14 research outputs found
Social deprivation as a risk factor for late presentation of proliferative diabetic retinopathy
PURPOSE: The aim of this study was to determine whether social deprivation is a risk factor for late presentation of patients with proliferative diabetic retinopathy and whether it affects their access to urgent laser treatment. METHODS: Using a 2:1 case: control design, 102 patients referred to a UK teaching hospital as part of the UK Diabetic Retinopathy National Screening Programme were identified for the period between 1 June 2010 to 1 June 2013. Social deprivation was scored using the Index of Multiple Deprivation 2010. Additional variables considered included age, duration of disease, ethnicity, and HbA(1c) at time of referral. RESULTS: The cases comprised 34 patients referred with proliferative (grade R3) retinopathy with a control group of 68 patients with lower retinopathy grades; two control patients were excluded due to incomplete data. On univariate analysis, R3 retinopathy was associated with higher social deprivation (P<0.001, Mann–Whitney U-test), and with higher HbA(1c) (11.5% vs 8.4%; P<0.001, Mann–Whitney U-test). Forward stepwise multivariable analysis showed that the association of R3 retinopathy with deprivation was significant even after adjusting for HbA(1c) (P=0.016). On univariate analysis South Asian ethnicity was also identified as being a risk factor for presentation with R3 retinopathy, but this was no longer significant when HbA(1c) was adjusted for in a forward stepwise logistic regression analysis. CONCLUSION: In our cohort social deprivation appears to be associated with late presentation of proliferative diabetic retinopathy. Our study supports the need to target these groups to reduce preventable blindness and to identify strategies which overcome barriers to care
A comparison of responses to raised extracellular potassium and endothelium-derived hyperpolarizing factor (EDHF) in rat pressurised mesenteric arteries
The present study examined the hypothesis that potassium ions act as an endothelium-derived hyperpolarizing factor (EDHF) released in response to ACh in small mesenteric arteries displaying myogenic tone. Small mesenteric arteries isolated from rats were set up in a pressure myograph at either 60 or 90 mmHg. After developing myogenic tone, responses to raising extracellular potassium were compared to those obtained with ACh (in the presence of nitric oxide synthase and cyclo- oxygenase inhibitors). The effects of barium and ouabain, or capsaicin, on responses to raised extracellular potassium or ACh were also determined. The effects of raised extracellular potassium levels and ACh on membrane potential, were measured using sharp microelectrodes in pressurised arteries. Rat small mesenteric arteries developed myogenic tone when pressurised. On the background of vascular tone set by a physiological stimulus (i.e pressure), ACh fully dilated the small arteries in a concentration-dependent manner. This response was relatively insensitive to the combination of barium and ouabain, and insensitive to capsaicin. Raising extracellular potassium produced a more inconsistent and modest vasodilator response in pressurised small mesenteric arteries. Responses to raising extracellular potassium were sensitive to capsaicin, and the combination of barium and ouabain. ACh caused a substantial hyperpolarisation in pressurized arteries, while raising extracellular potassium did not. These data indicate that K+ is not the EDHF released in response to ACh in myogenically active rat mesenteric small arteries. Since the hyperpolarization produced by ACh was sensitive to carbenoxolone, gap junctions are the likely mediator of EDH responses under physiological conditions
The modulation of no-mediated in porcine cerebral arteries by inducible nitric oxide synthase
EThOS - Electronic Theses Online ServiceGBUnited Kingdo
ACh produces a larger vasodilator response than raising extracellular potassium in myogenically-active mesenteric small arteries.
<p>Vasodilator responses to (A) ACh and (B) raised extracellular potassium in rat isolated mesenteric small arteries pressurised to 60 mmHg or 90 mmHg (in the presence of L-NAME and indomethacin). Following the development of stable myogenic tone, cumulative concentration response curves were constructed to ACh or potassium in random order in the same artery from <i>n</i> different animals. Each point represents the mean ± s.e.mean (n = 6–9).</p
Vasodilator responses to raised extracellular potassium correlate with the degree of myogenic tone.
<p>The relationship between the level of myogenic tone (in the presence of L-NAME (100 µM) and indomethacin (1 µM)) and the R<sub>max</sub> for ACh (<i>n</i> = 31) or raised extracellular potassium (<i>n</i> = 20) in rat isolated mesenteric arteries pressurised to 90 mmHg. Each point represents one experiment. The slope of the line fitted to the potassium data was significantly different from zero (<i>P</i><0.05) with an r<sup>2</sup> = 0.2387. The slope of the line fitted to the ACh data was not significantly different from zero.</p
ACh causes hyperpolarization in pressurized small arteries, while raising extracellular potassium does not.
<p>Summary data showing the change in membrane potential in smooth muscle cells from <i>n</i> different animals in response to ACh (1 µM) and raised extracellular potassium (+5 mM) at (A) 30 mmHg and (C) 90 mmHg. Following the successful impalement of a cell, responses to ACh or potassium were recorded in random order. Bars represent mean ± s.e.mean (<i>n</i> = 3–6). Representative trace recording (B) of the change in membrane potential of a rat mesenteric small artery held at 30 mmHg and exposed to ACh (1 µM) followed by raised extracellular potassium (+5 mM). The large deflections at the start and end of the trace recording reflect cell impalement and removal of the microelectrode, respectively.</p
Responses to raised extracellular potassium, but not ACh, are capsaicin sensitive.
<p>The effect of capsaicin on responses to raised extracellular potassium (A) or ACh (B) in rat isolated mesenteric small arteries at 90 mmHg. All experiments were carried out presence of L-NAME (100 µM and indomethacin (1 µM). Each point represents the mean ± s.e.mean. ***<i>P</i><0.001 capsaicin versus control; <i>n</i> = 4–5.</p
A phase 1 expansion cohort of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients (pts) with advanced gastric (GC) and gastroesophageal (GOJ) cancer.
A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers
Abstract
Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.
Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.
Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3–related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.
Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366–73. ©2017 AACR.</jats:p