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1.
Cell ; 177(5): 1232-1242.e11, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-31080064

RESUMEN

The activation of G proteins by G protein-coupled receptors (GPCRs) underlies the majority of transmembrane signaling by hormones and neurotransmitters. Recent structures of GPCR-G protein complexes obtained by crystallography and cryoelectron microscopy (cryo-EM) reveal similar interactions between GPCRs and the alpha subunit of different G protein isoforms. While some G protein subtype-specific differences are observed, there is no clear structural explanation for G protein subtype-selectivity. All of these complexes are stabilized in the nucleotide-free state, a condition that does not exist in living cells. In an effort to better understand the structural basis of coupling specificity, we used time-resolved structural mass spectrometry techniques to investigate GPCR-G protein complex formation and G-protein activation. Our results suggest that coupling specificity is determined by one or more transient intermediate states that serve as selectivity filters and precede the formation of the stable nucleotide-free GPCR-G protein complexes observed in crystal and cryo-EM structures.


Asunto(s)
Proteínas de Unión al GTP/química , Complejos Multienzimáticos/química , Receptores Acoplados a Proteínas G/química , Animales , Bovinos , Microscopía por Crioelectrón , Cristalografía por Rayos X , Humanos , Complejos Multienzimáticos/ultraestructura , Estructura Cuaternaria de Proteína , Ratas
2.
Cell ; 169(3): 407-421.e16, 2017 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-28431242

RESUMEN

The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the ß2-adrenergic receptor (ß2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the ß2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP.


Asunto(s)
Quinasa 5 del Receptor Acoplado a Proteína-G/química , Mamíferos/metabolismo , Receptores Adrenérgicos beta 2/química , Animales , Camélidos del Nuevo Mundo , Bovinos , Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Humanos , Espectrometría de Masas , Microscopía Electrónica , Modelos Moleculares , Simulación de Dinámica Molecular , Unión Proteica , Ratas , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo
3.
Mol Cell ; 81(2): 323-339.e11, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33321095

RESUMEN

The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca2+-binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic αN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.


Asunto(s)
Calcio/metabolismo , Calmodulina/química , Quinasa 5 del Receptor Acoplado a Proteína-G/química , Secuencia de Aminoácidos , Animales , Baculoviridae/genética , Baculoviridae/metabolismo , Sitios de Unión , Calmodulina/genética , Calmodulina/metabolismo , Clonación Molecular , Cristalografía por Rayos X , Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Células HEK293 , Humanos , Cinética , Simulación de Dinámica Molecular , Fosforilación , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Células Sf9 , Spodoptera , Especificidad por Sustrato , Termodinámica
4.
Int J Med Sci ; 21(2): 200-206, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38169660

RESUMEN

Purpose: This retrospective study assessed the value of histogram parameters of the apparent diffusion coefficient (ADC) map (HA) in differentiating between benign and malignant testicular tumors. We compared the diagnostic performance of two different volume-of-interest (VOI) placement methods: VOI 1, the entire tumor; VOI 2, the tumor excluding its cystic, calcified, hemorrhagic, and necrotic portions. Materials and methods: We retrospectively evaluated 45 patients with testicular tumors examined with scrotal contrast-enhanced magnetic resonance imaging. These patients underwent surgery with the pathological result of seven benign and 39 malignant tumors. We calculated the HA parameters, including mean, median, maximum, minimum, kurtosis, skewness, entropy, standard deviation (SD), mean of positive pixels, and uniformity of positive pixels by the two different VOI segmentation methods. We compared these parameters using the chi-square test, Mann-Whitney U test, and area under the receiver operating characteristic curve (AUC) to determine their optimal cut-off, sensitivity (Se), and specificity (Sp). Result: This study included 45 patients with 46 testicular lesions (seven benign and 39 malignant tumors), one of which had bilateral testicular seminoma. With the VOI 1 method, benign lesions had significantly lower maximum ADC (p = 0.002), ADC skewness (p = 0.017), and ADC variance (p = 0.000) than malignant lesions. In contrast, their minimum ADC was significantly higher ADC (p = 0.000). With the VOI 2 method, the benign lesions had significantly higher ADC SD (p = 0.048) and maximum ADC (p = 0.015) than malignant lesions. In contrast, their minimum ADC was significantly lower (p = 0.000). With the VOI 1 method, maximum ADC, ADC variance, and ADC skewness performed well in differentiating benign and malignant testicular lesions with cut-offs (Se, Sp, AUC) of 1846.000 (74.4%, 100%, 0.883), 39198.387 (79.5%, 85.7%, 0.868), and 0.893 (48.7%, 100%, 0.758). Conclusion: The HA parameters showed value in differentiating benign and malignant testicular neoplasms. The entire tumor VOI placement method was preferable to the VOI placement method excluding cystic, calcified, hemorrhagic, and necrotic portions in measuring HA parameters. Using this VOI segmentation, maximum ADC performed best in discriminating benign and malignant testicular lesions, followed by ADC variance and skewness.


Asunto(s)
Interpretación de Imagen Asistida por Computador , Neoplasias Testiculares , Masculino , Humanos , Estudios Retrospectivos , Interpretación de Imagen Asistida por Computador/métodos , Reproducibilidad de los Resultados , Imagen de Difusión por Resonancia Magnética/métodos , Curva ROC , Neoplasias Testiculares/diagnóstico por imagen , Neoplasias Testiculares/cirugía , Sensibilidad y Especificidad
5.
Int J Med Sci ; 21(9): 1640-1648, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39006836

RESUMEN

Objective: Our study aims to evaluate the value of 256-slice dual-energy computed tomography (DECT) in supporting prostatic artery embolization (PAE) under digital subtraction angiography (DSA) for benign prostatic hyperplasia (BPH). Methods: The study was conducted on 88 patients who underwent PAE to treat BPH from January 2022 to November 2023. Of these, 38 patients who had PAE without DECT were placed in group 1, while the other 50 patients with pre-interventional DECT were assigned to group 2. The results of DECT imaging of the prostate artery (PA) were compared with the results of DSA imaging. Test for statistically significant differences between the variables of the two research groups using the T - student test and Mann-Whitney test algorithms with p < 0.05 corresponding to a 95% confidence interval. The data were analyzed according to medical statistical methods using SPSS 20.0 software. Results: DECT can detect the PA origin in 96.1% of cases, identify atherosclerosis at the root of the artery with a sensitivity of 66.7% and a specificity of 89.5%, and present anastomosis with a sensitivity of 72.7% and a specificity of 72.2%. There is no statistically significant difference in PA diameter on DECT compared to DSA with 95% confidence. Group 2 used DECT for 3D rendering of the PA before PAE had procedure time reduced by 25.8%, fluoroscopy time reduced by 23.2%, dose-area product (DAP) reduced by 25.6%, contrast medium volume reduced by 33.1% compared to group 1 not using DECT, statistically significant with 95% confidence. Conclusion: DECT is a valuable method for planning before PAE to treat BPH. 3D rendering DECT of PA provides anatomical information that minimizes procedure time, fluoroscopy time, dose-area product, and contrast medium volume.


Asunto(s)
Angiografía de Substracción Digital , Embolización Terapéutica , Próstata , Hiperplasia Prostática , Humanos , Hiperplasia Prostática/diagnóstico por imagen , Hiperplasia Prostática/terapia , Masculino , Embolización Terapéutica/métodos , Anciano , Próstata/diagnóstico por imagen , Próstata/irrigación sanguínea , Próstata/patología , Angiografía de Substracción Digital/métodos , Persona de Mediana Edad , Arterias/diagnóstico por imagen , Resultado del Tratamiento , Tomografía Computarizada por Rayos X/métodos
6.
Am J Orthod Dentofacial Orthop ; 165(3): 294-302, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37906244

RESUMEN

INTRODUCTION: This study aimed to assess the transfer accuracy of a digital indirect bonding method for lingual brackets using double vacuum-formed trays in vivo. METHODS: Twenty-five patients in need of lingual orthodontic treatment were consecutively recruited. Bracket placement was performed on ideal setups, followed by fabricating indirect bonding trays through vacuum-forming on 3-dimensional printed models. Transfer accuracy was measured at each bracket after superimpositions of postbonding scans and reference data. One-tailed t tests were used to determine whether bracket deviations were within the limit of 0.5 mm and 2° for linear and angular dimensions, respectively. RESULTS: A total of 611 lingual brackets were evaluated. Mean linear transfer errors were 0.06 mm, 0.09 mm, and 0.12 mm, with frequencies of deviations within the 0.5 mm limit of 99.7%, 99.8%, and 98.0% for mesiodistal, buccolingual, and occlusogingival dimensions, respectively. Regarding angular measurements, mean transfer errors were 1.28°, 1.73°, and 2.96°, with frequencies of deviations within the 2° limit of 81.0%, 68.9%, and 51.1% for rotation, tip, and torque, respectively. Mean errors fell within the clinically accepted limits for all linear dimensions and rotation but exceeded the limit for tip and torque. CONCLUSIONS: Lingual bracket indirect bonding using double vacuum-formed trays fabricated on 3-dimensional printed models has high transfer accuracy in the mesiodistal, buccolingual, and occlusogingival dimensions and rotation. However, the transfer of tip and torque is less accurate.


Asunto(s)
Recubrimiento Dental Adhesivo , Soportes Ortodóncicos , Humanos , Vacio , Recubrimiento Dental Adhesivo/métodos , Modelos Dentales , Impresión Tridimensional
7.
Int J Med Sci ; 20(7): 985-992, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37324187

RESUMEN

Objective: Vietnam is endemic with tuberculosis (TB), which is highly prevalent in the community. TB tenosynovitis of the wrist and hand is uncommon. Because of its insidious progression and atypical presentations, it is often difficult to diagnose, leading to treatment delays. This study investigates the characteristics of clinical and subclinical signs and treatment outcomes of patients with TB tenosynovitis in Vietnam. Patients and Methods: This prospective longitudinal cross-sectional study included 25 TB tenosynovitis patients in the Rheumatology Clinic at University Medical Center Ho Chi Minh City. The diagnosis was made based on a tuberculous cyst in histopathological specimens. The data were collected through medical history, physical examination, and medical records, including demographics, signs, symptoms, condition duration, and related laboratory tests and imaging. The outcomes of all participants were assessed after 12 months of treatment. Results: The most common symptom of TB tenosynovitis was swelling of the hand and wrist, which was present in all patients. Its other symptoms included mild pain and numbness of the hand in 72% and 24% of patients, respectively. It can affect any site on the hand. Hand ultrasound findings included thickening of the synovial membrane (80%), peritendinous effusion (64%), and soft tissue swelling (88%). Most patients (18/22) had a good outcome after the treatment with anti-tubercular drugs. Conclusions: TB tenosynovitis progression is often insidious. Its most common symptoms are swelling of the hand and mild pain. Ultrasound is a useful tool to support the diagnosis. A histological examination confirms the diagnosis. Most cases respond and have a good outcome after 9-12 months of anti-tuberculosis treatment.


Asunto(s)
Tenosinovitis , Tuberculosis Osteoarticular , Humanos , Muñeca/diagnóstico por imagen , Muñeca/patología , Tenosinovitis/diagnóstico por imagen , Tenosinovitis/terapia , Estudios Transversales , Estudios Prospectivos , Tuberculosis Osteoarticular/diagnóstico por imagen , Tuberculosis Osteoarticular/tratamiento farmacológico , Resultado del Tratamiento
8.
Int J Med Sci ; 20(10): 1293-1299, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37786440

RESUMEN

OBJECTIVE: Radiofrequency catheter ablation (RFCA) is a safe and effective treatment for paroxysmal supraventricular tachycardia in adults. However, data on its use in children, particularly from low- and middle-income countries, are limited. This study aimed to evaluate the safety and efficacy of RFCA in children with paroxysmal supraventricular tachycardia from Vietnam. METHODS: A prospective study was conducted from January 2009 to July 2016 at the University Medical Center, Ho Chi Minh City, Vietnam. Ninety-five children diagnosed with paroxysmal supraventricular tachycardia were enrolled; 90 patients underwent cardiac electrophysiology and RFCA. The patients were followed up for 3-12 months, with a mean follow-up period of 7.5 ± 2.3 months. RESULTS: The average age of the patients was 10.5 ± 3 years, with the youngest patient being 4 years old; 46.3% of the patients were female and 53.7% were male. The patients' average weight was 35.2 ± 9.6 kg. Atrioventricular reentrant tachycardia accounted for 72.6% of the cases and atrioventricular nodal reentrant tachycardia for 27.4% of the cases; no patients had atrial tachycardia. The success rate of RFCA was 98.9% (89/90 patients). During the 12-month follow-up, 5.6% of the patients experienced recurrence but were successfully treated with a second ablation. No severe complications were reported during the procedure and follow-up. CONCLUSIONS: This study found RFCA to be a safe and effective treatment for paroxysmal supraventricular tachycardia in children. It demonstrated a high success rate and low recurrence and complication rates for RFCA in children, thereby highlighting the potential advantages of the procedure as a treatment option.


Asunto(s)
Ablación por Catéter , Taquicardia por Reentrada en el Nodo Atrioventricular , Taquicardia Supraventricular , Taquicardia Ventricular , Adulto , Humanos , Masculino , Niño , Femenino , Adolescente , Preescolar , Estudios Prospectivos , Taquicardia Supraventricular/epidemiología , Taquicardia Supraventricular/cirugía , Resultado del Tratamiento , Taquicardia Ventricular/cirugía , Taquicardia por Reentrada en el Nodo Atrioventricular/cirugía , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos
9.
Contemp Oncol (Pozn) ; 27(2): 71-79, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37794989

RESUMEN

Introduction: This study aimed to evaluate the treatment outcomes of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy alone or in combination with locoregional brain therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with brain metastases. Material and methods: A retrospective study involving 72 advanced EGFR-mutant NSCLC patients with brain metastases at the Vietnam National Cancer Hospital were conducted. Patients were divided into 2 groups: EGFR-TKI (erlotinib) monotherapy and EGFR-TKI combined with locoregional therapy (γ knife surgery - GKS or whole-brain radiation therapy). Evaluation criteria included clinical and laboratory characteristics, central nervous system (CNS) progression time, progression-free survival (PFS), overall survival (OS), T790M mutation rate, and adverse events. Results: Epidermal growth factor receptor tyrosine kinase inhibitor monotherapy patients had better performance status (PS), fewer CNS symptoms, and significantly fewer brain metastases (p < 0.05). Median PFS and OS were 11 and 25 months, respectively, in both groups. Patients with PS 0-1 had longer median PFS (15 months) than those with PS 2 (7 months) (p = 0.039). Exon 19 deletion patients in both groups had longer median OS (26 months) than those with L858R exon 21 (15 months) (p = 0.023). Patients with T790M mutation who received osimertinib after progression had longer median OS (41 months vs. 23 months, p = 0.0001). Median time to CNS progression was 13.9 months (48 patients). Longer time to CNS progression correlated with longer OS (R2 = 0.89). Conclusions: Epidermal growth factor receptor tyrosine kinase inhibitor therapy, with or without locoregional therapy, is effective for advanced EGFR-mutant NSCLC patients with brain metastases. Exon 19 deletion patients had better prognosis.

10.
Int J Med Sci ; 19(11): 1638-1647, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36237993

RESUMEN

Background: Thymic epithelial tumors (TETs) are clinically the most frequently encountered neoplasm of the prevascular mediastinum in adults. The role of chest magnetic resonance (MR) imaging has been increasingly stressed thanks to its excellent contrast resolution, freedom from ionizing radiation, and capability to provide additional information regarding tumors' cellular structure and vascularity. Methods: This study aimed to establish the relationship between the MR findings and pathological classification of TETs, focusing on diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) imaging. This retrospective cross-sectional study included 44 TET patients who underwent chest MR scanning. The tumors were classified into three groups according to the WHO classification: low-risk thymoma (LRT), high-risk thymoma (HRT), and non-thymoma (NT). Along with morphological characteristics, the apparent diffusion coefficient (ADC) value, time-intensity curve (TIC) pattern, and time to peak enhancement (TTP) of the tumors were recorded and compared between the three groups. Results: A smooth contour and complete or almost complete capsule were suggestive of LRTs. The median ADC value of the 44 tumors was 0.95 × 10-3 mm2/sec. Among the three groups, LRTs had the highest ADC values, while NTs had the lowest. The differences between the ADC values of the three groups were statistically significant (p = 0.006). Using an ADC cutoff of 0.82 × 10-3 mm2/sec to differentiate between LRTs and tumors of the two remaining groups, the area under the curve was 0.775, sensitivity was 100%, specificity was 50%, and accuracy was 65.91%. The washout (type 3) TIC pattern was the most prevalent, accounting for 45.45% of the population; this pattern was also predominantly observed in LRTs (71.43%). Although the median TTP of LRTs was lower than that of HRTs or NTs, no statistically significant differences were found between the TTPs of the three groups (p = 0.170). Conclusions: MR is a good imaging modality to preoperatively assess TETs. Morphological features, ADC value, TIC pattern, and TTP are helpful in preoperatively predicting TET pathology.


Asunto(s)
Neoplasias Glandulares y Epiteliales , Adulto , Medios de Contraste , Estudios Transversales , Humanos , Imagen por Resonancia Magnética/métodos , Neoplasias Glandulares y Epiteliales/diagnóstico por imagen , Estudios Retrospectivos , Neoplasias del Timo
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