Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary drivers of tumor growth and act ...as substrates for the hexosamine biosynthetic pathway (HBP). The HBP culminates in the production of an amino sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) that, along with other charged nucleotide sugars, serves as the basis for biosynthesis of glycoproteins and other glycoconjugates. These nutrient-driven post-translational modifications are highly altered in cancer and regulate protein functions in various cancer-associated processes. In this review, we discuss recent progress in understanding the mechanistic relationship between the HBP and cancer.
The hexosamine biosynthetic pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine, and acetyl-CoA. Increased flux through HBP leads to elevated ...post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteristic of cancer cells, and recent studies suggest that O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. This review summarizes our current understanding of changes of O-GlcNAc cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis, and the current challenges in targeting this pathway therapeutically.
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•O-GlcNAcylation levels are found elevated in nearly all cancers examined.•O-GlcNAc cycling enzymes O-GlcNAc transferase and O-GlcNAcase are altered in many cancers.•O-GlcNAcylation regulates many aspects of the “Hallmarks of Cancer”.•Reducing O-GlcNAcylation in cancer cells may be a potential treatment strategy.
The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation ...by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, and interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of endoplasmic reticulum (ER) stress and cancer cell apoptosis mediated through C/EBP homologous protein (CHOP). HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress, as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects. Human breast cancers with high levels of HIF-1α contain elevated OGT, and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α.
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•Reducing OGT and O-GlcNAcylation in cancer cells decreases cancer glycolysis•OGT regulates stability of HIF-1α via regulation of α-ketoglutarate levels•Reducing OGT levels or activity induces ER stress and apoptosis in cancer cells•Stable HIF-1α mutant or GLUT1 overexpression rescues OGT-mediated phenotypes
Multiple cancers contain elevated levels of O-GlcNAc transferase (OGT). Ferrer et al. show that OGT and O-GlcNAcylation play a critical role in cancer-driven glycolysis and stress survival signaling by regulating the degradation of the hypoxia-inducible factor 1 (HIF-1α).
•New GFP variants that allow for more general sets of barriers and solutions.•Problems solved to optimality through Integer Programming modeling.•Preprocessing algorithms and IP-based primal ...heuristics described in detail.•Two large publicly available sets of challenging instances based on actual forests.•Openly accessible best known bounds and solutions for more than a thousand instances.
In this paper, we introduce the Geometric Firefighter Routing Problem (gfrp) as a variant of the Geometric Firefighter Problem aiming to better model more realistic situations. We design an exact algorithm based on a core Linear Integer Programming formulation and propose additional sets of valid constraints to strengthen it. The algorithm also includes primal heuristics, and preprocessing procedures to reduce the model size. Besides, we generate two large sets of instances, tailored to the gfrp, and report on comprehensive experimental results for them. Thorough analysis validate the effectiveness of each major step of the algorithm and the overall performance of our approach.
To reduce the costs of maintaining a poliovirus immunization base in low-income areas, we assessed the extent of priming immune responses after the administration of inactivated poliovirus vaccine ...(IPV).
We compared the immunogenicity and reactogenicity of a fractional dose of IPV (one fifth of a full dose) administered intradermally with a full dose administered intramuscularly in Cuban infants at the ages of 4 and 8 months. Blood was collected from infants at the ages of 4 months, 8 months, 8 months 7 days, and 8 months 30 days to assess single-dose seroconversion, single-dose priming of immune responses, and two-dose seroconversion. Specimens were tested with a neutralization assay.
A total of 320 infants underwent randomization, and 310 infants (96.9%) fulfilled the study requirements. In the group receiving the first fractional dose of IPV, seroconversion to poliovirus types 1, 2, and 3 occurred in 16.6%, 47.1%, and 14.7% of participants, respectively, as compared with 46.6%, 62.8%, and 32.0% in the group receiving the first full dose of IPV (P<0.008 for all comparisons). A priming immune response to poliovirus types 1, 2, and 3 occurred in 90.8%, 94.0%, and 89.6% of participants, respectively, in the group receiving the fractional dose as compared with 97.6%, 98.3%, and 98.1% in the group receiving the full dose (P=0.01 for the comparison with type 3). After the administration of the second dose of IPV in the group receiving fractional doses, cumulative two-dose seroconversion to poliovirus types 1, 2, and 3 occurred in 93.6%, 98.1%, and 93.0% of participants, respectively, as compared with 100.0%, 100.0%, and 99.4% in the group receiving the full dose (P<0.006 for the comparisons of types 1 and 3). The group receiving intradermal injections had the greatest number of adverse events, most of which were minor in intensity and none of which had serious consequences.
This evaluation shows that vaccinating infants with a single fractional dose of IPV can induce priming and seroconversion in more than 90% of immunized infants. (Funded by the World Health Organization and the Pan American Health Organization; Australian New Zealand Clinical Trials Registry number, ACTRN12610001046099.).
•Starch properties like M, rrms and ρapp changed for the baking process.•The changes depend on the type of bread and the water content in the recipe.•A second population is present in bread with the ...highest resistant starch content.
In this study, molecular properties of wheat starch from three different types of breads were analyzed using asymmetric flow field-flow (AF4) connected to multi-angle light scattering (MALS) and differential refractive index (dRI) detectors. This analysis allowed the determination of molecular properties, i.e. molar mass (M), root-mean-square radius (rrms), apparent density (ρapp) and conformation. Complementary analyses, such as resistant starch and amylose content, were also performed. The results show that wheat starch extracted from breads can have different properties reflected in changes in M, rrms and ρapp. In addition, the results suggest that some of the changes in molecular properties may be related to the presence of resistant starch.
Recombination between herpesviruses has been seen in vitro and in vivo under experimental conditions. This has raised safety concerns about using attenuated herpesvirus vaccines in human and ...veterinary medicine and adds to other known concerns associated with their use, including reversion to virulence and disease arising from recurrent reactivation of lifelong chronic infection. We used high-throughput sequencing to investigate relationships between emergent field strains and vaccine strains of infectious laryngotracheitis virus (ILTV, gallid herpesvirus 1). We show that independent recombination events between distinct attenuated vaccine strains resulted in virulent recombinant viruses that became the dominant strains responsible for widespread disease in Australian commercial poultry flocks. These findings highlight the risks of using multiple different attenuated herpesvirus vaccines, or vectors, in the same populations.
O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA which catalyze the addition or ...removal of the UDP-GlcNAc moieties, respectively. Structural changes brought by this modification lead to alternations of protein stability, protein-protein interactions, and phosphorylation. Importantly, O-GlcNAcylation is a nutrient sensor by coupling nutrient sensing with cellular signaling. Elevated levels of OGT and O-GlcNAc have been reported in a variety of cancers and has been linked to regulation of multiple cancer signaling pathways. In this review, we discuss the most recent findings on the role of O-GlcNAcylation as a metabolic sensor in signaling pathways and immune response in cancer.
•The post-translational modification O-GlcNAcylation is found to be elevated in nearly all cancers.•This nutrient sensitive intracellular glycosylation can regulate a diverse set of cytosolic and nuclear proteins.•O-GlcNAcylation regulates signaling pathways including transcription, metabolic and immune regulation in cancer cells.•This review highlight most recent understanding of mechanisms by which O-GlcNAcylation regulates cancer cell signaling.
Abstract Background Extreme lateral interbody fusion (ELIF) is a powerful tool for interbody fusion and coronal deformity correction. However, evidence regarding the success of ELIF in decompressing ...foraminal, lateral recesses and central canal stenosis is lacking. The purpose of this study was to systematically review current literature on the potential and limitations of ELIF to indirectly decompress neural elements. Methods A systematic literature search in the PubMed, Cochrane and ScienceDirect databases was performed according to PRISM criteria. Information on study design, sample size, population, procedure, number and location of involved levels, follow-up time and complications, as well as information on conflict of interest was extracted and evaluated. Results 20 publications were selected for review including a total of 1080 patients. The majority of publications (90%) were retrospective case series. Most frequent indications for ELIF included degenerative disc disease, spinal stenosis, spondylolisthesis and degenerative scoliosis. The majority of studies revealed significant improvement in radiographic and clinical outcome after ELIF. Mean foraminal area, central canal area and subarticular diameter increased by 31.6mm2 , 28.5mm2 and 0.85mm, respectively. ELIF successfully improved foraminal stenosis, contradictory results were found for indirect decompression of central canal stenosis. Data on lateral recess stenosis were scarce. Conclusions Current data suggests ELIF to be an efficient technique in decompression of foraminal stenosis. Evidence on decompression of central canal or lateral recess stenosis via ELIF is low and results are inconsistent. Most studies are limited in study design, sample size and potential conflicts of interest.
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