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Expression of PBRM1 as a prognostic predictor in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitor.
Cai, W, Wang, Z, Cai, B, Yuan, Y, Kong, W, Zhang, J, Chen, Y, Liu, Q, Huang, Y, Huang, J, et al
International journal of clinical oncology. 2020;(2):338-346
Abstract
OBJECTIVE PBRM1, located on 3p21, functions as a tumor suppressor and somatic mutation of PBRM1 is frequent in clear cell renal cell carcinoma (ccRCC). This study aims to determine the influence of PBRM1 expression on the prognosis of patients with mRCC receiving tyrosine kinase inhibitor (TKI) treatment. METHODS We identified 116 mRCC patients who were administered sunitinib or sorafenib as first-line therapy, between January 2006 and December 2016 at our institution. PBRM1 expression was assessed by immunohistochemistry. The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS), log-rank test was used to compare the survival outcomes between patients with low and high PBRM1 expression levels, and the Cox proportional hazard regression model was used to estimate the prognostic value. Prognostic accuracy was determined using Harrell concordance index, and nomograms were built to evaluate the prognosis of mRCC. RESULTS Patients with low PBRM1 expression had significantly shorter median PFS (9 vs 26 months, P < 0.001) and OS (21 vs 44 months, P < 0.001) than those with high expression. Multivariate analysis showed that PBRM1 expression was an independent predictor of PFS (HR 1.975, P = 0.013) and OS (HR 2.282, P = 0.007). The model built by the addition of PBRM1 improved the C-index of PFS and OS to 0.72 and 0.82, respectively. CONCLUSIONS The expression of PBRM1 could be a significant prognostic factor for mRCC patients treated with targeted therapy, and it increases the prognostic accuracy of the established prognostic model.
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Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway.
Zhang, J, Posner, GH, Danilenko, M, Studzinski, GP
The Journal of steroid biochemistry and molecular biology. 2007;(1-5):140-9
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Abstract
Low calcemic analogs of vitamin D are candidates for differentiation therapy of human myeloid leukemias. We report here that the seco-steroid synthesized to have resistance to intracellular degradation and low calcemia-inducing activity, 1alpha-hydroxymethyl-3beta-16-ene-24,24-difluoro-25-hydroxy-vitamin D(3) (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB-4, and murine myeloid leukemia cells WEHI-3B D(-). JKF has differentiation-inducing potency which is slightly lower than the physiologically active form of vitamin D, 1,25(OH)(2)vitamin D(3) (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38MAP kinase, increases the differentiation efficiency of JKF to a level similar to the level observed when 1,25D is used in such combinations. We also show for the first time that SB inhibits the phosphorylation of MAPKAPK2, a downstream target of p38MAPK, but upregulates the phosphorylation of at least one of the isoforms of JNK (p46 JNK1) and of c-jun in all four human myeloid cell lines studied here. These studies indicate that the JNK1 pathway is positively associated with monocytic differentiation of several subtypes of myeloid leukemia cells arrested at different developmental stages. Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias.