Unlike glycolytic enzymes that directly catabolize glucose to pyruvate, the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs) control the conversion of fructose-6-phosphate to ...and from fructose-2,6-bisphosphate, a key regulator of the glycolytic enzyme phosphofructokinase-1 (PFK-1). One family member, PFKFB3, has been shown to be highly expressed and activated in human cancer cells, and derivatives of a PFKFB3 inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), are currently being developed in clinical trials. However, the effectiveness of drugs such as 3PO that target energetic pathways is limited by survival pathways that can be activated by reduced ATP and nutrient uptake. One such pathway is the process of cellular self-catabolism termed autophagy. We hypothesized that the functional glucose starvation induced by inhibition of PFKFB3 in tumor cells would induce autophagy as a pro-survival mechanism and that inhibitors of autophagy could increase the anti-tumor effects of PFKFB3 inhibitors.
We found that selective inhibition of PFKFB3 with either siRNA transfection or 3PO in HCT-116 colon adenocarcinoma cells caused a marked decrease in glucose uptake simultaneously with an increase in autophagy based on LC3-II and p62 protein expression, acridine orange fluorescence of acidic vacuoles and electron microscopic detection of autophagosomes. The induction of autophagy caused by PFKFB3 inhibition required an increase in reactive oxygen species since N-acetyl-cysteine blocked both the conversion of LC3-I to LC3-II and the increase in acridine orange fluorescence in acidic vesicles after exposure of HCT-116 cells to 3PO. We speculated that the induction of autophagy might protect cells from the pro-apoptotic effects of 3PO and found that agents that disrupt autophagy, including chloroquine, increased 3PO-induced apoptosis as measured by double staining with Annexin V and propidium iodide in both HCT-116 cells and Lewis lung carcinoma (LLC) cells. Chloroquine also increased the anti-growth effect of 3PO against LLCs in vivo and resulted in an increase in apoptotic cells within the tumors.
We conclude that PFKFB3 inhibitors suppress glucose uptake, which in turn causes an increase in autophagy. The addition of selective inhibitors of autophagy to 3PO and its more potent derivatives may prove useful as rational combinations for the treatment of cancer.
Summary
Diamond‐Blackfan anaemia (DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a ‘ribosomopathy’. We report a multi‐centre study focused on the ...analysis of rRNA processing of 53 Italian DBA patients using capillary electrophoresis analysis of rRNA maturation of the 40S and 60S ribosomal subunits. The ratio of 28S/18S rRNA was higher in patients with mutated ribosomal proteins (RPs) of the small ribosomal subunit. In contrast, patients with mutated RPs of the large ribosomal subunit (RPLs) had a lower 28S/18S ratio. The assay reported here would be amenable for development as a diagnostic tool.
Mutations in the human SBDS (Shwachman-Bodian-Diamond syndrome) gene are the most common cause of Shwachman-Diamond syndrome, an inherited bone marrow failure syndrome. In this issue of Genes & ...Development, Finch and colleagues (pp. 917-929) establish that SBDS functions in ribosome synthesis by promoting the recycling of eukaryotic initiation factor 6 (eIF6) in a GTP-dependent manner. This work supports the idea that a ribosomopathy may underlie this syndrome.
Lagrangian tracer simulations are deployed to investigate processes influencing vertical and horizontal dispersion of anthropogenic pollution in Fairbanks, Alaska, during the ALPACA-2022 field ...campaign. Simulations of carbon monoxide (CO), sulphur dioxide (SO2) and nitrogen oxides (NOx), including surface and elevated emissions, are highest at the surface under very cold stable conditions. Regional enhancements, simulated up to 200 m, are due to elevated power plant emissions above 50 m, with south-westerly pollutant outflow. Fairbanks regional pollution may be contributing to wintertime Arctic haze. Inclusion of a novel power plant plume rise treatment that considers the presence of surface and elevated temperature inversion layers leads to improved agreement with observed CO and NOx plumes with discrepancies attributed to, for example, displacement of plumes by modelled winds. At the surface, model results show that observed CO variability is largely driven by meteorology and to a lesser extent by emissions, although simulated tracers are sensitive to modelled vertical dispersion. Modelled underestimation of surface NOx during very cold polluted conditions is considerably improved following the inclusion of substantial increases in diesel vehicle NOx emissions at cold temperatures (e.g. a factor of 6 at -30 °C). In contrast, overestimation of surface SO2 is attributed to issues related to the vertical dispersion of elevated space heating emissions during strongly and weakly stable conditions. This study highlights the need for improvements to local wintertime Arctic anthropogenic surface and elevated emissions and improved simulation of Arctic stable boundary layers.
PhenoScanner is a curated database of publicly available results from large-scale genetic association studies. This tool aims to facilitate 'phenome scans', the cross-referencing of genetic variants ...with many phenotypes, to help aid understanding of disease pathways and biology. The database currently contains over 350 million association results and over 10 million unique genetic variants, mostly single nucleotide polymorphisms. It is accompanied by a web-based tool that queries the database for associations with user-specified variants, providing results according to the same effect and non-effect alleles for each input variant. The tool provides the option of searching for trait associations with proxies of the input variants, calculated using the European samples from 1000 Genomes and Hapmap.
PhenoScanner is available at www.phenoscanner.medschl.cam.ac.uk CONTACT: jrs95@medschl.cam.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
The essays in this collection honor Professor Ellis Sandoz, Hermann Moyse Jr. Distinguished Professor of Political Science, Louisiana State University, and founding director of the Eric Voegelin ...Institute for American Renaissance Studies, an institute located at Louisiana State University and devoted to research and publication in the fields of political philosophy, constitutional law, and Voegelin studies. The essays, each written especially for this volume, are grouped into the disciplines of philosophy, literature, and politics and range widely across these subjects, exploring writers as diverse as Xenophon, S?seki Natsume, Freud, and George Santayana and topics ranging from the leadership style of François Mitterrand and the Velvet Revolution to the nature of the Law and of the Political. Philosophy, Literature, and Politics is a fitting tribute to a man whose life's work has been formed by commitment to the philosophical enterprise and by a conviction in Eric Voegelin's contribution to that enterprise. The seventeen essays in this collection will be of particular interest to scholars of politics, comparative government, Japanese studies, political philosophy, and literary criticism.
Summary Background Acetabular dysplasia is a major predisposing factor for development of hip osteoarthritis (OA), and may result from alterations to chondrolabral loading. Subject-specific finite ...element (FE) modeling can be used to evaluate chondrolabral mechanics in the dysplastic hip, thereby providing insight into mechanics that precede OA. Objective To evaluate chondrolabral contact mechanics and congruency in dysplastic hips and normal hips using a validated approach to subject-specific FE modeling. Methods FE models of ten subjects with normal acetabula and ten subjects with dysplasia were constructed using a previously validated protocol. Labrum load support, and labrum and acetabular cartilage contact stress and contact area were compared between groups. Local congruency was determined at the articular surface for two simulated activities. Results The labrum in dysplastic hips supported 2.8–4.0 times more of the load transferred across the joint than in normal hips. Dysplastic hips did not have significantly different congruency in the primary load-bearing regions than normal hips, but were less congruent in some unloaded regions. Normal hips had larger cartilage contact stress than dysplastic hips in the few regions that had significant differences. Conclusions The labrum in dysplastic hips has a far more significant role in hip mechanics than it does in normal hips. The dysplastic hip is neither less congruent than the normal hip, nor subjected to elevated cartilage contact stresses. This study supports the concept of an outside–in pathogenesis of OA in dysplastic hips and that the labrum in dysplastic hips should be preserved during surgery.
The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary ...breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.
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