Real-Time Mobile Teleophthalmology for the Detection of Eye Disease in Minorities and Low Socioeconomics At-Risk Populations

Purpose: To examine the benefits and feasibility of a mobile, real-time, community-based, teleophthalmology program for detecting eye diseases in the New York metro area. Design: Single site, nonrandomized, cross-sectional, teleophthalmologic study. Methods: Participants underwent a comprehensive evaluation in a Wi-Fi-equipped teleophthalmology mobile unit. The evaluation consisted of a basic anamnesis with a questionnaire form, brief systemic evaluations and an ophthalmologic evaluation that included visual field, intraocular pressure, pachymetry, anterior segment optical coherence tomography, posterior segment optical coherence tomography, and nonmydriatic fundus photography. The results were evaluated in real-time and follow-up calls were scheduled to complete a secondary questionnaire form. Risk factors were calculated for different types of ophthalmological referrals. Results: A total of 957 participants were screened. Out of 458 (48%) participants that have been referred, 305 (32%) had glaucoma, 136 (14%) had narrow-angle, 124 (13%) had cataract, 29 had (3%) diabetic retinopathy, 9 (1%) had macular degeneration, and 97 (10%) had other eye disease findings. Significant risk factors for ophthalmological referral consisted of older age, history of high blood pressure, diabetes mellitus, Hemoglobin A1c measurement of ≥6.5, and stage 2 hypertension. As for the ocular parameters, all but central corneal thickness were found to be significant, including having an intraocular pressure \u3e21 mm Hg, vertical cup-to-disc ratio ≥0.5, visual field abnormalities, and retinal nerve fiber layer thinning. Conclusions: Mobile, real-time teleophthalmology is both workable and effective in increasing access to care and identifying the most common causes of blindness and their risk factors

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Identification of Serum Biomarkers for Biliary Tract Cancers by a Proteomic Approach Based on Time-of-Flight Mass Spectrometry

Biliary tract cancers (BTCs) are lethal malignancies currently lacking satisfactory methods for early detection and accurate diagnosis. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is a promising diagnostic tool for this disease. In this pilot study, sera samples from 50 BTCs and 30 cholelithiasis patients as well as 30 healthy subjects from a population-based case-control study were randomly grouped into training set (30 BTCs, 20 cholelithiasis and 20 controls), duplicate of training set, and blind set (20 BTCs, 10 cholelithiasis and 10 controls); all sets were analyzed on Immobilized Metal Affinity Capture ProteinChips via SELDI-TOF-MS. A decision tree classifier was built using the training set and applied to all test sets. The classification tree constructed with the 3,400, 4,502, 5,680, 7,598, and 11,242 mass-to-charge ratio (m/z) protein peaks had a sensitivity of 96.7% and a specificity of 85.0% when comparing BTCs with non-cancers. When applied to the duplicate set, sensitivity was 66.7% and specificity was 70.0%, while in the blind set, sensitivity was 95.0% and specificity was 75.0%. Positive predictive values of the training, duplicate, and blind sets were 82.9%, 62.5% and 79.2%, respectively. The agreement of the training and duplicate sets was 71.4% (Kappa = 0.43, u = 3.98, P &lt; 0.01). The coefficient of variations based on 10 replicates of one sample for the five differential peaks were 15.8–68.8% for intensity and 0–0.05% for m/z. These pilot results suggest that serum protein profiling by SELDI-TOF-MS may be a promising approach for identifying BTCs but low assay reproducibility may limit its application in clinical practice

The HDAC Inhibitor LBH589 Induces ERK-Dependent Prometaphase Arrest in Prostate Cancer via HDAC6 Inactivation and Down-Regulation

<div><p>Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest. The LBH589 treatment down-regulated HDAC6 and sustained ERK activation, and contributed to prometaphase arrest. Mechanistically, LBH589 inhibited HDAC6 activity, caused its dissociation from protein phosphatase PP1α, and increased 14-3-3ζ acetylation. Acetylated 14-3-3ζ released its mask effect on serine 259 of c-Raf and serine 216 of Cdc25C subsequent to de-phosphorylation by PP1α, which contributed to ERK activation. Enhanced ERK activity by LBH589 further down-regulated HDAC6 protein levels and sustained ERK activation by free-forward regulation. The sustained Cdc25C and ERK activation resulted in early M-phase (prometaphase) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC-3 cells. This study provides pre-clinical evidence that HDAC6 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation. This study also posits a novel mechanism of HDAC6 participation in regulating the c-Raf-PP1-ERK signaling pathway and contributing to M phase cell-cycle transition.</p> </div

HDAC6 down-regulation correlated with ERK activation in LBH589 treatment.

<p>(<b>A</b>) Screening of HDACs involved in ERK activation. The immuno-blottings of LBH589 treated cell lysates were performed with indicated antibodies. (<b>B</b>) LBH589 induced the down-regulation of HDAC6, which correlated with ERK activation in LNCaP but not in PC-3. (<b>C</b>) Knockdown of HDAC6 increased in ERK activity. 293T was transfected with siRNA of HDAC1, 3, 6, or non-targeting for 72 hours. The lysates were analyzed by immuno-blotting. (<b>D</b>) ERK activity was involved in LBH589-mediated HDAC6 down-regulation. Cell lysates from cells treated with LBH589 or combined with UO126 pre-treatment were immuno-blotted.</p

LBH589 induced ERK activation by modulating c-Raf activity.

<p>(<b>A</b>) Analysis of ROS production. The indicated cells were treated with 75 nM LBH589 for 24 h. ROS was measured as described in the Materials and Methods section. (<b>B</b>) The pattern of c-Raf signaling pathway on LBH589 treatment. The cells were treated with LBH589 for 24 h and the lysates were immuno-blotted with the indicated antibodies. α-catenin was a loading control.</p

LBH589 switched the PP1 interacting partner for ERK activation.

<p>(<b>A</b>) LBH589 induced Cdc25C-S216 dephosphorylation in a dose- and time-dependent manner. LNCaP was exposed to 75 nM LBH589 for various times or at indicated LBH589 concentrations for 24 h. Phosphorylation of Cdc25C-S216 was performed by immuno-blotting with Pi-Cdc25C-S216 antibody. (<b>B</b>–<b>C</b>) LBH589 treatment switched the PP1α interacting partner. The immuno-precipitations were conducted with anti-HDAC6 or anti-14-3-3ζ. The precipitated samples were analyzed by immuno-blotting using antibody against PP1α, 14-3-3ζ, Lys-Ac (Pan-acetylated lysine). IgG was a nonspecific pull-down control.</p