A Force-Balanced Control Volume Finite Element Method for Multi-Phase Porous Media Flow Modelling

Dr D. Pavlidis would like to acknowledge the support from the following research grants: Innovate UK ‘Octopus’, EPSRC ‘Reactor Core-Structure Re-location Modelling for Severe Nuclear Accidents’) and Horizon 2020 ‘In-Vessel Melt Retention’. Funding for Dr P. Salinas from ExxonMobil is gratefully acknowledged. Dr Z. Xie is supported by EPSRC ‘Multi-Scale Exploration of Multi-phase Physics in Flows’. Part funding for Prof Jackson under the TOTAL Chairs programme at Imperial College is also acknowledged. The authors would also like to acknowledge Mr Y. Debbabi for supplying analytic solutions.Peer reviewedPublisher PD

Clinical evaluation of the implementation of the first pilot Russian integrated program for an integrated approach to the management of diabetes mellitus “NORMA”

BACKGROUND: Despite progress in the treatment of patients with diabetes mellitus (DM), the problem of achieving target values of glycemic control remains relevant. In this regard, the search for new integrated solutions that could strengthen disease control and improve clinical outcomes becomes relevant.AIM: To assess the impact of the developed integrated approach to disease management on the clinical and metabolic outcomes of patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) participating in the “NORMA” pilot program for 3 and 6 months.MATERIALS AND METHODS: “NORMA” is the first Russian program designed to implement an integrated approach to DM management combines structured online education, blood glucose monitoring, supervision by endocrinologist, and administrative support. Interium retrospective analysis analysis of pre-existing data generated in the Program was performed from October 2020 to November 2021. Adults (≥18 years) with uncontrolled T1DM or T2DM on insulin (HbA1c>7,0%) with duration of DM ≥6 months were included. The following characteristics were considered: social-demographic parameters, duration of DM, complications, HbA1c, hypoglycemia events, daily insulin dose, patients’ perception of DM checklist (scaled 1-10), level of DM knowledge (questionnaire of 20 points).RESULTS: Data from 185 persons were analyzed: 132 with T1DM and 53 with T2DM, 67% women, the mean age was 41.3±14.4 years; the median DM duration was 12.0 [6.0; 19.0] years, 30 persons (16.3%) were free of any DM complications. Mean HbA1c decreased from 8.8±1.5% to 7.4±1.2% at month 3, and to 7.6±1.5% at month 6 (p<0.001). HbA1c <7.0% was achieved in 38.9% and 38.1% participants after 3 and 6 months, respectively. The total insulin dose has not changed within the program. The DM knowledge level after 3 months of Program increased significantly by 25.4±15.0% (p<0.001). The mean scores of patients’ perceptions of DM after 3 and 6 months increased by 2.1±10.2 % and 2.4±11.0 % (p<0.01), but the median scores (interquartile range) did not change: 0.00% (-3.00–6.00%) and 0.50% (-3.00–9.00%) respectively.CONCLUSION: In a real-life setting, the implementation of an integrated approach to the diabetes management was associated with the improvement of glycemic control without significant changes of total insulin dose

CREB Inhibits AP-2α Expression to Regulate the Malignant Phenotype of Melanoma

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype

Impact of bioenergy crop expansion on climate–carbon cycle feedbacks in overshoot scenarios

Stringent mitigation pathways frame the deployment of second-generation bioenergy crops combined with carbon capture and storage (CCS) to generate negative CO2 emissions. This bioenergy with CCS (BECCS) technology facilitates the achievement of the long-term temperature goal of the Paris Agreement. Here, we use five state-of-the-art Earth system models (ESMs) to explore the consequences of large-scale BECCS deployment on the climate–carbon cycle feedbacks under the CMIP6 SSP5-3.4-OS overshoot scenario keeping in mind that all these models use generic crop vegetation to simulate BECCS. First, we evaluate the land cover representation by ESMs and highlight the inconsistencies that emerge during translation of the data from integrated assessment models (IAMs) that are used to develop the scenario. Second, we evaluate the land-use change (LUC) emissions of ESMs against bookkeeping models. Finally, we show that an extensive cropland expansion for BECCS causes ecosystem carbon loss that drives the acceleration of carbon turnover and affects the CO2 fertilization effect- and climate-change-driven land carbon uptake. Over the 2000–2100 period, the LUC for BECCS leads to an offset of the CO2 fertilization effect-driven carbon uptake by 12.2 % and amplifies the climate-change-driven carbon loss by 14.6 %. A human choice on land area allocation for energy crops should take into account not only the potential amount of the bioenergy yield but also the LUC emissions, and the associated loss of future potential change in the carbon uptake. The dependency of the land carbon uptake on LUC is strong in the SSP5-3.4-OS scenario, but it also affects other Shared Socioeconomic Pathway (SSP) scenarios and should be taken into account by the IAM teams. Future studies should further investigate the trade-offs between the carbon gains from the bioenergy yield and losses from the reduced CO2 fertilization effect-driven carbon uptake where BECCS is applied

The Intracellular Localization of ID2 Expression Has a Predictive Value in Non Small Cell Lung Cancer

ID2 is a member of a subclass of transcription regulators belonging to the general bHLH (basic-helix-loophelix) family of transcription factors. In normal cells, ID2 is responsible for regulating the balance between proliferation and differentiation. More recent studies have demonstrated that ID2 is involved in tumor progression in several cancer types such as prostate or breast

AP2α controls the dynamic balance between miR-126&126∗ and miR-221&222 during melanoma progression

Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126∗ in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126∗, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufficient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses confirmed the reverse expression pattern of miR-126&126∗-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2α, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126∗. We showed the chance of restoring miR-126&126∗ expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc finger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2α expression, which in turn binds to and induces miR-126&126∗ transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126∗ toward miR-221&222. This circuitry, besides confirming the central role of AP2α in orchestrating melanoma development and/or progression, further displays the significance of these miRs in cancer and the option of utilizing them for novel therapeutics

The Dysregulation of Polyamine Metabolism in Colorectal Cancer Is Associated with Overexpression of c-Myc and C/EBP β

Colorectal cancer is one of the most common cancers in the world. It is well known that the chronic inflammation can promote the progression of colorectal cancer (CRC). Recently, a number of studies revealed a potential association between colorectal inflammation, cancer progression, and infection caused by enterotoxigenic Bacteroides fragilis (ETBF). Bacterial enterotoxin activates spermine oxidase (SMO), which produces spermidine and H2O2 as byproducts of polyamine catabolism, which, in turn, enhances inflammation and tissue injury. Using qPCR analysis, we estimated the expression of SMOX gene and ETBF colonization in CRC patients. We found no statistically significant associations between them. Then we selected genes involved in polyamine metabolism, metabolic reprogramming, and inflammation regulation and estimated their expression in CRC. We observed overexpression of SMOX, ODC1, SRM, SMS, MTAP, c-Myc, C/EBPβ (CREBP), and other genes. We found that two mediators of metabolic reprogramming, inflammation, and cell proliferation c-Myc and C/EBPβ may serve as regulators of polyamine metabolism genes (SMOX, AZIN1, MTAP, SRM, ODC1, AMD1, and AGMAT) as they are overexpressed in tumors, have binding site according to ENCODE ChIP-Seq data, and demonstrate strong coexpression with their targets. Thus, increased polyamine metabolism in CRC could be driven by c-Myc and C/EBPβ rather than ETBF infection

Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed

Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs