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Mirroring public ideologies and value systems in legislative discourse, stance not only functions as a powerful instrument for legislators to balance legal values and stakeholders' interests but also acts as a valuable reference for individuals to understand legislative texts. This study conducts a corpus-driven analysis of stance expressions in legislative discourse. Using three self-compiled corpora that incorporate data protection laws from the United States, the European Union, and China, we apply Hyland's stance model to contrastively analyse evidence of hedging, boosting, self-mention, and attitude markers across these jurisdictions and eventually propose a specialised research model of stance in law. This study unveils the nature of modesty and sufficient discursive space of data protection laws, as well as legislative values and public ideologies conveyed by different jurisdictions within the broader socio-legal cultural context. Besides uncovering the legal constructiveness of data protection laws, the results also suggest that the overall representation of stance in data protection legislation aligns with its performance in legislative discourse, which showcases a legislative tendency to achieve an overtly neutral appearance through covert stance expressions. [ABSTRACT FROM AUTHOR]

Assessing the impact of transforming resource-based cities (RBCs) through scientific evaluation is a crucial approach to gauge the efficacy of implementation of national locational policies. Drawing upon panel data encompassing 113 RBCs over the period 2006 to 2020, this study employs the difference-in-differences (DID) model to systematically evaluate the impact of location-oriented policies, represented by the "National Resource-Based Economic Transformation Comprehensive Supporting Reform Pilot Zone" (CRPZ), on the trajectory of green transition development (GTD) within RBCs. The results indicate, firstly, that the CRPZ has facilitated the GTD of RBCs, and a series of robustness tests confirm this conclusion, revealing a stimulating effect that evolves from initial suppression to subsequent promotion. Secondly, CRPZ can drive the GTD of RBCs by optimizing industrial structure and enhancing innovation capability, which shows that different marginal utilities are observed in its impact on the GTD of RBCs. Finally, the effectiveness of the CRPZ in promoting the GTD of RBCs is influenced by the degree of resource dependence, with a more pronounced impact on cities with higher levels of resource dependence. The conclusions of this study provide valuable insights for the ongoing evaluation of location-oriented policies and the promotion of GTD in RBCs. [ABSTRACT FROM AUTHOR]

Background: We combined the metabolic features of 18F-FDG-PET/CT and hematological inflammatory indicators to establish a predictive model of the outcomes of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiotherapy. Results: A predictive nomogram was developed based on sex, CEA, systemic immune-inflammation index (SII), mean SUV (SUVmean), and total lesion glycolysis (TLG). The nomogram presents nice discrimination that yielded an AUC of 0.76 (95% confidence interval: 0.66–0.86) to predict 1-year PFS, with a sensitivity of 63.6%, a specificity of 83.3%, a positive predictive value of 83.7%, and a negative predictive value of 62.9% in the training set. The calibration curves and DCA suggested that the nomogram had good calibration and fit, as well as promising clinical effectiveness in the training set. In addition, survival analysis indicated that patients in the low-risk group had a significantly longer mPFS than those in the high-risk group (16.8 months versus 8.4 months, P < 0.001). Those results were supported by the results in the internal and external test sets. Conclusions: The newly constructed predictive nomogram model presented promising discrimination, calibration, and clinical applicability and can be used as an individualized prognostic tool to facilitate precision treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Patients with gastric atrophy and intestinal metaplasia (IM) were at risk for gastric cancer, necessitating an accurate risk assessment. We aimed to establish and validate a diagnostic approach for gastric biopsy specimens using deep learning and OLGA/OLGIM for individual gastric cancer risk classification. Methods: In this study, we prospectively enrolled 545 patients suspected of atrophic gastritis during endoscopy from 13 tertiary hospitals between December 22, 2017, to September 25, 2020, with a total of 2725 whole-slide images (WSIs). Patients were randomly divided into a training set (n = 349), an internal validation set (n = 87), and an external validation set (n = 109). Sixty patients from the external validation set were randomly selected and divided into two groups for an observer study, one with the assistance of algorithm results and the other without. We proposed a semi-supervised deep learning algorithm to diagnose and grade IM and atrophy, and we compared it with the assessments of 10 pathologists. The model's performance was evaluated based on the area under the curve (AUC), sensitivity, specificity, and weighted kappa value. Results: The algorithm, named GasMIL, was established and demonstrated encouraging performance in diagnosing IM (AUC 0.884, 95% CI 0.862–0.902) and atrophy (AUC 0.877, 95% CI 0.855–0.897) in the external test set. In the observer study, GasMIL achieved an 80% sensitivity, 85% specificity, a weighted kappa value of 0.61, and an AUC of 0.953, surpassing the performance of all ten pathologists in diagnosing atrophy. Among the 10 pathologists, GasMIL's AUC ranked second in OLGA (0.729, 95% CI 0.625–0.833) and fifth in OLGIM (0.792, 95% CI 0.688–0.896). With the assistance of GasMIL, pathologists demonstrated improved AUC (p = 0.013), sensitivity (p = 0.014), and weighted kappa (p = 0.016) in diagnosing IM, and improved specificity (p = 0.007) in diagnosing atrophy compared to pathologists working alone. Conclusion: GasMIL shows the best overall performance in diagnosing IM and atrophy when compared to pathologists, significantly enhancing their diagnostic capabilities. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the brain and are closely associated with central nervous system inflammation and neurodegenerative diseases. It is known that mammalian target of rapamycin (mTOR) pathway plays an important role in the polarization of microglia. Castor1 has been identified as the cytosolic arginine sensor for the mTOR complex 1 (mTORC1) pathway, but the role of Castor1 in microglial polarization is still unknown. The purpose of this study was to explore the regulatory effect of Castor1 on microglial polarization and the underlying mechanism. The results demonstrated that Castor1 expression was significantly decreased in lipopolysaccharides (LPS) and interferon (IFN)-γ treated microglia. Castor1 overexpression inhibited the microglia M1 polarization by reducing the expression of M1 related markers. However, the expression of M2-related genes was promoted when Castor1 was overexpressed in IL-4 treated microglia. Mechanistically, Castor1 overexpression inhibited the activation of mTOR signaling pathway. In addition, after treatment with the mTOR activator MHY1485, the inhibitory effect of Castor1 overexpression on M1 polarization was attenuated, indicating that the regulation effects of Castor1 on M1 polarization was dependent on its inhibition of mTOR pathway. We propose that Castor1-mTOR signaling pathway could be considered as a potential target for treatment and intervention of central nervous system-related diseases by regulating microglia polarization. [ABSTRACT FROM AUTHOR]

Polycomb repressive complex 2 (PRC2) plays a key role in maintaining cell identity during differentiation. Methyltransferase activity of PRC2 on histone H3 lysine 27 is regulated by diverse cellular mechanisms, including posttranslational modification. Here, we report a unique phosphorylation-dependent mechanism stimulating PRC2 enzymatic activity. Residue S583 of SUZ12 is phosphorylated by casein kinase 2 (CK2) in cells. A crystal structure captures phosphorylation in action: the flexible phosphorylation-dependent stimulation loop harboring S583 becomes engaged with the catalytic SET domain through a phosphoserine-centered interaction network, stabilizing the enzyme active site and in particular S-adenosyl-methionine (SAM)-binding pocket. CK2-mediated S583 phosphorylation promotes catalysis by enhancing PRC2 binding to SAM and nucleosomal substrates and facilitates reporter gene repression. Loss of S583 phosphorylation impedes PRC2 recruitment and H3K27me3 deposition in pluripotent mESCs and compromises the ability of PRC2 to maintain differentiated cell identity.Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation. [ABSTRACT FROM AUTHOR]

Extensive research is currently being conducted into a variety of bio-inspired biomimetic nanoparticles (NPs) with new cell simulation functions across the fields of materials science, chemistry, biology, physics, and engineering. Cells such as erythrocytes, platelets, and stem cells have been engineered as new drug carriers. The platelet-derived drug delivery system, which is a new targeted drug delivery system (TDDS), can effectively navigate the blood circulatory system and interact with the complex tumor microenvironment; it appears to outperform traditional anticancer drugs; hence, it has attracted considerable research interest. In this review, we describe innovative studies and outline the latest progress regarding the use of platelets as tumor targeting and drug delivery vehicles; we also highlight opportunities and challenges relevant to the manufacture of tumor-related platelet TDDSs. [ABSTRACT FROM AUTHOR]

In plants, the HAK/KUP/KT family is the largest group of potassium transporters, and it plays an important role in mineral element absorption, plant growth, environmental stress adaptation, and symbiosis. Although these important genes have been investigated in many plant species, limited information is currently available on the HAK/KUP/KT genes for Pepper (Capsicum annuum L.). In the present study, a total of 20 CaHAK genes were identified from the pepper genome and the CaHAK genes were numbered 1 – 20 based on phylogenetic analysis. For the genes and their corresponding proteins, the physicochemical properties, phylogenetic relationship, chromosomal distribution, gene structure, conserved motifs, gene duplication events, and expression patterns were analyzed. Phylogenetic analysis divided CaHAK genes into four cluster (I–IV) based on their structural features and the topology of the phylogenetic tree. Purifying selection played a crucial role in the evolution of CaHAK genes, while whole-genome triplication contributed to the expansion of the CaHAK gene family. The expression patterns showed that CaHAK proteins exhibited functional divergence in terms of plant K+ uptake and salt stress response. In particular, transcript abundance of CaHAK3 and CaHAK7 was strongly and specifically up-regulated in pepper roots under low K+ or high salinity conditions, suggesting that these genes are candidates for high-affinity K+ uptake transporters and may play crucial roles in the maintenance of the Na+/K+ balance during salt stress in pepper. In summary, the results not only provided the important information on the characteristics and evolutionary relationships of CaHAKs, but also provided potential genes responding to potassium deficiency and salt stress. [ABSTRACT FROM AUTHOR]

Recent technological advancements have facilitated the imaging of specific neuronal populations at the single-axon level across the mouse brain. However, the digital reconstruction of neurons from a large dataset requires months of manual effort using the currently available software. In this study, we develop an open-source software called GTree (global tree reconstruction system) to overcome the above-mentioned problem. GTree offers an error-screening system for the fast localization of submicron errors in densely packed neurites and along with long projections across the whole brain, thus achieving reconstruction close to the ground truth. Moreover, GTree integrates a series of our previous algorithms to significantly reduce manual interference and achieve high-level automation. When applied to an entire mouse brain dataset, GTree is shown to be five times faster than widely used commercial software. Finally, using GTree, we demonstrate the reconstruction of 35 long-projection neurons around one injection site of a mouse brain. GTree is also applicable to large datasets (10 TB or higher) from various light microscopes. [ABSTRACT FROM AUTHOR]

In order to realize the effective monitoring of non-point source pollution of water resources in river tourist attractions, improve the accuracy of monitoring results, and ensure the safety of water resources, an online monitoring method of non-point source pollution of water resources in river tourist attractions is proposed. Analyze the causes of non-point source pollution of water resources, design a water pollution data collection and transmission device based on the analysis results, and use this device to realize the synchronous collection of non-point source water pollution data. Data is transmitted through the platform to manage monitoring point information, monitoring point distribution, and realizing historical records and other monitoring information, performing the trend fitting of the monitoring data in the server to issue an early warning, and displaying the fitting results through the software client, completing the online monitoring. The experimental results show that this method has higher monitoring efficiency and better authenticity. [ABSTRACT FROM AUTHOR]

This paper explores the impacts of the universal two-child policy on Beijing's population in the long term. It gives a detail estimation of Beijing population considering the latest fertility and immigration policy and can help related government department management population. The cohort-component method based on a net migration was applied to project population by age for Beijing from 2020 to 2050 in four fertility scenarios. The innovation is the estimation method of the mortality rate with the life table linked with life expectancy. The results show that, though the basic development trend of Beijing's population will not change essentially under the universal two-child policy, low birth rate and aging problems will be improved. Compared with the partial policy relaxation, the total population will be 876,478 persons more than that in 2050, the share of population aged 0–14 will increase 1.1 percentage points, and the aged dependency ratio will decrease 1.96 percentage points. Some measures should be taken to encourage more couples to have a second child and introduce more young talents to promote Beijing's prosperity. [ABSTRACT FROM AUTHOR]

Buschke-Löwenstein tumor (BLT) is a rare sexually transmitted disease, mostly described in clinical literature as case reports or small series. Here, we investigated the clinicopathologic features of BLT in a total of 38 cases retrieved from multiple academic institutions. The average age was 47.6 ± 12.8 (mean ± SD) years old at diagnosis. The male to female ratio was 4.4:1. Common presenting symptoms were pain/discomfort, bleeding, mass lesion, and discharge. It was frequently linked to smoking and positive human immunodeficiency virus status. The tumor size and thickness were 8.5 ± 6.6 cm and 1.5 ± 1.3 cm, respectively. Histologically, 19 (50%) cases had an invasive squamous cell carcinoma component and were associated with high-risk human papillomavirus infection. There was no lymphovascular or perineural invasion, or nodal metastasis at initial diagnosis. BLTs with invasion had higher frequency of dyskeratosis, neutrophilic microabscesses, and abnormal mitoses, but lower frequency of pushing border compared with BLTs without invasion. All patients underwent wide excision, and some also received chemoradiation therapy. After a median follow-up of 23 months (range 1-207), the recurrence rate was 23.7% and disease-specific mortality was 2.6%. In summary, we presented the largest case series of BLT to date to characterize its unique clinicopathologic features. Our study indicated that certain histologic features such as dyskeratosis, neutrophilic microabscess, and abnormal mitosis in the non-invasive portion may be important clues on lesional biopsy to predict the presence of underlying invasive carcinoma. [ABSTRACT FROM AUTHOR]

In this paper, hierarchical feedback loop analysis is employed to identify changes in the economic interactions among sectors during the process of structural transformation of the Chicago economy. The application in our paper differs from previous studies adopting this methodology as it focuses on the time dimension of change through analysis of feedback loops every 5 years from 1995 to 2010. A total of 36 hierarchical feedback loops for years 1995, 2000, 2005 and 2010 were obtained. The first two feedback loops captured the main character of the economic structure transformation. The linkages strength between five pairs of sectors which include linkages from hotels, personal and business services to construction, from finance and insurance to wholesale and retail trade, etc., accounted for 83.5% of the intensity change in the first feedback loop from 1995 to 2010. Structural change of linkages played little role in the complexity change of the second feedback loop. The change of linkages strength from wholesale and retail trade to construction, from rubber and miscellaneous plastics products to chemicals and allied products accounted for about 83.0% of this latter loop. The economic transformation of Chicago economy showed that the development of services has not come at the expense of the decline of industry. Over the period in question, the Chicago economy became more diversified. [ABSTRACT FROM AUTHOR]

Background: No true preliminary work has been performed and published on the use of the bipolar cautery devices for transection of the stomach when performed as a part of the sleeve gastrectomy or gastric wedge resection. The objective of this study was to investigate the feasibility and safety of substitution of linear surgical stapling devices for use of a bipolar electrosurgical sealing instrument in the performance of a totally robotic partial gastrectomy (TRPG).Methods: Ten female pigs were assigned to an intervention or control group. Intervention included TRPG with a robotic bipolar tissue coagulation device. In the control group, TRPG was performed using the staplers. Assessed outcomes included presence of the intraoperative and postoperative bleeding or leak and features of the sections from the stapled line or sutured line.Results: Mean operating time was (130 ± 31 min) and (87 ± 23 min) in the study and control groups (p = 0.03). Intraoperative gastroscopy revealed slow bleeding associated with the staple line in 3/5 control pigs; oozing was not appreciated in any of the study pigs (0/5). No leak was detected during intraoperative gastroscopy. No major complications were suspected postoperatively or identified at postmortem exam in either group. Mean injury width was (1.12 ± 0.93 mm) in the control group with greater mean injury width (7.88 ± 3.73 mm) in the study group (p = 0.001). Mean depth of ulceration was (0.99 ± 0.94 mm) in the control group, with greater mean ulceration depth (2.25 ± 0.84 mm) in the study group (p = 0.002).Conclusion: The study showed the technical feasibility of performing stapler-less gastric wedge resection. The electrocautery alone failed to demonstrate the technical feasibility which was obtained with the concomitant use of a tissue clamp and a suture. [ABSTRACT FROM AUTHOR]

The paper established a double filtering method (DFM) to visualize the skeleton industrial structure (SIS) of one economy and find its evolution rule. Different with the previous researches, this method is from a new view of industrial conjunctions combined by leading sectors to depict the industrial structure. It was proved that the leading sector selected by DFM must be key sector selected by Hirschman-Rasmussen method. Applied DFM to input-output tables of China, Japan and USA and MFA to Japan and USA, the results analysis showed that DFM could overtake the two main shortcomings of minimum flow analysis (MFA), scratch SIS of each economy with its own characteristics, visualize the general evolution rules of the industrial structure with crisscrossed conjunctions among leading sectors. [ABSTRACT FROM AUTHOR]

Given the weak early degradation characteristic information during early fault evolution in gearbox of wind turbine generator, traditional singular value decomposition (SVD)-based denoising may result in loss of useful information. A weak characteristic information extraction based on μ-SVD and local mean decomposition (LMD) is developed to address this problem. The basic principle of the method is as follows: Determine the denoising order based on cumulative contribution rate, perform signal reconstruction, extract and subject the noisy part of signal to LMD and μ-SVD denoising, and obtain denoised signal through superposition. Experimental results show that this method can significantly weaken signal noise, effectively extract the weak characteristic information of early fault, and facilitate the early fault warning and dynamic predictive maintenance. [ABSTRACT FROM AUTHOR]

The large wind generating set works under the varying operation conditions for years, generally the fault characteristic values of the rotary components based on the energy mode is coupled with other noises, so the fault trend can not be accurately predicted. With the wear fault of the high-speed gear of the wind generator as the research object, this paper proposes the trend prediction method of the wear fault of the high-speed gear based on the fusion of ultra-complete independent component analysis (UICA) and parameter estimation (PE), constructs the ultra-complete analysis model, separates the similar source signals more than mixing signals by using the UICA, and finds useful component with the features of the pure similar fault source signal as the basis. Based on the similarity between the similar fault source signal and fault source signal, this paper estimates the value domain of the magnification time of the similar shapes by using the PE, identifies the mapping between continuous and one-way varying magnification time domain and rotary component fault degree, establishes the fault degree judgment standard, and determines and predicts the fault degree and the fault trend based on the energy change trend diagram of the whole-lifecycle fault source signal of the high-speed gear. The above method is used to process the wear fault data of the high-speed gear. The results indicate that the above method has obvious effect in processing of the cycle sudden signals, so it indicates that this method has certain engineering application value and provides reference to solve the problem that the number of the independent vibration sources is more than it of the mixing signals in vibration analysis. [ABSTRACT FROM AUTHOR]

Background: Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or intramucosal cancer (IMC) on endoscopic forceps biopsies are referred to endoscopic therapy even though forceps biopsies do not reflect the disease extent accurately. Endoscopic mucosal resection (EMR) and endoscopic ultrasound (EUS) are frequently used for staging prior to endoscopic therapy. Our aims were to evaluate: (1) if endoscopic forceps biopsies correlated with EMR histology in these patients; (2) the utility of EUS compared to EMR; and (3) if accuracy of EUS varied based on grade of differentiation of tumor.Methods: This is a retrospective review of patients referred to endoscopic therapy of BE with HGD or early esophageal adenocarcinoma (EAC) who underwent EMR from 2006 to 2011. Age, race, sex, length of Barrett's segment, hiatal hernia size, number of endoscopies and biopsy results and EUS findings were abstracted.Results: A total of 151 patients underwent EMR. In 50 % (75/151) of patients, EMR histology was consistent with endoscopic forceps biopsy findings. EMR resulted in change in diagnosis with upstaging in 21 % (32/151) and downstaging in 29 % (44/151). In patients with HGD on EMR, EUS staging was T0 in 74.1 % (23/31) but upstaged in 25.8 % (8/31). In patients with IMC on EMR, EUS findings were T1a in 23.6 % (9/38), upstaged in 18.4 % (7/38) and downstaged in 57.8 % (22/38). EUS accurately identified EMR histology in all submucosal cancers. Grade of differentiation was reported in 24 cancers on EMR histology. There was no correlation between grade and EUS staging.Conclusions: EUS is of limited utility in accurate staging of BE patients with HGD or early EAC. Endoscopic forceps biopsy correlated with EMR findings in only 50 % of patients. Irrespective of the endoscopic forceps biopsy results, all BE patients with visible lesions should be referred to EMR. [ABSTRACT FROM AUTHOR]

Valosin-containing protein (VCP) was previously shown to exhibit high expression in colorectal cancer (CRC) tissues as compared with that in normal tissues; however, the role of VCP in human CRC cells has remained to be elucidated. Two colorectal cancer cell lines HCT116 and RKO were used in the experiment. We introduced lentiviral constructs expressing VCP to infect RKO cells and lenti-shRNA targeting VCP into HCT116 cells, respectively. Cell proliferation, invasion, apoptosis, and cell cycle arrest were subsequently examined by MTT assay, transwell chamber assay, flow cytometry, and western blot analysis, respectively. Furthermore, a subcutaneous tumor mouse model and lung metastasis model was used to investigate the effects of VCP on the growth and metastasis of CRC cells in vivo. VCP knockdown was shown to inhibit cell proliferation, chemoresistance and invasion, and induce apoptosis in the HCT116 CRC cells, whereas VCP over-expression suppressed apoptosis and chemoresponse, promoted proliferation and invasion of the RKO CRC cells. In addition, in the subcutaneous tumor and lung metastasis mouse model, VCP knockdown in HCT116 cells suppressed carcinogenesis and metastasis in vivo. The findings of the present study indicated that VCP is very important for the proliferation and metastasis of CRC; therefore, targeting VCP and its downstream targets may represent novel therapies for the treatment of CRC. [ABSTRACT FROM AUTHOR]

The paper explores the contribution of different factors affecting water use efficiency (WUE) of each sector and explores ways to improve WUE. A new Multi-Sector and Multi-Factors Logarithmic Mean Divisia Index (MLMDI) decomposition method was developed that enabled the identification of WUE by sector into 11 factors in terms of their order of importance. An application to Beijing at the 19 sector level was made for the period between 2002-2007. The water conservation effects of six measures proposed during the 12th-Five-Year-Plan of Beijing were assessed. It was found that, to decrease the transferred out and export of agriculture products and increasing water prices would be the top two most effective measures to promote water conservation. While the adjustment of direct water use structure would contribute in less significant way, the adjustment of industrial structure would have a negative effect. [ABSTRACT FROM AUTHOR]

In this paper, a prediction model on Chinese annual live hog supply was established. With cointegration test, backward and forward stochastic selection and other methods, four main factors (hog price, prices of inputs in hog production, the level of hog inventory, as well as emergency and government policy) were chosen from 16 relevant factors to establish the model and make improvement. Applied the improved model, annual live hog supply in China from 2013 to 2016 was predicted in three scenarios. The predicted results showed that if there were no major emergencies from 2013 to 2016, there would be an upward trend in Chinese live hog supply year by year. The supply of live hogs in China in 2013 would be about 707.663 million head, in 2014 would be between 715.935 and 742.969 million head, in 2015 between 734.458 and 779.413 million head, and in 2016 between 750.923 and 809.450 million head. [ABSTRACT FROM AUTHOR]

Background: Determining the benign or malignant nature of biliary strictures can be challenging. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. Objective: The purpose of this study was to investigate whether VEGF levels in bile aspirated during endoscopic retrograde cholangiography (ERCP) can distinguish pancreatic cancer from other causes of biliary stricture. Methods: Bile was directly aspirated in 53 consecutive patients from March 2012 to October 2012 during ERCP from the common bile duct including 15 with pancreatic cancer, 18 with primary sclerosing cholangitis (PSC), nine with cholangiocarcinoma (CCA), and 11 with benign biliary conditions (sphincter of Oddi and choledocholihiasis). Levels of VEGF in bile were measured. The diagnostic performance was then validated in a second, independent validation cohort of 18 patients (pancreatic cancer n = 10, benign n = 8). Results: A total of 53 consecutive patients were recruited. The median bile VEGF levels were significantly elevated in patients with pancreatic cancer (1.9 ng/ml (interquartile range [IQR] 0.7, 2.2) compared to those with benign biliary conditions (0.3 ng/ml [IQR 0.2, 0.6]; p < 0.001), PSC (0.7 ng/ml [IQR 0.5, 0.9]; p = 0.02) or CCA (0.4 ng/ml [IQR 0.1, 0.5]; p < 0.001). A VEGF cut-off value of 0.5 ng/ml distinguished pancreatic cancer from CCA with a sensitivity and specificity of 93.3 and 88.9 %, respectively, and area under curve (AUC) of 0.93, and from benign conditions with a sensitivity and specificity of 93.3 and 72.7 %, respectively, with AUC of 0.89. The diagnostic accuracy of biliary VEGF was confirmed in the second independent validation cohort. Conclusions: This study suggests that measurement of biliary VEGF-1 levels distinguishes patients with pancreatic cancer from other etiologies of biliary stricture. This may be particularly relevant in approaching patients with indeterminate biliary stricture. [ABSTRACT FROM AUTHOR]

Purpose: Eicosanoid-related enzymes have been implicated in the pathogenesis of various cancers. Little is known about the relevance of lipoxygenase pathway to ovarian cancer growth. In this study, we examined the role of 12-lipoxygenase (12-LOX), the main human 12-HETE generating enzyme, in the regulation of proliferation and survival in epithelial ovarian cancer. Methods: Immunohistological analysis of 12-LOX expression in high-grade serous ovarian carcinoma and normal ovarian epithelium tissues was performed. The presence of 12-LOX-12-HETE system was confirmed in two epithelial ovarian cancer (EOC) cell lines, OVCAR-3 and SK-OV-3, using RT-PCR, Western blot and LC/MS analysis. The effects of N-benzyl-N-hydroxy-5-phenyl-pentanamide (BMD-122), a specific 12-LOX inhibitor, on cell growth, survival, apoptosis, and cell signaling were determined. Results: We found that a significantly higher level of 12-LOX expression in high-grade serous ovarian carcinoma compared to normal ovarian epithelium. OVCAR-3 and SK-OV-3 were found to express high level of 12-LOX mRNA and protein. Both EOC increased their 12-HETE production when incubated with arachidonic acid. BMD-122 inhibited the EOC growth in a dose-dependent fashion. Purified 12-HETE significantly reversed such inhibitory effects of BMD-122. In addition, BMD-122 blocked the MAPK signaling pathway by inhibiting the phosphorylation of ERK and induced a ~20-30% increase in the EOC apoptosis. Down-regulation of the 12-LOX expression using 12-LOX siRNA also resulted in markedly reduction in cell growth. Conclusions: These data suggest that 12-LOX is involved in the regulation of ovarian cancer cell growth and survival and is a potential new therapeutic target. [ABSTRACT FROM AUTHOR]

A large body of evidence indicates that astrocytes play an important role in a range of brain functions through calcium (Ca2+) signaling. Experimentally evoking Ca2+ signaling is a useful technique for investigating the functions of astrocytes. However, conventional stimulation methods typically have poor spatio-temporal precision, and some are invasive. Our group has developed a technique to overcome these problems, in which astrocytes are photostimulated with a femtosecond laser. In the current study, we applied this method to a hippocampal neural network to explore astrocytic functions in detail. The results revealed that applying photostimulation to astrocytes in a cultured hippocampal astrocyte-neuron network caused the following changes: (i) Synchronous Ca2+ oscillations in neurons were induced; (ii) spontaneous Ca2+ synchrony instantaneously emerged; and (iii) high-frequency spontaneous Ca2+ synchrony was regulated. Thus, astrocytic Ca signaling evoked by photostimulation was found to modulate synchronous Ca2+ oscillations in hippocampal neurons. We propose that photostimulation with a femtosecond laser will serve as a powerful tool in investigating astrocytic functions at the network level. [ABSTRACT FROM AUTHOR]

Combined with the fluorescence labeling technique, two-photon microscopy excited with femtosecond pulse laser has become an important tool for neuroscience research. In this research, the calcium signals from neurons in rat cortex slice were monitored by a custom-built two-photon microscopy, and the spontaneous calcium signals and the pharmacological responses as well as the responses to femtosecond pulse laser stimulation were recorded. The results showed that the amplitude of the calcium signals increased in direct proportion to the corresponding electrical activities. Glutamate induced a calcium transient, but continuous application resulted in smaller response. Simultaneous monitoring of neuronal populations distinguished the neurons of different microcircuits. The femtosecond pulse laser induced local or global calcium signals in the pyramidal neurons. The approach of interrogation and control of neural activities using femtosecond pulse laser is non-contact, nondestructive, repeatable, and without any additional substrates, which will contribute to the development of neuroscience. [ABSTRACT FROM AUTHOR]

The pancreatic acinar-enriched miR-216a, miR-216b and miR-217 are encoded within the miR217HG. These miRNAs have been purported to play a tumor suppressive role as their expression is reduced in both human and mouse pancreatic ductal adenocarcinoma (PDAC). To examine this possibility, we generated individual, germline knockout (KO) mice of miR-216a, miR-216b or miR-217. Unlike our previous study showing germline deletion of the miR217HG was embryonic lethal, CRISPR-Cas9 deleted portions of the 5' seed region of the miRNAs produced live births. To investigate possible phenotypes during pancreatic acinar ductal metaplasia (ADM), pancreatic acini from wild type and KO mice were plated on collagen and allowed to transdifferentiate over 4 days. Acini from each of the three miRNA KO mice produced greater numbers of ducts compared to controls. Evaluation of the gene expression during in vitro ADM demonstrated an increase in Krt19 and a reduction in acinar genes (Carboxypeptidase A1, Amylase2a) on day 4 of the transdifferentiation. Recovery was delayed for the miR-216a and miR-216b KOs following caerulein-induced acute pancreatitis. Also predominate in the caerulein treated miR-216a and miR-216b KO mice was the presence of pancreatic duct glands (PDGs). To further establish a phenotype, miRNA KO mice were crossed with EL-KRASG12D (EK) mice and followed up to 13 months of age. While all mice developed severe dysplasia and cystic papillary neoplasms, there existed no apparent phenotypic difference in the miRNA KO/EK mice compared to EK mice. Our data does not support a tumor suppressor role for miR-216a, miR-216b or miR-217 in PDAC and emphasizes the need for phenotypic evaluation of miRNAs in complex in vivo models beyond that performed using cell culture. [ABSTRACT FROM AUTHOR]

Acquiring information on the precise distribution of a tumor is essential to evaluate intratumoral heterogeneity. Conventional hematoxylin and eosin staining, which has been used by pathologists for more than 100 years, is the gold standard of tumor diagnosis. However, it is difficult to stain entire tumor tissues with hematoxylin and eosin and then acquire the three-dimensional distribution of cells in solid tumors due to difficulties in the staining and rinsing. In this paper, we propose a modified hematoxylin and eosin staining method, in which delipidation and ultrasound waves were applied to enhance tissue permeability and accelerate dye diffusion. This improved hematoxylin and eosin staining method is termed iHE (intact tissue hematoxylin and eosin staining). We applied the iHE method to stain intact organs of mice, which were then sectioned and imaged sequentially. The results showed that the whole tissue was stained homogeneously. Combined with micro-optical sectioning tomography (MOST), the iHE method can be used for 3D volume imaging and to evaluate the intratumoral heterogeneity of the entire tumor tissue spatially. Therefore, this method may help to accurately diagnose the invasion stage of tumors and guide clinical treatments. [ABSTRACT FROM AUTHOR]