Phenotypic Screening of Chemical Libraries Enriched by Molecular Docking to Multiple Targets Selected from Glioblastoma Genomic Data.

Like most solid tumors, glioblastoma multiforme (GBM) harbors multiple overexpressed and mutated genes that affect several signaling pathways. Suppressing tumor growth of solid tumors like GBM without toxicity may be achieved by small molecules that selectively modulate a collection of targets across different signaling pathways, also known as selective polypharmacology. Phenotypic screening can be an effective method to uncover such compounds, but the lack of approaches to create focused libraries tailored to tumor targets has limited its impact.

Calcitriol and non-calcemic vitamin D analogue, 22-oxacalcitriol, attenuate developmental and pathological choroidal vasculature angiogenesis and .

Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has anti-angiogenic properties.

Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment.

: Plasma kallikrein is a  mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME.

Bufadienolides and anti-angiogenic homoisoflavonoids from Rhodocodon cryptopodus, Rhodocodon rotundus and Rhodocodon cyathiformis.

Background: Homoisoflavonoids have been shown to have potent anti-proliferative activities in endothelial cells over other cell types and have demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Three species of Rhodocodon (Scilloideaea subfamily of the Asparagaceae family), endemic to Madagascar, R. cryptopodus, R.

Evaluation of Cerebrospinal Fluid Pressure by a Formula and Its Role in the Pathogenesis of Glaucoma.

Purpose: To investigate potential associations between intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFP) in patients with primary open-angle glaucoma (POAG) and healthy subjects.

Methods: Forty-three subjects were recruited. Weight and height were measured to calculate body mass index (BMI), along with blood pressure, heart rate, visual acuity, and IOP.

The Influence of Translaminar Pressure Gradient and Intracranial Pressure in Glaucoma: A Review.

The current evidence associating intracranial pressure (ICP) with glaucoma, the translaminar pressure gradient hypothesis, and anatomic factors likely affecting the relationship between ICP and retrolaminar tissue pressure including the size of the optic canal and lamina cribrosa thickness are reviewed. In addition, the evidence of diurnal and positional variation on the translaminar pressure gradient, effects of glaucoma medications, evidence of ICP helping to maintain cerebrospinal fluid flow in the optic nerve to prevent glaucomatous damage, and the effect of intraocular pressure variation in glaucoma are also reviewed. We find that while low ICP is associated with glaucoma disease in most studies, evidence is mixed on how closely ICP matches retrolaminar tissue pressure, and it appears the relationship is affected by the size of the optic canal, thickness of the lamina cribrosa, and lymphatic outflow from the optic nerve.

Incidence and Management of Glaucoma or Glaucoma Suspect in the First Year After Pediatric Lensectomy.

Importance: Glaucoma can occur following cataract removal in children, and determining the risk for and factors associated with glaucoma and glaucoma suspect in a large cohort of children after lensectomy can guide clinical practice.

Objective: To estimate the incidence of glaucoma and glaucoma suspect and describe its management in the first year following lensectomy in children before 13 years of age.

Design, Setting, And Participants: A multicenter clinical research registry containing data for 1361 eyes of 994 children who underwent unilateral or bilateral lensectomy between June 2012 and July 2015 at 1 of 61 sites in the United States (n = 57), Canada (n = 3), and the United Kingdom (n = 1).

Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency.

Rationale: There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function.

Objective: We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function.

Methods And Results: Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2, Akita (type 1 diabetes mellitus), and ACE2-Akita mice.

Biofluid modeling of the coupled eye-brain system and insights into simulated microgravity conditions.

This work aims at investigating the interactions between the flow of fluids in the eyes and the brain and their potential implications in structural and functional changes in the eyes of astronauts, a condition also known as spaceflight associated neuro-ocular syndrome (SANS). To this end, we propose a reduced (0-dimensional) mathematical model of fluid flow in the eyes and brain, which is embedded into a simplified whole-body circulation model. In particular, the model accounts for: (i) the flows of blood and aqueous humor in the eyes; (ii) the flows of blood, cerebrospinal fluid and interstitial fluid in the brain; and (iii) their interactions.

Ocular changes in traumatic brain injury: A review.

Traumatic brain injury is represented by a penetrating or non-penetrating head injury, which causes disruption in the normal functioning of the brain. Traumatic brain injury has been an ardently debated topic of discussion due to its prevalence in media centric persons such as military personnel and athletes. Current assessments for traumatic brain injury have looked at vestibulo-ocular and vascular parameters to aid in diagnosis.

Gender Differences in Case Volume Among Ophthalmology Residents.

Importance: Although almost equal numbers of male and female medical students enter into ophthalmology residency programs, whether they have similar surgical experiences during training is unclear.

Objective: To determine differences for cataract surgery and total procedural volume between male and female residents during ophthalmology residency.

Design, Setting, Participants: This retrospective, longitudinal analysis of resident case logs from 24 US ophthalmology residency programs spanned July 2005 to June 2017.

Management of Glaucoma in Pregnancy.

Management of glaucoma during pregnancy represents a challenge for the physician. Important disease and patients' health decisions begin even before conception and continue throughout pregnancy and breastfeeding. The data on this topic is limited due to ethical and legal constraints and challenges of conducting large, prospective, and randomized clinical trials on this patient population.

Factors Associated With Retinal Vessel Diameters in an Elderly Population: the Thessaloniki Eye Study.

Purpose: To identify the factors associated with retinal vessel diameters in the population of the Thessaloniki Eye Study.

Methods: Cross-sectional population-based study (age ≥ 60 years). Subjects with glaucoma, late age-related macular degeneration, and diabetic retinopathy were excluded from the analyses.

Vascular dysfunction in retinitis pigmentosa.

The relationship between ocular haemodynamics and retinitis pigmentosa (RP) has not been fully understood. Reductions in blood flow have been established in RP patients by a variety of studies; however, questions have yet to be answered regarding the role of vascular dysfunction in photoreceptors (PR) degeneration, the causes of vascular dysfunction in RP, as well as the diagnostic, prognostic and perhaps therapeutic potential of measuring ocular haemodynamics in RP patients. While significant evidence supports the theory that vascular dysfunction is associated with but not the cause of PR death in retinitis pigmentosa, evidence suggests that vascular abnormalities in the foveal and parafoveal regions may exacerbate cone cell loss.

Waveform parameters of retrobulbar vessels in glaucoma patients with different demographics and disease severity.

Introduction: To identify novel velocity waveform parameters of the ophthalmic artery and central retinal artery by computer-aided image processing of Doppler ultrasonography measurements, and to evaluate correlations between the waveform parameters and different demographics and disease severity of open-angle glaucoma patients.

Methods: Thirty-six images of 36 open-angle glaucoma patients were considered. A semiautomated image processing code was used to detect the digitalized ophthalmic artery and central retinal artery velocity waveforms and to extract the waveform parameters.

The Diurnal Rhythm of Insulin Receptor Substrate-1 (IRS-1) and Kir4.1 in Diabetes: Implications for a Clock Gene Bmal1.

Purpose: Diabetes leads to the downregulation of the retinal Kir4.1 channels and Müller cell dysfunction. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in Müller cells.

Soluble Epoxide Hydrolase Inhibition for Ocular Diseases: Vision for the Future.

Ocular diseases cause visual impairment and blindness, imposing a devastating impact on quality of life and a substantial societal economic burden. Many such diseases lack universally effective pharmacotherapies. Therefore, understanding the mediators involved in their pathophysiology is necessary for the development of therapeutic strategies.

Effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing video content on ocular blood flow.

Background/aim: Blood flow deficiencies of the retinal and retrobulbar circulations have been previously reported in open-angle glaucoma (OAG) and other eye diseases. Herein we investigated the effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing a video content on ocular blood flow, intraocular pressure (IOP) and ocular perfusion pressure (OPP) in OAG and healthy subjects.

Methods: Thirty-five subjects, 25 with OAG (mild to moderate) and 10 healthy controls, were evaluated for blood pressure, IOP, OPP and retinal capillary blood flow before, immediately after, 30 min after and 60 min after using ReviView (a dichoptic video goggles device), which stimulates one eye with a DAS video image that is brighter and with greater contrast than the fellow eye (duration of exposure 30 min).

Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction.

The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging.

Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14.

The KIF14 locus is gained and overexpressed in various malignancies, with prognostic relevance. Its protein product, a mitotic kinesin, accelerates growth of normal mammary epithelial cells in vitro and retinoblastoma tumours in a mouse model, while KIF14 knockdown blocks growth of brain, liver, ovarian, breast, prostate, and other tumour cells and xenografts. However, the tumour-initiating effects of Kif14 overexpression have not been studied.

Effects of Sex Hormones on Ocular Blood Flow and Intraocular Pressure in Primary Open-angle Glaucoma: A Review.

Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and visual field loss. Some speculate that sex plays a role in the risk of developing POAG and that the physiological differences between men and women may be attributed to the variable effects of sex hormones on intraocular pressure, ocular blood flow, and/or neuroprotection. Estrogen, in the form of premenopausal status, pregnancy, and postmenopausal hormone therapy is associated with an increase in ocular blood flow, decrease in intraocular pressure and neuroprotective properties.

Femtosecond-assisted LASIK flaps resistant to lift secondary to corneal epithelial defects: Case reports and ex vivo studies.

Purpose: To evaluate why epithelial defects created before femtosecond laser ablation result in laser in situ keratomileusis (LASIK) flaps resistant to lift.

Setting: Boston Eye Group, Brookline, Massachusetts, USA.

Design: Case reports and ex vivo studies.