Scalable production and purification of engineered ARRDC1-mediated microvesicles in a HEK293 suspension cell system.

Engineering of human ARRDC1-mediated microvesicles (ARMMs) as non-viral vehicles for delivery of gene therapies bears the potential to enable novel therapeutic paradigms. We evaluated two scalable strategies to generate ARMMs loaded with protein cargo, by transient transfection or stable cell line-based production. The upstream ARMMs production processes utilized a suspension-adapted HEK293-derived line, termed 5B8.

Retrospective Study of Preoperative Laser Peripheral Iridotomy Versus Intraoperative Surgical Peripheral Iridectomy in Descemet Membrane Endothelial Keratoplasty.

Purpose: The aim of this study was to examine the outcomes of laser peripheral iridotomy (LPI) and surgical peripheral iridectomy (SPI) for Descemet membrane endothelial keratoplasty (DMEK) and DMEK with cataract extraction (triple DMEK).

Methods: This retrospective interventional study included 135 eyes of 135 patients who underwent DMEK alone or triple DMEK. Primary outcomes were graft detachments necessitating rebubbling, repeat grafts, and pupillary block.

Eye Protection for Patients With COVID-19 Undergoing Prolonged Prone-Position Ventilation.

Importance: Critically ill patients with coronavirus disease 2019 (COVID-19) who are unresponsive to maximum optimal ventilator settings may be in a prone position for at least 16 hours per day to improve oxygenation. This extended duration of prone positioning puts patients at risk of developing orbital compartment syndrome if direct pressure to the orbit and the globe occurs and concomitant protection of the eyes is not undertaken.

Objective: To report 2 cases of orbital compartment syndrome, as well as optic disc edema and retinal hemorrhages, in the setting of prolonged prone positioning of patients in the intensive care unit during the COVID-19 pandemic.

Surgical Outcomes of Epiretinal Membrane Removal Due to Combined Hamartoma of the Retina and RPE.

Background And Objective: To evaluate the surgical outcomes of epiretinal membrane (ERM) associated with combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) after vitrectomy and membrane peel.

Patients And Methods: A retrospective review of 15 patients who underwent pars plana vitrectomy with membrane peeling. No plasmin enzyme was used.

Experience of mismatch repair/microsatellite instability (MMR/MSI) testing among patients with advanced/metastatic colorectal cancer in the US.

We assessed knowledge and awareness of MMR/MSI testing among advanced/metastatic CRC patients in the US who had previously taken the test. A non-interventional, cross-sectional online survey was conducted among 150 US CRC patients invited through a research panel. Eligible patients had to be ≥18 years, with stage III or IV CRC (self-reported), had undergone MMR/MSI testing for CRC in past 12 months and could recall the test, and provided informed consent.

Mismatch Repair/Microsatellite Instability Testing Practices among US Physicians Treating Patients with Advanced/Metastatic Colorectal Cancer.

The study objective was to assess US physicians' Mismatch Repair/Microsatellite Instability (MMR/MSI) testing practices for metastatic colorectal cancer (mCRC) patients. A non-interventional, cross-sectional online survey was conducted among 151 physicians (91 oncologists, 15 surgeons and 45 pathologists) treating mCRC patients in the US. Eligible physicians were US-based with at least 5 years of experience treating CRC patients, had at least one mCRC patient in their routine care in the past 6 months, and had ordered at least one MMR/MSI test for CRC in the past 6 months.

T-cell lymphoblastic lymphoma involving the ocular adnexa: report of two cases and review of the current literature.

The majority of ocular adnexal lymphomas are B-cell in origin. We report two cases of T-cell lymphoblastic lymphoma (T-LBL) involving the ocular adnexa. One patient presented with a painless pink conjunctival lesion and inferior orbital fullness.

Dietary Flavonoid Intake Reduces the Risk of Head and Neck but Not Esophageal or Gastric Cancer in US Men and Women.

Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts. Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers.

Self-inflicted enucleations: Clinical features of seven cases.

We report the clinical presentation, radiography, and management outcomes of autoenucleations (AE). Charts of 7 patients evaluated at 4 institutions with AE were reviewed. Four males and three females had a mean age of 50 years (range 26-72 years).

Impact of Community Health Workers on Use of Healthcare Services in the United States: A Systematic Review.

Background: As the US transitions to value-based healthcare, physicians and payers are incentivized to change healthcare delivery to improve quality of care while controlling costs. By assisting with the management of common chronic conditions, community health workers (CHWs) may improve healthcare quality, but physicians and payers who are making choices about care delivery also need to understand their effects on healthcare spending.

Methods: We searched PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, PsycINFO, Embase, and Web of Science from the inception of each database to 22 June 2015.

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials.

Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice.

Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT) or quantitative nuclear magnetic resonance (QMR). Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR.

The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials.

RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.

Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs.

Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.

7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.

Dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)).

A series of dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described.

Design and SAR of selective T-type calcium channel antagonists containing a biaryl sulfonamide core.

T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.

Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride).

Two novel N-methyl-d-aspartate (NMDA) antagonists with unique chemical structures, EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride), were compared with CGS-19755 (Selfotel) in ligand binding, electrophysiology, and neuroprotection assays.

Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3).

Transient receptor potential (TRP) cation-selective channels are an emerging class of proteins that are involved in a variety of important biological functions including pain transduction, thermosensation, mechanoregulation, and vasorelaxation. Utilizing a bioinformatics approach, we have identified the full-length human TRPM3 (hTRPM3) as a member of the TRP family. The hTRPM3 gene is comprised of 24 exons and maps to human chromosome 9q-21.