Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus

<p>Abstract</p> <p>Background</p> <p>This study was conducted to investigate the expression of CXCR4 in portal vein tumor thrombus (PVTT) tissue and its possible role in the invasiveness of tumor thrombus cells.</p> <p>Methods</p> <p>We detected differential expression of CXCR4 between PVTT and hepatocellular carcinoma (HCC) by an immunohistochemical assay. Lentivirus-mediated RNA interference and a migration assay were performed on human primary cells derived from PVTT to study the impact of CXCR4 on the invasiveness of HCC.</p> <p>Results</p> <p>The expression of CXCR4 in tumor thrombus tissue was higher than that in HCC tissue. The invasion ratio of PVTT cells was significantly decreased (P < 0.05) after being infected with a CXCR4-targeting siRNA lentivirus, indicating that downregulation of CXCR4 by lentivirus-mediated RNA interference significantly impaired the invasive potential of PVTT.</p> <p>Conclusions</p> <p>These results indicate that CXCR4 is an effective curative target for hepatocellular carcinomas with PVTT.</p

Cardiovascular Response of Aged Outpatients With Systemic Diseases During Tooth Extraction: A Single-Center Retrospective Observational Study

BackgroundAged people are maintaining many natural teeth due to improved oral health. However, compromised general health and poor oral hygiene habits at earlier ages resulted in poor status of preserved teeth. Therefore, tooth extraction is required in many aged people. More knowledge is needed because there are many risk factors during the surgery in frail aged adults. The aim of this study was to evaluate the cardiovascular response of such a population during tooth extraction and analyze risk factors to provide clinical guidance.MethodsA retrospective study was performed on aged patients with systemic diseases who underwent tooth extraction. Data regarding demographic profiles and cardiovascular parameters of heart rate and blood pressure were collected preoperative, when local anesthesia was administered, at the beginning of tooth extraction, 5 min after tooth extraction, and postoperative. The effects of risk factors, including age, sex, and systemic diseases on these parameters were analyzed with a multilevel model.ResultsHeart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) of aged patients increased significantly when performing local anesthesia and tooth extraction. During the operation, the older patients (β = 2.011, P = 0.005) and the diabetics (β = 3.902, P &lt; 0.0001) were associated with higher SBP, while those with more tooth extractions exhibited higher HR (β = 0.893, P = 0.007). Women patients showed both significantly elevated HR (β = 1.687, P &lt; 0.0001) and SBP (β = 2.268, P &lt; 0.0001). However, for coronary artery disease patients, HR (β = −2.747, P &lt; 0.0001) and blood pressure [SBP (β = −4.094, P &lt; 0.0001) and DBP (β = −0.87, P = 0.016)] were markedly lower than those of patients without a diagnosis of coronary artery disease.ConclusionCardiovascular response of aged outpatients with systemic diseases during tooth extraction is quite significant. Age, sex, systemic diseases, and the number of tooth extraction could be risk factors closely associated with cardiovascular response. The findings might provide safety guidance for dentists on tooth extraction in this population

On internal waves propagating across a geostrophic front

Reflection and transmission of normally-incident internal waves propagating across a geostrophic front, like the Kuroshio or Gulf Stream, are investigated using a modified linear internal-wave equation. A transformation from depth to buoyancy coordinates converts the equation to a canonical partial differential equation, sharing properties with conventional internal-wave theory in the absence of a front. The equation type is determined by a parameter Δ, which is a function of horizontal and vertical gradients of buoyancy, the intrinsic frequency of the wave and the effective inertial frequency, which incorporates the horizontal shear of background geostrophic flow. In the northern hemisphere, positive vorticity of the front may produce Δ≤0, i.e., a “forbidden zone”, in which wave solutions are not permitted. Thus, Δ=0 is a virtual boundary that causes wave reflection and refraction, although waves may tunnel through forbidden zones that are weak or narrow. The slope of the surface and bottom boundaries in buoyancy coordinates (or the slope of the virtual boundary if a forbidden zone is present) determine wave reflection and transmission. The reflection coefficient for normally-incident internal waves depends on rotation, isopycnal slope, topographic slope and incident mode number. The scattering rate to high vertical modes allows a bulk estimate of the mixing rate, although the impact of internal-waves driven mixing on the geostrophic front is neglected

Up-Regulation of Mitochondrial Activity and Acquirement of Brown Adipose Tissue-Like Property in the White Adipose Tissue of Fsp27 Deficient Mice

Fsp27, a member of the Cide family proteins, was shown to localize to lipid droplet and promote lipid storage in adipocytes. We aimed to understand the biological role of Fsp27 in regulating adipose tissue differentiation, insulin sensitivity and energy balance. Fsp27−/− mice and Fsp27/lep double deficient mice were generated and we examined the adiposity, whole body metabolism, BAT and WAT morphology, insulin sensitivity, mitochondrial activity, and gene expression changes in these mouse strains. Furthermore, we isolated mouse embryonic fibroblasts (MEFs) from wildtype and Fsp27−/− mice, followed by their differentiation into adipocytes in vitro. We found that Fsp27 is expressed in both brown adipose tissue (BAT) and white adipose tissue (WAT) and its levels were significantly elevated in the WAT and liver of leptin-deficient ob/ob mice. Fsp27−/− mice had increased energy expenditure, lower levels of plasma triglycerides and free fatty acids. Furthermore, Fsp27−/− and Fsp27/lep double-deficient mice are resistant to diet-induced obesity and display increased insulin sensitivity. Moreover, white adipocytes in Fsp27−/− mice have reduced triglycerides accumulation and smaller lipid droplets, while levels of mitochondrial proteins, mitochondrial size and activity are dramatically increased. We further demonstrated that BAT-specific genes and key metabolic controlling factors such as FoxC2, PPAR and PGC1α were all markedly upregulated. In contrast, factors inhibiting BAT differentiation such as Rb, p107 and RIP140 were down-regulated in the WAT of Fsp27−/− mice. Remarkably, Fsp27−/− MEFs differentiated in vitro show many brown adipocyte characteristics in the presence of the thyroid hormone triiodothyronine (T3). Our data thus suggest that Fsp27 acts as a novel regulator in vivo to control WAT identity, mitochondrial activity and insulin sensitivity

FAK Promotes Early Osteoprogenitor Cell Proliferation by Enhancing mTORC1 Signaling

Focal adhesion kinase (FAK) has important functions in bone homeostasis but its role in early osteoprogenitor cells is unknown. We show herein that mice lacking FAK in Dermo1- expressing cells exhibited low bone mass and decreased osteoblast number. Mechanistically, FAK- deficient early osteoprogenitor cells had decreased proliferation and significantly reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, a central regulator of cell growth and proliferation. Furthermore, our data showed that the pharmacological inhibition of FAK kinase- dependent function alone was sufficient to decrease the proliferation and compromise the mineralization of early osteoprogenitor cells. In contrast to the Fak deletion in early osteoprogenitor cells, FAK loss in Col3.6 Cre- targeted osteoblasts did not cause bone loss, and Fak deletion in osteoblasts did not affect proliferation, differentiation, and mTORC1 signaling but increased the level of active proline- rich tyrosine kinase 2 (PYK2), which belongs to the same non- receptor tyrosine kinase family as FAK. Importantly, mTORC1 signaling in bone marrow stromal cells (BMSCs) was reduced if FAK kinase was inhibited at the early osteogenic differentiation stage. In contrast, mTORC1 signaling in BMSCs was not affected if FAK kinase was inhibited at a later osteogenic differentiation stage, in which, however, the concomitant inhibition of both FAK kinase and PYK2 kinase reduced mTORC1 signaling. In summary, our data suggest that FAK promotes early osteoprogenitor cell proliferation by enhancing mTORC1 signaling via its kinase- dependent function and the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2. © 2020 American Society for Bone and Mineral Research.Schematic model of the differential roles of FAK in the cells of osteoblast lineage. The model depicts the mechanisms of FAK action at three distinct stages of osteoblast lineage in which the roles of FAK have been addressed by genetic and pharmacological approaches as well as the respective Cre transgenes used to target Fak, including Dermo1- Cre (this study), Osterix- Cre,(10) Col3.6- Cre (this study), and Col2.3- Cre.(9) Red - indicates that the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/3/jbmr4029-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/2/jbmr4029_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/1/jbmr4029.pd

Screening and fermentation medium optimization of a strain favorable to Rice–fish Coculture

Rice–fish coculture (RF) is a small ecosystem in which microorganisms are widely distributed in the fish, water environment, soil, and plants. In order to study the positive effects of microorganisms on common carp and rice in the RF ecosystem, a total of 18 strains with growth-promoting ability were screened from common carp (Cyprinus carpio) gut contents, among which three strains had the ability to produce both DDP-IV inhibitors and IAA. The strain with the strongest combined ability, FYN-22, was identified physiologically, biochemically, and by 16S rRNA, and it was initially identified as Bacillus licheniformis. As the number of metabolites secreted by the strain under natural conditions is not sufficient for production, the FYN-22 fermentation medium formulation was optimized by means of one-factor-at-a-time (OFAT) experiments and response surface methodology (RSM). The results showed that, under the conditions of a soluble starch concentration of 10.961 g/l, yeast concentration of 2.366 g/l, NH4Cl concentration of 1.881 g/l, and FeCl3 concentration of 0.850 g/l, the actual measured number of FYN-22 spores in the fermentation broth was 1.913 × 109 CFU/ml, which was 2.575-fold improvement over the pre-optimization value. The optimized fermentation solution was used for the immersion operation of rice seeds, and, after 14 days of incubation in hydroponic boxes, the FYN-22 strain was found to have a highly significant enhancement of 48.31% (p &lt; 0.01) on the above-ground part of rice, and different degrees of effect on root length, fresh weight, and dry weight (16.73, 17.80, and 21.97%, respectively; p &lt; 0.05). This study may provide new insights into the fermentation process of Bacillus licheniformis FYN-22 and its further utilization in RF systems

Knowledge atlas of antibody-drug conjugates on CiteSpace and clinical trial visualization analysis

ObjectiveAntibody-drugs conjugates (ADCs) are novel drugs with highly targeted and tumor-killing abilities and developing rapidly. This study aimed to evaluate drug discovery and clinical trials of and explore the hotspots and frontiers from 2012 to 2022 using bibliometric methods.MethodsPublications on ADCs were retrieved between 2012 and 2022 from Web of Science (WoS) and analyzed with CiteSpace 6.1.R2 software for the time, region, journals, institutions, etc. Clinical trials were downloaded from clinical trial.org and visualized with Excel software.ResultsA total of 696 publications were obtained and 187 drug trials were retrieved. Since 2012, research on ADCs has increased year by year. Since 2020, ADC-related research has increased dramatically, with the number of relevant annual publications exceeding 100 for the first time. The United States is the most authoritative and superior country and region in the field of ADCs. The University of Texas MD Anderson Cancer Center is the most authoritative institution in this field. Research on ADCs includes two clinical trials and one review, which are the most influential references. Clinical trials of ADCs are currently focused on phase I and phase II. Comprehensive statistics and analysis of the published literature and clinical trials in the field of ADCs, have shown that the most studied drug is brentuximab vedotin (BV), the most popular target is human epidermal growth factor receptor 2 (HER2), and breast cancer may become the main trend and hotspot for ADCs indications in recent years.ConclusionAntibody-drug conjugates have become the focus of targeted therapies in the field of oncology. The innovation of technology and combination application strategy will become the main trend and hotspots in the future

GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×$10^{−19}$) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×$10^{−8}$), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×$10^{−4}$; rs455804: OR = 0.84, P = 6.92×$10^{−3}$). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC

Buddhist Vegetarian Restaurants and the Changing Meanings of Meat in Urban China

This article charts the changing meanings of meat in contemporary urban China and explores the role played by Buddhist vegetarian restaurants in shaping these changes. In Kunming, meat has long been a sign of prosperity and status. Its accessibility marked the successes of the economic reforms. Yet Kunmingers were increasingly concerned about excessive meat consumption and about the safety and quality of the meat supply. Buddhist vegetarian restaurants provided spaces where people could share meat-free meals and discuss and develop their concerns about meat-eating. While similar to and influenced by secular, Western vegetarianisms, the central role of Buddhism was reflected in discourses on karmic retribution for taking life and in a non-confrontational approach that sought to accommodate these discourses with the importance of meat in Chinese social life. Finally, the vegetarian restaurants spoke to middle-class projects of self-cultivation, and by doing so potentially challenged associations between meat-eating and social status