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1.
Phytomedicine ; 90: 153630, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34217968

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH), the most fatal subtype of stroke, has no disease-modifying treatment. Da-cheng-qi decoction (DCQ), composed of rhubarb, is one of the most commonly used Chinese traditional decoctions in ICH treatment. But the mechanism is not clear. Emodin is an active compound found in rhubarb. PURPOSE: To study the protective effects of DCQ on ICH and its possible mechanisms of action. METHODS: The ICH model was reproduced by injecting collagenase-VII into the left caudate putamen (CPu) of rats. DCQ and emodin were used to treat the ICH rats for 7 days. Behavior tests, proteomic analysis, morphological studies, and western blotting were performed. RESULTS: The neurological deficits in the ICH rats recovered with DCQ and emodin on the 14th day after ICH. The proteomics data revealed that DCQ significantly corrected the pathological signals in the CPu and hippocampus after ICH. The numbers of amoebic microglia in the CPu and M2 microglia in both CPu and hippocampus were significantly increased after DCQ and emodin treatment. The increase in GluN2B-containing NMDA receptor (NR2B) and postsynaptic density protein-95, activation of mitogen-activated protein kinase (MAPK) signals in the CPu, and secondary neurodegeneration (SND) in the hippocampus were significantly recovered in DCQ-treated rats. Inhibition of MAPK p38 (p38) in the hippocampus was observed after DCQ and emodin treatment. CONCLUSION: The protective effects of DCQ on ICH were confirmed in this study, and its mechanism may be related to the inhibition of MAPK and activation of M2 microglia. These results are beneficial to the development of ICH therapeutic targets.

2.
J Chem Phys ; 154(20): 204301, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34241176

RESUMO

We studied (NaSCN)2(H2O)n - clusters in the gas phase using size-selected anion photoelectron spectroscopy. The photoelectron spectra and vertical detachment energies of (NaSCN)2(H2O)n - (n = 0-5) were obtained in the experiment. The structures of (NaSCN)2(H2O)n -/0 up to n = 7 were investigated with density functional theory calculations. Two series of peaks are observed in the spectra, indicating that two types of structures coexist, the high electron binding energy peaks correspond to the chain style structures, and the low electron binding energy peaks correspond to the Na-N-Na-N rhombic structures or their derivatives. For the (NaSCN)2(H2O)n - clusters at n = 3-5, the Na-N-Na-N rhombic structures are the dominant structures, the rhombic four-membered rings start to open at n = 4, and the solvent separated ion pair (SSIP) type of structures start to appear at n = 6. For the neutral (NaSCN)2(H2O)n clusters, the Na-N-Na-N rhombic isomers become the dominant starting at n = 3, and the SSIP type of structures start to appear at n = 5 and become dominant at n = 6. The structural evolution of (NaSCN)2(H2O)n -/0 (n = 0-7) confirms the possible existence of ionic clusters such as Na(SCN)2 - and Na2(SCN)+ in NaSCN aqueous solutions.

3.
Antiviral Res ; : 105127, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34217752

RESUMO

In this study, a series of 10 quinoline analogues was evaluated for their in vitro antiviral activity against a panel of alpha- and beta-coronaviruses, including the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2), as well as the human coronaviruses (HCoV) 229E and OC43. Chloroquine and hydroxychloroquine were the most potent with antiviral EC50 values in the range of 0.12-12 µM. Chloroquine displayed the most favorable selectivity index (i.e. ratio cytotoxic versus antiviral concentration), being 165 for HCoV-OC43 in HEL cells. Potent anti-coronavirus activity was also observed with amodiaquine, ferroquine and mefloquine, although this was associated with substantial cytotoxicity for mefloquine. Primaquine, quinidine, quinine and tafenoquine only blocked coronaviruses replication at higher concentrations, while piperaquine completely lacked antiviral and cytotoxic effect. A time-of-addition experiment in HCoV-229E-infected HEL cells revealed that chloroquine interferes with viral entry at a post-attachment stage. Using confocal microscopy, no viral RNA synthesis could be detected upon treatment of SARS-CoV-2-infected cells with chloroquine. The inhibition of SARS-CoV-2 replication by chloroquine and hydroxychloroquine coincided with an inhibitory effect on the autophagy pathway as visualized by a dose-dependent increase in LC3-positive puncta. The latter effect was less pronounced or even absent with the other quinolines. In summary, we showed that several quinoline analogues, including chloroquine, hydroxychloroquine, amodiaquine, ferroquine and mefloquine, exhibit broad anti-coronavirus activity in vitro.

4.
Nat Genet ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267370

RESUMO

Tea is an important global beverage crop and is largely clonally propagated. Despite previous studies on the species, its genetic and evolutionary history deserves further research. Here, we present a haplotype-resolved assembly of an Oolong tea cultivar, Tieguanyin. Analysis of allele-specific expression suggests a potential mechanism in response to mutation load during long-term clonal propagation. Population genomic analysis using 190 Camellia accessions uncovered independent evolutionary histories and parallel domestication in two widely cultivated varieties, var. sinensis and var. assamica. It also revealed extensive intra- and interspecific introgressions contributing to genetic diversity in modern cultivars. Strong signatures of selection were associated with biosynthetic and metabolic pathways that contribute to flavor characteristics as well as genes likely involved in the Green Revolution in the tea industry. Our results offer genetic and molecular insights into the evolutionary history of Camellia sinensis and provide genomic resources to further facilitate gene editing to enhance desirable traits in tea crops.

5.
J Phys Chem Lett ; : 6773-6780, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34269586

RESUMO

Achieving high catalytic performance with high CO2 selectivity is critical for commercialization of direct ethanol fuel cells. Here, we report carbon-supported highly porous Pt2Ir alloy nanocrystals (p-Pt2Ir/C) for an ethanol oxidation reaction (EOR) that displays nearly 7.2-fold enhancement in mass activity and promotes antipoisoning ability and durability for the EOR as compared with the commercial Pt/C-JM. Moreover, the catalyst exhibits high CO2 selectivity, 3.4-fold at 0.65 V (vs. SCE) and 4.1-fold at 0.75 V (vs. SCE) higher as compared with the carbon-supported porous Pt nanocrystals (p-Pt/C). The highly porous structure is composed of interconnected one-dimensional (1D) rough branches with an average diameter of only 1.9 nm, largely promoting Pt utilization efficiency and accelerating mass transfer. The 1D rough branch surface exposed many atomic steps/corners endowed with abundant high activity sites. Alloying with Ir can significantly improve the antipoisoning ability, durability, and C-C bond cleavage ability, thereby evidently enhancing its EOR performance.

6.
Antiviral Res ; : 105127, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1293551

RESUMO

In this study, a series of 10 quinoline analogues was evaluated for their in vitro antiviral activity against a panel of alpha- and beta-coronaviruses, including the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2), as well as the human coronaviruses (HCoV) 229E and OC43. Chloroquine and hydroxychloroquine were the most potent with antiviral EC50 values in the range of 0.12-12 µM. Chloroquine displayed the most favorable selectivity index (i.e. ratio cytotoxic versus antiviral concentration), being 165 for HCoV-OC43 in HEL cells. Potent anti-coronavirus activity was also observed with amodiaquine, ferroquine and mefloquine, although this was associated with substantial cytotoxicity for mefloquine. Primaquine, quinidine, quinine and tafenoquine only blocked coronaviruses replication at higher concentrations, while piperaquine completely lacked antiviral and cytotoxic effect. A time-of-addition experiment in HCoV-229E-infected HEL cells revealed that chloroquine interferes with viral entry at a post-attachment stage. Using confocal microscopy, no viral RNA synthesis could be detected upon treatment of SARS-CoV-2-infected cells with chloroquine. The inhibition of SARS-CoV-2 replication by chloroquine and hydroxychloroquine coincided with an inhibitory effect on the autophagy pathway as visualized by a dose-dependent increase in LC3-positive puncta. The latter effect was less pronounced or even absent with the other quinolines. In summary, we showed that several quinoline analogues, including chloroquine, hydroxychloroquine, amodiaquine, ferroquine and mefloquine, exhibit broad anti-coronavirus activity in vitro.

7.
Insect Sci ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34263534

RESUMO

Insect CAPA neuropeptides are considered to affect water and ion balance by mediating the physiological metabolism activities of the Malpighian tubules. In previous studies, the CAPA-PK analogue 1895 (2Abf-Suc-FGPRLamide) was reported to decrease aphid fitness when administered through micro-injection or via topical application. However, a further statistically significant decrease in the fitness of aphids and an increased mortality could not be established with pairwise combinations of 1895 with other CAPA analogues. In this study, we assessed the topical application of new combinations of 1895 with five CAPA-PVK analogues on the fitness of aphids. We found that 1895 and CAPA-PVK analogue 2315 (ASG-[ß3 L]-VAFPRVamide) was statistically the most effective combination to control the peach potato aphid Myzus persicae nymphs via topical application, leading to 72% mortality. Additionally, the combination (1895+2315) was evaluated against a selection of beneficial insects, i.e. a pollinator (Bombus terrestris) and three natural enemies (Chrysoperla carnea, Nasonia vitripennis and Adalia bipunctata). We found no significant influence on food intake, weight increase and survival for the pollinator and the three representative natural enemies. These results could facilitate to further establish, and generate CAPA analogues as alternatives to broad spectrum and less friendly insecticides. This article is protected by copyright. All rights reserved.

8.
Nature ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34261126

RESUMO

An ideal anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse SARS-related coronaviruses (sarbecoviruses)4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

9.
Pediatr Surg Int ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264357

RESUMO

BACKGROUND: The disruptive effects on society and medical systems due to the coronavirus disease 2019 (COVID-19) pandemic are substantial and far-reaching. The effect of the pandemic on the quantity and quality of pediatric traumas is unclear and has a direct bearing on how scarce hospital resources should be allocated in a pandemic situation. METHODS: A retrospective review of the trauma registry was performed for trauma activations in the years 2018 through 2020 during the months of March, April, and May. Demographic and injury specific datapoints were compared across calendar years. RESULTS: There were 111, 100, and 52 trauma activations during the study interval in 2018, 2019, and 2020, respectively. There were fewer highest severity level activations in 2020 compared to 2018 and 2019 (1 vs 5 and 9; p < 0.01). The median Injury Severity Score was 5 in 2020 compared to 4 in both 2018 and 2019 (p < 0.01). More patients went directly to the operating room in 2020 compared to prior years (21.2% vs 8% and 6.1%; p < 0.01). There were fewer discharges from the emergency department (ED) (12.1% vs 36.6% and 32.7%). No increase in the number of child abuse reports and investigations was noted. There was no difference in the proportion of blunt versus penetrating trauma between years (p = 0.57). No pedestrians were struck by automobiles in 2020 compared to 12 and 14 in 2018 and 2019. However, there were a greater proportion of injuries from falls during 2020 compared to prior years. CONCLUSIONS: There were fewer trauma activations during the peak of the COVID pandemic compared to prior years. Due to the decrease in trauma volume during the peak of the pandemic, hospital resources could potentially be reallocated toward areas of greater need. LEVEL OF EVIDENCE: IV; Retrospective cohort study using historical controls.

10.
Nature ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34280951

RESUMO

The recent emergence of SARS-CoV-2 variants of concern (VOC)1-10 and the recurrent spillovers of coronaviruses11,12 in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1, B.1.427/B.1.429 VOC, as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile limited to the single substitution G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters against challenge with the prototypic SARS-CoV-2 and the B.1.351 VOC, suggesting this mAb is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34251167

RESUMO

Crystal phase engineering is a powerful strategy for regulating the performance of electrocatalysts toward many electrocatalytic reactions. Herein we demonstrate that Au@Pd1Cu concave nanocubes (CNCs) with an ordered body-centered cubic (bcc) PdCu alloy shell enclosed by many high active high-index facets can be adopted as highly active yet stable electrocatalysts for the ethanol oxidation reaction (EOR). These CNCs are more efficient than other nanocrystals with a disordered face-centered cubic (fcc) PdCu alloy surface and display high mass and specific activities of 10.59 A mgpd-1 and 33.24 mA cm-2, which are 11.7 times and 4.1 times higher than those of commercial Pd black, respectively. Our core-shell CNCs also exhibit robust durability with the weakest decay in activity after 250 potential-scanning cycles, as well as outstanding antipoisoning ability. Alloying with Cu and the ordered bcc phase surface can provide abundant OHads species to oxidize carbonaceous poison to avoid catalyst poisoning, and the exposed high-index facets on the surface can act as highly catalytic sites.

12.
Ann Surg ; 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34225299

RESUMO

OBJECTIVE: A large-scale multicenter retrospective cohort study was conducted to compare the short- and long-term outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer. SUMMARY OF BACKGROUND DATA: RG is being increasingly used worldwide, but data from large-scale multicenter studies on the short- and long-term oncologic outcomes of RG versus LG are limited. The potential benefits of RG compared with LG for gastric cancer remain controversial. METHODS: Data from eligible patients who underwent RG or LG for gastric cancer of 11 experienced surgeons from 7 centers in China between March 2010 and October 2019 were collected. The RG group was matched 1:1 with the LG group by using propensity score matching (PSM). The primary outcome was postoperative complications. RESULTS: After PSM, a well-balanced cohort of 3552 patients was included for further analysis. The occurrence of overall complications (12.6% vs 15.2%, P = 0.023) was lower in the RG group than in the LG group. RG was associated with less blood loss (126.8 vs 142.5 mL, P < 0.001) and more retrieved lymph nodes in total (32.5 vs 30.7, P < 0.001) and in suprapancreatic areas (13.3 vs 11.6, P < 0.001). The long-term oncological outcomes were comparable between the two groups. CONCLUSIONS: The results of this multicenter study demonstrate that RG is a safe and effective treatment for gastric cancer when performed by experienced surgeons, although longer operation time and higher costs are still concerns about RG. This study provides evidence suggesting that RG may represent an alternative surgical treatment to LG.

13.
Dis Markers ; 2021: 8824589, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211613

RESUMO

Background: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. Methods: First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. Results: We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. Conclusions: These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.

14.
World J Gastroenterol ; 27(21): 2895-2909, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34135560

RESUMO

BACKGROUND: Poorly differentiated gastric neuroendocrine neoplasms (PDGNENs) include gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma, which are highly malignant and rare tumors, and their incidence has increased over the past few decades. However, the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated. AIM: To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs. METHODS: The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively. RESULTS: Among the 232 patients with PDGNENs, 191 (82.3%) were male, with an average age of 62.83 ± 9.11 years. One hundred and thirteen (49.34%) of 229 patients had a stage III disease and 86 (37.55%) had stage IV disease. Three (1.58%) of 190 patients had no clinical symptoms, while 187 (98.42%) patients presented clinical symptoms. The tumors were mainly (89.17%) solitary and located in the upper third of the stomach (cardia and fundus of stomach: 115/215, 53.49%). Most lesions were ulcers (157/232, 67.67%), with an average diameter of 4.66 ± 2.77 cm. In terms of tumor invasion, the majority of tumors invaded the serosa (116/198, 58.58%). The median survival time of the 232 patients was 13.50 mo (7, 31 mo), and the overall 1-year, 3-year, and 5-year survival rates were 49%, 19%, and 5%, respectively. According to univariate analysis, tumor number, tumor diameter, gastric invasion status, American Joint Committee on Cancer (AJCC) stage, and distant metastasis status were prognostic factors for patients with PDGNENs. Multivariate analysis showed that tumor number, tumor diameter, AJCC stage, and distant metastasis status were independent prognostic factors for patients with PDGNENs. CONCLUSION: The overall prognosis of patients with PDGNENs is poor. The outcomes of patients with a tumor diameter > 5 cm, multiple tumors, and stage IV tumors are worse than those of other patients.


Assuntos
Tumores Neuroendócrinos , Neoplasias Gástricas , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia
15.
PLoS One ; 16(6): e0253658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161399

RESUMO

BACKGROUND: Diagnosis of tuberculosis (TB) is still difficult. The purpose of our study was to evaluate the diagnostic accuracy of Mycobacterium tuberculosis cell-free DNA (cfDNA) for diagnosing of TB. METHODS: We searched relevant databases for studies that used cfDNA to diagnose TB. We evaluated the accuracy of cfDNA compared with the composite reference standard (CRS) and culture. True positive, false positive, false negative, and true negative values for cfDNA were obtained first, then the estimated pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve (AUC) of cfDNA for diagnosing TB were calculated with 95% confidence intervals (CIs). Heterogeneity was determined using the I2 statistic. When the heterogeneity was obvious, the source of heterogeneity was further discussed. RESULTS: We included 14 independent studies comparing cfDNA with the CRS, and 4 studies compared with culture. The pooled sensitivity, specificity, PPV, NPV, DOR, and AUC of the SROC were 68%, 98%,99%, 62%, 83, and 0.97 as compared with the CRS, respectively. The pooled sensitivity, specificity, PPV, NPV, DOR, and AUC of the SROC were 48%, 91%, 92%, 60%, 5, and 0.88 as compared with culture, respectively. The heterogeneity between studies was significant. CONCLUSIONS: The accuracy of cfDNA testing for TB diagnosis was good compared with CRS and culture. cfDNA can be used for rapid early diagnosis of TB.

16.
J Chromatogr A ; 1651: 462302, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34119720

RESUMO

Phospholipids are one of the main nutrients in rice, which have a positive effect on cancer, coronary heart disease and inflammation. However, phospholipids will become small molecular volatile substances during the aging process of rice, resulting in change the flavor of rice. Therefore, mapping the concentration and the spatial distribution of phospholipids in rice are of tremendous significance in its function research. In this work, we established a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) imaging method for the spatial distribution analysis of phospholipids in rice. A total of 12 phospholipid compounds were found in the range of m/z 500-1000 through a series of conditions optimization. According to the results, lysophosphatidylcholine (LPC) species spread throughout the rice tissue sections and phosphatidylcholine (PC) species distributed in the bran and embryo (particularly in the scutellum). We also compared the signal intensities of phospholipids in different parts of white rice and brown rice by region of interest (ROI) analysis, which showed the relative content of PC species was higher in the embryo and gradually decreased until disappeared with the increase of processing degree during the processing of brown rice to white rice. The PC species on the surface of rice could be used as an important indicator to identify the processing degree of rice. Our work not only establish a MALDI-TOF-MS imaging method for spatial distribution analysis of rice, but also provide the necessary reference for ensuring food security, improving the eating quality of rice and the health benefits of consumers.


Assuntos
Análise de Alimentos/métodos , Oryza/química , Fosfolipídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Lasers , Lisofosfatidilcolinas/análise , Fosfatidilcolinas/análise
17.
Lancet ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34111416

RESUMO

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

18.
Stem Cells Dev ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128390

RESUMO

The corneal endothelium(CE) is vital for the cornea to maintain its transparency. However, CE dysfunction occurs due to aging, intraocular surgery, trauma, dystrophy, etc. Corneal transplantation is the only method to clinically treat CE dysfunction; however, this treatment strategy faces the disadvantages of a global cornea shortage, graft failure, and severe side effects. There is a recognized need for a substitute for the CE. Stem cells are becoming increasingly common for the treatment of human diseases. In fact, several studies have documented the induction of corneal endothelial-like cells (CECs) from stem cells, but an ideal procedure has not yet been established. Thus, this study aimed to explore a more efficient and robust differentiation method. We used a modified approach to differentiate induced pluripotent stem cells (iPSCs) into CECs. After the identification of differentiated CECs, the CECs were injected into the anterior chambers of the eyes of a rabbit model of bullous keratopathy. The rabbits were maintained in the eye-down position to ensure that the cells attached to the cornea. The results showed that corneal edema was alleviated in the rabbits injected with CECs compared with that in the rabbits belonging to the control group. This study extends the ability to differentiate iPSCs into CECs and provides a potential strategy for the treatment of reduced visual acuity caused by CE deficiency in the future.

19.
Environ Pollut ; 286: 117531, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34126519

RESUMO

Guadipyr, which combines neonicotinoid and semicarbazone functional groups in one molecule, exhibits good activity on several pests and high acute and chronic toxicity to silkworms (Bombyx mori). In this report, the effects of low-dose guadipyr on the midgut microbiota and immune system of silkworms were studied. Results showed that the structure and richness of the midgut microbiota of silkworms were altered after being treated with 5.25 mg/L (1/10 of LC50) of guadipyr. The abundance of Pseudomonas was evidently increased, whereas Curvibacter was substantially reduced, which might be related to the growth and immunity of silkworms. The expression of key genes in the Toll, IMD, and JAK/STAT pathways, which ultimately led to the downregulation of antimicrobial peptide genes (AMPs), such as CecA, Defensin1, Leb, and glv2, was reduced upon guadipyr exposure. Simultaneously, the suppression of steroid hormone 20-hydroxyecdysone receptor and response genes, such as BR-C Z4, was detected in the exposed groups. The decreased expression of these immune regulatory pathway-related and 20-hydroxyecdysone signal pathway-related genes indicated that the immune system of silkworms was affected by low-dose guadipyr. Our results revealed the negative effects of guadipyr on silkworms and highlighted the unneglectable toxicity of low-dose guadipyr to this economic insect. Given the risk, it is necessary to control the application of guadipyr in or around the mulberry fields.

20.
J Biomater Sci Polym Ed ; : 1-19, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34082651

RESUMO

Due to the insufficient endothelialization and the poor colonization of smooth muscle cells (SMCs), small-diameter vascular tissue engineering is still challenging. An ideal vascular graft is expected to effectively support the formation of endothelial monolayer and the colonization of SMCs. In this study, we proposed a bilayered scaffold with hierarchical pore size constructed from nano and microfibers by electrospinning PCL-PEG-PCL (PCE) and a blend of PCE and gelatin (PCEG) sequentially. The structural features of nano and microfibers were tuned by the concentration of PCE and the proportion of PCE/gelatin in electrospun solution respectively. The results demonstrated the best nanofiber morphology and relatively high mechanical properties were achieved in 18% PCE (w/v) (PCE18) and PCE and gelatin with a weight ratio of 7:3 (P7G3) at a concentration of 18% (w/v) electrospun membranes. The in vitro co-culturing studies of cells and membranes indicated all the PCE membranes supported the proliferation and spreading of endothelial cells and the further endothelialization of the membranous surface, while PCEG membranes facilitated the migration inward of SMCs. Taking the porosity and mechanical properties into consideration, PCE18 and P7G3 were chosen to construct the inner and outer layers of the bilayered scaffold with hierarchical pore size respectively. The circumferential ring test demonstrated that the bilayered scaffold has good mechanical property both in dry and wet state. After cells were co-cultured with this bilayered scaffold for 7 days, the results manifested a continuous endothelial monolayer has formed on the luminal surface and the SMCs have started to colonized from outer layers, indicating the vast potential of this bilayered scaffold in vascular remodeling and regeneration.

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