| 1. |
- Xu, An, et al.
(författare)
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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.
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| 2. |
- Bengtsson, Boel, et al.
(författare)
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Disc Hemorrhages and Treatment in the Early Manifest Glaucoma Trial.
- 2008
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Ingår i: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; Aug 7, s. 2044-2048
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the effect of intraocular pressure (IOP)-reducing treatment on the development of disc hemorrhages in patients with glaucoma. DESIGN: Prospective cohort study of patients in the Early Manifest Glaucoma Trial, followed up to 11 years (median = 8 years). PARTICIPANTS: Patients with newly detected glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no initial treatment (n = 126), followed with tonometry, perimetry, and ophthalmoscopy every 3 months, and fundus photography every 6 months. METHODS: Logistic regression expressed as odds ratios (OR) and 95% confidence intervals (CIs), analysis of variance, and Cox time-dependent models, expressed as hazard ratios (HRs) and CIs. MAIN OUTCOME MEASURES: Presence (yes/no) and frequency of disc hemorrhages. RESULTS: Disc hemorrhages were identified in approximately 55% of all patients, whether by ophthalmoscopy or review of photographs. In analyses including data up to the time of progression, disc hemorrhages were equally common among treated and control patients: 51.2% versus 45.2%, respectively (P = 0.34), based on ophthalmoscopy, and 50.4% versus 44.4%, respectively (P = 0.34), based on photographs. Gender was the only factor related to the presence of disc hemorrhages detected by both ophthalmoscopy (OR = 0.48; CI, 0.26-0.88; P = 0.022) and photographs (OR = 0.64; CI, 0.38-1.09; P = 0.099) for male patients. The frequency of disc hemorrhages over time did not differ between treated and control patients: 8.4% versus 8.5%, respectively (P = 0.93), based on ophthalmoscopy, and 12.4% versus 11.2%, respectively (P = 0.36), based on photographs. Disc hemorrhages were significantly associated with time to progression (HR = 1.02; CI, 1.01-1.04), and there was no evidence of interaction between treatment group and disc hemorrhages. CONCLUSIONS: IOP-reducing treatment was unrelated to the presence or frequency of disc hemorrhages. The results may suggest that disc hemorrhages cannot be considered an indication of insufficient IOP-lowering treatment, and that glaucoma progression in eyes with disc hemorrhages cannot be totally halted by IOP reduction. The results also suggest that disc hemorrhages do not occur in all patients with glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
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| 3. |
- Heijl, Anders, et al.
(författare)
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Intraocular pressure reduction with a fixed treatment protocol in the Early Manifest Glaucoma Trial.
- 2011
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 89, s. 749-754
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate: (i) the relationship between intraocular pressure (IOP) reduction attained with a fixed treatment protocol and the untreated IOP level; (ii) the consistency of IOP reduction over time; and (iii) whether there is a threshold pretreatment IOP level below which IOP reduction might be less effective. Results are based on 128 patients with glaucoma with field defects, who were randomized to the treatment arm of the Early Manifest Glaucoma Trial (EMGT). Methods: The EMGT fixed treatment protocol consisted of 360 degrees laser trabeculoplasty and topical betaxolol eye drops B.I.D. Treatment was unchanged as long as progression did not occur. Analyses assessed the initial IOP reduction after 3 months and also the mean reduction based on all follow-up values; IOP changes over time were evaluated with linear regression analysis. Factors influencing initial and mean IOP reduction were also explored using linear models. Results: Mean age at baseline was 68 years, and untreated baseline IOP ranged from 13 to 30.5 mmHg. On average, eyes with higher baseline IOP experienced larger pressure reductions than eyes with lower baseline IOP, whether expressed in mmHg or as percentages. Each mmHg of higher baseline IOP was associated with approximately 0.6 mmHg larger IOP reduction. IOP changed little over time, with 66% of patients changing less than 0.5 mmHg/year, and only 13% (17/128) changing >1.0 mmHg/year. The treatment protocol did not achieve any average IOP reduction in eyes with baseline pressures
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| 4. |
- Hyman, Leslie, et al.
(författare)
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Natural History of Intraocular Pressure in the Early Manifest Glaucoma Trial A 6-Year Follow-up
- 2010
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Ingår i: Archives of Ophthalmology. - 0003-9950. ; 128:5, s. 601-607
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To characterize intraocular pressure (IOP) changes during 6 years of follow-up among patients with early, newly diagnosed glaucoma randomized to no initial treatment in the Early Manifest Glaucoma Trial (control group) and to evaluate factors associated with IOP changes in this group. Methods: Early Manifest Glaucoma Trial control patients, aged 50 to 80 years at baseline, were followed up for 6 years or to the time of progression, when treatment could be initiated. After baseline, patients were followed up every 3 months with comprehensive ophthalmologic examinations, including Goldmann applanation tonometry. Change in IOP over 6 years was assessed by linear regression analyses. Results: At baseline, the median IOP of this cohort (N = 118) was 20.8 mm Hg and was higher for the 15 patients with exfoliation glaucoma (24.0 mm Hg vs 20.0 mm Hg for others; P = .005). In patients without exfoliation glaucoma, IOP remained stable during follow-up (median IOP change of -0.01 mm Hg/y; interquartile range, 0.85 mm Hg/y). In comparison, patients with exfoliation glaucoma showed a significantly larger median change of 0.96 mm Hg/y (interquartile range, 3.11 mm Hg/y) (P = .004). In the overall cohort, the only factor related to IOP change was exfoliation glaucoma (P < .001). Among patients without exfoliation glaucoma, no factors were associated with IOP change. Conclusions: In patients with early glaucoma, IOP remained stable without treatment during a 6-year period, regardless of baseline IOP, except for patients with exfoliation glaucoma, where IOP increased by almost 1 mm Hg annually. No factors, aside from exfoliation glaucoma, were related to longitudinal changes in IOP. These new natural history data may be useful in guiding management decisions for glaucoma treatment, particularly in patients with early disease or with exfoliation glaucoma.
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| 5. |
- Leske, M. Cristina, et al.
(författare)
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Predictors of long-term progression in the early manifest glaucoma trial
- 2007
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Ingår i: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 114:11, s. 1965-1972
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To determine progression factors at the end of the Early Manifest Glaucoma Trial (EMGT) based on all EMGT patients and evaluate separately patients with higher and lower baseline intraocular pressure (IOP; median split). Design: Cohort of clinical trial participants. Participants: Patients with early open-angle glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no immediate treatment (n = 126), examined every 3 months for up to 11 years. Methods: Cox proportional hazard analyses, expressed by hazard ratios (HRs) and 95% confidence intervals (Cls). Main Outcome Measure: Time to progression, defined by perimetric and photographic disc criteria. Results: Overall progression was 67% when follow-up ended (median, 8 years). Treatment approximately halved progression risk (HR, 0.53; 95% Cl, 0.39-0.72); results were similar for patients with higher and lower baseline IOP (HRs, 0.41 and 0.55). Baseline progression factors (HRs, 1.51-2.12; P<0.01) were higher IOP, exfoliation, bilateral disease, and older age, as previously reported. New baseline predictors were lower ocular systolic perfusion pressure in all patients (<= 160 mmHg; HR, 1.42; 95% Cl, 1.04-1.94), cardiovascular disease history (HR, 2.75; 95% Cl, 1.44-5.26) in patients with higher baseline IOP, and lower systolic blood pressure (BP) (<= 125 mmHg; HR, 0.46; 95% Cl, 0.21-1.02) in patients with lower baseline IOP. Postbaseline progression factors were IOP levels at follow-up, with 12% to 13% average increase per millimeter of mercury in all patients (HRs, 1.12-1.13 per mmHg higher) and similar results in patients with higher and lower baseline IOP (HRs, 1.15 and 1.13 per mmHg higher). Disc hemorrhages (HR, 1.02; 95% Cl, 1.01-1.03 per percent higher frequency) also predicted progression. Thinner central corneal thickness (CCT) (HR, 1.25; 95% Cl, 1.01-1.55 per 40 mu m lower) was a new significant factor, a result observed in patients with higher baseline IOP (HR, 1.42; 95% Cl, 1.05-1.92 per 40 mu m lower) but not lower baseline IOP, with significant IOP-CCT interaction. Conclusions: Treatment and follow-up IOP continued to have a marked influence on progression, regardless of baseline IOP. Other significant factors were age, bilaterality, exfoliation, and disc hemorrhages, as previously determined. Lower systolic perfusion pressure, lower systolic BP, and cardiovascular disease history emerged as new predictors, suggesting a vascular role in glaucoma progression. Another new factor was thinner CCT, with results possibly indicating a preferential CCT effect with higher IOP. Ophthalmology 2007,114: 1965-1972 (C) 2007 by the American Academy of Ophthalmology.
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