OBJECTIVETo detect the expression level of asparagine synthetase (ASNS) in patients with relapsed or refractory extranodal NK/T cell lymphoma and explore its clinical significance.

METHODSTen patients with relapsed or refractory extranodal NK/T cell lymphoma admitted in our department from January, 2013 to January, 2016 were analyzed. The diagnoses were confirmed by pathological and immunohistochemical examination following failed chemotherapies in all cases. Branched DNA-liquidchip technique (bDNA-LCT) was used for detecting ASNS mRNA expression in paraffin-embedded tissue sections in the 10 cases of relapsed or refractory extranodal NK/T cell lymphoma and in 5 cases of chronic rhinitis. The correlations were analyzed between ASNS expression and the clinicopathological features and outcomes of the patients with failed chemotherapy regimens containing asparaginasum.

RESULTSSix out of the 10 patients with relapsed or refractory extranodal NK/T cell lymphoma died due to diseaseprogression. The expression level of ASNS was significantly higher in the lymphoma tissues than in tissue specimens of chronic rhinitis (P<0.05). The expression level of ASNS was associated with the International Prognostic Index (P=0.023) in patients with relapsed or refractory extranodal NK/T cell lymphoma, and Kaplan-Meier curve showed that a high ASNS expression was correlated with a reduced overall survival and progression-free survival of the patients.

CONCLUSIONAsparaginasum-based chemotherapy regimens are recommended for treatment of relapsed or refractory extranodal NK/T cell lymphoma with low ASNS expressions.

Aspartate-Ammonia Ligase ; metabolism ; Disease-Free Survival ; Humans ; Lymphoma, Extranodal NK-T-Cell ; enzymology ; Recurrence

OBJECTIVETo explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia (T-ALL) cells and potential molecular mechanisms.

METHODSThe anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTT test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK.

RESULTSResveratrol inhibited the proliferation and induced apoptosis and autophagy in T-ALL cells in a dose and time-dependent manner. It also induced cell cycle arrest at G0/G1 phase via up regulating cyclin-dependent kinase (CDK) inhibitors p21 and p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins (Mcl-1 and Bcl-2) and increased the expression of proapoptotic proteins (Bax, Bim, and Bad), and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-II/LC3-I and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced.

CONCLUSIONOur findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p70S6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.

Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Autophagy ; drug effects ; Cell Culture Techniques ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Flow Cytometry ; Humans ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; enzymology ; pathology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; Stilbenes ; pharmacology ; T-Lymphocytes ; drug effects ; enzymology ; ultrastructure ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVETo use array-based comparative genomic hybridization (aCGH) technology to study the molecular cytogenetic abnormalities of anaplastic large cell lymphoma (ALCL) at genome level.

METHODSALK protein expression and molecular genetic abnormalities were detected by immunohistochemistry and fluorescence in situ hybridization, respectively, in 25 cases of ALCL. Any chromosomal gains/losses were detected by aCGH and correlated with ALK status.

RESULTSaCGH showed that chromosomal alterations in all 25 ALCL cases, and the frequency of chromosomal gains was higher than that of the losses. Chromosomal gains at 5p13.2, 3q21.1, 2q21.3, 3p25.1, 14q32.33, and 17q21.2 regions were detected in more than 50% of the ALCL cases; gains at 4q27, 6p22.1, 20p11.21, 2q22.3, 4q35.1, 1p36.22, 8p23.1, 8p12, 11q14.1, 12q13.13, and 19p13.3 regions were detected in 30%-50% of the ALCL cases; chromosomal losses at 3q26.1 and 3q26.31 regions were detected in 36.0% (9/25) and 24.0% (6/25) of the ALCL cases, respectively. Chromosomal gains at 2q21.3, 6p22.1 and 3p25.1 regions showed significant differences between ALK (+) and ALK (-) ALCL groups (P < 0.05).

CONCLUSIONSaCGH demonstrates complex molecular genetic variations in all ALCL cases. Gains at 2q21.3, 6p22.1 and 3p25.1 regions are significantly different between ALK (+) and ALK (-) ALCL groups, suggesting that the pathogenesis of ALK (+) and ALK (-) ALCL may involve different signaling pathway.

Adolescent ; Chromosome Aberrations ; Comparative Genomic Hybridization ; methods ; Female ; Gene Expression Profiling ; Humans ; In Situ Hybridization, Fluorescence ; Lymphoma, Large-Cell, Anaplastic ; enzymology ; genetics ; Male ; Paraffin Embedding ; Receptor Protein-Tyrosine Kinases ; genetics ; metabolism

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drosophila/enzymology/metabolism ; Drosophila Proteins/antagonists & inhibitors/metabolism ; Enzyme Activation/*drug effects ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Janus Kinase 3/*antagonists & inhibitors/metabolism ; Lymphoma/enzymology/*metabolism ; Phosphorylation/drug effects ; STAT Transcription Factors/antagonists & inhibitors/metabolism ; STAT3 Transcription Factor/*antagonists & inhibitors/metabolism ; Signal Transduction/*drug effects

OBJECTIVETo explore correlation of seven apoptosis-related proteins (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma (ALCL).

METHODSUsing immunohistochemistry and immunofluorescence double staining methods, the expressions of these seven apoptosis-associated proteins were studied to clarify their relationship with clinical outcomes of 36 ALK+ and 25 ALK-systemic ALCL patients enrolled between 1996 and 2006. The relationship of these apoptosis-regulating proteins with NPM-ALK status was also evaluated with the tyrosine inhibitor herbimycin A (HA) in vitro by immunocytochemistry, Western blotting and flow cytometric assays.

RESULTSThe presence of Hsp90α-, MDM2-, Bax-, Cytochrome C, and Cleaved caspase3-positive tumor cells was found significantly different in ALK+ and ALK-ALCLs, which was correlated with highly favorable clinical outcome. The Bcl-2- and p53-positive tumor cells were found in groups of patients with unfavorable prognosis. Inhibition of NPM-ALK by HA could reactivate the p53 protein and subsequent apoptosis-related proteins and therefore induced apoptosis in ALK+ ALCL cells.

CONCLUSIONOur results suggest that these seven proteins might be involved in apoptosis regulation and associated with clinical outcome of ALK+ systemic ALCLs. We also reveal a dynamic chain relation that NPM-ALK regulates p53 expression and subsequent apoptosis cascade in ALK+ ALCLs.

Adolescent ; Adult ; Aged ; Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Benzoquinones ; pharmacology ; Biomarkers, Tumor ; metabolism ; Blotting, Western ; Cell Culture Techniques ; Cell Survival ; drug effects ; Child ; Child, Preschool ; Disease-Free Survival ; Enzyme Inhibitors ; pharmacology ; Female ; Flow Cytometry ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Lactams, Macrocyclic ; pharmacology ; Lymphoma, Large-Cell, Anaplastic ; enzymology ; metabolism ; pathology ; Male ; Microscopy, Fluorescence ; Middle Aged ; Neoplasm Staging ; Prognosis ; Protein-Tyrosine Kinases ; metabolism ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; metabolism ; Retrospective Studies ; Rifabutin ; analogs & derivatives ; Young Adult

Achyranthes bidentata polysaccharide sulfate (ABPS) was a sulfated derivate derived from Achyranthes bidentata polysaccharide (ABP) which was isolated and identified from Chinese herb Achyranthes bidentata. The anti human immunodeficiency virus type 1 (HIV-1) activities were studied in vitro and in vivo. ABPS was found to inhibit HIV-1 reverse transcriptase and integrase with the 50% inhibiting concentration (IC60) of (2.948 +/- 0.556) micromol x L(-1) and (0.155 +/- 0.030) micromol x L(-1), respectively, but the parent compound ABP was not effective. ABPS inhibited HIV-1 P24 antigen with IC50 of (0.082 +/- 0.044) micromol x L(-1) and selective index (SI) of > (358 +/- 148) in MT-4 cell cultures acutely infected with HIV-1 IIIB virus, and with IC50 of (11.80 +/- 5.90) micromol x L(-1) and SI of > (24.2 +/- 12.1) in PBMC cell cultures acutely infected with clinical isolated zidovudine resistant HIV-1 virus, but there was no activity even at its concentration of 500 micromol x L(-1) in latent infection of H9/HIV-1 IIIB cell cultures. 5% sera taken from rats after intraperitoneal injection from rats with ABPS 125 mg x kg(-1) once or mice with 3 mg x kg(-1) qd for 20 days effectively inhibited HIV-1 P24 in MT-4 cell cultures, but those had no inhibitory effect when given orally. The results suggested that ABPS is a promising HIV-1 inhibitor, active on HIV-1 reverse transcriptase, integrase in vitro and HIV-1 P24 antigens in cell cultures, it was well absorbed by intraperitoneal injection but poor in oral bioavailability. It warrants further study.
Achyranthes ; chemistry ; Animals ; Antiviral Agents ; chemistry ; isolation & purification ; pharmacology ; Cell Line, Tumor ; Female ; HIV Core Protein p24 ; metabolism ; HIV Integrase ; metabolism ; HIV Reverse Transcriptase ; metabolism ; HIV-1 ; drug effects ; enzymology ; Humans ; Immune Sera ; pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Plants, Medicinal ; chemistry ; Polysaccharides ; chemistry ; isolation & purification ; pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; immunology ; pathology ; virology ; Random Allocation ; Rats ; Rats, Wistar ; Sulfates ; chemistry ; isolation & purification ; pharmacology

This study was to investigate the predictive factors influencing prognosis of non-Hodgkin's lymphoma (NHL). The clinical data on 125 cases of NHL were analyzed retrospectively. The results indicated that in 125 cases, the incidence of B cell NHL (B-NHL) was 68%, T cell NHL (T-NHL) was 28%, and uncertained cases were 4%. B-NHL was with more bone marrow involvement, while T-NHL was associated with more presence of B symptom, increased lactate dehydrogenase (LDH), advanced clinical stage and higher International Prognostic Index (IPI) scores. For T-NHL and B-NHL, the 3-year overall survival (OS) rate was 41.07% and 71.64% respectively. Age, B symptom, LDH level, and clinical stage were associated with OS. Immunophenotyping was not identified as a significant prognostic factor. The incidence of born marrow involvement was 31.2%, mainly in B-NHL. The involvement manner had no relationships with age, B symptom, LDH level and T/B immunophenotyping. Diffuse bone marrow involvement was often linked with hepatosplenomegaly, and its OS was shorter than that focal manner. In conclusion, age, B symptom, LDH level and clinical stage affect NHL survival, while immunophenotyping was not an independent prognostic factor for NHL. The manner of bone marrow involvement helped to predict prognosis.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Marrow ; pathology ; Child ; Child, Preschool ; China ; Female ; Humans ; Infant ; L-Lactate Dehydrogenase ; metabolism ; Lymphoma, B-Cell ; diagnosis ; Lymphoma, Non-Hodgkin ; diagnosis ; mortality ; pathology ; Lymphoma, T-Cell ; diagnosis ; enzymology ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Survival Rate ; Young Adult

The aim of this study was to investigate the expression of anaplastic lymphoma kinase (ALK) protein resulted from chromosome translocation in anaplastic large cell lymphoma (ALCL) and its relationship with the age and prognosis of patients with ALCL. The tissue microarray including 30 cases of ALCL and 2 normal control tissues were established, the expression of anaplastic lymphoma kinase (ALK) protein was detected by immunohistochemistry, the statistical analysis of detected results was carried out by SPSS software. The results showed that the ALK protein was expressed negatively in 2 cases of primary skin ALCL, but in 20 out of 28 cases of systematic ALCL the ALK protein was expressed positively and mainly located in cytoplasm and/or nucleus (71.4%). Clinically, the patients with ALK expression were younger than those without ALK expression (p < 0.05). The prognosis of patients with ALK expression was better than those without ALK expression (p < 0.05). It is concluded that there is a high incidence of ALK expression in ALCL, especially in younger group. ALK expression may be an useful and independent marker for the differential diagnosis and prognosis evaluation of ALCL.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 2 ; Female ; Humans ; Lymphoma, Large-Cell, Anaplastic ; enzymology ; genetics ; Male ; Middle Aged ; Prognosis ; Protein-Tyrosine Kinases ; genetics ; metabolism ; Receptor Protein-Tyrosine Kinases ; Translocation, Genetic ; Young Adult

Adenolymphoma ; enzymology ; metabolism ; Humans ; Lymphoma, T-Cell ; enzymology ; metabolism ; Lymphoma, T-Cell, Peripheral ; enzymology ; metabolism ; Male ; Middle Aged ; Nitric Oxide Synthase Type I ; metabolism ; Up-Regulation

PURPOSE: Anaplastic large cell lymphoma (ALCL), a CD30+ T-cell non-Hodgkin's lymphoma, represents only 2-8% of lymphoma overall. Information on the clinical findings of primary systemic ALCL in Korea is limited. Our aims were to report the clinical features and outcomes of primary systemic ALCL. PATIENTS and METHODS: We retrospectively reviewed the medical records of 36 adult patients diagnosed with primary systemic ALCL at Asan Medical Center from February 1995 through June 2006. RESULTS: Of 36 patients, 29 were male. The median age was 39 years (range, 17-67 years), and 26 (72%) presented with Ann Arbor stages III and IV. The most commonly involved extranodal sites were bone (n = 7) and soft tissue (n = 6). Thirty-two of all patients (89%) were treated with an anthracycline-based regimen including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) as induction chemotherapy; 16 (50%) achieved complete remission (CR), and 13 (41%) achieved partial remission (PR). Median overall survival (OS) and event-free survival (EFS) were 49 and 17 months, respectively. Univariate analysis showed that performance status (p = 0.035), international prognostic index (IPI) (p = 0.025), and age-adjusted IPI (p = 0.034) were significant prognostic factors for OS, whereas anaplastic lymphoma kinase (ALK) expression did not affect OS (p = 0.483). CONCLUSION: Our retrospective analysis of Korean primary systemic ALCL patients showed that median OS was 49 months and overall response to CHOP was 91%. Performance, IPI, and age-adjusted IPI were predictors of OS, whereas ALK expression did not have prognostic significance.
Adolescent ; Adult ; Aged ; Disease-Free Survival ; Female ; *Hospitals ; Humans ; Korea/epidemiology ; Lymphoma, Large-Cell, Anaplastic/enzymology/epidemiology/*pathology/therapy ; Male ; Middle Aged ; Neoplasm Staging ; Protein-Tyrosine Kinases/metabolism ; Survival Rate ; Time Factors