Ntative of primary GBM in terms of patterns of PKM isoform expression and PK activity, and in these cells the up-regulation of PKM1 in the face of high endogenous levels of PKM2 increased PKM activity and 125-65-5 suppressed growth, suggesting that optimal glioma growth is limited by high PK activity. Although the basis for this effect is unclear, the data are consistent with idea that the use of glucose for pyruvate and ATP production limits the ability of cells to create the macromolecules needed for increased proliferation [40], resulting in a generalized accumulation of cells G0/G1. The modulation of the end 15900046 products of PK activity may therefore be a reasonable strategy to inhibit growth of these GBM cells. In contrast, suppression of PKM2 levels in the face of low PKM1 levels also suppressed cell growth. Similar findings in other systems were attributed to levels of PK activity insufficient to sustain growth [6,40], although in the present study the PK activity levels in the PKM2 knock-down cell were comparable to those in primary GBM. An alternative explanation may be provided by recent studies showing that PKM2 not only has metabolic effects but can also translocate to the nucleus and facilitate cyclin D1 expression and cell cycle progression [28]. While the effects of PKM2 knock-down noted in the present study are consistent with the non-metabolic effects of PKM2, the accumulation of cells was not associated with a generalized slowing in cell cycle progression but rather a specific G2 arrest. It may therefore be possible that PKM2 has non-metabolic effects on regulators of the G2 checkpoint that cooperate with, or supersede, those related to cyclin D1. The present findings provide the first detailed picture of PKM expression and activity across a range of gliomas of different grades. These studies provide a more complex picture of PKM isoform regulation than previously described, and suggest that while PK activity is uniform across all grades of glioma, PKM2 expression is up-regulated not at the benign/malignant transition and not in a gradual manner related to tumor grade, but rather most dramatically in GBM. Therapeutic approaches targeting metabolic changes in glioma may therefore benefit from 4EGI-1 site considering glioma subtypes separately, and in particular in focusing on the potentially unique role of PKM2 over-expression in GBM.Author ContributionsConceived and designed the experiments: JM JP SZ JW SR RP. Performed the experiments: JM JP SZ. Analyzed the data: JM JP RP. Contributed reagents/materials/analysis tools: JP SZ JW. Wrote the paper: JM RP.
There is strong evidence that pregnant women and infants are at increased risk of severe illness following infection with influenza virus [1]. Hospitalization for respiratory illness related to seasonal influenza is more frequent in pregnant than in non pregnant women [2,3], and the risk of death in pregnant women increased during influenza pandemics compared to non-pandemic years [4]. The emergence of A/H1N1 influenza infection in Mexico and in Australia in early 2009 raised further awareness and concernworldwide. In June 2009, World Health Organization raised the pandemic alert level to the highest level of 6 [5]. In August 2009, researchers from the Centers for Disease Control and Prevention reported that 6/45 (13 ) patients who died from 2009 A/H1N1 influenza between mid-April and mid-June were pregnant women [6]. The disproportionately increased risk of mortality due to A/ H1N1 2009 influen.Ntative of primary GBM in terms of patterns of PKM isoform expression and PK activity, and in these cells the up-regulation of PKM1 in the face of high endogenous levels of PKM2 increased PKM activity and suppressed growth, suggesting that optimal glioma growth is limited by high PK activity. Although the basis for this effect is unclear, the data are consistent with idea that the use of glucose for pyruvate and ATP production limits the ability of cells to create the macromolecules needed for increased proliferation [40], resulting in a generalized accumulation of cells G0/G1. The modulation of the end 15900046 products of PK activity may therefore be a reasonable strategy to inhibit growth of these GBM cells. In contrast, suppression of PKM2 levels in the face of low PKM1 levels also suppressed cell growth. Similar findings in other systems were attributed to levels of PK activity insufficient to sustain growth [6,40], although in the present study the PK activity levels in the PKM2 knock-down cell were comparable to those in primary GBM. An alternative explanation may be provided by recent studies showing that PKM2 not only has metabolic effects but can also translocate to the nucleus and facilitate cyclin D1 expression and cell cycle progression [28]. While the effects of PKM2 knock-down noted in the present study are consistent with the non-metabolic effects of PKM2, the accumulation of cells was not associated with a generalized slowing in cell cycle progression but rather a specific G2 arrest. It may therefore be possible that PKM2 has non-metabolic effects on regulators of the G2 checkpoint that cooperate with, or supersede, those related to cyclin D1. The present findings provide the first detailed picture of PKM expression and activity across a range of gliomas of different grades. These studies provide a more complex picture of PKM isoform regulation than previously described, and suggest that while PK activity is uniform across all grades of glioma, PKM2 expression is up-regulated not at the benign/malignant transition and not in a gradual manner related to tumor grade, but rather most dramatically in GBM. Therapeutic approaches targeting metabolic changes in glioma may therefore benefit from considering glioma subtypes separately, and in particular in focusing on the potentially unique role of PKM2 over-expression in GBM.Author ContributionsConceived and designed the experiments: JM JP SZ JW SR RP. Performed the experiments: JM JP SZ. Analyzed the data: JM JP RP. Contributed reagents/materials/analysis tools: JP SZ JW. Wrote the paper: JM RP.
There is strong evidence that pregnant women and infants are at increased risk of severe illness following infection with influenza virus [1]. Hospitalization for respiratory illness related to seasonal influenza is more frequent in pregnant than in non pregnant women [2,3], and the risk of death in pregnant women increased during influenza pandemics compared to non-pandemic years [4]. The emergence of A/H1N1 influenza infection in Mexico and in Australia in early 2009 raised further awareness and concernworldwide. In June 2009, World Health Organization raised the pandemic alert level to the highest level of 6 [5]. In August 2009, researchers from the Centers for Disease Control and Prevention reported that 6/45 (13 ) patients who died from 2009 A/H1N1 influenza between mid-April and mid-June were pregnant women [6]. The disproportionately increased risk of mortality due to A/ H1N1 2009 influen.