• Variation between two near isogenic barley (Hordeum vulgare) cultivars in expression of the B subunit of the vacuolar ATPase in response to salinity.

      Wei, Wenxue; Bilsborrow, Paul E.; Hooley, Paul; Fincham, Daron A.; Forster, Brian P. (Wiley InterScience, 2001)
      A gene encoding the barley vacuolar ATPase subunit B (BSVAP) was differentially expressed between two near isogenic barley cultivars, Golden Promise and Maythorpe. This gene (BSVAP) was isolated by the mRNA differential display technique (DDRT-PCR). BSVAP was salt inducible under long-term salinity stress in the salt sensitive cultivar Maythorpe but less so in the relatively salt tolerant Golden Promise and was more highly expressed under control conditions in Maythorpe. The physiological consequences of altered vacuolar ATPase expression are discussed in relation to the salt sensitivity of Maythorpe.
    • Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression.

      Armesilla, Angel Luis; Lorenzo, Elisa; Gómez del Arco, Pablo; Martínez-Martínez, Sara; Alfranca, Arantzazu; Redondo, Juan Miguel (American Society for Microbiology, 1999)
      Vascular endothelial growth factor (VEGF) is a potent angiogenic inducer that stimulates the expression of tissue factor (TF), the major cellular initiator of blood coagulation. Here we show that signaling triggered by VEGF induced DNA-binding and transcriptional activities of nuclear factor of activated T cells (NFAT) and AP-1 in human umbilical vein endothelial cells (HUVECs). VEGF also induced TF mRNA expression and gene promoter activation by a cyclosporin A (CsA)-sensitive mechanism. As in lymphoid cells, NFAT was dephosphorylated and translocated to the nucleus upon activation of HUVECs, and these processes were blocked by CsA. NFAT was involved in the VEGF-mediated TF promoter activation as evidenced by cotransfection experiments with a dominant negative version of NFAT and site-directed mutagenesis of a newly identified NFAT site within the TF promoter that overlaps with a previously identified kappaB-like site. Strikingly, this site bound exclusively NFAT not only from nuclear extracts of HUVECs activated by VEGF, a stimulus that failed to induce NF-kappaB-binding activity, but also from extracts of cells activated with phorbol esters and calcium ionophore, a combination of stimuli that triggered the simultaneous activation of NFAT and NF-kappaB. These results implicate NFAT in the regulation of endothelial genes by physiological means and shed light on the mechanisms that switch on the gene expression program induced by VEGF and those regulating TF gene expression.
    • Vascular endothelial growth factor in astroglioma stem cell biology and response to therapy

      Knizetova, Petra; Darling, John L.; Bartek, Jiri (Wiley InterScience, 2008)
      Malignant astrogliomas are among the most aggressive, highly vascular and infiltrating tumours bearing a dismal prognosis, mainly due to their resistance to current radiation treatment and chemotherapy. Efforts to identify and target the mechanisms that underlie astroglioma resistance have recently focused on candidate cancer stem cells, their biological properties, interplay with their local microenvironment or 'niche', and their role in tumour progression and recurrence. Both paracrine and autocrine regulation of astroglioma cell behaviour by locally produced cytokines such as the vascular endothelial growth factor (VEGF) are emerging as key factors that determine astroglioma cell fate. Here, we review these recent rapid advances in astroglioma research, with emphasis on the significance of VEGF in astroglioma stem-like cell biology. Furthermore, we highlight the unique DNA damage checkpoint properties of the CD133-marker-positive astroglioma stem-like cells, discuss their potential involvement in astroglioma radioresistance, and consider the implications of this new knowledge for designing combinatorial, more efficient therapeutic strategies.
    • Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells.

      Brown, James E. P.; Onyango, David J.; Ramanjaneya, Manjunath; Conner, Alex C.; Patel, Snehal T.; Dunmore, Simon J.; Randeva, Harpal S. (Society for Endocinology, 2010)
      The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic beta-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic beta-cells. beta-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1beta (32-fold increase), HNF4alpha (16-fold increase) and nuclear factor kappaB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of beta-cell function-associated genes in mouse beta-cells.
    • Vitamin E correlates inversely with non-transferrin-bound iron in sickle cell disease.

      Marwah, S.S.; Wheelwright, D.; Blann, A.D.; Rea, C.; Beresford, R.; Phillips, Jonathan D.; Wright, J.; Bareford, D. (Wiley InterScience, 2001)
      Decreased serum vitamin E levels are found in homozygous sickle cell disease (SCD). Excessive transfusions may lead high non-transferrin-bound iron (NTBI). Hypothesizing a relationship between the two, vitamin E (measured using high performance liquid chromatography) was significantly lower in 30 SCD patients than in 30 age-/sex-matched controls (P < 0.001), but NTBI (bleomycin assay) was higher (P < 0.001). Vitamin E was lower in 10 transfused patients than in 20 non-transfused patients (P < 0.001) with a significant inverse correlation between the NTBI and vitamin E (r = -0.58, P < 0.001). NTBI associated with iron overload in SCD may increase the potential for oxidative damage and low vitamin E activity may compound this effect.
    • ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

      Ranson, Malcolm; Hammond, Lisa A.; Ferry, David R.; Kris, Mark; Tullo, Andrew; Murray, Philip I.; Miller, Vince; Averbuch, Steve; Ochs, Judy; Morris, Charles; et al. (American Society of Clinical Oncology, 2002)
      PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.