Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

The mutational profile of plasmablastic lymphoma has not been described. We performed a targeted, exonic next-generation sequencing analysis of 30 plasmablastic lymphoma cases with a Bcell lymphoma-dedicated panel and fluorescence in situ hybridization for the detection of MYC rearrangements. Complete phenotyping of the neoplastic and microenvironmental cell populations was also performed. We identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and three cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in Epstein-Barr virus (EBV)-positive disease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed consistent MYC expression, which was higher in cases with MYC rearrangements, together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironmental cell populations were heterogeneous and unrelated to EBV, with enrichment of tumor-associated macrophages (TAM) and PD1-positive T cells. PD-L1 was expressed in all cases in the TAM population but only in the neoplastic cells in five cases (4 of 14 EBV-positive cases). HLA expression was absent in the majority of cases of plasmablastic lymphoma. In summary, the mutational profile of plasmablastic lymphoma is heterogeneous and related to EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV-positive disease. An enrichment in TAM and PD1 reactive T lymphocytes is found in the microenvironment of plasmablastic lymphoma and a fraction of the neoplastic cells express PD-L1.     

Effects of Histidine and N-Acetylcysteine on Doxorubicin-Induced Cardiomyopathy in Rats

The amino acids histidine and n-acetylcysteine have many biological activities such as antioxidant effect. The present study investigated the effects of histidine and n-acetylcysteine on the heart lesions induced by doxorubicin (DOX) in rats. Forty-eight male Wistar rats were divided into two major groups treated intraperitoneally (i.p.) with normal saline and 4 mg/kg of DOX, respectively. Each group was further divided into four subgroups that were treated with separate and combined i.p. injections of histidine and n-acetylcysteine (NAC) at a same dose of 40 mg/kg. Electrocardiography (ECG) was recorded using lead II. The heart lesions were evaluated by light microscopy. Serum levels of creatine phosphokinase and lactate dehydrogenase and heart tissue malondialdehyde levels were measured. Histidine and especially NAC at a same dose of 40 mg/kg recovered ECG changes, improved heart lesions and prevented biochemical changes induced by DOX. Co-administration of histidine and NAC showed better responses when compared with them used alone. The results of the present study showed protective effects for histidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotective properties of histidine and NAC.