Zhiyuan Zhou

Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficiency that may influence the capacity of T cells to extract an efficient antitumor immune response. It has been confirmed that the B7-CD28 pathway may promote tumor immune evasion by providing a negative regulatory signal. The current study analyzed the expression of programmed death 1 (PD-1)/programmed death ligand (PD-L) in ENKL cell lines and tissues. The functional studies were performed to analyze the functional activity of PD-L1 interacting with effective T cells in ENKL. PD-L1 and PD-L2 mRNA levels in ENKL cell lines were markedly upregulated compared with those in normal natural killer cells. The proteins constitutively expressed in the 30 ENKL specimens were significantly higher than in the 20 rhinitis specimens. In addition, PD-L1 and PD-L2 expression were found to closely correlate with certain clinical histopathological parameters. Furthermore, the count of PD-1+ tumor-infiltrating T lymphocytes was found to negatively correlate with the expression of PD-L1 and PD-L2. The PD-1 expression in the CD4+ and CD8+ T-cell subsets of 20 ENKL patients prior to therapy were significantly higher than that of the 10 healthy volunteers. In the functional studies, the cytokines (interleukin-2 and interferon-γ) secreted by CD8+ T cells were inhibited by PD-L1 expression in SNK-6 cells and this was restored with the presence of the PD-L1 blocking antibody. However no direct effect of PD-L1 was identified on CD8+ T-cell apoptosis and CD8+ T-cell cytotoxicity, as assessed by the proliferation of SNK-6 cells in the presence or absence of the neutralizing anti-PD-L1 antibody. The results of the current study revealed that PD-Ls and PD-1 are aberrantly expressed in ENKL and, furthermore, PD-L1 expression in SNK-6 cells was found to inhibit the activity of CD8+ T-cell cytokine secretion. This indicated that the PD-Ls may prevent effective antitumor immunity in vivo by interacting with tumor T cells, which provides important evidence to delineate the cellular immune deficiency mechanism in ENKL. Therefore, PD-1/PD-Ls are predicted to become novel targets for ENKL immunotherapy.

A chemically sulfated polysaccharide derived from Ganoderma lucidum induces mitochondrial-mediated apoptosis in human osteosarcoma MG63 cells

To develop new anticancer agents, we prepared a sulfated polysaccharide (SCGLP1) from the fruiting bodies of Ganoderma lucidum, and the effect of SCGLP1 on human osteosarcoma MG63 cell line was investigated. Our result showed that treatment with SCGLP1 resulted in a significant inhibitory effect on cell proliferation and cell viability of MG63 cells in a dose- and time-dependent manner and caused apoptotic death in MG63 cells through an increase in G0/G1 phase arrest, but had minor cytotoxic effect on human normal osteoblast (NHOst) cells. Western blot analysis identified that SCGLP1-induced apoptosis was associated with an increased protein expression of proapoptotic Bax and Bad, decreased expression of antiapoptotic Bcl-2 and Bcl-XL, loss of mitochondrial membrane potential (Δψm), the release of mitochondrial cytochrome c to cytosol, and cleavage of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). In addition, pretreatment with the pan-caspase inhibitor (z-VAD-fmk) blocked the SCGLP1-induced apoptosis in MG63 cells. The data indicate that SCGLP1-induced apoptosis is primarily associated with caspase-3- and caspase-9-dependent apoptotic pathway.

Discovery and validation of the tumor-suppressive function of long noncoding RNA PANDA in human diffuse large B-cell lymphoma through the inactivation of MAPK/ERK signaling pathway

Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the development of cancer. By using the next generation HiSeq sequencing assay, we determined lncRNAs exhibiting differential expression between DLBCL patients and healthy controls. Then, RT-qPCR was performed for identification in clinical samples and cell materials, and lncRNA PANDA was verified to be down-regulated in DLBCL patients and have considerable diagnostic potential. In addition, decreased serum PANDA level was correlated to poorer clinical outcome and lower overall survival in DLBCL patients. Subsequently, we determined the experimental role of lncRNA PANDA in DLBCL progression. Luciferase reporter assay and chromatin immunoprecipitation assay suggested that lncRNA PANDA was induced by p53 and p53 interacts with the promoter region of PANDA. Cell functional assay further indicated that PANDA functioned as a tumor suppressor gene through the suppression of cell growth by a G0/G1 cell cycle arrest in DLBCL. More importantly, Cignal Signal Transduction Reporter Array and western blot assay showed that lncRNA PANDA inactivated the MAPK/ERK signaling pathway. In conclusion, our integrated approach demonstrates that PANDA in DLBCL confers a tumor suppressive function through inhibiting cell proliferation and silencing MAPK/ERK signaling pathway. Thus, PANDA may be a promising therapeutic target for patients with DLBCL.

Safety and efficacy of low-dose pre-phase before conventional-dose chemotherapy for ulcerative gastric diffuse large B-cell lymphoma.

Potentially fatal chemotherapy (CT)-related gastrorrhagia and gastric perforation in patients with gastric lymphoma present difficult problems to doctors. We retrospectively analyzed 54 patients with ulcerative gastric diffuse large B-cell lymphoma (G-DLBCL) to compare the safety and efficacy of low-dose pre-phase CT before 4–6 cycles of conventional-dose CT (n = 28) with 4–6 cycles of conventional-dose CT (n = 26) between October 2005 and August 2014. Patients who received low-dose pre-phase before conventional-dose CT showed a lower gastrorrhagia or gastric perforation rate (0% vs. 15.4%, p = 0.047) and higher complete response (CR) rate (78.6% vs. 46.2%, p = 0.023) and 5-year progression-free survival (PFS) rate (63% vs. 31%, p = 0.021) than patients who received conventional-dose CT alone. Our study suggests that low-dose pre-phase therapy before conventional-dose CT provides a safe and effective method for ulcerative G-DLBCL.

Recurrent mutations in epigenetic modifiers and the PI3K/AKT/mTOR pathway in subcutaneous panniculitis-like T-cell lymphoma

236–238. Rudiger, T., Gascoyne, R.D., Jaffe, E.S., de Jong, D., Delabie, J., De Wolf-Peeters, C., Poppema, S., Xern, L., Gisselbrecht, C., Wiedenmann, S. & Muller-Hermelink, H.K. (2002) Workshop on the relationship between nodular lymphocyte predominant Hodgkin’s lymphoma and T cell/ histiocyte-rich B cell lymphoma. Annals of Oncology, 13, 44–51. Shankar, A.G., Kirkwood, A.A., Hall, G.W., Hayward, J., O’Hare, P. & Ramsay, A.D. (2015) Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma A review of clinical outcome based on the histological variants. British Journal of Haematology, 171, 254–262. Shankar, A.G., Kirkwood, A.A., Depani, S., Bianchi, E., Hayward, J., Ramsay, A.D. & Hall, G.W. (2016) Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a report from the United Kingdom’s Children’s Cancer and Leukaemia Study Group. British Journal of Haematology, 173, 421–431. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman, J.W., Editors. (2008) World Health Organisation Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press.

Human immunodeficiency virus-negative plasmablastic lymphoma: A case report and literature review.

Rationale: Plasmablastic lymphoma (PBL) is a rare subtype of human immunodeficiency virus (HIV)-related non-Hodgkins lymphoma that predominantly manifests in the oral cavity. Patient concerns: Three cases of HIV-negative PBL were reported. Diagnoses: HIV-negative PBL Interventions: The patient had undergone chemotherapy. Outcomes: Clinical outcomes were very poor in Cases 1 and 3; Case 2, whose diagnosis suggested no bone marrow involvement, is still alive. Lessons subsections: These cases served to broaden the reported clinical spectrum of HIV-negative PBL. Clinicians and pathologists need to be familiar with lymphoma in the identified extra-oral PBL variation and there levant differential diagnosis procedures for this particular disease.

S100A9 and ORM1 serve as predictors of therapeutic response and prognostic factors in advanced extranodal NK/T cell lymphoma patients treated with pegaspargase/gemcitabine

Pegaspargase combined with gemcitabine have greatly improved the outcomes of advanced extranodal NK/T cell lymphoma (ENKL). However, patients frequently undergo recurrent disease due to chemoresistance, and few predictive parameters are available. The present study explored potential biomarkers to predict the therapeutic response of advanced ENKL treated with pegaspargase/gemcitabine and evaluate the prognostic significance. Through serum proteomic analysis, we identified 61 upregulated and 22 downregulated proteins in nonresponders compared with responders. We further validated that patients with unfavourable treatment outcomes displayed higher levels of S100A9 and ORM1 via enzyme-linked immunosorbent assay (ELISA). Moreover, the sensitivity and specificity for detecting refractory patients were 81.5% and 71.4% for S100A9 > 62.0 ng/ml, 85.2% and 77.1% for ORM1 > 1436 ug/ml, 100% and 57.1% for S100A9 combined with ORM1. Furthermore, in multivariate analysis elevated levels of S100A9 were associated with poor 2-year OS (40.2% vs. 76.6%, RR = 2.92, p = 0.005) and 2-year PFS (33.1% vs. 61.1%, RR = 2.61 p = 0.011). High ORM1 also predicted inferior 2-year OS (38.7% vs.76.1, RR = 2.46, p = 0.023) and 2-year PFS (18.4% vs. 73.2%, RR = 2.86, p = 0.009). Our results indicated that S100A9 and ORM1 could serve as reliable predictors of therapeutic response and independent prognostic factors of survival in advanced ENKL patients treated with pegaspargase/gemcitabine.

Pretreatment 14-3-3 epsilon level is predictive for advanced extranodal NK/T cell lymphoma therapeutic response to asparaginase-based chemotherapy

The aim of the present study was to identify the potential relevant biomarkers to predict the therapeutic response of advanced extranodal natural killer/T cell lymphoma(ENKTL) treated with asparaginase‐based treatment.