RESUMEN
Electrospun nanofibrous films containing different active agents were prepared and compared to improve the storage quality of blackberries. We added different essential oils, phenolic acids, microbial antagonists and plant growth regulators to poly(lactic acid)/polycaprolactone (PP) nanofilms and compared their antimicrobial properties against bacteria and fungi. Based on the results, oregano essential oil/PP (OPP), chlorogenic acid/PP (CPP), natamycin/PP (NPP) and methyl jasmonate/PP (MPP) were selected. The addition of active agents decreased the tensile strength and increased the elastic modulus and elongation at break. These active agents did not affect the thermal stability, water contact angle (except for NPP) or water permeability (except for NPP and MPP) of the nanofilms. Nanofilms also controlled the release of active agents and showed antioxidant activity and biosafety. Different nanofilms were applied to blackberry postharvest storage, and OPP contributed the lowest to deterioration in appearance, 'red small drupelets' phenomenon, decay rate, weight loss and softening. Among these nanofilms, the OPP nanofilm exhibited the best shelf-life extension of blackberry.
RESUMEN
Quinoa (Chenopodium quinoa Willd) is widely regarded as a versatile pseudo-cereal native to the Andes Mountains in South America. It has gained global recognition as a superfood due to its rich nutritional profile. While quinoa grains are well-known, there is an undiscovered potential in quinoa greens, such as sprouts, leaves, and microgreens. These verdant parts of quinoa are rich in a diverse array of essential nutrients and bioactive compounds, including proteins, amino acids, bioactive proteins, peptides, polyphenols, and flavonoids. They have powerful antioxidant properties, combat cancer, and help prevent diabetes. Quinoa greens offer comparable or even superior benefits when compared to other sprouts and leafy greens, yet they have not gained widespread recognition. Limited research exists on the nutritional composition and biological activities of quinoa greens, underscoring the necessity for thorough systematic reviews in this field. This review paper aims to highlight the nutritional value, bioactivity, and health potential of quinoa greens, as well as explore their possibilities within the food sector. The goal is to generate interest within the research community and promote further exploration and wider utilization of quinoa greens in diets. This focus may lead to new opportunities for enhancing health and well-being through innovative dietary approaches.
RESUMEN
Lost soil organic carbon (SOC) in degraded grasslands can be restored via the 'grazing exclusion' practice, but it was unknown how long (# of years) the restoration process can take. A synthesis of four decades of studies revealed that grazing exclusion increased SOC stocks in the topsoil (0-0.30 m) by 14.8 % (±0.8 Std Err), on average, compared to moderate-to-heavy grazing (MtH); During which SOC stock increased steadily, peaked in Year 18.5, and then declined. At peak, SOC stock was 42.5 % greater under grazing exclusion than under MtH due to 100.4 ± 4.2 % increase in aboveground biomass and 80.3 ± 33.5 % increase in root biomass. Grazing exclusion also increased soil C:N ratio by 7.6 % while decreasing bulk density by 9.4 %. Grazing exclusion could be ceased 18.5 years after initiation of grazing exclusion as plant biomass input balances carbon decomposition and SOC equilibrium occurs then additional benefits start diminishing.
RESUMEN
IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.
Asunto(s)
Glioblastoma , IMP Deshidrogenasa , Telomerasa , Humanos , Telomerasa/metabolismo , Telomerasa/antagonistas & inhibidores , Telomerasa/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Línea Celular Tumoral , IMP Deshidrogenasa/antagonistas & inhibidores , IMP Deshidrogenasa/metabolismo , IMP Deshidrogenasa/genética , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND: Early diagnosis of knee osteoarthritis is an important area of research in the field of clinical medicine. Due to the complexity in the MRI imaging sequences and the diverse structure of cartilage, there are many challenges in the segmentation of knee bone and cartilage. Relevant studies have conducted semantic fusion processing through splicing or summing forms, which results in reduced resolution and the accumulation of redundant information. OBJECTIVE: This study was envisaged to construct an MRI image segmentation model to improve the diagnostic efficiency and accuracy of different grade knee osteoarthritis by adopting the Dual Attention and Multi-scale Feature Fusion Segmentation network (DA-MFFSnet). METHODS: The feature information of different scales was fused through the Multi-scale Attention Downsample module to extract more accurate feature information, and the Global Attention Upsample module weighted lower-level feature information to reduce the loss of key information. RESULTS: The collected MRI knee images were screened and labeled, and the study results showed that the segmentation effect of DA-MFFSNet model was closer to that of the manually labeled images. The mean intersection over union, the dice similarity coefficient and the volumetric overlap error was 92.74%, 91.08% and 7.44%, respectively, and the accuracy of the differential diagnosis of knee osteoarthritis was 84.42%. CONCLUSIONS: The model exhibited better stability and classification effect. Our results indicated that the Dual Attention and Multi-scale Feature Fusion Segmentation model can improve the segmentation effect of MRI knee images in mild and medium knee osteoarthritis, thereby offering an important clinical value and improving the accuracy of the clinical diagnosis.
Asunto(s)
Imagen por Resonancia Magnética , Osteoartritis de la Rodilla , Humanos , Imagen por Resonancia Magnética/métodos , Osteoartritis de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Algoritmos , Interpretación de Imagen Asistida por Computador/métodosRESUMEN
Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.
Asunto(s)
Trastorno Depresivo Mayor , Hipocampo , Hipotálamo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/patología , Masculino , Femenino , Hipotálamo/metabolismo , Hipotálamo/diagnóstico por imagen , Adulto , Hipocampo/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Persona de Mediana Edad , Método Doble Ciego , Tomografía de Emisión de Positrones/métodos , Giro Dentado/metabolismo , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología , Citalopram/uso terapéutico , Sistema Hipotálamo-Hipofisario/metabolismo , Tamaño de los ÓrganosRESUMEN
Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.
Asunto(s)
Adenina , Estrés del Retículo Endoplásmico , Indoles , Miocarditis , Miocitos Cardíacos , eIF-2 Quinasa , Animales , Humanos , Masculino , Ratones , Adenina/análogos & derivados , Apoptosis , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Miocarditis/virología , Miocarditis/metabolismo , Miocarditis/patología , Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/virología , Miocitos Cardíacos/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Replicación ViralRESUMEN
PURPOSE: We evaluated the potential role of intravoxel incoherent motion (IVIM) in predicting the therapeutic response and peritumoral invasion in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). MATERIALS AND METHODS: We enrolled 47 patients previously treated with TACE between January 2018 and December 2021. We evaluated the IVIM-derived metrics [apparent diffusion coefficient (ADC), D, D*, f] in the TACE-treated, peritumoral, and parenchymal areas of the liver. RESULTS: The ADCtace and Dtace values (1.13 ± 0.22 × 10-3 m2/s vs 0.95 ± 0.13 × 10-3 mm2/s, 1.28 ± 0.27 × 10-3 mm2/s vs 1.07 ± 0.3 × 10-3 mm2/s, P < 0.05) were higher in the non-progressing groups than in the progressing groups in the TACE-treated areas. Dpt represented the D values in the peritumoral area, which can distinguish between the progressive and non-progressive groups with an AUC of 0.73. The Dstd values, which represent the D values in the peritumoral area normalized by the D values in the liver parenchyma in the non-progressing groups (1.10 ± 0.14 × 10-3 mm2/s), were higher than those of the progressing groups (0.93 ± 0.17 × 10-3 mm2/s). CONCLUSION: The ADCtace, Dtace, Dpt, and Dstd values reflect the changes in the microstructure of the progressive and non-progressive groups after TACE treatment, showing robust diagnostic performances in predicting the therapeutic response and peritumoral invasion.
Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/diagnóstico por imagen , Quimioembolización Terapéutica/métodos , Masculino , Femenino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Anciano , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Adulto , Hígado/patología , Hígado/diagnóstico por imagen , Curva ROCRESUMEN
Under the guidance of traditional Chinese medicine theory, the clinical research of auricular acupoint stimulation in the treatment of migraine has gained a lot, and the curative efficacy is definite, but its mechanism remains unclear. In the present paper, we discussed the efficacy of auricular acupoint stimulation including "transcutaneous auricular vagus nerve stimulation" (taVNS) in the treatment of migraine in recent years. Through bibliometric analysis, we screened out top 10 auricular acupoints (Shenmenï¼»TF4ï¼½, Pizhixiaï¼»AT4ï¼½, Jiaoganï¼»AH6aï¼½, Ganï¼»CO12ï¼½, Yidanï¼»CO11ï¼½, Neifenmiï¼»CO18ï¼½, Shenï¼»CO10ï¼½, Nieï¼»AT2ï¼½, Zhenï¼»AT3ï¼½ and Eï¼»AT1ï¼½) which were the most frequently used for migraine. Majority of these auricular acupoints just distributed in the region innervated by auricular vagus nerve. Thus, we thought that the analgesic effect of needling these auricular acupoints for migraine was produced by triggering the auricular vagus nerve, and concluded that the central mechanism underlying induction of analgesic effect by activating auricular vagus nerve may be achieved by activating the descending pain regulation pathway of the locus coeruleus nucleus and dorsal raphe nucleus. In addition, taVNS-induced 1) regulation of the activities of brain's default network and pain matrix, 2) activation of the cortical descending pain regulation pathway, and 3) inhibition of the neuroinflammatory response may also contribute to its ameliorating effect of migraine. This paper may provide ideas for the future research on the mechanism of auricular acupoint treatment of migraine.
Asunto(s)
Puntos de Acupuntura , Acupuntura Auricular , Trastornos Migrañosos , Estimulación del Nervio Vago , Nervio Vago , Humanos , Trastornos Migrañosos/terapia , Trastornos Migrañosos/fisiopatología , Nervio Vago/fisiología , AnimalesRESUMEN
Background and objectives: Growing studies show that gut microbiota is closely associated with depression. Acupuncture treatment could regulate the gut microbiota of many diseases. Here, we aim to observe the effect of electroacupuncture (EA) on gut microbiota in rats that showed depressive-like behavior. Materials and methods: The rats were randomly divided into normal group, chronic unpredictable mild stress model (CUMS) group, CUMS + electroacupuncture (EA) group, and CUMS + sham-electroacupuncture (Sham) group. The CUMS+EA rats were treated with EA stimulation at bilateral Zusanli (ST36) and Tianshu (ST25) acupoints for 2 weeks (0.7 mA, 2/100 Hz, 30 min/day). The rats in the sham EA group were treated with the same conditions without inserting needles and electrical stimulation. Behavioral tests were conducted by forced swimming test (FST), open field test (OFT), and sucrose preference test (SPT) to assess depression-like behavior in rats. The relative abundance of intestinal bacteria in rat feces was detected by 16S rRNA analysis. The expression of calcitonin-gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), somatostatin (SST), and adrenocorticotropic hormone (ACTH) in serum was detected by ELISA kit, and VIP, CGRP, and SST in the colon were detected by qRT-PCR and Western blot. Results: Chronic unpredictable mild stress model rats exhibited depressive-like behaviors and had differential abundance vs. control rats. CUMS significantly decreased the relative abundance of Bifidobacterium and Streptococcus at the genus level, CGRP in plasma (p < 0.05), and significantly increased the intestine propulsion rate, the mRNA and protein expression of VIP, SST, and mRNA in the colon, and ATCH in plasma (p < 0.05). EA rats with microbial profiles were distinct from CUMS rats. EA markedly reduced the depressive-like behaviors, significantly increased the intestine propulsion rate, the relative abundance of Bacteroidetes, Proteobacteria, and Actinobacteria at the phylum level, Bifidobacterium and Streptococcus at the genus level, and VIP and CGRP in plasma (p < 0.05), and significantly decreased Firmicutes, the ratio of Firmicutes to Bacteroidetes at the phylum level, ACTH and SST in plasma, and SST mRNA in the colon (p < 0.05). Conclusion: The antidepressant effect of EA at ST36 and ST25 is related to regulating intestinal flora and the neurotransmitter system. Our study suggests that EA contributes to the improvement of depression, and gut microbiota may be one of the mechanisms of EA effect.
RESUMEN
Major depressive disorder (MDD), a prevalent mental health issue, affects more than 8% of the US population, and almost 17% in the young group of 18-25 years old. Since Covid-19, its prevalence has become even more significant. However, the remission (being free of depression) rates of first-line antidepressant treatments on MDD are only about 30%. To improve treatment outcomes, researchers have built various predictive models for treatment responses and yet none of them have been adopted in clinical use. One reason is that most predictive models are based on data from subjective questionnaires, which are less reliable. Neuroimaging data are promising objective prognostic factors, but they are expensive to obtain and hence predictive models using neuroimaging data are limited and such studies were usually in small scale (N<100). In this paper, we proposed an advanced machine learning (ML) pipeline for small training dataset with large number of features. We implemented multiple imputation for missing data and repeated K-fold cross validation (CV) to robustly estimate predictive performances. Different feature selection methods and stacking methods using 6 general ML models including random forest, gradient boosting decision tree, XGBoost, penalized logistic regression, support vector machine (SVM), and neural network were examined to evaluate the model performances. All predictive models were compared using model performance metrics such as accuracy, balanced accuracy, area under ROC curve (AUC), sensitivity and specificity. Our proposed ML pipeline was applied to a training dataset and obtained an accuracy and AUC above 0.80. But such high performance failed while applying our ML pipeline using an external validation dataset from the EMBARC study which is a multi-center study. We further examined the possible reasons especially the site heterogeneity issue.
Asunto(s)
COVID-19 , Trastorno Depresivo Mayor , Humanos , Adolescente , Adulto Joven , Adulto , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Área Bajo la Curva , Benchmarking , COVID-19/diagnóstico por imagen , NeuroimagenRESUMEN
To cope with the yield loss caused by drought stress, new oat varieties with greater drought tolerance need to be selected. In this study, two oat varieties with different drought tolerances were selected for analysis of their phenotypes and physiological indices under moderate and severe soil drought stress. The results revealed significant differences in the degree of wilting, leaf relative water content (RWC), and SOD and CAT activity between the two oat genotypes under severe soil drought stress; moreover, the drought-tolerant variety exhibited a significant increase in the number of stomata and wax crystals on the surface of both the leaf and guard cells; additionally, the morphology of the guard cells was normal, and there was no significant disruption of the grana lamella membrane or the nuclear envelope. Furthermore, transcriptome analysis revealed that the expression of genes related to the biosynthesis of waxes and cell-wall components, as well as those of the WRKY family, significantly increased in the drought-tolerant variety. These findings suggest that several genes involved in the antioxidant pathway could improve drought tolerance in plants by regulating the increase/decrease in wax and cell-wall constituents and maintaining normal cellular water potential, as well as improving the ability of the antioxidant system to scavenge peroxides in oats.
RESUMEN
BACKGROUND: Social anhedonia is common within major depressive disorder (MDD) and associated with worse treatment outcomes. The orbitofrontal cortex (OFC) is implicated in both reward (medial OFC) and punishment (lateral OFC) in social decision making. Therefore, to understand the biology of social anhedonia in MDD, medial/lateral OFC metabolism, volume, and thickness, as well as structural connectivity to the striatum, amygdala, and ventral tegmental area/nucleus accumbens were examined. A positive relationship between social anhedonia and these neurobiological outcomes in the lateral OFC was hypothesized, whereas an inverse relationship was hypothesized for the medial OFC. The association between treatment-induced changes in OFC neurobiology and depression improvement were also examined. METHODS: 85 medication-free participants diagnosed with MDD were assessed with Wisconsin Schizotypy Scales to assess social anhedonia and received pretreatment simultaneous fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI), including structural and diffusion. Participants were then treated in an 8-week randomized placebo-controlled double-blind course of escitalopram. PET/MRI were repeated following treatment. Metabolic rate of glucose uptake was quantified from dynamic FDG-PET frames using Patlak graphical analysis. Structure (volume and cortical thickness) was quantified from structural MRI using Freesurfer. To assess structural connectivity, probabilistic tractography was performed on diffusion MRI and average FA was calculated within the derived tracts. Linear mixed models with Bonferroni correction were used to examine the relationships between variables. RESULTS: A significantly negative linear relationship between pretreatment social anhedonia score and structural connectivity between the medial OFC and the amygdala (estimated coefficient: -0.006, 95 % CI: -0.0108 - -0.0012, p-value = 0.0154) was observed. However, this finding would not survive multiple comparisons correction. No strong evidence existed to show a significant linear relationship between pretreatment social anhedonia score and metabolism, volume, thickness, or structural connectivity to any of the regions examined. There was also no strong evidence to suggest significant linear relationships between improvement in depression and percent change in these variables. CONCLUSIONS: Based on these multimodal findings, the OFC likely does not underlie social anhedonia in isolation and therefore should not be the sole target of treatment for social anhedonia. This is consistent with previous reports that other areas of the brain such as the amygdala and the striatum are highly involved in this behavior. Relatedly, amygdala-medial OFC structural connectivity could be a future target. The results of this study are crucial as, to our knowledge, they are the first to relate structure/function of the OFC with social anhedonia severity in MDD. Future work may need to involve a whole brain approach in order to develop therapeutics for social anhedonia.
Asunto(s)
Anhedonia , Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/patología , Depresión , Fluorodesoxiglucosa F18 , Encéfalo , Imagen por Resonancia Magnética/métodosRESUMEN
PURPOSE: Colorectal cancer (CRC) screening has been implemented in Tianjin, China since 2012. The objective was to estimate the neoplasia detection rate in a high-risk population by age and sex and to investigate the potential factors associated with colorectal neoplasia. PATIENTS AND METHODS: This study is based on data of the Tianjin CRC screening program from 2012 to 2020. Residents with a positive high-risk factors questionnaire (HRFQ) or a positive faecal immunochemical test (FIT) were identified as high-risk participants and were subsequently recommended for a free colonoscopy. RESULTS: A total of 4,117,897 eligible participants aged 40-74 years completed both a HRFQ and FIT, and 217,164 (5.3%) of them were identified as high-risk participants. Positive rates of preliminary screening increased with age and were higher in females than in males. For 57,971 participants undertaking colonoscopy, the detection rates of nonadvanced adenoma, advanced adenoma and CRC were 37.8%, 5.7% and 1.6%, respectively. Detection rates of advanced neoplasia increased from the age of 50 and were higher in males. For nonadvanced neoplasia, a strong increase was observed in males from the age of 40 and in females from the age of 50. Male sex had a greater impact on individuals aged 40-49 than on older individuals. Several factors including current smoking, drinking, and higher body mass index (BMI) were significantly associated with the presence of neoplasia, whereas, these associations were mainly restricted to individuals aged above 50 but not those aged 40-49 years. CONCLUSIONS: These findings support that age-specific risk stratification and sex-specific initiating ages for CRC screening should be recommended to improve the accuracy and effectiveness of current screening strategy.
Asunto(s)
Adenoma , Neoplasias Colorrectales , Femenino , Humanos , Masculino , Detección Precoz del Cáncer , Factores de Riesgo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Colonoscopía , Sangre Oculta , Adenoma/diagnóstico , Adenoma/epidemiología , Tamizaje MasivoRESUMEN
Background: CTNNB1 mutates in most hepatocellular carcinoma (HCC) which is the most familiar form of liver cancer with high heterogeneity. It is critical to create a specific prognostication methodology and to investigate additional treatment options for CTNNB1-mutant HCCs. Methods: A total of 926 samples in five independent cohorts were enrolled in this study, including 127 CTNNB1-mutant samples and 75 estimated CTNNB1-mutant samples. The prognostic signature was constructed by LASSO-Cox regression and evaluated by bioinformatics analyses. The selection of possible drug targets and agents was produced based on the expression profiles and drug sensitivity data of cancer cell lines in two databases. Results: A prognostic signature based on 15 genes categorized the CTNNB1-mutant HCCs into two groups with different risks. Compared to low-risk patients, high-risk patients had significantly inferior prognoses. ROC curve and multivariate analysis also indicated the superior performance of our signature on the prognosis estimation, particularly in CTNNB1-mutant HCCs. Besides, the nomogram was constructed according to the prognostic signature with excellent predictive performance confirmed by the calibration curve. Subsequently, we suggested that AT-7519 and PHA-793887 might be potential drug agents for high-risk patients. Conclusion: We established a 15-gene prognostic model, particularly in HCCs with CTNNB1 mutations with good predictive efficiency. Besides, we explored the potential drug targets and agents for patients with high risk. Our findings offered a fresh idea for personalized prognosis management in HCCs with CTNNB1 mutations and threw new insight for precise treatment in HCCs as well.
RESUMEN
Salmonella is an important foodborne pathogen, and recent epidemiological studies have shown high infection rates of Salmonella enterica subsp. enterica serotype Derby (S.Derby) in poultry in western China and other regions. S.Derby presents increasing concerns with the development of resistance to hypertonic environments; however, there are few reports investigating the mechanism of resistance. Therefore, in this study, we examined hypertonic adaptation in S.Derby at the physiological and molecular levels. The K-B paper method, wiping glass bead method, crystal violet staining, and RT-PCR combined with comparative genomics analysis were employed to characterize virulence, drug resistance, biofilm formation, and changes in gene expression of genes related to hypertonic adaptation in S.Derby. Hypertonic-adapted S.Derby exhibited resistance to OXA, AMP, PEN, and CEP antibiotics, and biofilm-forming ability was 1.25 times that of nonadapted S.Derby. RT-PCR results showed that compared with nonadapted S.Derby, the expression of virulence-related genes in hypertonic-adapted S.Derby increased by 2-3 times, that of biofilm-related genes increased by 2-4 times, and that of OXA, AMP, PEN, and CEP-related drug resistance genes was relatively high. Four hypertonic tolerance-related genes (otsA, proV, proW, omsV) were preliminarily identified in S.Derby. The expression of proW was always relatively high in hypertonic-adapted S.Derby, the expression of otsA gradually became higher than that of proW with increasing time of osmotic stress, and the expression of proV and omsV was only high in non-hypertonic-adapted S.Derby.
RESUMEN
IL-4 and IL-13 signaling via IL-4Rα plays key roles in the pathogenesis of atopic dermatitis (AD) and asthma. Rademikibart (formerly CBP-201), a next-generation human IgG4 kappa monoclonal antibody, blocks IL-4Rα-mediated signal transduction. We performed two phase I, randomized, double-blind, placebo-controlled trials. In a single-ascending dose trial, 40 healthy adults were randomized 3:1 to rademikibart (75-600 mg s.c., 300 mg i.v.) or placebo, with 12 weeks of follow-up. In the multiple-ascending dose trial, 31 adults with moderate-to-severe AD were randomized 4:1 to once weekly rademikibart (75-300 mg s.c.) or placebo for 4 weeks, plus 7 weeks of follow-up. Most treatment-emergent adverse events (TEAEs) were mild; none were serious. Two s.c. injection site reactions and one TEAE of conjunctivitis were reported, all were mild. Rapid and sustained improvements were observed in AD severity and in quality of life (QoL), without plateauing. At week 4, efficacy scores improved by a maximum of -74.4% (Eczema Area and Severity Index), -62.7% (body surface area), -52.8% (Pruritus Numerical Rating Scale [PNRS] severity), -54.4% (PNRS frequency), and - 69.9% (Dermatology Life Quality Index). Thymus activation regulated chemokine inflammatory biomarker concentrations decreased in both trials (-55.4% in the pooled rademikibart arms vs. +18.0% with placebo, at week 5, in patients with AD). Exposure to rademikibart increased in a greater than dose-proportional manner, suggesting nonlinear clearance. In summary, rademikibart was well-tolerated and associated with rapid and sustained improvements in eczematous lesions, pruritus, QoL, and inflammatory biomarker concentrations during 4 weeks of treatment. Efficacy responses did not plateau and were generally dose dependent. These promising findings support further development of rademikibart in patients with AD.
Asunto(s)
Anticuerpos Monoclonales , Dermatitis Atópica , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Biomarcadores , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Prurito/tratamiento farmacológico , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.
Asunto(s)
Antidepresivos , Depresión , Habénula , Ketamina , Receptores de N-Metil-D-Aspartato , Animales , Ratones , Antidepresivos/administración & dosificación , Antidepresivos/metabolismo , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Habénula/efectos de los fármacos , Habénula/metabolismo , Semivida , Ketamina/administración & dosificación , Ketamina/metabolismo , Ketamina/farmacocinética , Ketamina/farmacología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Tiempo , Unión ProteicaRESUMEN
BACKGROUND: C-reactive protein (CRP) is a prototypical acute phase protein in humans with the function of regulating immune cells. Serum CRP levels are elevated in multiple myeloma (MM), associated with MM cell proliferation and bone destruction. However, its direct effects on T lymphocytes in MM have not been elucidated. METHODS: Public data sets were used to explore the correlation of CRP levels with immune cell infiltration and cytotoxicity score of CD8+ T cells in MM. In vitro, repeated freeze-thaw myeloma cell lines were taken as tumor antigens to load dendritic cells (DCs) derived from HLA-A*0201-positive healthy donors. MM-specific cytotoxic T cells (MM-CTL) were obtained from T lymphocytes of the corresponding donors pulsed with these DCs. B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells were manipulated by transfecting with lentivirus encoding an anti-BCMA single-chain variable fragment. Then T cells from healthy controls, MM-CTLs and BCMA CAR-T cells were exposed to CRP and analyzed for cell proliferation, cytotoxicity, immunophenotypes. CRP binding capacity to T cells before and after Fc gamma receptors IIb (FcγRIIb) blockage, p38 mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were also detected. In vivo, both normal C57BL/6J mice and the Vk*MYC myeloma mouse models were applied to confirm the impact of CRP on T cells. RESULTS: CRP levels were negatively correlated with cell-infiltration and cytotoxicity score of CD8+ T cells in MM. In vitro experiments showed that CRP inhibited T-cell proliferation in a dose-dependent manner, impaired the cytotoxic activity and upregulated expression of senescent markers in CD8+ T cells. In vivo results validated the suppressive role of CRP in CD8+ T cells. CRP could bind to CD8+ T cells, mainly to the naïve T subset, while the binding was dramatically decreased by FcγRIIb blockage. Furthermore, CRP resulted in increased phosphorylation of p38 MAPK, elevated levels of reactive oxygen species and oxidized glutathione in CD8+ T cells. CONCLUSIONS: We found that CRP impaired immune response of CD8+ T cells via FcγRIIb-p38MAPK-ROS signaling pathway. The study casted new insights into the role of CRP in anti-myeloma immunity, providing implications for future immunotherapy in MM.