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1.
Med Image Anal ; 71: 102039, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33831595

RESUMO

Fully convolutional networks (FCNs), including UNet and VNet, are widely-used network architectures for semantic segmentation in recent studies. However, conventional FCN is typically trained by the cross-entropy or Dice loss, which only calculates the error between predictions and ground-truth labels for pixels individually. This often results in non-smooth neighborhoods in the predicted segmentation. This problem becomes more serious in CT prostate segmentation as CT images are usually of low tissue contrast. To address this problem, we propose a two-stage framework, with the first stage to quickly localize the prostate region, and the second stage to precisely segment the prostate by a multi-task UNet architecture. We introduce a novel online metric learning module through voxel-wise sampling in the multi-task network. Therefore, the proposed network has a dual-branch architecture that tackles two tasks: (1) a segmentation sub-network aiming to generate the prostate segmentation, and (2) a voxel-metric learning sub-network aiming to improve the quality of the learned feature space supervised by a metric loss. Specifically, the voxel-metric learning sub-network samples tuples (including triplets and pairs) in voxel-level through the intermediate feature maps. Unlike conventional deep metric learning methods that generate triplets or pairs in image-level before the training phase, our proposed voxel-wise tuples are sampled in an online manner and operated in an end-to-end fashion via multi-task learning. To evaluate the proposed method, we implement extensive experiments on a real CT image dataset consisting 339 patients. The ablation studies show that our method can effectively learn more representative voxel-level features compared with the conventional learning methods with cross-entropy or Dice loss. And the comparisons show that the proposed method outperforms the state-of-the-art methods by a reasonable margin.

2.
Am J Med Sci ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33647285

RESUMO

BACKGROUND: Irisin is a new muscle factor discovered in recent years that shows a strong association with metabolic diseases. However, its role in coronary artery disease (CAD) is still controversial. We performed this study to determine the relationship of serum irisin with the characteristics and prognosis of CAD. MATERIALS AND METHODS: Patients with acute coronary syndrome (ACS) (n = 355), stable coronary artery disease (SCAD) (n = 162), nonobstructive coronary artery disease (NO-CAD) (n = 126) and normal coronary arteries (n = 109) were enrolled. An enzyme-linked immunosorbent assay kit was used to measure serum irisin concentrations. Major adverse cardiovascular events (MACEs) of patients with SCAD (n = 132) and ACS (n = 331) after percutaneous coronary intervention (PCI) were recorded during a 12-month follow-up. Receiver-operator characteristic (ROC) curve analysis was used to explore predictors of CAD. Kaplan-Meier survival analysis and the Cox proportional hazards regression model were used to explore the association between serum irisin levels and MACEs. RESULTS: Serum irisin levels in patients with ACS, SCAD, NO-CAD and normal coronary arteries were 196.62±72.05 ng/ml, 216.81±79.69 ng/ml, 245.26±77.92 ng/ml and 300.17±76.74 ng/ml, respectively (p<0.001). ROC curve analysis indicated that serum irisin concentrations were a valuable biomarker of coronary lesions (AUC=0.799), CAD (AUC=0.734) and ACS (AUC=0.681). Survival analysis demonstrated that patients with high irisin levels exhibited a higher event-free survival rate in both the SCAD and ACS groups after successful PCI. CONCLUSIONS: Serum irisin levels were significantly decreased in patients with CAD. Patients with ACS exhibited the lowest serum irisin levels. Furthermore, serum irisin levels were interrelated with prognosis in patients with CAD after PCI.

4.
Environ Sci Technol ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683876

RESUMO

Emerging epidemiological evidence has associated exposure to polycyclic aromatic hydrocarbons (PAHs) with chronic diseases including cardiometabolic diseases and neurodegeneration. However, little information is available about their subacute effects, which may accumulate over years and contribute to chronic disease development. To fill this knowledge gap, we designed a natural experiment among 26 healthy young adults who were exposed to elevated PAHs for 10 weeks after traveling from Los Angeles to Beijing in 2014 and 2015. Serum was collected before, during, and after the trip for metabolomics analysis. We identified 50 metabolites that significantly changed 6-8 weeks after the travel to Beijing (FDR < 5%). The network analysis revealed two main independent modules. Module 1 was allocated to oxidative homeostasis-related response and module 2 to delayed enzymatic deinduction response. Remarkably, the module 1 metabolites were recovered 4-7 weeks after participants' return, while the module 2 metabolites were not. Urinary hydroxylated PAHs were significantly associated with metabolites from both modules, while PAH carboxylic acids, likely metabolites of alkylated PAHs, were only associated with antioxidation-related metabolites. These results suggested differential subacute effects of unsubstituted and alkylated PAHs. Further studies are warranted to elucidate the role of the reversibility of metabolite changes in adverse health effects of PAHs.

5.
J Immunol Res ; 2021: 5553425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681386

RESUMO

Background: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) serves as an effector for tumor growth in human malignancies. However, the mechanism of ERO1L on promoting metastasis of pancreatic ductal adenocarcinoma (PDAC) remains to be further explored. Methods: Bioinformatics analysis of public databases and large-scale metastatic PDAC sequencing was performed to determine the expression profile and prognostic value of ERO1L in PDAC. The effect of ERO1L on metastasis of PDAC was analyzed in vitro and in vivo, via cell biological, molecular, and biochemical approaches. Results: ERO1L in PDAC hepatic metastatic tissues were highly expressed and related to disease-free survival (DFS). Genetic silencing and pharmacological inhibition of ERO1L with EN460 suppressed cell migration and invasion of PDAC. Furthermore, EN460 also suppressed hepatic metastasis of PDAC in vivo. Using shRNAs and EN460 to inhibit the ERO1L expression in Capan-2 and MiaPaca-2 led to the remarkable change of EMT-related protein Vimentin and E-cadherin, which indicated that EMT acted as a key pathway for ERO1L to promote invasion, dissemination, colonization, and growth of hepatic metastasis in PDAC. Conclusion: Our findings uncover ERO1L contributes to hepatic metastasis in PDAC via epithelial-mesenchymal transition (EMT) process and indicate a promising therapeutic strategy for PDAC hepatic metastasis.

6.
Sci Total Environ ; 778: 145812, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33721648

RESUMO

Certain studies suggest that air pollution could be a risk factor for obesity, but the evidence on the association between air pollution exposure and obesity in adults is limited. This study aims to examine the association between long-term exposure to fine particulate matter (PM2.5) and obesity-related traits in Chinese adults. Thus, a cross-sectional study was conducted based on a nationally representative sample of 91, 121 adults from 31 provinces in China. Integrated the data from satellites, chemical transport model, and ground observations, annual average concentrations of PM2.5 was obtained at the township level using a machine learning method. The information on body weight, height, and waist circumference (WC) were obtained from a questionnaire survey. The general obesity and abdominal obesity status were classified based on body mass index (BMI) and WC, respectively. Logistic and multivariate linear regression models were used to examine the association between PM2.5 and obesity-related traits, along with the examination of potential effect modifications. After adjustment for covariates, a 10 µg/m3 increase in PM2.5 concentration was associated with 8.0% [95% confidence interval (CI): 1.0%, 10.0%] and 10% (95% CI: 9.0%, 11.0%) increases in odds for general obesity and abdominal obesity, respectively. The odds ratios associated with per 10 µg/m3 PM2.5 increase were significantly greater in individuals of older age (≥60 years), of Han ethnicity, with lower socioeconomic status (SES), cooking without using a ventilation device, using unclean household fuels, having near-home pollution sources, and doing no physical exercise. These findings suggest that long-term exposure to ambient PM2.5 increase obesity risk in Chinese adults. It has significant significance to reduce air pollution to reducing the burden of obesity, particularly for the susceptible populations.

7.
Cell Death Dis ; 12(3): 273, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723230

RESUMO

Chronic pancreatitis (CP) is characterized by a wide range of irreversible fibro-inflammatory diseases with largely ambiguous pathogenesis. Although neddylation pathway has been implicated in regulating immune responses, whether the dysregulation of neddylation is involved in the progression of CP and how neddylation regulates the inflammatory microenvironment of CP have not yet been reported. Here, we demonstrate that global inactivation of neddylation pathway by MLN4924 significantly exacerbates chronic pancreatitis. The increased M2 macrophage infiltration, mediated by the upregulated chemokine (C-C motif) ligand 5 (CCL5), is responsible for the enhanced pancreatitis-promoting activity of MLN4924. Both CCL5 blockade and macrophage depletion contribute to alleviating pancreatic fibrosis and inflammation in MLN4924-treated CP mice. Mechanistic investigation identifies that inactivation of Cullin-RING ligases (CRLs) stabilizes cellular levels of hypoxia-inducible factor 1α (HIF-1α), which increases CCL5 expression by promoting CCL5 transactivation. Clinically, UBE2M expression remarkably decreases in human CP tissues compared with normal specimens and the levels of CCL5 and M2 marker CD163 are negatively correlated with UBE2M intensity, suggesting that neddylation is involved in the pathogenesis of pancreatitis. Hence, our studies reveal a neddylation-associated immunopathogenesis of chronic pancreatitis and provide new ideas for the disease treatment.

8.
FASEB J ; 35(5): e21428, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33774861

RESUMO

This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.

9.
Cancer Lett ; 508: 47-58, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33766751

RESUMO

Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC.

10.
Environ Sci Technol ; 55(6): 3867-3875, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33621071

RESUMO

Concerns on nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) in the environment have mainly arisen from their mutagenic and carcinogenic effects. The objective of this study is to investigate whether nitro-PAH exposures are associated with biomarkers of cardiovascular pathophysiology. In a panel study design, urines and blood samples were collected up to four times with a 2-week interval from 89 healthy adults. We measured 1-naphthylamine, 2-naphthylamine, 9-aminophenanthrene, 2-aminofluorene, and 1-aminopyrene as biomarkers of nitro-PAH exposures. We measured three urinary metabolites of arachidonic acid (AA) including 20-hydroxyeicosatetraenoic acid (20-HETE) from the cytochrome P450 (CYP) pathway, 8-isoprostane from the nonenzymatic pathway, and 11-dehydro-thromboxane B2 (11-dhTXB2) from the cyclooxygenase (COX) pathway. Urinary malondialdehyde, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 6-sulfatoxymelatonin (aMT6s) were measured to reflect systemic oxidative stress. Plasma concentrations of the soluble P-selectin and von Willebrand factor (vWF) were measured as biomarkers of platelet activation and endothelial dysfunction. We found that increased urinary concentrations of amino-PAHs were significantly associated with increased 20-HETE, 11-dhTXB2, and 8-OHdG and with decreased 8-isoprostane and aMT6s. Increased amino-PAHs were positively associated with P-selectin and vWF, respectively. These results suggest that exposure to nitro-PAHs increases systemic oxidative stress and alters AA metabolism toward CYP and COX pathways, leading to an increased cardiovascular disease risk.

11.
Vet Microbiol ; 254: 109010, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33631701

RESUMO

Extended-spectrum cephalosporin (ESC) resistance investigated in Salmonella and E. coli from the same chicken was to improve the understanding of the inter-species transmission of ESC resistance determinants in Salmonella and E. coli from a single chicken individual. Fifteen (13.6%) farms and 44 (8.0%) chicken individuals were positive for ESC-resistant E. coli and/or Salmonella, 8 farms (7.3%) and 12 (2.2%) individuals were simultaneously positive for ESC-resistant E. coli and Salmonella. The genetic diversity of ESC resistance determinants in E. coli and Salmonella was observed. Most E. coli isolates (67.6%) produced CTX-M-type of blaCTX-M-55, and 9 isolates (24.3%) produced CMY-type of blaCMY-2. Most Salmonella isolates (94.1%) produced blaCTX-M-15. Two broiler chicken farms were simultaneously positive for blaCMY-2- and blaCTX-M-15-harboring E. coli and Salmonella isolates. Whole-plasmid sequence for the transferable plasmid harboring blaCMY-2 showed genomic diversity of the plasmids from Salmonella and E. coli sourced from the same chicken. The genetic arrangement of blaCMY-2 in Salmonella was IS1294b-ΔISEcp1-blaCMY-2-blc-sugE and ISEcp1-blaCMY-2-blc-sugE in E. coli located on multi-host plasmids of IncI1-pST-2 and IncI1-pST-12. In conclusion, the study illustrates the genetic diversity of ESC resistance determinants in E. coli and Salmonella in a single chicken. Considering the possibility of transmission of antimicrobial resistance to humans through the food chain, a large reservoir of ESC resistance in chicken which could be co-infected with ESC-resistant E. coli and Salmonella poses a serious risk of potential transmission of ESC-resistant E. coli and Salmonella, and their transferable ESC resistant gene, to human simultaneously.

12.
Cell Rep ; 34(6): 108706, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33567279

RESUMO

Administration of probiotics to regulate the immune system is a potential anti-tumor strategy. However, oral administration of probiotics is ineffective because of the poor inhabitation of exogenous bacteria in host intestines. Here we report that smectite, a type of mineral clay and established anti-diarrhea drug, promotes expansion of probiotics (especially Lactobacillus) in the murine gut and subsequently elicits anti-tumor immune responses. The ion-exchangeable microstructure of smectite preferentially promotes lactic acid bacteria (LABs) to form biofilms on smectite in vitro and in vivo. In mouse models, smectite laden with LAB biofilms (Lactobacillus and Bifidobacterium) inhibits tumor growth (when used alone) and enhances the efficacy of chemotherapy or immunotherapy (when used in combination with either of them) by activating dendritic cells (DCs) via Toll-like receptor 2 (TLR2) signaling. Our findings suggest oral administration of smectite as a promising strategy to enrich probiotics in vivo for cancer immunotherapy.

13.
Helicobacter ; 26(2): e12786, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33596339

RESUMO

BACKGROUND: Pathogens capable of impacting gastrointestinal tract tumor development are located in the oral cavity, but whether these oral bacteria are able to colonize the gastric mucosa in gastric cancer (GC) patients and whether Helicobacter pylori infection can influence this process remains to be established. METHODS: Microbial 16S rDNA deep sequencing was conducted to characterize bacteria present in paired gastric mucosa and tongue coating samples in 27 patients with superficial gastritis (SG) and 11 GC patients. RESULTS: While the overall composition of the gastric mucosa and tongue coating microbiomes differed substantially, certain bacteria were present in both of these communities. The co-occurrence of bacteria between the tongue coating and gastric mucosa differed significantly between SG and GC patients. Of the 15 most abundant shared oral bacteria genera (the core shared oral bacteria), which were associated with differences in microbiota composition between these tongue coating and gastric mucosa, three were enriched in the gastric mucosa of GC patients relative to SG patients, whereas, 12 were depleted in GC patient samples. Furthermore, the prevalence and relative abundance of these core shared oral bacteria in the gastric mucosa were also linked to H. pylori infection status, and the core shared oral bacteria were also associated with the overall composition of the gastric mucosal microbiome. CONCLUSIONS: Helicobacter pylori infections are linked to the co-occurrence of bacteria in the oral microbiome and the gastric mucosal microbiome. Ectopic colonization of oral microbes may be a primary driver of H. pylori-induced gastric microbial dysbiosis in patients with GC.

14.
Environ Sci Technol ; 55(5): 3101-3111, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33555874

RESUMO

Fine particulate matter (PM2.5) with a higher oxidative potential has been thought to be more detrimental to pulmonary health. We aim to investigate the associations between personal exposure to PM2.5 oxidative potential and pulmonary outcomes in asthmatic children. We measured each of the 43 asthmatic children 4 times for airway mechanics, lung function, airway inflammation, and asthma symptom scores. Coupling measured indoor and outdoor concentrations of PM2.5 mass, constituents, and oxidative potential with individual time-activity data, we calculated 24 h average personal exposures 0-3 days prior to a health outcome measurement. We found that increases in daily personal exposure to PM2.5 oxidative potential were significantly associated with increased small, large, and total airway resistance, increased airway impedance, decreased lung function, and worsened scores of individual asthma symptoms and the total symptom score. Among the PM2.5 constituents, organic matters largely of indoor origin contributed the greatest to PM2.5 oxidative potential. Given that the variability in PM2.5 oxidative potential was a stronger driver than PM2.5 mass for the variability in the respiratory health outcomes, it is suggested to reduce PM2.5 oxidative potential, particularly by reducing the organic matter constituent of indoor PM2.5, as a targeted source control strategy in asthma management.

16.
Aging (Albany NY) ; 13(5): 7627-7643, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33626512

RESUMO

Evidence suggests that nicotine intake promotes atherosclerosis. We enrolled 100 patients with coronary heart disease (CHD) and found that plaque burden, TXNIP expression, and inflammatory chemokine levels were higher in smokers than non-smokers. Additionally, patients with higher TXNIP expression in peripheral blood mononuclear cells (PBMCs) had a higher Gensini Scores and higher plasma IL-1ß and IL-18 levels. Treating bone marrow-derived macrophages (BMDMs) with nicotine in vitro led to enhanced lipid phagocytosis, chemotaxis, and increased production of reactive oxygen species (ROS), which activated TXNIP/NLRP3 inflammasome signaling and promoted pyroptosis, as evidenced by caspase-1 cleavage and increased production of IL-1ß, IL-18, and gasdermin D. Nicotine intake by ApoE(-/-) mice fed a high-fat diet recapitulated those phenotypes. The effects of nicotine on pyroptotic signaling were reversed by N-acetyl-cysteine, a ROS scavenger. Silencing TXNIP in vivo reversed the effects of nicotine on macrophage invasion and vascular injury. Nicotine also induced pyroptotic macrophages that contributed to the apoptotic death of endothelial cells. These findings suggest that nicotine accelerates atherosclerosis in part by promoting macrophage pyroptosis and endothelial damage. Therefore, targeting the TXNIP/NLRP3-mediated pyroptotic pathway in macrophages may ameliorate nicotine-induced endothelial damage.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33404175

RESUMO

Metal-organic frameworks (MOFs)-based yolk-shell nanostructures have drawn enormous attention recently due to their multifunctionality. However, the regulations of the size and morphology of yolk-shell nanostructures are still limited by the unclear formation mechanism. Herein, we first demonstrated a solvent-dependent adsorption-driven mechanism for synthesizing yolk-shelled MOFs-based nanostructures coated with mesoporous SiO2 shells (ZIF-8@mSiO2 ) with tunable size and morphology. The selective and competitive adsorption of methanol (CH3 OH) and water (H2 O) on ZIF-8 core were found to have decisive effects on inducing the morphology evolution of yolk-shell nanostructures. The obtained yolk-shelled ZIF-8@mSiO2 nanostructures show great promise in generating acoustic cavitation effect for sonodynamic cancer therapy in vitro. We believe that this work will not only help us to design novel MOFs-based yolk-shell nanostructures, but also promote the widespread application of MOFs materials.

18.
Environ Int ; 147: 106342, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33401175

RESUMO

Given a large fraction of people's exposure to urban PM2.5 occur indoors, reducing indoor PM2.5 levels may offer a more feasible and immediate way to save substantial lives and economic losses attributable to PM2.5 exposure. We aimed to estimate the premature mortality and economic loss reductions associated with achieving the newly established Chinese indoor air guideline and a few hypothetical indoor PM2.5 guideline values. We used outdoor PM2.5 concentrations from 1497 monitoring sites in 339 Chinese cities in 2015, coupled with a steady-state mass balance model, to estimate indoor concentrations of outdoor-infiltrated PM2.5. Using province-specific time-activity patterns for urban residents, we estimated outdoor and indoor exposures to PM2.5 of outdoor origin. We then proceeded to use localized census-based concentration-response models and the value of statistical life estimates to calculate premature deaths and economic losses attributable to PM2.5 exposure across urban China. Finally, we estimated potentially avoidable mortality and corresponding economic losses by meeting the current 24-hour based guideline and various hypothetical indoor limits for PM2.5. In 2015 in urban areas of mainland China, the city-specific annual mean outdoor and indoor PM2.5 concentrations ranged 9-108 µg/m3 and 5-56 µg/m3, respectively. Indoor exposures contributed 62%-91% daily and 68%-83% annually to the total time-weighted exposures. The potential reductions in total deaths and economic losses for the scenario in which daily indoor concentrations met the current guideline of 75 µg/m3, 37.5 µg/m3, and 25 µg/m3 were 16.9 (95% CI: 0.7-62.1) thousand, 87.7 (95% CI: 9.7-197.7) thousand, and 165.5 (95% CI: 30.8-304.0) thousand, respectively. The corresponding reductions in economic losses were 5.7 (95% CI: 0.2-34.8) billion, 29.4 (95% CI: 2.4-109.6) billion, and 55.2 (95% CI: 7.7-168.0) billion US Dollars, respectively. Deaths and economic losses would be reduced exponentially within the range of 0-75 µg/m3 for hypothetical indoor PM2.5 limits. The findings demonstrate the effectiveness of reducing indoor concentrations of outdoor-originated PM2.5 in saving substantial lives and economic losses in China. The analysis provides quantitative evidence to support the implementation of an indoor air quality guideline or standard for PM2.5.

19.
Genome Biol ; 22(1): 4, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397441

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. RESULTS: We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. CONCLUSION: Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

20.
Cardiovasc Eng Technol ; 12(2): 232-249, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33483917

RESUMO

PURPOSE: The dynamics of biological capsules and red blood cells in shear flows has been studied extensively with experimental, analytical, and numerical methods. In particular, the effects of various parameters, including the shear rate or shear stress, membrane elasticity, capsule shape, and interior fluid viscosity, have been investigated carefully. The role of the membrane viscosity for capsule deformation dynamics has not been examined adequately. In previous studies, the so-called energy dissipation ratio has been used to account for the membrane viscosity effect by increasing the interior viscosity; however, the applicability and accuracy of this treatment have not been evaluated carefully. METHODS: In this study, using the recently developed finite-difference scheme for immersed boundary simulations of viscoelastic membranes, we conduct comprehensive numerical simulations of the deformation processes of an originally spherical capsule in shear flows with various combinations of membrane and interior fluid viscosities. RESULTS: Our results show that the membrane and interior fluid viscosity have similar however different effects on the capsule deformation dynamics. While the capsule deformation decreases with both membrane and interior fluid viscosities, a typical decrease-then-increase variation is observed for the inclination angle as the membrane viscosity increases, instead of the monotonic decrease in the inclination angle with the interior fluid viscosity increase. Also, although both large membrane and interior fluid viscosity values can introduce oscillations in the capsule deformation and inclination, larger aptitudes and slow decay processes are noticed at larger membrane viscosities. The variations of other dynamic parameters of the capsule, including the circumference, average membrane velocity, and rotation frequency, are also analyzed, and an intuitive mechanism is proposed to relate the membrane velocity and rotation frequency to the capsule deformation and inclination angle. The simple mechanism is then applied to explain the spoon-like variation patterns for membrane velocity and rotation frequency observed in our results. Furthermore, we examine the validity of the energy dissipation ratio approach based on the mathematical functional dependence. CONCLUSIONS: Our results and analysis show that the dissipation ratio is a system and process dependent variable and it cannot be treated as a constant even for the same capsule. This research is valuable for a better understanding of the complex capsule dynamics in flows and also suggests that the membrane viscosity needs to be considered explicitly for accurate and reliable results in future studies.

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