Chen, L. (L)
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- Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A(Federation of American Society of Experimental Biology, 2002) Chen, L. (L); Corrales, F.J. (Fernando José); Lu, S.C. (Shelly C.); Huang, Z.Z. (Zong-Zhi); Avila, M.A. (Matías Antonio); Kanel, G. (G.); Ruiz Garcia-Trevijano, E. (Elena); Martinez-Cruz, L.A. (L. Alfonso); Mato, J.M. (José María); Martinez-Chantar, M.L. (María Luz)In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
- Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation(National Academy of Sciences, 2001) Chen, L. (L); Corrales, F.J. (Fernando José); Huang, Z.Z. (Zong-Zhi); Avila, M.A. (Matías Antonio); Lu, S.Z. (S. Z.); An, W.G. (Won G.); Kanel, G. (G.); Mato, J.M. (José María); Álvarez, L. (Lluis)Liver-specific and nonliver-specific methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (AdoMet), the principal biological methyl donor. Mature liver expresses MAT1A, whereas MAT2A is expressed in extrahepatic tissues and is induced during liver growth and dedifferentiation. To examine the influence of MAT1A on hepatic growth, we studied the effects of a targeted disruption of the murine MAT1A gene. MAT1A mRNA and protein levels were absent in homozygous knockout mice. At 3 months, plasma methionine level increased 776% in knockouts. Hepatic AdoMet and glutathione levels were reduced by 74 and 40%, respectively, whereas S-adenosylhomocysteine, methylthioadenosine, and global DNA methylation were unchanged. The body weight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was increased 40%. The Affymetrix genechip system and Northern and Western blot analyses were used to analyze differential expression of genes. The expression of many acute phase-response and inflammatory markers, including orosomucoid, amyloid, metallothionein, Fas antigen, and growth-related genes, including early growth response 1 and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, knockout mice are more susceptible to choline-deficient diet-induced fatty liver. At 8 months, knockout mice developed spontaneous macrovesicular steatosis and predominantly periportal mononuclear cell infiltration. Thus, absence of MAT1A resulted in a liver that is more susceptible to injury, expresses markers of an acute phase response, and displays increased proliferation.
- Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients(Elsevier, 2017) Fernandez-Sanmamed, M. (Miguel); Perez-Gracia, J.L. (Jose Luis); Fusco, J.P. (Juan Pablo); González-Martín, A. (Antonio); Rodriguez-Ruiz, M.E. (María Esperanza); Oñate, C. (Carmen); Alfaro, C. (Carlos); Martin-Algarra, S. (Salvador); Andueza, M.P. (Maria P.); Gurpide, A. (Alfonso); Morgado, J.M. (José Mário); Wang, J. (Jiong); Chen, L. (L); Melero, I. (Ignacio); Gonzalez, A. (A.); Pérez, G. (G.); Bacchiocchi, A. (A.); Halaban, R. (R.); Kluger, H. (Harriet); Sznol, M. (Mario)Background Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients and methods Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2–4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann–Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. Results Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P = 0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P = 0.013). Early changes in serum IL-8 levels (2–4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression.