Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through ...modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
To describe the spectral-domain optical coherence tomography (SD OCT) features of peripheral retinal findings using an ultra-widefield (UWF) steering technique to image the retinal periphery.
...Observational study.
A total of 68 patients (68 eyes) with 19 peripheral retinal features.
Spectral-domain OCT-based structural features.
Nineteen peripheral retinal features, including vortex vein, congenital hypertrophy of the retinal pigment epithelium, pars plana, ora serrata pearl, typical cystoid degeneration (TCD), cystic retinal tuft, meridional fold, lattice and cobblestone degeneration, retinal hole, retinal tear, rhegmatogenous retinal detachment, typical degenerative senile retinoschisis, peripheral laser coagulation scars, ora tooth, cryopexy scars (retinal tear and treated retinoblastoma scar), bone spicules, white without pressure, and peripheral drusen, were identified by peripheral clinical examination. Near-infrared scanning laser ophthalmoscopy images and SD OCT of these entities were registered to UWF color photographs.
Spectral-domain OCT resolved structural features of all peripheral findings. Dilated hyporeflective tubular structures within the choroid were observed in the vortex vein. Loss of retinal lamination, neural retinal attenuation, retinal pigment epithelium loss, or hypertrophy was seen in several entities, including congenital hypertrophy of the retinal pigment epithelium, ora serrata pearl, TCD, cystic retinal tuft, meridional fold, lattice, and cobblestone degenerations. Hyporeflective intraretinal spaces, indicating cystoid or schitic fluid, were seen in ora serrata pearl, ora tooth, TCD, cystic retinal tuft, meridional fold, retinal hole, and typical degenerative senile retinoschisis. The vitreoretinal interface, which often consisted of lamellae-like structures of the condensed cortical vitreous near or adherent to the neural retina, appeared clearly in most peripheral findings, confirming its association with many low-risk and vision-threatening pathologies, such as lattice degeneration, meridional folds, retinal breaks, and rhegmatogenous retinal detachments.
Ultra-widefield steering-based SD OCT imaging of the retinal periphery is feasible with current commercially available devices and provides detailed anatomic information of the peripheral retina, including benign and pathologic entities, not previously imaged. This imaging technique may deepen our structural understanding of these entities and their potentially associated macular and systemic pathologies, and may influence decision-making in clinical practice, particularly in areas with teleretinal capabilities but poor access to retinal specialists.
Quiescence in stem cells is traditionally considered as a state of inactive dormancy or with poised potential. Naive mouse embryonic stem cells (ESCs) can enter quiescence spontaneously or upon ...inhibition of MYC or fatty acid oxidation, mimicking embryonic diapause in vivo. The molecular underpinning and developmental potential of quiescent ESCs (qESCs) are relatively unexplored. Here we show that qESCs possess an expanded or unrestricted cell fate, capable of generating both embryonic and extraembryonic cell types (e.g., trophoblast stem cells). These cells have a divergent metabolic landscape comparing to the cycling ESCs, with a notable decrease of the one-carbon metabolite S-adenosylmethionine. The metabolic changes are accompanied by a global reduction of H3K27me3, an increase of chromatin accessibility, as well as the de-repression of endogenous retrovirus MERVL and trophoblast master regulators. Depletion of methionine adenosyltransferase Mat2a or deletion of Eed in the polycomb repressive complex 2 results in removal of the developmental constraints towards the extraembryonic lineages. Our findings suggest that quiescent ESCs are not dormant but rather undergo an active transition towards an unrestricted cell fate.
The eye's zonular fibers normally have a high cysteine content that is essential for maintaining chemical bonds that anchor the lens to the ciliary body.1 Decreased levels of cysteine and accumulated ...levels of homocysteine that additionally inhibit microfibril cross-linking lead to progressive weakening of zonular fibers, causing eventual subluxation of the lens early in life in patients with homocystinuria.2 Unlike Marfan's syndrome, in which the lens is often displaced superiorly, lens subluxation in homocystinuria classically occurs in the inferior direction.3,4 Surgical intervention is indicated when there is a high degree of refractive error, astigmatism that cannot be corrected with spectacles or contact lenses, complete luxation of the lens, retinal detachment, lens-induced glaucoma, or uveitis. 10.1016/0002-9394(73)91149-5 PMID 4633235 Rajesh C. Rao was supported by the National Eye Institute (R01EY030989), the National Cancer Institute (P30CA046592, to the University of Michigan Rogel Comprehensive Cancer Center), and Research to Prevent Blindness (Departmental Grant to the University of Michigan Kellogg Eye Center and Career Advancement Award to RCR), and received funding from the Beatrice and Reymont Paul Foundation, March Hoops to Beat Blindness, the Taubman Institute, the Leonard G. Miller Endowed Professorship and Ophthalmic Research Fund at the Kellogg Eye Center, and the Grossman, Elaine Sandman, Marek and Maria Spatz (endowed fund), Greenspon, Dunn, Avers, Boustikakis, Sweiden, and Terauchi research funds. From the Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan (OM, RCR); and the Department of Pathology, Department of Human Genetics, Center of Computational Medicine and Bioinformatics, Center for RNA Biomedicine, Rogel Comprehensive Cancer Center, and A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, Michigan, and the Division of Ophthalmology, Surgery Section, VA Ann Arbor Healthsystem, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan (RCR).
IMPORTANCE: Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS). OBJECTIVE: To evaluate the disease course in PPS-associated ...maculopathy after drug cessation. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019. MAIN OUTCOMES AND MEASURES: Change in visual acuity and retinal imaging characteristics over time. RESULTS: Of the 11 included patients, all were female, and the median (interquartile range IQR) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year. CONCLUSIONS AND RELEVANCE: These retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.
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