Aims/hypothesisThe aim of this multicentre, randomised, controlled crossover study was to determine the efficacy of adding continuous glucose monitoring (CGM) to insulin pump therapy (CSII) in type 1 diabetes.MethodsChildren and adults (n = 153) on CSII with HbA1c 7.5–9.5% (58.5–80.3 mmol/mol) were randomised to (CGM) a Sensor On or Sensor Off arm for 6 months. After 4 months’ washout, participants crossed over to the other arm for 6 months. Paediatric and adult participants were separately electronically randomised through the case report form according to a predefined randomisation sequence in eight secondary and tertiary centres. The primary outcome was the difference in HbA1c levels between arms after 6 months.ResultsSeventy-seven participants were randomised to the On/Off sequence and 76 to the Off/On sequence; all were included in the primary analysis. The mean difference in HbA1c was –0.43% (–4.74 mmol/mol) in favour of the Sensor On arm (8.04% [64.34 mmol/mol] vs 8.47% [69.08 mmol/mol]; 95% CI −0.32%, −0.55% [−3.50, −6.01 mmol/mol]; p < 0.001). Following cessation of glucose sensing, HbA1c reverted to baseline levels. Less time was spent with sensor glucose <3.9 mmol/l during the Sensor On arm than in the Sensor Off arm (19 vs 31 min/day; p = 0.009). The mean number of daily boluses increased in the Sensor On arm (6.8 ± 2.5 vs 5.8 ± 1.9, p < 0.0001), together with the frequency of use of the temporary basal rate (0.75 ± 1.11 vs 0.26 ± 0.47, p < 0.0001) and manual insulin suspend (0.91 ± 1.25 vs 0.70 ± 0.75, p < 0.018) functions. Four vs two events of severe hypoglycaemia occurred in the Sensor On and Sensor Off arm, respectively (p = 0.40).Conclusions/interpretationContinuous glucose monitoring was associated with decreased HbA1c levels and time spent in hypoglycaemia in individuals with type 1 diabetes using CSII. More frequent self-adjustments of insulin therapy may have contributed to these effects.Trial registrationClinicalTrials.gov registration no. NCT00598663.FundingThe study was funded by Medtronic International Trading Sarl Switzerland.
Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory  subunit, CK2, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2 gene in mice leads to postimplantation lethality. Mutant embryos were reduced in size at embryonic day 6.5 (E6.5). They did not exhibit signs of apoptosis but did show reduced cell proliferation. Mutant embryos were resorbed at E7.5. In vitro, CK2 ؊/؊ morula development stopped after the blastocyst stage. Attempts to generate homozygous embryonic stem (ES) cells failed. By using a conditional knockout approach, we show that lack of CK2 is deleterious for mouse ES cells and primary embryonic fibroblasts. This is in contrast to what occurs with yeast cells, which can survive without functional CK2. Thus, our study demonstrates that in mammals, CK2 is essential for viability at the cellular level, possibly because it acquired new functions during evolution.Protein kinase CK2 is a pleiotropic and highly conserved protein kinase with more than 300 substrates described to date. It seems to be involved in controlling a large panel of normal cellular functions such as gene expression, protein synthesis, cell cycle, and proliferation, as well as pathological processes such as carcinogenesis and viral tumorigenesis (12, 33). Recently, its function in protecting cells against apoptosis has been reported (1).CK2 is a tetrameric holoenzyme generally composed of two catalytic subunits, ␣ and ␣Ј, and two regulatory  subunits which combine to form an ␣␣Ј 2 , ␣ 2  2 , or ␣Ј 2  2 heterotetramer. The catalytic CK2 subunits ␣ and ␣Ј belong to the eukaryotic protein kinase superfamily. In contrast, the regulatory  subunit is a unique protein encoded by a single gene in mammals (3) and does not belong to a known protein family.CK2 has several functions in the holoenzyme complex. Reconstitution experiments with recombinant purified subunits have demonstrated that CK2 modulates the activity of CK2. Depending on the substrate, CK2 activates or downregulates the activity of the catalytic subunit (24). CK2 also confers stability to the holoenzyme complex (18) and seems to mediate interaction with a number of substrates (19).The crystal structure elucidations of the isolated CK2 subunit (5) and of the holoenzyme complex (28) indicate that the  subunit exists as a dimer and is the building block of the CK2 holoenzyme bridging the two catalytic subunits. The crystal structure is also consistent with the suggested flexible role of the  subunit as a docking partner for other protein kinases and other interacting partners in the cell (28).Functional and biochemical studies have indicated that fractions of both the catalytic and regulatory subunits may exist separately. A population of CK2␣ that binds to protein phosphatase 2A is free of CK2 (16). Moreover, CK2 fractions devoid of the catalytic subunit, but probably involved in complexes with other prote...
Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The 111In-labelled DOTA-conjugated ZEGFR:2377 Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-ZEGFR:2377. DOTA-ZEGFR:2377 was labelled with 57Co (T1/2 = 271.8 d), 55Co (T1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide 68Ga (T1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope 57Co was used in animal studies. Both 57Co-DOTA-ZEGFR:2377 and 68Ga-DOTA-ZEGFR:2377 demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-ZEGFR:2377 were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, 57Co-DOTA-ZEGFR:2377 demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for 68Ga-DOTA-ZEGFR:2377. The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-ZEGFR:2377 and further development should concentrate on this radionuclide as a label.
Glioblastoma multiforme is the most common primary brain tumor and one of the most aggressive types of cancer in adults. Survival signaling and apoptosis resistance are hallmarks of malignant glioma cells. However, recent studies have shown that other types of cell death such as autophagy can be induced in malignant glioma cells. This suggests that stimulation of this process may be explored in new therapeutic strategies against glioblastoma multiforme. Protein kinase CK2 is a highly conserved and constitutively active enzyme that promotes numerous cellular processes such as survival, proliferation and differentiation. CK2 has been found elevated in several malignancies including brain tumors, and to confer resistance against chemotherapeutic agents and apoptotic stimuli. Recently, we have shown that the siRNA-mediated downregulation of CK2 leads to cell death in DNA-PK-proficient human glioblastoma cells. We show, here, that lack of CK2 results in significant induction of autophagic cell death in two human glioblastoma cell lines, M059K and T98G, as indicated by the positive staining of cells with the acidotropic dye acridine orange, and the specific recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosome membranes. Induction of autophagy is accompanied by CK2-dependent decreased phosphorylation of p70 ribosomal S6 and AKT kinases and significantly reduced expression levels of Raptor. In contrast, phosphorylation and activity levels of ERK1/2 are enhanced suggesting an inhibition of the PI3K/AKT/mTORC1 and activation of the ERK1/2 pathways. Furthermore, siRNA-mediated silencing of CK2 results in increased mitochondrial superoxide production in both glioblastoma cell lines. However, mitochondrial reactive oxygen species release correlates with induction of autophagy only in T98G cells. Taken together, our findings identify CK2 as a novel component of the autophagic machinery and underline the potential of its downregulation to kill glioblastoma cells by overcoming the resistance to multiple anticancer agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.