| 181. |
- Lee, Chunsik, et al.
(författare)
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VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway
- 2023
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Ingår i: SIGNAL TRANSDUCTION AND TARGETED THERAPY. - : SPRINGERNATURE. - 2095-9907 .- 2059-3635. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
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| 182. |
- Li, Kaihui, et al.
(författare)
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Three‐dimensional discrete element simulation of indirect tensile behaviour of a transversely isotropic rock
- 2020
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Ingår i: International Journal for Numerical and Analytical Methods in Geomechanics. - : John Wiley & Sons. - 0363-9061 .- 1096-9853. ; 44:13, s. 1812-1832
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the development of a three‐dimensional discrete element model using flat‐joint and smooth‐joint contact models to investigate the effect of anisotropy on the tensile behaviour of slate, a transversely isotropic rock, under Brazilian testing from both macro and microscales. The effect of anisotropy is further realised by exploring the influence of foliation orientations (β and ψ ) on the tensile strength, fracture pattern, microcracking and stress distribution of the transversely isotropic rock. The variation of tensile strength with foliation orientation is presented. The cross‐weak‐plane fracture growth observed in laboratory is reproduced, and the criterion for which to form is also given from the aspect of foliation orientation. Furthermore, the proportional variations of microcracks well account for the effects of foliation orientation on the tensile strength and failure pattern. Finally, it is found that the existence of weak planes increases both the heterogeneity and the anisotropy of stress distributions within the transversely isotropic rock, with the degree of influence varying with the foliation orientation.
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| 183. |
- Li, XB, et al.
(författare)
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Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix
- 2023
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 72:4, s. 710-721
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Tidskriftsartikel (refereegranskat)abstract
- Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis.DesignTPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 onTCF21DNA hypermethylation. Pericyte-conditionalTcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling.ResultsThirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21highTPCs, termed ‘matrix–pericytes’, was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM).Tcf21depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21highTPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impairTCF21DNA hypermethylation in TCF21highTPCs.ConclusionThis study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.
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| 184. |
- Li, Zheng, et al.
(författare)
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A Review of Spatter in Laser Powder Bed Fusion Additive Manufacturing: In Situ Detection, Generation, Effects, and Countermeasures
- 2022
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Ingår i: Micromachines. - : MDPI AG. - 2072-666X. ; 13:8
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Forskningsöversikt (refereegranskat)abstract
- Spatter is an inherent, unpreventable, and undesired phenomenon in laser powder bed fusion (L-PBF) additive manufacturing. Spatter behavior has an intrinsic correlation with the forming quality in L-PBF because it leads to metallurgical defects and the degradation of mechanical properties. This impact becomes more severe in the fabrication of large-sized parts during the multi-laser L-PBF process. Therefore, investigations of spatter generation and countermeasures have become more urgent. Although much research has provided insights into the melt pool, microstructure, and mechanical property, reviews of spatter in L-PBF are still limited. This work reviews the literature on the in situ detection, generation, effects, and countermeasures of spatter in L-PBF. It is expected to pave the way towards a novel generation of highly efficient and intelligent L-PBF systems.
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| 185. |
- Lim, Sharon, et al.
(författare)
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VEGFR2-Mediated Vascular Dilation as a Mechanism of VEGF-Induced Anemia and Bone Marrow Cell Mobilization
- 2014
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Ingår i: Cell Reports. - : Elsevier (Cell Press): OAJ / Elsevier. - 2211-1247. ; 9:2, s. 569-580
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF-and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.
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| 186. |
- Lin, Zhen, et al.
(författare)
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Outcomes after readmission at the index or nonindex hospital following acute myocardial infarction complicated by cardiogenic shock
- 2021
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Ingår i: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 44:2, s. 200-209
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the prevalence and outcomes of readmission to nonindex hospitals after an admission for acute myocardial infarction complicated by cardiogenic shock (AMI-CS). We aimed to determine the rate of nonindex readmissions following AMI-CS and to evaluate its association with clinical factors, hospitalization cost, length of stay (LOS), and in-hospital mortality rates.HYPOTHESIS: Nonindex readmission may lead to worse in-hospital outcomes.METHODS: We reviewed the data of inpatients with AMI-CS between 2010 and 2017 using the National Readmission Database. The survey analytical methods recommended by the Healthcare Cost and Utilization Project were used for national estimates. Multiple regression models were used to evaluate the predictors of nonindex readmission, and its association with hospitalization cost, LOS, and in-hospital mortality rates.RESULTS: Of 238 349 patients with AMI-CS, 28028 (11.76%) had an unplanned readmission within 30 days. Of these patients, 7423 (26.48%) were readmitted to nonindex hospitals. Compared with index readmission, nonindex readmission was associated with higher hospitalization costs (p < .0001), longer LOS (p < .0001), and increased in-hospital mortality rates (p = .0016). Patients who had a history of percutaneous coronary intervention, received intubation/mechanical ventilation, or left against medical advice during the initial admission had greater odds of a nonindex readmission.CONCLUSIONS: Over one-fourth of readmissions following AMI-CS were to nonindex hospitals. These admissions were associated with higher hospitalization costs, longer LOS, and higher in-hospital mortality rates. Further studies are needed to evaluate whether a continuity of care plan in the acute hospital setting can improve outcomes after AMI-CS.
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| 187. |
- Luo, Zhengyi, et al.
(författare)
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Demand Flexibility of Residential Buildings : Definitions, Flexible Loads, and Quantification Methods
- 2022
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Ingår i: Engineering. - : Elsevier Ltd. - 2095-8099. ; 16, s. 123-140
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Tidskriftsartikel (refereegranskat)abstract
- This paper reviews recent research on the demand flexibility of residential buildings in regard to definitions, flexible loads, and quantification methods. A systematic distinction of the terminology is made, including the demand flexibility, operation flexibility, and energy flexibility of buildings. A comprehensive definition of building demand flexibility is proposed based on an analysis of the existing definitions. Moreover, the flexibility capabilities and operation characteristics of the main residential flexible loads are summarized and compared. Models and evaluation indicators to quantify the flexibility of these flexible loads are reviewed and summarized. Current research gaps and challenges are identified and analyzed as well. The results indicate that previous studies have focused on the flexibility of central air conditioning, electric water heaters, wet appliances, refrigerators, and lighting, where the proportion of studies focusing on each of these subjects is 36.7%, 25.7%, 14.7%, 9.2%, and 8.3%, respectively. These flexible loads are different in running modes, usage frequencies, seasons, and capabilities for shedding, shifting, and modulation, while their response characteristics are not yet clear. Furthermore, recommendations are given for the application of white-, black-, and grey-box models for modeling flexible loads in different situations. Numerous static flexibility evaluation indicators that are based on the aspects of power, temporality, energy, efficiency, economics, and the environment have been proposed in previous publications, but a consensus and standardized evaluation framework is lacking. This review can help readers better understand building demand flexibility and learn about the characteristics of different residential flexible loads, while also providing suggestions for future research on the modeling techniques and evaluation metrics of residential building demand flexibility.
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| 188. |
- Mascher, Martin, et al.
(författare)
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A chromosome conformation capture ordered sequence of the barley genome
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 544:7651, s. 427-433
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Tidskriftsartikel (refereegranskat)abstract
- Cereal grasses of the Triticeae tribe have been the major food source in temperate regions since the dawn of agriculture. Their large genomes are characterized by a high content of repetitive elements and large pericentromeric regions that are virtually devoid of meiotic recombination. Here we present a high-quality reference genome assembly for barley (Hordeum vulgare L.). We use chromosome conformation capture mapping to derive the linear order of sequences across the pericentromeric space and to investigate the spatial organization of chromatin in the nucleus at megabase resolution. The composition of genes and repetitive elements differs between distal and proximal regions. Gene family analyses reveal lineage-specific duplications of genes involved in the transport of nutrients to developing seeds and the mobilization of carbohydrates in grains. We demonstrate the importance of the barley reference sequence for breeding by inspecting the genomic partitioning of sequence variation in modern elite germplasm, highlighting regions vulnerable to genetic erosion.
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| 189. |
- McNabb, Sarah, et al.
(författare)
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Meta-analysis of 16 studies of the association of alcohol with colorectal cancer
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:3, s. 861-873
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (<= 1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
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| 190. |
- Murphy, Neil, et al.
(författare)
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Body mass index and molecular subtypes of colorectal cancer
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:2, s. 165-173
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m(2) = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control).Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
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