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1.
Sci Rep ; 11(1): 7470, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811251

RESUMO

AXIN1 mutations are observed in 8-10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing ß-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear ß-catenin accumulation nor clearly enhanced expression of ß-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced ß-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control ß-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to ß-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the ß-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of ß-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on ß-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced ß-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing ß-catenin signaling.

2.
Biochem Biophys Res Commun ; 554: 206-213, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33813076

RESUMO

Osteosarcoma is the most common primary bone tumor in children, teenagers and adolescents. Cancer stem cells (CSCs) have the function to self-renew and keep the phenotype of tumor, causing clinical treatment failure. Therefore, developing effective therapies to inhibit osteosarcoma progression is urgently necessary. Glycogen synthase kinase 3ß (GSK-3ß)is highly expressed in osteosarcoma. In the present study, we made an exploration on the anti-tumor effect of tideglusib (TID), a small-molecule inhibitor of GSK-3ß, and revealed the underlying mechanisms. Here, we found that TID markedly reduced the cell viability of different osteosarcoma cell lines. Cell cycle arrest distributed in G2/M was markedly up-regulated in TID-incubated osteosarcoma cells through enhancing p21 expression levels. Apoptosis was evidently induced in osteosarcoma cells via blocking Caspase-3 activation. Consistently, tumor growth was effectively suppressed in an established murine xenograft model with few toxicity and side effects in vivo. Furthermore, TID markedly repressed stem-cell-like activity in osteosarcoma cells through down-regulating NOTCH1 expression. Notably, rescuing NOTCH1 significantly abolished the role of TID in reducing cell proliferation and sarcosphere-formation. Mechanistically, we found that TID-inhibited NOTCH1 expression was associated with the blockage of AKT/GSK-3ß signaling pathway. In summary, we for the first time provided evidence that TID could effectively inhibit osteosarcoma progression through repressing cell proliferation, inducing apoptosis, suppressing stem-cell-like properties via down-regulating AKT/GSK-3ß/NOTCH1 signaling pathway. Thus, TID may be a promising therapeutic strategy for osteosarcoma treatment without side effects.

3.
Hepatology ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33829508

RESUMO

BACKGROUND & AIMS: Due to their inherent characteristics, the function of group-2 innate lymphoid cells (ILC2s) varies in a context-dependent manner. ILC2s are involved in certain liver diseases; however, their involvement in hepatocellular carcinoma (HCC) is unknown. In the present study, we assessed the role of an HCC-derived ILC2 population in tumor progression. APPROACH & RESULTS: Through fluorescence activated cell sorting and single-cell RNA sequencing, we discovered that ILC2s were highly enriched in human HCC and correlated significantly with tumor recurrence and worse progression free as well as overall survival in patients. Mass cytometry identified a subset of HCC-derived ILC2s that had lost the expression of killer cell lectin-like receptor subfamily G, member 1 (KLRG1). Distinct from their circulating counterparts, these hepatic ILC2s highly expressed CD69 and an array of tissue resident-related genes. Furthermore, reduction of E-cadherin in tumor cells caused the loss of KLRG1 expression in ILC2s, leading to their increased proliferation and subsequent accumulation in HCC sites. The KLRG1- ILC2 subset showed elevated production of chemotaxis factors, including C-X-C motif chemokine ligand (CXCL)-2 and CXCL8, which in turn recruited neutrophils to form an immunosuppressive microenvironment, leading to tumor progression. Accordingly, restoring KLRG1 in ILC2s, inhibiting CXCL2 in ILC2s, or depleting neutrophils, inhibited tumor progression in a murine HCC model. CONCLUSION: We identified HCC-associated ILC2s as an immune regulatory cell type that promotes tumor development, suggesting that targeting these ILC2s might lead new treatments for HCC.

4.
Minerva Med ; 112(2): 314, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33829748

RESUMO

This article was published in volume 111 issue 6 of publishing year 2020 with a wrong authors' byline. The correct authors' byline is: Shanshan LI 1 *, Youxu ZHAO 2, Jing ZHAO 3, Lei MOU 4 1 Department of Encephalopathy II, Rizhao Hospital of Traditional Chinese Medicine, Rizhao, China; 2 Ju County Hospital of Traditional Chinese Medicine, Rizhao, China; 3 Zibo Central Hospital, Zibo, China; 4 Department of Neurology, Rizhao Hospital of Traditional Chinese Medicine, Rizhao, China *Corresponding author: Shanshan Li, Department of Encephalopathy II, Rizhao Hospital of Traditional Chinese Medicine, Rizhao, China. E-mail: uucik4@163.com.

5.
Biomed Chromatogr ; : e5140, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830528

RESUMO

Due to the complexity of the composition of herbal and dietary supplement (HDS), it is a challenging problem to efficiently screen and identify active or toxic compounds. Psoralea corylifolia L. (PCL) is selected as the object to establish a methodology for rapid screening and identification of hepatotoxic compounds. High-content imaging and ultra-performance liquid chromatography and high-resolution mass spectrometry were used in this study to detect the hepatotoxicity and identified unknown compounds in PCL samples. Then, putative toxic compounds which are highly related to hepatotoxicity were screened by spectrum-toxicity correlation analysis, and verified the toxicity intensity by high-content imaging. The maximum non-toxic dose of processed samples with good detoxification effect reduced more than 9 times compared to unprocessed raw medicinal materials. Spectrum-toxicity correlation analysis showed that bavachinin A, bavachin, isobavachalcone, and neobavaisoflavone had high correlation with hepatotoxicity of PCL, and psoralen and isopsoralen had low correlation with the hepatotoxicity. This study verified the hepatotoxicity of this six putative compound monomers, proving the results of spectrum-toxicity correlation analysis. Based on the correlation analysis of high-resolution mass spectrometry of detection compounds and high-content imaging hepatocyte toxicity data, the potential toxic compound of HDS products can be quickly and accurately screened.

6.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 35(3): 209-211;215, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33794603

RESUMO

Objective: To study whether the warm/cold air injection sequence affects the test results in the caloric test, and provide a basis for the specification and quality control of the caloric test. Methods:Video nystagmography and warm and cold air stimulation apparatus were applied for caloric test. Thirty healthy volunteers (60 ears) were divided into two groups of 15 (30 ears) each. The first group was given cold air stimulation followed by warm air stimulation, and the second group was given heat followed by cold. The differences in nystagmus maximal slow phase velocity (SPV), semicircular canal paresis (CP) and dominant preponderance (DP) were compared between the two groups of subjects under different perfusion sequences of caloric test. Results:The intensity of nystagmus evoked by subjects in group 1 (cold first and then warm) and group 2 (warm first and then cold) were similar. Paired t-test showed that intra-group analysis of the SPV values of the two groups, comparison of the intensity of nystagmus evoked by different temperatures of the same ear or different sides of ear with the same temperature, the difference was not statistically significant (all P>0.05). Independent samples t-test showed that between-group analysis of SPV values of two groups, the intensity of nystagmus induced by the same and different temperature stimuli in the ipsilateral ear, the difference was not statistically significant (all P>0.05). Independent samples t-test showed that the CP values of the two groups were analyzed between groups, and the difference was not statistically significant (all P>0.05). Independent samples t-test showed that DP values of both groups were in the normal range and the difference was not statistically significant (all P>0.05). Conclusion:Different perfusion sequences of warm and cold air do not affect the results of caloric tests, and the order of warm and cold air stimulation is not the normative and quality control research direction of caloric test.


Assuntos
Testes Calóricos , Nistagmo Patológico , Temperatura Baixa , Temperatura Alta , Humanos , Perfusão
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(4): 309-312, 2021 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-33834453

RESUMO

OBJECTIVE: To evaluate the efficacy of non-invasive prenatal testing (NIPT) in the prenatal screening and its role in the system of prenatal diagnosis. METHODS: A total of 22 649 singleton pregnant women who were registered and finally delivered or had induced labor at Beijing Obstetrics and Gynecology Hospital of Capital Medical University were enrolled. The routes of prenatal screening were analyzed to evaluate the efficacy of prenatal screening. Meanwhile, 9268 pregnant women who underwent invasive prenatal diagnosis procedure were enrolled. The indications and results of prenatal diagnosis were analyzed to evaluate the effectiveness of prenatal screening. RESULTS: 60.24% of singleton pregnant women have opted for Down syndrome screening, and their age was mainly under 35. The proportion of women opted for NIPT was 34.74%, and were mainly between 35 and 39. The overall diagnostic rate of trisomy 21, 18 and 13 trisomy for those with high risk by NIPT was 0.89%, which yielded a positive predictive value of 75.71%. For those with moderate risk by serum screening, 0.30% was predicted with a high risk by NIPT. Among women undergoing prenatal diagnosis, 63.04% and 21.22% had the indication of advanced age or high risk by serum screening, and the positive predictive values were 5.1% and 5.13%, respectively. By contrast, 2.30% of women undergoing prenatal diagnosis had a high risk by NIPT, which yielded a positive predictive value of 54.46%. CONCLUSION: With the change of the age composition of pregnant women and increase in the complexity of pregnancy in China, to build a prenatal screening system based on NIPT will be helpful to improve the efficiency of the current system of prenatal screening and diagnosis.

8.
Appetite ; 163: 105239, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33794258

RESUMO

There is a continuous increase in the number of studies dealing with consumers' willingness to pay (WTP) price premiums for sustainable food products. This research focused on a broad area of sustainable food products, including different sustainable attributes using a meta-analysis of 80 worldwide studies. The publication bias was verified using the funnel plot and Egger's test. In addition, the subgroup analysis and meta-regression were applied to classify the source of heterogeneity. The results suggest that the overall WTP premium for sustainability (in percentage terms) is 29.5% on average. Furthermore, gender, region, sustainable attributes and food categories influence the average WTP estimates and their heterogeneity. Results also indicate that the WTP estimate conducted by hypothetical approach (choice experiment and contingent valuation method) is higher than non-hypothetical one due to hypothetical bias. In addition, the WTP estimate from the CVM is higher than that from the CE. Additionally, the WTP value of organic attribute is higher than the other sustainable attributes. The subgroup analysis indicates that the fruit &vegetable category has the highest WTP estimate while the seafood receives the lowest one. Results also highlight that Asian WTP estimates, in percentage terms, are higher than those obtained in North America and similar to those from Europe. In addition, positive WTP estimates are shown independent of the food categories, region or methods, denoting the presence of great market potential for sustainable products worldwide. The findings of this research can be used as a guide by food producers, marketers and policymakers when making decisions related to the sustainability of food products.

9.
Environ Int ; 153: 106548, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33838617

RESUMO

BACKGROUND: Evidence of maternal exposure to ambient air pollution on congenital heart defects (CHD) has been mixed and are still relatively limited in developing countries. We aimed to investigate the association between maternal exposure to air pollution and CHD in China. METHOD: This longitudinal, population-based, case-control study consecutively recruited fetuses with CHD and healthy volunteers from 21 cities, Southern China, between January 2006 and December 2016. Residential address at delivery was linked to random forests models to estimate maternal exposure to particulate matter with an aerodynamic diameter of ≤ 1 µm (PM1), ≤2.5 µm, and ≤10 µm as well as nitrogen dioxides, in three trimesters. The CHD cases were evaluated by obstetrician, pediatrician, or cardiologist, and confirmed by cardia ultrasound. The CHD subtypes were coded using the International Classification Diseases. Adjusted logistic regression models were used to assess the associations between air pollutants and CHD and its subtypes. RESULTS: A total of 7055 isolated CHD and 6423 controls were included in the current analysis. Maternal air pollution exposures were consistently higher among cases than those among controls. Logistic regression analyses showed that maternal exposure to all air pollutants during the first trimester was associated with an increased odds of CHD (e.g., an interquartile range [13.3 µg/m3] increase in PM1 was associated with 1.09-fold ([95% confidence interval, 1.01-1.18]) greater odds of CHD). No significant associations were observed for maternal air pollution exposures during the second trimester and the third trimester. The pattern of the associations between air pollutants and different CHD subtypes was mixed. CONCLUSIONS: Maternal exposure to greater levels of air pollutants during the pregnancy, especially the first trimester, is associated with higher odds of CHD in offspring. Further longitudinal well-designed studies are warranted to confirm our findings.

10.
Lancet Planet Health ; 5(4): e191-e199, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33838734

RESUMO

BACKGROUND: Epidemiological evidence on short-term association between ambient carbon monoxide (CO) and mortality is inconclusive and limited to single cities, regions, or countries. Generalisation of results from previous studies is hindered by potential publication bias and different modelling approaches. We therefore assessed the association between short-term exposure to ambient CO and daily mortality in a multicity, multicountry setting. METHODS: We collected daily data on air pollution, meteorology, and total mortality from 337 cities in 18 countries or regions, covering various periods from 1979 to 2016. All included cities had at least 2 years of both CO and mortality data. We estimated city-specific associations using confounder-adjusted generalised additive models with a quasi-Poisson distribution, and then pooled the estimates, accounting for their statistical uncertainty, using a random-effects multilevel meta-analytical model. We also assessed the overall shape of the exposure-response curve and evaluated the possibility of a threshold below which health is not affected. FINDINGS: Overall, a 1 mg/m3 increase in the average CO concentration of the previous day was associated with a 0·91% (95% CI 0·32-1·50) increase in daily total mortality. The pooled exposure-response curve showed a continuously elevated mortality risk with increasing CO concentrations, suggesting no threshold. The exposure-response curve was steeper at daily CO levels lower than 1 mg/m3, indicating greater risk of mortality per increment in CO exposure, and persisted at daily concentrations as low as 0·6 mg/m3 or less. The association remained similar after adjustment for ozone but was attenuated after adjustment for particulate matter or sulphur dioxide, or even reduced to null after adjustment for nitrogen dioxide. INTERPRETATION: This international study is by far the largest epidemiological investigation on short-term CO-related mortality. We found significant associations between ambient CO and daily mortality, even at levels well below current air quality guidelines. Further studies are warranted to disentangle its independent effect from other traffic-related pollutants. FUNDING: EU Horizon 2020, UK Medical Research Council, and Natural Environment Research Council.

11.
Nanotechnology ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33799309

RESUMO

Various polydopamine (PDA) nanospheres were synthesized by utilizing triblock copolymer Pluronic F127 and 1,3,5-trimethylbenzene (TMB) as soft templates. Precise morphology control of polydopamine nanospheres was realized from solid polydopamine nanospheres (PDANSs) to hollow polydopamine nanospheres (H-PDANSs), mesoporous polydopamine nanospheres (MPDANSs) and hollow mesoporous polydopamine nanospheres (H-MPDANSs) by adjusting the weight ratio of TMB to F127. The inner diameter of the prepared H-MPDANSs can be controlled in the range of 50-100 nm, and the outer diameter is about 180 nm. Furthermore, the thickness of hollow mesoporous spherical shell can be adjusted by changing the amount of dopamine (DA). The H-MPDANSs have good biocompatibility, excellent photothermal properties, high drug loading capacity, and outstanding sustainable drug release properties. In addition, both NIR laser irradiation and acid pH can facilitate the controlled release of doxorubicin (DOX) from H-MPDANSs@DOX.

12.
J Bone Miner Res ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33852188

RESUMO

Primary hypertrophic osteoarthropathy (PHO) is a rare disease inherited as a recessive or irregular dominant trait and characterized by digital clubbing, pachydermia and periostosis. Biallelic mutations in HPGD and SLCO2A1, disturbing prostaglandin E2 (PGE2 ) catabolism and leading to increased circulating PGE2 level, cause PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2), respectively. However, no causative genes have been reported for PHO autosomal dominant (PHOAD). Here, we performed Sanger sequencing and the whole-genome sequencing (WGS) on DNA samples from seven Chinese PHOAD families, and after excluding other single nucleotide variants (SNVs), structural variations (SVs) and copy number variations (CNVs) in the genomes, we reported six SLCO2A1 monoallelic mutations (c.1660G>A [p.G554R], c.664G>A [p.G222R], c.1106G>A [p.G369D], c.1065dupA [p.Q356TfsX77], c.1293delT [p.S432AfsX48] and c.1807C>T [p.R603X]) in the probands and affected family members. Then, in five other PHO families with probands carrying SLCO2A1 biallelic mutations, we verified that parents with SLCO2A1 monoallelic mutations also displayed PHO manifestations, which further confirmed the pathogenicity of SLCO2A1 monoallelic mutations and illustrated the allelic nature of PHOAD and PHOAR2. Subsequently, through comparison of 7 PHOAD probands and 50 PHOAR2 patients, we found onset age in puberty and skewed penetrance rate were similar in both PHO types, but symptoms and signs of PHOAD were milder, including less severe pachydermia (p=0.027) and periostosis (p=0.005), and less frequent cutis verticis gyrata (p=0.011), acne (p=0.005), arthralgia (p=0.037) and anemia (p=0.023). The median urinary PGE2 level in PHOAD probands was almost half that in PHOAR2 patients (PHOAD 277.58 ng/mmoL creatinine, PHOAR2 473.19 ng/mmoL creatinine; p=0.038). Moreover, through the 3-month trial of oral administration of Etoricoxib, an effective response similar to that we reported previously in PHOAR2 patients was observed in PHOAD probands. In conclusion, our findings confirm that SLCO2A1 monoallelic mutations are the cause of PHOAD and broaden phenotypic spectrum of PHO. This article is protected by copyright. All rights reserved.

13.
Bioelectrochemistry ; 140: 107804, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33813145

RESUMO

Alpha-fetoprotein (AFP) has become a specific tumor marker of primary liver cancer in clinical diagnosis. In this work, we prepared worm-like platinum (WL Pt) nanomaterial via chemical etching without organic solvents and ultra-high temperature. Due to its small particle size and the formation of surface vacancies during the etching process, it had a large specific surface area, and thus exhibited superior electrocatalytic activity for the reduction of hydrogen peroxide. Combining the signal amplification based on hydrogen peroxide reduction and the specific recognition of antigen with antibody, we constructed a simple label-free electrochemical immunosensor with a sandwich-like structure. The developed electrochemical immunosensor showed a wide linear range (0.0001-100 ng mL-1), a low detection limit (0.028 pg mL-1), good selectivity and stability. Further, the immunosensor was comparable with enzyme-linked immunosorbent assay (ELISA) and had a good accuracy for AFP detection in human serum samples proving the feasibility of potential application, which is expect to become one of the most promising method in early diagnosis and clinical analysis for liver cancer.

14.
Int Immunopharmacol ; 96: 107587, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819732

RESUMO

Psoriasis is a chronic and relapsing disorder with considerable negative effects on patients' quality of life. The finer details associated with the molecular mechanism of psoriasis and its pathogenesis remain somewhat elusive. Extensive studies have highlighted the crucial role of microRNAs (miRNAs) in the development of psoriasis. Hence, the current study aimed to investigate the effect of miR-383 on a psoriasis rat model and elucidate the underlying molecular mechanism. The rat psoriasis model was established via imiquimod (IMQ) induction followed by verification of miR-383 and LCN2 expression in the skin tissues of the models. ELISA was conducted to determine the secretion of inflammatory factors. Keratinocyte proliferation and apoptosis was evaluated by MTT assay and flow cytometric analysis. Down-regulation of miR-383 and up-regulation of LCN2 were detected in the psoriasis rat model. Our data indicated that miR-383 targeted LCN2 by binding to its 3'UTR and inhibited JAK/STAT pathway activation. Notably, miR-383 overexpression or LCN2 knockdown attenuated psoriasis-like symptoms, suppressed inflammatory response, reduced the expression of JAK3 and STAT3, ceased keratinocyte proliferation, and promoted the apoptosis. The findings of our study suggest that miR-383 may inhibit LCN2 and inactivate the JAK/STAT pathway, suppressing the progression of psoriasis in a rat model. This study provided novel insights into the pathogenesis of psoriasis and offered potential targets for psoriasis treatment.

15.
Leuk Res ; 105: 106574, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33836480

RESUMO

INTRODUCTION: Procalcitonin (PCT) and C-reactive protein (CRP) are known inflammatory markers of severe infection; however, their ability to differentiate between infections of different origins is not clear yet. In this study, we evaluated PCT and CRP as markers of infection in hematopoietic stem cell transplantation (HSCT) patients. METHODS: Blood samples were collected to determine serum concentrations of PCT, CRP, d-Dimer, and to perform blood culture analysis. Based on blood culture results, the patients were divided into two groups-positive blood culture (n = 271) patients and negative blood culture patients (n = 668); the negative blood culture group served as the control. The positive blood culture group was further divided into three groups based on the etiological agent of infection. PCT and CRP concentrations were compared, and ROC curve, sensitivity, specificity, and cutoff values were calculated. RESULTS: PCT levels in infected patients were significantly higher than those in control patients (p < 0.001); similarly, CRP and d-Dimer levels were also higher among infected patients when compared with those in the controls. A PCT level of 0.51 ng/mL was the best threshold for detecting the infection, with an AUC-ROC of 0.877, whereas the best threshold for CRP was 49.20 mg/L. PCT levels were the highest in patients with gram-negative bacteremia as compared to in those with gram-positive bacteremia and fungal infection. The optimal cutoff value of PCT for the detection of gram-negative and gram-positive infection was 1.63 ng/mL. CONCLUSION: PCT seems to be a useful marker for the diagnosis of systemic infection in HSCT patients, probably better than CRP and d-Dimer.

16.
Environ Int ; 154: 106556, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33862401

RESUMO

BACKGROUND: DNA methylation is a potential biological mechanism through which residential greenness affects health, but little is known about its association with greenness and whether the association could be modified by genetic background. We aimed to evaluate the association between surrounding greenness and genome-wide DNA methylation and potential gene-greenness interaction effects on DNA methylation. METHODS: We measured blood-derived DNA methylation using the HumanMethylation450 BeadChip array (Illumina) for 479 Australian women, including 66 monozygotic, 66 dizygotic twin pairs, and 215 sisters of these twins. Surrounding greenness was represented by Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) within 300, 500, 1000 or 2000 m surrounding participants' home addresses. For each cytosine-guanine dinucleotide (CpG), the associations between its methylation level and NDVI or EVI were evaluated by generalized estimating equations, after adjusting for age, education, marital status, area-level socioeconomic status, smoking behavior, cell-type proportions, and familial clustering. We used comb-p and DMRcate to identify significant differentially methylated regions (DMRs). For each significant CpG, we evaluated the interaction effects of greenness and single-nucleotide polymorphisms (SNPs) within ±1 Mb window on its methylation level. RESULTS: We found associations between surrounding greenness and blood DNA methylation for one CpG (cg04720477, mapped to the promoter region of CNP gene) with false discovery rate [FDR] < 0.05, and for another 9 CpGs with 0.05 ≤ FDR < 0.10. For two of these CpGs, we found 33 SNPs significantly (FDR < 0.05) modified the greenness-methylation association. There were 35 significant DMRs related to surrounding greenness that were identified by both comb-p (Sidak p-value < 0.01) and DMRcate (FDR < 0.01). Those CpGs and DMRs were mapped to genes related to many human diseases, such as mental health disorders and neoplasms as well as nutritional and metabolic diseases. CONCLUSIONS: Surrounding greenness was associated with blood DNA methylation of many loci across human genome, and this association could be modified by genetic variations.

17.
Toxics ; 9(3)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804264

RESUMO

BACKGROUND: Limited evidence is available on the health effects of particulate matter (PM including PM2.5 with an aerodynamic diameter ≤ 2.5 µm; PM10, ≤ 10 µm; PM2.5-10, 2.5-10 µm) during the pandemic of COVID-19 in Italy. The aims of the study were to examine the associations between all-cause mortality and PM in the pandemic period and compare them to the normal periods (2015-2019). METHODS: We collected daily data regarding all-cause mortality (stratified by age and gender), and PM concentrations for 107 Italian provinces from 1 January 2015 to 31 May 2020. A time-stratified case-cross design with the distributed lag non-linear model was used to examine the association between PM and all-cause mortality. We also compared the counts and fractions of death attributable to PM in two periods. RESULTS: Italy saw an increase in daily death counts while slight decreases in PM concentrations in pandemic period. Each 10 µg/m3 increase in PM was associated with much higher increase in daily all-cause mortality during the pandemic period compared to the same months during 2015-2019 (increased mortality rate: 7.24% (95%CI: 4.84%, 9.70%) versus 1.69% (95%CI: 1.12%, 2.25%) for PM2.5; 3.45% (95%CI: 2.58%, 4.34%) versus 1.11% (95%CI: 0.79%, 1.42%) for PM10; 4.25% (95%CI: 2.99%, 5.52%) versus 1.76% (95%CI: 1.14%, 2.38%) for PM2.5-10). The counts and fractions of deaths attributable to PM were higher in 2020 for PM2.5 (attributable death counts: 20,062 versus 3927 per year in 2015-2019; attributable fractions: 10.2% versus 2.4%), PM10 (15,112 versus 3999; 7.7% versus 2.5%), and PM2.5-10 (7193 versus 2303; 3.7% versus 1.4%). CONCLUSION: COVID-19 pandemic increased the vulnerability and excess cases of all-cause mortality associated with short-term exposure to PM2.5, PM2.5-10, and PM10 in Italy, despite a decline in air pollution level.

18.
Mol Neurobiol ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675499

RESUMO

Huntington's disease (HD) is a neurodegenerative disorder caused by a trinucleotide repeat expansion in the huntingtin gene. Transcriptomic dysregulations are well-documented in HD and alterations in small non-coding RNAs (sncRNAs), particularly microRNAs (miRNAs), could underpin that phenomenon. Additionally, environmental enrichment (EE), which is used to model a stimulating lifestyle in pre-clinical research, has been shown to ameliorate HD-related symptoms. However, the mechanisms mediating the therapeutic effects of EE remain largely unknown. This study assessed the effect of EE on sncRNA expression in the striatum of female R6/1 transgenic HD mice at 12 weeks (prior to over motor deficits) and 20 weeks (fully symptomatic) of age. When comparing wild-type and R6/1 mice in the standard housing condition, we found 6 and 64 miRNAs that were differentially expressed at 12 and 20 weeks of age, respectively. The 6 miRNAs (miR-132, miR-212, miR-222, miR-1a, miR-467a, and miR-669c) were commonly dysregulated at both time points. Additionally, genotype had minor effects on the levels of other sncRNAs, in particular, 1 piRNA was dysregulated at 12 weeks of age, and at 20 weeks of age 11 piRNAs, 1 tRNA- and 2 snoRNA-derived fragments were altered in HD mice. No difference in the abundance of other sncRNA subtypes, including rRNA- and snRNA- derived fragments, were observed. While EE improved locomotor symptoms in HD, we found no effect of the housing condition on any of the sncRNA populations examined. Our findings show that HD mainly affects miRNAs and has a minor effect on other sncRNA populations. Furthermore, the therapeutic effects of EE are not associated with the rescue of these dysregulated sncRNAs and may therefore exert these experience-dependent effects via other molecular mechanisms.

19.
Cell Death Differ ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686256

RESUMO

Although ß-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their functions and regulation in Parkinson's disease (PD) remain poorly defined. In this study, we show that the expression of ß-arrestin 1 (ARRB1) and ß-arrestin 2 (ARRB2) is reciprocally regulated in PD mouse models, particularly in microglia. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including dopaminergic neuron loss, neuroinflammation and microglia activation in vivo, and microglia-mediated neuron damage in vitro. We also demonstrate that ARRB1 and ARRB2 produce adverse effects on inflammation and activation of the inflammatory STAT1 and NF-κB pathways in primary cultures of microglia and macrophages and that two ARRBs competitively interact with the activated form of p65, a component of the NF-κB pathway. We further find that ARRB1 and ARRB2 differentially regulate the expression of nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, as revealed by RNA sequencing, and that in the gain- and loss-of-function studies, Nprl3 mediates the functions of both ARRBs in microglia inflammatory responses. Collectively, these data demonstrate that two closely related ARRBs exert opposite functions in microglia-mediated inflammation and the pathogenesis of PD which are mediated at least in part through Nprl3 and provide novel insights into the understanding of the functional divergence of ARRBs in PD.

20.
BMC Cancer ; 21(1): 282, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726687

RESUMO

BACKGROUND: Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. METHODS: Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. RESULTS: Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1-8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. CONCLUSION: This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.

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