RESUMEN
Prostate cancer (PCa) patients with mismatch repair (MMR) genes mutations are potentially responsive to immune checkpoint blockade (ICB). However, aberrations in MMR genes were rare in PCa and there is evidence that MMR genes mutations are highly ethnic specific. Thus, the prevalence and clinical characteristics of this subgroup in Chinese PCa patients are largely unknown. Furthermore, why some of these patients do not respond to ICB also remains unclear. Here, we analyzed the sequencing data from 3338 Chinese PCa patients to profile the mutation spectrum of the MMR genes. We found that in metastatic disease, the pathogenic mutation frequency of MMR genes in Chinese PCa patients was higher than that in the Caucasus population (4.8 vs 2.2%, P = 0.006) and the mutation carriers responded poorer to androgen deprive therapy (ADT) and abiraterone than non-carriers. Besides, we reported a multi-institutional cases series of 11 PCa patients with mismatch repair deficiency (dMMR) or microsatellite instability high (MSI-H) who received programmed cell death receptor-1 (PD-1) inhibitors, and performed multiplex immunohistochemistry (mIF) to explore the relationship between tumor immune microenvironment (TIME) and response to ICB. The results showed that the responders had higher density of intratumoral CD8+ T cells than non-responders. Our data suggested MMR genes mutations may be more common in Chinese PCa patients, and it is associated with poorer response to hormonal therapies. We propose that the density of intratumoral CD8+ T cells could be a promising predictor to help further subdivide the population of PCa patients who can benefit from immunotherapy.
Asunto(s)
Neoplasias Colorrectales , Neoplasias de la Próstata , Humanos , Masculino , Linfocitos T CD8-positivos/patología , Reparación de la Incompatibilidad de ADN/genética , Pueblos del Este de Asia , Inestabilidad de Microsatélites , Mutación , Prevalencia , Receptor de Muerte Celular Programada 1 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Microambiente TumoralRESUMEN
Dental caries is a chronic and destructive disease and matrix metalloproteinase-2 (MMP-2) plays a major role in caries. The inhibitory mechanisms of theaflavins [theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B), and theaflavin-3,3'-digallate (TF3)] on MMP-2 were investigated using techniques such as enzyme inhibition kinetics, multi-spectral methods, molecular docking, and molecular dynamics simulations. The results showed that TF1, TF2A, TF2B, and TF3 all competitively and reversibly inhibited MMP-2 activity. Fluorescence spectra and molecular docking indicated that four theaflavins spontaneously bind to MMP-2 through noncovalent interactions, driven by hydrogen bonds and hydrophobic interactions, constituting a static quenching mechanism and resulting in an altered tryptophan residue environment around MMP-2. Molecular dynamic simulations demonstrated that four theaflavins can form stable, compact complexes with MMP-2. In addition, the order of theaflavins' ability to inhibit MMP-2 was found to be TF1 > TF2B > TF2A > TF3. Interestingly, the order of binding capacity between MMP-2 and TF1, TF2A, TF2B, and TF3 was consistent with the order of inhibitory capacity, and was opposite to the order of steric hindrance of theaflavins. This may be due to the narrow space of the active pocket of MMP-2, and the smaller the steric hindrance of theaflavins, the easier it is to enter the active pocket and bind to MMP-2. This study provided novel insights into theaflavins as functional components in the exploration of natural MMP-2 inhibitors.
Asunto(s)
Biflavonoides , Catequina , Metaloproteinasa 2 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Biflavonoides/química , Biflavonoides/farmacología , Catequina/química , Catequina/farmacología , Catequina/análogos & derivados , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Cinética , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/química , Humanos , Enlace de Hidrógeno , Espectrometría de Fluorescencia , Ácido Gálico/análogos & derivadosRESUMEN
Electrochemical sensors show distinct advantages over other types of sensors in the rapid detection of microorganisms. Here, we attempted to construct a label-free electrochemical immunosensor based on an Fe3O4-ionic liquid (IL)-modified electrode to rapidly detect Salmonella in milk. The excellent ionic conductivity of the IL facilitated sensor construction, and the large surface area of nano-Fe3O4 provided numerous sites for subsequent experiments. An antibody was fixed on the Fe3O4-IL complex with polyglutamic acid modification by a simple infusion method. The microstructure of the Fe3O4-IL composites was investigated by scanning electron microscopy, and the elements and structures of the composites were analyzed by energy dispersive X-ray and Fourier transform infrared spectroscopy. Under optimized experimental conditions, the detection range of the constructed sensor was 3.65 × 102-3.65 × 108 CFU mL-1, and the LOD was 1.12 × 102 CFU mL-1 (S/N = 3). In addition, the prepared electrochemical immunosensor is convenient for detecting foodborne pathogens because of its outstanding stability, good selectivity, and repeatability.
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Técnicas Biosensibles , Líquidos Iónicos , Animales , Líquidos Iónicos/química , Límite de Detección , Leche/química , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Inmunoensayo , Salmonella , ElectrodosRESUMEN
This study aimed to evaluate the effect of theaflavins [TFs] on the process of dentin erosion and investigation the potential mechanism. For erosion kinetics of the dentin, 7 experimental groups (n = 5) treated with 10% ethanol [EtOH] (negative control) are erosion for 1, 2, 3, 4, 5, 6, and 7 d erosion cycles (4 cycles/d). For the effect of TFs on dentin erosion, 6 experimental groups (n = 5) were treated with 1% epigallocatechin gallate [EGCG], 1% chlorhexidine [CHX], 1%, 2%, 4%, and 8% TFs for the 30 s and then subjected to erosion cycles (4 cycles/d for 7 d). The erosive dentin wear (µm) and surface morphology were evaluated and compared by laser scanning confocal microscope and scanning electron microscopy. The matrix metalloproteinase inhibition effects of TFs were investigated using in situ zymography and molecular docking. TFs-treated collagen was investigated by ultimate microtensile strength, Fourier-transform infrared spectroscopy, and molecular docking. Data were analyzed by ANOVA, Tukey's test (P < 0.05). The TFs-treated groups (7.56 ± 0.39, 5.29 ± 0.61, 3.28 ± 0.33, and 2.62 ± 0.99 µm for 1%, 2%, 4%, and 8% TFs) had significantly lower erosive dentin wear than the negative control group (11.23 ± 0.82 µm), and the effect was concentration-dependent at low concentrations (P < 0.05). TFs inhibit matrix metalloproteinase [MMP]. Moreover, TFs crosslink dentin collagen and cause hydrophilic changes in dentin collagen. TFs preserve organic matrix within the demineralized dentin by inhibiting MMP activity and simultaneously improving collagen's resistance to enzymes, both of which contribute to preventing or slowing down the progression of dentin erosion.
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Antioxidantes , Erosión de los Dientes , Humanos , Simulación del Acoplamiento Molecular , Antioxidantes/farmacología , Colágeno/farmacología , Metaloproteinasas de la Matriz/farmacología , Dentina , Erosión de los Dientes/prevención & controlRESUMEN
Objective: This study aimed to identify ROS1 fusion partners in Chinese patients with solid tumors. Methods: Next-generation sequencing (NGS) analysis was used to detect ROS1 rearrangement in 45,438 Chinese patients with solid tumors between 2015 and 2020, and the clinical characteristics and genetic features of gene fusion were evaluated. H&E staining of the excised tumor tissues was conducted. Samples with a tumor cell content ≥ 20% were included for subsequent DNA extraction and sequencing analysis. Results: A total of 92 patients with ROS1 rearrangements were identified using next-generation sequencing, and the most common histological type lung cancer. From the 92 ROS1 fusion cases, 24 ROS1 fusion partners had been identified, including 14 novel partners and 10 reported partners. Of these, CD74, EZR, SDC4, and TPM3 were the four most frequently occurring partners. Fourteen novel ROS1 fusion partners were detected in 16 patients, including DCBLD1-ROS1, FRK-ROS1, and VGLL2-ROS1. In many patients, the ROS1 breakpoint was located between exons 32 and 34. Conclusion: This study describes 14 novel ROS1 fusion partners based on the largest ROS1 fusion cohort, and the ROS1 breakpoint was mostly located between exons 32 and 34. Additionally, next-generation sequencing is an optional method for identifying novel ROS1 fusions.
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The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive.
Asunto(s)
Neuronas GABAérgicas/fisiología , Conducta Predatoria/fisiología , Zona Incerta/fisiología , Animales , RatonesRESUMEN
OBJECTIVES: To examine the psychometric properties of the Chinese version of the C-Compassion Fatigue (CF)-Short Scale among 4 independent samples of Chinese emergency workers (medical workers and firefighters). DESIGN: Cross-sectional. SETTING: 6 hospitals in Zhejiang Province and 12 fire stations in Shanghai. PARTICIPANTS: Emergency workers (medical and firefighters) were consecutively recruited and divided into 4 groups: the MW1 group (medical workers, n=167), the FF1 group (firefighters, n=157), the MW2 group (medical workers, n=265) and the FF2 group (firefighters, n=231). INTERVENTIONS: All patients completed the C-CF-Short Scale to identify factors associated with compassion fatigue. The MW1 and FF1 groups were used for the exploratory analyses. The MW2 and FF2 groups were used for the confirmatory factor analyses. PRIMARY AND SECONDARY OUTCOME MEASURES: Factor loading, correlations with previously validated questionnaires (the Ego-Resiliency Scale, the Social Support Questionnaire and the Job Pressure Scale) and Cronbach's α coefficient were tested for each factor. RESULTS: The C-CF-Short Scale demonstrated excellent construct validity and good internal consistency. Specifically, the results of exploratory factor analyses in the MW1 and FF1 groups showed that secondary trauma and job burnout were associated with compassion fatigue in these emergency workers. The confirmatory factor analyses in the MW2 and FF2 groups indicated that all the fit indices of the 2-factor model were satisfactory. Finally, the Cronbach's α coefficient of each factor was excellent. CONCLUSIONS: The findings suggest that the C-CF-Short Scale has good psychometric properties and can be applied to study Chinese emergency workers.