Endothelial cells are known to bind to laminin, and two peptides derived from the laminin A (CTFALRGDNP) and B1 (CDPGYIGSR) chains block the capillary-like tube formation on a laminin-rich basement membrane matrix, Matrigel. In the present study, we have used various in vitro and in vivo assays to investigate the angiogenic-biologic effects of a third active site in the laminin A chain, CSRARKQAASIKVAVSADR (designated PA22-2) on endothelial cells. The SIKVAV-containing peptide was as active as the YIGSR-containing peptide for endothelial cell attachment but was less active than either the RGD-containing peptide or intact laminin. Endothelial cells seeded on this peptide appeared fibroblastic with many extended processes, unlike the normal cobblestone morphology observed on tissue culture plastic. In addition, in contrast to normal tube formation on Matrigel, short irregular structures formed, some of which penetrated the matrix and sprouting was more apparent. Analysis of endothelial cell conditioned media of cells cultured in the presence of this peptide indicated degradation of the Matrigel and zymograms demonstrated active collagenase IV (gelatinase) at 68 and 62 Kd. A murine in vivo angiogenesis assay and the chick yolk sac/chorioallantoic membrane assays with the peptide demonstrated increased endothelial cell mobilization, capillary branching, and vessel formation. These data suggest that the -SIKVAV-site may play an important role in initiating branching and formation of new capillaries from the parent vessels, a behavior that is observed in vivo in response to tumor growth or in the normal vascular response to injury.
Background/Aims Risks and benefits of simeprevir plus sofosbuvir in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virologic responses (SVR) of simeprevir plus sofosbuvir with and without ribavirin in patients with Child-Pugh (CP)-B/C vs. CP-A cirrhosis and compared to matched untreated controls. Methods Multicenter cohort of adults with HCV genotype 1 and cirrhosis treated with simeprevir plus sofosbuvir with/without ribavirin for 12 weeks. Controls were matched on treatment center, age, CP class and model for end-stage liver disease (MELD) score. Results Of 160 patients treated with simeprevir plus sofosbuvir with/without ribavirin, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (IQR 8–11). SVR12 was achieved by 73% of CP-B/C vs. 91% of CP-A (p<0.01). CP-B/C vs. CP-A had more early treatment discontinuations (11% vs. 1%), adverse events requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%) and hepatic decompensating events (20% vs. 3%) (all p<0.01). There were 2 deaths: 1 CP-B/C (liver-related) and 1 CP-A (not liver-related). In multivariate analysis, CP-B/C independently predicted lack of SVR12 (OR 0.27, 95% CI 0.08–0.92). In comparing simeprevir plus sofosbuvir treated patients vs. matched untreated controls, adverse events requiring hospitalization (9% vs. 13%, p=0.55), infections (8% vs. 6%, p=0.47) and events of decompensation (9% vs. 10%, p=0.78) occurred at similar frequency. Conclusions Simeprevir plus sofosbuvir with/without ribavirin has lower efficacy and higher rates of adverse events in patients with CP-B/C cirrhosis compared to CP-A. The frequency of adverse safety outcomes were similar to matched untreated controls, suggesting safety events reflect the natural history of cirrhosis and are not related to treatment.
Hepatitis C virus (HCV) is spontaneously cleared in 15% to 45% of individuals during primary infection. To define the role of alcohol, race, and HBV or HIV coinfections in natural HCV clearance, we examined these parameters in 203 spontaneously HCV-recovered subjects (HCV Ab+/RNA-subjects without prior antiviral therapy) and 293 chronically HCV-infected patients (HCV Ab+/RNA+). Subjects were identified from 1,454 HCV anti-
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