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In relationship with the pathway of negative regulation of leukocyte activation, we here found that Al-CPI upregulated the expression of cytotoxic T-lymphocyte associated protein 4 ( CTLA4 ) ( Supplementary Figure S3 ), an inhibitory receptor acting as a major negative regulator of T-cell responses

54 The cancer cells cause the drug resistance via providing the multiple copies of the Dihydrofolate reductase gene (could target enzyme of methotrexate)