Matrix glycoprotein differentially changes in liver regeneration and cirrhosis : Glycosylation alters ligand binding in matrix remodeling

Background Vitronectins (VN) are multifunctional adhesive glycoproteins that are present in plasma and the extracellular matrix of most tissues. We previously reported that the collagen-binding activity of VN is enhanced by a change in glycosylation in vitro and during liver regeneration after partial hepatectomy in vivo [Uchibori-Iwaki et al., Glycobiology (2000) 10, 865-874]. Plasma concentrations of VN declined in rats during liver regeneration 24 h after partial hepatectomy, while carbohydrate concentrations of VN decreased to 2/3 of that in sham-operated rats. Carbohydrate composition and lectin reactivity indicated that the N-glycan structures and sialylation significantly changed without affecting the peptide portion after partial hepatectomy. VN from partially hepatectomized rats were found to exhibit markedly enhanced binding to type I collagen. The enzymatic deglycosylation of VN demonstrated that collagen binding increased by 1.2 times after deN-glycosylation of VN, while it increased by more than 2.9 times after desialylation. To elucidate the biological significance of glycan modulation, changes of VN in cirrhosis were studied and compared with those during liver regeneration. Methods VNs purified from patients' and normal plasma were examined for plasma concentration and collagen-binding activity by ELISA, reactivity against lectins by dot blotting, and carbohydrate composition. Results Plasma concentrations of VN declined in chronic liver diseases in the order of hepatitis>cirrhosis>hepatocellular carcinoma with cirrhosis. Lectin reactivity and carbohydrate analyses of purified VN. from cirrhotic plasma (LC-VN) indicated that sialylation was elevated. LC-VN exhibited decreased binding to type I collagen. Collagen-binding studies of plasma before and after urea-treatment indicated that the active form of VN increased in cirrhotic plasma. Conclusions The attenuated collagen-binding activity of LC-VN is attributable to a change of glycosylation. The increase of active VN in cirrhotic plasma may contribute to the matrix incorporation of VN. These findings suggest that the collagen binding activity of VN is modulated by the alteration of peptide glycosylation during liver regeneration after partial hepatectomy and during the pathological processes, which may contribute to the tissue remodeling processes

Evaluation of two prognostic indices for adult T‐cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan

Aggressive adult T‐cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL‐PI and Japan Clinical Oncology Group (JCOG)‐PI, in a cohort from Okinawa. The PIs were originally developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three‐year OS rates for ATL‐PI were 35.9% (low‐risk, n = 66), 10.4% (intermediate‐risk, n = 256), and 1.6% (high‐risk, n = 111), and those for JCOG‐PI were 22.4% (moderate‐risk, n = 176) and 5.3% (high‐risk, n = 257). The JCOG‐PI moderate‐risk group included both the ATL‐PI low‐ and intermediate‐risk groups. ATL‐PI more clearly identified the low‐risk patient subgroup than JCOG‐PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three‐year OS rates for ATL‐PI were 34.5% (low‐risk, n = 42), 9.2% (intermediate‐risk, n = 109), and 12.5% (high‐risk, n = 8). Those for JCOG‐PI were 22.4% (moderate‐risk, n = 95) and 7.6% (high‐risk, n = 64). The low‐risk ATL‐PI group had a better prognosis than the JCOG‐PI moderate‐risk group, suggesting that ATL‐PI would be more useful than JCOG‐PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL‐related deaths in Okinawa, was not a prognostic factor in this study