Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 65
Filtrar
1.
Mol Neurobiol ; 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602656

RESUMEN

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Despite various treatment approaches, a significant number of patients continue to experience uncontrolled seizures, leading to refractory epilepsy. The emergence of novel anti-epileptic drugs, such as perampanel (PER), has provided promising options for effective epilepsy treatment. However, the specific mechanisms underlying the therapeutic effects of PER remain unclear. This study aimed to investigate the intrinsic molecular regulatory mechanisms involved in the downregulation of GluA2, a key subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, following epileptic seizures. Primary mouse hippocampal neurons were cultured and subjected to an epilepsy cell model. The expression levels of GluA2 and autophagy-related proteins were assessed using Western blotting and real-time fluorescent quantitative PCR. Immunofluorescence and immunohistochemistry techniques were employed to investigate the nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1). Additionally, status epilepticus animal models were established to further validate the findings. The epilepsy cell model exhibited a significant decrease in GluA2 expression, accompanied by elevated levels of autophagy-related proteins. Immunofluorescence analysis revealed the nuclear translocation of CRTC1, which correlated with the expression of autophagy-related genes. Treatment with an autophagy inhibitor reversed the decreased expression of GluA2 in the epilepsy cell model. Furthermore, the calcium/calmodulin-dependent protein phosphatase inhibitor FK506 and CaN overexpression affected the dephosphorylation and nuclear translocation of CRTC1, consequently influencing GluA2 expression. Animal model results further supported the involvement of these molecular mechanisms in epilepsy. Our findings suggest that the downregulation of GluA2 following epileptic seizures involves the activation of autophagy and the regulation of CRTC1 nuclear translocation. These intrinsic molecular regulatory mechanisms provide potential targets for developing novel therapeutic strategies to alleviate refractory epilepsy and preserve cognitive functions in patients.

2.
IEEE Trans Image Process ; 33: 2835-2850, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38598373

RESUMEN

Within the tensor singular value decomposition (T-SVD) framework, existing robust low-rank tensor completion approaches have made great achievements in various areas of science and engineering. Nevertheless, these methods involve the T-SVD based low-rank approximation, which suffers from high computational costs when dealing with large-scale tensor data. Moreover, most of them are only applicable to third-order tensors. Against these issues, in this article, two efficient low-rank tensor approximation approaches fusing random projection techniques are first devised under the order-d ( d ≥ 3 ) T-SVD framework. Theoretical results on error bounds for the proposed randomized algorithms are provided. On this basis, we then further investigate the robust high-order tensor completion problem, in which a double nonconvex model along with its corresponding fast optimization algorithms with convergence guarantees are developed. Experimental results on large-scale synthetic and real tensor data illustrate that the proposed method outperforms other state-of-the-art approaches in terms of both computational efficiency and estimated precision.

3.
J Appl Toxicol ; 44(2): 235-244, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37650462

RESUMEN

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM-induced ototoxicity in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC-1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM-mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM-induced ototoxicity with therapeutic implications for PQQ.


Asunto(s)
Gentamicinas , Ototoxicidad , Humanos , Gentamicinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cofactor PQQ/farmacología , Cofactor PQQ/uso terapéutico , Cofactor PQQ/metabolismo , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Ototoxicidad/metabolismo , Células Ciliadas Auditivas/metabolismo , Antibacterianos/metabolismo , Apoptosis
4.
Front Neurol ; 14: 1287032, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37885477

RESUMEN

[This corrects the article DOI: 10.3389/fneur.2022.1054704.].

5.
BMC Cancer ; 23(1): 328, 2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37038185

RESUMEN

BACKGROUND: DTL has been found to be related with multiple cancers. However, comprehensive analyses, which identify the prediction value of DTL in diagnosis, prognosis, immune infiltration and treatment, have rarely been reported so far. METHODS: Combined with the data online databases, the gene expression, gene mutation, function enrichment and the correlations with the immunity status and clinical indexes of DTL were analyzed. Expression of DTL and the degree of immune cell infiltration were examined by immunofluorescence (IF) and immunohistochemistry (IHC) and analyzed by statistical analysis. Furthermore, the influences of DTL on the cell cycle, cell proliferation and apoptosis were detected by live cell imaging, IF and flow cytometric (FC) analysis. Genomic stability assays were conducted by chromosome slide preparation. RESULTS: DTL was widely expressed in various cells and tissues, while it was overexpressed in tumor tissues except acute myeloid leukemia (LAML). Pan-cancer bioinformatics analysis showed that the expression of DTL was correlated with the prognosis, immunotherapy, and clinical indexes in various cancers. In addition, gene set enrichment analysis (GSEA) uncovered that DTL was enriched in oocyte meiosis, pyrimidine metabolism, the cell cycle, the G2M checkpoint, mTORC1 signaling and E2F targets. Furthermore, the overexpression of DTL, and its association with immune cell infiltration and clinical indexes in liver hepatocellular carcinoma (LIHC), bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) were verified in our study. It was also verified that overexpression of DTL could regulate the cell cycle, promote cell proliferation and cause genomic instability in cultured cells, which may be the reason why DTL plays a role in the occurrence, progression and treatment of cancer. CONCLUSIONS: Collectively, this study suggested that DTL is of clinical value in the diagnosis, prognosis and treatment of various cancers, and may be a potential biomarker in certain cancers.


Asunto(s)
Carcinoma Hepatocelular , Carcinoma de Células Transicionales , Neoplasias Hepáticas , Neoplasias de la Vejiga Urinaria , Humanos , Pronóstico , Biomarcadores , Inmunoterapia , Proteínas Nucleares
6.
Braz. j. otorhinolaryngol. (Impr.) ; 88(supl.3): 66-72, Nov.-Dec. 2022. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1420822

RESUMEN

Abstract Objectives: Although the cause of Meniere's disease (MD) is not fully understood, endolymphatic hydrops is widely believed to be responsible for MD. Previous studies have used Air-Conducted Sound (ACS)-induced Vestibular Evoked Myogenic Potentials (VEMPs) to evaluate otolithic function in patients with MD. However, the use of Galvanic Vestibular Stimulation-VEMPs (GVS-VEMPs) with other vestibular tests in MD has been rare. This study aimed to explore the application of galvanic VEMPs in assessing MD. Methods: Normal individuals and patients with unilateral definite MD were included in this retrospective study. All participants underwent pure tone audiometry. Ocular and cervical VEMPs induced by GVS, and ACS were recorded. The characteristic parameters of VEMPs (n1 latency, p1 latency, amplitude, and AR) were analyzed. Results: The provocation rates of GVS-VEMPs did not differ between MD patients and control individuals. Compared with ACS, GVS could evoke potentials with longer latencies. MD patients presented GVS-VEMPs with lower amplitudes and ACS-cVEMP with shorter latencies and had a higher response rate in GVS-oVEMP. However, no differences or correlations were found in the characteristic parameters of GVS-VEMPs among the different stages of MD. Conclusions: GVS is as effective as ACS for inducing VEMP, and GVS-VEMP recording can detect retrolabyrinthine degeneration in MD. Further research is needed to assess the utility of GVS-VEMP in the evaluation of MD severity. Level of evidence: Level 4.

7.
Braz. j. otorhinolaryngol. (Impr.) ; 88(supl.3): 139-146, Nov.-Dec. 2022. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1420845

RESUMEN

Abstract Objective: Subjective Visual Vertical (SVV) and Subjective Visual Horizontal (SVH) values may reflect bilateral utricle asymmetry. Bilateral utricle static tension balance can be used to evaluate bilateral otolith lesions and otolith-related central neuropathy. Few studies have examined Virtual Reality (VR)-assisted SVV and SVH values at various head-tilt angles across age groups. The present study aimed to determine the effects of age on VR-assisted SVV and SVH values at different head-tilt angles. Methods: We divided 180 healthy subjects into 6 age groups (n = 30 in each group). VR-assisted SVV and SVH measurements were performed at 9 head-tilt angles (head held vertically, 0°; head tilted 30°, 45°, 60°, and 90° to the left/right) in the roll plane. Results: SVV and SVH values significantly differed with head-tilt angle (p < 0.05). No significant difference was detected in the SVH and SVV values between different age groups (p = 0.632 and p = 0.810, respectively), and no interaction between the age group and the head-tilt angle was found for the SVH and SVV values (p = 0.670 and p = 0.084, respectively). Conclusion: These results suggest that age may have little effect on VR-assisted SVV and SVH at different head-tilt angles. Therefore, VR-assisted SVV and SVH can be evaluated as an effective, fast, and simple way to evaluate utricle function. Level of Evidence: Level 4.

8.
Braz J Otorhinolaryngol ; 88 Suppl 3: S139-S146, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36319565

RESUMEN

OBJECTIVE: Subjective Visual Vertical (SVV) and Subjective Visual Horizontal (SVH) values may reflect bilateral utricle asymmetry. Bilateral utricle static tension balance can be used to evaluate bilateral otolith lesions and otolith-related central neuropathy. Few studies have examined Virtual Reality (VR)-assisted SVV and SVH values at various head-tilt angles across age groups. The present study aimed to determine the effects of age on VR-assisted SVV and SVH values at different head-tilt angles. METHODS: We divided 180 healthy subjects into 6 age groups (n = 30 in each group). VR-assisted SVV and SVH measurements were performed at 9 head-tilt angles (head held vertically, 0°; head tilted 30°, 45°, 60°, and 90° to the left/right) in the roll plane. RESULTS: SVV and SVH values significantly differed with head-tilt angle (p < 0.05). No significant difference was detected in the SVH and SVV values between different age groups (p = 0.632 and p = 0.810, respectively), and no interaction between the age group and the head-tilt angle was found for the SVH and SVV values (p = 0.670 and p = 0.084, respectively). CONCLUSION: These results suggest that age may have little effect on VR-assisted SVV and SVH at different head-tilt angles. Therefore, VR-assisted SVV and SVH can be evaluated as an effective, fast, and simple way to evaluate utricle function. LEVEL OF EVIDENCE: Level 4.


Asunto(s)
Membrana Otolítica , Realidad Virtual , Humanos , Percepción Visual
9.
Front Pediatr ; 10: 1022836, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36340702

RESUMEN

Objective: The treatment timing of ureteropelvic junction obstruction (UPJO) in infants remains controversial. This study aimed to compare the recovery effect of renal morphology of immediate and delayed laparoscopic pyeloplasty in infants with severe UPJO. Methods: The infants with severe UPJO-induced hydronephrosis who underwent laparoscopic pyeloplasty according to their age at the time of surgery [the immediate treatment (IT) group: ≤1 month of birth, the delayed treatment (LT) group: 3-6 months of birth] in our center between 2010 and 2019 were enrolled in this study. Ultrasonography was used to assess renal morphology, including anteroposterior diameter (APD) of a pelvic, parenchymal thickness (PT), polar length (PL), and Society of Fetal Urology (SFU) grade. Preoperative and postoperative renal morphological outcomes at 6, 12, and 24 months were measured and compared. Results: During this period, a total of 135 patients were assigned to receive either IT (n = 73) or LT (n = 62) and were included for analysis. There were no significant differences in renal morphology indices at baseline between groups of IT and LT. The APD, PT, and PL in both groups all recovered to certain degrees compared with those at baseline, however, the IT group recovered more significantly than the LT group. Despite there being no significant difference in SFU grade between the two groups before and after surgery, the reduction of SFU grade in the IT group was more significant than that in the LT group during the 6-, 12- and 24-month follow-up periods. The PL, SFU, and APD were greater in the IT group than in the LT group at 6, 12, and 24 months of follow-up. At 6 months PL was not significantly higher between the two groups, while the outcome was significantly different at 12 months and 24 months. Conclusion: Immediate laparoscopic pyeloplasty for the infant with severe ureteropelvic junction obstruction is effective, and it can accelerate the recovery of renal morphological indices in infants with severe UPJO-induced hydronephrosis.

10.
Acta Otolaryngol ; 142(6): 499-504, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35732019

RESUMEN

BACKGROUND: At present, there is no consensus on the optimal methods for the diagnosis of vestibular dysfunction. OBJECTIVE: To explore the advantages of bone-conducted vibration (BCV) related vestibular-evoked myogenic potentials (VEMPs). MATERIAL AND METHODS: Fifty patients with otitis media volunteered for VEMP examination. They were randomly selected with air-conducted sound and BCV stimulation VEMPs assessed in both ears. RESULTS: The provocation rate of BCV-VEMPs was significantly higher than that of air-conducted sound VEMPs. Among 50 affected ears, there was no significant difference in the provocation rate of BCV-VEMPs between patients with air-bone conduction gaps lower or higher than 20 dB. There was no significant difference in the provocation rate of BCV-VEMPs between both ears in 30 patients with unilateral otitis media and the comparison of BCV-oVEMP parameters made no significant difference in amplitude, N1 latency, P1 latency, or N1-P1 duration, except for the threshold. A comparison of BCV-cVEMP parameters between affected and healthy ears revealed no significant difference between groups in terms of threshold, amplitude, N1 latency, P1 latency, or n1-p1 duration. CONCLUSIONS AND SIGNIFICANCE: BCV-VEMPs may be stably induced in patients with conductive hearing loss.


Asunto(s)
Otitis Media , Potenciales Vestibulares Miogénicos Evocados , Conducción Ósea/fisiología , Humanos , Otitis Media/diagnóstico , Sonido , Potenciales Vestibulares Miogénicos Evocados/fisiología , Vibración
11.
Braz J Otorhinolaryngol ; 88 Suppl 3: S66-S72, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35469706

RESUMEN

OBJECTIVES: Although the cause of Meniere's disease (MD) is not fully understood, endolymphatic hydrops is widely believed to be responsible for MD. Previous studies have used Air-Conducted Sound (ACS)-induced Vestibular Evoked Myogenic Potentials (VEMPs) to evaluate otolithic function in patients with MD. However, the use of Galvanic Vestibular Stimulation-VEMPs (GVS-VEMPs) with other vestibular tests in MD has been rare. This study aimed to explore the application of galvanic VEMPs in assessing MD. METHODS: Normal individuals and patients with unilateral definite MD were included in this retrospective study. All participants underwent pure tone audiometry. Ocular and cervical VEMPs induced by GVS, and ACS were recorded. The characteristic parameters of VEMPs (n1 latency, p1 latency, amplitude, and AR) were analyzed. RESULTS: The provocation rates of GVS-VEMPs did not differ between MD patients and control individuals. Compared with ACS, GVS could evoke potentials with longer latencies. MD patients presented GVS-VEMPs with lower amplitudes and ACS-cVEMP with shorter latencies and had a higher response rate in GVS-oVEMP. However, no differences or correlations were found in the characteristic parameters of GVS-VEMPs among the different stages of MD. CONCLUSIONS: GVS is as effective as ACS for inducing VEMP, and GVS-VEMP recording can detect retrolabyrinthine degeneration in MD. Further research is needed to assess the utility of GVS-VEMP in the evaluation of MD severity. LEVEL OF EVIDENCE: Level 4.


Asunto(s)
Hidropesía Endolinfática , Enfermedad de Meniere , Potenciales Vestibulares Miogénicos Evocados , Humanos , Potenciales Vestibulares Miogénicos Evocados/fisiología , Enfermedad de Meniere/diagnóstico , Estudios Retrospectivos , Membrana Otolítica
12.
Methods Mol Biol ; 2313: 143-150, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34478135

RESUMEN

Large-scale transient expression in Chinese Hamster Ovary (CHO) cells provides a rapid protein production method with a potential start-to-end alignment advantage for biotherapeutics drug discovery. In this chapter, experimental protocols are illustrated for transient expression of therapeutic glycoproteins with improved galactosylation and sialylation in ExpiCHO-S™ system. To reduce the production cost, we also describe a novel procedure for PEI-mediated transfection in ExpiCHO-S™ cells that supports therapeutic protein expression comparable to the level with ExpiFectamine™-based transfection.


Asunto(s)
Transfección , Animales , Células CHO , Cricetinae , Cricetulus , Procesamiento Proteico-Postraduccional , Proteínas Recombinantes
13.
Front Neurol ; 13: 1054704, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36874359

RESUMEN

Genetic susceptibility is one of the most important causes of otitis media (OM). Mutant Galnt2 homozygote (Galnt2 tm1Lat/tm1Lat) mimics human otitis media in comparable pathology and causes hearing loss. Otitis media is characterized by effusion and dysregulated mucosa proliferation and capillary expansion in the middle ear cavity, which is associated with hearing loss. The mucociliary dysfunction could be seen in the middle ear cavity (MEC) in a patient harboring the disease that develops in severity with age by a scanning electron microscope. Tumor necrosis factor alpha (TNF-α), transforming growth factor-beta 1 (TGF-ß1), Muc5ac, and Muc5b upregulate the expression in the middle ear, which correlates with inflammation, craniofacial development, and mucin secretion. The mouse model with a mutation in the Galnt2 (Galnt2 tm1Lat/tm1Lat) was explored in this study as a novel model of human otitis media.

14.
Pathol Oncol Res ; 27: 1609852, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34566519

RESUMEN

Introduction: Gastric cancer is one of the most common cancers. Although some progress has been made in the treatment of gastric cancer with the improvement of surgical methods and the application of immunotherapy, the prognosis of gastric cancer patients is still unsatisfactory. In recent years, there has been increasing evidence that tumor mutational load (TMB) is strongly associated with survival outcomes and response to immunotherapy. Given the variable response of patients to immunotherapy, it is important to investigate clinical significance of TMB and explore appropriate biomarkers of prognosis in patients with gastric cancer (GC). Material and Methods: All data of patients with gastric cancer were obtained from the database of The Cancer Genome Atlas (TCGA). Samples were divided into two groups based on median TMB. Differently expressed genes (DEGs) between the high- and low-TMB groups were identified and further analyzed. We identified TMB-related genes using Lasso, univariate and multivariate Cox regression analysis and validated the survival result of 11 hub genes using Kaplan-Meier Plotter. In addition, "CIBERSORT" package was utilized to estimate the immune infiltration. Results: Single nucleotide polymorphism (SNP), C > T transition were the most common variant type and single nucleotide variant (SNV), respectively. Patients in the high-TMB group had better survival outcomes than those in the low-TMB group. Besides, eleven TMB-related DEGs were utilized to construct a prognostic model that could be an independent risk factor to predict the prognosis of patients with GC. What's more, the infiltration levels of CD4+ memory-activated T cells, M0 and M1 macrophages were significantly increased in the high-TMB group compared with the low-TMB group. Conclusions: Herein, we found that patients with high TMB had better survival outcomes in GC. In addition, higher TMB might promote immune infiltration, which could provide new ideas for immunotherapy.


Asunto(s)
Mutación/genética , Neoplasias Gástricas/genética , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Macrófagos/metabolismo , Masculino , Células T de Memoria/metabolismo , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Neoplasias Gástricas/metabolismo , Microambiente Tumoral/genética
15.
Sci Rep ; 11(1): 8921, 2021 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-33903632

RESUMEN

GDF15 is a distant TGF-ß family member that induces anorexia and weight loss. Due to its function, GDF15 has attracted attention as a potential therapeutic for the treatment of obesity and its associated metabolic diseases. However, the pharmacokinetic and physicochemical properties of GDF15 present several challenges for its development as a therapeutic, including a short half-life, high aggregation propensity, and protease susceptibility in serum. Here, we report the design, characterization and optimization of GDF15 in an Fc-fusion protein format with improved therapeutic properties. Using a structure-based engineering approach, we combined knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, improved solubility and protease resistance. In addition, we identified a set of mutations at the receptor binding site of GDF15 that show increased GFRAL binding affinity and led to significant half-life extension. We also identified a single point mutation that increases p-ERK signaling activity and results in improved weight loss efficacy in vivo. Taken together, our findings allowed us to develop GDF15 in a new therapeutic format that demonstrates better efficacy and potential for improved manufacturability.


Asunto(s)
Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor 15 de Diferenciación de Crecimiento/farmacología , Fragmentos Fc de Inmunoglobulinas/farmacología , Proteínas Recombinantes de Fusión/farmacología , Pérdida de Peso/efectos de los fármacos , Animales , Células CHO , Cricetulus , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Glicosilación , Humanos , Ratones , Mutación Puntual , Ingeniería de Proteínas
16.
Sci Rep ; 11(1): 4644, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-33633296

RESUMEN

This study aimed to construct convention-radiomics CT nomogram containing conventional CT characteristics and radiomics signature for distinguishing fat-poor angiomyolipoma (fp-AML) from clear-cell renal cell carcinoma (ccRCC). 29 fp-AML and 110 ccRCC patients were enrolled and underwent CT examinations in this study. The radiomics-only logistic model was constructed with selected radiomics features by the analysis of variance (ANOVA)/Mann-Whitney (MW), correlation analysis, and Least Absolute Shrinkage and Selection Operator (LASSO), and the radiomics score (rad-score) was computed. The convention-radiomics logistic model based on independent conventional CT risk factors and rad-score was constructed for differentiating. Then the relevant nomogram was developed. Receiver operation characteristic (ROC) curves were calculated to quantify the accuracy for distinguishing. The rad-score of ccRCC was smaller than that of fp-AML. The convention-radioimics logistic model was constructed containing variables of enhancement pattern, VUP, and rad-score. To the entire cohort, the area under the curve (AUC) of convention-radiomics model (0.968 [95% CI 0.923-0.990]) was higher than that of radiomics-only model (0.958 [95% CI 0.910-0.985]). Our study indicated that convention-radiomics CT nomogram including conventional CT risk factors and radiomics signature exhibited better performance in distinguishing fp-AML from ccRCC.


Asunto(s)
Angiomiolipoma/diagnóstico , Carcinoma de Células Renales/diagnóstico , Neoplasias Renales/diagnóstico , Diagnóstico Diferencial , Humanos , Nomogramas
17.
MAbs ; 13(1): 1850395, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33459147

RESUMEN

We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.


Asunto(s)
Anticuerpos Biespecíficos/inmunología , Complejo CD3/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Receptores de Enterotoxina/inmunología , Animales , Anticuerpos Biespecíficos/farmacocinética , Anticuerpos Biespecíficos/uso terapéutico , Línea Celular Tumoral , Femenino , Humanos , Hibridomas , Macaca fascicularis/inmunología , Macaca fascicularis/metabolismo , Ratones Endogámicos BALB C , Neoplasias/inmunología , Neoplasias/metabolismo , Ingeniería de Proteínas/métodos , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/farmacocinética , Anticuerpos de Cadena Única/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismo
18.
J Health Psychol ; 26(13): 2552-2562, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-32383399

RESUMEN

This study examines the mediating role of negative automatic thoughts on the link between childhood maltreatment and young adult depression, and the moderating role of self-compassion in this indirect link. College students (N = 578) completed self-report questionnaires assessing the mentioned study variables. The results showed that childhood maltreatment was positively associated with young adult depression via negative automatic thoughts. Moreover, self-compassion moderated this indirect link such that participants with low self-compassion demonstrated a stronger indirect link than those with high self-compassion. These findings highlight the important role of self-compassion in countering the adverse outcomes of childhood maltreatment.


Asunto(s)
Maltrato a los Niños , Empatía , Niño , Depresión , Humanos , Estudiantes , Encuestas y Cuestionarios , Adulto Joven
19.
Front Oncol ; 10: 1017, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32766129

RESUMEN

Purpose: This study aimed to explore the role of delta-radiomics in differentiating pre-invasive ground-glass nodules (GGNs) from invasive GGNs, compared with radiomics signature. Materials and Methods: A total of 464 patients including 107 pre-invasive GGNs and 357 invasive GGNs were embraced in radiomics signature analysis. 3D regions of interest (ROIs) were contoured with ITK software. By means of ANOVA/MW, correlation analysis, and LASSO, the optimal radiomic features were selected. The logistic classifier of radiomics signature was constructed and radiomic scores (rad-scores) were calculated. A total of 379 patients including 48 pre-invasive GGNs and 331 invasive GGNs with baseline and follow-up CT examinations before surgeries were enrolled in delta-radiomics analysis. Finally, the logistic classifier of delta-radiomics was constructed. The receiver operating characteristic curves (ROCs) were built to evaluate the validity of classifiers. Results: For radiomics signature analysis, six features were selected from 396 radiomic features. The areas under curve (AUCs) of logistic classifiers were 0.865 (95% CI, 0.823-0.900) in the training set and 0.800 (95% CI, 0.724-0.863) in the testing set. The rad-scores of invasive GGNs were larger than those of pre-invasive GGNs. As the follow-up interval went on, more and more delta-radiomic features became statistically different. The AUC of the delta-radiomics logistic classifier was 0.901 (95% CI, 0.867-0.928), which was higher than that of the radiomics signature. Conclusion: The radiomics signature contributes to distinguish pre-invasive and invasive GGNs. The rad-scores of invasive GGNs were larger than those of pre-invasive GGNs. More and more delta-radiomic features appeared to be statistically different as follow-up interval prolonged. Delta-radiomics is superior to radiomics signature in differentiating pre-invasive and invasive GGNs.

20.
BMC Surg ; 20(1): 165, 2020 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-32703179

RESUMEN

BACKGROUND: Flexible fiberoptic bronchoscopy is a rapid, cost effective and safe procedure. AIM: To analyze demographic information and endoscopic findings in adult patients with airway foreign body aspiration and its removal. METHODS: Fifty-seven adults (40 males, 17 females; average age 40 years old) with airway foreign body aspiration were analyzed. Cough (37, 65%) was the most common clinical presentation. The most common foreign body was bone followed by dental prosthesis and food debris. RESULTS: In the current study, 42 out of the 57 (74%) airway foreign bodies were successfully removed under flexible fiberoptic bronchoscopy. However, it was failed in 15 patients and thus, rigid bronchoscopy was used to remove foreign bodies successfully in 13 of the 15 patients. Thoracotomy was performed for the 2 patients whose foreign body removal was unsuccessful even with rigid bronchoscopy. CONCLUSION: The findings of the current study revealed that flexible fiberoptic bronchoscopy is a safe and effective procedure for the removal of adult airway foreign bodies in the majority of cases. Rigid bronchoscopy can be a backup procedure in case flexible bronchoscopy is failed.


Asunto(s)
Broncoscopía , Cuerpos Extraños , Aspiración Respiratoria/cirugía , Adolescente , Adulto , Anciano , Bronquios/diagnóstico por imagen , Bronquios/cirugía , Broncoscopía/instrumentación , Broncoscopía/métodos , Femenino , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/cirugía , Humanos , Masculino , Persona de Mediana Edad , Aspiración Respiratoria/diagnóstico por imagen , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...