Collagen IV is the major protein found in basement membranes. It comprises 3 heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity. We constructed linear maps of the collagen IV heterotrimers (‘interactomes’) that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype-phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms and muscle Cramps (HANAC) syndrome, and early onset Alport syndrome respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets.
The Alport dot-and-fleck retinopathy results primarily from abnormalities in the ILM/nerve fiber layer rather than in Bruch's membrane. Thinning of the ILM/nerve fiber layer contributes to the retinopathy, lozenge, and macular hole, possibly through interfering with nutrition of the overlying retina or clearance of metabolic by-products.
Objective To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re‐intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the ‘Improving Outcomes Guidance’ (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high‐output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation. Patients and Methods RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30‐day, 90‐day, and 1‐year all‐cause postoperative mortality; median LoS; complication and re‐intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers’ annual case volume and mortality. Results In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30‐day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30‐day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1‐year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re‐ intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977–0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988–0.993), and significantly reduced rates of re‐intervention. Conclusion Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re‐intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.
Multidrug resistant prostate cancer cell lines DU 0.03 and PC 0.03 were established from the parental prostate cancer cell lines DU145 and PC-3 respectively by stepwise selection in doxorubicin (DOX) from 0.001 to 0.03 m mg/ml. As cells adapted to each concentration of DOX. the drug concentration was increased by 0.001 m mg/ml. The chemosensitivity of each line was determined by growth inhibition assay. The DU 0.03 and PC 0.03 lines exhibit a 5 ± 10-fold and 1.3 ± 2.8-fold increase in resistance to anthracyclines, vinblastine (VLB) and mitozantrone (Mito), respectively. Verapamil (5 m mM) partially reversed the resistance to the anthracycline and completely reversed the resistance to VLB and Mito. Drug kinetic studies measured by intracellular accumulation of 3 H-daunorubicin demonstrated a 3 fold decrease in the level of intracellular 3 H-daunorubicin in the PC 0.03 and DU 0.03 resistant lines compared with their respective parental line. This effect was partially reversed by 5 m mM verapamil. The expression of MDR1 and MRP genes was analysed by Northern blotting and RT-PCR. P-glycoprotein (Pgp) and MRP protein were tested by immunocytochemistry staining using the monoclonal antibodies J-SB1. C219 and MRK16 (Pgp) and MRPm6 and MRPr1 (MRP). Neither Northern blot analysis nor the more sensitive RT-PCR demonstrated detectable MDR1 transcripts in any of the prostate cancer cell lines and the three Pgp monoclonal antibodies failed to reveal expression of Pgp.A 2 ± 4-fold increase in MRP1 mRNA levels in the drug resistant DU 0.03 and PC 0.03 lines were demonstrated by both Northern blotting and RT-PCR consistent with the ®ndings observed after staining by the two speci®c monoclonal antibodies, MRPm6 and MRPr1. Southern blot analysis demonstrated a 2-fold increase in the MRP1 gene copy number in the PC 0.03 line but not in the DU 0.03 line, suggesting that the overexpression of the MRP gene was regulated at the level of transcription in the latter line. We conclude that MRP1 not MDR1 overexpression. contributes to acquired drug resistance in these two prostate cancer cell lines. Prostate Cancer and Prostatic Diseases (2000) 3, 66±75.
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