The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds ...directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent ...keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy.
A retrospective chart review examined adult patients with herpes simplex (HSV) and zoster (HZO) keratitis at a single institution. Patients who suffered a poor outcome (defined as visually ...significant corneal scarring, neurotrophic keratitis, secondary glaucoma, or requiring corneal surgery) were identified and each outcome type was analyzed in relation to age, sex, diabetes mellitus, immunosuppression, and a prior history of ≥2 ocular procedures.
Advanced age, diabetes mellitus, and a prior history of ≥2 ocular procedures may be risk factors for poor outcomes in HSV, but not HZO, keratitis. In HSV, older age and DM were specifically associated with visually significant corneal scarring, while older age and male sex were associated with secondary glaucoma. Future prospective studies are warranted to determine the ideal management (including prophylaxis) in patients with these characteristics.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
While Slicer activity of Argonaute is central to RNAi, conserved roles of slicing in endogenous regulatory biology are less clear, especially in mammals. Biogenesis of erythroid Dicer-independent ...mir-451 involves Ago2 catalysis, but mir-451-KO mice do not phenocopy Ago2 catalytic-dead (Ago2-CD) mice, suggesting other needs for slicing. Here, we reveal mir-486 as another dominant erythroid miRNA with atypical biogenesis. While it is Dicer dependent, it requires slicing to eliminate its star strand. Thus, in Ago2-CD conditions, miR-486-5p is functionally inactive due to duplex arrest. Genome-wide analyses reveal miR-486 and miR-451 as the major slicing-dependent miRNAs in the hematopoietic system. Moreover, mir-486-KO mice exhibit erythroid defects, and double knockout of mir-486/451 phenocopies the cell-autonomous effects of Ago2-CD in the hematopoietic system. Finally, we observe that Ago2 is the dominant-expressed Argonaute in maturing erythroblasts, reflecting a specialized environment for processing slicing-dependent miRNAs. Overall, the mammalian hematopoietic system has evolved multiple conserved requirements for Slicer-dependent miRNA biogenesis.
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•Conserved, erythroid miR-486 requires slicing of its passenger strand by Ago2•miR-486/451 are the dominant slicing-dependent miRNAs in the hematopoietic compartment•Their loss together explains the erythroid phenotype of Ago2 slicing-deficient mice•Erythroid tissue has conserved signature of Ago2-only expression in mouse and human
Jee et al. reveal that a major conserved rationale for mammalian Argonaute2 slicing is for the combined maturation of miR-486 and miR-451, miRNAs necessary for erythroid development. Their loss phenocopies the erythroid defects of slicing-deficient mice, and this slicing requirement explains the unique Ago2-only expression pattern found in erythroid tissue.
A 79-year-old woman had uneventful femtosecond laser–assisted cataract surgery including paired laser astigmatic keratotomies (AKs) in the right eye. Three weeks postoperatively, a corneal infiltrate ...developed in the superotemporal AK incision. Cultures grew methicillin-resistant Staphylococcus aureus . The infection was treated with topical fortified vancomycin and tobramycin; full resolution required several months of therapy. Five months after cataract surgery, the patient presented with a second stromal infiltrate, also in the superotemporal AK incision. Despite negative cultures, the infiltrate resolved quickly on a short course of broad-spectrum fortified antibiotics. At 6 months, the corrected distance visual acuity was 20/30. This case demonstrates that infectious keratitis can occur following uneventful femtosecond laser–assisted AK performed concurrently with cataract surgery. We reviewed the literature on infectious keratitis following refractive keratotomy and femtosecond laser–assisted procedures. Several recommendations to prevent these infections are proposed. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.
Abstract Purpose Moraxella atlantae is a rare pathogen. Keratitis from this organism has never been specifically reported or described. In this report we provide the first clinical description and ...photograph of Moraxella atlantae infectious keratitis. Observations A 41 year-old man presented with a three day history of left eye pain. He was found to have a corneal ring ulcer and infiltrate from which Moraxella atlantae was cultured. The patient was successfully treated with intensive topical gatifloxacin (0.5%) and fortified tobramycin (1.5%); oral doxycycline was added to reduce corneal thinning. The patient's infection resolved with a residual scar and final best corrected visual acuity of 20/200 OS. Conclusions and Importance Moraxella atlantae can present as a ring-shaped infectious corneal infiltrate and ulcer. Ring infiltrates have been observed with other microorganisms, including several other gram negative bacteria and classically, acanthamoeba. Frequently presumed to be purely immunologic, corneal ring infiltrates can have a number of other etiologies, including infectious and toxic. There are different types of immunologic rings as well, making differentiation of corneal rings sometimes difficult for the ophthalmologic generalist and subspecialist alike. In this paper we discuss characteristics of various corneal ring infiltrates, along with their immune pathophysiology. Infectious rings are distinguished from immunologic Wessely rings.
To identify factors predictive of serious ocular injury requiring urgent consultation by ophthalmology in patients presenting with blunt trauma orbital fractures.
This is a retrospective study of ...adult patients diagnosed with orbital fractures after blunt trauma at a university medical center emergency room. Patient records were examined over a three-year period. Data including mechanism of injury, fracture location, ocular symptoms, and examination findings were recorded. Ocular injuries were divided into three levels of severity: mild, moderate, and severe. Fracture characteristics, patient demographics, and examination findings were analyzed using multinomial regression to identify risk factors for more severe injury.
One hundred and eighty-six patients met inclusion criteria. For 29.6% of patients, urgent ophthalmologic consultation was required. Ruptured globes occurred in 2.2% of injuries. There was a statistically significant association between severe ocular injury and three examination findings: poor vision (OR 14.5; p < 0.001), afferent pupillary defect (OR 44.8; p < 0.001), and abnormal pupillary reaction (OR 28.0; p < 0.001). Likewise, blurry vision (OR 3.6; p = 0.018), ocular pain (OR 3.7; p = 0.011), and facial pain (OR 4.4; p = 0.031) were also associated with an increased risk of severe ocular injury. Abnormal pupillary reaction was associated with moderate injury (OR 4.5; p = 0.041). Demographic factors, mechanism of injury, anti-coagulant use, fracture location, diplopia, no documented vision, subconjunctival hemorrhage, chemosis, and motility restriction were not associated with injury severity.
Most patients who presented to the emergency room with an orbital fracture did not require urgent ophthalmologic consultation. The presence of blurry vision, ocular pain, facial pain, poor vision, and afferent pupillary defect significantly increased the odds of severe injury. Abnormal pupillary reaction was associated with both moderate and severe injury.
Purpose To determine whether a structured biometry course improves refractive outcomes of resident phacoemulsification. Setting Northeast Veterans Administration Hospital, Northport, New York, USA. ...Design Retrospective case study. Methods Phacoemulsification surgeries performed by residents before and after a biometry curriculum were reviewed. The inclusion criterion was phacoemulsification performed by residents. Patients with fewer than 3 months of follow-up were excluded. The main outcome measure—the mean absolute difference between the target and final refraction—was compared using a linear mixed model. Results Phacoemulsification surgeries performed by 4 residents before (n = 223) and by 4 residents after (n = 242) a biometry curriculum was implemented were reviewed. All measured preoperative factors were similar in both groups, including age, visual acuity, axial length, steep and flat keratometry values, astigmatism, anterior chamber depth, and lens thickness. Before the biometry course was instituted, 10% of patients had a mean absolute difference of less than 0.25 diopter (D); the percentage was 35% afterward. The mean absolute difference was less than 0.50 D in 40% before the curriculum was initiated and 70% after. The mean absolute difference was less than 1.00 D in 75% before the curriculum was initiated versus 94% after (all P < .05). The corrected distance visual acuities were similar in both groups, with 83% and 80%, respectively, having an acuity of at least 20/25 ( P > .05). Conclusion Residents’ refractive predictions significantly improved after a formal biometry curriculum, showing that improvements in resident surgical outcomes are possible with structured curriculums reinforcing outcome measures. Financial Disclosure None of the authors has a financial or proprietary interest in any material or method mentioned.
We describe a case of Classic Kaposi's sarcoma in a functionally monocular patient following a COVID19 vaccine booster and provide compelling evidence that suggests the booster was a relevant ...co-factor in the initiation of the disease process.
The patient presented with red, irritated conjunctival area described as “bubbling” in her right eye. While her past medical history includes hypercholesterolemia and hypertension, she had no history of a compromised immune system. Her ophthalmologic history is more complex including treatment for glaucoma. The patient has 20/20 uncorrected vision OD and LP OS. Due to her ocular co-morbidities, the patient initially received interferon alpha 2-B qid for 6 weeks. However, topical therapy failed to decrease the size of the conjunctival lesions. After referral to Radiation Oncology, the right eye/orbit was treated with electron beam therapy for 1 month which caused a marked decrease in the size and vascularity of the conjunctival lesions. A slow improvement continued during followup.
In that the vaccine booster preceded the cancer, it appears etiologic to the appearance of Kaposi's sarcoma. The patient's monocular vision and glaucoma complicated her treatment. This case expands on current concepts of cofactors needed for the development of Kaposi's sarcoma in that vaccine booster administration was relevant to tumor progression and both clinical and mechanistic evidence is presented to support this hypothesis.
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