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1.
Foods ; 13(7)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38611331

RESUMEN

In this study, the effect of different heating temperatures (80, 90, 100, and 121 °C) on the physicochemical and volatile flavor properties of fried mantles (Argentinian shortfin) was investigated. The squid mantles were soaked in a maltose syrup solution (20% w/v) for 10 s and fried in soybean oil for 10 s (160 °C), vacuum-packed, and processed at different temperatures for 10 min. Then, the squid mantles were subjected to colorimetric analysis, sensory evaluation, free amino acid analysis, and texture profile analysis. In addition, the volatile organic compounds (VOCs) in the squid mantles were analyzed. The results revealed that lower treating temperatures (80 and 90 °C) improved the chromatic and textural properties, along with organoleptic perception. Additionally, the content of amino acid in the squid mantles treated at 121 °C was significantly lower than that of the samples treated at other temperatures (p < 0.05). Headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) was used to detect 41 VOCs, including their monomers and dimers. Among these detected VOCs, the contents of alcohols, ketones, and pyrazines were positively correlated with temperature. However, the content of aldehydes in the squid mantles gradually decreased as the heating temperature increased (p < 0.05). The combined HS-GC-IMS and E-nose results revealed that the lower temperatures (80 and 90 °C) were more suitable for flavor development and practical processing. This study provides valuable information for properly controlling the heating process of squid products, as well as flavor and practical applications for the aquatic industry.

3.
Artículo en Inglés | MEDLINE | ID: mdl-38018274

RESUMEN

OBJECTIVE: HELLP syndrome is a severe complication of hypertensive disorders of pregnancy that can cause multiple organ dysfunction and maternal death in a short period of time. Although HELLP syndrome is more common in patients with pre-eclampsia (PE), there is currently no effective way to identify high-risk individuals who may progress from gestational hypertension (GH) to PE complicated with HELLP syndrome. This study aimed to establish and validate a prediction model for PE complicated with HELLP syndrome, providing a basis for early detection and identification of high-risk individuals in clinical practice. METHODS: This retrospective case-control study collected data on 326 patients with GH and 139 patients with PE complicated with HELLP syndrome from January 2015 to December 2019. An additional 206 patients with GH and 70 patients with PE complicated with HELLP syndrome who were treated from January 2020 to December 2022 were collected for external validation. General and clinical data were collected, and single-and multiple-factor logistic regression analyses were used to screen for independent factors affecting PE complicated with HELLP syndrome. The diagnostic performance of different indicators was evaluated using ROC curves. A prediction model for PE complicated with HELLP syndrome was constructed, and its efficacy was verified using ROC curves. RESULTS: The results of single-factor analysis showed that age, SBP, DBP, MAP, hemoglobin, AST, ALT, cholinesterase, alkaline phosphatase, gamma-glutamyl transferase, total protein, total bilirubin, direct bilirubin, indirect bilirubin, BUN, UA, creatinine, APTT, international normalized ratio of prothrombin, D-dimer, fibrinogen, fibrinogen degradation products, Ca, and aspartate-aminotransferase to platelet ratio index (APRI) were factors influencing PE with HELLP syndrome. The results of multiple-factor logistic regression analysis showed that MAP, APRI, CHE, FDP, and Ca were independent factors affecting PE complicated with HELLP syndrome. Based on these results, a prediction model was established, with Y = 9.861 + 2.998APRI + 0.055MAP + 0.014FDP - 0.005CHE - 7.452*Ca. CONCLUSIONS: The predictive model for PE complicated with HELLP syndrome includes APRI, MAP, FDP, CHE, and Ca. This model can be used as a quantitative tool for predicting and evaluating the development of GH into PE complicated with HELLP syndrome.

5.
SAGE Open Med Case Rep ; 11: 2050313X231173789, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37745087

RESUMEN

Pregnant women are more likely to face cardiovascular disease than non-pregnant women. However, abdominal aortic aneurysm is an extremely rare complication of pregnancy. Abdominal aortic aneurysms in pregnancy are difficult to identify in the early stage and are often diagnosed only when the symptoms have manifested. We report the case of a multiparous 35-year-old patient with a history of abnormal ascending aorta and ruled-out Marfan syndrome by genetic testing. After a multidisciplinary medical team evaluation, she delivered a live baby by cesarean section at 37 weeks of gestation, and the abdominal aortic aneurysm was repaired simultaneously. This case offers evidence-based recommendations for obstetricians to carry out preventive imaging examination for pregnant women with similar risk factors and provide successful experience in prenatal examination for similar diseases.

6.
Nat Commun ; 14(1): 4816, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37558666

RESUMEN

Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.


Asunto(s)
Oxígeno , Factores de Transcripción , Animales , Humanos , Oxígeno/metabolismo , Factores de Transcripción/metabolismo , Hipoxia , Colesterol/metabolismo , Esteroles , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Mamíferos/metabolismo
7.
Materials (Basel) ; 16(15)2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37570178

RESUMEN

There has been little research on the impact resistance of mortar-rock slope protection structures. To ensure that the mortar-rock interface has good adhesion properties under the action of impact loading, in this paper, based on fracture mechanics theory, a theoretical impact model was established for mortar-rock binary material. Dynamic fracture tests were carried out on mortar-rock interfaces using the split-Hopkinson pressure bar (SHPB) system. The Brazilian disc (CSTBD) specimen was prepared with one half in granite and the other half in mortar. The specimen used for the dynamic impact test was 48 mm in diameter and 25 mm thick. The effects caused by the change in interface inclination and interface shape on the dynamic fracture mode were discussed. The dynamic model parameters were obtained for different inclination angles and interfaces. The results show that both the interface inclination and interface shape have significant effects on the dynamic mechanical properties of the mortar-rock binary material. The fracture modes of the mortar-rock specimens can be classified into three types. When the interface inclination is 0°, the specimen shows shear damage with an interface fracture; when the interface inclination is in the range of 0-90°, the dynamic splitting strength of the mortar-rock material increases with increasing interface inclination, and the interface undergoes composite fracture; and when the interface inclination is 90°, the dynamic splitting strength of the specimen reaches its peak, and the interface undergoes tensile fracture. The mortar-rock interface damage follows the M-C criterion. The roughness of the interface shape has a large influence on the dynamic splitting strength of the specimens. The rougher the interface shape, the higher the interface cleavage strength and the higher the peak load that causes the material to damage. The results of this study can provide a reference for the design of mortar-rubble structures to meet the demand for impact resistance and have strong engineering application value.

8.
Front Public Health ; 11: 1061453, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37056655

RESUMEN

Background: Digestive diseases are very common worldwide and account for considerable health care use and expenditures. However, there are no global population-based estimates of the disease burden and temporal trend of digestive diseases. Methods: Annual case numbers, age-standardized rates of prevalence, incidence, death, and disability-adjusted life-years (DALYs), and their estimated annual percentage changes (EAPCs) for digestive diseases between 1990 and 2019 were derived from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019. The association between digestive disease burden and the sociodemographic index (SDI) was investigated. We also calculated DALYs attributable to risk factors that had evidence of causation with digestive diseases. Results: Globally, in 2019, there were 88.99 million DALYs due to digestive diseases (3.51% of global DALYs). Digestive diseases were the 13th leading cause of DALYs globally in 2019. Global digestive disease DALYs were highest in the middle SDI quintile and in South Asia and were higher in males than females in 2019. Cirrhosis and other chronic liver diseases constituted the highest proportion of categorized digestive disease DALY burdens globally. From 1990 to 2019, the global age-standardized DALY rate of digestive diseases decreased from 1570.35 in 1990 to 1096.99 in 2019 per 1,00,000 population, with the EAPC being -1.32 (95% confidence interval [CI] -1.36 to -1.27). In 2019, the largest contributor to digestive disease DALYs at the global level, for both sexes, was alcohol use. Conclusion: The results of this systematic analysis suggest that the global burden of digestive diseases is substantial and varies markedly according to age, sex, SDI, and geographical region. These results provide comprehensive and comparable estimates that can potentially inform efforts toward digestive disease control worldwide.


Asunto(s)
Costo de Enfermedad , Carga Global de Enfermedades , Masculino , Femenino , Humanos , Años de Vida Ajustados por Calidad de Vida , Factores de Riesgo , Cirrosis Hepática
9.
Nature ; 615(7951): 300-304, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36859542

RESUMEN

Gram-negative bacteria surround their cytoplasmic membrane with a peptidoglycan (PG) cell wall and an outer membrane (OM) with an outer leaflet composed of lipopolysaccharide (LPS)1. This complex envelope presents a formidable barrier to drug entry and is a major determinant of the intrinsic antibiotic resistance of these organisms2. The biogenesis pathways that build the surface are also targets of many of our most effective antibacterial therapies3. Understanding the molecular mechanisms underlying the assembly of the Gram-negative envelope therefore promises to aid the development of new treatments effective against the growing problem of drug-resistant infections. Although the individual pathways for PG and OM synthesis and assembly are well characterized, almost nothing is known about how the biogenesis of these essential surface layers is coordinated. Here we report the discovery of a regulatory interaction between the committed enzymes for the PG and LPS synthesis pathways in the Gram-negative pathogen Pseudomonas aeruginosa. We show that the PG synthesis enzyme MurA interacts directly and specifically with the LPS synthesis enzyme LpxC. Moreover, MurA was shown to stimulate LpxC activity in cells and in a purified system. Our results support a model in which the assembly of the PG and OM layers in many proteobacterial species is coordinated by linking the activities of the committed enzymes in their respective synthesis pathways.


Asunto(s)
Membrana Externa Bacteriana , Pared Celular , Pseudomonas aeruginosa , Pared Celular/metabolismo , Lipopolisacáridos/metabolismo , Membrana Externa Bacteriana/química , Membrana Externa Bacteriana/metabolismo , Pseudomonas aeruginosa/citología , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/metabolismo , Peptidoglicano/biosíntesis , Peptidoglicano/metabolismo
10.
Int J Public Health ; 68: 1605664, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36960409

RESUMEN

Objectives: Whether Internet use improves older people's health is an open question. This study empirically investigated the impact of Internet use on older people's mental health with a focus on the heterogeneity among subgroups. Method: Data come from the 2018 China Health Retirement Longitudinal Study (n = 8,505). An instrumental variable quantile regression method (IVQR) combines the instrumental variable and quantile regression to resolve the endogeneity and heterogeneity generally challenged in ordinary least squares (OLS). Results: Although Internet use generally improves older people's mental health, there is enormous heterogeneity in the effects on older adults with different mental health conditions. Specifically, Internet use only has a mitigating impact on older adults with poor mental health. Those heterogeneities are also found between rural and urban residents but not between genders. Conclusion: Our findings shed light on active and healthy aging strategies. Two policy priorities include, on the one hand, the Internet user environment should be improved in parallel with Internet technology; on the other hand, multiple measurements are urgent to be developed to deal with the heterogeneity and unevenness of the impact of Internet technology on older people.


Asunto(s)
Uso de Internet , Salud Mental , Humanos , Masculino , Femenino , Anciano , Estudios Longitudinales , Jubilación/psicología , Análisis de Regresión , China , Internet
11.
BMJ Open ; 13(3): e065186, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36977543

RESUMEN

OBJECTIVES: We aimed to provide the most updated estimates on the global burden of inflammatory bowel disease (IBD) to improve management strategies. DESIGN: We extracted data from the Global Burden of Disease (GBD) 2019 database to evaluate IBD burden with different measures in 204 countries and territories from 1990 to 2019. SETTING: Studies from the GBD 2019 database generated by population-representative data sources identified through a literature review and research collaborations were included. PARTICIPANTS: Patients with an IBD diagnosis. OUTCOMES: Total numbers, age-standardised rates of prevalence, mortality and disability-adjusted life-years (DALYs), and their estimated annual percentage changes (EAPCs) were the main outcomes. RESULTS: In 2019, there were approximately 4.9 million cases of IBD worldwide, with China and the USA having the highest number of cases (911 405 and 762 890 (66.9 and 245.3 cases per 100 000 people, respectively)). Between 1990 and 2019, the global age-standardised rates of prevalence, deaths and DALYs decreased (EAPCs=-0.66,-0.69 and -1.04, respectively). However, the age-standardised prevalence rate increased in 13 out of 21 GBD regions. A total of 147 out of 204 countries or territories experienced an increase in the age-standardised prevalence rate. From 1990 to 2019, IBD prevalent cases, deaths and DALYs were higher among females than among males. A higher Socio-demographic Index was associated with higher age-standardised prevalence rates. CONCLUSIONS: IBD will continue to be a major public health burden due to increasing numbers of prevalent cases, deaths and DALYs. The epidemiological trends and disease burden of IBD have changed dramatically at the regional and national levels, so understanding these changes would be beneficial for policy makers to tackle IBD.


Asunto(s)
Carga Global de Enfermedades , Enfermedades Inflamatorias del Intestino , Masculino , Femenino , Humanos , Años de Vida Ajustados por Calidad de Vida , Prevalencia , Enfermedades Inflamatorias del Intestino/epidemiología , Salud Global , Factores de Riesgo
12.
Front Immunol ; 14: 1321616, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38264665

RESUMEN

Background: Soft tissue sarcoma (STS) is a highly heterogeneous musculoskeletal tumor with a significant impact on human health due to its high incidence and malignancy. Long non-coding RNA (lncRNA) and Neutrophil Extracellular Traps (NETs) have crucial roles in tumors. Herein, we aimed to develop a novel NETsLnc-related signature using machine learning algorithms for clinical decision-making in STS. Methods: We applied 96 combined frameworks based on 10 different machine learning algorithms to develop a consensus signature for prognosis and therapy response prediction. Clinical characteristics, univariate and multivariate analysis, and receiver operating characteristic curve (ROC) analysis were used to evaluate the predictive performance of our models. Additionally, we explored the biological behavior, genomic patterns, and immune landscape of distinct NETsLnc groups. For patients with different NETsLnc scores, we provided information on immunotherapy responses, chemotherapy, and potential therapeutic agents to enhance the precision medicine of STS. Finally, the gene expression was validated through real-time quantitative PCR (RT-qPCR). Results: Using the weighted gene co-expression network analysis (WGCNA) algorithm, we identified NETsLncs. Subsequently, we constructed a prognostic NETsLnc signature with the highest mean c-index by combining machine learning algorithms. The NETsLnc-related features showed excellent and stable performance for survival prediction in STS. Patients in the low NETsLnc group, associated with improved prognosis, exhibited enhanced immune activity, immune infiltration, and tended toward an immunothermal phenotype with a potential immunotherapy response. Conversely, patients with a high NETsLnc score showed more frequent genomic alterations and demonstrated a better response to vincristine treatment. Furthermore, RT-qPCR confirmed abnormal expression of several signature lncRNAs in STS. Conclusion: In conclusion, the NETsLnc signature shows promise as a powerful approach for predicting the prognosis of STS. which not only deepens our understanding of STS but also opens avenues for more targeted and effective treatment strategies.


Asunto(s)
Trampas Extracelulares , ARN Largo no Codificante , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Pronóstico , Aprendizaje Automático
13.
Nanoscale ; 14(37): 13651-13660, 2022 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-36082755

RESUMEN

Poor rate capability, the biggest barrier to potential applications of electrochemical actuators (ECAs), is primarily resulted from symmetric electrochemical reactions. This makes it extremely difficult for ECAs to actuate above 1 Hz while maintaining sufficient displacement retainability compared with their actuations at relatively low frequencies, particularly when working in liquids. Here, tungsten trisulfide (WS3) assisted tungsten disulfide nano onions are synthesized through a one-step laser-assisted strategy. Using the irreversibility of WS3 in adsorbing hydrogen in an acidic solution, the electrochemical reaction of tungsten sulfide nano onions is tailored to realize an asymmetric redox reaction for breaking the symmetry of the electrical double layer and battery-like process. Experiments demonstrate that the ECA's response rate (0.24 mm-1 s-1) is at least 10 times faster than that of the previously reported ECAs. Moreover, this ECA can actuate at 30 Hz and reaches top performance in liquids at 4 Hz with long-term durability (>90% after 23 000 cycles), which is comparable to that of electromagnetic and electrothermal actuators. To understand the electrochemical actuation of tungsten sulfide from the atomic scale to the macroscopic scale, density functional theory calculations are conducted and an electrochemomechanical coupling model is proposed. A new generation of subvolt electric-driven actuators used in underwater robotics can be developed by modulating the electrochemical response and chemomechanical coupling effect.

14.
Nat Metab ; 4(6): 711-723, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35739397

RESUMEN

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.


Asunto(s)
NAD , Neoplasias , Proliferación Celular , Electrones , Humanos , Hipoxia , Lípidos , NAD/metabolismo
15.
Ann Med ; 54(1): 1372-1384, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35579516

RESUMEN

BACKGROUND: Because trends in the epidemiology and burden of gastroesophageal reflux disease (GERD) are changing, reinvestigating the geographical differences and trend changes is essential. Here we evaluated the latest epidemiologic patterns and trends for GERD, using data from Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: Annual case numbers, age-standardized rates of prevalence, incidence, and years of life lived with disability (YLDs), and their estimated annual percentage changes (EAPCs) for GERD between 1990 and 2019 were derived from the GBD 2019 study. Association between GERD burden and socio-demographic index (SDI) was also investigated. RESULTS: In 2019, there were 783.95 million cases of GERD globally. Between 1990 and 2019, the total number of prevalent cases, incident cases, and YLDs increased by 77.53%, 74.79%, and 77.19%, respectively. The global age-standardized incidence rate (ASIR) and age-standardized YLD rate (ASYR) increased during this period (EAPC = 0.06 and 0.05, respectively). Tropical Latin America and East Asia had the highest and lowest age-standardiZed prevalence rate (ASPR), ASIR, and ASYR in 2019, respectively. From 1990 to 2019, prevalent cases, incident cases, YLDs, and their corresponding age-standardized rates of GERD were higher in females than males in all years. Higher SDI was associated with lower ASPR, ASIR, and ASYR of GERD in 2019. CONCLUSIONS: GERD will continue to be a major public health burden due to increasing numbers of prevalent cases, incident cases, and YLDs. In order to tackle this troublesome disease, it is crucial to understand the changes in both global and regional trends in epidemiology and the burden for policymakers and other stakeholders. Key messagesThis is the most updated estimate on GERD epidemiology globally, including 204 countries, some of which were not assessed before.The overall burden of GERD continued to worsen with the prevalent cases increasing by 77.53% from 441.57 million in 1990 to 783.95 million in 2019.GERD is likely to remain a common reason for consultation in primary care, and our data may allow for health service provision planning.


Asunto(s)
Reflujo Gastroesofágico , Carga Global de Enfermedades , Femenino , Reflujo Gastroesofágico/epidemiología , Salud Global , Humanos , Incidencia , Masculino , Prevalencia , Años de Vida Ajustados por Calidad de Vida
16.
Nature ; 599(7884): 302-307, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34671163

RESUMEN

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.


Asunto(s)
Glucemia/metabolismo , Dieta Baja en Carbohidratos , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Neoplasias/metabolismo , Neoplasias/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Aloinjertos , Animales , Restricción Calórica , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Dieta Cetogénica , Líquido Extracelular/química , Ácidos Grasos Insaturados/metabolismo , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Nutrientes/análisis , Nutrientes/sangre , Estearoil-CoA Desaturasa/metabolismo , Microambiente Tumoral/efectos de los fármacos
18.
Adv Sci (Weinh) ; 8(12): 2100166, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34194942

RESUMEN

Success in anticancer immune therapy relies on stimulation of tumor antigen-specific T lymphocytes and effective infiltration of the T cells into tumor tissue. Here, a therapeutic vaccine that promotes proliferation and tumor infiltration of antigen-specific T cells in both inflamed and noninflamed tumor types is described. The vaccine consists of STING agonist 2'3'-cGAMP, TLR9 ligand CpG, and tumor antigen peptides that are loaded into nanoporous microparticles (µGCVax). µGCVax is effective in inhibiting lung metastatic melanoma, primary breast cancer, and subcutaneous colorectal cancer in their respective murine models, including functional cure of HER2-positive breast cancer. Mechanistically, µGCVax potently stimulates type I interferon expression in dendritic cells, and promotes CD8+ and CD103+ dendritic cell maturation and migration to lymph nodes and other lymphatic tissues. Antitumor responses are dependent on TLR9 and interferon α/ß receptor signaling, and to a less extent on STING signaling. These results demonstrate a high potential for µGCVax in mediating antitumor immunity in personalized cancer therapy.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Linfocitos T/inmunología , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
19.
Life Sci ; 277: 119569, 2021 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-33961855

RESUMEN

AIMS: Long noncoding RNA (LncRNA) urothelial cancer associated 1 (UCA1) was dysregulated in colorectal cancers (CRC) and promoted tumor progression of CRC. The aims of this study are to further investigate the underlying mechanism. MAIN METHODS: Short hairpin RNAs (shRNAs) were applied for gene knockdown. microRNA mimic and pcDNA-UCA1 plasmids were transfected for miR-495 and UCA1 overexpression, respectively. MTT was applied to determine cell viability and sensitivity of 5-fluorouracil (FU). Transwell assays were performed to evaluate cell migration/invasion. Angiogenesis was evaluated by tube formation. Western blotting and quantitative PCR were utilized for protein and mRNA detection, respectively. The interaction of UCA1, miR-495 and SP1/SP3 were explored by dual-luciferase assay. RNA pulldown was adopted to determine the UCA1/miR-495 interaction. KEY FINDINGS: UCA1 was significantly upregulated in CRC tissues. UCA1 enhanced cell proliferation, migration/invasion, angiogenesis, epithelial-mesenchymal transition, and resistance to 5-FU in CRC cell lines. MiR-495 was inversely correlated to the expression of UCA1. The results indicated that UCA1 sponged miR-495, leading to the disinhibition of SP1/SP3 expression. SP1/SP3 induced the expression of DNA methyltransferases and, in turn, contributed to UCA1 mediated tumor-promoting actions. Reduction of SP1/SP3 exerted anti-cancer effects, which can be reversed by forced expression of UCA1. SIGNIFICANCE: UCA1-miR-495-SP1/SP3 axis is dysregulated in CRC and contributed to malignant phenotypes of CRC. UCA1-SP1/SP3 may form a positive feedback loop in CRC.


Asunto(s)
Neoplasias Colorrectales/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , China , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , ARN Largo no Codificante/metabolismo , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp3/genética , Factor de Transcripción Sp3/metabolismo
20.
J Infect Dis ; 223(7): 1120-1131, 2021 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-33367830

RESUMEN

BACKGROUND: To determine how serologic antibody testing outcome links with virus neutralization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we evaluated individuals for SARS-CoV-2 antibody level and viral neutralization. METHODS: We compared serum Ig levels across platforms of viral antigens and antibodies with 15 positive and 30 negative SARS-CoV-2 controls followed by viral neutralization assessment. We then applied these platforms to a clinically relevant cohort of 114 individuals with unknown histories of SARS-CoV-2 infection. RESULTS: In controls, the best-performing virus-specific antibody detection platforms were SARS-CoV-2 receptor binding domain (RBD) IgG (sensitivity 87%, specificity 100%, positive predictive value [PPV] 100%, negative predictive value [NPV] 94%), spike IgG3 (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%), and nucleocapsid protein (NP) IgG (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%). Neutralization of positive and negative control sera showed 100% agreement. Twenty individuals with unknown history had detectable SARS-CoV-2 antibodies with 16 demonstrating virus neutralization. Spike IgG3 provided the highest accuracy for predicting serologically positive individuals with virus neutralization activity (misidentified 1/20 unknowns compared to 2/20 for RBD and NP IgG). CONCLUSIONS: The coupling of virus neutralization analysis to a spike IgG3 antibody test is optimal to categorize patients for correlates of SARS-CoV-2 immune protection status.


Asunto(s)
Prueba Serológica para COVID-19/métodos , COVID-19/diagnóstico , Pruebas de Neutralización/métodos , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/aislamiento & purificación , COVID-19/sangre , COVID-19/epidemiología , COVID-19/inmunología , Ensayo de Inmunoadsorción Enzimática , Reacciones Falso Positivas , Femenino , Humanos , Inmunidad Humoral , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/aislamiento & purificación , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , SARS-CoV-2/aislamiento & purificación , Sensibilidad y Especificidad , Estudios Seroepidemiológicos , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven
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