Intracellular calcium transients are necessary for platelet-derived growth factor but not extracellular matrix protein–induced vascular smooth muscle cell migration

AbstractPurposeVascular smooth muscle cell (SMC) migration is a critical component of the hyperplastic response that leads to recurrent stenosis after interventions to treat arterial occlusive disease. We investigated the relationship between intracellular calcium ([Ca2+]i) and migration of vascular SMCs in response to platelet-derived growth factor (PDGF) and extracellular matrix (ECM) proteins.MethodsHuman saphenous vein SMCs were used for all experiments. SMC migration in response to agonists was measured with a microchemotaxis assay. A standard fluorimetric assay was used to assess changes in [Ca2+]i in response to the various combinations of growth factors and ECM proteins.ResultsThe calcium ionophore A23187 produced a rapid rise in [Ca2+]i and a corresponding 60% increase in SMC migration, whereas chelation of [Ca2+]i with BAPTA (1,2-bis [aminophenoxy] ethane-N,N,N′,N′-tetraacetic acid) produced a fivefold decrease in PDGF-induced chemotaxis, suggesting that [Ca2+]i is both sufficient and necessary for SMC migration. Stimulation of SMCs with PDGF produced an early peak followed by a late plateau in [Ca2+]i. To establish a relationship between temporal fluctuations in [Ca2+]i and SMC migration, SMCs were pretreated with caffeine and ryanadine, which eliminated the initial peak but not the late plateau in [Ca2+]i, and had no effect on chemotaxis in response to PDGF. Incubation of SMCs with nickel chloride eliminated the late plateau, but had no effect on the initial peak in [Ca2+]i, and reduced PDGF-stimulated migration by fivefold. We then evaluated the role of calcium in SMC migration induced by ECM proteins such as laminin, fibronectin, and collagen types I and IV. All four matrix proteins stimulated SMC migration, but none produced an elevation in [Ca2+]i. Moreover, preincubation of SMCs with caffeine and ryanadine or nickel chloride had no effect on ECM protein-induced chemotaxis.Conclusion[Ca2+]i transients are necessary for PDGF but not ECM protein-induced SMC chemotaxis. Moreover, the ability of PDGF to stimulate vascular SMC migration appears dependent on influx of extracellular calcium through membrane channels.AbstractClinical relevanceRecurrent stenosis after angioplasty or surgical bypass remains a significant challenge in treating vascular occlusive disease. In addition to growth factors, extracellular matrix (ECM) proteins may be potent agonists of this process. In this study we show that the influx of extracellular calcium is an important mechanism for platelet-derived growth factor–induced smooth muscle cell migration but not ECM-induced migration. Of note, in clinical trials calcium channel blockers failed to inhibit recurrent stenosis. Our data provide mechanistic insight to help explain this negative outcome in that therapies designed to inhibit restenosis depend on the effects of both growth factors and ECM proteins

Anatomical patterns of recurrence following biochemical relapse after post‐prostatectomy salvage radiation therapy: a multi‐institutional study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138303/1/bju13792.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138303/2/bju13792_am.pd

Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes?:Systematic review

background: It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations. methods: Systematic review of the literature and narrative synthesis. results: We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma. conclusions: This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo