KSI-301 is an intravitreal anti-vascular endothelial growth factor (VEGF) agent in clinical trials for the treatment of neovascular age-related macular degeneration (nAMD), diabetic retinopathy, ...diabetic macular edema (DME), and retinal vein occlusion (RVO). Its antibody-biopolymer conjugate structure is designed to decrease clearance from the eye and increase the duration of the effect.
This article briefly discusses the impact and mechanisms of nAMD, DME, and RVO and evaluates currently approved anti-VEGF therapies. It progresses to examine a new agent, KSI-301 and the results from numerous clinical trials in these disease areas.
Despite varied results in the phase 2b/3 study for nAMD, there is potential for KSI-301 to serve as a durable therapy for VEGF-mediated retinal disorders. Ongoing phase 3 trials for nAMD, DME, and RVO will provide additional evidence on its efficacy, duration, and safety profiles.
The transferable potentials for phase equilibria (TraPPE) force field aims to be accurate, computationally efficient and applicable to a wide range of chemical compounds, state points and ...thermophysical properties. When new users wish to implement TraPPE models into their chosen simulation program, they face several obstacles: the TraPPE models are dispersed over many separate publications and misinterpretations of the primary literature are possible; the TraPPE force field makes specific choices for standard conventions that may require non-trivial code modifications for some simulation software. Therefore, the TraPPE developers report here a resource website and online searchable parameter and property database designed to provide new and experienced users with tools for successful implementation and validation (http://www.chem.umn.edu/groups/siepmann/trappe/).
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
PURPOSE:Descemet stripping endothelial keratoplasty (DSEK), currently the most common procedure for managing corneal endothelial dysfunction, may be repeated following DSEK failure from a variety of ...causes. This multicenter study reports the risk factors and outcomes of repeat DSEK.
METHODS:This was an institutional review board-approved multicenter retrospective chart review of patients who underwent repeat DSEK. Twelve surgeons from 5 Midwest academic centers and 3 private practice groups participated. The Eversight Eye Bank provided clinical indication and donor graft data. We also assessed the role of the learning curve by comparing cohorts from the first and second 5-year periods.
RESULTS:A total of 121 eyes from 121 patients who underwent repeat DSEK were identified. The average age of the patients was 70 ± 12 years. The most common indication for repeat DSEK was late endothelial graft failure without rejection (58%, N = 63). Average preoperative and 12-month postoperative repeat DSEK corrected distance visual acuities were 20/694 and 20/89, respectively. Visual acuity outcomes, endothelial cell density, and cell loss did not significantly vary between the 2 cohorts. Initial graft rebubble rates for the first and second cohorts were 51% and 25%. The presence of glaucoma, prior glaucoma surgery, or a history of penetrating (full thickness) keratoplasty did not significantly affect visual outcomes. The median, mean, and range of intraocular pressures before repeat DSEK were 15.0, 15.7, and 6 to 37 mm Hg, respectively. Patients with higher intraocular pressures before repeat DSEK had improved postoperative corrected distance visual acuities.
CONCLUSIONS:Repeating DSEK improves vision following failed or decompensated DSEK surgery. Higher preoperative repeat DSEK IOPs were associated with improved visual outcomes, and initial graft rebubble rates, which decreased over time, were likely due to surgeon experience.
We present a case of a patient with worsening visual acuity and dense vitreal debris who was found to have vitreal transthyretin amyloid (ATTR) infiltration. Cardiac workup, performed to identify ...systemic amyloidosis, demonstrated focal myocardial amyloid infiltration on pyrophosphate (PYP) scintigraphy and cardiac magnetic resonance (CMR), resulting in a diagnosis of subclinical ATTR cardiac amyloidosis (ATTR-CA). Patient was identified as a carrier of p.S70R mutation which results in an aggressive ATTR phenotype. Patient is tolerating transthyretin silencer therapy well. Through this case, we discuss the role of a multimodality imaging approach for the diagnosis of subclinical ATTR-CA.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Autoimmune Disorders and the Eye Thompson, Lisa; Patrianakos, Thomas; Garcia, James ...
Disease-a-month
70, Issue:
5
Journal Article
Peer reviewed
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Incidence and Outcomes of Acute Lung Injury Rubenfeld, Gordon D; Caldwell, Ellen; Peabody, Eve ...
The New England journal of medicine,
10/2005, Volume:
353, Issue:
16
Journal Article
Peer reviewed
Open access
Acute lung injury is a syndrome of hypoxemic respiratory failure and bilateral pulmonary infiltrates. In this prospective, population-based study, the incidence of acute lung injury was 79 cases per ...100,000 person-years. The authors estimate that each year there are 190,000 cases of acute lung injury in the United States, resulting in 75,000 deaths, which suggests a much larger public health impact than previously reported.
In this prospective study, the incidence of acute lung injury was 79 cases per 100,000 person-years. The authors estimate that each year there are 190,000 cases in the United States, resulting in 75,000 deaths, which suggests a much larger public health impact than previously reported.
Acute lung injury is a syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that is associated with both pulmonary and nonpulmonary risk factors and that is not primarily due to left atrial hypertension.
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Despite recent advances in our understanding of the pathophysiology, treatment, and long-term outcome of acute lung injury, prospective, population-based data on the incidence and outcome of acute lung injury in the United States have not been available.
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There has, however, been a prospective, population-based study of patients with acute respiratory distress syndrome (ARDS), a subtype of acute lung injury characterized by more severe . . .
Human roseolovirus U20 and U21 are type I membrane glycoproteins that have been implicated in immune evasion by interfering with recognition of classical and non-classical MHC proteins. U20 and U21 ...are predicted to be type I glycoproteins with extracytosolic immunoglobulin-like domains, but detailed structural information is lacking. AlphaFold and RoseTTAfold are next generation machine-learning-based prediction engines that recently have revolutionized the field of computational three-dimensional protein structure prediction. Here, we review the structural biology of viral immunoevasins and the current status of computational structure prediction algorithms. We use these computational tools to generate structural models for U20 and U21 proteins, which are predicted to adopt MHC-Ia-like folds with closed MHC platforms and immunoglobulin-like domains. We evaluate these structural models and place them within current understanding of the structural basis for viral immune evasion of T cell and natural killer cell recognition.
Introduction Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I ...disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined. Methods We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches. Results We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 – ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
