the control cohort. The estimated 12-month mean hospitalization costs ($14,353 [95% CI: $14,037-$14,690]), outpatient costs ($6,891 [95% CI: $6,706-$7,070]), and prescription drug costs ($1,104 [95% CI: $1,054-$1,142]) were higher in the pneumonia cohort than in the control cohort. CONCLUSION: This study demonstrated elevated health care resource use and costs in patients with COPD after acquiring pneumonia compared to those without pneumonia.

12.
Expert Rev Pharmacoecon Outcomes Res ; 13(2): 191-200, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23570430

RESUMEN

Electronic medical records (EMRs) have become a common source of data for outcomes research. This review discusses trends in EMR data use for outcomes research as well as strengths and limitations, and likely future developments to help optimize value and use of EMR data for outcomes research. EMR-based studies reporting treatment outcomes published between 2007 and 2012 were predominantly from the USA and Europe. There has been a substantial increase in the number of EMR-based outcomes studies published from 2007-2008 (n = 28) to 2010-2011 (n = 55). Many studies evaluated biometric and laboratory test outcomes in common chronic conditions. However, researchers are expanding the scope of evaluated diseases and outcomes using advanced techniques, such as natural language processing and linking EMRs to other patient-level data to overcome issues with missing data or data that cannot be accessed using standard queries. These advances will help to expand the scope and sophistication of outcomes research in the coming years.


Asunto(s)
Registros Electrónicos de Salud , Sistemas de Registros Médicos Computarizados , Evaluación de Resultado en la Atención de Salud/métodos , Recolección de Datos/métodos , Europa (Continente) , Humanos , Estados Unidos
13.
Dev Cell ; 23(3): 624-36, 2012 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-22975330

RESUMEN

Previous studies have raised the possibility that Wnt signaling may regulate both neural progenitor maintenance and neuronal differentiation within a single population. Here we investigate the role of Wnt/ß-catenin activity in the zebrafish hypothalamus and find that the pathway is first required for the proliferation of unspecified hypothalamic progenitors in the embryo. At later stages, including adulthood, sequential activation and inhibition of Wnt activity is required for the differentiation of neural progenitors and negatively regulates radial glia differentiation. The presence of Wnt activity is conserved in hypothalamic progenitors of the adult mouse, where it plays a conserved role in inhibiting the differentiation of radial glia. This study establishes the vertebrate hypothalamus as a model for Wnt-regulated postembryonic neural progenitor differentiation and defines specific roles for Wnt signaling in neurogenesis.


Asunto(s)
Hipotálamo/citología , Neurogénesis , Células Madre/citología , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Pez Cebra/crecimiento & desarrollo , Animales , Hipotálamo/metabolismo , Ratones , Neuroglía/citología , Neuroglía/metabolismo , Células Madre/metabolismo , Pez Cebra/embriología
14.
ISRN Obes ; 2012: 734682, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-24533209

RESUMEN

Introduction. Most dietary questionnaires are not created for use in a clinical setting for an adult health exam. We created the Healthy Eating Vital Sign (HEVS) to assess eating behaviors associated with excess weight. This study investigated the validity and reliability of the HEVS. Methods. Using a cross-sectional study design, participants responded to the HEVS and the Block Food Frequency Questionnaire (BFFQ). We analyzed the data descriptively, and, with Pearson's correlation and Cronbach coefficient alpha. Results. We found moderate correlation (rho > 0.3) between multiple items of the HEVS and BFFQ. The Cronbach's alpha was 0.49. Conclusion. Our results support the criterion validity and internal reliability of the HEVS as compared to the BFFQ. The HEVS can help launch a dialogue between patients and providers to monitor and potentially manage dietary behaviors associated with many chronic health conditions, including obesity.

15.
BMC Dev Biol ; 11: 73, 2011 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-22136118

RESUMEN

BACKGROUND: Mutations in APC, a negative regulator of the Wnt/ß-catenin pathway, can cause cancer as well as profound developmental defects. In both cases, affected cells adopt a proliferative progenitor state and fail to differentiate. While the upregulation of some target genes of Wnt/ß-catenin signaling has been shown to mediate these phenotypes in individual tissues, it is unclear whether a common mechanism underlies the defects in APC mutants. RESULTS: Here we show that stat3, a known oncogene and a target of ß-catenin in multiple tissues, is upregulated in apc mutant zebrafish embryos. We further demonstrate that Jak/Stat signaling is necessary for the increased level of proliferation and neural progenitor gene expression observed in apc mutants. CONCLUSIONS: Together, our data suggest that the regulation of Jak/Stat signaling may represent a conserved mechanism explaining the expansion of undifferentiated cells downstream of APC mutations.


Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/genética , Quinasas Janus/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Madre/citología , Proteínas de Pez Cebra/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Secuencia de Bases , Embrión no Mamífero/metabolismo , Quinasas Janus/genética , Datos de Secuencia Molecular , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células Madre/metabolismo , Activación Transcripcional , Vía de Señalización Wnt/genética , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
16.
Am J Physiol Cell Physiol ; 298(6): C1572-82, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20457829

RESUMEN

The insertion of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors into the plasma membrane and removal via internalization are essential for regulating synaptic strength, which underlies the basic mechanism of learning and memory. The retinocollicular pathway undergoes synaptic refinement during development and shows a wide variety of long-term synaptic changes; however, still little is known about its underlying molecular regulation. Here we report a rapid developmental long-term potentiation (LTP)/long-term depression (LTD) switch and its intracellular mechanism at the rat retinocollicular pathway from postnatal day 5 (P5) to P14. Before P9, neurons always exhibited LTP, whereas LTD was observed only after P10. Blockade of GluR2/3-glutamate receptor-interacting protein (GRIP)/AMPA-receptor-binding protein (ABP)/protein interacting with C kinase 1 (PICK1) interactions with pep2-SVKI could sustain the LTP after P10. This suggests that the LTP/LTD switch relied on PDZ protein activities. Selective interruption of GluR2/3-PICK1 binding by pep2-EVKI blocked the long-lasting effects of both LTP and LTD, suggesting a role for PICK1 in the maintenance of long-term synaptic plasticity. Interestingly, synaptic expression of GRIP increased more than twofold from P7 to P11, whereas ABP and PICK1 expression levels remained stable. Blockade of spontaneous retinal input suppressed this increase and abolished the LTP/LTD switch. These results suggest that the increased GRIP synaptic expression may be a key regulatory factor in mediating the activity-dependent developmental LTP/LTD switch, whereas PICK1 may be required for both LTP and LTD to maintain their long-term effects.


Asunto(s)
Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Proteínas del Tejido Nervioso/metabolismo , Dominios PDZ , Neuronas Retinianas/metabolismo , Colículos Superiores/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica , Factores de Edad , Animales , Animales Recién Nacidos , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto , Potenciales Evocados , Potenciales Postsinápticos Excitadores , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Péptidos y Proteínas de Señalización Intracelular , Cinética , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Proteínas Nucleares/metabolismo , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Neuronas Retinianas/efectos de los fármacos , Colículos Superiores/efectos de los fármacos , Colículos Superiores/crecimiento & desarrollo , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos
17.
J Biol Chem ; 283(44): 29681-9, 2008 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-18772145

RESUMEN

The xanthine oxidoreductase gene (XOR) encodes an important source of reactive oxygen species and uric acid, and its expression is associated with various human diseases including several forms of cancer. We previously reported that basal human XOR (hXOR) expression is restricted or repressed by E-box and TATA-like elements and a cluster of transcriptional proteins, including AREB6-like proteins and DNA-dependent protein kinase (DNA-PK). We now demonstrate that the cluster contains the tumor suppressors SAFB1, BRG1, and SAF-A. We further demonstrate that SAFB1 silencing increases hXOR expression and that SAFB1 directly binds to the E-box. Multiple studies in vitro and in vivo including pulldown, immunoprecipitation and chromatin immunoprecipitation analyses indicate that SAFB1, Ku86, and BRG1 associate with each other. The results suggest that the SAFB1 complex binds to the hXOR promoter in a chromatin environment and plays a critical role in restricting hXOR expression via its direct interaction with the E-box, DNA-PK, and tumor suppressors. Moreover, we demonstrate that the cytokine, oncostatin M (OSM), induces the phosphorylation of SAFB1 and that the OSM-induced hXOR mRNA expression is significantly inhibited by silencing the DNA-PK catalytic subunit or SAFB1 expression. The present studies for the first time demonstrate that hXOR is a tumor suppressor-targeted gene and that the phosphorylation of SAFB1 is regulated by OSM, providing a molecular basis for understanding the role of SAFB1-regulated hXOR transcription in cytokine stimulation and tumorigenesis.


Asunto(s)
Antígenos Nucleares/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas Asociadas a Matriz Nuclear/metabolismo , Oncostatina M/metabolismo , Receptores de Estrógenos/metabolismo , Xantina Deshidrogenasa/metabolismo , Núcleo Celular/metabolismo , Inmunoprecipitación de Cromatina , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Autoantígeno Ku , Modelos Biológicos , Fosforilación , Proteínas Recombinantes/química , Transcripción Genética
18.
Neuroreport ; 15(5): 823-8, 2004 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-15073523

RESUMEN

We generated the small interference RNAs to specifically silence the expression of neural salient serine/arginine rich protein 1 (NSSR1) and showed that the inhibition of NSSR1 expression in mouse embryonic carcinoma cells (P19) reduces neuronal differentiation. By contrast, its over-expression promotes the differentiation. Neither inhibition nor over-expression shows distinct effect on cell proliferation. The over-expression increases the inclusion of NCAM L1 exon2 while the inhibition reduces the inclusion. The splicing of kinase insert free isoform of TrkC (TrkC-K1) is increased by the over-expression. The results demonstrate that NSSR1 promotes neuronal differentiation and the splicing of NCAML1 exon2 and TrkC-K1.


Asunto(s)
Proteínas Portadoras/fisiología , Diferenciación Celular/fisiología , Proteínas de Neoplasias/fisiología , Neuronas/patología , Proteínas de Unión al ARN/fisiología , Proteínas Represoras/fisiología , Empalme Alternativo , Animales , Northern Blotting/métodos , Western Blotting/métodos , Bromodesoxiuridina/metabolismo , Carcinoma , Recuento de Células , Proteínas de Ciclo Celular , Línea Celular Tumoral , Embrión de Mamíferos , Exones , Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica , Ratones , Moléculas de Adhesión de Célula Nerviosa/genética , Moléculas de Adhesión de Célula Nerviosa/metabolismo , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/farmacología , Receptor trkC/genética , Receptor trkC/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Transfección/métodos , Tubulina (Proteína)/metabolismo
19.
Neuroreport ; 14(14): 1847-50, 2003 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-14534433

RESUMEN

Neural salient serine-/arginine-rich protein 1 (NSSR1) is a newly identified SR protein that regulates pre-mRNA splicing. In the present study, we demonstrated the neural specialization of NSSR1 protein expression in humans and mice. Strong immunoreactive signals to NSSR1 were observed in mouse cerebral neurons, cerebellar Purkinje cells, pyramidal neurons in CA1, CA2 and CA3 regions of the hippocampus and granule cells in the dentate gyrus. In primarily cultured mouse neural progenitor cells (NPCs), at the undifferentiated status, NSSR1 transcripts were detected, but not the proteins. In comparison, in differentiated NPCs both NSSR1 transcripts and proteins were expressed and significantly up-regulated. The results suggest that NSSR1 is important in regulation of brain function and neural differentiation, possibly via regulating the neural-specific alternative splicing of genes.


Asunto(s)
Encéfalo/citología , Proteínas Portadoras/metabolismo , Proteínas de Neoplasias/metabolismo , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/metabolismo , Células Madre/metabolismo , Animales , Western Blotting , Química Encefálica , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Diferenciación Celular/fisiología , Células Cultivadas , Chlorocebus aethiops , Feto , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones , Proteínas de Neoplasias/genética , ARN Mensajero/biosíntesis , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de Empalme Serina-Arginina , Testículo/metabolismo , Transfección
20.
Intervirology ; 45(3): 183-7, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12403924

RESUMEN

OBJECTIVE: To examine the expression of DNA-dependent protein kinase (DNA-PK); including DNA-PKcs, Ku70 and Ku80 in human neuroectodermal tumor cells with or without retroviral DNA integration. METHODS: RT-PCR assay was used to examine the transcript of DNA-PK. Western blot and immunocytochemistry assays were used to examine the protein level of DNA-PK. RESULTS: The expression of DNA-PKcs was similar in the cells with or without retroviral DNA integration, but the expression of Ku (both mRNA and protein for Ku70 and only protein for Ku80) was higher in cells with retroviral DNA integration than in cells without retroviral DNA integration. CONCLUSION: The expression of Ku but not the expression of DNA-PKcs is induced by retroviral DNA integration. Ku70 may play an important role in the regulation of Ku function in response to retroviral DNA integration.


Asunto(s)
Antígenos Nucleares , ADN Helicasas , Proteínas de Unión al ADN/metabolismo , Tumores Neuroectodérmicos/virología , Proteínas Nucleares/metabolismo , Retroviridae/fisiología , Integración Viral , Proteína Quinasa Activada por ADN , Proteínas de Unión al ADN/genética , Vectores Genéticos , Humanos , Autoantígeno Ku , Tumores Neuroectodérmicos/metabolismo , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Retroviridae/patogenicidad , Células Tumorales Cultivadas
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