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Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.
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Administración Cutánea , Atorvastatina , Hiperlipidemias , Micelas , Agujas , Hiperlipidemias/tratamiento farmacológico , Animales , Atorvastatina/química , Atorvastatina/administración & dosificación , Atorvastatina/farmacología , Ratas , Tamaño de la Partícula , Materiales Biocompatibles/química , Polímeros/química , Ensayo de Materiales , Ratas Sprague-Dawley , Sistemas de Liberación de Medicamentos , MasculinoRESUMEN
Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5, PM10, O3, and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings.
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Contaminantes Atmosféricos , Contaminación del Aire , Disfunción Cognitiva , Demencia , Masculino , Femenino , Humanos , Anciano , Estudios de Cohortes , Estudios de Casos y Controles , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Disfunción Cognitiva/epidemiología , China/epidemiología , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
INTRODUCTION: The prevalence and risk factors for subjective cognitive decline (SCD) and its correlation with objective cognition decline (OCD) among community-dwelling older adults is inconsistent. METHODS: Older adults underwent neuropsychological and clinical evaluations to reach a consensus on diagnoses. RESULTS: This study included 7486 adults without mild cognitive impairment and dementia (mean age: 71.35 years [standard deviation = 5.40]). The sex-, age-, and residence-adjusted SCD prevalence was 58.33% overall (95% confidence interval: 58.29% to 58.37%), with higher rates of 61.25% and 59.87% in rural and female subgroups, respectively. SCD global and OCD language, SCD memory and OCD global, SCD and OCD memory, and SCD and OCD language were negatively correlated in fully adjusted models. Seven health and lifestyle factors were associated with an increased risk for SCD. DISCUSSION: SCD affected 58.33% of older adults and may indicate concurrent OCD, which should prompt the initiation of preventative intervention for dementia. HIGHLIGHTS: SCD affects 58.33% of older adults in China. SCD may indicate concurrent objective cognitive decline. Difficulty finding words and memory impairments may indicate a risk for AD. The presence of SCD may prompt preventative treatment initiation of MCI or dementia. Social network factors may be initial targets for the early prevention of SCD.
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Disfunción Cognitiva , Demencia , Humanos , Femenino , Anciano , Estudios de Cohortes , Prevalencia , Vida Independiente , Disfunción Cognitiva/psicología , Cognición , Envejecimiento , Factores de Riesgo , Demencia/etiología , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Despite the improved access to health services in China, inadequate diagnosis and management of dementia are common issues, especially in rural regions. OBJECTIVE: The Hubei Memory & Aging Cohort Study was designed as a prospective study in Central China to determine the prevalence, incidence, and risk factors for dementia and mild cognitive impairment (MCI) among urban and rural older adults. METHODS: From 2018-2020, participants aged ≥65 years were screened, and data regarding their life behaviors, families, socio-economic status, physical and mental health, social and psychological factors, and cognition were collected. Diagnoses of MCI and dementia were made via consensus diagnosis using the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. RESULTS: Of 8,221 individuals who completed their baseline clinical evaluation, 4,449 (54.1%) were women and 3,164 (38.4%) were from remote rural areas (average age: 71.96 years; mean education period: 7.58 years). At baseline, 25.98%(95%confidence interval [CI]: 24.99-26.96) and 7.24%(95%CI: 6.68-7.80) of the participants were diagnosed with MCI and dementia, respectively. Prevalence showed a strong relationship with age. The substantial disparities between rural and urban regions in MCI and dementia prevalence and multiple dementia-related risk factors were revealed. Especially for dementia, the prevalence rate in rural areas was 2.65 times higher than that in urban regions. CONCLUSION: Our results suggested that public health interventions are urgently needed to achieve equitable diagnosis and management for people living with dementia in the communities across urban and rural areas.
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Disfunción Cognitiva/epidemiología , Anciano , Anciano de 80 o más Años , China/epidemiología , Femenino , Humanos , Incidencia , Modelos Logísticos , Masculino , Pruebas Neuropsicológicas , Prevalencia , Estudios Prospectivos , Proyectos de Investigación , Factores de Riesgo , Población Rural , Población UrbanaRESUMEN
BACKGROUND: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce. METHODS: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis. Prevalence and weighted PAFs of eight modifiable risk factors (six classical: less childhood education, hearing impairment, depression, physical inactivity, diabetes, and social isolation, and two novels: olfactory decline and being unmarried) for all-cause dementia were estimated. RESULTS: Overall, CMDS included 17,589 respondents aged ≥ 65 years, 55.6% of whom were rural residents. The age- and sex-adjusted prevalence for all-cause dementia was 9.11% (95% CI 8.96-9.26), 5.19% (5.07-5.31), and 11.98% (11.8-12.15) in the whole, urban, and rural areas of China, respectively. Further, the overall weighted PAFs of the eight potentially modifiable risk factors were 53.72% (95% CI 52.73-54.71), 50.64% (49.4-51.89), and 56.54% (55.62-57.46) in the whole, urban, and rural areas of China, respectively. The eight risk factors' prevalence differed between rural and urban areas. Lower childhood education (PAF: 13.92%) and physical inactivity (16.99%) were primary risk factors in rural and urban areas, respectively. CONCLUSIONS: The substantial urban-rural disparities in the prevalence of dementia and its risk factors exist, suggesting the requirement of resident-specific dementia-prevention strategies.
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Demencia , Población Rural , Niño , China/epidemiología , Estudios Transversales , Demencia/epidemiología , Humanos , Prevalencia , Factores de Riesgo , Población UrbanaRESUMEN
ß-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the ß-secretase enzyme that initiates production of the toxic amyloid-ß peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the Bace1 gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after Bace1 gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
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Envejecimiento/metabolismo , Secretasas de la Proteína Precursora del Amiloide/deficiencia , Ácido Aspártico Endopeptidasas/deficiencia , Axones/metabolismo , Hipocampo/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Animales Recién Nacidos , Apoptosis , Ácido Aspártico Endopeptidasas/metabolismo , Cognición , Epilepsia/patología , Epilepsia/fisiopatología , Eliminación de Gen , Hipocampo/patología , Hipocampo/fisiopatología , Potenciación a Largo Plazo , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Vaina de Mielina/metabolismo , Neurogénesis , Fenotipo , Especificidad por SustratoRESUMEN
BACKGROUND: Investigations on the effects of malaria infection on cancer mortality are limited except for the incidence of Burkitt's lymphoma (BL) in African children. Our previous murine lung cancer model study demonstrated that malaria infection significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. This study aims to assess the possible associations between malaria incidence and human cancer mortality. METHODS: We compiled data on worldwide malaria incidence and age-standardized mortality related to 30 types of cancer in 56 countries for the period 1955-2008, and analyzed their longitudinal correlations by a generalized additive mixed model (GAMM), adjusted for a nonlinear year effect and potential confounders such as country's income levels, life expectancies and geographical locations. RESULTS: Malaria incidence was negatively correlated with all-cause cancer mortality, yielding regression coefficients (log scale) of -0.020 (95%CI: -0.027,-0.014) for men (P < 0.001) and-0.020 (95%CI: -0.025,-0.014) for women (P < 0.001). Among the 29 individual types of cancer studied, malaria incidence was negatively correlated with colorectum and anus (men and women), colon (men and women), lung (men), stomach (men), and breast (women) cancer. CONCLUSIONS: Our analysis revealed a possible inverse association between malaria incidence and the mortalities of all-cause and some types of solid cancers, which is opposite to the known effect of malaria on the pathogenesis of Burkitt's lymphoma. Activation of the whole immune system, inhibition of tumor angiogenesis by Plasmodium infection may partially explain why endemic malaria might reduce cancer mortality at the population level.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-ß protein (Aß) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aß deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.
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Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Trastornos del Conocimiento , Terapia Cognitivo-Conductual/métodos , Enfermedad de Alzheimer/genética , Amiloide/genética , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/patología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/rehabilitación , Modelos Animales de Enfermedad , Femenino , Masculino , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microvasos/patología , Actividad Motora/genética , Actividad Motora/fisiología , Mutación/genética , Presenilina-1/genética , Tiempo de Reacción/genética , Tiempo de Reacción/fisiología , Refuerzo en Psicología , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Dermatomyositis (DM) complicated with non-small cell lung cancer (NSCLC) is not rare, and could rapidly develop into severe lung cancer [performance-status score (PS) between 2 and 4]. Moreover, tumor has remarkable heterogeneity, and it is not possible to properly target treatments in cases of relapse without knowing pathological diagnosis. We retrospectively analyzed the diagnosis and treatment of a patient with DM complicated with NSCLC, which developed into severe lung cancer with heterogeneity of the tumor during chemotherapy. In this report, we addressed that in patients with severe lung cancer, both the cancer and factors associated with exacerbation should be simultaneously managed to reduce the PS score and avoid unnecessary delay. A second biopsy is important for proper management of the tumor with heterogeneity.
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BACKGROUND/AIMS: Radixin has recently been shown to correlate with the metastasis of gastric cancer, but the pathogenesis is elusive. Adhesion proteins contribute to the regulation of metastasis, and thus this study sought to investigate the role of radixin in the migration, invasion and adhesion of gastric cancer cells, as well as its interaction with adhesion proteins in vitro. METHODS: Radixin stable knockdown human gastric carcinoma SGC-7901 cells were constructed. Alterations in the migration, invasion and adhesion ability were examined by matrigel-coated plate and transwell assays. The expression pattern of adhesion proteins, including E-cadherin, ß-catenin and claudin-1, was determined by quantitative real-time PCR and western blot. Possible involvement of NF-κB/snail pathway was also evaluated. RESULTS: Stable knockdown of radixin significantly suppressed migration and invasion, but enhanced adhesion in SGC-7901 cells. The expression of E-cadherin was manifestly increased in radixin knockdown cells, whereas the expression of ß-catenin and claudin-1 was unchanged. The nuclear exclusion of NF-κB followed by conspicuous reduction of snail expression was involved in the regulation of E-cadherin expression. CONCLUSIONS: Radixin knockdown suppresses the metastasis of SGC-7901 cells in vitro by up-regulation of E-cadherin. The NF-κB/snail pathway contributes to the regulation of E-cadherin in response to depletion of radixin.
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Cadherinas/genética , Proteínas del Citoesqueleto/metabolismo , Técnicas de Silenciamiento del Gen , Proteínas de la Membrana/metabolismo , FN-kappa B/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Regulación hacia Arriba/genética , Antígenos CD , Cadherinas/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/genética , Células Clonales , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Microfilamentos/metabolismo , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Studies have shown that tiotropium once daily reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD. Mechanisms underlying the effects of the muscarinic receptor antagonist tiotropium on COPD have not been fully understood. OBJECTIVE: In this study, we investigated whether improvement in neural respiratory drive is responsible for reducing dyspnea during exercise and improving exercise tolerance in COPD. METHODS: Twenty subjects with severe COPD were randomized into two groups: no treatment (Control, n = 10, 63.6 ± 4.6 years, FEV1 29.6 ± 13.3%pred) or inhaled tiotropium 18 µg once daily for 1 month (n = 10, 66.5 ± 5.4 years, FEV1 33.0 ± 11.1%pred). All subjects were allowed to continue their daily medications other than anti-cholinergics during the study. Constant cycle exercise with 75% of maximal workload and spirometry were performed before and 1 month after treatment. Diaphragmatic EMG (EMGdi) and respiratory pressures were recorded with multifunctional esophageal catheter. Efficiency of neural respiratory drive, defined as the ratio of minute ventilation (VE) and diaphragmatic EMG (VE/EMGdi%max), was calculated. Modified British Medical Research Council Dyspnea Scale (mMRC) was used for the evaluation of dyspnea before and after treatment. RESULTS: There was no significant difference in spirometry before and after treatment in both groups. Diaphragmatic EMG decreased significantly at rest (28.1 ± 10.9% vs. 22.6 ± 10.7%, P < 0.05) and mean efficiency of neural respiratory drive at the later stage of exercise increased (39.8 ± 2.9 vs. 45.2 ± 3.9, P < 0.01) after 1-month treatment with tiotropium. There were no remarkable changes in resting EMGdi and mean efficiency of neural respiratory drive post-treatment in control group. The score of mMRC decreased significantly (2.5 ± 0.5 vs. 1.9 ± 0.7, P < 0.05) after 1-month treatment with tiotropium, but without significantly difference in control group. CONCLUSION: Tiotropium significantly reduces neural respiratory drive at rest and improves the efficiency of neural respiratory drive during exercise, which might account for the improvement in exercise tolerance in COPD.
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Tolerancia al Ejercicio/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Derivados de Escopolamina/farmacología , Anciano , Disnea/tratamiento farmacológico , Disnea/etiología , Prueba de Esfuerzo , Volumen Espiratorio Forzado , Humanos , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Espirometría , Bromuro de TiotropioRESUMEN
Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid-ß (Aß) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aß fibril formation, and this inhibitory activity was localized to the N-terminal residues 1-64, a fragment designated MBP1. Here, we show that the modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aß accumulation in brain. The levels of insoluble Aß and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was because of a reduction in the size of fibrillar plaques rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aß fibril formation in vitro and demonstrate the ability of MBP1 to reduce Aß pathology and improve behavioral performance.
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Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteína Básica de Mielina/fisiología , Agregación Patológica de Proteínas/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Conducta , Encéfalo/patología , Modelos Animales de Enfermedad , Ratones Transgénicos , Proteína Básica de Mielina/químicaRESUMEN
The fibrillar assembly and deposition of amyloid ß (Aß) protein, a key pathology of Alzheimer disease, can occur in the form of parenchymal amyloid plaques and cerebral amyloid angiopathy (CAA). Familial forms of CAA exist in the absence of appreciable parenchymal amyloid pathology. The molecular interplay between parenchymal amyloid plaques and CAA is unclear. Here we investigated how early-onset parenchymal amyloid plaques impact the development of microvascular amyloid in transgenic mice. Tg-5xFAD mice, which produce non-mutated human Aß and develop early-onset parenchymal amyloid plaques, were bred to Tg-SwDI mice, which produce familial CAA mutant human Aß and develop cerebral microvascular amyloid. The bigenic mice presented with an elevated accumulation of Aß and fibrillar amyloid in the brain compared with either single transgenic line. Tg-SwDI/Tg-5xFAD mice were devoid of microvascular amyloid, the prominent pathology of Tg-SwDI mice, but exhibited larger parenchymal amyloid plaques compared with Tg-5xFAD mice. The larger parenchymal amyloid deposits were associated with a higher loss of cortical neurons and elevated activated microglia in the bigenic Tg-SwDI/Tg-5xFAD mice. The periphery of parenchymal amyloid plaques was largely composed of CAA mutant Aß. Non-mutated Aß fibril seeds promoted CAA mutant Aß fibril formation in vitro. Further, intrahippocampal administration of biotin-labeled CAA mutant Aß peptide accumulated on and adjacent to pre-existing parenchymal amyloid plaques in Tg-5xFAD mice. These findings indicate that early-onset parenchymal amyloid plaques can serve as a scaffold to capture CAA mutant Aß peptides and prevent their accumulation in cerebral microvessels.
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Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/fisiopatología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/metabolismo , Circulación Cerebrovascular , Placa Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Animales , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Corteza Cerebral/patología , Humanos , Ratones , Ratones Transgénicos , Mutación , Placa Amiloide/genética , Placa Amiloide/patologíaRESUMEN
OBJECTIVE: The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy. PATIENTS AND METHODS: One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy. RESULTS: The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001). CONCLUSIONS: Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.
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BACKGROUND: Abnormal accumulation of amyloid ß-protein (Aß) in the brain plays an important role in the pathogenesis \of Alzheimer's disease (AD). Aß monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the Aß chaperone proteins, which bind to Aß and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel Aß chaperone protein and a potent inhibitor for Aß fibril assembly in vitro. METHODS: In this study, we determined whether the absence of MBP would influence Aß pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal Aß pathology. RESULTS: Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble Aß and parenchymal plaque deposition at an early age. The expression of transgene encoded human AßPP, the levels of C-terminal fragments generated during Aß production and the intracellular Aß were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma Aß or cerebrospinal fluid Aß, suggesting these clearance routes were unaltered in bigenic Tg-5xFAD/MBP-/- mice. However, MBP-/- mice and bigenic Tg-5xFAD/MBP-/- mice exhibited elevated reactive astrocytes and activated microglia compared with Tg-5xFAD mice. The Aß degrading enzyme matrix metalloproteinase 9 (MMP-9), which is expressed by activated glial cells, was significantly increased in the Tg-5xFAD/MBP-/- mice. CONCLUSIONS: These findings indicate that the absence of MBP decreases Aß deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an Aß degrading enzyme.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Inflamación/metabolismo , Proteína Básica de Mielina/deficiencia , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Immunoblotting , Inmunohistoquímica , Ratones , Ratones Noqueados , Ratones TransgénicosRESUMEN
Three closely related proteins, ezrin, radixin, and moesin (ERM), which primarily act as a linker between the plasma membrane and the cytoskeleton, are involved in many cellular functions, including regulation of actin cytoskeleton, control of cell shape, adhesion and motility, and modulation of signaling pathways. Although, ezrin is now recognized as a key component in tumor metastasis, the functional role of the radixin and moesin in tumor metastasis has not been established. In the present study, we chose highly metastatic human gastric carcinoma SGC-7901 cells, which express all of the ERM proteins as a model to examine the functional roles of these proteins in tumor metastasis. Ezrin, radixin or moesin stable knockdown SGC-7901 cell lines were established using siRNA methodology. In vitro cell migration and invasion studies showed that either ezrin, radixin or moesin specific deficiency in the cells caused the substantial reduction of the cell migration and invasion. Western blotting and immunofluorescence analysis showed that the expression of E-cadherin was also significantly increased when any member of ERM proteins was downregulated. Our results indicated that these three ERM proteins play similar roles in the SGC-7901 cell metastatic potential and their roles of upregulating the expression of E-cadherin may be important in tumor progression.
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Proteínas del Citoesqueleto/genética , Proteínas de la Membrana/genética , Proteínas de Microfilamentos/genética , ARN Interferente Pequeño/biosíntesis , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular/genética , Proteínas del Citoesqueleto/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Invasividad Neoplásica/genética , Interferencia de ARNRESUMEN
The purpose of this study is mainly lies in using the RFID technology with function such identifying, tracking and the repetition read-write characteristic, applies in the newborn newborn's identity identification, from the delivery room birth until to discharged from hospital. Through this system to establish, Improve the accuracy of drug delivery, guarantees the newborn identity identification effectively the safety control.
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Sistemas de Identificación de Pacientes/normas , Ondas de Radio , Maternidades , Humanos , Recién Nacido , Medidas de Seguridad , TaiwánRESUMEN
PURPOSE: The purpose of the study was to evaluate the effects of anchorage by Twin-wires on canine retraction. METHODS: A sample of 15 patients with severe anterior crowding was selected (6 males, 9 females, age average: 13.7 years). All patients underwent removal of the four first premolars during orthodontic treatment. Retraction of canine was achieved by using 0.018 stainless steel wire and NiTi wire. Anchorage reinforcement as a result of this movement was evaluated. The length and width of the dental arch models were measured. Self-control t test was used for data analysis. RESULTS: The length and width of the dental arches, the canine and molar relationships remained unchanged after orthodontic treatment. CONCLUSION: Application of Twin-wires leads to canine retraction and sufficient anchorage consolidation.