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BACKGROUND AND AIMS: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. APPROACH AND RESULTS: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005). CONCLUSIONS: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.
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BACKGROUND: Malaria affects 24 million children globally, resulting in nearly 500,000 child deaths annually in low- and middle-income countries (LMICs). Recent studies have provided evidence that severe malaria infection results in sustained impairment in cognition and behaviour among young children; however, a formal meta-analysis has not been published. The objective was to assess the association between severe malaria infection with cognitive and behavioural outcomes among children living in LMICs. METHODS: Six online bibliographic databases were searched and reviewed in November 2022. Studies included involved children < 18 years of age living in LMICs with active or past severe malaria infection and measured cognitive and/or behaviour outcomes. The quality of studies was assessed. Definitions of severe malaria included cerebral malaria, severe malarial anaemia, and author-defined severe malaria. Results from all studies were qualitatively summarized. For studies with relevant data on attention, learning, memory, language, internalizing behaviour and externalizing behaviour, results were pooled and a meta-analysis was performed. A random-effects model was used across included cohorts, yielding a standardized mean difference between the severe malaria group and control group. RESULTS: Out of 3,803 initial records meeting the search criteria, 24 studies were included in the review, with data from 14 studies eligible for meta-analysis inclusion. Studies across sub-Saharan Africa assessed 11 cohorts of children from pre-school to school age. Of all the studies, composite measures of cognition were the most affected areas of development. Overall, attention, memory, and behavioural problems were domains most commonly found to have lower scores in children with severe malaria. Meta-analysis revealed that children with severe malaria had worse scores compared to children without malaria in attention (standardized mean difference (SMD) -0.68, 95% CI -1.26 to -0.10), memory (SMD -0.52, 95% CI -0.99 to -0.06), and externalizing behavioural problems (SMD 0.45, 95% CI 0.13-0.78). CONCLUSION: Severe malaria is associated with worse neuropsychological outcomes for children living in LMICs, specifically in attention, memory, and externalizing behaviours. More research is needed to identify the long-term implications of these findings. Further interventions are needed to prevent cognitive and behavioural problems after severe malaria infection. TRIAL REGISTRATION: This systematic review was registered under PROSPERO: CRD42020154777.
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Países en Desarrollo , Malaria Cerebral , Niño , Preescolar , Humanos , Cognición , Malaria Cerebral/complicaciones , Malaria Cerebral/epidemiología , África del Sur del SaharaRESUMEN
Experimental studies suggest that abnormal levels of Ca, Mg and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n 150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n 459) were randomly selected from the general population and frequency matched to cases by age, sex and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of Ca (936 v. 1026 mg/d) and dietary intake of Mg (315 v. 331 mg/d) and phosphorus (1350 v. 1402 mg/d) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of Ca, Mg and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of Ca, Mg and phosphorus were significantly associated with the risk of pancreatic cancer.
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Calcio de la Dieta/administración & dosificación , Magnesio , Neoplasias Pancreáticas , Fósforo/administración & dosificación , Estudios de Casos y Controles , Dieta , Humanos , Magnesio/administración & dosificación , Minerales , Minnesota/epidemiología , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/etiología , Neoplasias PancreáticasRESUMEN
Dioxin-like polychlorinated biphenyls (DLPCBs) are ubiquitous persistent pollutants that cause adverse effects in many environmental organisms. DLPCBs in marine sediments can be absorbed by benthic organisms, bioaccumulate, and biomagnify through the food chain and threaten animal and human health. There are no reports of DLPCBs concentrations in the Zhanjiang Gulf seabed. This study was designed to investigate the concentration of DLPCBs in the Zhanjiang coastal sediment and histopathological changes in zebrafish (Diano rerio) embryos exposed to environmentally relevant concentrations of DLPCBs. Of the five sites selected, two sites TS and JSW contained DLPCBs at concentrations of 0.08 and 22.54 ng/g dry sediment, respectively. Two groups of zebrafish embryos were used. One group was exposed to 3.75, 7.5, 15, 30, and 60 mg/ml of DLPCBs extracted from the sediments sampled from the TS site and the second group to 4.375, 8.75, 17.5, 35, and 70 mg/ml of DLPCBs from JSW site from 0.75 h post-fertilization (hpf) to 96 hpf. The zebrafish exposed to 60 and 70 mg/ml of DLPCBs at 96 hpf displayed gross histopathological changes with cardiac lesions including pericardial edema being the most deleterious. Other changes observed were hydropic degeneration of gill filaments and hepatocytes, loss of intestinal folds, and uninflated swim bladder. It appears that only a few sites of the Zhanjiang gulf are contaminated with DLPCBs. This is the first report of histopathological changes in the gills, hepatocytes, intestines, heart, and the swim bladder in zebrafish embryos exposed to DLPCBs from a coastal sediment. Further studies with sampling at different stages of development are required to identify which organ/tissue is most sensitive to DLPCBs.
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Embrión no Mamífero/efectos de los fármacos , Monitoreo del Ambiente , Bifenilos Policlorados/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/embriología , Animales , Sedimentos Geológicos/química , Humanos , Dibenzodioxinas Policloradas/toxicidad , Contaminantes Químicos del Agua/análisisRESUMEN
This study aimed to investigate the effect of microRNA-30b (miR-30b) in rat myocardial ischemic-reperfusion (I/R) injury model. We randomly divided Sprague-Dawley (SD) rats (n = 80) into five groups: 1) control group; 2) miR-30b group; 3) sham-operated group; 4) I/R group, and 5) I/R+miR-30b group. Real-time quantitative polymerase chain reaction, immunohistochemical staining and Western blot analysis were conducted. TUNEL assay was employed for testing cardiomyocyte apoptosis. Our results showed that miR-30b levels were down-regulated in I/R group and I/R + miR-30b group compared with sham-operated group (both P < 0.05). However, miR-30b level in I/R + miR-30b group was higher than I/R group (P < 0.05). Markedly, the apoptotic rate in I/R group showed highest in I/R group (P < 0.05). Additionally, the results illustrated that protein levels of Bcl-2, Bax, and caspase-3 were at higher levels in ischemic regions in I/R group, comparing to sham-operated group (all P < 0.05), while Bcl-2/Bax was reduced (P < 0.05). Bcl-2 level and Bcl-2/Bax were obviously increased in I/R + miR-30b group by comparison with I/R group, and expression levels of Bax and caspase-3 were down-regulated (all P < 0.05). We also found that in I/R + miR-30b group, KRAS level was apparently lower and p-AKT level was higher by comparing with I/R group (both P < 0.05). Our study indicated that miR-30b overexpression had anti-apoptotic effect on early phase of rat myocardial ischemia injury model through targeting KRAS and activating the Ras/Akt pathway.
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MicroARNs/genética , MicroARNs/metabolismo , Isquemia Miocárdica/patología , Daño por Reperfusión Miocárdica/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Apoptosis , Caspasa 3/genética , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
The primary objective of this study investigated the role of microRNA-320 (miR-320) on left ventricular remodeling in the rat model of myocardial ischemia-reperfusion (I/R) injury, and we intended to explore the myocardial mechanism of miR-320-mediated myocardium protection. We collected 120 male Wistar rats (240-280 g) in this study and then randomly divided them into three groups: (1) sham surgery group (sham group: n=40); (2) ischemia-reperfusion model group (I/R group: n=40); and (3) I/R model with antagomir-320 group (I/R+antagomir-320 group: n=40). Value changes of heart function in transesophageal echocardiography were recorded at various time points (day 1, day 3, day 7, day 15 and day 30) after surgery in each group. Myocardial sections were stained with hematoxylin and eosin (H&E) and examined with optical microscope. The degree of myocardial fibrosis was assessed by Sirius Red staining. Terminal dUTP nick end-labeling (TUNEL) and qRT-PCR methods were used to measure the apoptosis rate and to determine the miR-320 expression levels in myocardial tissues. Transesophageal echocardiography showed that the values of left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP) and ±dp/dtmax in the I/R group were obviously lower than those in the sham group, while the left ventricular end-diastolic pressure (LVEDP) value was higher than that in the sham group. The values of LVEF, LVFS, LVSP and ±dp/dtmax showed a gradual decrease in the I/R group, while the LVEDP value showed an up tendency along with the extension of reperfusion time. The H&E staining revealed that rat myocardial tissue in the I/R group presented extensive myocardial damage; for the I/R+antagomir-320 group, however, the degree of damage in myocardial cells was obviously better than that of the I/R group. The Sirius Red staining results showed that the degree of myocardial fibrosis in the I/R group was more severe along with the extension of the time of reperfusion. For the I/R+antagomir-320 group, the degree of myocardial fibrosis was less severe than that in the I/R group. Tissues samples in both the sham and I/R+antagomir-320 groups showed a lower apoptosis rate compared to I/R group. The qRT-PCR results indicated that miR-320 expression in the I/R group was significantly higher than that in both the sham and I/R+antagomir-320 groups. The expression level of miR-320 is significantly up-regulated in the rat model of myocardial I/R injury, and it may be implicated in the prevention of myocardial I/R injury-triggered left ventricular remodeling.
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MicroARNs/metabolismo , Daño por Reperfusión/patología , Animales , Apoptosis , Modelos Animales de Enfermedad , Ecocardiografía , Fibrosis/patología , Hemodinámica , Masculino , MicroARNs/antagonistas & inhibidores , Miocardio/metabolismo , Miocardio/patología , Oligorribonucleótidos Antisentido/metabolismo , Ratas , Ratas Wistar , Daño por Reperfusión/genética , Regulación hacia Arriba , Remodelación Ventricular/genéticaRESUMEN
OBJECTIVE: To analyze the risk factors for grade ≥2 ARE in patients with cervical cancer receiving concurrent chemoradiotherapy. METHODS: A total of 273 patients with cervical cancer receiving concurrent chemoradiotherapy at our hospital were retrospectively enrolled. The patients were divided into training and validation groups. Clinical parameters were analyzed using univariate analysis and multivariate logistic regression analysis. A nomogram model was established based on the independent risk factors selected using multivariate logistic regression. The areas under the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram. The patients were divided into low-score and high-score groups based on the scores calculated using the nomogram model and compared. RESULTS: Malnutrition, monocyte-lymphocyte ratio ≥0.82 after radiotherapy, platelet-lymphocyte ratio <307.50 after radiotherapy, and bowelbag volume receiving at least 5 and 40 Gy were independent risk factors for grade ≥2 ARE and were incorporated into the nomogram ( P <0.05). The ROC curve, calibration curve, and DCA suggested that the nomogram had good discrimination, concordance, and net benefit in the clinical. A medium nomogram score of 146.50 points was used as the cutoff point, and the incidence of grade ≥2 ARE in the high-score group was higher than that in the low-score group ( P <0.05). CONCLUSION: The nomogram model for grade ≥2 ARE has good predictive ability and clinical utility, and is convenient for clinicians to identify high-risk groups and develop early prevention and treatment strategies.
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Quimioradioterapia , Enteritis , Nomogramas , Traumatismos por Radiación , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/patología , Quimioradioterapia/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Enteritis/etiología , Traumatismos por Radiación/etiología , Traumatismos por Radiación/patología , Factores de Riesgo , Anciano , Curva ROCRESUMEN
Wastewater treatment produces a large amount of sludge, where the minimizing of the disposed sludge is essential for environmental protection. The co-combustion of sludge with coal is a preferable method for sewage sludge disposal from the economic and environmental perspective. The co-combustion of sludge has been widely used in the industry with the advantages of large processing capacity. The melting characteristics of ash are an important criterion for the selection of the co-combustion methods and furnace types. In this study, two types of sludge and four types of coal with different ash melting points were selected, where the ash melting behavior upon co-combustion is investigated by experimental and thermodynamical approaches. Especially, the slag fluidity upon co-combustion is explored via a modified inclined plane method. It has been found that the presence of SiO2 and CaO in sludge substantially enhances its fusion temperature owing to the high content of CaO, while SiO2 acts as a solvent, facilitating the co-melting of other oxides and raising the sludge fusion temperature. Fe2O3 exhibits a specific mass fraction within the range of 10-20%. Furthermore, the presence of CaO and SiO2 prohibits the flow ability of the slag at high temperatures, and Fe2O3 promotes the flow ability for sludge at high temperatures. With increasing base/acid ratio, the sludge flow velocity increases remarkably and peaks at 1.6. The interaction between Fe-Ca and Si-AI significantly affects the fluidity significantly. The findings are expected to optimize the condition of co-combustion and desirable furnace design for the incineration of sludge.
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Infection by Helicobacter pylori, a prevalent global pathogen, currently requires antibiotic-based treatments, which often lead to antimicrobial resistance and gut microbiota dysbiosis. Here, we develop a non-antibiotic approach using sonodynamic therapy mediated by a lecithin bilayer-coated poly(lactic-co-glycolic) nanoparticle preloaded with verteporfin, Ver-PLGA@Lecithin, in conjunction with localized ultrasound exposure of a dosage permissible for ultrasound medical devices. This study reveals dual functionality of Ver-PLGA@Lecithin. It effectively neutralizes vacuolating cytotoxin A, a key virulence factor secreted by H. pylori, even in the absence of ultrasound. When coupled with ultrasound exposure, it inactivates H. pylori by generating reactive oxygen species, offering a potential solution to overcome antimicrobial resistance. In female mouse models bearing H. pylori infection, this sonodynamic therapy performs comparably to the standard triple therapy in reducing gastric infection. Significantly, unlike the antibiotic treatments, the sonodynamic therapy does not negatively disrupt gut microbiota, with the only major impact being upregulation of Lactobacillus, which is a bacterium widely used in yogurt products and probiotics. This study presents a promising alternative to the current antibiotic-based therapies for H. pylori infection, offering a reduced risk of antimicrobial resistance and minimal disturbance to the gut microbiota.
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Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Femenino , Animales , Ratones , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Lecitinas , Antibacterianos/farmacología , Antibacterianos/uso terapéuticoRESUMEN
OBJECTIVE: Experimental studies suggest that carotenoids and tocopherols modulate pancreatic carcinogenesis because they have antioxidant and other functions. We investigated the associations between intakes of these compounds and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. METHODS: The present analysis included 150 cases of pancreatic cancer recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic and 459 controls randomly selected from the general population and frequency matched to cases by age, sex, and race. The intakes of carotenoids and tocopherols were assessed with a validated food frequency questionnaire. Unconditional logistic regression analysis was performed to evaluate the associations of interest. RESULTS: The energy-adjusted intake of lutein/zeaxanthin was significantly lower in cases (2410 µg/day) than in controls (3020 µg/day). After adjustment for confounders, persons in the fourth quartile of lutein/zeaxanthin intake had a reduced risk of pancreatic cancer compared with those in the first quartile [odds ratio (OR) (95% CI): 0.40 (0.17-0.91)]. There were no significant associations with intakes of other carotenoids and tocopherols considered and with a composite score created from all individual carotenoids examined. We did not detect any significant interactions of intakes of carotenoids and tocopherols with age, sex, cigarette smoking, or alcohol intake in relation to pancreatic cancer risk. CONCLUSION: The present study suggests an inverse association between lutein/zeaxanthin intake and pancreatic cancer risk, but a potential beneficial effect was not observed for other carotenoids and tocopherols.
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BACKGROUND: Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. METHODS: FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. RESULTS: In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). CONCLUSION: Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.
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Ferroptosis , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Pronóstico , Ferroptosis/genética , Inestabilidad de Microsatélites , Microambiente Tumoral/genéticaRESUMEN
The commercialization in 2016 of genetically engineered seeds tolerant to dicamba and/or 2,4-dichlorophenoxyacetic acid (2,4-D) has caused a rapid increase in the use of these herbicides. New questions about the reproductive and chronic health effects of long-term exposure to these herbicides have been raised. To assess exposure to dicamba and other pesticides of interest in the Heartland Study, a birth cohort study based in the United States, a new analytical method was needed. The present study describes the development and validation of this new solid phase extraction and liquid chromatography-tandem mass spectrometry method that detects simultaneously 13 pesticides or their metabolites in 250 µL of urine. More specifically, the method allows the analysis of dicamba, 2,4-D and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), which are herbicides, of malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPy), 2-diethylamino-6-methylpyrimidin-4-ol (DEAMPY) and 2-isopropyl-6-methyl-4-pyrimidinol (IMPY), which are metabolites of organophosphate insecticides, and finally of cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA), trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA), 3-Phenoxybenzoic acid (3-PBA), 4-Fluoro-3-phenoxybenzoic acid (4-F-3-PBA) and cis-3-(2,2-Dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DBCA), which are metabolites of synthetic pyrethroids insecticides. The method was validated under ISO/IEC 17025 guidance. The limit of detection (LOD) in urine samples was 0.10 µg/L for dicamba, while the LOD for other analytes ranged between 0.0038 µg/L and 0.091 µg/L. Accuracy was evaluated by analyzing samples from two External Quality Assessment Schemes, namely G-EQUAS and OSEQAS. Preliminary results obtained following the analysis of 91 urine samples taken from pregnant women enrolled in the Heartland Study are presented here. This method is suitable for human biomonitoring studies.
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Herbicidas , Insecticidas , Plaguicidas , Piretrinas , Humanos , Femenino , Embarazo , Plaguicidas/análisis , Insecticidas/análisis , Dicamba , Espectrometría de Masas en Tándem , Cromatografía Liquida , Ácidos Carboxílicos , Estudios de Cohortes , Piretrinas/metabolismo , Herbicidas/análisis , Biomarcadores/orina , Fenoles/análisis , Ácido 2,4-Diclorofenoxiacético , Exposición a Riesgos Ambientales/análisisRESUMEN
Radiotherapy is an important means of tumor treatment, but radiotherapy resistance has been a difficult problem in the comprehensive treatment of clinical tumors. The mechanisms of radiotherapy resistance include the repair of sublethal damage and potentially lethal damage of tumor cells, cell repopulation, cell cycle redistribution, and reoxygenation. These processes are closely related to the regulation of epigenetic modifications. Histone deacetylases (HDACs), as important regulators of the epigenetic structure of cancer, are widely involved in the formation of tumor radiotherapy resistance by participating in DNA damage repair, cell cycle regulation, cell apoptosis, and other mechanisms. Although the important role of HDACs and their related inhibitors in tumor therapy has been reviewed, the relationship between HDACs and radiotherapy has not been systematically studied. This article systematically expounds for the first time the specific mechanism by which HDACs promote tumor radiotherapy resistance in vivo and in vitro and the clinical application prospects of HDAC inhibitors, aiming to provide a reference for HDAC-related drug development and guide the future research direction of HDAC inhibitors that improve tumor radiotherapy resistance.
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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.
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The inability of commercial personal protective equipment (PPE) to inactivate microbes in the droplets/aerosols they intercept makes used PPE a potential source of cross-contamination. To make PPE spontaneously and continuously antimicrobial, we incorporate PPE with oxidase-like catalysts, which efficiently convert O2 into reactive oxygen species (ROS) without requiring any externally applied stimulus. Using a single-atom catalyst (SAC) nanoparticle containing atomically dispersed copper atoms as the reactive centers (Cu-SAC) and a silver-palladium bimetallic alloy nanoparticle (AgPd0.38) as models for oxidase-like catalysts, we show that the incorporation of oxidase-like catalysts enables PPE to inactivate bacteria in the droplets/aerosols they intercept without requiring any externally applied stimulus. Notably, this approach works both for PPE that are fibrous and woven such as a commercial KN95 facial respirator and for those made of solid plastics such as an apron. This work suggests a feasible and global approach for preventing PPE from spreading infectious diseases.
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Antiinfecciosos , Equipo de Protección Personal , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Oxidorreductasas , Personal de Salud , Aerosoles , Antiinfecciosos/farmacologíaRESUMEN
Acting by producing reactive oxygen species (ROS) in situ, nanozymes are promising as antimicrobials. ROS' intrinsic inability to distinguish bacteria from mammalian cells, however, deprives nanozymes of the selectivity necessary for an ideal antimicrobial. Here we report that nanozymes that generate surface-bound ROS selectively kill bacteria over mammalian cells. This result is robust across three distinct nanozymes that universally generate surface-bound ROS, with an oxidase-like silver-palladium bimetallic alloy nanocage, AgPd0.38, being the lead model. The selectivity is attributable to both the surface-bound nature of ROS these nanozymes generate and an unexpected antidote role of endocytosis. Though surface-bound, the ROS on AgPd0.38 efficiently eliminated antibiotic-resistant bacteria and effectively delayed the onset of bacterial resistance emergence. When used as coating additives, AgPd0.38 enabled an inert substrate to inhibit biofilm formation and suppress infection-related immune responses in mouse models. This work opens an avenue toward biocompatible nanozymes and may have implication in our fight against antimicrobial resistance.
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Antibacterianos/farmacología , Antiinfecciosos/química , Nanopartículas/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Antiinfecciosos/farmacología , Biopelículas/efectos de los fármacos , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Timely awareness of hypertension is among the most crucial components in reducing the burden of hypertension. However, there is limited information about the awareness of hypertension in northern China. Therefore, in this cross-sectional study, we aimed to investigate the awareness of hypertension and its associated factors in the Jilin province in China; the study was conducted between July 2014 and December 2015 in four cities and four rural counties in the Jilin province as part of a national study. A stratified multistage random-sampling method was used to select a representative sample: a total of 15,206 participants aged ≥15 years were initially recruited, among which 14,956 were finally included in the survey. The awareness of hypertension in the Jilin province was found to be 42.3%. Moreover, the awareness of hypertension was associated with age, sex, region, marital status, body mass index, and family history of hypertension or coronary artery disease. Employment was associated with a lower awareness in rural areas, whereas high education was associated with a higher awareness in urban areas. Policies targeting specific subgroups may be helpful in increasing the awareness of hypertension in the Jilin province.
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Conocimientos, Actitudes y Práctica en Salud , Alfabetización en Salud , Hipertensión , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Actitud Frente a la Salud , China/epidemiología , Información de Salud al Consumidor , Estudios Transversales , Femenino , Alfabetización en Salud/normas , Alfabetización en Salud/estadística & datos numéricos , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Hipertensión/prevención & control , Hipertensión/psicología , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , Prevalencia , Factores SocioeconómicosRESUMEN
In the present study, proteins differentially expressed between gastric cancer tissue and paratumoral normal gastric tissues were screened, and the function of the highly expressed protein C1QTNF6 in gastric carcinoma was investigated. The differential expression of mRNAs extracted from the tumor and adjacent tissues was analyzed using GeneChip assay. An AGS siC1QTNF6 cell line was constructed using shRNAC1QTNF6 lentivirus. The cell invasion and migration ability of C1QTNF6knockdown cells were determined by Transwell chamber migration and wound healing assays, respectively. The effects of C1QTNF6 on AGS cell cycle distribution and apoptosis were detected using a FACScan flow cytometer. The results demonstrated that the expression of 109 genes was increased and the expression of 129 was decreased in tumor tissues. Among these genes, the C1QTNF6 gene was highly expressed in tumor tissues and the AGS7901 cell line. C1QTNF6knockdown decreased the cell growth, and the proliferative and migration ability, as well as increasing the apoptosis of gastric carcinoma cells. In addition, the number of AGS cells in the G2/M phase was significantly increased after 5 days of C1QTNF6shRNA lentivirus infection. The results of the present study indicated that C1QTNF6 serves an important role in the development of gastric carcinoma. C1QTNF6 is involved in promoting the proliferation and migration, and in reducing the apoptosis of gastric carcinoma cells. These results provided a potential therapeutic target for the treatment of gastric carcinoma.
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Movimiento Celular/genética , Colágeno/metabolismo , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Colágeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , ARN Interferente Pequeño/metabolismo , Estómago/patología , Neoplasias Gástricas/genética , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: This study aimed to investigate the prevalence and distribution of hypertension and its related factors in Jilin province, China. DESIGN: A cross-sectional study in four cities and four rural counties in Jilin as part of a national Chinese study. PARTICIPANTS AND SETTING: A total of 15 206 participants who were ≥15 years old and were selected using a stratified multistage random sampling method. MAIN OUTCOME MEASURES: The prevalence of hypertension. RESULTS: The prevalence of hypertension in Jilin province was 24.7%. Moreover, the prevalence of hypertension increased with age in both sexes, and was higher in men than in women. The modifiable factors that were associated with hypertension were body mass index, smoking and alcohol drinking. The risk factors identified are similar to those in southern China, except smoking, which has no association with hypertension prevalence in the South. CONCLUSIONS: Age, sex, body mass index, smoking and alcohol drinking were risk factors of hypertension. Control of these related risk factors, especially smoking, may be helpful in the treatment and management of hypertension in Jilin province.
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Consumo de Bebidas Alcohólicas/efectos adversos , Índice de Masa Corporal , Hipertensión/epidemiología , Hipertensión/etiología , Obesidad/complicaciones , Fumar/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Población Rural , Factores Sexuales , Adulto JovenRESUMEN
BACKGROUND: Hypertension is a significant global public health problem and recognized as an important risk factor for cardiovascular diseases. This study was designed to assess the current prevalence of hypertension and to explore risk factors associated with hypertension by urban and rural status to guide the prevention and control of hypertension in Jilin province. METHODS: A multi-stage stratified random cluster sampling method was used to obtain data on hypertension, which was investigated by physical examination and face-to-face questionnaire in July 2014-December 2015. Sample data were analyzed by complex weighted statistical analysis to estimate blood pressure levels and prevalence of hypertension in the province. Multivariable logistic regression analysis was used to identify factors influencing hypertension rates. RESULTS: The prevalence of hypertension was significantly higher in rural areas than urban areas (25.93% versus 22.73%, respectively). The rates of hypertension known (46.7% versus 38.1%, respectively), control (13.7% versus 5.0%, respectively), and controlled among treated subjects (38.3% versus 17.5%, respectively) were higher in urban areas than in rural areas (all p < 0.001), while the treatment rate was not statistically significantly different between urban and rural areas (35.9% versus 28.4%, respectively). After adjusting for demographic covariates, hypertension prevalence in rural areas was still significantly greater than in urban areas (adjusted OR = 1.22; 95%CI: 1.10, 1.36; p < 0.001). Common risk factors for hypertension among urban and rural residents included older age; male; married; employed; less education; overweight/obese; greater abdominal waist circumference; family history of hypertension, stroke, or coronary heart disease; current smoker; alcohol consumption; higher visceral adiposity index; and higher body fat percentage. CONCLUSIONS: This study identified an increased risk for hypertension in rural regions of Jilin province, suggesting that rural hypertension screening and treatment guidelines should receive greater attention.