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1.
Gene ; 764: 145099, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32861879

RESUMO

Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors' age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.

2.
Food Chem ; 334: 127558, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32711269

RESUMO

Shellfishes contain plasmalogens correlating to the functions of brain, heart, etc. Herein, a mild acid hydrolysis and hydrophilic interaction chromatography (HILIC) tandem mass spectrometry method was developed for analyzing plasmalogens in six shellfish species. A total of 19 plasmalogen molecular species were successfully identified, including nine phosphatidylcholine plasmalogen (plasPC), seven phosphatidylethanolamine plasmalogen (plasPE), and three phosphatidylserine plasmalogen (plasPS). The quantitative results indicated that mussel (32 µg·mg-1) possessed the highest content of plasmalogens, followed by oyster (21 µg·mg-1) and razor clam (15 µg·mg-1). The statistic models showed that the plasPE P-18:0/20:5 (m/z 748), plasPE P-16:0/22:2 & P-18:0/20:2 (m/z 754) and plasPS were the most contributing difference between shellfishes. The results indicated that this method was sensitive and precise to determine plasmalogens in shellfish, and mussel was demonstrated to be a good choice for the large-scale preparation of plasmalogens.

3.
Toxicol Appl Pharmacol ; 408: 115264, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022284

RESUMO

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.

4.
Zhongguo Zhen Jiu ; 40(10): 1027-33, 2020 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-33068341

RESUMO

OBJECTIVE: To establish and promote the non-contact doctor-patient interactive diagnosis and treatment mode based on mobile internet for the treatment of coronavirus disease 2019 (COVID-19) with moxibustion therapy, and to observe the feasibility and effectiveness of the model in the pandemic. METHODS: A total of 43 first-line medical staff and 149 suspected and confirmed cases with COVID-19 [18 cases in medical observation period, 17 cases of mild type (cold dampness and stagnation in the lung), 24 cases of ordinary type (cold-dampness accumulated in the lung) and 90 cases in recovery period (qi deficiency of spleen and lung)] were included. A non-contact doctor-patient interactive diagnosis and treatment platform was established for the treatment of COVID-19 with indirect moxibustion plaster based on mobile internet. By the platform, the patients were instructed to use indirect moxibustion plaster in treatment. For the first-line medical staff and patients in the medical observation period, Zusanli (ST 36), Qihai (CV 6) and Zhongwan (CV 12) were selected. For the mild cases (cold dampness and stagnation in the lung) and the cases of ordinary type (cold-dampness accumulated in the lung), Hegu (LI 4), Taichong (LR 3), Zusanli (ST 36) and Guanyuan (CV 4) were selected. In the recovery period (qi deficiency of spleen and lung), Dazhui (GV 14), Feishu (BL 13), Geshu (BL 17), Zusanli (ST 36) and Kongzui (LU 6) were used. The treatment was given once daily for 40 min each time. The intervention lasted for 10 days. After intervention, the infection rate and the improvement in the symptoms and psychological status of COVID-19 were observed in clinical first-line medical staff and COVID-19 patients. RESULTS: In 10 days of intervention with indirect moxibustion plaster, there was "zero" infection among medical staff. Of 43 first-line physicians and nurses, 33 cases had some physical symptoms and psychological discomforts, mainly as low back pain, poor sleep and anxiety. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 78.8% (26/33) and the curative rate was 36.4% (12/33). Regarding the improvements in psychological discomforts, the effective rate was 58.3% (14/24) and the curative rate was 37.5 (9/24). Of 149 patients, 133 cases had the symptoms and psychological discomforts. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 81.2% (108/133) and the curative rate was 34.6% (46/133). Regarding the improvements in psychological discomforts, the effective rate was 76.5% (52/68) and the curative rate was 57.4 % (39/68). CONCLUSION: It is feasible to apply the indirect moxibustion plaster technique based on mobile internet to the treatment COVID-19. This mode not only relieves the symptoms such as cough and fatigue, improves psychological state, but also possibly prevents the first-line medical staff from COVID-19.

5.
Zhongguo Zhen Jiu ; 40(10): 1103-7, 2020 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-33068354

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on the expressions of nuclear transcription factors-kappa B (NF-κB) p65, NF-κB inhibitor (IκB) α and IκB kinase (IKK) ß in rats with acute myocardial ischemia-reperfusion injury (MIRI) and to explore the mechanism of EA on heart meridian in relieving MIRI. METHODS: A total of 40 SD rats were randomized into a sham-operation group, a model group, an EA heart meridian group and an EA lung meridian group, 10 rats in each one. In the EA heart meridian group, acupuncture was applied to "Shenmen" (HT 7) and "Tongli" (HT 5). In the EA lung meridian group, acupuncture was applied to "Taiyuan" (LU 9) and "Lieque" (LU 7). In these two groups, EA was exerted for 20 min each time, 1 V in voltage and 2 Hz in frequency once a day. A total of 7-day EA stimulation was required before model duplication. In the model group, the EA heart meridian group and the EA lung meridian group, using ligating left anterior descending coronary artery to establish the acute MIRI models. In the sham-operation group, the chest was open, but no ligation was exerted, just the needle was penetrated through the corresponding sites for one time. The electrocardiogram (ECG) was detected and ST segment displacement was analyzed. Using Western blot method, the relative expressions of NF-κB p65, IκBα and IKKß in myocardial tissue were determined in each group. Using ELISA method, the levels of serum IL-1ß and IL-10 were determined in each group. RESULTS: Compared with the sham-operation group, ST segment displacement value was elevated 30 min after ligating and reperfusion for 120 min in the model group (P<0.05), and the value in the EA heart meridian group was lower than the model group and the EA lung meridian group (P<0.05). Compared with the sham-operation group, the expressions of NF-κB p65 and IKKß in myocardial tissue were increased (P<0.05) and the expression of IκBα reduced in the rats of the model group (P<0.05). Compared with the model group, the expressions of NF-κB p65 and IKKß in myocardial tissue were reduced (P<0.05) and the expressions of IκBα increased in the rats of the EA heart meridian group and the EA lung meridian group (P<0.05). Compared with the EA lung meridian group, the expressions of NF-κB p65 and IKKß in myocardial tissue were reduced (P<0.05) and the expression of IκBα increased in the rats of the EA heart meridian group (P<0.05). Compared with the sham-operation group, the serum level of IL-1ß was increased (P<0.05) and IL-10 reduced in the model group (P<0.05). Compared with the model group, the serum level of IL-1ß was reduced (P<0.05) and IL-10 increased in the EA heart meridian group and the level of IL-1ß was was reduced in the EA lung meridian group (P<0.05). Compared with the EA lung meridian group, the serum level of IL-1ß was reduced (P<0.05) and IL-10 increased in the EA heart meridian group (P<0.05). CONCLUSION: Electroacupuncture preconditioning at heart meridian acupoints obviously alleviates acute MIRI. IKK/IκB/NF-κB signaling pathway possibly participates in the protective mechanism of electroacupuncture preconditioning on acute MIRI.

6.
Nanoscale Horiz ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048097

RESUMO

Correction for 'Two-dimensional polar metal of a PbTe monolayer by electrostatic doping' by Tao Xu et al., Nanoscale Horiz., 2020, 5, 1400-1406, DOI: 10.1039/D0NH00188K.

7.
J Adv Nurs ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048358

RESUMO

AIM: To quantify the effect of mind-body interventions on stress in pregnant women. DESIGN: A systematic review and meta-analysis of randomized controlled trials was performed. DATA SOURCES: PubMed, Embase, CENTRAL, Web of Science and PsycINFO were searched from each database inception to January 2020. REVIEW METHODS: Randomized controlled trials regarding mind-body interventions for stress in pregnant women were included. Methodological quality was evaluated using the Cochrane Collaboration 'Risk of Bias' tool and meta-analysis was performed via RevMan 5.3. Subgroup analysis and publication bias assessment were conducted. Post hoc sensitivity analysis was performed to investigate the source of heterogeneity. RESULTS: In total, 28 studies comprising 1944 participants were included. The overall meta-analysis showed that antenatal stress of pregnant women in the mind-body interventions groups showed significant high improvements (SMD=-0.94; 95% CI [-1.25, -0.63]; p < .00001) compared with the control groups. Results of subgroup analyses indicated that all types of mind-body interventions including mindfulness intervention, cognitive behavioural therapy, relaxation techniques and yoga were beneficial to antenatal stress. Both groups and individual formats mind-body interventions were effective. 4-8 weeks mind-body interventions were seemed as the optimal choice. Moreover, mind-body interventions were concomitant with reducing antenatal anxiety and depression. CONCLUSION: Mind-body interventions are promising approaches for stress reduction in pregnant women. Nevertheless, the results should be interpreted with caution because of high heterogeneity and publication bias. Further high-quality studies are needed to verify the findings. IMPACT: Mind-body interventions have been widely implemented to ameliorate antenatal stress, but conflicting results were found across studies. This systematic review and meta-analysis suggested that mind-body interventions are relatively safe and convenient and can successfully promote antenatal stress. The suggestions proposed in this review may be useful for developing a scientific mind-body interventions regimen and encouraging the application of mind-body interventions in pregnant women, thereby managing antenatal stress effectively.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33050057

RESUMO

This paper focuses on the fire risk assessment for commercial complex, as the variety of fire accidental triggers inside could be a big threat to the public fire safety, leading to catastrophic loss in human lives and properties. Both the qualitative and quantitative analysis were imposed on a typical large commercial complex to recognize the potential fire-causative factors in this paper. Applying the fault tree analysis, the basic events leading to fire are acquired, and they are then further reclassified based on the analytic hierarchy process. Taking the damage of the accident as the target layer and the fire-causative factors, the equipment operation factors and firefighting factors as the criterion layer, the assessment index is well established. The risk of each factor is quantitatively evaluated, and the effect of each factor on the target layer is analyzed. The result of the fault tree analysis and analytic hierarchy process shows good consistency, in which human behavior is the main factor leading to the fire occurrence, followed by the combustible material, the rescue speed and the staff assignment factors. The results are beneficial for general decisions and measures in public fire safety management.

9.
Chem Commun (Camb) ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030471

RESUMO

Correction for 'Enantioselective and regioselective aza-Friedel-Crafts reaction of electron-rich phenols with isatin-derived ketimines' by Liu Cai et al., Chem. Commun., 2020, 56, 10361-10364, DOI: 10.1039/D0CC04966B.

10.
J Comp Eff Res ; 9(14): 985-1002, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33025800

RESUMO

Aim: Breast cancer is a leading cause of cancer among women. Because guidelines on screening for breast cancer for certain ages are controversial, many experts advocate the use of shared decision making (SDM) using validated decision aids (DAs). Recent studies have concluded that DAs are beneficial; however, the results have great heterogeneity. Therefore, further studies are needed to improve understanding of these tools. Objective: This systematic review and meta-analysis aimed to investigate the impact of using web-based DAs in women aged 50 years and below facing the decision to be screened for breast cancer in comparison with usual care. Methods: PubMed, Web of Science, Embase and the Cochrane CENTRAL databases were searched up to February 2020 for studies assessing web-based DAs for women making a breast cancer screening decision and reported quality of decision-making outcomes. Using a random-effects model or a fixed-effects model, meta-analyses were conducted pooling results using mean differences (MD), standardized mean differences (SMD) and relative risks (RR). Results: Of 1097 unique citations, three randomized controlled trials and two before-after studies met the study eligibility criteria. Compared with usual care, web-based DAs increased knowledge (SMD = 0.69; 95% CI: 0.57-0.80; p < 0.00001), reduced decision conflict and increased the proportion of women who made an informed choice (RR = 1.86; 95% CI: 1.38 to 2.50; p < 0.0001), but did not change the intention of women deciding to be screened or affect decision regret. Conclusion: This analysis showed the positive effect of web-based DAs on patient-centered outcomes in breast cancer screening. In the future, more internet devices and free or larger discount WI-FI should be established to ensure more women can benefit from this effective tool.

11.
Ann Palliat Med ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-33040557

RESUMO

BACKGROUND: Gut microbiota play an important role in the inflammation. This study aimed to investigate whether exogenous probiotics could improve the intestinal barrier function effect via attenuating inflammation and immunomodulation to improve the clinical outcomes in critically ill patients. METHODS: A single-blind, randomized controlled trial was performed in a respiratory intensive care unit (RICUs). Patients assigned to the intervention group received probiotics Clostridium butyricum until death or discharge. Stool and blood samples were collected on the 1st day and 15th day of administration. Primary clinical outcomes and clinical manifestations were recorded during the follow-up period. RESULTS: There were 61 patients in this study, with 28 patients receiving probiotics. There were no differences in the mortality and hospital stay between intervention group and control group. In addition, the duration of fever (% of hospital stays) was significantly shorter in the intervention group as compared to control group (4.85% vs. 12.94%, P=0.00). The incidence of constipation significantly reduced in the intervention group (17.86% vs. 42.42%, P=0.04). The overall ratio of gastrointestinal adverse effects was comparable between them. Bactericides significantly decreased after probiotic intervention (Δm=-0.69, P=0.048), while Escherichia coli and Enterococcus tended to decrease in the intervention group (Δm=-0.65, P=0.08; Δm=-0.52, P=0.22) on the day 15. No fluctuation was observed in the Bifidobacterium and Lactobacillus after probiotic intervention. CONCLUSIONS: Our study fails to show the beneficial effects of probiotics on the primary clinical outcomes in critically ill patients. The intestinal barrier is damaged, and probiotics may reduce the burden of Gm-bacteria from the gut.

12.
Food Chem ; 340: 128128, 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-33010646

RESUMO

In this research, a novel signal-on aptasensor for highly sensitive detection of zearalenone (ZEN) was reported based on target-induced amplification strategy. Specifically, chitosan functionalized acetylene black and multi-walled carbon nanotubes (CS@AB-MWCNTs) nanocomposite with large specific surface area and excellent conductivity was synthesized and served as the sensing platform. In addition, carboxylated graphene oxide-labeled ZEN binding aptamer (CGO-ZBA) would specifically recognized with ZEN to detach from the electrode, allowing the electrochemical signal of [Fe(CN)6]3-/4- increased more obviously. Under the optimal conditions, the proposed aptasensor exhibited exceptional detection performances for ZEN with a linear range from 10 fg mL-1 to 1 ng mL-1 and a low limit of detection of 3.64 fg mL-1. Given its great sensitivity, excellent selectivity, satisfactory stability and reproducibility, this method would provide a promising application for ZEN and other biomolecules by replacing the corresponding nucleicacidsequences.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33021938

RESUMO

Deep models are commonly treated as black-boxes and lack interpretability. Here, we propose a novel approach to interpret deep image classifiers by generating discrete masks. Our method follows the generative adversarial network formalism. The deep model to be interpreted is the discriminator while we train a generator to explain it. The generator is trained to capture discriminative image regions that should convey the same or similar meaning as the original image from the model's perspective. It produces a probability map from which a discrete mask can be sampled. Then the discriminator is used to measure the quality of the sampled mask and provide feedbacks for updating. Due to the sampling operations, the generator cannot be trained directly by back-propagation. We propose to update it using policy gradient. Furthermore, we propose to incorporate gradients as auxiliary information to reduce the search space and facilitate training. We conduct both quantitative and qualitative experiments on the ILSVRC dataset. Experimental results indicate that our method can provide reasonable explanations for predictions and outperform existing approaches. In addition, our method can pass the model randomization test, indicating that it is reasoning the attribution of network predictions.

14.
Int J Biochem Cell Biol ; : 105862, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33045372

RESUMO

During the orthodontic tooth movement, cells in periodontal ligament could differentiate into osteoblasts to synthesize alveolar bone as well as affect the proliferation, migration and differentiation of mesenchymal stem cells, which also contribute to bone remodeling. However, the mechanism is still largely elusive. Here, we evaluated the expression of CREB at the tension site of mouse periodontal ligament under orthodontic mechanical strain and in the cyclic tension strain treated human periodontal ligament cells. Then, through gain and loss of function analysis, we revealed that CREB in PDLCs promotes SDF-1 and FGF2 secretion, which enhance the migration and osteoblastic differentiation of BMSCs. We further discovered that CREB transcriptionally activates FGF2 and SDF-1 expressions by binding to the promoter regions. In conclusion, this study confirms that CREB is an upregulated gene in periodontal ligament under orthodontic tension strain stimulation and plays an important role in regulating BMSCs' physiological activity in orthodontic tension strain-induced bone formation.

15.
Int Urol Nephrol ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037521

RESUMO

PURPOSE: To present our experience of laparoscopic and robotic ureteroplasty using onlay flap or graft for the management of long proximal or middle ureteral strictures and summarize our treatment strategies for these challenging scenarios. METHODS: From March 2018 to January 2020, 53 patients with long proximal/middle ureteral strictures (2-6 cm) who underwent laparoscopic or robotic onlay flap/graft ureteroplasty were retrospectively enrolled. Different reconstruction techniques were chosen based on our management strategy: pelvic flap (PF) was the first choice for proximal stricture if pelvic tissue was sufficient for repair, while appendiceal flap (AF) was preferred over oral mucosa graft for both proximal and middle strictures. RESULTS: A total of 28 PFs, 9 AFs and 16 lingual mucosa grafts (LMGs) onlay ureteroplasty were performed successfully, with 33 laparoscopic procedures and 20 robotic procedures being undertaken. No intraoperative complications or conversion occurred. The median stricture length was 4 cm (range 2-6 cm). Compared with laparoscopic procedures, robotic procedures showed significantly shorter operative time (P = 0.008), shorter postoperative hospital stay (P = 0.011) but higher hospital cost (P < 0.001). At a mean follow-up of 12.8 months, the overall success rate was 94.3%. There was no difference in postoperative complications or the success rate between the approaches. CONCLUSION: Laparoscopic and robotic onlay flap/graft ureteroplasty can be safe and feasible to repair long proximal/middle ureteral strictures while robotic procedures showed higher efficiency, faster recovery but higher cost. Our algorithmic strategies may provide beneficial references for their standardization and dissemination into clinical care.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33038071

RESUMO

This study aimed to determine whether high-fat diet (HFD) could cause growth, behavioural, biochemical and morphological changes in young female rabbits. Thirty-six female rabbits were randomly divided into two groups fed with either a high-fat diet (HFD) or a standard normal diet (SND) for 5 weeks. Growth and behavioural changes were recorded during the 5-week feeding period. Tissue samples, including blood and adipose tissue, were obtained after slaughter. HFD rabbits weighed more by the end of the feeding period, had a higher percent body weight and adipose tissue weight change and had longer body and bust lengths than SND rabbits. HFD rabbits significantly reduced their feed intake and feeding frequency during the fourth and fifth weeks. HFD rabbits also showed lower frequency of drinking and resting and increased stereotypical behaviour. Besides, HFD rabbits showed significant physiological abnormalities. HFD rabbits had higher serum cholesterol (TC) and triglycerides (TG) levels than SND rabbits at the end of the feeding period, and higher free fatty acid (FFA) levels than rabbits in the SND group after the third week of feeding. Serum thyroxine (T4) increased significantly in week 2 and week 5 and triiodothyronine (T3) increased significantly in week four. However, there was no significant change in serum glucose (GLU) and insulin (INS) levels. Additionally, HFD reduced the area and diameter of perirenal and subcutaneous fat cells and increased their density. Our findings suggest that HFD rabbits had higher weight gains, accumulation of fat, and more behavioural changes than SND rabbits. Although high levels of fat in the diet had a low impact on hyperglycaemia, it could lead to hyperlipidemia and hyperthyroidism. Our results also suggest that sustained HFD may cause the proliferation of adipocytes in young female rabbits.

17.
J Immunol Res ; 2020: 5746832, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015198

RESUMO

Immune tolerance research is essential for kidney transplantation. Other than antibody and T cell-mediated immune rejection, macrophage-mediated innate immunity plays an important role in the onset phase of transplantation rejection. However, due to the complexity of the kidney environment as well as its diversity and low abundance, studies pertaining to monocyte/macrophages in kidney transplantation require further elucidation. In this study, kidney samples taken from healthy human adults and biopsy specimens from patients undergoing rejection following kidney transplantation were analysed and studied. By conducting a single-cell RNA analysis, the type and status of monocyte/macrophages in kidney transplantation were described, in which monocyte/macrophages were observed to form two different subpopulations: resident and infiltrating monocyte/macrophages. Furthermore, previously defined genes were mapped to all monocyte/macrophage types in the kidney and enriched the differential genes of the two main subpopulations using gene expression databases. Considering that various cases of rejection may be of the monocyte/macrophage type, the present data may serve as a reference for studies regarding immune tolerance following kidney transplantation.

18.
JAMA Netw Open ; 3(10): e2013770, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017026

RESUMO

Importance: Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non-small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established. Objectives: To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay. Design, Setting, and Participants: This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019. Exposure: Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test. Results: A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × µg/mL; for 500-L group: 12 331.42 [2472.58] hour × µg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti-PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively. Conclusions and Relevance: In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.

19.
Science ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004674

RESUMO

Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity and neurogenesis. In zebrafish and chick, transition from the quiescence to reactivity is essential for retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I (NFI) transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice following injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.

20.
J Mol Neurosci ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33006106

RESUMO

Frontotemporal dementia (FTD) is a heterogeneous disease both clinically and pathologically. Genetic mutation in microtubule-associated protein tau (MAPT) is the most common cause of FTD, and the phenotype is related to the mutation location. However, the phenotype and genotype correlation varies somewhat among different cohorts and ethnicities. Whole-genome next-generation sequencing (NGS) was carried out for 1351 patients with dementia at Peking Union Medical College Hospital. MAPT variations classified as pathogenic and of uncertain significance were identified. Demographic information, clinical presentations, and neuroimaging were collected, and the phenotype-genotype correlation was analyzed with a concurrent literature review. Twenty-four patients were enrolled; 8 patients carrying the D177V mutation are discussed separately. The average onset age was young, and most of them had a positive family history. Cognitive dysfunction, behavior, and personality changes as well as aphasia were the most common presentations. Most structural MRIs showed asymmetrical atrophy of the temporal lobe, with/without similar changes in the frontal lobe. L266V carriers presented with youngest onset typical behavior variant FTD or aphasia; P301L carriers presented with behavior variant FTD or aphasia. Functional MRI and molecular imaging also showed that the involved areas were similar to those with structural atrophy. D296N carriers presented atypical parkinsonism and cognitive dysfunction at older ages. Eight D177V carriers had extraordinarily different manifestations. The clinical phenotype of most of them was not FTD, though cerebral vascular lesions were obvious in some of them. MAPT mutation is rare in Chinese dementia patients. The phenotype and genotype correlation is specific and overlaps. The D177V mutation is possibly not directly pathogenic in our cohort. Some of the variants might increase the genetic risk of neurodegenerative diseases.

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