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1.
PLoS Pathog ; 20(6): e1012260, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38885242

RESUMEN

Adeno-associated virus (AAV) serotypes from primates are being developed and clinically used as vectors for human gene therapy. However, the evolutionary mechanism of AAV variants is far from being understood, except that genetic recombination plays an important role. Furthermore, little is known about the interaction between AAV and its natural hosts, human and nonhuman primates. In this study, natural AAV capsid genes were subjected to systemic evolutionary analysis with a focus on selection drives during the diversification of AAV lineages. A number of positively selected sites were identified from these AAV lineages with functional relevance implied by their localization on the AAV structures. The selection drives of the two AAV2 capsid sites were further investigated in a series of biological experiments. These observations did not support the evolution of the site 410 of the AAV2 capsid driven by selection pressure from the human CD4+ T-cell response. However, positive selection on site 548 of the AAV2 capsid was directly related to host humoral immunity because of the profound effects of mutations at this site on the immune evasion of AAV variants from human neutralizing antibodies at both the individual and population levels. Overall, this work provides a novel interpretation of the genetic diversity and evolution of AAV lineages in their natural hosts, which may contribute to their further engineering and application in human gene therapy.


Asunto(s)
Proteínas de la Cápside , Dependovirus , Evolución Molecular , Selección Genética , Dependovirus/genética , Dependovirus/inmunología , Humanos , Animales , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Variación Genética , Terapia Genética
2.
J Cell Mol Med ; 28(7): e18165, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38494845

RESUMEN

Clear cell renal cell carcinoma (ccRCC) is a commonly occurring and highly aggressive urological malignancy characterized by a significant mortality rate. Current therapeutic options for advanced ccRCC are limited, necessitating the discovery of novel biomarkers and therapeutic targets. Carboxypeptidase A4 (CPA4) is a zinc-containing metallocarboxypeptidase with implications in various cancer types, but its role in ccRCC remains unexplored. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized in order to investigate the differential expression patterns of CPA4. The expression of CPA4 in ccRCC patients was further verified using immunohistochemical (IHC) examination of 24 clinical specimens. A network of protein-protein interactions (PPI) was established, incorporating CPA4 and its genes that were expressed differentially. Functional enrichment analyses were conducted to anticipate the contribution of CPA4 in the development of ccRCC. To validate our earlier study, we conducted real-time PCR and cell functional tests on ccRCC cell lines. Our findings revealed that CPA4 is overexpressed in ccRCC, and the higher the expression of CPA4, the worse the clinical outcomes such as TNM stage, pathological stage, histological grade, etc. Moreover, patients with high CPA4 expression had worse overall survival, disease-specific survival and progress-free interval than patients with low expression. The PPI network analysis highlighted potential interactions contributing to ccRCC progression. Functional enrichment analysis indicated the involvement of CPA4 in the regulation of key pathways associated with ccRCC development. Additionally, immune infiltration analysis suggested a potential link between CPA4 expression and immune response in the tumour microenvironment. Finally, cell functional studies in ccRCC cell lines shed light on the molecular mechanisms underlying the role of CPA4 in promoting ccRCC formation. Overall, our study unveils CPA4 as a promising biomarker with prognostic potential in ccRCC. The identified interactions and pathways provide valuable insights into its implications in ccRCC development and offer a foundation for future research on targeted therapies. Further investigation of CPA4's involvement in immune responses may contribute to the development of immunotherapeutic strategies for ccRCC treatment.


Asunto(s)
Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Biomarcadores , Neoplasias Renales/genética , Proliferación Celular/genética , Microambiente Tumoral/genética
3.
Protein Expr Purif ; 215: 106410, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38040273

RESUMEN

Cytokeratin 19 fragment (CYFRA21-1) serves as a crucial tumor marker in the context of lung cancer patients, playing a pivotal role as a calibrator in the realm of in vitro diagnostics. Nevertheless, during practical application, it has come to light that the recombinantly synthesized full-length CYFRA21-1 antigen exhibits suboptimal stability at the requisite concentration, while the utilization of natural antigens incurs a substantial cost. To address this issue, our investigation harnessed a strategic approach whereby the soluble fragment of cytokeratin 19 (Aa244-400) was integrated into the pET32a vector, subsequently being expressed within E. coli through a fusion with the TrxA protein. This process involved induction of protein expression through 0.2 mM IPTG at 16 °C for a duration of 16 h. After induction, the target protein was purified through Ni affinity and ion exchange chromatography. Subsequent characterization of the targeted protein was executed through the SEC-HPLC technique. The attained CYFRA21-1 antigen, as generated within this study, was effectively incorporated into a chemiluminescence-based in vitro diagnostic detection kit. The results indicate that the fusion protein exhibited commendable reactivity and stability, manifesting a deviation of less than 10 % following incubation at 37 °C for 7 days. Importantly, the production yield achieved a notable magnitude of 300 mg/L, thus rendering it a cost-effective and scalable alternative to natural antigens for clinical diagnostic applications.


Asunto(s)
Queratina-19 , Neoplasias Pulmonares , Humanos , Queratina-19/genética , Queratina-19/análisis , Escherichia coli/genética , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/análisis , Proteínas
4.
BMC Nephrol ; 25(1): 174, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773467

RESUMEN

BACKGROUND: Chronic kidney disease (CKD) is a common postoperative complication in patients who undergo radical nephrectomy for renal tumours. However, the factors influencing long-term renal function require further investigation. OBJECTIVE: This study was designed to investigate the trends in renal function changes and risk factors for renal function deterioration in renal tumour patients after radical nephrectomy. METHODS: We monitored changes in renal function before and after surgery for 3 years. The progression of renal function was determined by the progression and degradation of CKD stages. Univariate and multivariate logistic regression analyses were used to analyse the causes of renal function progression. RESULTS: We analysed the data of 329 patients with renal tumours who underwent radical nephrectomies between January 2013 and December 2018. In this study, 43.7% of patients had postoperative acute kidney injury (AKI), and 48.3% had CKD at advanced stages. Further research revealed that patients' renal function stabilized 3 months after surgery. Additionally, renal function changes during these 3 months have a substantial impact on the progression of long-term renal function changes in patients. CONCLUSION: AKI may be an indicator of short-term postoperative changes in renal function. Renal function tests should be performed in patients with AKI after radical nephrectomy to monitor the progression of functional impairment, particularly within the first 3 months after radical nephrectomy.


Asunto(s)
Lesión Renal Aguda , Neoplasias Renales , Nefrectomía , Complicaciones Posoperatorias , Insuficiencia Renal Crónica , Humanos , Nefrectomía/efectos adversos , Masculino , Neoplasias Renales/cirugía , Femenino , Persona de Mediana Edad , Lesión Renal Aguda/etiología , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/fisiopatología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Anciano , Progresión de la Enfermedad , Factores de Riesgo , Tasa de Filtración Glomerular , Riñón/fisiopatología , Estudios Retrospectivos , Pruebas de Función Renal
5.
Sensors (Basel) ; 23(5)2023 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-36905027

RESUMEN

Precise nanostructure geometry that enables the optical biomolecular delivery of nanosensors to the living intracellular environment is highly desirable for precision biological and clinical therapies. However, the optical delivery through membrane barriers utilizing nanosensors remains difficult due to a lack of design guidelines to avoid inherent conflict between optical force and photothermal heat generation in metallic nanosensors during the process. Here, we present a numerical study reporting significantly enhanced optical penetration of nanosensors by engineering nanostructure geometry with minimized photothermal heating generation for penetrating across membrane barriers. We show that by varying the nanosensor geometry, penetration depths can be maximized while heat generated during the penetration process can be minimized. We demonstrate the effect of lateral stress induced by an angularly rotating nanosensor on a membrane barrier by theoretical analysis. Furthermore, we show that by varying the nanosensor geometry, maximized local stress fields at the nanoparticle-membrane interface enhanced the optical penetration process by four-fold. Owing to the high efficiency and stability, we anticipate that precise optical penetration of nanosensors to specific intracellular locations will be beneficial for biological and therapeutic applications.


Asunto(s)
Nanopartículas , Nanoestructuras , Nanotecnología
6.
Int Wound J ; 20(7): 2634-2639, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36880410

RESUMEN

A meta-analysis study to assess the outcome of enhanced recovery (ER) after radical cystectomy (RC) on wound dehiscence was performed. A comprehensive literature examination till January 2023 was implemented and 1457 linked studies were appraised. The picked studies contained 772 open RC subjects in the picked studies' baseline, 436 of them were enhanced recovery after RC, and 336 were open RC. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of enhanced recovery after RC on wound dehiscence after open RC by the dichotomous styles and a fixed or random model. The ER after RC caused significantly lower wound dehiscence (OR, 0.51; 95% CI, 0.30-0.89, P = .02) with low heterogeneity (I2  = 46%) compared with open RC. The ER after RC caused significantly lower wound dehiscence compared with open RC. Thorough precaution should be taken when commerce with the consequences because a limited number of studies were found and selected for this meta-analysis.


Asunto(s)
Cistectomía , Neoplasias de la Vejiga Urinaria , Humanos , Cistectomía/efectos adversos , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/cirugía , Complicaciones Posoperatorias/etiología , Tiempo de Internación
7.
Mov Disord ; 37(9): 1807-1816, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36054272

RESUMEN

BACKGROUND: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. OBJECTIVE: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. METHODS: A prospective, diagnostic case-control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug-naïve patients with PD, and 185 non-PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. RESULTS: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%-96%), 95% (95% CI: 93%-97%), and 19.16 (95% CI: 13.52-27.16) and 0.10 (95% CI: 0.05-0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug-naïve were 89% (95% CI: 75%-96%), 86% (95% CI: 81%-91%), and 6.6 (95% CI: 4.51-9.66) and 0.13 (95% CI: 0.05-0.32), respectively. CONCLUSIONS: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost-effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Animales , Estudios de Casos y Controles , Perros , Humanos , Enfermedad de Parkinson/diagnóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Perros de Trabajo
8.
Mol Biol Rep ; 49(1): 303-312, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34743272

RESUMEN

BACKGROUND: As an alpine plant, Rhododendron chrysanthum (R. chrysanthum) has evolved cold resistance mechanisms and become a valuable plant resource with the responsive mechanism of cold stress. METHODS AND RESULTS: We adopt the phosphoproteomic and proteomic analysis combining with physiological measurement to illustrate the responsive mechanism of R. chrysanthum seedling under cold (4 °C) stress. After chilling for 12 h, 350 significantly changed proteins and 274 significantly changed phosphoproteins were detected. Clusters of Orthologous Groups (COG) analysis showed that significantly changed phosphoproteins and proteins indicated cold changed energy production and conversion and signal transduction. CONCLUSIONS: The results indicated photosynthesis was inhibited under cold stress, but cold induced calcium-mediated signaling, reactive oxygen species (ROS) homeostasis and other transcription regulation factors could protect plants from the destruction caused by cold stress. These data provide the insight to the cold stress response and defense mechanisms of R. chrysanthum leaves at the phosphoproteome level.


Asunto(s)
Fosfoproteínas/química , Fosfoproteínas/metabolismo , Proteómica/métodos , Rhododendron/crecimiento & desarrollo , Señalización del Calcio , Respuesta al Choque por Frío , Regulación de la Expresión Génica , Modelos Moleculares , Fotosíntesis , Hojas de la Planta/crecimiento & desarrollo , Hojas de la Planta/metabolismo , Proteínas de Plantas/metabolismo , Conformación Proteica , Especies Reactivas de Oxígeno/metabolismo , Rhododendron/metabolismo
9.
J Acoust Soc Am ; 151(5): 3043, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35649924

RESUMEN

A polyurethane-based tissue mimicking material (TMM) and blood mimicking material (BMM) for the acoustic and thermal characterization of high intensity therapeutic ultrasound (HITU) devices has been developed. Urethane powder and other chemicals were dispersed into either a high temperature hydrogel matrix (gellan gum) or degassed water to form the TMM and BMM, respectively. The ultrasonic properties of both TMM and BMM, including attenuation coefficient, speed of sound, acoustical impedance, and backscatter coefficient, were characterized at room temperature. The thermal conductivity and diffusivity, BMM viscosity, and TMM Young's modulus were also measured. Importantly, the attenuation coefficient has a nearly linear frequency dependence, as is the case for most soft tissues and blood at 37 °C. Their mean values are 0.61f1.2 dB cm-1 (TMM) and 0.2f1.1 dB cm-1 (BMM) based on measurements from 1 to 8 MHz using a time delay spectrometry (TDS) system. Most of the other relevant physical parameters are also close to the reported values of soft tissues and blood. These polyurethane-based TMM and BMM are appropriate for developing standardized dosimetry techniques, validating numerical models, and determining the safety and efficacy of HITU devices.


Asunto(s)
Poliuretanos , Terapia por Ultrasonido , Acústica , Fantasmas de Imagen , Viscosidad
10.
Sensors (Basel) ; 23(1)2022 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-36616919

RESUMEN

Dynamic detection in challenging lighting environments is essential for advancing intelligent robots and autonomous vehicles. Traditional vision systems are prone to severe lighting conditions in which rapid increases or decreases in contrast or saturation obscures objects, resulting in a loss of visibility. By incorporating intelligent optimization of polarization into vision systems using the iNC (integrated nanoscopic correction), we introduce an intelligent real-time fusion algorithm to address challenging and changing lighting conditions. Through real-time iterative feedback, we rapidly select polarizations, which is difficult to achieve with traditional methods. Fusion images were also dynamically reconstructed using pixel-based weights calculated in the intelligent polarization selection process. We showed that fused images by intelligent polarization selection reduced the mean-square error by two orders of magnitude to uncover subtle features of occluded objects. Our intelligent real-time fusion algorithm also achieved two orders of magnitude increase in time performance without compromising image quality. We expect intelligent fusion imaging photonics to play increasingly vital roles in the fields of next generation intelligent robots and autonomous vehicles.


Asunto(s)
Iluminación , Óptica y Fotónica , Algoritmos , Diagnóstico por Imagen
11.
Int Wound J ; 19(8): 1990-1999, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35419950

RESUMEN

We performed a meta-analysis to evaluate the safety of benign prostatic hyperplasia wound after surgical removal in subjects on anticoagulant or antiplatelet therapy. A systematic literature search up to December 2021 was done and 19 studies included 5715 benign prostatic hyperplasia subjects at the start of the study; 1501 of them were on anticoagulant/antiplatelet therapy, and 4214 were control. We calculated the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) to evaluate the safety of benign prostatic hyperplasia wound after surgical removal in subjects on anticoagulant or antiplatelet therapy by the dichotomous or continuous methods with a random or fixed-influence model. Anticoagulant/antiplatelet therapy had significantly higher bleeding complication (OR, 1.88; 95% CI, 1.36-2.60, P < .001), higher blood transfusion (OR, 2.15; 95% CI, 1.63-2.83, P < .001), lower operation time (MD, -3.53; 95% CI, -6.80-0.27, P = .03), higher catheterization time (MD, 0.30 95% CI, 0.06-0.53, P = .01), longer length of hospital stay (MD, 0.82; 95% CI, 0.37-1.26, P < .001) and higher thromboembolic events (OR, 2.88; 95% CI, 1.26-6.62, P = .01) compared to control in benign prostatic hyperplasia subjects. Anticoagulant/antiplatelet therapy had a significantly higher bleeding complication, higher blood transfusion, lower operation time, higher catheterization time, longer length of hospital stay and higher thromboembolic events compared to control in benign prostatic hyperplasia subjects. Further studies are required.


Asunto(s)
Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/cirugía , Hiperplasia Prostática/complicaciones , Anticoagulantes/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tempo Operativo
12.
Small ; 17(21): e2007610, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33856109

RESUMEN

Optical manipulation and imaging of nano-objects with nanometer precision is highly desirable for nanomaterial and biological studies due to inherent noninvasiveness. However, time constraints and current segregated experimental systems for nanoimaging and nanomanipulation limits real-time super-resolution imaging with spatially enhanced manipulation. Here, an integrated nanoscopic correction (iNC) method to enable multimodal nanomanipulation-nanoimaging is reported. The iNC consists of a multimodal voltage-tunable power modulator, polarization rotator, and polarizer. Using the iNC, plasmonic nano-objects which are below the diffraction limit and which can be distinguished by direct observation without post processing are demonstrated. Furthermore, such direct observations with enhanced nanometer spatial stability and millisecond high speed are shown. Precise trapping and rapid rotation of gold nanorods with the iNC are demonstrated successfully. With non-invasive post-processing free nanoimaging and nanomanipulation, it is anticipated that the iNC will make contributions in the nanomaterial and biological sciences requiring precision optics.


Asunto(s)
Nanoestructuras , Nanotubos , Diagnóstico por Imagen , Oro , Óptica y Fotónica
13.
Small ; 17(5): e2006044, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33448125

RESUMEN

The development of sustainable methods for energy-intensive water treatment processes continues to be a challenging issue. Plasmonic-semiconductor nanoparticles, which absorb large amounts of sunlight in the visible range for conversion into chemical energy efficiently, can form the basis of a sustainable water treatment method. However, the potential uses of plasmonic semiconductor particles for water treatment have not been fully explored yet because of the limitations associated with the imbalance between light capture, charge transfer, and the required recycling steps for the particles themselves. Herein, a significantly improved visible-light-induced water treatment method that uses a plasmo-semiconductor nanogap bridge array (PNA) is reported. As an arrangement of antenna-reactors, the PNA enables the balancing of the largely enhanced electromagnetic field in the plasmonic nanogap coupling region and optimal separation of charge carriers in the semiconductor. The simultaneous effects of visible-light absorption and charge transfer lead to the generation of a highly enhanced visible-light-induced OH radical (•OH). Consequently, visible-light-induced 5-log N/N0 water disinfection and 100% chemical decomposition for sustainable water treatment were demonstrated. Owing to the large light absorption, charge carrier utilization, and array-oriented scalability, the PNA will be valuable in various sustainable energy and environmental applications.


Asunto(s)
Puntos Cuánticos , Purificación del Agua , Luz , Semiconductores , Luz Solar
14.
Med Sci Monit ; 27: e933220, 2021 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-34667142

RESUMEN

BACKGROUND In this study, cardiac magnetic resonance imaging was used to investigate the characteristics of patients who have total coronary occlusion but manifest with non-ST-segment elevation myocardial infarction (NSTEMI), and we assessed the extent of infarct transmurality and myocardial necrosis size in NSTEMI patients. MATERIAL AND METHODS We enrolled all patients diagnosed at our hospital with subtotal or total occlusion of the culprit artery (TOCA), based on the coronary angiography, who successfully underwent PCI within 12 h of admission, and who had CMR imaging performed within 2 days after the PCI. RESULTS Based on 12-lead ECG findings, 48% of patients were categorized as having STEMI and 52% as having NSTEMI. TOCA was detected by coronary angiography in 43% of NSTEMI patients, and in 60% and 33% of normal ST segment and ST-segment depression MI patients, respectively. The transmural segments were found in 78% of STEMI patients and 31% of NSTEMI patients (P<0.05). Transmural infarction segments were found in 64% of NSTEMI patients with TOCA and in 8% of NTOCA patients (P<0.05). Moreover, the number of transmural segments in ST-segment depression MI patients was the lowest (P<0.05). Infarct size in STEMI patients was significantly larger than in patients with NSTEMI (P<0.05), whereas there was no statistically significant difference in patients with normal ST segment and ST-segment depression MI patients (P>0.05). CONCLUSIONS Identification TOCA by coronary angiography and transmural infarction by DE-MRI can be challenging in AMI patients with non-ST-segment elevation. In approximately 30% of non-ST-segment elevation MI patients, transmural infarction was detected by DE-MRI. Therefore, TOCA accompanied by transmural infarction in non-ST-segment-elevation MI patients is not uncommon.


Asunto(s)
Angiografía por Resonancia Magnética/métodos , Infarto del Miocardio sin Elevación del ST/diagnóstico por imagen , Oclusión Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad
15.
Gene Ther ; 26(6): 264-276, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31110296

RESUMEN

The prevalence of adeno-associated virus (AAV) has been investigated in bat populations, but little is known about the biological properties of this virus. In this study, four full-length bat AAV capsid genes were isolated in China, with their amino acid sequences sharing 61% identity with those of AAV2 on average. These capsid genes could package AAV particles in combination with AAV2 rep and ITRs, albeit at a lower efficiency. Bat AAVs could only slightly infect mouse liver but could transduce mouse muscle to some extent after systemic administration with a higher muscle/liver ratio than that of primate AAVs. Bat AAV 10HB showed moderate muscle transduction, similar to that of AAV2, during direct intramuscular injection and, compared with other AAV serotypes, was also relatively efficient in resisting human antibody neutralization after intramuscular injection. Evolutionary analysis revealed a number of codons in bat AAV capsid genes subject to positive selection, with sites corresponding to V259 and N691 in 10HB capsids being localized on the surface of the AAV2 capsid. Mutagenesis studies indicated that the positive selection in bat AAV capsids is driven by their tropism evolution in host species. Taken together, the results of this study indicate that bat AAV 10HB vector has the possible applications for muscular gene therapy, especially in the presence of human AAV neutralizing antibodies.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Dependovirus/inmunología , Terapia Genética/métodos , Vectores Genéticos/inmunología , Evasión Inmune , Animales , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Quirópteros , Dependovirus/genética , Técnicas de Transferencia de Gen/efectos adversos , Terapia Genética/efectos adversos , Vectores Genéticos/genética , Células HEK293 , Células HT29 , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Músculo Esquelético/metabolismo
16.
Acta Neuropathol ; 137(6): 919-937, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30810811

RESUMEN

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Mutación Missense , Proteínas del Tejido Nervioso/metabolismo , Procesamiento Proteico-Postraduccional , Proteinopatías TDP-43/metabolismo , Animales , Caspasas Iniciadoras , Células Cultivadas , Cuerpo Estriado/metabolismo , Citoplasma/metabolismo , Proteínas de Unión al ADN/genética , Dependovirus/genética , Femenino , Vectores Genéticos/administración & dosificación , Vectores Genéticos/metabolismo , Fuerza de la Mano , Humanos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Dominios Proteicos , Transporte de Proteínas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Especificidad de la Especie , Organismos Libres de Patógenos Específicos , Fracciones Subcelulares/metabolismo , Sustancia Negra/metabolismo , Proteinopatías TDP-43/genética , Proteinopatías TDP-43/patología
17.
J Acoust Soc Am ; 143(6): 3365, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29960483

RESUMEN

Time delay spectrometry (TDS) is extended for broadband characterization of plastics (low-density polyethylene, LDPE) and tissue-mimicking material (TMM). The results suggest that TDS and the conventional broadband pulse method give comparable measurements for frequency-dependent attenuation coefficient and phase velocity near the center frequency, where signal-to-noise ratio is high. However, TDS measurements show enhanced bandwidth for attenuation coefficient of 30%-40% (LDPE) and 89%-100% (TMM) and for phase velocity of 43% (LDPE) and 36% (TMM) for a single transmitter/receiver pair. In addition, TDS provides measurements of dispersion that are consistent with predictions based on the Kramers-Kronig relations to within 5 m/s over the band from 2 to 12 MHz in LDPE and to within 1 m/s in TMM over the band from 0.5 to 29 MHz.


Asunto(s)
Fantasmas de Imagen , Polietileno/química , Ondas Ultrasónicas , Ultrasonografía/instrumentación , Simulación por Computador , Diseño de Equipo , Modelos Teóricos , Movimiento (Física) , Análisis Numérico Asistido por Computador , Reproducibilidad de los Resultados , Análisis Espectral/métodos , Factores de Tiempo
18.
J Acoust Soc Am ; 139(5): 2624, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27250156

RESUMEN

A technique useful for performing derating at acoustic powers where significant harmonic generation occurs is illustrated and validated with experimental measurements. The technique was previously presented using data from simulations. The method is based upon a Gaussian representation of the propagation modes, resulting in simple expressions for the modal quantities, but a Gaussian source is not required. The nonlinear interaction of modes within tissue is estimated from the nonlinear interaction in water, using appropriate amounts of source reduction and focal-point reduction derived from numerical simulations. An important feature of this nonlinear derating method is that focal temperatures can be estimated with little additional effort beyond that required to determine the focal pressure waveforms. Hydrophone measurements made in water were used to inform the derating algorithm, and the resulting pressure waveforms and increases in temperature were compared with values directly measured in tissue phantoms. For a 1.05 MHz focused transducer operated at 80 W and 128 W, the derated pressures (peak positive, peak negative) agreed with the directly measured values to within 11%. Focal temperature rises determined by the derating method agreed with values measured using a remote thermocouple technique with a difference of 17%.


Asunto(s)
Tratamiento con Ondas de Choque Extracorpóreas/métodos , Dinámicas no Lineales , Procesamiento de Señales Asistido por Computador , Ondas Ultrasónicas , Ultrasonido/métodos , Tratamiento con Ondas de Choque Extracorpóreas/instrumentación , Movimiento (Física) , Distribución Normal , Fantasmas de Imagen , Presión , Reproducibilidad de los Resultados , Temperatura , Factores de Tiempo , Transductores , Ultrasonido/instrumentación , Agua
19.
J Acoust Soc Am ; 137(4): 1704-13, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25920823

RESUMEN

For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively).

20.
Zhongguo Fei Ai Za Zhi ; 27(6): 431-440, 2024 Jun 20.
Artículo en Zh | MEDLINE | ID: mdl-39026494

RESUMEN

Lung cancer is the most common malignant tumor and the second most common malignant tumor in terms of mortality in the world. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Currently, the first-line standard treatment for advanced NSCLC is immunotherapy and targeted therapy. Although these treatments prolong the survival of patients, acquired drug resistance is still inevitable. Antibody-drug conjugates (ADCs) are a new type of anti-tumor drug made by coupling cytotoxic payloads to specific monoclonal antibodies via linkers. Compared with chemotherapy drugs, ADCs have the advantages of accurate recognition, local release, and high patient tolerance. In recent years, they have shown good clinical benefits in the treatment of NSCLC. This article provides an overview of the mechanism of action of ADCs, clinical studies progress in advanced NSCLC, and existing problems and challenges.
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Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunoconjugados , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Inmunoconjugados/uso terapéutico , Antineoplásicos/uso terapéutico , Animales , Anticuerpos Monoclonales/uso terapéutico
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