Lymphoma of SJL/J mice strain, 3

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Takahashi, Masanori; Takeichi, Sanae; Otsuka, Hisashi

1976-01-01

This paper describes influences of 7, 12-dimethylbenz (α) anthracene (DMBA) and 60 Co irradiation in lymphoma, together with the past results. The influences of DMBA in the lymphoma were studied 265 days (an average) after the subcutaneous administration of 1 mg/day of DMBA in 35 mice, and 246 days after it accompanied with the extraction of the thymus. Eight hundred rads (200 rads/ week four times) intermittent systemic irradiation was given to 26 mice, and to 16 mice after the extraction of the thymus. The influences on the lymphoma were studied 233 days later (an average) in the former and 544 days later (an average) in the latter. Lymphoma occurred 242 days later (an average) in 20 of the 35 mice with the administration of DMBA (57.1%), and 260 days later (an average) in 13 of the 42 mice with the administration of DMBA accompanied with the extraction of the thymus (30.9%). It occurred 231 days later (an average) in 22 of the 26 mice with 60 Co irradiation (84.6%), and 561 days later (an average) in 12 of the 16 mice with 60 Co irradiation accompanied with the extraction of the thymus (75%). Lymphosarcoma occurred 211 days after the administration of DMBA in 37%, and 208 days after the irradiation of 60 Co in 53.8%. However, it did not occur in animals in which the thymus had been extracted. The frequency of thymic lymphoma was high in animals with the administration of N-nitrosobutylurea. Although the occurrence of lymphosarcoma was controlled after the extraction of the thymus, reticulosarcoma occurred. The time of occurrence of lymphoma and the frequency of its occurrence by tissues were the same in the mice with extraction of the thymus as in controls. The SJL/J strain mice seemed to be independent of the thymus. (Kanao, N.)

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

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Ehrke, M J; Verstovsek, S; Maccubbin, D L; Ujházy, P; Zaleskis, G; Berleth, E; Mihich, E

2000-07-01

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL/6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several host anti-tumor cytolytic effector functions of splenocytes and thymocytes were evaluated throughout the treatment period and in long-term survivors (LTS). DOX treatment alone resulted in a moderate (approx. 20%) increase in life span but no cures. TNF-alpha alone, at any tested dose or schedule, had little or no positive effect on survival. The combinations of DOX and TNF-alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combinations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80%) of LTS. The host defense activities examined included those of splenic and thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cells as well as splenic tumoricidal macrophages. Although most activities were modulated by tumor growth and/or treatment, only CTL responsiveness appeared to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment period. Finally, ex vivo analyses of splenocytes and thymocytes together with the rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory. Copyright 2000 Wiley-Liss, Inc.

[Establishment and identification of mouse lymphoma cell line EL4 expressing red fluorescent protein].

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Li, Yan-Jie; Cao, Jiang; Chen, Chong; Wang, Dong-Yang; Zeng, Ling-Yu; Pan, Xiu-Ying; Xu, Kai-Lin

2010-02-01

This study was purposed to construct a lentiviral vector encoding red fluorescent protein (DsRed) and transfect DsRed into EL4 cells for establishing mouse leukemia/lymphoma model expressing DsRed. The bicistronic SIN lentiviral transfer plasmid containing the genes encoding neo and internal ribosomal entry site-red fluorescent protein (IRES-DsRed) was constructed. Human embryonic kidney 293FT cells were co-transfected with the three plasmids by liposome method. The viral particles were collected and used to transfect EL4 cells, then the cells were selected by G418. The results showed that the plasmid pXZ208-neo-IRES-DsRed was constructed successfully, and the viral titer reached to 10(6) U/ml. EL4 cells were transfected by the viral solution efficiently. The transfected EL4 cells expressing DsRed survived in the final concentration 600 microg/ml of G418. The expression of DsRed in the transfected EL4 cells was demonstrated by fluorescence microscopy and flow cytometry. In conclusion, the EL4/DsRed cell line was established successfully.

[Regulatory T cells inhibit proliferation of mouse lymphoma cell line EL4 in vitro].

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Zhang, Chen; Kong, Yan; Guo, Jun; Ying, Zhi-Tao; Yuan, Zhi-Hong; Zhang, Yun-Tao; Zheng, Wen; Song, Yu-Qin; Li, Ping-Ping; Zhu, Jun

2010-10-01

This study was aimed to investigate the effect of regulatory T (Treg) cells on the T cell lymphoma EL4 cells and its mechanism in vitro. C57BL/6 mouse Treg cells were isolated by magnetic cell sorting (MACS). The purity of Treg cells and their expression of Foxp3 were identified by flow cytometry (FCM) and PT-PCR respectively. The suppression of Treg cells on EL4 cells was detected by 3H-TdR method. At the same time, enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of cytokine TGF-β1 and IL-10. The results showed that CD4+CD25+ T cells could be successfully isolated by MACS with the purity reaching 94.52% and the expression of Foxp3 reaching 84.72%. After sorting, the expression of Foxp3 mRNA could be detected by RT-PCR. 3H-TdR assay confirmed that regulatory T cells could suppress the proliferation of EL4 cells with or without antigen presenting cells (APC) or dendritic cells (DC), APC or DC might effectively enhance the suppression. In addition, DC alone also suppressed the proliferation. TGF-β1 and IL-10 could be detected in the supernatant by ELISA. It is concluded that the Treg cells can obviously suppress the proliferation of T cell lymphoma cells in vitro, APC or DC can enhance this suppressive effect, while the DC alone also can suppress the proliferation of EL4 cells, the TGF-β1 and IL-10 cytokine pathway may be one of the mechanisms of suppression.

The short term effects of Low-dose-rate Radiation on EL4 Lymphoma Cell

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Bong, Jin Jong; Kang, Yu Mi; Shin, Suk Chull; Choi, Moo Hyun; Choi, Seung Jin; Kim, Hee Sun; Lee, Kyung Mi

2012-01-01

To determine the biological effects of low-dose-rate radiation ( 137 Cs, 2.95 mGy/h) on EL4 lymphoma cells during 24 h, we investigated the expression of genes related to apoptosis, cell cycle arrest, DNA repair, iron transport, and ribonucleotide reductase. EL4 cells were continuously exposed to low-dose-rate radiation (total dose: 70.8 mGy) for 24 h. We analyzed cell proliferation and apoptosis by trypan blue exclusion and flow cytometry, gene expression by real-time PCR, and protein levels with the apoptosis ELISA kit. Apoptosis increased in the Low-dose-rate irradiated cells, but cell number did not differ between non- (Non-IR) and Low-dose-rate irradiated (LDR-IR) cells. In concordance with apoptotic rate, the transcriptional activity of ATM, p53, p21, and Parp was upregulated in the LDR-IR cells. Similarly, Phospho-p53 (Ser15), cleaved caspase 3 (Asp175), and cleaved Parp (Asp214) expression was upregulated in the LDR-IR cells. No difference was observed in the mRNA expression of DNA repair-related genes (Msh2, Msh3, Wrn, Lig4, Neil3, ERCC8, and ERCC6) between Non-IR and LDR-IR cells. Interestingly, the mRNA of Trfc was upregulated in the LDR-IR cells. Therefore, we suggest that short-term Low-dose-rate radiation activates apoptosis in EL4 lymphoma cells.

The short term effects of Low-dose-rate Radiation on EL4 Lymphoma Cell

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Bong, Jin Jong; Kang, Yu Mi; Shin, Suk Chull; Choi, Moo Hyun; Choi, Seung Jin; Kim, Hee Sun [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd, Seoul (Korea, Republic of); Lee, Kyung Mi [Global Research Lab, BAERI Institute, Dept. of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of)

2012-06-15

To determine the biological effects of low-dose-rate radiation ({sup 137}Cs, 2.95 mGy/h) on EL4 lymphoma cells during 24 h, we investigated the expression of genes related to apoptosis, cell cycle arrest, DNA repair, iron transport, and ribonucleotide reductase. EL4 cells were continuously exposed to low-dose-rate radiation (total dose: 70.8 mGy) for 24 h. We analyzed cell proliferation and apoptosis by trypan blue exclusion and flow cytometry, gene expression by real-time PCR, and protein levels with the apoptosis ELISA kit. Apoptosis increased in the Low-dose-rate irradiated cells, but cell number did not differ between non- (Non-IR) and Low-dose-rate irradiated (LDR-IR) cells. In concordance with apoptotic rate, the transcriptional activity of ATM, p53, p21, and Parp was upregulated in the LDR-IR cells. Similarly, Phospho-p53 (Ser15), cleaved caspase 3 (Asp175), and cleaved Parp (Asp214) expression was upregulated in the LDR-IR cells. No difference was observed in the mRNA expression of DNA repair-related genes (Msh2, Msh3, Wrn, Lig4, Neil3, ERCC8, and ERCC6) between Non-IR and LDR-IR cells. Interestingly, the mRNA of Trfc was upregulated in the LDR-IR cells. Therefore, we suggest that short-term Low-dose-rate radiation activates apoptosis in EL4 lymphoma cells.

Delayed growth of EL4 lymphoma in SR-A-deficient mice is due to upregulation of nitric oxide and interferon-gamma production by tumor-associated macrophages.

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Komohara, Yoshihiro; Takemura, Kenichi; Lei, Xiao Feng; Sakashita, Naomi; Harada, Mamoru; Suzuki, Hiroshi; Kodama, Tatsuhiko; Takeya, Motohiro

2009-11-01

Class A scavenger receptors (SR-A, CD204) are highly expressed in tumor-associated macrophages (TAM). To investigate the function of SR-A in TAM, wild-type and SR-A-deficient (SR-A(-/-)) mice were injected with EL4 cells. Although these groups of mice did not differ in the numbers of infiltrating macrophages and lymphocytes and in neovascularization, SR-A(-/-) mice had delayed growth of EL4 tumors. Expression of inducible nitric oxide (NO) synthase and interferon (IFN)-gamma mRNA increased significantly in tumor tissues from SR-A(-/-) mice. Engulfment of necrotic EL4 cells induced upregulation of NO and IFN-gamma production by cultured macrophages, and production of NO and IFN-gamma increased in SR-A(-/-) macrophages in vitro. IFN-beta production by cultured macrophages was also elevated in SR-A(-/-) macrophages in vitro. These results suggested that the antitumor activity of macrophages increased in SR-A(-/-) mice because of upregulation of NO and IFN-gamma production. These data indicate an important role of SR-A in regulating TAM function by inhibiting toll-like receptor (TLR)4-IFN-beta signaling.

Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice

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Yasumizu, R.; Hiai, H.; Sugiura, K.

1988-01-01

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/J mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis

Genetic Recombination Between Stromal and Cancer Cells Results in Highly Malignant Cells Identified by Color-Coded Imaging in a Mouse Lymphoma Model.

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Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kousuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

2017-12-01

The tumor microenvironment (TME) promotes tumor growth and metastasis. We previously established the color-coded EL4 lymphoma TME model with red fluorescent protein (RFP) expressing EL4 implanted in transgenic C57BL/6 green fluorescent protein (GFP) mice. Color-coded imaging of the lymphoma TME suggested an important role of stromal cells in lymphoma progression and metastasis. In the present study, we used color-coded imaging of RFP-lymphoma cells and GFP stromal cells to identify yellow-fluorescent genetically recombinant cells appearing only during metastasis. The EL4-RFP lymphoma cells were injected subcutaneously in C57BL/6-GFP transgenic mice and formed subcutaneous tumors 14 days after cell transplantation. The subcutaneous tumors were harvested and transplanted to the abdominal cavity of nude mice. Metastases to the liver, perigastric lymph node, ascites, bone marrow, and primary tumor were imaged. In addition to EL4-RFP cells and GFP-host cells, genetically recombinant yellow-fluorescent cells, were observed only in the ascites and bone marrow. These results indicate genetic exchange between the stromal and cancer cells. Possible mechanisms of genetic exchange are discussed as well as its ramifications for metastasis. J. Cell. Biochem. 118: 4216-4221, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Autophagy contributes to apoptosis in A20 and EL4 lymphoma cells treated with fluvastatin.

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Qi, Xu-Feng; Kim, Dong-Heui; Lee, Kyu-Jae; Kim, Cheol-Su; Song, Soon-Bong; Cai, Dong-Qing; Kim, Soo-Ki

2013-11-08

Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. However, the relationship between apoptosis and autophagy in lymphoma cells exposed to statins remains unclear. The objective of this study was to elucidate the potential involvement of autophagy in fluvastatin-induced cell death of lymphoma cells. We found that fluvastatin treatment enhanced the activation of pro-apoptotic members such as caspase-3 and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells. The process was accompanied by increases in numbers of annexin V alone or annexin V/PI double positive cells. Furthermore, both autophagosomes and increases in levels of LC3-II were also observed in fluvastatin-treated lymphoma cells. However, apoptosis in fluvastatin-treated lymphoma cells could be blocked by the addition of 3-methyladenine (3-MA), the specific inhibitor of autophagy. Fluvastatin-induced activation of caspase-3, DNA fragmentation, and activation of LC3-II were blocked by metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggest that autophagy contributes to fluvastatin-induced apoptosis in lymphoma cells, and that these regulating processes require inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.

Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells.

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Knoepp, Stewart M; Chahal, Manpreet S; Xie, Yuhuan; Zhang, Zhihong; Brauner, Daniel J; Hallman, Mark A; Robinson, Stephanie A; Han, Shujie; Imai, Masaki; Tomlinson, Stephen; Meier, Kathryn E

2008-09-01

The phosphatidylcholine-using phospholipase D (PLD) isoform PLD2 is widely expressed in mammalian cells and is activated in response to a variety of promitogenic agonists. In this study, active and inactive hemagglutinin-tagged human PLD2 (HA-PLD2) constructs were stably expressed in an EL4 cell line lacking detectable endogenous PLD1 or PLD2. The overall goal of the study was to examine the roles of PLD2 in cellular signal transduction and cell phenotype. HA-PLD2 confers PLD activity that is activated by phorbol ester, ionomycin, and okadaic acid. Proliferation and Erk activation are unchanged in cells transfected with active PLD2; proliferation rate is decreased in cells expressing inactive PLD2. Basal tyrosine phosphorylation of focal adhesion kinase (FAK) is increased in cells expressing active PLD2, as is phosphorylation of Akt; inactive PLD2 has no effect. Expression of active PLD2 is associated with increased spreading and elongation of cells on tissue culture plastic, whereas inactive PLD2 inhibits cell spreading. Inactive PLD2 also inhibits cell adhesion, migration, and serum-induced invasion. Cells expressing active PLD2 form metastases in syngeneic mice, as do the parental cells; cells expressing inactive PLD2 form fewer metastases than parental cells. In summary, active PLD2 enhances FAK phosphorylation, Akt activation, and cell invasion in EL4 lymphoma cells, whereas inactive PLD2 exerts inhibitory effects on adhesion, migration, invasion, and tumor formation. Overall, expression of active PLD2 enhances processes favorable to lymphoma cell metastasis, whereas expression of inactive PLD2 inhibits metastasis.

TGF-beta1 expression in EL4 lymphoma cells overexpressing growth hormone.

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Farmer, John T; Weigent, Douglas A

2006-03-01

Our previous studies show that growth hormone overexpression (GHo) upregulates the expression of the IGF-1R and IGF-2R resulting in the protection of the EL4 lymphoma cell line from apoptosis. In this study, we report that GHo also increases TGF-beta1 protein expression measured by luciferase promoter assay, Western analysis, and ELISA. Further, the data show that antibody to TGF-betaR2 decreases TGF-beta1 promoter activity to the level of vector alone control cells. GHo cells treated with (125)I-rh-latent TGF-beta1 showed increased activation of latent TGF-beta1 as measured by an increase in the active 24kDa, TGF-beta1 compared to vector alone control cells. The ability of endogenous GH to increase TGF-beta1 expression is blocked in EL4 cells by antisense but not sense oligodeoxynucleotides or in cells cultured with antibody to growth hormone (GH). The data suggest that endogenous GH may protect from apoptosis through the IGF-1R receptor while limiting cellular growth through increased expression and activation of TGF-beta1.

The inhibition of apoptosis in EL4 lymphoma cells overexpressing growth hormone.

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Arnold, Robyn E; Weigent, Douglas A

2004-01-01

The antiapoptotic action of exogenous growth hormone (GH) has been reported for several lymphoid cell lines; however, the potential role of endogenous GH in apoptosis has not been thoroughly investigated. This study was designed to investigate the effects of endogenous GH on apoptosis induced by methyl methanesulfonate (MMS) in a T cell lymphoma overexpressing GH (GHo). The results of these experiments have shown that in EL4 lymphoma cells, overexpression of GH sustained viability after exposure to MMS compared to control cells. The extent of DNA fragmentation measured by ladder formation on agarose gels was reduced in GHo cells following treatment with MMS, when compared to control cells. Adding exogenous GH to control cells and treatment of GHo cells with antibodies to GH had no effect on MMS-induced DNA ladder formation. In further studies, DNA microarray analysis suggested a marked decrease in the constitutive expression of bax, BAD, and caspases 3, 8, and 9 in GHo cells compared to controls. In addition, after treatment with MMS, the activities of caspases 2, 3, 6, 8, and 9 were all lower than control in GHo cells. Western blot analysis detected an increase in Bcl-2 while the levels of nuclear factor kappa B (NFkappaB) remained unchanged in GHo cells. Treatment of EL4 cells with antisense deoxyoligonucleotides to GH and specific inhibitors of NFkappaB (SN-50) increased DNA fragmentation. GHo cells show increased levels of phosphorylated Akt and GSK-3, suggesting inactivation of this proapoptotic protein. The results, taken together with our previous data which showed increased nitric oxide formation in GHo cells, suggest a possible mechanism for the antiapoptotic effects of endogenous GH through the production of nitric oxide and support the idea that endogenous GH may play an important role in the survival of lymphocytes exposed to stressful stimuli. Copyright 2004 S. Karger AG, Basel

Pretreatment of low dose radiation reduces radiation-induced apoptosis in mouse lymphoma (EL4) cells.

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Kim, J H; Hyun, S J; Yoon, M Y; Ji, Y H; Cho, C K; Yoo, S Y

1997-06-01

Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose of gamma-rays (0.01 Gy) 4 or 20 hrs prior to high dose gamma-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low and high dose gamma-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRFB), respectively during adaptation period, the period from low dose gamma-ray irradiation to high dose gamma-ray irradiation, was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein and RNA synthesis.

Axl acts as a tumor suppressor by regulating LIGHT expression in T lymphoma

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Young, Kon-Ji; Park, A-Reum; Choi, Ha-Rim; Lee, Hwa-Youn; Kim, Su-Man; Chung, Byung Yeoup; Park, Chul-Hong; Choi, Hyo Jin; Ko, Young-Hyeh; Bai, Hyoung-Woo; Kang, Hyung-Sik

2017-01-01

Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activation of effector immune cells at tumor sites. We observed that mouse EL4 and human Jurkat T lymphoma cells that stably overexpressed Axl also showed high expression of LIGHT. When Jurkat-Axl cells were treated with Gas6, a ligand for Axl, LIGHT expression was upregulated through activation of the PI3K/AKT signaling pathway and transcriptional induction by Sp1. The lytic activity of cytotoxic T lymphocytes and natural killer cells was enhanced by EL4-Axl cells. In addition, tumor volume and growth were markedly reduced due to enhanced apoptotic cell death in EL4-Axl tumor-bearing mice as compared to control mice. We also observed upregulated expression of CCL5 and its receptor, CCR5, and enhanced intratumoral infiltration of cytotoxic T lymphocytes and natural killer cells in EL4-Axl-bearing mice as compared to mock controls. These data strongly suggested that Axl exerts novel tumor suppressor effects by inducing upregulation of LIGHT in the tumor microenvironment of T lymphoma. PMID:28423548

Phospholipase D2 Enhances Epidermal Growth Factor-Induced Akt Activation in EL4 Lymphoma Cells

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Manpreet S. Chahal

2010-07-01

Full Text Available Phospholipase D2 (PLD2 generates phosphatidic acid through hydrolysis of phosphatidylcholine. PLD2 has been shown to play a role in enhancing tumorigenesis. The epidermal growth factor receptor (EGFR can both activate and interact with PLD2. Murine lymphoma EL4 cells lacking endogenous PLD2 present a unique model to elucidate the role of PLD2 in signal transduction. In the current study, we investigated effects of PLD2 on EGF response. Western blotting and RT-PCR were used to establish that both parental cells and PLD2 transfectants express endogenous EGFR. Levels of EGFR protein are increased in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. EGF stimulates proliferation of EL4 cells transfected with active PLD2, but not parental cells or cells transfected with inactive PLD2. EGF-mediated proliferation in cells expressing active PLD2 is dependent on the activities of both the EGFR and the PI3K/Akt pathway, as demonstrated by studies using protein kinase inhibitors. EGF-induced invasion through a synthetic extracellular matrix is enhanced in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. Taken together, the data suggest that PLD2 acts in concert with EGFR to enhance mitogenesis and invasion in lymphoma cells.

Phospholipase D2 Enhances Epidermal Growth Factor-Induced Akt Activation in EL4 Lymphoma Cells.

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Chahal, Manpreet S; Brauner, Daniel J; Meier, Kathryn E

2010-07-02

Phospholipase D2 (PLD2) generates phosphatidic acid through hydrolysis of phosphatidylcholine. PLD2 has been shown to play a role in enhancing tumorigenesis. The epidermal growth factor receptor (EGFR) can both activate and interact with PLD2. Murine lymphoma EL4 cells lacking endogenous PLD2 present a unique model to elucidate the role of PLD2 in signal transduction. In the current study, we investigated effects of PLD2 on EGF response. Western blotting and RT-PCR were used to establish that both parental cells and PLD2 transfectants express endogenous EGFR. Levels of EGFR protein are increased in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. EGF stimulates proliferation of EL4 cells transfected with active PLD2, but not parental cells or cells transfected with inactive PLD2. EGF-mediated proliferation in cells expressing active PLD2 is dependent on the activities of both the EGFR and the PI3K/Akt pathway, as demonstrated by studies using protein kinase inhibitors. EGF-induced invasion through a synthetic extracellular matrix is enhanced in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. Taken together, the data suggest that PLD2 acts in concert with EGFR to enhance mitogenesis and invasion in lymphoma cells.

Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice

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Muto, H; Sakata-Yanagimoto, M; Nagae, G; Shiozawa, Y; Miyake, Y; Yoshida, K; Enami, T; Kamada, Y; Kato, T; Uchida, K; Nanmoku, T; Obara, N; Suzukawa, K; Sanada, M; Nakamura, N; Aburatani, H; Ogawa, S; Chiba, S

2014-01-01

TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30–83%) or peripheral T-cell lymphoma, not otherwise specified (10–49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2 gt/gt ) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans

Immune cells from SR/CR mice induce the regression of established tumors in BALB/c and C57BL/6 mice

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Koch, Janne; Hau, Jann; Pravsgaard Christensen, Jan

2013-01-01

of resistance to EL-4 lymphoma cells and J774A.1 monocyte-macrophage cancer cells. The cancer resistance against S180 sarcoma cells could be transferred to susceptible non-resistant BALB/c mice as well as C57BL/6 mice after depletion of both CD4+/CD8+ leukocytes and B-cells from SR/CR mice. In the responding...

Systemic treatment with n-6 polyunsaturated fatty acids attenuates EL4 thymoma growth and metastasis through enhancing specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines.

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Salem, Mohamed Labib

2005-06-01

Recently, there has been a great interest in the effects of different types of n-6 polyunsaturated acids (n-6 PUFAs) upon the immune system and cancer development. However, the effects of n-6 PUFAs are still controversial and as yet undefined. The present study aimed to investigate the anti-tumor effects of n-6 PUFAs against EL4 thymoma and the associated immune mechanisms. To this, sesame oil, a vegetable oil enriched with n-6 PUFAs, or free linoleic acid (LA) were administered intraperitoneally into C57BL/6 mice before and after challenge with EL4 lymphoma cells. Treatment with either sesame oil or LA attenuated the growth and metastasis of EL4 lymphoma. The anti-tumor effect of LA was superior to that of sesame oil, and associated with an increase in the survival rate of the tumor-bearing mice. In addition, both sesame oil and LA showed dose-dependent anti-lymphoma growth in vitro. Treatment with LA generated significant increases in the anti-lymphoma cytolytic and cytostatic activities of T cells and macrophages, respectively, and enhanced production of IL-2 and IFN-gamma while decreased production of IL-4, IL-6 and IL-10. In summation, the results suggest that n-6 PUFAs, represented by LA, can attenuate EL4 lymphoma growth and metastasis through enhancing the specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines. These findings might be of great importance for a proper design of systemic nourishment with PUFAs emulsions for cancer patients.

RasGRP1 confers the phorbol ester-sensitive phenotype to EL4 lymphoma cells.

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Han, Shujie; Knoepp, Stewart M; Hallman, Mark A; Meier, Kathryn E

2007-01-01

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to the tumor promoter phorbol 12-myristate 13-acetate (PMA). In sensitive EL4 cells, PMA causes robust Erk mitogen-activated protein kinase activation that results in growth arrest. In resistant cells, PMA induces minimal Erk activation, without growth arrest. PMA stimulates IL-2 production in sensitive, but not resistant, cells. The role of RasGRP1, a PMA-activated guanine nucleotide exchange factor for Ras, in EL4 phenotype was examined. Endogenous RasGRP1 protein is expressed at much higher levels in sensitive than in resistant cells. PMA-induced Ras activation is observed in sensitive cells but not in resistant cells lacking Ras-GRP1. PMA induces down-regulation of RasGRP1 protein in sensitive cells but increases RasGRP1 in resistant cells. Transfection of RasGRP1 into resistant cells enhances PMA-induced Erk activation. In the reverse experiment, introduction of small interfering RNA (siRNA) for RasGRP1 suppresses PMA-induced Ras and Erk activations in sensitive cells. Sensitive cells incubated with siRNA for RasGRP1 exhibit the PMA-resistant phenotype, in that they are able to proliferate in the presence of PMA and do not secrete IL-2 when stimulated with PMA. These studies indicate that the PMA-sensitive phenotype, as previously defined for the EL4 cell line, is conferred by endogenous expression of RasGRP1 protein.

Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

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Puebla-Osorio, Nahum; Miyahara, Yasuko; Coimbatore, Sreevidya; Limón-Flores, Alberto Y; Kazimi, Nasser; Ullrich, Stephen E; Zhu, Chengming

2011-01-01

The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. UVB-irradiated p53 +/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19 + , CD5 + , B220 + , IgM + and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. UV-irradiated p53 +/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The

Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

Directory of Open Access Journals (Sweden)

Ullrich Stephen E

2011-01-01

Full Text Available Abstract Background The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. Methods UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. Results UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19 translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. Conclusion UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal

Differential Expression of FAK and Pyk2 in Metastatic and Non-metastatic EL4 Lymphoma Cell Lines

OpenAIRE

Zhang, Zhihong; Knoepp, Stewart M.; Ku, Hsun; Sansbury, Heather M.; Xie, Yuhuan; Chahal, Manpreet S.; Tomlinson, Stephen; Meier, Kathryn E.

2011-01-01

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12-myristate 13-acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk-mediated growth arrest. In resistant cells, PMA induces a low level of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant cells are more adherent to culture substrate than are sensitive cells. In this study, the roles of the protein tyrosine kinases...

Human adipose tissue-derived mesenchymal stem cells inhibit T-cell lymphoma growth in vitro and in vivo.

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Ahn, Jin-Ok; Chae, Ji-Sang; Coh, Ye-Rin; Jung, Woo-Sung; Lee, Hee-Woo; Shin, Il-Seob; Kang, Sung-Keun; Youn, Hwa-Young

2014-09-01

Human mesenchymal stem cells (hMSCs) are thought to be one of the most reliable stem cell sources for a variety of cell therapies. This study investigated the anti-tumor effect of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) on EL4 murine T-cell lymphoma in vitro and in vivo. The growth-inhibitory effect of hAT-MSCs on EL4 tumor cells was evaluated using a WST-1 cell proliferation assay. Cell-cycle arrest and apoptosis were investigated by flow cytometry and western blot. To evaluate an anti-tumor effect of hAT-MSCs on T-cell lymphoma in vivo, CM-DiI-labeled hAT-MSCs were circumtumorally injected in tumor-bearing nude mice, and tumor size was measured. hAT-MSCs inhibited T-cell lymphoma growth by altering cell-cycle progression and inducing apoptosis in vitro. hAT-MSCs inhibited tumor growth in tumor-bearing nude mice and prolonged survival time. Immunofluorescence analysis showed that hAT-MSCs migrated to tumor sites. hAT-MSCs suppress the growth of T-cell lymphoma, suggesting a therapeutic option for T-cell lymphoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Differential immunotoxic effects of ethanol on murine EL-4 lymphoma and normal lymphocytes is mediated through increased ROS production and activation of p38MAPK.

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Premachandran, Sudha; Khan, Nazir M; Thakur, Vikas S; Shukla, Jyoti; Poduval, T B

2012-08-01

Ethanol has been used to achieve thymic depletion in myasthenia gravis patients. Ethanol (95%) has also been used widely in the therapy of many tumors including hepatocellular carcinoma. In light of these findings, we delineated the differential immunotoxic behavior and mechanism of lower concentration of ethanol towards murine EL-4 lymphoma and its normal counterpart lymphocytes. EL-4 lymphoma and normal lymphocytes were cultured with ethanol (0%-5%) for 6 h and cytotoxicity was measured by various methods. EL-4 cells treated with ethanol showed concentration-dependent loss of viability at 2%-5% ethanol concentration and exhibit proliferative arrest at preG1 stage. Acridine-orange and ethidium-bromide staining indicated that ethanol induced death in EL-4 cells, by induction of both apoptosis and necrosis which was further supported by findings of DNA-fragmentation and trypan blue dye exclusion test. However, treatment of lymphocytes with similar concentration of ethanol did not show any death-associated parameters. Furthermore, ethanol induced significantly higher ROS generation in EL-4 cells as compared to lymphocytes and caused PARP cleavage and activation of apoptotic proteins like p53 and Bax, in EL-4 cells and not in normal lymphocytes. In addition, ethanol exposure to EL-4 cells led to phosphorylation of p38MAPK, and upregulation of death receptor Fas (CD95). Taken together, these results suggest that ethanol upto a concentration of 5% caused no significant immunotoxicity towards normal lymphocytes and induced cell death in EL-4 cells via phosphorylation of p38MAPK and regulation of p53 leading to further activation of both extrinsic (Fas) and intrinsic (Bax) apoptotic markers.

Dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro

International Nuclear Information System (INIS)

Liu Shuchun; Lu Zhe; Li Yanbo; Kang Shunai; Gong Shouliang; Zhao Wenju

2008-01-01

Objective: To observe the dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro in order to reveal the possible mechanism of biological effect and adaptive response induced by low dose radiation. Methods: The experiment was divided into D2 (challenging dose), D1 (inductive dose) + D2 and sham-irradiation groups. EL-4 lymphoma cells were irradiated with D1 (75 mGy, 6.25-200.00 mGy·mm -1 ) and D2(1.5 Gy, 287 mGy·min -1 ), the time interval between D1 and D2 was 6 h. The percentage of apoptosis and each cell cycle phase were measured with flow cytometry. Results: When the dose rates of D1 were 6.25-50.00 mGy·min -1 , the percentages of apoptosis in the D1 + D2 group were significantly lower than those in the D2 group (P 0 /G 1 phase cells decreased significantly (P -1 , D2 is 1.5 Gy (287 mGy·min -1 ), and the time interval between D1 and D2 is 6 h, the adaptive response of apoptosis and cell cycle progression in EL-4 lymphoma cells in vitro could be induced. (authors)

Lymphoma induction by heterocyclic amines in Eu-pim-1 transgenic mice

DEFF Research Database (Denmark)

Sørensen, Ilona Kryspin; Kristiansen, E.; Mortensen, Alicja

1997-01-01

The usefulness of transgenic E mu-pim-1 mice bearing in their genome the pim-1 oncogene supplemented with an upstream immunoglobulin enhancer and a downstream murine leukaemia virus long terminal repeat, as sensitive test organisms was studied in two short-term carcinogenicity studies. The mice...... to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver, lung and forestomach carcinogen in mice. We found that transgenic E mu-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to IQ treatment. PhIP feeding of E mu-pim-1 mice...... not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E mu-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males...

Adaptive response of apoptosis in EL-4 lymphoma cells induced by low dose radiation and its mechanism

International Nuclear Information System (INIS)

Liu Shuchun; Gong Pingsheng; Wang Zhicheng; Sun Liguang; Gong Shouliang

2008-01-01

EL-4 lymphoma cells were irradiated with the inductive doses (D1: 25-200 mGy, dose rate: 12.5mGy/min) and the challenging dose (D2:0.5-3.0 Gy, dose rate: 287 mGy/min), and the time interval between D1 and D2 was 6 h. The percentage of cell apoptosis and the expressive levels of cell apoptosis-associated gene pro- reins were measured with flow cytometry. The percentages of cell apoptosis in the D1 + D2 group with 25-100 mGy (D1) and 1.5 Gy (D2) or 75 mGy (D1) and 25-200 mGy (D2) were significantly lower than those in the D2 group. As compared with the D2 group, the positive percentage of cell Bcl-2 protein expression increased somewhat, and Bax decreased significantly, meanwhile the ratio of Bcl-2/Bax increased significantly and p53 decreased somewhat in D1 + D2 group with 25-100 mGy (D1) and 1.5 Gy (D2). The adaptive response of EL-4 lymphoma cell apoptosis could be induced by pre-irradiation with 25-100 mGy. Meantime, the expressive levels of cell apoptosis-associated gene Bcl-2, Bax and p53 proteins could change accordingly with cell apoptosis. These gene protein changes may play an important role in the mechanism of the adaptive response. (authors)

Cyclosporine promotes the induction of thymic lymphomas in C57BL/6 mice initiated by a single dose of γ-radiation

International Nuclear Information System (INIS)

Yabu, Koji; Warty, V.S.; Gorelik, E.; Shinozuka, Hisashi

1991-01-01

We previously demonstrated that a single dose of γ-radiation (350 rads) was able to induce thymic lymphomas in C57BL mice when followed by promoting treatment with oral cyclosporine (CsA), a non-genotoxic immunosuppressant. We have now tested the efficacy of various doses of γ-radiation as an initiator of CsA promotion of the induction of thymic lymphomas in male C57BL mice. The effects of oral CsA on the splenic natural killer (NK) cell activity of non-irradiated and irradiated (400 rads, 1X) mice were tested by the standard 51 Cr release assays against YAC-1 cells. The cumulative incidence of thymic lymphomas induced by a single dose of γ-radiation at 100, 200, 400 and 600 rads were 10, 25, 63 and 75% respectively, after 42 weeks of CsA promotion. The splenic NK cell activity in non-irradiated mice given CsA for 4 weeks was twice as high as that in the control mice. CsA inhibited poly I:C-induced augmentation of the splenic NK cell activity. In mice given a single dose (400 rads) of γ-radiation and CsA for 4 weeks, a similar but reduced enhancement of the splenic NK cell activity as seen in non-irradiated mice was observed. These results indicate that the efficacy of CsA promotion in the induction of thymic lymphomas is dependent on the initiating doses of γ-radiation, and that CsA enhances host splenic NK cell activity during the early stage of tumor promotion. (author)

Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone.

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Farmer, John T; Weigent, Douglas A

2007-01-01

In the present study, we report the upregulation of functional IGF-2Rs in cells overexpressing growth hormone (GH). EL4 lymphoma cells stably transfected with an rGH cDNA overexpression vector (GHo) exhibited an increase in the binding of (125)I-IGF-2 with no change in the binding affinity compared to vector alone controls. An increase in the expression of the insulin-like growth factor-2 receptor (IGF-2R) in cells overexpressing GH was confirmed by Western blot analysis and IGF-2R promoter luciferase assays. EL4 cells produce insulin-like growth factor-2 (IGF-2) as detected by the reverse transcription-polymerase chain reaction (RT-PCR); however, no IGF-2 protein was detected by Western analysis. The increase in the expression of the IGF-2R resulted in greater levels of IGF-2 uptake in GHo cells compared to vector alone controls. The data suggest that one of the consequences of the overexpression of GH is an increase in the expression of the IGF-2R.

Myc contribution to γ-ray induced thymic lymphomas in mice of different genetic predispositions

International Nuclear Information System (INIS)

Sato, Toshihiro

2008-01-01

Myc gene has been suggested to be one of radiation targets in early genesis of γ ray-induced thymic lymphoma where Myc trisomy often occurs, and Myc activation results in p53 activation and apoptosis. The purpose of this study is to see the effects of radiation and mutation on Myc activation in the mouse. The lymphoma was induced by a single exposure of 3 Gy γ ray in BALB/c Bcl11b/Rit+/- and MSM p53-/- mice at 4 weeks after birth and by 4 weekly exposures of 2.5 Gy in p53+/- mouse. Genetic allele analysis for trisomy identification in the lymphoma was done by quantitative PCR using brain DNA as a control. Myc trisomy was found in the lymphoma of p53+/- mouse in 62% (23/37 animals) and of p53+/+, 66% (23/25), a similar frequency, suggesting that the target of radiation was not only the Myc activation. In addition, Myc trisomy frequency was 15% (4/27) in the lymphoma of Bcl11b+/+p53+/- and 36% (9/25), in heterozygote Bcl11b+/-. This finding suggested that the functional failure of Bcl11b reduced the contribution of Myc trisomy to the genesis. It was concluded that contribution of Myc trisomy to genesis of the lymphoma was dependent on genetic predisposition, and Myc-activated-, Bcl11b/Rit1-signal pathways played a parallel role in the genesis. (R.T.)

Baicalein induces cell death in murine T cell lymphoma via inhibition of thioredoxin system.

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Patwardhan, Raghavendra S; Pal, Debojyoti; Checker, Rahul; Sharma, Deepak; Sandur, Santosh K

2017-10-01

We have earlier demonstrated the radioprotective potential of baicalein using murine splenic lymphocytes. Here, we have studied the effect of baicalein on murine T cell lymphoma EL4 cells and investigated the underlying mechanism of action. We observed that baicalein induced a dose dependent cell death in EL4 cells in vitro and significantly reduced the frequency of cancer stem cells. Previously, we have reported that murine and human T cell lymphoma cells have increased oxidative stress tolerance capacity due to active thioredoxin system. Hence, we monitored the effect of baicalein on thioredoxin system in EL4 cells. Docking studies revealed that baicalein could bind to the active site of thioredoxin reductase. Baicalein treatment led to significant reduction in the activity of thioredoxin reductase and nuclear levels of thioredoxin-1 thereby increasing ASK1 levels and caspase-3 activity. Interestingly, CRISPR-Cas9 based knock-out of ASK1 or over-expression of thioredoxin-1 abolished anti-tumor effects of baicalein in EL4 cells. Further, baicalein administration significantly reduced intra-peritoneal tumor burden of EL4 cells in C57BL/6 mice. Thus, our study describes anti-tumor effects of baicalein in EL4 cells via inhibition of thioredoxin system. Copyright © 2017 Elsevier Ltd. All rights reserved.

Reduction of Myeloid-derived Suppressor Cells and Lymphoma Growth by a Natural Triterpenoid

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Radwan, Faisal F. Y.; Hossain, Azim; God, Jason M.; Leaphart, Nathan; Elvington, Michelle; Nagarkatti, Mitzi; Tomlinson, Stephen; Haque, Azizul

2016-01-01

Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A’s anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen presentation and CD4+ T cell recognition of lymphoma in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. PMID:25142864

Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid.

Science.gov (United States)

Radwan, Faisal F Y; Hossain, Azim; God, Jason M; Leaphart, Nathan; Elvington, Michelle; Nagarkatti, Mitzi; Tomlinson, Stephen; Haque, Azizul

2015-01-01

Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A's anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen (Ag) presentation and CD4+ T cell recognition of lymphoma cells in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. © 2014 Wiley Periodicals, Inc.

Establishment of imageable model of T-cell lymphoma growing in syngenic mice

Czech Academy of Sciences Publication Activity Database

Větvička, David; Hovorka, Ondřej; Kovář, Lubomír; Říhová, Blanka

2009-01-01

Roč. 29, č. 11 (2009), s. 4513-4518 ISSN 0250-7005 R&D Projects: GA AV ČR IAA400200702; GA AV ČR KAN200200651; GA ČR GD310/08/H077 Institutional research plan: CEZ:AV0Z50200510 Keywords : Imageable model * EL-4 T- cell lymphoma * whole body imaging Subject RIV: EC - Immunology Impact factor: 1.428, year: 2009

Farnesyl transferase inhibitors induce extended remissions in transgenic mice with mature B cell lymphomas

Directory of Open Access Journals (Sweden)

Refaeli Yosef

2008-05-01

Full Text Available Abstract Background We have used a mouse model based on overexpression of c-Myc in B cells genetically engineered to be self-reactive to test the hypothesis that farnesyl transferase inhibitors (FTIs can effectively treat mature B cell lymphomas. FTIs are undergoing clinical trials to treat both lymphoid and non-lymphoid malignancies and we wished to obtain evidence to support the inclusion of B cell lymphomas in future trials. Results We report that two FTIs, L-744,832 and SCH66336, blocked the growth of mature B cell lymphoma cells in vitro and in vivo. The FTI treatment affected the proliferation and survival of the transformed B cells to a greater extent than naïve B cells stimulated with antigen. In syngeneic mice transplanted with the transgenic lymphoma cells, L-744,832 treatment prevented the growth of the tumor cells and the morbidity associated with the resulting lymphoma progression. Tumors that arose from transplantation of the lymphoma cells regressed with as little as three days of treatment with L-744,832 or SCH66336. Treatment of these established lymphomas with L-744,832 for seven days led to long-term remission of the disease in approximately 25% of animals. Conclusion FTI treatment can block the proliferation and survival of self-reactive transformed B cells that overexpress Myc. In mice transplanted with mature B cell lymphomas, we found that FTI treatment led to regression of disease. FTIs warrant further consideration as therapeutic agents for mature B cell lymphomas and other lymphoid tumors.

Radiation leukemia virus and x-irradiation induce in C57BL/6 mice two distinct T-cell neoplasms: a growth factor-dependent lymphoma and a growth factor-independent lymphoma

International Nuclear Information System (INIS)

Haas, Martin; Rothenberg, Ellen; Bogart, M.H.; Jones, O.W.

1987-01-01

Two different classes of neoplastic T cells were isolated from radiation leukemia virus (RadLV)-inoculated and from X-ray-treated C57BL/6 mice. One consisted of growth factor-dependent T-cell lymphoma (FD-TCL) lines which were established from the spleens and thymuses of treated mice within a day of lymphoma detection. Non-thymic, factor-dependent TCL cells produced interleukin-2 upon lectin stimulation, and were autostimulatory because they secreted growth factor(s) constitutively. In vivo, FD-TCL cells that were injected intraperitoneally or intravenously homed to the spleen, proliferated in it and killed the injected mice. The isolation and study of FD-TCL cells was facilitated by their cultivation on stromal hematopoietic monolayers in supplemented ''lymphocyte medium'', until an autostimulating, self-sustaining concentration of FD-TCL cells was obtained. FD-TCL cells could not be grown from lymphoid tissue of normal, control mice. In contrast, T-cell lymphoma (TCL) lines, which were established from virus-induced thymomas which had been kept in situ for 4-6 weeks after detection, consisted of factor-independent cells that possessed an aneuploid karyotype. The phenotypic markers of TCL cells differed from those of FD-TCL cells, suggesting heterogeneity in the stages of differentiation at which cells can give rise to growth factor-independent (TCL) and to growth factor-dependent (FD-TCL) lines. (author)

The inhibition of superoxide production in EL4 lymphoma cells overexpressing growth hormone.

Science.gov (United States)

Arnold, Robyn E; Weigent, Douglas A

2003-05-01

A substantial body of research exists to support the production of growth hormone by cells of the immune system. However, the function and mechanism of action of lymphocyte-derived growth hormone remain largely unelucidated. Since, it has been found that exogenous growth hormone (GH) primes neutrophils for the production of reactive oxygen intermediates (ROI) and in particular superoxide (O2-), we investigated the role of GH on the production of O2- in T cells. Furthermore, we examined whether endogenous and exogenous GH act similarly. Our studies show that overexpression of GH in EL4, a T-cell lymphoma cell line, results in a decrease in the production of O2- compared to control cells, as detected using the fluorescent dye, dihydroethidium. O2- production in control cells was not affected by treatment with inhibitors of xanthine oxidase or a non-specific NADPH-oxidase inhibitor. However, treatment with diallyl sulfide, an inhibitor of cytochrome P450 2E1 mimicked the reduction in O2- production seen in cells overexpressing GH. Although no significant change could be detected in CYP2E1 protein levels, CYP2E1 activity was found to be greater in control EL4 than in cells overexpressing GH. Both the decrease in O2- production and the lower CYP2E1 activity in GH overexpressing cells could be abrogated by treatment with N(G)-monomethyl-L-arginine, an inhibitor of nitric oxide synthase. The overexpression of GH protects cells from apoptosis induced by isoniazid, a CYP2E1 inducer, suggesting a role for nitric oxide as a mediator in the regulation of xenobiotic metabolism and apoptosis-protection by lymphocyte GH.

Integrated modulation of phorbol ester-induced Raf activation in EL4 lymphoma cells.

Science.gov (United States)

Han, Shujie; Meier, Kathryn E

2009-05-01

The EL4 murine lymphoma cell line exists in variant phenotypes that differ with respect to responses to the tumor promoter phorbol 12-myristate 13-acetate (PMA1). Previous work showed that "PMA-sensitive" cells, characterized by a high magnitude of PMA-induced Erk activation, express RasGRP, a phorbol ester receptor that directly activates Ras. In "PMA-resistant" and "intermediate" EL4 cell lines, PMA induces Erk activation to lesser extents, but with a greater response in intermediate cells. In the current study, these cell lines were used to examine mechanisms of Raf-1 modulation. Phospho-specific antibodies were utilized to define patterns and kinetics of Raf-1 phosphorylation on several sites. Further studies showed that Akt is constitutively activated to a greater extent in PMA-resistant than in PMA-sensitive cells, and also to a greater extent in resistant than intermediate cells. Akt negatively regulates Raf-1 activation (Ser259), partially explaining the difference between resistant and intermediate cells. Erk activation exerts negative feedback on Raf-1 (Ser289/296/301), thus resulting in earlier termination of the signal in cells with a higher level of Erk activation. RKIP, a Raf inhibitory protein, is expressed at higher levels in resistant cells than in sensitive or intermediate cells. Knockdown of RKIP increases Erk activation and also negative feedback. In conclusion, this study delineates Raf-1 phosphorylation events occurring in response to PMA in cell lines with different extents of Erk activation. Variations in the levels of expression and activation of multiple signaling proteins work in an integrated fashion to modulate the extent and duration of Erk activation.

Transplantability of human lymphoid cell line, lymphoma, and leukemia in splenectomized and/or irradiated nude mice

International Nuclear Information System (INIS)

Watanabe, S.; Shimosato, Y.; Kuroki, M.; Sato, Y.; Nakajima, T.

1980-01-01

The effects of splenectomy and/or whole-body irradiation of nude mice before xenotransplantation of lymphoid cell lines, lymphoma, and leukemia were studied. Transplantation after whole-body irradiation resulted in the increased ''take'' rate of three cultured cell lines (two of T-cell-derived acute lymphocytic leukemia and one of B-cell derived acute lymphocytic leukemia) and in the tumorous growth of Burkitt-derived Raji and spontaneously transformed lymphoblastoid cell lines. With splenectomy plus irradiation as a pretreatment, tumorous growth occurred in four other cell lines which were not transplantable after irradiation only (two cell lines of Epstein-Barr virus-transformed cord blood cells and one each of null acute lymphocytic leukemia and nodular lymphoma-derived cell lines). Direct transplantation of leukemia and lymphoma cells into the pretreated mice was successful in 7 of 24 cases (29%). B-cell-derived diffuse large lymphoid lymphoma was transplantable in three of seven cases (43%). However, lymphoma and leukemia of peripheral T-cell origin was difficult to transplant even with pretreatment, and only one pleomorphic T-cell lymphoma grew to a significant size (2 cm). One tumor each of B-cell-derived diffuse large lymphoid and T-cell diffuse lymphoblastic lymphoma became transplantable

Inactivation of the small GTP binding protein Rho induces multinucleate cell formation and apoptosis in murine T lymphoma EL4.

Science.gov (United States)

Moorman, J P; Bobak, D A; Hahn, C S

1996-06-01

The small G-protein Rho regulates the actin microfilament-dependent cytoskeleton. Exoenzyme C3 of Clostridium botulinum ADP-ribosylates Rho at Asn41, a modification that functionally inactivates Rho. Using a Sindbis virus-based transient gene expression system, we studied the role of Rho in murine EL4 T lymphoma cells. We generated a double subgenomic infectious Sindbis virus (dsSIN:C3) recombinant which expressed C3 in >95% of EL4 cells. This intracellular C3 resulted in modification and inactivation of virtually all endogenous Rho. dsSIN:C3 infection led to the formation of multinucleate cells, likely by inhibiting the actin microfilament-dependent step of cytokinesis. Intriguingly, in spite of the inhibition of cytokinesis, karyokinesis continued, with the result that cells containing a nuclear DNA content as high as 16N (eight nuclei) were observed. In addition, dsSIN:C3-mediated inactivation of Rho was a potent activator of apoptosis in EL4 cells. To discern whether the formation of multinucleate cells was responsible for the activation of apoptosis, 5-fluorouracil (5-FUra) was used to induce cell cycle arrest. As expected, EL4 cells treated with 5-FUra were prevented from forming multinucleate cells upon infection with dsSIN:C3. dsSIN:C3 infection, however, still caused marked apoptosis in 5-FUra-treated cells, indicating that this activation of apoptosis was independent of multinucleate cell formation.

Study on biodistribution and imaging of radioiodinated antisense oligonucleotides in nude mice bearing human lymphoma

International Nuclear Information System (INIS)

Wang, R.F.; Shen, J.; Zhang, C.L.; Liu, M.; Guo, F.Q.

2005-01-01

The incidence of sporadic lymphoma has risen due to an increase in immunosuppressed patients, particularly those with human immunodeficiency virus (HIV) infection. Sometimes suspect lymphoma has an undetectable location and we can not get the pathological specimen. Management of lymphoma is also difficult because the persistence of a significant number of residual tumor cells after intensive treatment. These relative failures can be attributed to make us choose this study for opening a new diagnostic and therapeutic field of lymphoma from molecular level. Immunoglobulin (Ig) heavy chain framework region (FR) of V1 family have been verified to be a major determinant of malignant phenotype of V1 family B-cell lymphoma. Most of targets for tumor antisense therapy study are protooncogenes, such as c-myc, bc1-2, which are broad -spectrum tumor imaging agents. The aim of this study was to investigate the possibility of using radioiodine labeled FR antisense oligonucleotides (ASONs) as an imaging agent or antisense therapeutic radiopharmaceutical in lymphoma. A 18-mer partial phosphorothioate oligonucleotide sequence was synthesized and grafted in 5 ' with a tyramine group which was further labeled with 125 I or 131 I using the chloramine T method. Normal CD-1 mice were injected via a tail vein with 148 kBq of 125 I-FR-ASON (2∼3 μ g). Animals were sacrificed at 1, 2, 4 and 24 h and tissue samples were studied. Liposome-mediated 3.33 MBq of 131 I-FR-ASON (7 ∼ 9μ g) was injected intratumorally into tumor-bearing BALB/c mice (6 weeks after inoculation of 10 7 Namalwa cells) meanwhile liposome-mediated 131 I labeled sense oligonucleotides served as controls. Biodistribution was monitored by sequential scintigraphy and organ radioactivity measurement 24 h after injection. The percentage of the injected dose per gram (%ID/g) of tumor and tumor/ non-tumor tissue ratios (T/NT) were calculated for each group of mice and the difference between two groups was assessed. The 5

[Relationship between sensitivity of tumor cells to chemotherapeutic agent in vivo and in vitro: experiment with mouse lymphoma cells].

Science.gov (United States)

Li, Chuan-gang; Li, Mo-lin; Shu, Xiao-hong; Jia, Yu-jie; Liu, Yong-ji; Li, Ming

2007-06-12

To study the relationship of the sensitivity of tumor cells to chemotherapeutic agent between in vivo and in vitro. Mouse lymphoma cells of the line E14 were cultured and melphalan resistant EL4 cell line (EL4/melphalan) was established by culturing EL4 cells with continuous low-concentration and intermittent gradually-increasing-concentration of melphalan in vitro. MTT assay was used to evaluate the drug sensitivity and the resistance index of the EL4/melphalan cells to melphalan was calculated. EL4/melphalan and EL4 cells of the concentration of 5 x 10(8)/L were inoculated separately into 20 C57BL/6 mice subcutaneously. 12 days later, the EL4 and EL4/melphalan tumor-bearing mice were randomly divided into 2 groups respectively, 5 mice in each group. Treatment groups were given 7.5 mg/kg melphalan intraperitoneally, and control groups were given the same volume of normal saline. The tumor size was observed every other day. Compared with the EL4 cells, the EL4/melphalan cells had no obvious changes morphologically. They could grow in RPMI 1640 medium containing 5 mg/ml melphalan. The resistance index was 2.87 against melphalan. After the treatment of melphalan of the dose 7.5 mg/kg, the tumor sizes of the treatment groups and control groups inoculated with both EL4 cells and the EL4/melphalan cells gradually decreased at the similar speed, and about one week later all tumors disappeared. However, the tumors of the control groups grew progressively and all the mice died at last. The chemotherapeutic effects of tumors in vivo have nothing to do with the effects of the chemotherapeutic agents on tumor cells in vitro. The tumor cells resistant to melphalan in vitro remain sensitive to the drug in vivo.

RRR-alpha-tocopheryl succinate inhibits EL4 thymic lymphoma cell growth by inducing apoptosis and DNA synthesis arrest.

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Yu, W; Sanders, B G; Kline, K

1997-01-01

RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) treatment of murine EL4 T lymphoma cells induced the cells to undergo apoptosis. After 48 hours of VES treatment at 20 micrograms/ml, 95% of cells were apoptotic. Evidence for the induction of apoptosis by VES treatments is based on staining of DNA for detection of chromatin condensation/fragmentation, two-color flow-cytometric analyses of DNA content, and end-labeled DNA and electrophoretic analyses for detection of DNA ladder formation. VES-treated EL4 cells were blocked in the G1 cell cycle phase; however, apoptotic cells came from all cell cycle phases. Analyses of mRNA expression of genes involved in apoptosis revealed decreased c-myc and increased bcl-2, c-fos, and c-jun mRNAs within three to six hours after treatment. Western analyses showed increased c-Jun, c-Fos, and Bcl-2 protein levels. Electrophoretic mobility shift assays showed increased AP-1 binding at 6, 12, and 24 hours after treatment and decreased c-Myc binding after 12 and 24 hours of VES treatment. Treatments of EL4 cells with VES+RRR-alpha-to-copherol reduced apoptosis without effecting DNA synthesis arrest. Treatments of EL4 cells with VES+rac-6-hydroxyl-2, 5,7,8-tetramethyl-chroman-2-carboxylic acid, butylated hydroxytoluene, or butylated hydroxyanisole had no effect on apoptosis or DNA synthesis arrest caused by VES treatments. Analyses of bcl-2, c-myc, c-jun, and c-fos mRNA levels in cells receiving VES + RRR-alpha-tocopherol treatments showed no change from cells receiving VES treatments alone, implying that these changes are correlated with VES treatments but are not causal for apoptosis. However, treatments with VES + RRR-alpha-tocopherol decreased AP-1 binding to consensus DNA oligomer, suggesting AP-1 involvement in apoptosis induced by VES treatments.

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice.

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Zhong, Y; Jiang, L; Hiai, H; Toyokuni, S; Yamada, Y

2007-10-18

LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor 1alpha promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavy-chain gene rearrangement analyses. Mammalian two-hybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment

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Nicol B.M.

2002-01-01

Full Text Available Sialic acid changes in Dalton's lymphoma cells and other tissues of 10-12-week-old Swiss albino mice were investigated in relation to tumour growth in vivo and following cyclophosphamide (ip, 200 mg/kg body weight or cisplatin (ip, 8 mg/kg body weight treatment. Three to four animals of both sexes were used in each experimental group. The sialic acid level of tumour cells (0.88 µmol/g increased with tumour progression (1.44-1.59 µmol/g; P<=0.05 in mice. Sialic acid concentration in other tissues (liver, kidney, testes and brain also increased (~40, 10, 30 and 58%, respectively in the tumour-bearing hosts as compared with that in the respective tissues of normal mice. In vivo cyclophosphamide or cisplatin treatment resulted in an overall decrease of sialic acid contents in the tissues. Cyclophosphamide was more efficient in lowering tissue sialic acid than cisplatin (P<=0.01, ANOVA. It is suggested that sialic acid residues could be an important factor contributing to the manifestation of malignant properties in cancer cells in general and Dalton's lymphoma cells in particular. A significant decrease in the sialic acid content of Dalton's lymphoma cells after cisplatin or cyclophosphamide treatment may bring about specific changes in tumour cells which could be associated with tumour regression.

Molecular characterization of non-thymic lymphomas in mice exposed to continuous low-dose-rate g-ray irradiation

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Takabatake, T.; Fujikawa, K.; Nakamura, S.; Tanaka, S.; Tanaka, I.; Tanaka-Braga III, I.; Sunaga, Y.; Ichinoche, K.; Sato, F.; Tanaka, K.; Matsumoto, T.

2004-01-01

To investigate the effects of continuous low-dose-rate irradiation on life span and neoplasm incidence, SPE B6C3 F1 mice were irradiated with 137Cs-ray at dose-rates of 20, 1 and 0.05 mGy/day with accumulated doses equivalent to 8000, 40 and 20 mGy, respectively. Examination of a total of 3,000 irradiated and 1,000 non-irradiated control mice showed that the life spans of the both sexes irradiated at 20 mGy/day, respectively. Examination of a total of 3,000 irradiated and 1,000 non-irradiated control mice showed that the life spans of the both sexes irradiated at 20 mGy/day were significantly shorter than that of the non-irradiated group. No significant difference in the cause of death and mortality rates was found between the groups. However, non-thymic lymphomas, the most common lethal neoplasm, showed a tendency to develop at an earlier age in mice irradiated with 20 mGy/day, regardless of sex. to obtain clues on the molecular mechanisms underlying the earlier development of non-thymic lymphomas in 20 mGy/day irradiated group, detailed molecular characterizations of non-thymic lymphomas with respect to B-cell or T-cell origin was done by detecting rearrangements in immunoglobulin heavy gene and in T-cell receptor b-and g chain genes by Southem hybridization method. to determine whether the early development of non-thymic lymphomas in 20 mGy/day irradiated group is associated wi the any recurrent chromosomal imbalance such as deletions and amplifications, the genome-wide scanning is also currently in progress by both LOH and array CGH methods. Present data obtained by LOH method show that deletions in parts of chromosomes 11 and 12 were more frequent than in chromosomes 2, 4 and 14 in both the non-irradiated control and 20 mGy/day irradiated groups. this work is supported by grants from Aomori Prefecture, Japan. (Author)

Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice

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Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.; Yan, Mingshan

2009-01-01

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin's lymphoma xenografts.

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Paola Secchiero

Full Text Available BACKGROUND: Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL, significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM mesenchymal stem cells (MSC on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL. METHODOLOGY/PRINCIPAL FINDINGS: The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV(- Burkitt-type BJAB, median survival = 46 days and an aggressive (EBV(+ B lymphoblastoid SKW6.4, median survival = 27 days behavior in nude-SCID mice. Intra-peritoneal (i.p. injection of MSC (4 days after i.p. injection of lymphoma cells significantly increased the overall survival at an optimal MSC:lymphoma ratio of 1:10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days. Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.

Studies on a transplantable C57BL/6 mouse lymphoma

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Kendall, C.E.

1977-01-01

A C57BL/6 mouse lymphoma was demonstrated to be of T cell origin by treating the lymphoma cells with anti-Thy 1.2 antisera in a complement-dependent cytotoxicity test. The lymphoma's growth pattern was described using flow microfluorometric determinations and spleen weight progression. C-type particles were identified in electron micrographs of the lymphoma. C57BL/6 mice were immunized against the lymphoma by injecting x-ray inactivated lymphoma cells into the mice. Protection of immunized mice against live lymphoma cells demonstrated tumor antigens on the lymphoma cells. The success of immunization was found to depend on: route of injection, antigen dosage, state of the antigen, number of injections and the vaccination-challenge interval. Attempts were made to passively transfer immunity from immunized C57BL/6 mice which had survived lymphoma challenge to non-treated, syngeneic mice. The route of immunization in the donors influenced the success of passively transferred immunity in the recipients. Serum from days 1 to 3 and days 11 to death (day 17) had an enhancing effect on lymphoma growth. However, sera from days 5 to 9 retarded lymphoma growth. The C57BL/6 lymphoma cells were injected into rabbits and other strains of mice to demonstrate tumor specificity. The lymphoma did not grow in rabbits and only grew in one mouse strain. This strain had the same major histocompatibility loci as C57BL/6 mice. Crosses were made between C57BL/6 mice and a resistant strain of mice (DBA/2 mice). The F 1 hybrids were found to be less susceptible to the lymphoma than the C57BL/6 strain. Sublethal x-irradiation of the F 1 mice decreased its ability to resist the C57BL/6 lymphoma. Immunization with x-ray inactivated C57BL/6 lymphoma cells increased survival after challenge with lymphoma in the F 1 mice

In vivo imaging of T cell lymphoma infiltration process at the colon.

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Ueda, Yoshibumi; Ishiwata, Toshiyuki; Shinji, Seiichi; Arai, Tomio; Matsuda, Yoko; Aida, Junko; Sugimoto, Naotoshi; Okazaki, Toshiro; Kikuta, Junichi; Ishii, Masaru; Sato, Moritoshi

2018-03-05

The infiltration and proliferation of cancer cells in the secondary organs are of great interest, since they contribute to cancer metastasis. However, cancer cell dynamics in the secondary organs have not been elucidated at single-cell resolution. In the present study, we established an in vivo model using two-photon microscopy to observe how infiltrating cancer cells form assemblages from single T-cell lymphomas, EL4 cells, in the secondary organs. Using this model, after inoculation of EL4 cells in mice, we discovered that single EL4 cells infiltrated into the colon. In the early stage, sporadic elongated EL4 cells became lodged in small blood vessels. Real-time imaging revealed that, whereas more than 70% of EL4 cells did not move during a 1-hour observation, other EL4 cells irregularly moved even in small vessels and dynamically changed shape upon interacting with other cells. In the late stages, EL4 cells formed small nodules composed of several EL4 cells in blood vessels as well as crypts, suggesting the existence of diverse mechanisms of nodule formation. The present in vivo imaging system is instrumental to dissect cancer cell dynamics during metastasis in other organs at the single-cell level.

Interferon-γ Promotes Inflammation and Development of T-Cell Lymphoma in HTLV-1 bZIP Factor Transgenic Mice.

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Yu Mitagami

2015-08-01

Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is an etiological agent of several inflammatory diseases and a T-cell malignancy, adult T-cell leukemia (ATL. HTLV-1 bZIP factor (HBZ is the only viral gene that is constitutively expressed in HTLV-1-infected cells, and it has multiple functions on T-cell signaling pathways. HBZ has important roles in HTLV-1-mediated pathogenesis, since HBZ transgenic (HBZ-Tg mice develop systemic inflammation and T-cell lymphomas, which are similar phenotypes to HTLV-1-associated diseases. We showed previously that in HBZ-Tg mice, HBZ causes unstable Foxp3 expression, leading to an increase in regulatory T cells (Tregs and the consequent induction of IFN-γ-producing cells, which in turn leads to the development of inflammation in the mice. In this study, we show that the severity of inflammation is correlated with the development of lymphomas in HBZ-Tg mice, suggesting that HBZ-mediated inflammation is closely linked to oncogenesis in CD4+ T cells. In addition, we found that IFN-γ-producing cells enhance HBZ-mediated inflammation, since knocking out IFN-γ significantly reduced the incidence of dermatitis as well as lymphoma. Recent studies show the critical roles of the intestinal microbiota in the development of Tregs in vivo. We found that even germ-free HBZ-Tg mice still had an increased number of Tregs and IFN-γ-producing cells, and developed dermatitis, indicating that an intrinsic activity of HBZ evokes aberrant T-cell differentiation and consequently causes inflammation. These results show that immunomodulation by HBZ is implicated in both inflammation and oncogenesis, and suggest a causal connection between HTLV-1-associated inflammation and ATL.

Analyses of susceptibility to radiation-induced tumors: Prkdc, a candidate modifier of lymphomas

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Mori, Nobuko; Okumoto, Masaaki; Nakao, Ren

2003-01-01

BALB/cHeA (BALB/c) mice are susceptible to radiation-induced lymphomas, while STS/A (STS) mice are resistant. To analyze the difference in susceptibility between these two strains of mice, we have performed 3 independent studies: 1) mapping of apoptosis susceptibility gene Rapopl (chromosome 16) and identification of Prkdc as a candidate modifier of apoptosis as well as lymphomas, 2) analysis of congenic lines for Lyr, a gene responsible for the lymphoma resistance of STS mice on chromosome 4, 3) genetic analyses of lymphoma susceptibility using a backcross [(BALB/c x STS)F 1 x STS]. Analysis of Rapopl congenic lines indicated a minor contribution of the STS allele at the Rapopl (Prkdc) locus to the lymphoma resistance of STS mice. On the other hand, homozygous STS alleles at Lyr had a substantial, but less potent, effect on radiation lymphomagenesis. Furthermore, there was no single marker where the potent resistance of the STS mice was achieved with the homozygous STS alleles. These results suggest potential involvement of another loci in the resistance of STS mice. (author)

Mtf-1 lymphoma-susceptibility locus affects retention of large thymocytes with high ROS levels in mice after γ-irradiation

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Maruyama, Masaki; Yamamoto, Takashi; Kohara, Yuki; Katsuragi, Yoshinori; Mishima, Yukio; Aoyagi, Yutaka; Kominami, Ryo

2007-01-01

Mouse strains exhibit different susceptibilities to γ-ray-induced thymic lymphomas. Our previous study identified Mtf-1 (metal responsive transcription factor-1) as a candidate susceptibility gene, which is involved in the radiation-induced signaling pathway that regulates the cellular reactive oxygen species (ROS). To reveal the mechanism for the increased susceptibility conferred by Mtf-1 locus, we examined early effects of γ-ray on ROS levels in vivo and its difference between Mtf-1 susceptible and resistant congenic mice. Here, we show the detection of clonally growing thymocytes at 4 weeks after irradiation, indicating the start of clonal expansion at a very early stage. We also show that large thymocytes with higher ROS levels and a proliferation capacity were more numerous in the Mtf-1 susceptible mice than the resistant mice when examined at 7 days after irradiation, although such tendency was not found in mice lacking one allele of Bcl11b tumor suppressor gene. This high retention of the large thymocytes, at a high risk for ROS-induced mutation, is a compensatory proliferation and regeneration response to depletion of the thymocytes after irradiation and the response is likely to augment the development of prelymphoma cells leading to thymic lymphomas

GRANULOCYTE INFILTRATION AND EXPRESSION OF THE PRO-ANGIOGENIC BV8 PROTEIN IN EXPERIMENTAL EL4 AND LEWIS LUNG CARCINOMA TUMORS.

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Jiang, Kan; Kwak, Hyeongil; Tosato, Giovanna

2013-01-18

Although Vascular Endothelial Growth Factor (VEGF)-targeted therapies have shown efficacy in the treatment of certain advanced cancers, benefits to patients have been modest, which is attributed to tumor resistance to VEGF neutralization. Recent efforts to identify new targets to inhibit tumor angiogenesis have identified Bv8 (prokineticin 2), a myeloid cell-derived protein that promotes endothelial cell growth and tumor angiogenesis, but many mechanistic aspects of the pro-tumorigenic function of Bv8 are unclear. Here we demonstrate that CD11b+, Ly6C+, Ly6G+ granulocytes are the predominant cell source of Bv8 expression in bone marrow, spleen and in tumor tissues. Using granulocyte-deficient Growth factor independence-1 (Gfi1)-null mutant mice and normal littermates, we found that EL4 lymphoma tumors grow significantly larger in the granulocyte and Bv8-deficient mutant mice in comparison to the normal mice that display abundant tumor-associated granulocytes and Bv8 expression. Conversely, Lewis lung carcinoma (LLC-1) tumors grew to a significantly greater size in the normal mice in comparison to the Gfi1-null mice, but normal granulocyte tumor infiltration was modest. Quantitative analysis of tissue vascularization showed that EL4 and LLC-1 tumors from normal and Gfi1-mutant mice are similarly vascularized. These results confirm the critical contribution of the tumor microenvironment in determining the rate of tumor progression independently of tumor angiogenesis, and reveal some of the complexities of granulocyte and Bv8 functions in modulating tumor growth.

Different mechanisms for the resistance of C3H and STS strain mice to the development of thymic lymphomas following fractionated whole-body irradiation

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Aizawa, Shiro; Kamisaku, Hitoko

1999-01-01

B10 strain mice are extremely susceptible for induction of thymic lymphomas by fractionated whole-body irradiation (FI), whereas C3H and STS mice are fairly resistant. In the present study, we constructed radiation bone marrow chimeras in the reciprocal donor-host combinations of susceptible and resistant mice with use of Thy1 markers that allow to determine genetic origins of donor- and host-type thymocytes, and then to analyze the influence of host/thymic environment on the strain-dependent susceptibility to thymic lymphomagenesis. B10.Thy1.1→C3H, B10.Thy1.1→STS as well as B10.Thy1.1→B10 bone marrow chimeras manifested a high incidence of thymic lymphomas after FI-treatment, whereas C3H. Thy1.1→B10 and STS→B10 as well as C3H→C3H and STS→STS chimeras manifested a low incidence of thymic lymphoma. Furthermore, FI-treatment of [B10.Thy1.1+C3H]→B10 mixed chimeras resulted in the generation of similar numbers of thymic lymphomas of B10 and C3H origins, whereas FI-treatment of [B10.Thy1.1+STS]→B10 mixed chimeras preferentially induced thymic lymphomas of B10 origin. These results indicated that host environments of C3H and STS resistant mice are not inhibitory for the development of thymic lymphomas, genetic factors responsible for the strain-dependent susceptibility and/or resistance to FI-induced lymphomagenesis exert their effects entirely on bone-marrow derived cells, and the resistance of STS mice to FI-induced thymic lymphomagenesis is an intrinsic property of thymocytes as the targets of thymic lymphoma induction, whereas bone marrow-derived thymic stroma cells seem to play a significant role in the resistance of C3H mice for the induction of thymic lymphomas. (author)

Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment.

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Liu, Yang; Pandeswara, Srilakshmi; Dao, Vinh; Padrón, Álvaro; Drerup, Justin M; Lao, Shunhua; Liu, Aijie; Hurez, Vincent; Curiel, Tyler J

2017-01-15

mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1-8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell-dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L + CD8 + central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520-31. ©2016 AACR. ©2016 American Association for Cancer Research.

Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB.

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Singh, Narendra P; Singh, Udai P; Hegde, Venkatesh L; Guan, Hongbing; Hofseth, Lorne; Nagarkatti, Mitzi; Nagarkatti, Prakash S

2011-08-01

Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth. Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-κB) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-κB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-κB. These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-κB, leading to suppression of tumor growth. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The hypoxic cytotoxin SR 4233 increases the effectiveness of radioimmunotherapy in mice with human non-Hodgkin's lymphoma xenografts.

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Wilder, R B; McGann, J K; Sutherland, W R; Waller, E K; Minchinton, A I; Goris, M L; Knox, S J

1994-01-01

To determine if either the hypoxic cell radiosensitizer etanidazole (SR 2508) or the hypoxic cytotoxin SR 4233 could improve the effectiveness of radioimmunotherapy. LC4 (an IgG1 monoclonal antibody directed toward malignant T cells) and MB-1 (an irrelevant isotype-matched control antibody) were injected intraperitoneally into severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts in order to determine the distribution of the antibodies in the tumors and normal tissues as a function of time. Computerized-pO2-histography was used to measure the median oxygen tension in the tumors. Tumor-bearing mice were treated with: (a) LC4; (b) 90Y-LC4; (c) 90Y-MB-1; (d) whole body irradiation delivered via an external 137Cs source; (e) etanidazole and 90Y-LC4; (f) SR 4233 and 90Y-LC4; (g) etanidazole; and (h) SR 4233. An additional group of mice received no treatment and served as controls. A tumor growth delay assay was used to assess the effectiveness of the different treatment regimens. LC4 accumulated in the tumors to a significantly greater extent than MB-1 (p LC4 by itself was able to produce a minor decrease in tumor size (control vs. LC4; p = 0.001). 90Y-LC4 produced greater tumor growth delay than LC4 alone (LC4 vs. 90Y-LC4; p = 0.01); however, the Yttrium-90 caused neutropenia and weight loss. The 90Y-labeled tumor-specific and non-specific antibodies both exerted greater tumor growth delay than externally delivered whole body irradiation (p LC4 (90Y-LC4 vs etanidazole and 90Y-LC4, p = 0.13). SR 4233, on the other hand, did enhance the tumor growth delay produced by 90Y-LC4 (90Y-LC4 vs. SR 4233 and 90Y-LC4, p = 0.046). The neutropenia and weight loss caused by 90Y-LC4 were exacerbated slightly (< 10%) by the administration of SR 4233. A first generation hypoxic cytotoxin, SR 4233, was able to enhance the tumor growth delay produced by radioimmunotherapy in severe combined immunodeficient phenotype mice with human cutaneous T cell

Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

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Takayuki Mito

Full Text Available Mitochondrial DNA (mtDNA mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0 mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

CD4 expression on EL4 cells as an epiphenomenon of retroviral transduction and selection.

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Logan, Grant J; Spinoulas, Afroditi; Alexander, Stephen I; Smythe, Jason A; Alexander, Ian E

2004-04-01

The EL4 murine tumour cell line, isolated from a chemically induced lymphoma over 50 years ago, has been extensively exploited in immunological research. The conclusions drawn from many of these studies have been based on the presumption that EL4 cells maintain a stable phenotype during experimental manipulation. To the contrary, we have observed 100-fold greater expression of cell surface CD4 (CD4(high)) on a subpopulation of EL4 cells following retroviral transduction and G418 selection when compared with unmodified populations. Although the mechanism responsible for this effect remains to be elucidated, the unexpected expression of CD4, a molecule that functions as both a coreceptor with the T-cell receptor and ligand for the pro-inflammatory cytokine IL-16, has the potential to influence experimental outcomes. Upregulation of CD4 should be excluded when EL4 cells are utilized in experiments requiring a consistent immuno-phenotype.

Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2-interacting mediator knock-out mice.

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Wang, Y M; Zhang, G Y; Wang, Y; Hu, M; Zhou, J J; Sawyer, A; Cao, Q; Wang, Y; Zheng, G; Lee, V W S; Harris, D C H; Alexander, S I

2017-05-01

Regulatory T cells (T regs ) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of T regs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of T regs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of T regs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2-interacting mediator (Bim) knock-out mice by transient depleting T regs . Bim is a pro-apoptotic member of the B cell lymphoma 2 (Bcl-2) family. Bim knock-out (Bim -/- ) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that T reg depletion in Bim -/- mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild-type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17α, interferon (IFN)-γ and tumour necrosis factor (TNF)-α were increased significantly after T reg depletion in Bim -/- mice. This study demonstrates that transient depletion of T regs leads to enhanced self-reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim-deficient mice. © 2017 British Society for Immunology.

PD-1/CTLA-4 Blockade Inhibits Epstein-Barr Virus-Induced Lymphoma Growth in a Cord Blood Humanized-Mouse Model.

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Shi-Dong Ma

2016-05-01

Full Text Available Epstein-Barr virus (EBV infection causes B cell lymphomas in humanized mouse models and contributes to a variety of different types of human lymphomas. T cells directed against viral antigens play a critical role in controlling EBV infection, and EBV-positive lymphomas are particularly common in immunocompromised hosts. We previously showed that EBV induces B cell lymphomas with high frequency in a cord blood-humanized mouse model in which EBV-infected human cord blood is injected intraperitoneally into NOD/LtSz-scid/IL2Rγnull (NSG mice. Since our former studies showed that it is possible for T cells to control the tumors in another NSG mouse model engrafted with both human fetal CD34+ cells and human thymus and liver, here we investigated whether monoclonal antibodies that block the T cell inhibitory receptors, PD-1 and CTLA-4, enhance the ability of cord blood T cells to control the outgrowth of EBV-induced lymphomas in the cord-blood humanized mouse model. We demonstrate that EBV-infected lymphoma cells in this model express both the PD-L1 and PD-L2 inhibitory ligands for the PD-1 receptor, and that T cells express the PD-1 and CTLA-4 receptors. Furthermore, we show that the combination of CTLA-4 and PD-1 blockade strikingly reduces the size of lymphomas induced by a lytic EBV strain (M81 in this model, and that this anti-tumor effect requires T cells. PD-1/CTLA-4 blockade markedly increases EBV-specific T cell responses, and is associated with enhanced tumor infiltration by CD4+ and CD8+ T cells. In addition, PD-1/CTLA-4 blockade decreases the number of both latently, and lytically, EBV-infected B cells. These results indicate that PD-1/CTLA-4 blockade enhances the ability of cord blood T cells to control outgrowth of EBV-induced lymphomas, and suggest that PD-1/CTLA-4 blockade might be useful for treating certain EBV-induced diseases in humans.

Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL.

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Lu Dai

Full Text Available Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL, which arises preferentially in the setting of infection with human immunodeficiency virus (HIV. Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

Distribution of trace elements in the brain of EL (epilepsy) mice.

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Hirate, Maki; Takeda, Atsushi; Tamano, Haruna; Enomoto, Shuichi; Oku, Naoto

2002-09-01

The association of essential trace elements with epileptic seizures is poorly understood. On the basis of the evidences that the release of zinc from the brain of epilepsy (EL) mice, an animal model of genetically determined epilepsy, is enhanced by the induction of seizures and that alteration of zinc homeostasis is responsive to susceptibility to seizures, the distribution of trace elements in the brain was studied using EL mice and ddY mice, which form the genetic background for the inbred EL mice. The multitracer technique was applied to determine the distribution of trace elements. Twenty-four hours after intravenous injection of the multitracer, the concentration of 65Zn and 56Co in the brain of untreated EL mice was higher than in ddY mice, while the concentration of 65Zn and 56Co in the brain was decreased in seized EL mice. 75Se concentration in the hippocampus, cerebral cortex and cerebellum of untreated EL mice was lower than in ddY mice, while 75Se concentration in the hippocampus was increased in seized EL mice. 83Rb, an element of homologous series to potassium, concentration in the hippocampus and cerebral cortex of untreated EL mice was lower than in ddY mice, and 83Rb concentration in the cerebral cortex was decreased in seized EL mice. The movement of zinc, cobalt and selenium in the brain may be altered by enhancement of susceptibility to seizures. These results suggest that alteration of homeostasis of zinc, cobalt and selenium in the brain may be involved in the susceptibility, development or termination of seizures in EL mice. Copyright 2002 Elsevier Science B.V.

Radioimmunotherapy of human lymphoma in athymic, nude mice as monitored by 31P nuclear magnetic resonance

International Nuclear Information System (INIS)

Adams, D.A.; DeNardo, G.L.; DeNardo, S.J.; Matson, G.B.; Epstein, A.L.; Bradbury, E.M.

1985-01-01

Human B cell lymphoma (Raji) growing in athymic, nude mice has been successfully treated with a single pulse dose of 131 I-labeled monoclonal antibody (Lym-1) specific for this tumor. Sequential in vivo measurements of phosphate metabolites in the tumors by 31 P surface coil nuclear magnetic resonance showed a significant initial decrease of phosphocreatine following radioimmunotherapy. Diminution of relative ATP to Pi peak area ratio suggesting tissue damage occurred within 3-4 days. The sequence of alterations of nuclear magnetic resonance spectra from tumors of treated mice were strikingly different from sequential nuclear magnetic resonance spectra obtained from tumors of control mice. These observations lead us to conclude that 31 P surface coil nuclear magnetic resonance is a promising non-invasive method for assessing and predicting the efficacy of radioimmunotherapy. Further spatial discrimination of the region of tissue observed by the surface coil nuclear magnetic resonance experiment is under exploration in an effort to increase the utility of these methods

Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice.

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Canela, Andrés; Martín-Caballero, Juan; Flores, Juana M; Blasco, María A

2004-05-01

Here we describe a new mouse model with constitutive expression of the catalytic subunit of telomerase (Tert) targeted to thymocytes and peripheral T cells (Lck-Tert mice). Two independent Lck-Tert mouse lines showed higher incidences of spontaneous T-cell lymphoma than the corresponding age-matched wild-type controls, indicating that constitutive expression of Tert promotes lymphoma. Interestingly, T-cell lymphomas in Lck-Tert mice were more disseminated than those in wild-type controls and affected both lymphoid and nonlymphoid tissues, while nonlymphoid tissues were never affected with lymphoma in age-matched wild-type controls. Importantly, these roles of Tert constitutive expression in promoting tumor progression and dissemination were independent of the role of telomerase in telomere length maintenance, since telomere length distributions on a single-cell basis were identical in Lck-Tert and wild-type thymocytes. Finally, Tert constitutive expression did not interfere with telomere capping in Lck-Tert primary thymocytes, although it resulted in greater chromosomal instability upon gamma irradiation in Lck-Tert primary lymphocytes than in controls, suggesting that Tert overexpression may interfere with the cellular response to DNA damage.

The experimental study on biodistribution and radioimmunoimaging of 131I labeled anti-lymphoma Fab antibody in nude mice bearing human B cell lymphoma

International Nuclear Information System (INIS)

Yang Xiaochun; Zhang Meihua; Shen Junkang; Shen Yongmei; Shi Yizhen; Liu Zengli

2008-01-01

Objective: Radioimmunoimaging is still an interesting study in the domain of nuclear medicine. The aim of this study was to evaluate the biodistribution and radioimmunoimaging of 131 I-Fab anti- body in nude mice beating human B cell lymphoma. Methods: The immunoreactivity of Fab antibody to Raji cells was analyzed by immunohistochemistry and flow cytometry. Fab antibody and CD20 monoclonal antibody (as control) were labeled with 131 I using Iodogen method. 131 I-Fab antibody or 131 I-CD20 was injected into nude mice bearing B cell lymphoma via tail veins. The biodistribution and radioimmunoimaging results were obtained at 2, 4, 8 and 24 h postinjection, respectively. Results: The results of immunohistochemistry and flow cytometry indicated that both Fab antibody and 131 I-Fab antibody could bind strongly with membrane antigens on Raji cells, and the binding rate reached above 87%. Clear tumor image was obtained at 8 h after injection with 131 I-Fab and elimination was observed at 24 h postinjection. The clear tumor image for 131 I-CD20 antibody was obtained at 24 h post injection. The biodistribution in vivo showed that the percentage activities of injection dose per gram of tumor (% ID/g) of 131 I-Fab group at 2, 4, 8 h postinjection were higher than that of 131 I-CD20 antibody [(1.37±0.28), (1.84±0.13), (2.21±0.15)% ID/g vs (0.33±0.06), (0.62±0.08), (1.46±0.24)% ID/g, respectively; F=52.22, 278.42 and 29.00, all P 131 I-Fad and 131 I-CD20 groups at 2, 4, 8 and 24 h were [(0.22±0.03)-(5.44± 0.31)] vs[(0.04±0.01)-(3.10±0.29)], [(0.43±0.11) - (21.01±3.97)] vs [(0.11±0.05) - (7.99±1.81)], [(1.09±0.07) -(20.28±2.77)] vs [(0.48±0.06) - (23.55±1.69)], [(1.12± 0.02) - (10.29±1.78)] vs [(2.32 ± 0.34) - (33.23±6.83)], respectively. Conclusion: 131 I-Fab anti- body has advantages of small molecular weight, excellent targeting characteristics, early imaging and fast elimination, which indicates the potential application value in diagnosing B cell

Identification of differentially expressed proteins in spontaneous thymic lymphomas from knockout mice with deletion of p53

DEFF Research Database (Denmark)

Honoré, Bent; Buus, Søren; Claësson, Mogens H

2008-01-01

ABSTRACT: BACKGROUND: Knockout mice with a deletion of p53 spontaneously develop thymic lymphomas. Two cell lines (SM5 and SM7), established from two independent tumours, exhibited about fifty to seventy two-fold differentially expressed proteins compared to wild type thymocytes by two-dimensiona......ABSTRACT: BACKGROUND: Knockout mice with a deletion of p53 spontaneously develop thymic lymphomas. Two cell lines (SM5 and SM7), established from two independent tumours, exhibited about fifty to seventy two-fold differentially expressed proteins compared to wild type thymocytes by two...... alpha type 3, transforming acidic coiled-coil containing protein 3, mitochondrial ornithine aminotransferase and epidermal fatty acid binding protein and down-regulation of adenylosuccinate synthetase, tubulin beta-3 chain, a 25 kDa actin fragment, proteasome subunit beta type 9, cofilin-1 and glia...

Ascorbyl stearate and ionizing radiation potentiate apoptosis through intracellular thiols and oxidative stress in murine T lymphoma cells.

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Mane, Shirish D; Kamatham, Akhilender Naidu

2018-02-01

Ascorbyl stearate (Asc-s) is a derivative of ascorbic acid with better anti-tumour efficacy compared to its parent compound ascorbic acid. In this study, we have examined radio-sensitizing effect of Asc-s in murine T cell lymphoma (EL4) cells at 4 Gy. Asc-s and radiation treatment reduced cell proliferation, induced apoptosis in a dose dependent manner by arresting the cells at S/G2-M phase of cell cycle. It also decreased the frequency of cancer stem cells per se, with significantly higher decrease in combination with radiation treatment./Further, Asc-s and radiation treatment increased the level of reactive oxygen species (ROS), drop in mitochondrial membrane potential (MMP) and increased caspase-3 activity resulting in apoptosis of EL4 cells. Further it also significantly decreased GSH/GSSG ratio due to binding of Asc-s with thiols. The increase in oxidative stress induced by Asc-s and radiation treatment was abrogated by thiol antioxidants in EL4 cells. Interestingly, this redox modulation triggered significant increase in protein glutathionylation in a time dependent manner. Asc-s treatment resulted in glutathionylation of IKK, p50-NF-kB and mutated p53, thereby inhibiting cancer progression during oxidative stress. Asc-s quenches GSH ensuing Asc-s + GSH adduct thereby further modulating GSH/GSSG ratio as evident from HPLC and docking studies. The anti-tumour effect of Asc-s along with radiation was studied by injecting EL4 cells in synegenicC57/BL6 male mice. Intraperitoneal injection of Asc-s followed by radiation exposure at 4 Gy to the tumour bearing mice resulted in radio-sensitization which is evident from significant regression of tumour as evident from tumour burden index. The survival study supports the data that Asc-s pre-treatment enhances radio-sensitization in murine lymphoma. Our data, suggest that Asc-s and ionizing radiation induced cell cycle arrest and apoptosis by perturbing redox balance through irreversible complexes of thiols with Asc

Salmonella Immunotherapy Improves the Outcome of CHOP Chemotherapy in Non-Hodgkin Lymphoma-Bearing Mice

Science.gov (United States)

Bascuas, Thais; Moreno, María; Grille, Sofía; Chabalgoity, José A.

2018-01-01

We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients’ conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP–Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting. PMID:29410666

Bovine lactoferricin induces caspase-independent apoptosis in human B-lymphoma cells and extends the survival of immune-deficient mice bearing B-lymphoma xenografts.

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Furlong, Suzanne J; Mader, Jamie S; Hoskin, David W

2010-06-01

Although current treatments based on the use of B-cell-specific anti-CD20 monoclonal antibodies and aggressive combinatorial chemotherapy have improved the survival of patients suffering from B-cell non-Hodgkin's lymphoma (NHL), some individuals fail to respond to treatment and relapses remain common. New and more effective treatments for B-cell NHL are therefore required. Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that is cytotoxic for several human tumor cell lines but does not harm healthy cells. Here we show that in vitro treatment with LfcinB caused Raji and Ramos human B-lymphoma cells to die by apoptosis, as indicated by DNA fragmentation, chromatin condensation, and nuclear disintegration. LfcinB killed B-lymphoma cells more efficiently at low serum concentrations and was inhibited in the presence of exogenous bovine serum albumin, suggesting partial neutralization of cationic LfcinB by anionic serum components. LfcinB-induced apoptosis in B-lymphoma cells was caspase-independent since caspase-3 activation was not detected by Western blotting and the general caspase inhibitor z-VAD-fmk did not prevent LfcinB-induced DNA fragmentation. Importantly, immune-deficient SCID/beige mice that were inoculated intravenously with Ramos B-lymphoma cells in order to model B-cell NHL exhibited extended survival following systemic administration of LfcinB, indicating that LfcinB warrants further investigation as a novel therapeutic agent for the possible treatment of B-cell NHL. Copyright 2010 Elsevier Inc. All rights reserved.

NK cell activite in C157BL/Ka mice during the development of radiation induced thymic lymphomas

International Nuclear Information System (INIS)

Noel, A.; Schaaf-Lafontaine, N.; Defresne, M.P.; Boniver, J.

1985-01-01

Treatment of C57BL/Ka mice with a split dose whole-body irradiation (four weekly irradiations of 1,75 Gy) induces the development of thymic lymphomas. NK activity of spleen cells has been determined at several internals after leukemogenic treatment. Two days after irradiations, NK activity is normal and decreases strongly after one week. This period of decline persists during about one month. Then, NK activity restores and reaches control values. Lymphomas appear in spite of NK activity restauration. The diminution of NK activity during the preleukemic period could favour preleukemic cells apparition [fr

The production of nitric oxide in EL4 lymphoma cells overexpressing growth hormone.

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Arnold, Robyn E; Weigent, Douglas A

2003-01-01

Growth hormone (GH) is produced by immunocompetent cells and has been implicated in the regulation of a multiplicity of functions in the immune system involved in growth and activation. However, the actions of endogenous or lymphocyte GH and its contribution to immune reactivity when compared with those of serum or exogenous GH are still unclear. In the present study, we overexpressed lymphocyte GH in EL4 lymphoma cells, which lack the GH receptor (GHR), to determine the role of endogenous GH in nitric oxide (NO) production and response to genotoxic stress. Western blot analysis demonstrated that the levels of GH increased approximately 40% in cells overexpressing GH (GHo) when compared with cells with vector alone. The results also show a substantial increase in NO production in cells overexpressing GH that could be blocked by N(G)-monomethyl-L-arginine (L-NMMA), an L-arginine analogue that competitively inhibits all three isoforms of nitric oxide synthase (NOS). No evidence was obtained to support an increase in peroxynitrite in cells overexpressing GH. Overexpression of GH increased NOS activity, inducible nitric oxide synthase (iNOS) promoter activity, and iNOS protein expression, whereas endothelial nitric oxide synthase and neuronal nitric oxide synthase protein levels were essentially unchanged. In addition, cells overexpressing GH showed increased arginine transport ability and intracellular arginase activity when compared with control cells. GH overexpression appeared to protect cells from the toxic effects of the DNA alkylating agent methyl methanesulfonate. This possibility was suggested by maintenance of the mitochondrial transmembrane potential in cells overexpressing GH when compared with control cells that could be blocked by L-NMMA. Taken together, the data support the notion that lymphocyte GH, independently of the GH receptor, may play a key role in the survival of lymphocytes exposed to stressful stimuli via the production of NO.

NKT Cell Responses to B Cell Lymphoma.

Science.gov (United States)

Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B; Page, Carly; Younger, Kenisha M; Tiper, Irina V; Frieman, Matthew; Kimball, Amy S; Webb, Tonya J

2014-06-01

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.

Genetic analysis of resistance to radiation lymphomagenesis with recombinant inbred strains of mice

International Nuclear Information System (INIS)

Okumoto, M.; Nishikawa, R.; Imai, S.; Hilgers, J.

1990-01-01

Induction of lymphomas by radiation in mice is controlled by genetic factors. We analyzed the genetic control of radiation lymphomagenesis using the CXS series of recombinant inbred strains derived from two progenitor strains: one highly susceptible to radiation induction of lymphoma [BALB/cHeA (C)] and one extremely resistant [STS/A (S)]. The best concordances between strain distribution patterns of genetic markers and resistance (or susceptibility) to radiation lymphomagenesis were observed in a region with the b and Ifa genes on chromosome 4. This indicates that one major locus controls the incidence of radiogenic lymphomas in mice. We designated this locus as the Lyr (lymphoma resistance) locus. Backcrosses of (CXS)F1 to the two progenitor strains showed an intermediate incidence of lymphomas between their parental mice and did not significantly differ from (CXS)F1 mice. This and previous observations that (CXS)F1 mice also showed an intermediate incidence, differing from both progenitor strains, indicate that more genes are involved in the resistance (or susceptibility) to lymphoma induced by irradiation

Proteomic characterization of EL4 lymphoma-derived tumors upon chemotherapy treatment reveals potential roles for lysosomes and caspase-6 during tumor cell death in vivo.

Science.gov (United States)

Kramer, David A; Eldeeb, Mohamed A; Wuest, Melinda; Mercer, John; Fahlman, Richard P

2017-06-01

The murine mouse lymphoblastic lymphoma cell line (EL4) tumor model is an established in vivo apoptosis model for the investigation of novel cancer imaging agents and immunological treatments due to the rapid and significant response of the EL4 tumors to cyclophosphamide and etoposide combination chemotherapy. Despite the utility of this model system in cancer research, little is known regarding the molecular details of in vivo tumor cell death. Here, we report the first in-depth quantitative proteomic analysis of the changes that occur in these tumors upon cyclophosphamide and etoposide treatment in vivo. Using a label-free quantitative proteomic approach a total of 5838 proteins were identified in the treated and untreated tumors, of which 875 were determined to change in abundance with statistical significance. Initial analysis of the data reveals changes that may have been predicted, such as the downregulation of ribosomes, but demonstrates the robustness of the dataset. Analysis of the dataset also reveals the unexpected downregulation of caspase-3 and an upregulation of caspase-6 in addition to a global upregulation of lysosomal proteins in the bulk of the tumor. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

B7-2 Expressed on EL4 Lymphoma Suppresses Antitumor Immunity by an Interleukin 4–dependent Mechanism

OpenAIRE

Stremmel, C.; Greenfield, E.A.; Howard, E.; Freeman, G.J.; Kuchroo, V.K.

1999-01-01

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the “second signal” pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4–B7-1 cells are completely rejected in sy...

Release of zinc from the brain of El (epilepsy) mice during seizure induction.

Science.gov (United States)

Takeda, A; Hanajima, T; Ijiro, H; Ishige, A; Iizuka, S; Okada, S; Oku, N

1999-05-15

Brain distribution after i.v. injection of 65ZnCl2 into El mice, an animal model of genetically determined epilepsy, was studied by autoradiography to study the utilization of zinc in the brain. The distribution of 65Zn in the brain of El mice 6 days after injection was almost the same as that of ddY (normal) mice, suggesting that the uptake of zinc by the brain of El mice is normal. To study the movement of zinc in the brain in the course of seizure induction, the concentrations of 65Zn in the brain of seizure-afflicted and untreated control El mice were compared 20 days after 65Zn injection. The concentration of 65Zn in the brain of seized El mice was overall lower than that of control El mice; the concentration of 65Zn was decreased notably in the piriform cortex and amygdaloid nuclei complex during convulsion. These results suggest that the release of zinc from the El mouse brain is enhanced during convulsion. The decrease in actively functioning zinc in the brain may be associated with the increase in susceptibility to seizure in the El mouse. Copyright 1999 Elsevier Science B.V.

Local cerebral blood flow and glucose metabolism during seizure in spontaneously epileptic El mice

International Nuclear Information System (INIS)

Hosokawa, Chisa; Ochi, Hironobu; Yamagami, Sakae; Kawabe, Joji; Kobashi, Toshiko; Okamura, Terue; Yamada, Ryusaku

1995-01-01

Local cerebral blood flow and glucose metabolism were examined in spontaneously epileptic El mice using autoradiography with 125 I-IMP and 14 C-DG in the interictal phase and during seizure. El (+) mice that developed generalized tonic-clonic convulsions and El (-) mice that received no stimulation and had no history of epileptic seizures were examined. The seizure non-susceptible, maternal strain ddY mice were used as control. Uptake ratios for IMP and DG in mouse brain were calculated using the autoradiographic density. In the interictal phase, the pattern of local cerebral blood flow of El (+) mice was similar to that of ddY and El (-) mice, and glucose metabolism in the hippocampus was higher in El (+) mice than in El (-) and ddY mice, but flow and metabolism were nearly matched. During seizure, no significant changed blood flow and increased glucose metabolism in the hippocampus, the epileptic focus, and no markedly changed blood flow and depressed glucose metabolism in other brain regions were observed and considered to be flow-metabolism uncoupling. These observations have never been reported in clinical or experimental studies of epilepsy. Seizures did not cause large regional differences in cerebral blood flow. Therefore, only glucose metabolism is useful for detection of the focus of secondary generalized seizures in El mice, and appeared possibly to be related to the pathophysiology of secondary generalized epilepsy in El mice. (author)

Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone.

Science.gov (United States)

Weigent, Douglas A; Arnold, Robyn E

2005-03-01

Almost all of the previous studies with growth hormone (GH) have been done with exogenously supplied GH and, therefore, involve actions of the hormone through its receptor. However, the actions of endogenous or lymphocyte GH are still unclear. In a previous study, we showed that overexpression of GH (GHo) in a lymphoid cell line resulted in protection of the cells to apoptosis mediated by nitric oxide (NO). In the present study, we show that the protection from apoptosis could be transferred to control cells with culture fluids obtained from GHo cells and blocked by antibodies to the insulin-like growth factor-1 (IGF-1) or antibodies to the IGF-1-receptor (IGF-1R). Northern and Western blot analysis detected significantly higher levels of IGF-1 in cells overexpressing GH. An increase in the expression of the IGF-1R in GHo cells was also detected by Western blot analysis, (125)I-IGF-1 binding and analysis of IGF-1R promoter luciferase constructs. Transfection of GHo cells with a dominant negative IGF-1R mutant construct blocked the generation of NO and activation of Akt seen in GHo cells compared to vector alone control EL4 cells. The results suggest that one of the consequences of the overexpression of GH, in cells lacking the GH receptor, is an increase in the expression of IGF-1 and the IGF-1R which mediate the protection of EL4 lymphoma cells from apoptosis.

Improvement of macrophage dysfunction by administration of anti-transforming growth factor-beta antibody in EL4-bearing hosts.

Science.gov (United States)

Maeda, H; Tsuru, S; Shiraishi, A

1994-11-01

An experimental therapy for improvement of macrophage dysfunction caused by transforming growth factor-beta (TGF-beta) was tried in EL4 tumor-bearing mice. TGF-beta was detected in cell-free ascitic fluid from EL4-bearers, but not in that from normal mice, by western blot analysis. The ascites also showed growth-suppressive activity against Mv1Lu cells, and the suppressive activity was potentiated by transient acidification. To investigate whether the functions of peritoneal macrophages were suppressed in EL4-bearers, the abilities to produce nitric oxide and tumor necrosis factor-alpha (TNF-alpha) upon lipopolysaccharide (LPS) stimulation were measured. Both abilities of macrophages in EL4-bearing mice were suppressed remarkably on day 9, and decreased further by day 14, compared with non-tumor-bearing controls. TGF-beta activity was abrogated by administration of anti-TGF-beta antibody to EL4-bearing mice. While a large amount of TGF-beta was detected in ascitic fluid from control EL4-bearers, little TGF-beta was detectable in ascites from EL4-bearers given anti-TGF-beta antibody. Furthermore, while control macrophages exhibited little or no production of nitric oxide and TNF-alpha on LPS stimulation in vitro, macrophages from EL4-bearers administered with anti-TGF-beta antibody showed the same ability as normal macrophages. These results clearly indicate that TGF-beta contributes to macrophage dysfunction and that the administration of specific antibody for TGF-beta reverses macrophage dysfunction in EL4-bearing hosts.

Effect of Bcl11b genotypes and γ-radiation on the development of mouse thymic lymphomas

International Nuclear Information System (INIS)

Yoshikai, Yoshihiro; Sato, Toshihiro; Morita, Shinichi; Kohara, Yuki; Takagi, Ritsuo; Mishima, Yukio; Kominami, Ryo

2008-01-01

Bcl11b is a haploinsufficient tumor suppressor gene and expressed in many tissues such as thymus, brain and skin. Irradiated Bcl11b +/- heterozygous mice mostly develop thymic lymphomas, but the preference of Bcl11b inactivation for thymic lymphomas remains to be addressed. We produced Bcl11b +/- heterozygous and Bcl11b wild-type mice of p53 +/- background and compared their incidence of γ-ray induced thymic lymphomas. Majority of the tumors in p53 +/- mice were skin tumors, and only 5 (36%) of the 14 tumors were thymic lymphomas. In contrast, Bcl11b +/- p53 +/- doubly heterozygous mice developed thymic lymphomas at the frequency of 27 (79%) of the 34 tumors developed (P = 0.008). This indicates the preference of Bcl11b impairment for thymic lymphoma development. We also analyzed loss of the wild-type alleles in the 27 lymphomas, a predicted consequence given by γ-irradiation. However, the loss frequency was low, only six (22%) for Bcl11b and five (19%) for p53. The frequencies did not differ from those of spontaneously developed thymic lymphomas in the doubly heterozygous mice, though the latency of lymphoma development markedly differed between them. This suggests that the main contribution of irradiation at least in those mice is not for the tumor initiation by inducing allelic losses but probably for the promotion of thymic lymphoma development

iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo

Science.gov (United States)

Bassiri, Hamid; Das, Rupali; Guan, Peng; Barrett, David M.; Brennan, Patrick J.; Banerjee, Pinaki P.; Wiener, Susan J.; Orange, Jordan S.; Brenner, Michael B.; Grupp, Stephan A.; Nichols, Kim E.

2013-01-01

Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T-lymphoma. PMID:24563871

iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo .

Science.gov (United States)

Bassiri, Hamid; Das, Rupali; Guan, Peng; Barrett, David M; Brennan, Patrick J; Banerjee, Pinaki P; Wiener, Susan J; Orange, Jordan S; Brenner, Michael B; Grupp, Stephan A; Nichols, Kim E

2014-01-01

Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we found that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially induced by iNKT cell agonists of varying T-cell receptor (TCR) affinities, such as OCH, α-galactosyl ceramide, and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of TCR signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell–deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma. ©2013 AACR.

Studies on radiation-induced thymic lymphomagenesis in B10 strain mice

International Nuclear Information System (INIS)

Muto, Masahiro

1989-01-01

Using B10.Thy 1 congenic strain mice, we reexamined the earlier results by Kaplan and others that lymphomas could develop from lymphocytes present in the nonirradiated parental thymuses grafted into thymectomized, fractionally irradiated H-2 semiincompatible recipient mice. The results indicated that 37 out of 91 thymectomized and irradiated B10.Thy 1.2 mice developed lymphomas of which 75 % were shown to have originated from grafted thymuses. The evidence was not obtained that supported the involvement of endogenous MuLV or some kind of transmissible agents during thymic lymphomagenesis. We found, with intrathymic injection assay, that 'preneoplastic' cells that will eventually develop into thymic lymphomas under the influence of thymic microenvironment first appeared in the thymuses about 4-8 days after irradiation. These thymic prelymphoma cells 'thymus-dependent' preneoplastic cells were detected in 26.1 % of the test donor thymuses when examined at 14 days and in more than 63 % 21 and 31 days after irradiation. It was found that lymphomagenic irradiation resulted in the anomalous appearance of CD4 + and/or CD8 + thymocytes bearing IL-2 receptor (IL-2R) which were different from normal thymocyte subpopulations. Thymic prelymphoma cells existed mainly in CD4 - CD8 - and CD4 - CD8 + thymocyted subpopulations and also in CD4 + CD8 + subpopulation. T cell lymphomas derived from CD4 - CD8 - prelymphoma cells had mainly CD4 - CD8 - or CD4 - CD8 + phenotypes. T cell lymphomas developed from CD4 - CD8 + prelymphoma cells mainly expressed CD4 - CD8 + or CD4 + CD8 + phenotype. T cell lymphomas originated from CD4 + CD8 + prelymphoma cells were mainly CD4 + CD8 + but some CD4 - CD8 + or CD4 + CD8 - cells were also present. These T cell lymphomas expressed IL-2R on various levels. The development of thymic prelymphoma cells is discussed in view of thymocyte differentiation. (J.P.N)

Single-mass mutations associated with mouse lymphomas

International Nuclear Information System (INIS)

Guerrero, I.; Berman, J.W.; Diamond, L.E.; Newcomb, E.W.; Villasante, A.

1986-01-01

The authors study the induction of mouse lymphomas after treatment with a chemical carcinogen, nitrosomethyl urea (NMU), or with gamma irradiation. The koplan fractionated gamma radiation scheme and an established protocol for NMU tumor formation were chosen as protocols for induction of mouse lymphomas. In both cases, the mice developed thymic lymphomas with up to 90% incidence. In NMU induction, the latency period is shorter than irradiation

Expression of the Eukaryotic Translation Initiation Factors 4E and 2α in Non-Hodgkin’s Lymphomas

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Wang, Songtao; Rosenwald, Igor B.; Hutzler, Michael J.; Pihan, German A.; Savas, Lou; Chen, Jane-Jane; Woda, Bruce A.

1999-01-01

Transition of cells from quiescence to proliferation requires an increase in the rate of protein synthesis, which is regulated in part by two key translation initiation factors, 4E and 2α. The expression and activity of both factors are increased transiently when normal resting cells are stimulated to proliferate. They are constitutively elevated in oncogene transformed cultured cells, and overexpression of either initiation factor in rodent cells makes them tumorigenic. In this study we investigate an association between the expression of translation initiation factors and lymphomagenesis. We have analyzed the expression of the protein synthesis initiation factors 4E and 2α by immunohistochemistry in reactive lymph nodes and several types of non-Hodgkin’s lymphoma representing a wide range of clinical behaviors based on the Revised European-American Lymphoma behavioral classification. The study included 7 benign lymph nodes with follicular hyperplasia, 26 indolent lymphomas (6 marginal zone lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas, grades 1 and 2), 16 moderately aggressive lymphomas (8 mantle cell lymphomas and 8 follicular lymphomas, grade 3), 24 aggressive lymphomas (14 large-B-cell lymphomas and 10 anaplastic large-cell lymphomas), and 15 highly aggressive lymphomas (7 lymphoblastic lymphomas and 8 Burkitt’s lymphomas). Strong expression of initiation factors 4E and 2α was demonstrated in the germinal centers of reactive follicles. Minimal or no expression was seen in the mantle zones and surrounding paracortices, indicating that high expression of initiation factors 4E and 2α is associated with the active proliferation of lymphocytes. Most cases of aggressive and highly aggressive lymphomas showed strong expression of initiation factors 4E and 2α, in contrast to the cases of indolent and moderately aggressive lymphoma, in which their expression was intermediate between the germinal centers and the mantles of reactive

The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction.

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Riedlinger, Gregory; Adams, Jonathan; Stehle, John R; Blanks, Michael J; Sanders, Anne M; Hicks, Amy M; Willingham, Mark C; Cui, Zheng

2010-05-03

Spontaneous regression/complete resistance (SR/CR) mice are a unique colony of mice that possess an inheritable, natural cancer resistance mediated primarily by innate cellular immunity. This resistance is effective against sarcoma 180 (S180) at exceptionally high doses and these mice remain healthy. In this study, we challenged SR/CR mice with additional lethal transplantable mouse cancer cell lines to determine their resistance spectrum. The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry. In comparison to wild type (WT) mice, SR/CR mice showed significantly higher resistance to all cancer cell lines tested. However, SR/CR mice were more sensitive to MethA sarcoma (MethA), B16 melanoma (B16), LL/2 lung carcinoma (LL/2) and J774 lymphoma (J774) than to sarcoma 180 (S180) and EL-4 lymphoma (EL-4). Further mechanistic studies revealed that this lower resistance to MethA and LL/2 was due to the inability of these cancer cells to attract SR/CR leukocytes, leading to tumor cell escape from resistance mechanism. This escape mechanism was overcome by co-injection with S180, which could attract SR/CR leukocytes allowing the mice to resist higher doses of MethA and LL/2. S180-induced cell-free ascites fluid (CFAF) co-injection recapitulated the results obtained with live S180 cells, suggesting that this chemoattraction by cancer cells is mediated by diffusible molecules. We also tested for the first time whether SR/CR mice were able to resist additional cancer cell lines prior to S180 exposure. We found that SR/CR mice had an innate resistance against EL-4 and J774. Our results suggest that the cancer resistance in SR/CR mice is based on at least two separate processes: leukocyte migration/infiltration to the site of cancer cells and recognition of common surface properties on cancer cells. The infiltration of SR

The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction

International Nuclear Information System (INIS)

Riedlinger, Gregory; Adams, Jonathan; Stehle, John R Jr; Blanks, Michael J; Sanders, Anne M; Hicks, Amy M; Willingham, Mark C; Cui, Zheng

2010-01-01

Spontaneous regression/complete resistance (SR/CR) mice are a unique colony of mice that possess an inheritable, natural cancer resistance mediated primarily by innate cellular immunity. This resistance is effective against sarcoma 180 (S180) at exceptionally high doses and these mice remain healthy. In this study, we challenged SR/CR mice with additional lethal transplantable mouse cancer cell lines to determine their resistance spectrum. The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry. In comparison to wild type (WT) mice, SR/CR mice showed significantly higher resistance to all cancer cell lines tested. However, SR/CR mice were more sensitive to MethA sarcoma (MethA), B16 melanoma (B16), LL/2 lung carcinoma (LL/2) and J774 lymphoma (J774) than to sarcoma 180 (S180) and EL-4 lymphoma (EL-4). Further mechanistic studies revealed that this lower resistance to MethA and LL/2 was due to the inability of these cancer cells to attract SR/CR leukocytes, leading to tumor cell escape from resistance mechanism. This escape mechanism was overcome by co-injection with S180, which could attract SR/CR leukocytes allowing the mice to resist higher doses of MethA and LL/2. S180-induced cell-free ascites fluid (CFAF) co-injection recapitulated the results obtained with live S180 cells, suggesting that this chemoattraction by cancer cells is mediated by diffusible molecules. We also tested for the first time whether SR/CR mice were able to resist additional cancer cell lines prior to S180 exposure. We found that SR/CR mice had an innate resistance against EL-4 and J774. Our results suggest that the cancer resistance in SR/CR mice is based on at least two separate processes: leukocyte migration/infiltration to the site of cancer cells and recognition of common surface properties on cancer cells. The infiltration of SR

Rituximab Treatment Prevents Lymphoma Onset in Gastric Cancer Patient-Derived Xenografts

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Simona Corso

2018-05-01

Full Text Available Patient-Derived Xenografts (PDXs, entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer.More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas. The ability of grafted samples to develop lymphomas did not correlate with patient outcome, nor with the histotype, the lymphocyte infiltration level, or the EBV status of the original gastric tumor, impeding from foreseeing lymphoma onset. Interestingly, lymphoma development was significantly more frequent when primary rather than metastatic samples were grafted.Notably, the development of such lympho-proliferative disease could be prevented by a short rituximab treatment upon mice implant, without negatively affecting gastric carcinoma engraftment.Due to the high frequency of human lymphoma onset, our data show that a careful histologic analysis is mandatory when generating gastric cancer PDXs. Such care would avoid misleading results that could occur if testing of putative gastric cancer therapies is performed in lymphoma PDXs. We propose rituximab treatment of mice to prevent lymphoma development in PDX models, averting the loss of human-derived samples.

Regulation of immune responses in SJL and F1 hybrid mice by gamma-irradiated syngeneic lymphoma cells

International Nuclear Information System (INIS)

Katz, I.R.; Nagase, F.; Bell, M.K.; Ponzio, N.M.; Thorbecke, G.J.

1984-01-01

Syngeneic mixed lymphocyte-stimulating la+ lymphomas of SJL mice [reticulum cell sarcoma(s) (RCS)] were found to modulate immune responses in vivo. Simultaneous injection of 2 X 10(7) gamma-irradiated or glutaraldehyde-fixed RCS cells with the antigen sheep red blood cells (SRBC) or 2,4,6-trinitrophenol (TNP)-Ficoll markedly suppressed the subsequent plaque-forming cell response in the spleen. The suppression of the anti-SRBC response was prevented by pretreatment of the mice with cyclophosphamide, whereas the suppression of the anti-TNP-Ficoll response was not affected. RCS injection induced high interferon serum titers within 24 hours after injection, which were not prevented by pretreatment with cyclophosphamide. Injection of gamma-irradiated RCS cells (gamma-RCS) or RCS cell extract 2 days prior to antigen enhanced the anti-SRBC but markedly suppressed the anti- TNP-Ficoll response. Injection of RCS both on day -2 and day 0 enhanced the anti-SRBC response. SJL mice 8-9 months of age showed much less or no suppression when gamma-RCS cells were injected on day 0. Certain F1 hybrids of SJL also showed the gamma-RCS-induced suppression of the anti-SRBC response. Suppression was seen in SJL X BALB.B but not in SJL X BALB/c mice and in SJL X A.TH but not in SJL X A.TL mice, suggesting an I-region effect. F1 hybrids of SJL by B10 background mice showed no significant suppression. Enhancement of the anti-SRBC response by prior injection of gamma-RCS was seen in all F1 hybrid mice examined

Basic study on apoptosis induction into cancer cells U-937 and EL-4 by ultrasound exposure.

Science.gov (United States)

Takeuchi, Shinichi; Udagawa, Yoshiko; Oku, Yumiko; Fujii, Takuma; Nishimura, Hiroyuki; Kawashima, Norimichi

2006-12-22

Recently, the low invasive cancer treatments with small aftereffects have been considered. We are studying on the suppression methods of cancer cell proliferation with ultrasound. Cancer cells of mouse T lymphoma (EL-4) have been used in our study. The human histitocytic lymphoma cells (U-937) was used in this time. The cancer cells were cultured in a culture medium of RPMI1640. The standing wave acoustic field was formed in a water tank of our ultrasound exposure system by a vibrating plate driven with a Langevine type transducer. The U-937 and EL-4 were exposed to ultrasound in the acoustic field with spatial average acoustic intensity of 350 mW/cm(2) at 150 kHz. The viable rate of EL-4 decreased with the lapse of culture time after ultrasound exposure. U-937 did not show the remarkable decrease tendency. The proliferation of U-937 which exposed to ultrasound with 700 mW/cm(2) was suppressed. It can be thought that apoptosis was induced in the cancer cells in this condition. We observed the morphological change on the U-937 exposed to ultrasound with this condition. The morphological changes by apoptosis like the shrink of cells, formation of apoptotic bodies etc. can be observed with an optical microscope and a phase contrast microscope.

Modification of radiation-induced murine thymic lymphoma incidence by curcumin

International Nuclear Information System (INIS)

Dange, P.S.; Yadav, H.D.; Kumar, Vimalesh; Bhilwade, H.N.; Pandey, B.N.; Sarma, H.D.

2017-01-01

Curcumin is a known antioxidant, preventing radiation damage including carcinogenesis. However, concentration and feeding schedule of curcumin in modification of radiation induced thymic lymphoma incidence in vivo model has not been studied. We report here modification of incidence of γ-radiation-induced thymic lymphoma in mice fed with different doses of curcumin (0.05 to 1 %) in diet. Results: Female Swiss mice (6-8 weeks) fed with normal diet and exposed to 3 Gy whole body "6"0Co γ-irradiation (WBI) showed 85 % incidence of thymic lymphoma (TL) at 120 days post-irradiation. A concentration of 1 % curcumin was found the most effective in TL incidence prevention than other fed concentrations. The TL incidence was remarkably reduced when curcumin was fed to the mice before than after the radiation exposure. These results suggest modification of TL incidence by curcumin in irradiated mice involving DNA damage and apoptotic death mechanisms

Effects of Edaravone on Hippocampal Antioxidants in EL Mice.

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Baba, Asami; Kawakami, Yasuhiko; Saito, Kenichi; Murashima, Yoshiya L; Itoh, Yasuhiko

2016-01-01

The role of oxidative stress in susceptibility to seizures has been the focus of several recent studies. The aim of the present study was to evaluate the antiepileptic effects of the free radical scavenger edaravone on EL mice, a strain that is highly susceptible to convulsive seizures. EL mice were treated intraperitoneally with edaravone or saline for 1 week. The levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and 3 isozymes of superoxide dismutase (SOD) (cytoplasmic copper- and zinc-containing SOD, extracellular SOD, and mitochondrial manganese-containing SOD) were measured in the hippocampus, and electroencephalograms (EEGs) were used to evaluate seizure sensitivity. Hippocampal levels of GSSG were lower in the edaravone group than in the untreated control group, and the GSH/GSSG ratio, Cu/Zn-SOD, and EC-SOD activities were higher in the edaravone group. Edaravone shortened the duration of interictal spike discharges and clinically suppressed epileptic seizures. Edaravone increases antioxidant potency and reduces seizure susceptibility in EL mice, making it a promising novel antiepileptic agent.

IgG4-producing lymphoma arising in a patient with IgG4-related disease.

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Igawa, Takuro; Hayashi, Toshiaki; Ishiguro, Kazuya; Maruyama, Yumiko; Takeuchi, Mai; Takata, Katsuyoshi; Yoshino, Tadashi; Sato, Yasuharu

2016-12-01

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.

Extracts of Crinum latifolium inhibit the cell viability of mouse lymphoma cell line EL4 and induce activation of anti-tumour activity of macrophages in vitro.

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Nguyen, Hoang-Yen T; Vo, Bach-Hue T; Nguyen, Lac-Thuy H; Bernad, Jose; Alaeddine, Mohamad; Coste, Agnes; Reybier, Karine; Pipy, Bernard; Nepveu, Françoise

2013-08-26

Crinum latifolium L. (CL) leaf extracts have been traditionally used in Vietnam and are now used all over the world for the treatment of prostate cancer. However, the precise cellular mechanisms of the action of CL extracts remain unclear. To examine the effects of CL samples on the anti-tumour activity of peritoneal murine macrophages. The properties of three extracts (aqueous, flavonoid, alkaloid), one fraction (alkaloid), and one pure compound (6-hydroxycrinamidine) obtained from CL, were studied (i) for redox capacities (DPPH and bleaching beta-carotene assays), (ii) on murine peritoneal macrophages (MTT assay) and on lymphoma EL4-luc2 cells (luciferine assay) for cytotoxicity, (iii) on macrophage polarization (production of ROS and gene expression by PCR), and (iv) on the tumoricidal functions of murine peritoneal macrophages (lymphoma cytotoxicity by co-culture with syngeneic macrophages). The total flavonoid extract with a high antioxidant activity (IC50=107.36 mg/L, DPPH assay) showed an inhibitory action on cancer cells. Alkaloid extracts inhibited the proliferation of lymphoma cells either by directly acting on tumour cells or by activating of the tumoricidal functions of syngeneic macrophages. The aqueous extract induced mRNA expression of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) indicating differentiation of macrophages into pro-inflammatory M1 polarized macrophages. The total flavonoid, alkaloid extracts and an alkaloid fraction induced the expression of the formyl peptide receptor (FPR) on the surface of the polarized macrophages that could lead to the activation of macrophages towards the M1 phenotype. Aqueous and flavonoid extracts enhanced NADPH quinine oxido-reductase 1 (NQO1) mRNA expression in polarized macrophages which could play an important role in cancer chemoprevention. All the samples studied were non-toxic to normal living cells and the pure alkaloid tested, 6-hydroxycrinamidine, was not

Expression of a truncated Hmga1b gene induces gigantism, lipomatosis and B-cell lymphomas in mice.

Science.gov (United States)

Fedele, Monica; Visone, Rosa; De Martino, Ivana; Palmieri, Dario; Valentino, Teresa; Esposito, Francesco; Klein-Szanto, Andres; Arra, Claudio; Ciarmiello, Andrea; Croce, Carlo M; Fusco, Alfredo

2011-02-01

HMGA1 gene rearrangements have been frequently described in human lipomas. In vitro studies suggest that HMGA1 proteins have a negative role in the control of adipocyte cell growth, and that HMGA1 gene truncation acts in a dominant-negative fashion. Therefore, to define better the role of the HMGA1 alterations in the generation of human lipomas, we generated mice carrying an Hmga1b truncated (Hmga1b/T) gene. These mice develop a giant phenotype together with a drastic expansion of the retroperitoneal and subcutaneous white adipose tissue. We show that the activation of the E2F pathway likely accounts, at least in part, for this phenotype. Interestingly, the Hmga1b/T mice also develop B-cell lymphomas similar to that occurring in Hmga1-knockout mice, supporting a dominant-negative role of the Hmga1b/T mutant also in vivo. Copyright © 2010 Elsevier Ltd. All rights reserved.

IgG4-related disease simulating Hodgkin lymphoma in a child

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D. Eric Ewing, MD

2016-06-01

Full Text Available Immunoglobulin (Ig G4-related disease is a recently described syndrome characterized by mass forming lymphoplasmacytic tissue infiltration and elevated serum IgG4 concentrations usually affecting middle-aged or older individuals. Lymphadenopathy is frequently observed and is sometimes the first or only manifestation of the disease. We report a case of IgG4-related disease mimicking Hodgkin lymphoma in a 13-year-old girl. The patient presented with progressive unilateral cervical lymphadenopathy of several months duration. Biopsy showed follicular hyperplasia with progressive transformation of germinal centers. Interfollicular areas were expanded by small lymphocytes, histiocytes, eosinophils and fibrosis with occasional CD30 positive cells initially concerning for interfollicular Hodgkin lymphoma. Immunohistochemical analysis revealed an intrafollicular plasmacytosis with an IgG4-positive/IgG-positive plasma cell ratio of 50% supporting a diagnosis of IgG4-related lymphadenopathy, progressively transformed germinal centers type. Laboratory studies were supportive with elevated serum IgG4 (178 mg/dL and IgE (30.40 kU/L levels along with an elevated serum IgG4/IgG ratio (0.16. Very few cases of IgG4-related disease have been described in children. Within this age group, there is considerable clinical overlap between IgG4-related disease associated lymphadenopathy and Hodgkin lymphoma. In addition, lymphadenopathy secondary to IgG4-related disease demonstrates substantial histologic diversity with the potential to simulate the inflammatory background and fibrosis of Hodgkin lymphoma. The importance of accurate diagnosis is underscored by the prognostic implications considering the marked response of the syndrome to steroid therapy. In addition, appropriate follow up is critical to monitor for relapse and additional organ involvement.

Low CD4/CD8 T-cell ratio associated with inflammatory arthropathy in human T-cell leukemia virus type I Tax transgenic mice.

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Takeo Ohsugi

Full Text Available BACKGROUND: Human T-cell leukemia virus type I (HTLV-1 can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATL as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. A transgenic mouse that expresses HTLV-1 Tax also develops T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. The aim of this study was to identify the primary T-cell subsets involved in the development of arthropathy in Tax transgenic mice. PRINCIPAL FINDINGS: By 24 months of age, Tax transgenic mice developed severe arthropathy with a cumulative incidence of 22.8%. The pathological findings of arthropathy in Tax transgenic mice were similar to those seen in human rheumatoid arthritis or mouse models of rheumatoid arthritis, with synovial proliferation and a positive rheumatoid factor. Before the onset of spontaneous arthropathy, young and old Tax transgenic mice were not sensitive to collagen and did not develop arthritis after immunization with type II collagen. The arthropathic Tax transgenic mice showed a significantly decreased proportion of splenic CD4(+ T cells, whereas the proportion of splenic CD8(+ T cells was increased. Regulatory T cells (CD4(+CD25(+Foxp3(+ were significantly decreased and CD8(+ T cells that expressed the chemokine receptor CCR4 (CD8(+CCR4(+ were significantly increased in arthropathic Tax transgenic mice. The expression of tax mRNA was strong in the spleen and joints of arthropathic mice, with a 40-fold increase compared with healthy transgenic mice. CONCLUSIONS: Our findings reveal that Tax transgenic mice develop rheumatoid-like arthritis with proliferating synovial cells in the joints; however, the proportion of different splenic T-cell subsets in these mice was completely different from other commonly used animal models of rheumatoid arthritis. The crucial T-cell subsets in arthropathic Tax transgenic mice appear to resemble

A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

International Nuclear Information System (INIS)

Ono, K; Sato, T; Iyama, S; Tatekoshi, A; Hashimoto, A; Kamihara, Y; Horiguchi, H; Kikuchi, S; Kawano, Y; Takada, K; Hayashi, T; Miyanishi, K; Sato, Y; Takimoto, R; Kobune, M; Kato, J

2014-01-01

Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death

S100A9 interaction with TLR4 promotes tumor growth.

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Eva Källberg

Full Text Available By breeding TRAMP mice with S100A9 knock-out (S100A9(-/- animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/- and TLR4(-/-, but not in RAGE(-/- animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b(+ cells. Lastly, treatment of mice with a small molecule (ABR-215050 that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.

S100A9 Interaction with TLR4 Promotes Tumor Growth

Science.gov (United States)

Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

2012-01-01

By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies. PMID:22470535

Conjunctival Lymphoma

DEFF Research Database (Denmark)

Kirkegaard, Marina M; Rasmussen, Peter K; Coupland, Sarah E

2016-01-01

IMPORTANCE: To date, the clinical features of the various subtypes of conjunctival lymphoma (CL) have not been previously evaluated in a large cohort. OBJECTIVE: To characterize subtype-specific clinical features of CL and their effect on patient outcome. DESIGN, SETTING, AND PARTICIPANTS...... age was 61.3 years, and 55.1% (145 of 263) were female. All lymphomas were of B-cell type. The most frequent subtype was extranodal marginal zone lymphoma (EMZL) (68.4% [180 of 263]), followed by follicular lymphoma (FL) (16.3% [43 of 263]), mantle cell lymphoma (MCL) (6.8% [18 of 263]), and diffuse...... large B-cell lymphoma (DLBCL) (4.6% [12 of 263). Conjunctival lymphoma commonly manifested in elderly individuals (age range, 60-70 years old), with EMZL having a female predilection (57.8% [104 of 180]) and MCL having a marked male predominance (77.8% [14 of 18]). Unlike EMZL and FL, DLBCL and MCL were...

Anti-apoptotic A1 is not essential for lymphoma development in Eµ-Myc mice but helps sustain transplanted Eµ-Myc tumour cells.

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Mensink, Mark; Anstee, Natasha S; Robati, Mikara; Schenk, Robyn L; Herold, Marco J; Cory, Suzanne; Vandenberg, Cassandra J

2018-03-01

The transcription factor c-MYC regulates a multiplicity of genes involved in cellular growth, proliferation, metabolism and DNA damage response and its overexpression is a hallmark of many tumours. Since MYC promotes apoptosis under conditions of stress, such as limited availability of nutrients or cytokines, MYC-driven cells are very much dependent on signals that inhibit cell death. Stress signals trigger apoptosis via the pathway regulated by opposing fractions of the BCL-2 protein family and previous genetic studies have shown that the development of B lymphoid tumours in Eµ-Myc mice is critically dependent on expression of pro-survival BCL-2 relatives MCL-1, BCL-W and, to a lesser extent, BCL-X L , but not BCL-2 itself, and that sustained growth of these lymphomas is dependent on MCL-1. Using recently developed mice that lack expression of all three functional pro-survival A1 genes, we show here that the kinetics of lymphoma development in Eµ-Myc mice and the competitive repopulation capacity of Eµ-Myc haemopoietic stem and progenitor cells is unaffected by the absence of A1. However, conditional loss of a single remaining functional A1 gene from transplanted A1-a -/- A1-b fl/fl A1-c -/- Eµ-Myc lymphomas slowed their expansion, significantly extending the life of the transplant recipients. Thus, A1 contributes to the survival of malignant Eµ-Myc-driven B lymphoid cells. These results strengthen the case for BFL-1, the human homologue of A1, being a valid target for drug development for MYC-driven tumours.

Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice.

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Nakamoto, Yurie; Shiotani, Tadashi; Watabe, Shigeo; Nabeshima, Toshitaka; Yoshii, Mitsunobu

2004-10-01

Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5-4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5-4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam > oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.

Antinociceptive effects of Cremophor EL orally administered to mice

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Z. Tabarelli

2003-01-01

Full Text Available Surfactants are frequently used to improve solubilization of lipophilic drugs. Cremophor EL (CrEL is a polyoxyethylated castor oil surfactant used to solubilize water-insoluble drugs such as anesthetic, antineoplastic, immunosuppressive and analgesic drugs, vitamins and new synthetic compounds, including potential analgesics. The antinociceptive effect of CrEL (3.2, 6.4 and 10.6 g/kg, in 10 ml/kg body weight, by gavage on the abdominal writhing response induced by intraperitoneal administration of acetic acid (0.8%, 10 ml/kg body weight and on the tail immersion test was investigated in mice. Control animals received castor oil (10 ml/kg body weight or saline (0.9% NaCl, 10 ml/kg body weight. CrEL reduced nociception in a dose-dependent manner in both tests. At 10.6 g/kg, CrEL caused antinociception similar to that induced by dipyrone (300 mg/kg, by gavage in the abdominal writhing test, and antinociception similar to that induced by morphine (20 mg/kg, by gavage in the tail immersion test. The effect of castor oil was similar to that of saline in both assays. These data indicate that the appropriate controls should be used when evaluating the effects of potential antinociceptive agents dissolved in CrEL.

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells.

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Ogasawara, Takashi; Kohashi, Yuko; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hatano, Masahiko; Hirata, Hirokuni; Fukushima, Yasutsugu; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi; Arima, Masafumi

2018-01-01

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate T H 2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4 + T cell-derived memory T H 2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4 + T (MPT) cells and their derived T H 2 (MPT H 2) cells, Bcl6 -manipulated mice , highly conserved intron enhancer (hcIE)-deficient mice , and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated T H 2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPT H 2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPT H 2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPT H 2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPT H 2 cells in T H 2 immune responses related to the pathogenesis of allergies.

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells

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Ogasawara, Takashi; Kohashi, Yuko; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hatano, Masahiko; Hirata, Hirokuni; Fukushima, Yasutsugu; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi; Arima, Masafumi

2018-01-01

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3′ distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies. PMID:29696026

OPD4-positive T-cell lymphoma of the liver in systemic lupus erythematosus.

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Tsutsumi, Y; Deng, Y L; Uchiyama, M; Kawano, K; Ikeda, Y

1991-11-01

Primary malignant lymphoma of the liver occupying the right lobe, 14 x 9 x 7 cm in size, developed in a 30-year-old man with a 4-year history of autoimmune hemolytic anemia. The diagnosis of systemic lupus erythematosus (SLE) accompanying thrombocytopenia had been made clinically 10 months earlier. The liver biopsy specimen revealed diffuse proliferation of large lymphoma cells expressing the activated helper/inducer T-cell phenotype (LCA+, UCHL1+, OPD4+, LN3+, MT1-, L26-, MB1-, Leu M1-, Ki-1-, KP1-). The lymphoma was successfully treated by chemotherapy and irradiation. Intractable thrombocytopenia provoked fatal esophageal hemorrhage. At autopsy, no lymphomatous lesion was identified, and the hepatic right lobe contained an encapsulated necrotic lesion without any viable tumor cells. The bone marrow revealed marked hyperplasia of erythroid and megakaryocytic series. Extramedullary hematopoiesis was demonstrated in the liver, spleen and lymph nodes. This is the second case of primary hepatic T-cell lymphoma associated with SLE.

Age and sex dependence in tumorigenesis in mice by continuous low-dose-rate gamma-ray whole-body irradiation

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Otsu, Hiroshi; Kobayashi, Shigeru; Furuse, Takeshi; Noda, Yuko; Shiragai, Akihiro; Sato, Fumiaki.

1992-01-01

We investigated the dependency of sex and age in mice in the induction of neoplasms by gamma-rays from cesium-137 at a low dose rate of 0.375Gy/22h/day. Thymic lymphomas occurred significantly at the same incidence in both sexes, and more frequently when younger mice were exposed to radiation. Strain C57BL/6J mice were divided into 8 groups, which were whole-body irradiated with a total dose of 39Gy for 105 days each. The exposure was begun at 28 days of age (male:AM1, female:AF1), and then stepwise increasing the starting age by 105 days, i.e., from 133 days (AM2 and AF2), from 238 days (AM3 and AF3), and from 343 days (AM4 and AF4), respectively. Unirradiated mice served as control (UM and UF). The incidence of thymic lymphomas was about 60 % in AM1, AM2, AF1 and AF2, 40 % in AM3 and AF3 and 20 % in AF4 and AF4, demonstrating no sex dependency, but a distinct age dependency, for lymphomogenesis. It was proven that mice showed a tendency to become less susceptible to radiation induced thymic lymphoma with increasing age. Concomitantly, life-shortening also was caused, and the greater the degree of life-shortening was, the younger the mice were the start of exposure. Life-shortening was attributed to thymic lymphoma, and hemorrhage and infectious diseases due to the depletion of bone marrow cells. (author)

iNKT cells suppress the CD8+ T cell response to a murine Burkitt's-like B cell lymphoma.

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Ryan L Bjordahl

Full Text Available The T cell response to B cell lymphomas differs from the majority of solid tumors in that the malignant cells themselves are derived from B lymphocytes, key players in immune response. B cell lymphomas are therefore well situated to manipulate their surrounding microenvironment to enhance tumor growth and minimize anti-tumor T cell responses. We analyzed the effect of T cells on the growth of a transplantable B cell lymphoma and found that iNKT cells suppressed the anti-tumor CD8(+ T cell response. Lymphoma cells transplanted into syngeneic wild type (WT mice or Jalpha18(-/- mice that specifically lack iNKT cells grew initially at the same rate, but only the mice lacking iNKT cells were able to reject the lymphoma. This effect was due to the enhanced activity of tumor-specific CD8(+ T cells in the absence of iNKT cells, and could be partially reversed by reconstitution of iNKT cells in Jalpha 18(-/- mice. Treatment of tumor-bearing WT mice with alpha -galactosyl ceramide, an activating ligand for iNKT cells, reduced the number of tumor-specific CD8(+ T cells. In contrast, lymphoma growth in CD1d1(-/- mice that lack both iNKT and type II NKT cells was similar to that in WT mice, suggesting that type II NKT cells are required for full activation of the anti-tumor immune response. This study reveals a tumor-promoting role for iNKT cells and suggests their capacity to inhibit the CD8(+ T cell response to B cell lymphoma by opposing the effects of type II NKT cells.

Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma.

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Thomas Han

Full Text Available Although several therapeutic options have become available for patients with Cutaneous T-cell Lymphoma (CTCL, no therapy has been curative. Recent studies have demonstrated that CTCL cells overexpress the CC chemokine receptor 4 (CCR4.In this study, a xenograft model of CTCL was established and a recombinant adeno-associated viral serotype 8 (AAV8 vector expressing a humanized single-chain variable fragment (scFv-Fc fusion (scFvFc or "minibody" of anti-CCR4 monoclonal antibody (mAb h1567 was evaluated for curative treatment. Human CCR4+ tumor-bearing mice treated once with intravenous infusion of AAV8 virions encoding the h1567 (AAV8-h1567 minibody showed anti-tumor activity in vivo and increased survival. The AAV8-h1567 minibody notably increased the number of tumor-infiltrating Ly-6G+ FcγRIIIa(CD16A+ murine neutrophils in the tumor xenografts over that of AAV8-control minibody treated mice. Furthermore, in CCR4+ tumor-bearing mice co-treated with AAV8-h1567 minibody and infused with human peripheral blood mononuclear cells (PBMCs, marked tumor infiltration of human CD16A+ CD56+ NK cells was observed. The h1567 minibody also induced in vitro ADCC activity through both mouse neutrophils and human NK cells.Overall, our data demonstrate that the in vivo anti-tumor activity of h1567 minibody is mediated, at least in part, through CD16A+ immune effector cell ADCC mechanisms. These data further demonstrate the utility of the AAV-minibody gene transfer system in the rapid evaluation of candidate anti-tumor mAbs and the potency of h1567 as a potential novel therapy for CTCL.

Phenotypic characterization of thymic prelymphoma cells of B10 mice treated with split-dose irradiation

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Muto, M.; Kubo, E.; Kamisaku, H.; Sado, T.

1990-01-01

Using an intrathymic injection assay on B10 Thy-1 congenic mice, it was demonstrated that thymic prelymphoma cells first developed within the thymuses from 4 to 8 days after split-dose irradiation and were detected in more than 63% of the test donor thymuses when examined at 21 and 31 days after irradiation. Moreover, some mice (25%) at 2 mo after split-dose irradiation had already developed thymic lymphomas in their thymuses. To characterize these thymic prelymphoma cells, the thymocytes from B10 Thy-1.1 mice 1 mo after irradiation were stained with anti-CD4 and anti-CD8 mAb and were sorted into four subpopulations. These fractionated cells were injected into the recipient thymuses to examine which subpopulation contained thymic prelymphoma cells. The results indicated that thymic prelymphoma cells existed mainly in CD4- CD8- and CD4- CD8+ thymocyte subpopulations and also in CD4+ CD8+ subpopulation. T cell lymphomas derived from CD4- CD8- prelymphoma cells had mainly CD4- CD8- or CD4- CD8+ phenotypes. T cell lymphomas developed from CD4- CD8+ prelymphoma cells mainly expressed CD4- CD8+ or CD4+ CD8+ phenotype. T cell lymphomas originating from CD4+ CD8+ prelymphoma cells were mainly CD4+ CD8+ but some CD4- CD8+ or CD4+ CD8- cells were also present. These thymic prelymphoma cells were further characterized phenotypically in relation to their expression of the marker defined by the mAb against J11d marker and TL-2 (thymus-leukemia) Ag, which is not expressed on normal thymocytes of B10.Thy-1.2 or B10.Thy-1.1 strain, but appears on the thymocytes of lymphomagenic irradiated mice. The results indicated that the prelymphoma cells existed in J11d+, TL-2+ cells

Suppressive effects of Lactobacillus casei cells, a bacterial immunostimulant, on the incidence of spontaneous thymic lymphoma in AKR mice.

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Watanabe, T

1996-06-01

The mean survival age of female AKR/J mice was significantly prolonged, the enlargement of thymus was markedly suppressed, and the proliferation of ecotropic and recombinant murine leukemia viruses (MuLV) was markedly inhibited when 8-week-old female AKR/J mice were injected intraperitoneally (i.p.) with heat-killed Lactobacillus casei cells twice weekly for 8 weeks. In contrast, such actions of heat-killed L. casei cells were not seen in 20-week-old female AKR/J mice. The leukemogenic activity of the cell-free extract of thymus from adult female AKR/J mice in newborn female AKR/J mice was drastically reduced by i.p. treatment with heat-killed L. casei cells. The difference in adjuvant effectiveness of heat-killed L. casei cells on 8- and 20-week-old animals may be dependent on the difference in the enhancing activity of the cell-mediated immune systems between the groups induced by heat-killed L. casei cells, and, as a result, on the difference in the degree of proliferation of ecotropic and recombinant MuLV in thymus, which consequently causes thymic lymphoma.

Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma.

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Kinowaki, Yuko; Kurata, Morito; Ishibashi, Sachiko; Ikeda, Masumi; Tatsuzawa, Anna; Yamamoto, Masahide; Miura, Osamu; Kitagawa, Masanobu; Yamamoto, Kouhei

2018-02-20

Regulation of oxidative stress and redox systems has important roles in carcinogenesis and cancer progression, and for this reason has attracted much attention as a new area of cancer therapeutic targets. Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, has biological important functions such as signaling cell death by suppressing peroxidation of membrane phospholipids. However, few studies exist on the expression and clinical relevance of GPX4 in malignant lymphomas such as diffuse large B-cell lymphoma. In this study, we assessed the expression of GPX4 immunohistochemically. GPX4 was expressed in 35.5% (33/93) cases of diffuse large B-cell lymphoma. The GPX4-positive group had poor overall survival (P = 0.0032) and progression-free survival (P = 0.0004) compared with those of the GPX4-negative group. In a combined analysis of GPX4 and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, there was a negative correlation between GPX4 and 8-hydroxydeoxyguanosine (P = 0.0009). The GPX4-positive and 8-hydroxydeoxyguanosine-negative groups had a significantly worse prognosis than the other groups in both overall survival (P = 0.0170) and progression-free survival (P = 0.0005). These results suggest that the overexpression of GPX4 is an independent prognostic predictor in diffuse large B-cell lymphoma. Furthermore, in vitro analysis demonstrated that GPX4-overexpressing cells were resistant to reactive oxygen species-induced cell death (P = 0.0360). Conversely, GPX4-knockdown cells were sensitive to reactive oxygen species-induced cell death (P = 0.0111). From these data, we conclude that GPX4 regulates reactive oxygen species-induced cell death. Our results suggest a novel therapeutic strategy using the mechanism of ferroptosis, as well as a novel prognostic predictor of diffuse large B-cell lymphoma.

Early radiation effects in highly apoptotic murine lymphoma xenografts monitored by 31P magnetic resonance spectroscopy

International Nuclear Information System (INIS)

Sakurai, Hideyuki; Mitsuhashi, Norio; Murata, Osamu; Kitamoto, Yoshizumi; Saito, Yoshihiro; Hasegawa, Masatoshi; Akimoto, Tetsuo; Takahashi, Takeo; Nasu, Sachiko; Niibe, Hideo

1998-01-01

Purpose: Phosphorus-31 magnetic resonance spectra ( 31 P-MRS) were obtained from highly apoptotic murine lymphoma xenografts before and up to 24 hr following graded doses of radiation ranging from 2 to 30 Gy. Radiation-induced apoptosis was also estimated up to 24 hr by scoring apoptotic cells in tumor tissue. Methods and Materials: Highly apoptotic murine lymphoma cells, EL4, were subcutaneously transplanted into C57/BL mice. At 7 days after transplantation, radiation was given to the tumor with a single dose at 3, 10, and 30 Gy. The β-ATP/Pi, PME/Pi, and β-ATP/PME values were calculated from the peak area of each spectrum. Radiation-induced apoptosis was scored with counting apoptotic cells on hematoxylin and eosin stained specimens (%apoptosis). Results: The values of % apoptosis 4, 8, and 24 hr after radiation were 21.8, 19.6, and 4.6% at 3 Gy, 35.1, 25.6, and 14.8% at 10 Gy, 38.4, 38.0, and 30.6% at 30 Gy, respectively (cf. 4.4% in control). There was no correlation between early change in β-ATP/Pi and % apoptosis at 4 hr after radiation when most of the apoptosis occurred. An early decrease in PME/Pi was observed at 4 hr after radiation dose at 30 Gy. For each dose, the values of β-ATP/Pi 24 hr after radiation were inversely related to radiation dose. Conclusion: The increase in β-ATP/Pi observed by 31 P-MRS was linked to the degree of histological recovery from radiation-induced apoptosis

Inhibition of Rac controls NPM–ALK-dependent lymphoma development and dissemination

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Colomba, A [INSERM, U1048, Université Toulouse III, Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse (France); Giuriato, S; Dejean, E [Centre de Recherches en Cancérologie de Toulouse, UMR1037-Université Toulouse III, IFR150-IFRBMT, Toulouse (France); Thornber, K [INSERM, U1048, Université Toulouse III, Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse (France); Delsol, G [Centre de Recherches en Cancérologie de Toulouse, UMR1037-Université Toulouse III, IFR150-IFRBMT, Toulouse (France); Tronchère, H [INSERM, U1048, Université Toulouse III, Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse (France); Meggetto, F [Centre de Recherches en Cancérologie de Toulouse, UMR1037-Université Toulouse III, IFR150-IFRBMT, Toulouse (France); Payrastre, B; Gaits-Iacovoni, F [INSERM, U1048, Université Toulouse III, Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse (France)

2011-06-01

Nucleophosmin-anaplastic lymphoma kinase (NPM–ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM–ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM–ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM–ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.

Inhibition of Rac controls NPM–ALK-dependent lymphoma development and dissemination

International Nuclear Information System (INIS)

Colomba, A; Giuriato, S; Dejean, E; Thornber, K; Delsol, G; Tronchère, H; Meggetto, F; Payrastre, B; Gaits-Iacovoni, F

2011-01-01

Nucleophosmin-anaplastic lymphoma kinase (NPM–ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM–ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM–ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM–ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas

High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a {sup 177}Lu-based CD22-specific radioimmunoconjugate and rituximab

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Weber, Tobias; Boetticher, Benedikt; Keller, Armin; Schlegelmilch, Anne; Jaeger, Dirk; Krauss, Juergen [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); Mier, Walter; Kraemer, Susanne; Leotta, Karin [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Sauter, Max; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Grosse-Hovest, Ludger [University of Tuebingen, Department of Immunology, Tuebingen (Germany); Arndt, Michaela A.E. [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); German Cancer Research Center (DKFZ), Immunotherapy Program, National Center for Tumor Diseases, Heidelberg (Germany)

2016-03-15

Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter {sup 177}Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of {sup 177}Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1{sup null}) interleukin-2 receptor common gamma chain (IL2r γ {sup null}) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. {sup 177}Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the {sup 177}Lu-labelled anti-CD22 IgG than of {sup 177}Lu-labelled rituximab. Treatment with {sup 177}Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with {sup 177}Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with {sup 177}Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for

Primary Cutaneous CD4-Positive Small/Medium Pleomorphic T-cell Lymphoma – A Case Report

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Micković Milena

2016-12-01

Full Text Available Primary cutaneous CD4-positive small- to medium-sized pleomorphic T-cell lymphoma is a provisional entity in the 2005 WHO-EORTC classification for cutaneous lymphomas. It is a rare condition and, in most cases, it has a favorable clinical course and prognosis. Primary cutaneous CD4-positive small/medium pleomorphic T-cell lymphoma (PCSM-TCL is defined as a cutaneous T-cell lymphoma with predominantly small- to medium-sized CD4-positive pleomorphic T-cells without a history of patches and plaques typical of mycosis fungoides. PCSM-TCL usually presents as a solitary plaque or tumor on the head, neck, trunk or upper extremities and it is considered to have indolent clinical behavior. Histologically, it is characterized by a dense infiltration of small/medium-sized pleomorphic T-cells that involves the entire dermal thickness, often with nodular extension into the hypodermis. Using immunohistochemical staining, the majority of the reported cases proved to be CD3, CD4 positive and CD8, CD30 negative. However, due to the rarity and heterogeneity of the PCSM-TCL, precise clinicopathologic characteristics of PCSM-TCL have not been well characterized and the optimal treatment for this group of lymphomas is yet to be defined. Dermatologists and pathologists should be aware of this entity in order to avoid unnecessary aggressive treatments.

Alteration of strain background and a high omega-6 fat diet induces earlier onset of pancreatic neoplasia in EL-Kras transgenic mice.

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Cheon, Eric C; Strouch, Matthew J; Barron, Morgan R; Ding, Yongzeng; Melstrom, Laleh G; Krantz, Seth B; Mullapudi, Bhargava; Adrian, Kevin; Rao, Sambasiva; Adrian, Thomas E; Bentrem, David J; Grippo, Paul J

2011-06-15

Diets containing omega-6 (ω-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of ω-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in ω-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras(G12D) (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high ω-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in ω-6 fatty acid. Copyright © 2010 UICC.

Binding of human beta 2-microglobulin to murine EL4 thymoma cells upregulates MHC class I heavy-chain epitopes, inhibits IL-2 secretion and induces resistance to killing by natural killer cells

DEFF Research Database (Denmark)

Claësson, M H; Nissen, Mogens Holst

1994-01-01

line (ABLS-8), X63 B-lymphoma cells and YAC cells did not bind h beta 2m. In two of the T lymphomas, EL4 and BW5147, binding of h beta 2m led to an increase in major histocompatibility complex class I (MHC-I) heavy-chain epitope expression as measured by anti-H-2K/D antibody binding and FACS analysis....... EL4 cells which had bound h beta 2m decreased their rate of constitutive IL-2 secretion and became resistant to activated natural killer (NK) cell killing. The present data suggest the binding of h beta 2m to mouse T cells leads to conformational changes of MHC-I heavy chains which influence both...

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

International Nuclear Information System (INIS)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

2015-01-01

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

Energy Technology Data Exchange (ETDEWEB)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn

2015-10-15

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

Science.gov (United States)

Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

2017-07-01

Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Complicated biallelic inactivation of Pten in radiation-induced mouse thymic lymphomas

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Yamaguchi, Yu [Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522 (Japan); Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Takabatake, Takashi; Kakinuma, Shizuko; Amasaki, Yoshiko; Nishimura, Mayumi; Imaoka, Tatsuhiko; Yamauchi, Kazumi; Shang, Yi [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Miyoshi-Imamura, Tomoko [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Genetic Counseling Program, Graduate School of Humanities and Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyou-ku, Tokyo 112-8610 (Japan); Nogawa, Hiroyuki [Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522 (Japan); Kobayashi, Yoshiro [Department of Biomolecular Science, Faculty of Science, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510 (Japan); Shimada, Yoshiya, E-mail: y_shimad@nirsgo.jp [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan)

2010-04-01

Inactivation of the phosphatase and tensin homolog gene (Pten) occurs via multiple tissue-dependent mechanisms including epigenetic silencing, point mutations, insertions, and deletions. Although frequent loss of heterozygosity around the Pten locus and plausible involvement of epigenetic silencing have been reported in radiation-induced thymic lymphomas, the proportion of lymphomas with inactivated Pten and the spectrum of causal aberrations have not been extensively characterized. Here, we assessed the mode of Pten inactivation by comprehensive analysis of the expression and alteration of Pten in 23 radiation-induced thymic lymphomas developed in B6C3F1 mice. We found no evidence for methylation-associated silencing of Pten; rather, complex structural abnormalities comprised of missense and nonsense mutations, 1- and 3-bp insertions, and focal deletions were identified in 8 of 23 lymphomas (35%). Sequencing of deletion breakpoints suggested that aberrant V(D)J recombination and microhomology-mediated rearrangement were responsible for the focal deletions. Seven of the 8 lymphomas had biallelic alterations, and 4 of them did not express Pten protein. These Pten aberrations coincided with downstream Akt phosphorylation. In conclusion, we demonstrate that Pten inactivation is frequently biallelic and is caused by a variety of structural abnormalities (rather than by epigenetic silencing) and is involved in radiation-induced lymphomagenesis.

Cell-surface antigens associated with dualtropic and thymotropic murine leukemia viruses inducing thymic and nonthymic lymphomas

International Nuclear Information System (INIS)

Haas, M.; Patch, V.

1980-01-01

Unique type-specific antigens were detected on cells infected with dualtropic and thymotropic viruses and x-ray-induced T cell- and B cell-malignant lymphomas of C57BL/6 mice. These findings support the contention that T cell lymphoma (TCL)-inducing and B cell lymphoma (BCL)-indcing viruses isolated from x-irradiated C57BL/6 mice are env gene recombinants in which ecotropic gene sequences have been substituted by xenotropic sequences. We found that unique antigenicities are associated with each TCL-inducing and BCL-inducing dualtropic virus, and that the thymotropic TCL-inducing virus isolates represent a separate serologic group. These virus mapping experiments indicated that many serologically different recombinant viruses can be isolated from C57BL/6 mice. It is suggested that many distinct recombinant viruses may exist in lymphomagenic C57BL/6 mice, some of which are associated with specific lyphoma induction

Impact of N-acetylcysteine on antitumor activity of doxorubicin and landomycin A in NK/Ly lymphoma-bearing mice

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Yu. S. Kozak

2018-04-01

Full Text Available N-acetylcysteine (NAC is a dietary supplement demonstrating antioxidant and liver protecting effects that is widely used in clinics. NAC is considered to possess potential therapeutic activity for health disorders characterized by generation of free oxygen radicals, as well as potential for decreasing negative side effects of various drugs. However, the mechanisms of such tissue-protective actions of NAC remain poorly understood. The main aim of this work was to study therapeutic effects of NAC applied together with the “gold standard” of chemotherapy doxorubicin (Dx or the novel experimental drug landomycin A (LA to mice bearing NK/Ly lymphoma. It was revealed that NAC significantly decreased the nephrotoxicity of Dx (measured as creatinine level, possessed moderate immunomodulating activity (as revealed by an increase in number of cytotoxic T-lymphocytes, and partially increased survival of NK/Ly lymphoma-bearing animals treated with Dx. On the contrary, there was little tissue-protective effect of NAC towards LA due to the weak side effects of this anticancer drug, however, the combined use of NAC and LA significantly increased survival (60+ days of LA-treated animals with NK/Ly lymphoma. Summarizing, NAC possesses a moderate tissue-protective activity towards Dx action but lacks a major therapeutic effect. However, in the case of LA action, NAC significantly increases its anticancer activity with no impact on its negative side effects. Further studies of the molecular mechanisms underlying that activity of NAC towards the action of LA are in progress.

Role of iNOS in Bystander Signaling Between Macrophages and Lymphoma Cells

International Nuclear Information System (INIS)

Ghosh, Somnath; Maurya, Dharmendra Kumar; Krishna, Malini

2008-01-01

Purpose: The present report describes the bystander effects of radiation between similar and dissimilar cells and the role of iNOS in such communication. Materials and Methods: EL-4 and RAW 264.7 cells were exposed to 5 Gy γ-irradiation. The medium from irradiated cells was transferred to unirradiated cells. Results: Irradiated EL-4 cells as well as those cultured in the presence of medium from γ-irradiated EL-4 cells showed an upregulation of NF-κB, iNOS, p53, and p21/waf1 genes. The directly irradiated and the bystander EL-4 cells showed an increase in DNA damage, apoptosis, and NO production. Bystander signaling was also found to exist between RAW 264.7 (macrophage) and EL-4 (lymphoma) cells. Unstimulated or irradiated RAW 264.7 cells did not induce bystander effect in unirradiated EL-4 cells, but LPS stimulated and irradiated RAW 264.7 cells induced an upregulation of NF-κB and iNOS genes and increased the DNA damage in bystander EL-4 cells. Treatment of EL-4 or RAW 264.7 cells with L-NAME significantly reduced the induction of gene expression and DNA damage in the bystander EL-4 cells, whereas treatment with cPTIO only partially reduced the induction of gene expression and DNA damage in the bystander EL-4 cells. Conclusions: It was concluded that active iNOS in the irradiated cells was essential for bystander response

Endoscopic staging of low-grade gastric malt lymphoma Estadificación por ecoendoscopia en el linfoma gástrico tipo malt de bajo grado

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M. J. Varas

2006-03-01

Full Text Available Introduction: endoscopic ultrasonography (EUS has already proven useful in the assessment of submucosal lesions, and the staging of gastrointestinal cancer, particularly gastric MALT-type lymphoma. The goal of this paper was EUS staging. Patients and method: 24 patients (10 females, 14 males with a median age of 56 years and possibly gastric MALT lymphoma (25 cases were studied using videoendoscopy, biopsies, and echoendoscopy with 7.5- and 20-MHz radial EUS, and also with 12- and 20-MHz miniprobes (MPs. Nineteen patients were definitely evaluated (7 females, 12 males as having 20 MALT-type lymphomas, as five patients were post-hoc disregarded when an invasive, high-grade gastric lymphoma (3c or plasmocytoma (2c was subsequently demonstrated. Of these 19 patients, all had T1 lesions except for two with T2 lesions; one patient had a gastroduodenal T1 lymphoma. Echographic findings with MPs were compared to EUS (gold standard and histology both before and after eradication. Then, patients were followed up every 1-3-6 months using videoendoscopy and MPs. Results: echoendoscopy correctly identified T stages in 90% of cases. MPs identified T stages in 88% of cases, and N stages in 33% of cases, with results being slightly inferior to those obtained with conventional EUS (91 vs. 45%; they were consequently used for follow-up. After eradication, all but two patients are in complete remission and have been followed every 1-3-6 months using MPs without echographic abnormalities, except for a patient who relapsed.Introducción: la ultrasonografía endoscópica (USE ha demostrado ya su utilidad en la evaluación de las lesiones submucosas, en la estadificación del cáncer digestivo en general, y del linfoma gástrico tipo MALT en particular. El objetivo de este trabajo fue la estadificación por USE. Pacientes y método: veinticuatro enfermos (10 mujeres y 14 varones con edad media de 56 años y con posible linfoma gástrico tipo MALT (25 casos fueron

Atypical IgG4+ Plasmacytic Proliferations and Lymphomas: Characterization of 11 Cases.

Science.gov (United States)

Bledsoe, Jacob R; Wallace, Zachary S; Deshpande, Vikram; Richter, Joshua R; Klapman, Jason; Cowan, Andrew; Stone, John H; Ferry, Judith A

2017-09-01

To report the clinicopathologic features of monotypic immunoglobulin G4+ (IgG4+) lymphoid and plasmacytic proliferations. Cases were identified from the pathology files. Pathology and clinical materials were reviewed. Eleven cases of monotypic IgG4+ proliferations were identified at nodal, orbital, or salivary sites. Six cases (three men, three women; age, 57-94 years) met criteria for lymphoma or plasma cell neoplasia. Most contained frequent Mott cells. Five cases (three men, two women; age, 40-80 years) had restricted proliferations of atypical/monotypic IgG4+ plasma cells in a background of reactive lymphoid hyperplasia or inflammation. Monotypic IgG4+ proliferations include lymphomas, plasmacytic neoplasms, and a previously uncharacterized group of proliferations not meeting criteria for conventional hematolymphoid neoplasia. Distinct features included prominent Mott cells and/or monotypic plasma cells within follicles. The proliferations were infrequently associated with IgG4-related disease (IgG4-RD). Our findings raise questions regarding the relationship between clonal IgG4+ proliferations, reactive/inflammatory processes, and IgG4-RD. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

[Autologous regulatory T cells can suppress the proliferation of lymphoma cell line in vitro].

Science.gov (United States)

Ying, Zhi-Tao; Guo, Jun; Ren, Jun; Kong, Yan; Yuan, Zhi-Hong; Liu, Xi-Juan; Zhang, Chen; Zheng, Wen; Song, Yu-Qin; Zhang, Yun-Tao; Zhu, Jun

2009-06-01

This study was aimed to investigate the suppressive effect of regulatory T (Treg) cells on the T cell lymphoma EL4 cell line and to explore its mechanism. C57BL/6 Mouse Treg cells were isolated by MACS (magnetic cell sorting). The purity and the expression of Foxp3 were detected by flow cytometry. The suppressive effect of sorted Treg cells on EL4 cells was detected by MTT assay. The secretion of TGF-beta1 and IL-10 was examined by enzyme-linked immunosorbent assay (ELISA). The results showed that CD4(+)CD25(+) T cells could be successfully isolated by MACS with the purity reaching 91.6% and the expression level of Foxp3 was 78.9%. The ratio of viable cells was more than 95%. Regulatory T cells could suppress the proliferation of EL4 cells effectively in the presence of antigen presenting cells (APCs). And the suppressive effect was most significant at 1:1 ratio. In addition, the suppression still existed without APCs. TGF-beta1 and IL-10 could not be detected by ELISA. It is concluded that the Treg cells can suppress T lymphoma cell in vitro. The suppressive effect of Treg cells works in dose-dependent manner, but not in cytokine-dependent manner. The mechanism of this suppression may take effect through cell-cell contact.

Sarcoma de Kaposi y linfomas no hodgkinianos asociados con infección por el virus de inmunodeficiencia humana HIV associated to Kaposi's sarcoma and non-Hodgkin lymphomas

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Bertha Beatriz Socarrás Ferrer

2004-04-01

Full Text Available El SIDA es producido por el virus de la inmunodeficiencia humana, tiene la particularidad de infectar y destruir las células del sistema inmune, lo que producen un estado de inmunosupresión irreversible y progresivo en el organismo que se hace susceptible a múltiples infecciones virales, micóticas y bacterianas. Se describen múltiples neoplasias en estos pacientes, pero solo algunos muestran directa relación con el virus de la inmunodeficiencia humana, y su aparición implica el diagnóstico del SIDA: sarcoma de Kaposi, linfomas no hodgkinianos, linfoma cerebral primario y carcinoma de cérvix uterino. El tratamiento de estos pacientes es difícil debido a los problemas provocados por la infección del virus de inmunodeficiencia humana que debilita el sistema inmunitarioAIDS is produced by HIV. It has the particularity of infecting and destroying the immune system cells, producing an irreversible and progressive immunodepression state in the organism, which makes it susceptible to multiple viral, mycotic and bacterial infections. Several neoplasias are described in these patients, but only some of them show a direct relation to the HIV and its appearance implies the AIDS diagnosis: Kaposi’s sarcoma, non-hodgkin lymphomas, primary brain lymphoma and uterine cervix carcinoma. The treatment of these patients is difficult due to the problems provoked by the HIV infection that weakens the immunity system

Study on expression of SH2 domain-containing protein tyrosine phosphatase SHP-1 and SHP-2 in γ-ray irradiation-induced thymus lymphoma in mice

International Nuclear Information System (INIS)

Huang Dingde; Chen Qi; Han Ling; Cai Jianming; Li Bailong; Huang Yuecheng; Gao Jianguo; Sun Suping

2003-01-01

Objective: To investigate the expression of SH2 domain containing-protein tyrosine phosphatase SHP-1 and SHP-2 in γ-ray irradiation-induced thymus lymphoma in mice. Methods: Altogether 338 BALB/c mice were randomly divided into irradiation groups and controls. Irradiation groups which were irradiated with γ-rays included canceration groups confirmed with histology and uncanceration groups. The controls were fed synchronistically with irradiation groups. The expression of SHP-1 and SHP-2 was detected with Western blot in thymus cells. Results: The expression of SHP-1 in canceration groups was much higher than that in uncanceration groups and controls significantly, while the expression of SHP-2 in canceration groups was higher than that in uncanceration groups and controls. When authors detected the expression of SHP-2 with Western blot, the authors found another protein with a molecular weight of 55x10 3 , which expression in canceration groups was higher than that in uncanceration groups and controls. Conclusion: The expression of SH2 domain-containing protein tyrosine phosphatase SHP-1 and SHP-2 is significantly increased in canceration groups, suggesting that SHP-1 and SHP-2 may be related with γ-ray induced thymus lymphoma in mice. Further research is expected on the relationship between development of cancer and SHP-1 and SHP-2

Psoriasis and risk of malignant lymphoma

DEFF Research Database (Denmark)

Kamstrup, M R; Skov, L; Zachariae, C

2018-01-01

In patients with psoriasis, the risk of lymphoma has been a subject of controversy and data from larger studies are limited1-4 . We therefore investigated the 5-year risk of new-onset Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) (excluding cutaneous T-cell lymphoma [CTCL]), and CTCL...

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

Science.gov (United States)

Ortega-Molina, Ana; Boss, Isaac W; Canela, Andres; Pan, Heng; Jiang, Yanwen; Zhao, Chunying; Jiang, Man; Hu, Deqing; Agirre, Xabier; Niesvizky, Itamar; Lee, Ji-Eun; Chen, Hua-Tang; Ennishi, Daisuke; Scott, David W; Mottok, Anja; Hother, Christoffer; Liu, Shichong; Cao, Xing-Jun; Tam, Wayne; Shaknovich, Rita; Garcia, Benjamin A; Gascoyne, Randy D; Ge, Kai; Shilatifard, Ali; Elemento, Olivier; Nussenzweig, Andre; Melnick, Ari M; Wendel, Hans-Guido

2015-10-01

The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.

A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma.

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Afshin Beheshti

Full Text Available Extensive epidemiological data have demonstrated an exponential rise in the incidence of non-Hodgkin lymphoma (NHL that is associated with increasing age. The molecular etiology of this remains largely unknown, which impacts the effectiveness of treatment for patients. We proposed that age-dependent circulating microRNA (miRNA signatures in the host influence diffuse large B cell lymphoma (DLBCL development. Our objective was to examine tumor development in an age-based DLBCL system using an inventive systems biology approach. We harnessed a novel murine model of spontaneous DLBCL initiation (Smurf2-deficient at two age groups: 3 and 15 months old. All Smurf2-deficient mice develop visible DLBCL tumor starting at 15 months of age. Total miRNA was isolated from serum, bone marrow and spleen and were collected for all age groups for Smurf2-deficient mice and age-matched wild-type C57BL/6 mice. Using systems biology techniques, we identified a list of 10 circulating miRNAs being regulated in both the spleen and bone marrow that were present in DLBCL forming mice starting at 3 months of age that were not present in the control mice. Furthermore, this miRNA signature was found to occur circulating in the blood and it strongly impacted JUN and MYC oncogenic signaling. In addition, quantification of the miRNA signature was performed via Droplet Digital PCR technology. It was discovered that a key miRNA signature circulates throughout a host prior to the formation of a tumor starting at 3 months old, which becomes further modulated by age and yielded calculation of a 'carcinogenic risk score'. This novel age-based circulating miRNA signature may potentially be leveraged as a DLBCL risk profile at a young age to predict future lymphoma development or disease progression as well as for potential innovative miRNA-based targeted therapeutic strategies in lymphoma.

Initial thoracic involvement in lymphoma. CT assessment; Afectacion toracica inicial en el linfom. Valoracion con TC

Energy Technology Data Exchange (ETDEWEB)

Bustos, A.; Corredoira, J.; Ferreiros, J.; Cabeza, B.; Jorquera, M.; Pedrosa, I.; Martinez, R.; Fernandez, C. [Hospital Clinico San Carlos. Madrid (Spain)

2002-07-01

To analyze the initial thoracic involvement by CT in a consecutive series of patients with lymphoma. A retrospective analysis was made of thoracic CT studies made at the time of diagnosis of 259 patients with lymphoma. Mediastinal pulmonary, pleural, pericardial and chest wall involvement was assessed by CT. Of 259 patients (129 men y 130 women), 56 had Hodgkin's disease (HD) and 203 had non-Hodgkin lymphoma (NHL). Forty-two percent (42.5%, 110/259) of the patients had chest involvement on CT: 33 of 56 patients with HD (58.9%) and 77 of 203 patients with NHL (37.9%). All the patients with thoracic HD and 71.4% of patients with thoracic NHL, had mediastinal lymph node involvement. of the patients with thoracic involvement 12.1% (4/33) of the patient with HD and 23.3% (18/77) of the patients with NHL had pulmonary involvement. Thoracic involvement on CT was more frequent in HD. Mediastinal lymph node involvement was the most common finding fundamentally in HD. Pulmonary disease always occurred in the presence of mediastinal lymph node involvement in HD but could occur as an isolated finding in NHL. (Author) 24 refs.

Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas

DEFF Research Database (Denmark)

Marquard, L.; Poulsen, C.B.; Gjerdrum, L.M.

2009-01-01

AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim was to det......AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim...... was to determine HDAC expression in DLBCL and PTCL which has not previously been investigated. METHODS AND RESULTS: The expression of HDAC1, HDAC2, HDAC6 and acetylated histone H4 was examined immunohistochemically in 31 DLBCL and 45 PTCL. All four markers showed high expression in both DLBCL and PTCL compared...

Modulation of radiation-induced apoptosis and G2/M block in murine T-lymphoma cells

International Nuclear Information System (INIS)

Palayoor, S.T.; Macklis, R.M.; Bump, E.A.; Coleman, C.N.

1995-01-01

Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to 137 Cs γ irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of γ radiation. We studied the effect of several pharmacological agents on the radiation-induced G 2 /M block and DNA fragmentation. The agents which reduced the radiation-induced G 2 /M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G 2 /M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G 2 /M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G 2 /M block, and to use this effect in the treatment of patients with malignant disease. 59 refs., 7 figs

Mechanism of infectivity of a murine leukemia virus in adult mice

International Nuclear Information System (INIS)

Levy, R.L.; Barrington, M.H.; Lerner, R.A.; Dixon, F.J.

1976-01-01

Infection of adult BALB/c mice with murine leukemia virus (MuLV) induces typical thymic lymphomas. Expression of virus was measured by using a radioimmunoassay for murine P-30, a virion core protein. Nineteen days after injection of MuLV-S into adult mice, there were 0.3μg P-30/ml of serum. X-irradiation permitted the early expression of high levels of viremia, when given before or after MuLV-S administration, and it also hastened the development of lymphomas. Seventeen to 21 days after injection of MuLV-S into x-irradiated (600 rads) adult mice, there were 2.7 μg of P-30/ml of serum. The virus produced by infected adult mice was infectious and oncogenic when given to newborn mice. Several lines of evidence are presented that suggest the mechanism by which x-irradiation permits early expession of virion proteins and lymphomas is not immunosuppression

Co-targeting of Tiam1/Rac1 and Notch ameliorates chemoresistance against doxorubicin in a biomimetic 3D lymphoma model

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Ikram, Muhammad; Lim, Yeseon; Baek, Sun-Yong; Jin, Songwan; Jeong, Young Hun; Kwak, Jong-Young; Yoon, Sik

2018-01-01

Lymphoma is a heterogeneous disease with a highly variable clinical course and prognosis. Improving the prognosis for patients with relapsed and treatment-resistant lymphoma remains challenging. Current in vitro drug testing models based on 2D cell culture lack natural tissue-like structural organization and result in disappointing clinical outcomes. The development of efficient drug testing models using 3D cell culture that more accurately reflects in vivo behaviors is vital. Our aim was to establish an in vitro 3D lymphoma model that can imitate the in vivo 3D lymphoma microenvironment. Using this model, we explored strategies to enhance chemosensitivity to doxorubicin, an important chemotherapeutic drug widely used for the treatment of hematological malignancies. Lymphoma cells grown in this model exhibited excellent biomimetic properties compared to conventional 2D culture including (1) enhanced chemotherapy resistance, (2) suppressed rate of apoptosis, (3) upregulated expression of drug resistance genes (MDR1, MRP1, BCRP and HIF-1α), (4) elevated levels of tumor aggressiveness factors including Notch (Notch-1, -2, -3, and -4) and its downstream molecules (Hes-1 and Hey-1), VEGF and MMPs (MMP-2 and MMP-9), and (5) enrichment of a lymphoma stem cell population. Tiam1, a potential biomarker of tumor progression, metastasis, and chemoresistance, was activated in our 3D lymphoma model. Remarkably, we identified two synergistic therapeutic oncotargets, Tiam1 and Notch, as a strategy to combat resistance against doxorubicin in EL4 T and A20 B lymphoma. Therefore, our data suggest that our 3D lymphoma model is a promising in vitro research platform for studying lymphoma biology and therapeutic approaches. PMID:29416753

Radiation-induced interphase death observed in human T-cell lymphoma cells established as a nude mouse tumor line

International Nuclear Information System (INIS)

Igarashi, T.; Yoshida, S.; Miyamoto, T.

1990-01-01

Interphase death of cells occurs physiologically in healthy animal tissues as well as in tissues pathologically injured by radiation or drugs. An active self-destruction process has been found to play a major role in the interphase death of highly radiosensitive cells. However, the mechanism of this radiation-induced interphase death in human lymphoma has not yet been studied in detail. In the present study, we examined a lymphoma derived from a child lymphoblastic lymphoma bearing CD1, CD4, and CD8 antigens and established in nude mice. Low-dose x-irradiation of this lymphoma induced interphase cell death with characteristic morphological and biological changes of an active self-destruction process, i.e., changes in cell surface appearance seen using scanning electron microscopy and nuclear fragmentation accompanied with an increase in free DNA. The process was proved to require protein synthesis. It was concluded that the radiosensitivity of this T-cell lymphoma of common thymic type is mainly due to the occurrence of the active self-destruction process

CpG oligodeoxynucleotide induces apoptosis and cell cycle arrest in A20 lymphoma cells via TLR9-mediated pathways.

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Qi, Xu-Feng; Zheng, Li; Kim, Cheol-Su; Lee, Kyu-Jae; Kim, Dong-Heui; Cai, Dong-Qing; Qin, Jun-Wen; Yu, Yan-Hong; Wu, Zheng; Kim, Soo-Ki

2013-07-01

Recent studies have suggested that the anti-cancer activity of CpG-oligodeoxynucleotides (CpG-ODNs) is owing to their immunomodulatory effects in tumor-bearing host. The purpose of this study is to investigate the directly cytotoxic activity of KSK-CpG, a novel CpG-ODN with an alternative CpG motif, against A20 and EL4 lymphoma cells in comparison with previously used murine CpG motif (1826-CpG). To evaluate the potential cytotoxic effects of KSK-CpG on lymphoma cells, cell viability assay, confocal microscopy, flow cytometry, DNA fragmentation, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used. We found that KSK-CpG induced direct cytotoxicity in A20 lymphoma cells, but not in EL4 lymphoma cells, at least in part via TLR9-mediated pathways. Apoptotic cell death was demonstrated to play an important role in CpG-ODNs-induced cytotoxicity. In addition, both mitochondrial membrane potential decrease and G1-phase arrest were involved in KSK-CpG-induced apoptosis in A20 cells. The activities of apoptotic molecules such as caspase-3, PARP, and Bax were increased, but the activation of p27 Kip1 and ERK were decreased in KSK-CpG-treated A20 cells. Furthermore, autocrine IFN-γ partially contributed to apoptotic cell death in KSK-CpG-treated A20 cells. Collectively, our findings suggest that KSK-CpG induces apoptotic cell death in A20 lymphoma cells at least in part by inducing G1-phase arrest and autocrine IFN-γ via increasing TLR9 expression, without the need for immune system of tumor-bearing host. This new understanding supports the development of TLR9-targeted therapy with CpG-ODN as a direct therapeutic agent for treating B lymphoma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tumor localization of 131I-labeled antibodies by radionuclide imaging

International Nuclear Information System (INIS)

Ghose, T.; Tai, J.; Aquino, J.; Guclu, A.; Norvell, S.; MacDondald, A.

1975-01-01

Intravenous injections of 131 I-labeled anti-EL4 lymphoma antibodies showed progressive localization of radioactivity in EL4 transplants but not in B16 melanoma in mice carrying both tumors. Normal rabbit globulin labeled with 131 I did not localize in either tumor and cleared more slowly from the internal organs. Metastatic localization of intravenous 131 I-labeled anti-tumor antibodies was also observed in two cancer patients. (U.S.)

Modulation of radiation-induced apoptosis and G{sub 2}/M block in murine T-lymphoma cells

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Palayoor, S.T.; Macklis, R.M.; Bump, E.A.; Coleman, C.N. [Harvard Medical School, Boston, MA (United States)

1995-03-01

Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to {sup 137}Cs {gamma} irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of {gamma} radiation. We studied the effect of several pharmacological agents on the radiation-induced G{sub 2}/M block and DNA fragmentation. The agents which reduced the radiation-induced G{sub 2}/M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G{sub 2}/M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G{sub 2}/M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G{sub 2}/M block, and to use this effect in the treatment of patients with malignant disease. 59 refs., 7 figs.

Combination of arsenic and interferon-α inhibits expression of KSHV latent transcripts and synergistically improves survival of mice with primary effusion lymphomas.

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El Hajj, Hiba; Ali, Jihane; Ghantous, Akram; Hodroj, Dana; Daher, Ahmad; Zibara, Kazem; Journo, Chloé; Otrock, Zaher; Zaatari, Ghazi; Mahieux, Renaud; El Sabban, Marwan; Bazarbachi, Ali; Abou Merhi, Raghida

2013-01-01

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.

Identification of IgH gene rearrangement and immunophenotype in an animal model of Epstein-Barr virus-associated lymphomas.

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Zhang, Yang; Peng, Xueqin; Tang, Yunlian; Gan, Xiaoning; Wang, Chengkun; Xie, Lu; Xie, Xiaoli; Gan, Runliang; Wu, Yimou

2016-10-01

Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma. Because the susceptible hosts of EB virus are limited to human and cotton-top tamarins (Saguinus oedipus), there have been no appropriate animal models until the lymphoma model induced by EBV in human peripheral blood lymphocyte (hu-PBL)/SCID chimeric mice was reported. However, it is still controversial whether the EBV-associated lymphoma induced in hu-PBL/SCID mice is a monoclonal tumor. In this study, we transplanted normal human peripheral blood lymphocytes (hu-PBL) from six donors infected with EBV into SCID mice to construct hu-PBL/SCID chimeric mice. The induced tumors were found in the mediastinum or abdominal cavity of SCID mice. Microscopic observation exhibited tumor cells that were large and had a plasmablastic, centroblastic or immunoblastic-like appearance. Immunophenotyping assays showed the induced tumors were LCA-positive, CD20/CD79a-positive (markers of B cells), and CD3/CD45RO-negative (markers of T cells). A human-specific Alu sequence could be amplified by Alu-PCR. This confirmed that induced tumors were B-cell lymphomas originating from the transplanted human lymphocytes rather than mouse cells. EBER in situ hybridization detected positive signals in the nuclei of the tumor cells. Expression of EBV-encoded LMP1, EBNA-1, and EBNA-2 in the tumors was significantly positive. PCR-based capillary electrophoresis analysis of IgH gene rearrangement revealed a monoclonal peak and single amplification product in all six cases of induced tumors. This indicated that EBV can induce monoclonal proliferation of human B lymphocytes and promotes the development of lymphoma. J. Med. Virol. 88:1804-1813, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma

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Stenson, Mary J.; Maurer, Matthew J.; Wellik, Linda E.; Link, Brian; Hege, Kristen; Dogan, Ahmet; Sotomayor, Eduardo; Witzig, Thomas; Gupta, Mamta

2015-01-01

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4EWT) but not cap-mutant eIF4E (eIF4Ecap mutant) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients. PMID:25839159

Human recombinant Fab fragment from combinatorial libraries of a B-cell lymphoma patient recognizes core protein of chondroitin sulphate proteoglycan 4.

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Egami, Yoko; Narushima, Yuta; Ohshima, Motohiro; Yoshida, Akira; Yoneta, Naruki; Masaki, Yasufumi; Itoh, Kunihiko

2018-01-01

CD antigens are well known as therapeutic targets of B-cell lymphoma. To isolate therapeutic antibodies that recognize novel targets other than CD antigens, we constructed a phage display combinatorial antibody Fab library from bone marrow lymphocytes of B-cell lymphoma patient. To eliminate antibodies reactive with known B-cell lymphoma antigen, non-hematopoietic and patient's sera reactive HeLaS3 cells was selected as a target of whole cell panning. Five rounds of panning against live HeLaS3 cells retrieved single Fab clone, termed AHSA (Antibody to HeLa Surface Antigen). Using phage display random peptide library, LSYLEP was identified as an epitope sequence of AHSA. LC-MS/MS analysis of AHSA-precipitated HeLaS3 cell lysates detected several fragments corresponding to the sequence of chondroitin sulphate proteoglycan 4 (CSPG4) core protein. Since LSYLEP sequence was at the position of 313-318 of CSPG4, we considered that CSPG4 was AHSA-associated antigen. Double staining of CSPG4-postive MDA-MB-435S cells with AHSA and anti-CSPG4 rabbit antibody showed identical staining position, and reduced AHSA reactivity was observed in CSPG4-siRNA treated MDA-MB-435S cells. In conclusion, we retrieved a human Fab from antibody library of B-cell lymphoma patient, and identified CSPG4 as a recognizing antigen. AHSA may have potential benefits for development of CSPG4-targeting theranostics for B-cell lymphoma. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Radiation carcinogenesis in mouse thymic lymphomas

International Nuclear Information System (INIS)

Kominami, Ryo; Niwa, Ohtsura

2006-01-01

Ionizing radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of radiation-induced mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the ''indirect mechanism'' for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility. (author)

Vitamin E - its status and role in leukemia and lymphoma

International Nuclear Information System (INIS)

Dasgupta, J.; Das, S.; Sanyal, U.

1993-01-01

A comparative study has been performed on the relationship between vitamin E and immuno-function in normal and malignant condition in human and murine systems. Further, the effects of supplemental vitamin E on tumor take, host survival and tumor growth has been studied in a transplantable lymphoma in mice. Vitamin E was assayed in serum samples from normal subjects and from patient with leukemia and lymphoma by high performance liquid chromatography (HPLC) The murine group included Dalton's ascite lymphoma (DL), Schwartz lymphoblastic leukemia (SVL) and Moloney lymphoblastic leukemia (MVL). Serum vitamin E was found to be lower than that of the normal controls in all cases of leukemia and lymphoma both in human and lymphoma. Supplementary vitamin E administered at the initial phase of development of murine lymphomas reduced the rate of tumor growth, improved host survival and elevated serum vitamin E level. Vitamin E supplementation also activated specific induced blastogenesis of peripheral blood lymphocytes (PBL) and elevated serum IgG level. IgM remained unaltered and and macrophage activity did not seem to be affected. The present findings indicated a low status of vitamin E in tumor bearing host and beneficial effect of supplemental vitamin E on the host which was mediated by the host immune system. (author)

FDG-PET in lymphomas

International Nuclear Information System (INIS)

Knapp, W. H.

2009-01-01

Lymphomas are a heterogeneous group of neoplasms in which two major subtypes are distinguished, Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL). The incidence of lymphomas is about 20 per 100000 inhabitants (Jemal et al 2002) and 7-8 times higher than that of HD. Since NHL has a worse prognosis, the death rates of NHL are 14 times higher than those for HD. Lymphomas account for about 4 % of all cancer incidences. In USA, lymphomas are the fifth most frequent cancer type diagnosed and the third most frequent form of cancer death (Jemal et al 2002). Concerning HD, there is a preponderance for males with a gender ratio of 1.33 for incidence and 1.12 for mortality. For NHL incidences and mortality rates of genders are almost equal. HL comprises different subtypes among which nodular sclerosis is the most frequent one (60-70 %). Other histopathologic subtypes are those of mixed cellularity, lymphocyte reach and lymphocyte depleted characteristics. The most frequent subgroup of NHL are B-cell lymphomas (80-90 % of all NHL). Two thirds of this subgroup are diffuse large B-cell lymphomas, one third follicular lymphomas. Other (less frequent) subtypes are mantle cell, peripheral T-cell, anaplastic large-cell-lymphomas etc. For NHL increasing incidence has been observed in the last decades. Within 15 years the incidence increased by 50 % in the USA (Jemal et al 2002). Etiology of lymphomas is still unknown. In a certain proportion of NHL viral causes are assumed. Diagnosis is based on histology (needle biopsy) with consecutive sub typing. Prognosis depends on stage, expansion state, histology and proliferation rates. (author)

Combination of arsenic and interferon-α inhibits expression of KSHV latent transcripts and synergistically improves survival of mice with primary effusion lymphomas.

Directory of Open Access Journals (Sweden)

Hiba El Hajj

Full Text Available BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV is the etiologic agent of primary effusion lymphomas (PEL. PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. METHODOLOGY/PRINCIPAL FINDINGS: Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. CONCLUSION/SIGNIFICANCE: These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.

ESMO Consensus Conference on malignant lymphoma

DEFF Research Database (Denmark)

Buske, C; Hutchings, M; Ladetto, M

2018-01-01

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommen......The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop...... of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3......) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including...

Lymphoma classification update: B-cell non-Hodgkin lymphomas.

Science.gov (United States)

Jiang, Manli; Bennani, N Nora; Feldman, Andrew L

2017-05-01

Lymphomas are classified based on the normal counterpart, or cell of origin, from which they arise. Because lymphocytes have physiologic immune functions that vary both by lineage and by stage of differentiation, the classification of lymphomas arising from these normal lymphoid populations is complex. Recent genomic data have contributed additional complexity. Areas covered: Lymphoma classification follows the World Health Organization (WHO) system, which reflects international consensus and is based on pathological, genetic, and clinical factors. A 2016 revision to the WHO classification of lymphoid neoplasms recently was reported. The present review focuses on B-cell non-Hodgkin lymphomas, the most common group of lymphomas, and summarizes recent changes most relevant to hematologists and other clinicians who care for lymphoma patients. Expert commentary: Lymphoma classification is a continually evolving field that needs to be responsive to new clinical, pathological, and molecular understanding of lymphoid neoplasia. Among the entities covered in this review, the 2016 revision of the WHO classification particularly impact the subclassification and genetic stratification of diffuse large B-cell lymphoma and high-grade B-cell lymphomas, and reflect evolving criteria and nomenclature for indolent B-cell lymphomas and lymphoproliferative disorders.

Pembrolizumab and Vorinostat in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, or Hodgkin Lymphoma

Science.gov (United States)

2018-04-23

Grade 3a Follicular Lymphoma; Grade 3b Follicular Lymphoma; Recurrent Classical Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Classical Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice.

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Huo, Xueyun; Li, Zhenkun; Zhang, Shuangyue; Li, Changlong; Guo, Meng; Lu, Jing; Lv, Jianyi; Du, Xiaoyan; Chen, Zhenwen

2017-10-01

Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation.

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Liu, Yu; Wen, Pei-Hao; Zhang, Xin-Xue; Dai, Yang; He, Qiang

2018-05-02

Acute liver injury is characterized by fibrosis, inflammation and apoptosis, leading to liver failure, cirrhosis or cancer and affecting the clinical outcome in the long term. However, no effective therapeutic strategy is currently available. Breviscapine, a mixture of flavonoid glycosides, has been reported to have multiple biological functions. The present study aimed to investigate the effects of breviscapine on acute liver injury induced by CCl4 in mice. C57BL/6 mice were subjected to intraperitoneal injection with CCl4 for 8 weeks with or without breviscapine (15 or 30 mg/kg). Mice treated with CCl4 developed acute liver injury, as evidenced by histological analysis, Masson trichrome and Sirius Red staining, accompanied with elevated levels of alanine aminotransferase and aspartate aminotransferase. Furthermore, increases in pro‑inflammatory cytokines, chemokines and apoptotic factors, including caspase‑3 and poly(ADP ribose) polymerase‑2 (PARP‑2), were observed. Breviscapine treatment significantly and dose‑dependently reduced collagen deposition and the fibrotic area. Inflammatory cytokines were downregulated by breviscapine through inactivating Toll‑like receptor 4/nuclear factor-κB signaling pathways. In addition, co‑administration of breviscapine with CCl4 decreased the apoptotic response by enhancing B‑cell lymphoma-2 (Bcl‑2) levels, while reducing Bcl‑2‑associated X protein, apoptotic protease activating factor 1, caspase‑3 and PARP activity. Furthermore, CCl4‑induced oxidative stress was blocked by breviscapine through improving anti‑oxidants and impeding mitogen‑activated protein kinase pathways. The present study highlighted that breviscapine exhibited liver‑protective effects against acute hepatic injury induced by CCl4 via suppressing inflammation and apoptosis.

Cytotoxic T lymphocyte recognition of HLA-A/B antigens introduced into EL4 cells by cell-liposome fusion.

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Engelhard, V H; Powers, G A; Moore, L C; Holterman, M J; Correa-Freire, M C

1984-01-01

HLA-A2 and -B7 antigens were introduced into EL4 (H-2b) cells by cell-liposome fusion and were used as targets or stimulators for cytotoxic T lymphocytes (CTL) generated in C57B1/6 (H-2b) mice. It was found that such EL4-HLA cells were not recognized by CTL that had been raised against either a human cell line bearing these HLA antigens or the purified HLA-A2 and -B7 antigens reconstituted into liposomes. In addition, EL4-HLA cells were not capable of inducing CTL that could recognize a human cell line bearing HLA-A2 and -B7 antigens. Instead, EL4-HLA cells induced CTL that specifically lysed EL4-HLA cells and not human cells expressing HLA-A2 and -B7. CTL recognition required the presence of HLA antigens on the EL4 cell surface and was inhibited by antibodies against either H-2b or HLA-A/B. Monoclonal antibody binding studies showed that the expected polymorphic determinants of the HLA-A2 and -B7 antigens were still present on EL4-HLA cells. However, the specificity of CTL or their precursors that are capable of recognizing HLA-A2 or -B7 was altered after these antigens became associated with the EL4 surface. Possible explanations for these results are discussed.

Enhanced efficacy of gemcitabine in combination with anti-CD20 monoclonal antibody against CD20+ non-Hodgkin's lymphoma cell lines in vitro and in scid mice

Directory of Open Access Journals (Sweden)

Jin Fang

2005-08-01

Full Text Available Abstract Background Despite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL, chemotherapy remains a cornerstone of therapy. While purine nucleoside analogs have significant activity in low grade NHL, the pyrimidine nucleoside analog gemcitabine has been less extensively studied, but has important activity. Use of the anti-CD20 monoclonal antibody rituximab in combination with chemotherapy for B-NHL is becoming prevalent in clinical practice, but has not been extensively studied in pre-clinical models. Methods We have tested the activity of gemcitabine ± rituximab in vitro and in scid/human NHL xenograft models. We used two t(14;18+, CD20+ follicular B cell NHL cell lines, DoHH2 a transformed NHL line and WSU-FSCCL isolated from pleural fluid of a patient with indolent NHL. Results Gemcitabine is cytotoxic to DoHH2 and WSU-FSCCL cells in vitro, and the IC50 is 2–3 fold lower in the presence of rituximab. Apoptosis is also enhanced in the presence of rituximab. Clearance of NHL cells from ascites in scid mice is prolonged by the combination, as compared with either agent alone. Most importantly, survival of scid mice bearing human NHL cells is significantly prolonged by the combination of gemcitabine + rituximab. Conclusion Based on our pre-clinical data showing prolonged survival of mice bearing human lymphoma cell line xenografts after treatment with gemcitabine + anti-CD20 antibody, this combination, expected to have non-overlapping toxicity profiles, should be explored in clinical trials.

Change of Serum IgG4 in Patients with Ocular Adnexal Marginal Zone B Cell Lymphoma Associated with IgG4-Related Ophthalmic Disease After Treatment.

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Wu, Yuan-Hung; Wang, Lei-Chi; Yen, Sang-Hue; Yu, Wei-Kuang; Kao, Shu-Ching; Kau, Hui-Chuan; Tsai, Chieh-Chih; Liu, Catherine Jui-Ling

2017-09-01

To investigate the change of serum IgG4 concentrations correlated with clinical evolution in patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-related ophthalmic disease (IgG4-ROD). Three consecutive patients with histopathologically confirmed ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD were evaluated. Two patients received radiotherapy and 1 patient received steroid therapy. Treatment outcome was evaluated by clinical symptoms, radiologic examination, and change of serum IgG4 level in these patients. All patients had elevated serum IgG4 before treatment (462, 338, and 780 mg/dL respectively.) The 2 patients who received radiotherapy achieved complete remission and the serum IgG4 decreased to 345 and 92 mg/dL, respectively. The patient who underwent systemic steroid achieved partial remission and the serum IgG4 decrease to 161 mg/dL. Our study showed elevated serum IgG4 in all patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD. In addition, the elevated serum IgG4 may decrease or keep stable after treatment, accompanied by improvement in clinical symptoms and reduction of lesions.

Lennert's Lymphoma

International Nuclear Information System (INIS)

Narayanrao, Suresh T.; Pillai, R.; Nada, Aymen; Hasan, Suhel

2005-01-01

Lymphoepithelioid cell lymphoma (Lennert's lymphoma) is a rare morphological variant of peripheral T-cell lymphoma characterized by the presence of numerous clusters of epithelioid histiocytes without formation of discrete granulomas and the intervening atypical lymphocytes. Lennert's lymphoma is often misinterpreted as granulomatous lymphadenitis or Hodgkin's disease. This report describes fine needle aspiration cytology and histological findings in a case of Lennert's lymphoma. (author)

Malignant lymphoma in african lions (panthera leo).

Science.gov (United States)

Harrison, T M; McKnight, C A; Sikarskie, J G; Kitchell, B E; Garner, M M; Raymond, J T; Fitzgerald, S D; Valli, V E; Agnew, D; Kiupel, M

2010-09-01

Malignant lymphoma has become an increasingly recognized problem in African lions (Panthera leo). Eleven African lions (9 male and 2 female) with clinical signs and gross and microscopic lesions of malignant lymphoma were evaluated in this study. All animals were older adults, ranging in age from 14 to 19 years. Immunohistochemically, 10 of the 11 lions had T-cell lymphomas (CD3(+), CD79a(-)), and 1 lion was diagnosed with a B-cell lymphoma (CD3(-), CD79a(+)). The spleen appeared to be the primary site of neoplastic growth in all T-cell lymphomas, with involvement of the liver (6/11) and regional lymph nodes (5/11) also commonly observed. The B-cell lymphoma affected the peripheral lymph nodes, liver, and spleen. According to the current veterinary and human World Health Organization classification of hematopoietic neoplasms, T-cell lymphoma subtypes included peripheral T-cell lymphoma (4/11), precursor (acute) T-cell lymphoblastic lymphoma/leukemia (2/11), chronic T-cell lymphocytic lymphoma/leukemia (3/11), and T-zone lymphoma (1/11). The single B-cell lymphoma subtype was consistent with diffuse large B-cell lymphoma. Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) testing by immunohistochemistry on sections of malignant lymphoma was negative for all 11 lions. One lion was seropositive for FeLV. In contrast to domestic and exotic cats, in which B-cell lymphomas are more common than T-cell lymphomas, African lions in this study had malignant lymphomas that were primarily of T-cell origin. Neither FeLV nor FIV, important causes of malignant lymphoma in domestic cats, seems to be significant in the pathogenesis of malignant lymphoma in African lions.

Dark reticular cells in the thymus of mice

Energy Technology Data Exchange (ETDEWEB)

Jaerplid, B [Foersvarets Forskningsanstalt, Stockholm (Sweden)

1974-01-01

The morphology and distribution of dark reticular cells in the thymus of normal mice, of irradiated mice, and of mice with thymic lymphoma are described. It is concluded that dark cells are epithelial reticular cells and the hypothesis is suggested that dark and light epithelial reticular cells may be different modes of expression of the same cell type. (auth)

CT findings in primary pulmonary lymphomas

International Nuclear Information System (INIS)

Cardinale, Luciano; Allasia, Marco; Cataldi, Aldo; Ferraris, Fabrizio; Fava, Cesare; Parvis, Guido

2005-01-01

Purpose. To describe the CT findings of pathologically confirmed primary pulmonary lymphomas. Materials and methods. The CT examinations of 11 patients with pathologically proven primary pulmonary lymphoma (9 BALT lymphomas and 2 non-BALT lymphomas) were retrospectively reviewed by three radiologists. Evaluated findings included morphology (consolidation, mass, nodule), number and distribution of lesions. Other CT findings such as air bronchogram, lymphadenopathy atelectasis and pleural effusion were also assessed. Results. Pulmonary lesions were depicted as air-space consolidation (pneumonia-like) in 5 patients (45%), tumour-like rounded opacity in 4 (36%), and nodules in 4 (36%). Multiple and bilateral long lesions were seen in 3 patients (27%). Air bronchogram was present in 7 patients (63%), lymphadenopathy in 3 (27%), atelectasis in 4 (36%) and pleural effusion in only 1 (9%). Conclusions. Our results agree with previous studies regarding lesion patterns and their relative frequency. A smaller number of nodules and of multiple lesions were found compared with some previous studies. The most frequent pattern was airspace consolidation [it

Mantle Cell Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Marginal Zone Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Epstein-Barr Virus in Classical Hodgkin Lymphoma

International Nuclear Information System (INIS)

Azhar, M.; Din, H. U.; Muhammad, I.; Hashmi, S. N.; Akhtar, F.

2016-01-01

Background: Epstein-Barr virus plays an important role in pathogenesis of Hodgkin lymphoma. The first patient with Epstein-Barr positive Reed Sternberg cells was described in 1985. Since then association between Epstein-Barr virus and Hodgkin lymphoma has been shown in many parts of the world and its occurrence shows significant variation from continent to continent and from country to country. Method: The study was carried out at department of histopathology, Armed Forces Institute of Pathology from 27th April 2013 to 10th March 2014. A total of 55 cases of classical Hodgkin lymphoma were included in the study. Results: Out of 55 patients, 38 (69 percent) were male and 17 (31 percent) were female. The age of the patients ranged between 4-67 years with an average age of 29.4±21.72 years. Out of these, 44 cases (80 percent) were positive for latent membrane protein-1. Among positive cases 32 (72.72 percent) were male and 12 (27.28 percent) were female. Based upon histological subtypes MCHL was the commonest as a whole accounting for 87.3 percent as well as among both genders. Out of total 55 cases, 79.16 percent (38/48) of mixed cellularity Hodgkin lymphoma cases showed positivity for latent membrane protein-1 while 83.33 percent (5/6) cases of nodular sclerosis Hodgkin lymphoma and 100 percent (1/1) cases of lymphocyte depleted Hodgkin lymphoma showed positivity. No case of lymphocyte predominant classical Hodgkin lymphoma was diagnosed during the study. 80 percent of our classical Hodgkin lymphoma cases showed association with EBV expression. A total of 79.16 percent cases of mixed cellularity Hodgkin lymphoma showed LMP1 expression while 100 percent of lymphocyte depleted Hodgkin lymphoma showed LMP1 expression. Conclusion: The highest expression seen in lymphocyte depleted Hodgkin lymphoma subtype in contrast to mixed cellularity requires to be confirmed by a larger scale study comprising of substantial number of patients of lymphocyte depleted Hodgkin lymphoma

Immunologic mechanism of the suppressive effect of low dose radiation on thymic lymphoma induced by radiation

International Nuclear Information System (INIS)

Li Xiujuan; Yang Ying; Li Xiuyi; Liu Shuzheng

1999-01-01

To study immunologic mechanism of the suppressive effect of low dose radiation (LDR) on thymic lymphoma (TL) induced by high dose radiation (HDR). The authors adopted the model that C57BL/6J mice were administered whole body irradiation with 1.75 Gy X-rays one time every week for 4 weeks to induce TL. It was examined that splenic NK cytotoxic activity, IL-2 and γ-IFN secretion activity, peritoneal macrophage phagocytosis and its TNF-α secretion activity in mice with different dose 1 month after irradiation. The results showed that all the immunologic functions mentioned above in mice given 75 mGy 12 h before 1.75 Gy every time were higher than that in mice given only 1.75 Gy, and approached to the sham-irradiation mice. It suggested that the suppressive effect of LDR on TL induced by HDR may be related to the adaptive response induced by LDR and decreasing immunological functions damage caused by HDR

Benzene exposure and risk of non-Hodgkin lymphoma.

Science.gov (United States)

Smith, Martyn T; Jones, Rachael M; Smith, Allan H

2007-03-01

Exposure to benzene, an important industrial chemical and component of gasoline, is a widely recognized cause of leukemia, but its association with non-Hodgkin lymphoma (NHL) is less clear. To clarify this issue, we undertook a systematic review of all case-control and cohort studies that identified probable occupational exposures to benzene and NHL morbidity or mortality. We identified 43 case-control studies of NHL outcomes that recognized persons with probable occupational exposure to benzene. Forty of these 43 (93%) studies show some elevation of NHL risk, with 23 of 43 (53%) studies finding statistically significant associations between NHL risk and probable benzene exposure. We also identified 26 studies of petroleum refinery workers reporting morbidity or mortality for lymphomas and all neoplasms and found that in 23 (88%), the rate of lymphoma morbidity or mortality was higher than that for all neoplasms. A substantial healthy-worker effect was evident in many of the studies and a comprehensive reevaluation of these studies with appropriate adjustments should be undertaken. Numerous studies have also reported associations between benzene exposure and the induction of lymphomas in mice. Further, because benzene is similar to alkylating drugs and radiation in producing leukemia, it is plausible that it might also produce lymphoma as they do and by similar mechanisms. Potential mechanisms include immunotoxicity and the induction of double-strand breaks with subsequent chromosome damage resulting in translocations and deletions. We conclude that, overall, the evidence supports an association between occupational benzene exposure and NHL.

Protection afforded by pre- or post-treatment with 4-phenylbutyrate against liver injury induced by acetaminophen overdose in mice.

Science.gov (United States)

Shimizu, Daisuke; Ishitsuka, Yoichi; Miyata, Keishi; Tomishima, Yoshiro; Kondo, Yuki; Irikura, Mitsuru; Iwawaki, Takao; Oike, Yuichi; Irie, Tetsumi

2014-09-01

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100-200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X-box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP-induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4-PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP

STAT3/5-dependent IL9 overexpression contributes to neoplastic cell survival in mycosis fungoides

DEFF Research Database (Denmark)

Vieyra-Garcia, Pablo A.; Wei, Tianling; Naym, David Gram

2016-01-01

preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice.  Results...

The cellular cancer resistance of the SR/CR mouse

DEFF Research Database (Denmark)

Koch, Janne; Hau, Jann; Jensen, Henrik Elvang

2012-01-01

The SR/CR mouse phenotype, first described in 1999 in BALB/c and later bred into C57BL/6 mice, is resistant to cancer formation following high doses of cancer cells administered intraperitoneally. The tumor cell targeting and destruction mechanisms have not been identified. By fluorescence-activa...... controls. Importantly, this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4....

Lymphoma of the eyelid

DEFF Research Database (Denmark)

Svendsen, Frederik Holm; Heegaard, Steffen

2017-01-01

Lymphoma of the eyelid constitutes 5% of ocular adnexal lymphoma. In previously published cases, 56% of lymphomas of the eyelid are of B-cell origin and 44% are of T-cell origin. The most frequent B-cell lymphomas are extranodal marginal zone lymphoma (27 cases-14%) and diffuse large B......-cell lymphoma (18 cases-9%). T-cell lymphomas are most frequently mycosis fungoides (25 cases-13%), extranodal natural killer/T-cell, nasal-type lymphoma (12 cases-6%), and primary cutaneous anaplastic large-cell lymphoma (12 cases-6%). This distribution differs from the distribution of ocular adnexal lymphoma...... and that of cutaneous lymphoma. The majority of subtypes occur in elderly patients, except for lymphoblastic lymphoma of B-cell and T-cell origin and Burkitt lymphoma, which occur in children and adolescents. Several subtypes have a male predominance, including peripheral T-cell lymphoma and Burkitt lymphoma. Only...

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

DEFF Research Database (Denmark)

Choudhari, Ramesh; Minero, Valerio Giacomo; Menotti, Matteo

2016-01-01

Increasing evidence suggests that Rho family GTPases could have a critical role in the biology of T-cell lymphoma. In ALK-rearranged anaplastic large cell lymphoma (ALCL), a specific subtype of T-cell lymphoma, the Rho family GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity. In ...

Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

Science.gov (United States)

2018-04-10

Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Primary Cutaneous B-Cell Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Non-Hodgkin Lymphoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

Transgenic Mice Over-Expressing RBP4 Have RBP4-Dependent and Light-Independent Retinal Degeneration.

Science.gov (United States)

Du, Mei; Phelps, Eric; Balangue, Michael J; Dockins, Aaron; Moiseyev, Gennadiy; Shin, Younghwa; Kane, Shelley; Otalora, Laura; Ma, Jian-Xing; Farjo, Rafal; Farjo, Krysten M

2017-08-01

Transgenic mice overexpressing serum retinol-binding protein (RBP4-Tg) develop progressive retinal degeneration, characterized by microglia activation, yet the precise mechanisms underlying retinal degeneration are unclear. Previous studies showed RBP4-Tg mice have normal ocular retinoid levels, suggesting that degeneration is independent of the retinoid visual cycle or light exposure. The present study addresses whether retinal degeneration is light-dependent and RBP4-dependent by testing the effects of dark-rearing and pharmacological lowering of serum RBP4 levels, respectively. RBP4-Tg mice reared on normal mouse chow in normal cyclic light conditions were directly compared to RBP4-Tg mice exposed to chow supplemented with the RBP4-lowering compound A1120 or dark-rearing conditions. Quantitative retinal histological analysis was conducted to assess retinal degeneration, and electroretinography (ERG) and optokinetic tracking (OKT) tests were performed to assess retinal and visual function. Ocular retinoids and bis-retinoid A2E were quantified. Dark-rearing RBP4-Tg mice effectively reduced ocular bis-retinoid A2E levels, but had no significant effect on retinal degeneration or dysfunction in RBP4-Tg mice, demonstrating that retinal degeneration is light-independent. A1120 treatment lowered serum RBP4 levels similar to wild-type mice, and prevented structural retinal degeneration. However, A1120 treatment did not prevent retinal dysfunction in RBP4-Tg mice. Moreover, RBP4-Tg mice on A1120 diet had significant worsening of OKT response and loss of cone photoreceptors compared to RBP4-Tg mice on normal chow. This may be related to the very significant reduction in retinyl ester levels in the retina of mice on A1120-supplemented diet. Retinal degeneration in RBP4-Tg mice is RBP4-dependent and light-independent.

Follicular non-Hodgkin's lymphoma

International Nuclear Information System (INIS)

Hayashi, D.; Lee, J.C.; Devenney-Cakir, B.; Zaim, S.; Ounadjela, S.; Solal-Celigny, P.; Juweid, M.; Guermazi, A.

2010-01-01

Follicular non-Hodgkin's lymphoma (NHL) is a unique subtype of NHL, which is indolent, incurable with a high prevalence of residual mass after treatment, and may transform to more aggressive NHL. The aim of this review is to (1) describe the histological and flow cytometry characteristics of follicular NHL; (2) introduce the Follicular Lymphoma International Prognostic Index 2 (FLIPI-2), which allows better treatment selection and patient stratification for clinical trials; (3) illustrate the classic and atypical ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET)/CT appearance of follicular NHL; and (4) characterize the appearance of nodal and extranodal follicular NHL with pathological correlation. Imaging is essential in every step of the management of patients with follicular lymphoma. Overall survival is improved with better predictive tools and new targeted biological therapies. Radiologists should be aware of possible active residual mass, indolent recurrence, transformation, and association with other primary cancers in patients treated for follicular lymphoma.

Expression of antigens coded in murine leukemia viruses on thymocytes of allogeneic donor origin in AKR mice following syngeneic or allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Wustrow, T.P.; Good, R.A.

1985-01-01

Removal of T-lymphocytes from marrow inoculum with monoclonal antibody plus complement permitted establishment of long-lived allogeneic chimeras between C57BL/6 and AKR/J mice. Development of leukemia was prevented for 15 mo. Protection from leukemia occurred with both young (4 wk) and older (4 mo) recipients. AKR mice reconstituted with syngeneic marrow or control AKR mice all developed leukemia-lymphoma before 1 yr of age. During spontaneous lymphomagenesis in AKR mice, amplified expression of gag or env gene-coded virus antigens on the surface of thymocytes preceded leukemia development and evidence for amplification of other virus genes. These changes generally appeared before 6 mo. Similar viral gene expression and viral gene amplification occurred in the thymus and spleen cells of leukemia-resistant chimeric mice. Using monoclonal antibodies to Mr 70,000 glycoprotein epitopes characteristic of ecotropic, xenotropic, or dualtropic viruses, antigens marking each virus form were found on thymocytes of allogeneic 4-wk and 4-mo chimeras as well as on the cells of AKR mice and of AKR mice reconstituted with syngeneic marrow. Flow cytometric analysis showed amplification of the virus genes in mice protected from leukemia-lymphoma by allogeneic bone marrow transplantation from leukemia-resistant mice. Allogeneic chimeras and syngeneically transplanted mice both showed evidence of accelerated viremia and of recombinant virus formation. The findings suggest that an event essential to leukemogenesis which occurs within the AKR lymphoid cells or their environment is lacking in the allogeneic chimeras. The nature of this influence of a resistance gene or genes introduced into AKR mice by allogeneic bone marrow transplantation deserves further study

MALT LYMPHOMA OF PALATE AND ORBIT

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VIVIANA ANDREA CIFUENTES NAVAS

2018-05-01

Full Text Available TITLE: Malt palate and orbit lymphoma  Authors: CIFUENTES NAVAS-Viviana Andrea; MARTÍN PASCUAL- María Consolación; FERNÁNDEZ RODRÍGUEZ- Ana; ALONSO MESONERO- Marta; CHAVIANO GRAHJERA-Juan; MORAIS PÉREZ-Darío. INTRODUCTIONMALT-type lymphomas are lymphoid proliferations originated in the glandular epithelium of organs like the stomach, the salivary and lacrimal glands, and even, we can find lymphoid neoformations of non-epithelial localization, like in the orbital soft tissue. The lymphomas of the mucosal-associated lymphatic tissue (MALT represent only 0.2-0.3% and constitute a well-defined group of non-Hodgkin lymphomas of B origin. In the field of oral pathology, the salivary glands, tonsils and palate are mainly affected, it is more rare to find it in jugal mucosa.We present a rare case of MALT lymphoma with involvement of the palate and orbit. MATERIAL AND METHODS84-year-old patient with multiple pathologies. Derived from his primary care physician due to pharyngeal complaints of 4 to 5 days of evolution, associated with a painful palate lesion.He presented in right hemipaladar a tumoration of elastic consistency in submucosa, ulcerated in the center, with normal neck. Also left orbital tumor that limits the visual field. RESULTSCT and MRI of the neck report mass of 4x4 x2.5 cm in right hemipaladar, noninfiltrating concordant with possible lymphoma. The orbital MRI describes an intra and extra nasal left nasal lesion of 2.3x1.2x2 cm with characteristics consistent with lymphoma. CT of the neck: It demostrates a great mass of right hemipaladar, with lobulated contours and homogeneous enhancement of 40x32x25 mm, in intimate contact with medial pterygoid muscle, although there were no signs of infiltration, the rest of the edges being well delimited. Images characteristics look like a lymphoma, without being able to rule out other etiologies. MRI of the neck: It demostrates a diffuse thickening of right side of the soft palate that

Immunity against mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N-butyl-N-nitrosourea.

Science.gov (United States)

Tsujimura, Kunio; Obata, Yuichi; Matsudaira, Yasue; Ozeki, Satoshi; Taguchi, Osamu; Nishida, Keiko; Okanami, Yuko; Akatsuka, Yoshiki; Kuzushima, Kiyotaka; Takahashi, Toshitada

2004-11-01

Mouse thymus-leukemia antigens (TL) are aberrantly expressed on T lymphomas in C57BL/6 (B6) and C3H/He (C3H) mice, while they are not expressed on normal T lymphocytes in these strains. When N-butyl-N-nitrosourea (NBU), a chemical carcinogen, was administered orally to B6 and C3H strains, lymphoma development was slower than in T3(b)-TL gene-transduced counterpart strains expressing TL ubiquitously as self-antigens, suggesting that anti-TL immunity may play a protective role. In addition, the development of lymphomas was slightly slower in C3H than in B6, which seems to be in accordance with the results of skin graft experiments indicating that both cellular and humoral immunities against TL were stronger in C3H than B6 mice. The interesting finding that B lymphomas derived from a T3(b)-TL transgenic strain (C3H background) expressing a very high level of TL were rejected in C3H, but not in H-2K(b) transgenic mice (C3H background), raises the possibility that TL-specific effector T cell populations are eliminated and/or energized to a certain extent by interacting with H-2K(b) molecules.

Aberrant Expression of ID2 protein and its correlation with EBV-LMP1 and P16(INK4A) in Classical Hodgkin Lymphoma in China

International Nuclear Information System (INIS)

Zhao, Po; Lu, Yali; Liu, Lin; Zhong, Mei

2008-01-01

The relationships between the expression of ID2, EBV-LMP1 and P16(INK4A) in Chinese classical Hodgkin lymphoma are unknown and need exploring. Samples of classical Hodgkin lymphoma from 60 Chinese patients were analyzed for the expression of ID2, EBV-LMP1 and p16(INK4A) proteins by immunohistochemistry. ID2 protein was expressed in 83.3% of this group of classical Hodgkin lymphoma, staining strongly in both cytoplasm and nucleus of the Hodgkin and Reed-Sternberg (HRS) cells. EBV-LMP1 and P16(INK4A) were overexpressed in 85.0% and 71.7% of Hodgkin lymphoma, respectively. EBV-LMP1 was noted in the cytoplasm, membrane and nucleus of HRS cells; P16(INK4A) was in the nucleus and cytoplasm. Microscopically, ID2, EBV-LMP1 and P16(INK4A) staining distinguished the HRS cells from the complex background of lymphocytes. ID2 was positively correlated with EBV-LMP1(P < 0.01), but P16(INK4A) was inversely related to EBV-LMP1 (P < 0.05). It is suggested that ID2, EBV-LMP1 and P16(INK4A) could play an important role in the evolution of classical Hodgkin lymphoma, and be considered as potential adjunct markers to identify HRS cells in diagnosis

The carcinogenic effects of fetal and postnatal radiation in female mice

International Nuclear Information System (INIS)

Kusama, Tomoko; Yoshizawa, Yasuo

1982-01-01

The present study was designed to investigate the carcinogenic effects of fetal and postnatal irradiation in female mice. The C57BL/6J mice were subjected to whole-body exposure to 1-Gy or 4-Gy 137 Cs γ-ray irradiation on the 15th fetal day or the 30th postnatal day. Following this, all mice were observed throughout their respective life spans under conventional rearing conditions. The tumor incidence rate, average latent period and distributions of various tumors were used as the quantitative parameters of radiation-induced carcinogenesis. The following conclusions can be draw: (1) The mean life span of mice that underwent 4-Gy irradiation at the age of 30 days was shorter than that of non-irradiated control mice. (2) In control mice, the tumor incidence was 75.7%. (3) In order to estimate the mean age and tumor incidence, an adjustment for competing death is necessary. (4) The adjusted tumor incidences of thymic lymphoma and breast tumor of the irradiated groups were not different from those of control group. On the other hand, there was a significant difference between the two in the adjusted incidence of reticular tissue neoplasm. (author)

Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[a,l]pyrene: The importance of in utero vs. lactational exposure

International Nuclear Information System (INIS)

Castro, David J.; Loehr, Christiane V.; Fischer, Kay A.; Pereira, Clifford B.; Williams, David E.

2008-01-01

The fetus and neonate cannot be viewed as 'little adults'; they are highly sensitive to toxicity from environmental chemicals. This phenomenon contributes to the fetal basis of adult disease. One example is transplacental carcinogenesis. Animal models demonstrate that environmental chemicals, to which pregnant women are daily exposed, can increase susceptibility of the offspring to cancer. It is uncertain to what degree in utero vs. lactational exposure contributes to cancer, especially for hydrophobic chemicals such as polyhalogenated biphenyls, ethers, dioxins, furans, etc., which can partition into breast milk. We developed a pregnant mouse model in which exposure to the polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), during late gestation, produces an aggressive T-cell lymphoma in offspring between 3 and 6 months of age. Survivors exhibit multiple lung and liver (males) tumors. Here, we adopt a cross-foster design with litters born to dams treated with DBP exchanged with those born to dams treated with vehicle. Exposure to DBP in utero (about 2 days) produced significantly greater mortality than residual DBP exposure only through breast milk (3 weeks of lactation). As previously observed pups in all groups with an ahr b-1/d ('responsive') genotype were more susceptible to lymphoma mortality than ahr d/d ('non-responsive') siblings. At termination of the study at 10 months, mice exposed in utero also had greater lung tumor multiplicity than mice exposed only during lactation. Our results demonstrate that short exposure to DBP during late gestation presents a greater risk to offspring than exposure to this very hydrophobic PAH following 3 weeks of nursing

Composite Lymphoma : EBV-positive Classic Hodgkin Lymphoma and Peripheral T-cell Lymphoma A Case Report

NARCIS (Netherlands)

Gualco, Gabriela; Chioato, Lucimara; Van Den Berg, Anke; Weiss, Lawrence M.; Bacchi, Carlos E.

Composite lymphomas are rare and defined as hematopoietic neoplasms with more than I malignant lymphomatous clone showing different phenotypic features. Of all possible combinations between non-Hodgkin lymphomas, B cell or T cell, and Hodgkin lymphoma, the least frequent are the ones combining

Doxorubicin attached to HPMA copolymer via amide bond modifies the glycosylation pattern of EL4 cells.

Science.gov (United States)

Kovar, Lubomir; Etrych, Tomas; Kabesova, Martina; Subr, Vladimir; Vetvicka, David; Hovorka, Ondrej; Strohalm, Jiri; Sklenar, Jan; Chytil, Petr; Ulbrich, Karel; Rihova, Blanka

2010-08-01

To avoid the side effects of the anti-cancer drug doxorubicin (Dox), we conjugated this drug to a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone. Dox was conjugated via an amide bond (Dox-HPMA(AM), PK1) or a hydrazone pH-sensitive bond (Dox-HPMA(HYD)). In contrast to Dox and Dox-HPMA(HYD), Dox-HPMA(AM) accumulates within the cell's intracellular membranes, including those of the Golgi complex and endoplasmic reticulum, both involved in protein glycosylation. Flow cytometry was used to determine lectin binding and cell death, immunoblot to characterize the presence of CD7, CD43, CD44, and CD45, and high-performance anion exchange chromatography with pulsed amperometric detector analysis for characterization of plasma membrane saccharide composition. Incubation of EL4 cells with Dox-HPMA(AM) conjugate, in contrast to Dox or Dox-HPMA(HYD), increased the amounts of membrane surface-associated glycoproteins, as well as saccharide moieties recognized by peanut agglutinin, Erythrina cristagalli, or galectin-1 lectins. Only Dox-HPMA(AM) increased expression of the highly glycosylated membrane glycoprotein CD43, while expression of others (CD7, CD44, and CD45) was unaffected. The binding sites for galectin-1 are present on CD43 molecule. Furthermore, we present that EL4 treated with Dox-HPMA(AM) possesses increased sensitivity to galectin-1-induced apoptosis. In this study, we demonstrate that Dox-HPMA(AM) treatment changes glycosylation of the EL4 T cell lymphoma surface and sensitizes the cells to galectin-1-induced apoptosis.

Non-Hodgkin lymphoma in Romania: a single-centre experience.

Science.gov (United States)

Fetica, Bogdan; Achimas-Cadariu, Patriciu; Pop, Bogdan; Dima, Delia; Petrov, Ljubomir; Perry, Anamarija M; Nathwani, Bharat N; Müller-Hermelink, Hans K; Diebold, Jacques; MacLennan, Kenneth A; Fulop, Annamaria; Blaga, Mihaiela L; Coza, Daniela; Nicula, Florian Al; Irimie, Alexandru; Weisenburger, Dennis D

2017-06-01

Epidemiologic studies of non-Hodgkin lymphoma (NHL) in Eastern Europe are scarce in the literature. We report the experience of the "Ion Chiricuta" Institute of Oncology in Cluj-Napoca (IOCN), Romania, in the diagnosis and outcome of patients with NHL. We studied 184 consecutive NHL patients diagnosed in the Pathology Department of IOCN during the years 2004-2006. We also obtained epidemiological data from the Northwestern (NW) Cancer Registry. In the IOCN series, the most common lymphoma subtype was diffuse large B-cell lymphoma (43.5%), followed by the chronic lymphocytic leukaemia/small lymphocytic lymphoma (21.2%). T-cell lymphomas represented a small proportion (8.2%). The median age of the patients was 57 years, with a male-to-female ratio of 0.94. Patients with indolent B-cell lymphomas had the best overall survival, whereas those with mantle cell lymphoma had the worst survival. The NW Cancer Registry data showed that the occurrence of NHL in the NW region of Romania was higher in men [world age-standardized incidence rate/100 000 (ASR)-5.9; 95% CI 5.1-6.6] than in women (ASR-4.1; 95% CI 3.5-4.7) with age-standardized male-to-female ratio of 1.44 (p = 0.038). Chronic lymphocytic leukaemia/small lymphocytic lymphoma was the most common NHL in the NW region of Romania, accounting for 43% of all cases, followed by diffuse large B-cell lymphoma (36%). The 5-year, age-standardized cumulative relative survival for NHL in the County of Cluj in NW Romania, for the period of 2006-2010, was 51.4%, with 58.4% survival for men and 43.2% for women. Additional studies of NHL in Eastern Europe are needed. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Pediatric Type Follicular Lymphoma: A Rare Entity with Excellent Prognosis

Science.gov (United States)

2018-01-19

YYYY) 12. REPORT TYPE 19/01/2018 Poster 4. TITLE AND SUBTITLE Pediatric -Type Follicular Lymphoma: A Rare Entity with Excellent Prognosis 6. AUTHOR(S...lymphoma is common in older adults but rare in pediatric and young adult patients. Pediatric follicular lymphoma comprises a only 6.5% of childhood... Pediatric follicular lymphoma is defined by a localized high grade appearing lymphoma that lacks these gene rearrangements. Other diagnoses to rule out

Expression of CD56 and Epstein-Barr virus in nasal/nasopharyngeal lymphoma

International Nuclear Information System (INIS)

Lee, Seung Sook; Cho, Kyung Ja

1997-12-01

We examined malignant lymphomas and polymorphic reticulosis of nasal cavity, nasopharynx, and palate, diagnosed at Korea Cancer Center Hospital from 1987 to 1996. With immunophenotypic study, we reclassified nasal/nasopharyngeal lymphomas into three categories: CD56-positive T/NK lymphoma, CD56-negative lymphoma and B-cell lymphoma. Malignant lymphomas of nasal cavity, nasopharynx and palate were 95 patient, that comprised 11% of the total lymphoma cases, and it was the most common extranodal lymphoma. Twenty-five percent were B-cell lymphomas and 75 % were T/NK lymphomas. According to site, nasal cavity was the most frequent and 91 % of nasal cavity lymphomas were T/NK type. CD56-positive T/NK comprised 82 % of total T/NK lymphomas and CD56-negative cases were 18 %. In 89 % of total T/NK lymphomas, many tumor cells expressed EBER-1 in their nuclei (CD56+ T/NK lymphoma: 97 % of EBV expression, CD56-T-cell lymphoma; 60%). Only one case (5%) of B-cell lymphoma showed EBER-1 positivity in a few cells. CD56+ T/NK lymphomas showed significantly more angiocentricity and severe necrosis than CD56- cases. Although it has no statistical significance, T/NK lymphomas has a tendency to lower survival rates than B-cell lymphomas at 1 year and 2 year. CD56+ T/NK lymphomas has a tendency to lower survival than CD56- T/NK lymphomas (p > 0.05). Our results of this project will serve important basic materials in diagnosing and studying lymphoma. (author). 25 refs., 4 tabs., 4 figs

J chain and myocyte enhancer factor 2B are useful in differentiating classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.

Science.gov (United States)

Moore, Erika M; Swerdlow, Steven H; Gibson, Sarah E

2017-10-01

Although most classical Hodgkin lymphomas (CHLs) are easily distinguished from nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and primary mediastinal large B-cell lymphoma (PMBL), cases with significant CD20 expression cause diagnostic confusion. Although the absence of OCT-2 and BOB.1 are useful in these circumstances, a variable proportion of CHLs are positive for these antigens. We investigated the utility of J chain and myocyte enhancer factor 2B (MEF2B) in the diagnosis of CHL; NLPHL; PMBL; T-cell/histiocyte-rich large B-cell lymphoma (TCRLBL); and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL, compared with OCT-2 and BOB.1. J chain and MEF2B highlighted lymphocyte predominant (LP) cells in 20/20 (100%) NLPHLs and were negative in 43/43 (100%) CHLs. Fourteen of 15 (93%) PMBLs and 4/4 (100%) TCRLBLs were MEF2B positive, whereas 67% of PMBLs and 50% of TCRLBLs were J chain positive. Three of 3 B-cell lymphomas, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL, were negative for J chain and MEF2B. J chain and MEF2B were 100% sensitive and specific for NLPHL versus CHL. MEF2B was 100% sensitive and 98% specific for PMBL versus CHL. Whereas loss of OCT-2 and/or BOB.1 expression had a sensitivity of only 86% and specificity of 100% for CHL versus NLPHL, PMBL, and TCRLBL, lack of both J chain and MEF2B expression was 100% sensitive and 97% specific. J chain and MEF2B are highly sensitive and specific markers of NLPHL versus CHL; are particularly useful in highlighting LP cells; and, with rare exception, are of greater utility than OCT-2 and BOB.1 in differentiating CHL from NLPHL and other large B-cell lymphomas. Copyright © 2017 Elsevier Inc. All rights reserved.

Immunomodulatory Effects of Hemagglutinin- (HA- Modified A20 B-Cell Lymphoma Expanded as a Brain Tumor on Adoptively Transferred HA-Specific CD4+ T Cells

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Valentin P. Shichkin

2014-01-01

Full Text Available Previously, the mouse A20 B-cell lymphoma engineered to express hemagglutinin (HA antigen (A20HA was used as a systemic tumor model. In this work, we used the A20HA cells as a brain tumor. HA-specific CD4+ T cells were transferred intravenously in a tail vein 5 days after A20HA intracranial inoculation and analyzed on days 2, 9, and 16 after the adoptive transfer by different methods. The transferred cells demonstrated state of activation as early as day 2 after the adoptive transfer and most the of viable HA-specific cells became anergic on day 16. Additionally, symptoms of systemic immunosuppression were observed in mice with massive brain tumors at a late stage of the brain tumor progression (days 20–24 after the A20HA inoculation. Despite that, a deal of HA-specific CD4+ T cells kept the functional activity even at the late stage of A20HA tumor growth. The activated HA-specific CD4+ T cells were found also in the brain of brain-tumor-bearing mice. These cells were still responding to reactivation with HA-peptide in vitro. Our data support an idea about sufficient role of both the tumor-specific and -nonspecific mechanisms inducing immunosuppression in cancer patients.

Genetic analysis of radiation-induced mouse thymic lymphomas

International Nuclear Information System (INIS)

Kominami, R.; Wakabayashi, Y.; Niwa, O.

2003-01-01

Mouse thymic lymphomas are one of the classic models of radiation-induced malignancies, and the model has been used for the study of genes involved in carcinogenesis. ras oncogenes are the first isolate which undergoes mutations in 10 to 30 % of lymphomas, and p16INK4a and p19ARF in the INK4a-ARF locus are also frequently inactivated. In our previous study, the inactivation of Ikaros, a key regurator of lymphoid system, was found in those lymphomas, and it was suggested that there are other responsible genes yet to be discovered. On the other hand, genetic predisposition to radiation-induced lymphoma often differs in different strains, and this reflects the presence of low penetrance genes that can modify the impact of a given mutation. Little study of such modifiers or susceptibility genes has been performed, either. Recent availability of databases on mouse genome information and the power of mouse genetic system underline usefulness of the lymphoma model in search for novel genes involved, which may provide clues to molecular mechanisms of development of the radiogenic lymphoma and also genes involved in human lymphomas and other malignancies. Accordingly, we have carried out positional cloning for the two different types of tumor-related genes. In this symposium, our current progress is presented that includes genetic mapping of susceptibility/ resistance loci on mouse chromosomes 4, 5 and 19, and also functional analysis of a novel tumor suppressor gene, Rit1/Bcl11b, that has been isolated from allelic loss (LOH) mapping and sequence analysis for γ -ray induced mouse thymic lymphomas

Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis

International Nuclear Information System (INIS)

He, Xin; Chen, Zhigang; Fu, Tao; Jin, Xueli; Yu, Teng; Liang, Yun; Zhao, Xiaoying; Huang, Liansheng

2014-01-01

Ki-67 is a nuclear protein involved in cell proliferation regulation, and its expression has been widely used as an index to evaluate the proliferative activity of lymphoma. However, its prognostic value for lymphoma is still contradictory and inconclusive. PubMed and Web of Science databases were searched with identical strategies. The impact of Ki-67 expression on survival with lymphoma and various subtypes of lymphoma was evaluated. The relationship between Ki-67 expression and Diffuse Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) was also investigated after the introduction of a CD-20 monoclonal antibody rituximab. Furthermore, we evaluated the association between Ki-67 expression and the clinical-pathological features of lymphoma. A total of 27 studies met the inclusion criteria, which comprised 3902 patients. Meta-analysis suggested that high Ki-67 expression was negatively associated with disease free survival (DFS) (HR = 1.727, 95% CI: 1.159-2.571) and overall survival (OS) (HR = 1.7, 95% CI: 1.44-2) for lymphoma patients. Subgroup analysis on the different subtypes of lymphoma suggested that the association between high Ki-67 expression and OS in Hodgkin Lymphoma (HR = 1.511, 95% CI: 0.524-4.358) was absent, while high Ki-67 expression was highly associated with worse OS for Non-Hodgkin Lymphoma (HR = 1.777, 95% CI: 1.463-2.159) and its various subtypes, including NK/T lymphoma (HR = 4.766, 95% CI: 1.917-11.849), DLBCL (HR = 1.457, 95% CI: 1.123-1.891) and MCL (HR = 2.48, 95% CI: 1.61-3.81). Furthermore, the pooled HRs for MCL was 1.981 (95% CI: 1.099-3.569) with rituximab and 3.123 (95% CI: 2.049-4.76) without rituximab, while for DLBCL, the combined HRs for DLBCL with and without rituximab was 1.459 (95% CI: 1.084-2.062) and 1.456 (95% CI: 0.951-2.23) respectively. In addition, there was no correlation between high Ki-67 expression and the clinical-pathological features of lymphoma including the LDH level, B symptoms, tumor stage

Peripheral T-Cell Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Angioimmunoblastic T-Cell Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Anaplastic Large Cell Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

Science.gov (United States)

2017-04-17

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Waldenström Macroglobulinemia

IL-4 deficiency is associated with mechanical hypersensitivity in mice.

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Nurcan Üçeyler

Full Text Available Interleukin-4 (IL-4 is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko mice to characterize their pain behavior before and after chronic constriction injury (CCI of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS of IL-4 ko mice in comparison with wildtype (wt mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001, while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF, IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014. Remarkably, CCI induced TNF (p<0.01, IL-1β (p<0.05, IL-10 (p<0.05, and IL-13 (p<0.001 gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion.

Membrane raft organization is more sensitive to disruption by (n-3) PUFA than nonraft organization in EL4 and B cells.

Science.gov (United States)

Rockett, Benjamin Drew; Franklin, Andrew; Harris, Mitchel; Teague, Heather; Rockett, Alexis; Shaikh, Saame Raza

2011-06-01

Model membrane and cellular detergent extraction studies show (n-3) PUFA predominately incorporate into nonrafts; thus, we hypothesized (n-3) PUFA could disrupt nonraft organization. The first objective of this study was to determine whether (n-3) PUFA disrupted nonrafts of EL4 cells, an extension of our previous work in which we discovered an (n-3) PUFA diminished raft clustering. EPA or DHA treatment of EL4 cells increased plasma membrane accumulation of the nonraft probe 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate by ~50-70% relative to a BSA control. Förster resonance energy transfer imaging showed EPA and DHA also disrupted EL4 nanometer scale nonraft organization by increasing the distance between nonraft molecules by ~25% compared with BSA. However, changes in nonrafts were due to an increase in cell size; under conditions where EPA or DHA did not increase cell size, nonraft organization was unaffected. We next translated findings on EL4 cells by testing if (n-3) PUFA administered to mice disrupted nonrafts and rafts. Imaging of B cells isolated from mice fed low- or high-fat (HF) (n-3) PUFA diets showed no change in nonraft organization compared with a control diet (CD). However, confocal microscopy revealed the HF (n-3) PUFA diet disrupted lipid raft clustering and size by ~40% relative to CD. Taken together, our data from 2 different model systems suggest (n-3) PUFA have limited effects on nonrafts. The ex vivo data, which confirm previous studies with EL4 cells, provide evidence that (n-3) PUFA consumed through the diet disrupt B cell lipid raft clustering.

Malignant lymphoma of the conjunctiva

DEFF Research Database (Denmark)

Kirkegaard, Marina M.; Coupland, Sarah E.; Prause, Jan U.

2015-01-01

Conjunctival lymphomas constitute 25% of all ocular adnexal lymphomas. The majority are B-cell non-Hodgkin lymphomas (NHLs) (98%), whereas conjunctival T-cell NHLs are rare (2%). The most frequent subtype of conjunctival B-cell lymphoma is extranodal marginal zone lymphoma (EMZL; 81%), followed...... by follicular lymphoma (8%), diffuse large B-cell lymphoma (3%), and mantle cell lymphoma (3%). Extranodal marginal zone lymphoma occurs slightly more often in women and, along with follicular lymphoma, presents late in the seventh decade of life, whereas diffuse large B-cell lymphoma and especially mantle cell...... lymphoma have a predilection for the male gender and typically present in the eighth decade. Extranodal marginal zone lymphoma and follicular lymphoma present most frequently in the forniceal and bulbar conjunctiva. Conjunctival diffuse large B-cell lymphoma, mantle cell lymphoma and T-cell NHLs...

Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies

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Mantis John G

2004-10-01

Full Text Available Abstract Background The high fat, low carbohydrate ketogenic diet (KD was developed as an alternative to fasting for seizure management. While the mechanisms by which fasting and the KD inhibit seizures remain speculative, alterations in brain energy metabolism are likely involved. We previously showed that caloric restriction (CR inhibits seizure susceptibility by reducing blood glucose in the epileptic EL mouse, a natural model for human multifactorial idiopathic epilepsy. In this study, we compared the antiepileptic and anticonvulsant efficacy of the KD with that of CR in adult EL mice with active epilepsy. EL mice that experienced at least 15 recurrent complex partial seizures were fed either a standard diet unrestricted (SD-UR or restricted (SD-R, and either a KD unrestricted (KD-UR or restricted (KD-R. All mice were fasted for 14 hrs prior to diet initiation. A new experimental design was used where each mouse in the diet-restricted groups served as its own control to achieve a 20–23% body weight reduction. Seizure susceptibility, body weights, and the levels of plasma glucose and β-hydroxybutyrate were measured once/week over a nine-week treatment period. Results Body weights and blood glucose levels remained high over the testing period in the SD-UR and the KD-UR groups, but were significantly (p Conclusions The results indicate that seizure susceptibility in EL mice is dependent on plasma glucose levels and that seizure control is more associated with the amount than with the origin of dietary calories. Also, CR underlies the antiepileptic and anticonvulsant action of the KD in EL mice. A transition from glucose to ketone bodies for energy is predicted to manage EL epileptic seizures through multiple integrated changes of inhibitory and excitatory neural systems.

Extra-nodal lymphoma. A survey of Japan lymphoma radiation therapy group

International Nuclear Information System (INIS)

Oguchi, Masahiko; Ikeda, Hiroshi; Nakamura, Shigeo

2002-01-01

The purpose of this study was to examine, retrospectively, national-wide clinical data of patients with localized extranodal non-Hodgkin's lymphoma (NHL) who were treated by radiation therapy with or without chemotherapy. The survey was carried out at 25 radiation oncology institutions in Japan in 1998. In 1999, according to the Revised European American Lymphoma (REAL) classification, central pathological review conducted at Aichi cancer center was carried out for the data from 7 radiation oncology institutions. The 5-year progression free survival rates (PFS) were calculated to identify prognostic factors. Survey: Data from 1, 141 patients with stage I and II NHL were recruited from 1988 through 1992. Of them, 787 patients, who were treated using definitive radiotherapy with or without chemotherapy for intermediate and high-grade lymphomas in Working Formulation, constituted the core of this study. Primary tumors arose mainly from extra-nodal organs (71%) in the head and neck (Waldeyer's ring: 41%, thyroid gland: 7%, nasal cavities: 5%, oral cavities: 4%, sinus: 3%, orbital structures: 3%, skin: 2% and etc.). The median age of 60 years for patients with extra-nodal NHL was higher than that of 56 years for patients with nodal NHL (p<0.01). Female were dominant in incidence of extra-nodal NHL arising from the thyroid gland, skin and gastrointestinal tract. The percentage of stage I to the extra-nodal NHL from orbit, sino-nasal presentation was higher than that of other NHLs. The percentage of stage II to the extra-nodal NHL from Waldeyer's ring and thyroid gland was higher than that of other NHLs. Central pathological review was carried out for pathological data from 79 patients (Waldeyer's ring: 45, thyroid gland: 19, sinonasal cavities: 15). Of these, diffuse large B cell lymphoma (DLBCL) composed 63% of all patients, mucosa associated lyumphoid tissue lymphoma (MALT-L): 16%, Natural Killer/T cell lymphoma (NK/T-L): 11%, and mantle cell lymphoma: 5% in REAL

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

Science.gov (United States)

Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng; Qi, Jiwei; Cai, Lisi; Dwight, Timothy A; Xu, Yongjin; Xu, Rongsong; Dodd, Rory; Toms, Angela; Parillon, Lois; Lu, Xiaohui; Anjum, Rana; Zhang, Sen; Wang, Frank; Keats, Jeffrey; Wardwell, Scott D; Ning, Yaoyu; Xu, Qihong; Moran, Lauren E; Mohemmad, Qurish K; Jang, Hyun Gyung; Clackson, Tim; Narasimhan, Narayana I; Rivera, Victor M; Zhu, Xiaotian; Dalgarno, David; Shakespeare, William C

2016-05-26

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

Immunohistochemical Profile of Hodgkin and Non-Hodgkin Lymphoma

International Nuclear Information System (INIS)

Shahid, R.; Gulzar, R.; Avesi, L.; Hassan, S.; Danish, F.; Mirza, T.

2016-01-01

Objective: To analyze the frequencies of histological types of lymphoma, diagnosed with complete immunohistochemical profile in younger and older age group. Study Design: Cross-sectional analytical study. Place and Duration of Study: Dow Diagnostic Research and Reference Laboratory, Dow University of Health Sciences, Karachi, from January 2009 to September 2013. Methodology: Consecutive cases of lymphomas, which were diagnosed using immunohistochemistry, were analyzed according to WHO classification. Frequency and percentages for different types of lymphomas were calculated. Hodgkin and non-Hodgkin lymphomas characteristics in two age groups of less than and more than 40 years were compared, applying chi-square test. Results: Out of the 318 cases, 79 (25 percentage) were Hodgkin Lymphomas (HL) and 239 (75 percentage) were Non-Hodgkin Lymphomas (NHL). Mixed Cellularity Hodgkin Lymphoma (MCHL) was the commonest (n=48). Amongst the NHL, 215 (89.95 percentage) were B cell lymphomas and 24 (10.05percentage) were T-cell lymphomas. Diffuse Large B-Cell Lymphoma (DLBCL) was the commonest lymphoma (n=165, 69.95 percentage of NHL). Anaplastic T-Cell Lymphoma (ALCL, n=10) was the commonest T-cell lymphoma. The frequency of HL was significantly higher in the younger age group and that of NHL was higher in the older age group (p < 0.001). Primary lymph node involvement was reported in 175 (55 percentage) and cervical lymph node was the most frequent site. Extra nodal involvement was seen in 93 (29 percentage) of all cases and was reported in 87 (36.4 percentage) of NHL and 6 (7.5 percentage) of HL. The most common extra nodal site was the gastrointestinal tract. Conclusion: Hodgkin lymphoma comprises 25 percentage and non-Hodgkin lymphoma comprises 75 percentage of all lymphomas. Both occur in younger age groups than reported in the West. B-cell NHL is three times more common than T-cell lymphoma. DLBCL is the most frequent lymphoma. ALCL is the most common T-cell, and mixed

Linfomas asociados con la infección por el virus de la inmunodeficiencia humana: subtipos histológicos y asociación con los virus de Epstein Barr y Herpes-8 AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8

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Marcelo Corti

2010-04-01

Full Text Available Los linfomas no Hodgkin (LNH constituyen la segunda neoplasia definitoria de Sida más frecuente. En el presente trabajo se evaluaron 48 casos de linfomas asociados con la enfermedad debida al virus de la inmunodeficiencia humana (HIV diagnosticados en la División Histopatología del Instituto de Investigaciones Hematológicas de la Academia Nacional de Medicina. Se incluyeron en la investigación 5 mujeres y 43 hombres con una mediana de edad al momento del diagnóstico de la neoplasia de 37 años. La evaluación morfológica se realizó en cortes coloreados con hematoxilina-eosina, estudio inmunohistoquímico para la detección del virus de Epstein Barr (VEB en 48/48 casos, y mediante sonda oligonucleotídica biotinilada para la detección del ADN del Herpes virus humano tipo-8 (HHV-8 en 14/14 linfomas plasmoblásticos (LP. Todos fueron linfomas de fenotipo B, con un curso clínico agresivo y enfermedad neoplásica avanzada al momento del diagnóstico. Se pudo demostrar la fuerte asociación del VEB con los linfomas asociados al sida, con frecuencias que variaron según el subtipo histológico: 16/21 (76% para los linfomas difusos de grandes células; 1/3 casos (33% de linfomas de Burkitt y 3/4 (75% en los linfomas primarios del sistema nervioso central. Globalmente, el genoma del VEB se detectó en 20/28 (71% de las muestras de biopsias de LNH de esta serie. La detección del HHV-8 resultó negativa en los 14 LP. Los linfomas de Hodgkin fueron más frecuentes en varones,18/20 (90%, con un curso clínico agresivo y franco predominio de los subtipos histológicos de peor pronóstico (90% de casos. En estas neoplasias también se comprobó una frecuente asociación patogénica con el VEB (90% de casos.Non-Hodgkin lymphomas (NHL of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL diagnosed at the

Composite lymphoma: Mycosis fungoides with hodgkin′s lymphoma

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Mehta Jalpa

2005-01-01

Full Text Available Mycosis fungoides (MF is a malignant lymphoma, primarily of the skin and is characterized by infiltration of the skin by atypical T-cells which have a tendency for epidermotropism. Hodgkins disease (HD is considered to be a malignant lymphoma affecting predominantly the lymph nodes and characterized by presence of Reed- Sternberg cells on histopathology, though, the exact origin of the Reed Sternberg cell and the nature of the malignant cell is not known yet. Few cases of association of mycosis fungoides with Hodgkin′s lymphoma have been reported in the literature. It was reported in the past that when mycosis fungoides spreads to the lymph nodes and other viscera it frequently gets transformed into a more common lymphoma like Hodgkin′s lymphoma. However it has now been proved that the two malignancies are distinct and that such patients probably have a tumour diathesis.

The Four types of Tregs in malignant lymphomas

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Wang Jing

2011-12-01

Full Text Available Abstract Regulatory T cells (Tregs are a specialized subpopulation of CD4+ T cells, which act to suppress the activation of other immune cells. Tregs represent important modulators for the interaction between lymphomas and host microenvironment. Lymphomas are a group of serious and frequently fatal malignant diseases of lymphocytes. Recent studies revealed that some lymphoma T cells might adopt a Treg profile. Assessment of Treg phenotypes and genotypes in patients may offer prediction of outcome in many types of lymphomas including diffuse large B-cell lymphoma, follicular lymphoma, cutaneous T cell lymphoma, and Hodgkin's lymphoma. Based on characterized roles of Tregs in lymphomas, we can categorize the various roles into four groups: (a suppressor Tregs; (b malignant Tregs; (c direct tumor-killing Tregs; and (d incompetent Tregs. The classification into four groups is significant in predicting prognosis and designing Tregs-based immunotherapies for treating lymphomas. In patients with lymphomas where Tregs serve either as suppressor Tregs or malignant Tregs, anti-tumor cytotoxicity is suppressed thus decreased numbers of Tregs are associated with a good prognosis. In contrast, in patients with lymphomas where Tregs serve as tumor-killing Tregs and incompetent Tregs, anti-tumor cytotoxicity is enhanced or anti-autoimmune Tregs activities are weakened thus increased numbers of Tregs are associated with a good prognosis and reduced numbers of Tregs are associated with a poor prognosis. However, the mechanisms underlying the various roles of Tregs in patients with lymphomas remain unknown. Therefore, further research is needed in this regard as well as the utility of Tregs as prognostic factors and therapy strategies in different lymphomas.

Immune selection of tumor cells in TCR β-chain transgenic mice.

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Silaeva, Yulia Yu; Grinenko, Tatyana S; Vagida, Murad S; Kalinina, Anastasia A; Khromykh, Ludmila M; Kazansky, Dmitry B

2014-10-01

The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (K(d)I(d)D(b)) mice to allogeneic EL4 (H-2(b)) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2K(b) molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a compromised proliferative response in mixed-lymphocyte response assays and were unable to reject transplanted allogeneic EL4 cells. During the immune response to EL4 cells, CD8(+) T-lymphocytes with endogenous β-chains accumulated predominantly in the spleen of transgenic mice and only a small part of the T-lymphocytes expressing transgenic β-chains became CD8(+)CD44(+)CD62L(-) effectors. Then, instead of a full elimination of tumor cells as in wild-type mice, a reproducible prolonged equilibrium phase and subsequent escape was observed in transgenic mice that resulted in death of 90% of the mice in 40-60 days after grafting. Prolonged exposure of tumor cells to the pressure of the immune system in transgenic mice in vivo resulted in a stable loss of H-2K(b) molecules on the EL4 cell surface. Genetic manipulation of the T-lymphocyte repertoire was sufficient to reproduce the classic pattern of interactions between tumor cells and the immune system, usually observed in reliable syngeneic models of anti-tumor immunity. This newly-developed model could be used in further studies of immunoregulatory circuits common for transplantational and anti-tumor immune responses.

A Case of Diffuse Large B-Cell Lymphoma Mimicking Primary Effusion Lymphoma-Like Lymphoma

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Daisuke Usuda

2017-11-01

Full Text Available A 93-year-old female was transferred to the emergency ward of our hospital due to disturbance of consciousness and hypotension. Computed tomography showed bilateral pleural and pericardial effusion without evidence of tumor masses or lymphadenopathy. Cytodiagnosis of pleural effusion revealed proliferation of atypical lymphoid-like cells with pan-B surface markers. We suspected primary effusion lymphoma-like lymphoma; however, the monoclonality of these cells was not confirmed. Cytodiagnosis of bone marrow revealed lymphoma cells with monoclonal B-cell markers. These findings prompted a diagnosis of diffuse large B-cell lymphoma with bone marrow invasion. In the case of pericardial or pleural effusion, clinicians should consider carefully both hematological malignancy and its classification.

Linfoma no Hodgkin primario de mama, revisión de la literatura y presentación de un caso Primary non-Hodgkin breast lymphoma, literature review and a case a presentation

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Caridad Verdecia Cañizares

2011-06-01

Full Text Available El linfoma no Hodgkin primario de la mama es una entidad poco frecuente en pediatría y representa el 0,4 al 0,5 % de todos los tumores mamarios malignos. Debido a que carecen de características propias, tanto clínicas, citológicas como ecográficas, resulta muy difícil establecer el diagnóstico preoperatorio. Se presenta el caso de un linfoma no Hodgkin primario de la mama en una paciente de 3 años que llegó en estadio avanzado de la enfermedad, y se subraya la importancia del tratamiento en un equipo multidisciplinario.The primary non-Hodgkin breast lymphoma is a not frequent entity in children and account for the 0,4 to 0,5% of the malignant breast tumors. Due to they lack of own clinical, cytological and echography features, it is very difficult to made the preoperative diagnosis. This is the case of a primary non-Hodgkin breast lymphoma in a patient aged 3 with an advanced stage of disease, emphasizing the significance of treatment in a multidisciplinary staff.

Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study.

Science.gov (United States)

Schommers, Philipp; Gillor, Daniel; Hentrich, Marcus; Wyen, Christoph; Wolf, Timo; Oette, Mark; Zoufaly, Alexander; Wasmuth, Jan-Christian; Bogner, Johannes R; Müller, Markus; Esser, Stefan; Schleicher, Alisa; Jensen, Björn; Stoehr, Albrecht; Behrens, Georg; Schultze, Alexander; Siehl, Jan; Thoden, Jan; Taylor, Ninon; Hoffmann, Christian

2018-05-01

Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate. Copyright © 2018 Ferrata Storti Foundation.

Membrane Raft Organization Is More Sensitive to Disruption by (n-3) PUFA Than Nonraft Organization in EL4 and B Cells123

Science.gov (United States)

Rockett, Benjamin Drew; Franklin, Andrew; Harris, Mitchel; Teague, Heather; Rockett, Alexis; Shaikh, Saame Raza

2011-01-01

Model membrane and cellular detergent extraction studies show (n-3) PUFA predominately incorporate into nonrafts; thus, we hypothesized (n-3) PUFA could disrupt nonraft organization. The first objective of this study was to determine whether (n-3) PUFA disrupted nonrafts of EL4 cells, an extension of our previous work in which we discovered an (n-3) PUFA diminished raft clustering. EPA or DHA treatment of EL4 cells increased plasma membrane accumulation of the nonraft probe 1,1′-dilinoleyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate by ~50–70% relative to a BSA control. Förster resonance energy transfer imaging showed EPA and DHA also disrupted EL4 nanometer scale nonraft organization by increasing the distance between nonraft molecules by ~25% compared with BSA. However, changes in nonrafts were due to an increase in cell size; under conditions where EPA or DHA did not increase cell size, nonraft organization was unaffected. We next translated findings on EL4 cells by testing if (n-3) PUFA administered to mice disrupted nonrafts and rafts. Imaging of B cells isolated from mice fed low- or high-fat (HF) (n-3) PUFA diets showed no change in nonraft organization compared with a control diet (CD). However, confocal microscopy revealed the HF (n-3) PUFA diet disrupted lipid raft clustering and size by ~40% relative to CD. Taken together, our data from 2 different model systems suggest (n-3) PUFA have limited effects on nonrafts. The ex vivo data, which confirm previous studies with EL4 cells, provide evidence that (n-3) PUFA consumed through the diet disrupt B cell lipid raft clustering. PMID:21525263

Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma

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Shet Tanuja

2010-07-01

Full Text Available Objective: This series of six intestinal T cell lymphomas (ITCL attempts to document enteropathy-associated T cell lymphoma (EATCL in India. Materials and Methods: A total of six ITCL were selected from 170 gastrointestinal lymphomas in last 10 years. Results: The cases studied included EATCL (4, ITCL with a CD4 positive phenotype (1 and ITCL NK/T cell type (1. Of the four EATCL, two occurred in the ileum, one in right colon and one in duodenum. In three EATCL cases, there was history of celiac disease or lactose intolerance and enteropathic changes were noted in the adjacent mucosa. These tumors had CD3+/CD8+/CD56 (+/-/CD4-/ Granzyme B+ immunophenotype. One EATCL was monomorphic small cell type (type II EATCL with a CD3+/CD8-CD56+/CD4-/ Granzyme B+ phenotype. EBER- ISH (Epstein Barr virus coded RNA′s- in situ hybridization revealed positive tumor cells in ITCL NK/T cell type and in bystander cells in three EATCL. Conclusion: ITCL are rare in Indian patients but do occur and comprise a mixture of the enteropathic and non-enteropathic subtypes.

Immunohistochemical expression study of proapoptotic BH3-only protein bad in canine nonneoplastic tissues and canine lymphomas.

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Dettwiler, M; Croci, M; Vaughan, L; Guscetti, F

2013-09-01

The BH3-only protein Bad is a proapoptotic Bcl-2 family member that acts as a sensitizer in intrinsic apoptosis by inactivating antiapoptotic members through heterodimer formation. Bad has been shown to contribute to tumorigenesis, including lymphoma formation in humans and mice, through alteration in expression or functional status. Here, its immunohistochemical expression was analyzed in canine nonneoplastic and lymphoma tissues using tissue microarrays. Bad was expressed in the cytoplasm of a wide range of nonneoplastic tissues, especially epithelial cells. Nonneoplastic lymph nodes displayed weak immunostaining in the follicular germinal centers only. Immunoblotting supported these observations but also revealed presence of nonspecific labeling in some organs. Of 81 lymphomas, 29 (35.8%) displayed moderate to strong immunohistochemical Bad labeling, and a significant expression increase was found in lymphomas (especially B cell and double negative) compared to nonneoplastic lymph nodes. These findings warrant further investigations of the functional status, the involvement of partner proteins, and a possible impact of Bad on prognosis in canine lymphoma.

Influence of dietary zinc on convulsive seizures and hippocampal NADPH diaphorase-positive neurons in seizure susceptible EL mouse.

Science.gov (United States)

Nagatomo, I; Akasaki, Y; Uchida, M; Kuchiiwa, S; Nakagawa, S; Takigawa, M

1998-04-13

Adequate, high and deficient dietary levels of zinc (Zn) were compared in seizure-susceptible EL mice with respect to convulsions and to nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive hippocampal neurons. Diaphorase positivity is associated with nitric oxide (NO) production. Convulsive seizures in the EL mice given the various diets did not differ over 1-4 weeks, but convulsions in EL mice given the Zn-deficient diet for 4 weeks were more effectively suppressed by injection of zonisamide (ZNS) (75 mg/kg intraperitoneally) than in mice receiving high- or adequate-Zn diet for the same period. Numbers of NADPH diaphorase-positive neurons in the CA1/CA2 region of the hippocampal formation were significantly higher in mice given the Zn-deficient diet for 4 weeks than in mice fed adequate Zn. Mice receiving the high-Zn diet for the same period had significantly fewer NADPH diaphorase-positive neurons in the subiculum than mice with adequate Zn. These results suggest that Zn deficiency inhibits convulsive seizures of EL mice, and that dietary Zn influences numbers of NO producing neurons in the hippocampal formation. Copyright 1998 Elsevier Science B.V.

IgG4-positive extranodal marginal zone lymphoma arising in Hashimoto's thyroiditis: clinicopathological and cytogenetic features of a hitherto undescribed condition.

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Tan, Char-Loo; Ong, Yew-Kwang; Tan, Soo-Yong; Ng, Siok-Bian

2016-05-01

Hashimoto's thyroiditis was recently divided into IgG4-plasma cell-rich and IgG4-plasma cell-poor subtypes. The former, also known as IgG4 thyroiditis, is associated with clinical, serological, sonographic and morphological features that are distinctive from those of the non-IgG4 subgroup. We describe an interesting case of IgG4-positive mucosa-associated lymphoid tissue (MALT) lymphoma arising in a background of IgG4 thyroiditis. The thyroid gland showed typical features of IgG4 thyroiditis, including characteristic patterns of fibrosis. A dense lymphoplasmacytic infiltrate diffusely involved the entire gland without formation of a destructive tumour mass. Lymphoepithelial lesions were prominent. There were abundant IgG4-positive plasma cells, with the IgG4/IgG ratio exceeding 40%. The IgG4-positive plasma cells were monotypic for kappa light chain, and there was monoclonal IGH rearrangement. Fluorescence in-situ hybridization revealed IGH translocation without translocation of MALT1, bcl-10, or FOXP1. This represents the first case of IgG4-producing MALT lymphoma associated with IgG4 thyroiditis. IGH translocation with an unknown partner gene was identified. We suggest the performance of serum and immunohistochemical investigations for IgG and IgG4 in all cases of Hashimoto's thyroiditis to diagnose IgG4 thyroiditis. In addition, clonality assays and light chain studies are useful to exclude a low-grade lymphoma arising in this context. © 2015 John Wiley & Sons Ltd.

Role of combination chemotherapy in non-Hodgkin's lymphoma in children

International Nuclear Information System (INIS)

Dutta, H.S.; Chandra, A.B.; Mitter, M.; Mukherjee, D.; Batabyal, S.; Samaddar, A.S.; Mukherjee, S.

1980-01-01

Eighteen children suffering from Non-Hodgkin's lymphoma were studied. Of these eighteen children, eight (44.4 percent) had well differentiated diffuse lymphocytic lymphoma and six (33.3 percent) had poorly differentiated diffuse lymphocytic lymphoma and four (22.3 percent) had histiocytic lymphoma. Histological study was based on the concept of Rappaport (1966). Children belonging to Stage IIB were treated with radiotherapy followed by combination chemotherapy and those with Stage IIIB and Stage IVB were treated with combination chemotherapy utilising cyclophosphamide, oncovin and prednisolone. The result of combination chemotherapy (COP) was dramatic and appears to have resulted in long term disease free survival. In well differentiated diffuse lymphocytic lymphoma in Stage IIB the life expectancy of two children was extended to 12 years with well maintained remission for 9.5 years. Recurrence rate was 44.4 percent. Death rate was 61.1 percent and median survival time was 26.7 months. In histiocytic lymphomas the results were unsatisfactory. Median survival time was 9.5 months. (author)

Borrelia infection and risk of non-Hodgkin lymphoma

DEFF Research Database (Denmark)

Schollkopf, C.; Melbye, M.; Munksgaard, L.

2008-01-01

Reports of the presence of Borrelia burgdorferi DNA in malignant lymphomas have raised the hypothesis that infection with B. burgdorferi may be causally related to non-Hodgkin lymphoma (NHL) development. We conducted a Danish-Swedish case-control study including 3055 NHL patients and 3187.......9-2.0]). However, in analyses of NHL subtypes, self-reported history of B. burgdorferi infection (OR = 2.5 [1.2-5.1]) and seropositivity for anti-Borrelia antibodies (OR = 3.6 [1.8-7.4]) were both associated with risk of mantle cell lymphoma. Notably, this specific association was also observed in persons who did...... not recall Borrelia infection yet tested positive for anti-Borrelia antibodies (OR = 4.2 [2.0-8.9]). Our observations suggest a previously unreported association between B. burgdorferi infection and risk of mantle cell lymphoma Udgivelsesdato: 2008/6/15...

Primary lymphoma of the brain

Science.gov (United States)

Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy

NARCIS (Netherlands)

Hoeve, M A; Gisbertz, I A; Schouten, H C; Schuuring, E; Bot, F J; Hermans, J; Hopman, A; Kluin, P M; Arends, J E; van Krieken, J H

1999-01-01

Gastric MALT lymphoma is a distinct entity related to Helicobacter pylori gastritis. Some studies suggest a role for trisomy 3 in the genesis of these lymphomas, but they mainly focused on low-grade MALT lymphoma. Gastric MALT lymphoma, however, comprises a spectrum from low- to high-grade cases.

Hodgkin lymphoma - children

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... families share common experiences may help ease your stress. American Childhood Cancer Organization - www.acco.org Leukemia and ... Cancer - Hodgkin lymphoma - children; Childhood Hodgkin lymphoma ... Cancer Institute website. Childhood Hodgkin lymphoma treatment (PDQ) - health professional ...

[Sonographically detectable splenic disorders in dogs with malignant lymphoma].

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Eberhardt, F; Köhler, C; Krastel, D; Winter, K; Alef, M; Kiefer, I

2015-01-01

To evaluate the frequency of different sonographic splenic disorders in dogs with different anatomic forms of malignant lymphoma. Additionally, the occurrence of the moth-eaten pattern in the parenchyma of the spleen in patients with diseases other than lymphoma should be investigated. Retrospective analysis of patient data collected from dogs histologically or cytologically diagnosed with malignant lymphoma and for which ultrasonographic images were available before the initiation of therapy. Patient data from dogs with a moth-eaten pattern within the splenic parenchyma were evaluated separately. Exclusion criterion was the administration of cytostatic agents prior to diagnosis. In 84% of 164 dogs with malignant lymphoma, an altered pattern of the spleen was diagnosed ultrasonographically. Ninety-four of these 137 patients had a moth-eaten pattern of the splenic parenchyma and 43 dogs displayed abnormalities in the form of splenomegaly, coarse echotexture or other changes of the parenchyma. When a moth-eaten pattern was diagnosed, the affected dogs suffered significantly more often from a multicentric lymphoma (95%) than from any other anatomical lymphoma form. Only one dog displayed a moth-eaten pattern of the splenic parenchyma without diagnosis of a malignant lymphoma. The positive predictive value of the moth-eaten pattern for malignant lymphoma was 99% and, in particular, for the multicentric lymphoma this was 95%. In total, 84% of the 164 dogs displayed a multicentric lymphoma, 5% a mediastinal or a cutaneous lymphoma, respectively, 4% a gastrointestinal lymphoma, and one animal had an ocular or renal lymphoma, respectively. Sonographic changes of the spleen are often diagnosed in dogs with malignant lymphoma, independent of the anatomical lymphoma form. When the moth-eaten pattern is observed, it is very likely that the affected dog suffers from a malignant lymphoma, most probably a multicentric lymphoma.

Preparation of the radiopharmaceutical {sup 131}I-Anti-CD20 for the treatment of lymphomas; Preparacion del radiofarmaco {sup 131}I-Anti-CD20 para el tratamiento de linfomas

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Pantoja H, I E

2004-07-01

At the present time they are considered to the lymphomas like a problem of first magnitude since has happened it is necessary to be the fifth cancer cause in the world. Different treatments focused to the lymphoma like the chemotherapy and the radiotherapy, have been employees to counteract the No-Hodgkin lymphoma, without these they don't exclude the healthy tissue of the toxicity. It is for it that is taking a new direction with the employment of the directed radioimmunotherapy since this it allows to kill wicked cells selectively with radiation dose joined to the apoptosis and cytotoxicity induced by the own one bio molecule. The radioimmunotherapy with radiolabelled antibodies directed to the surface antigen CD20 represents a new modality for the treatment of No-Hodgkin lymphoma and potentially other illnesses. In this work the parameters of optimization are presented for the preparation, control of quality and evaluation of the stability in vitro and in vivo of the monoclonal antibody anti-CD20 labelled with {sup 131} I for the treatment of No-Hodgkin lymphoma. The anti-CD20 labelled by the chloramine-T method with high radiochemical purity (>98%), it is stable in solution for but of a half life of the radionuclide (8.04 days) The {sup 131} I-anti-CD20 doesn't present dehalogenation in vitro (human serum) during 24 h of incubation at 37 C. According to the tests carried out to establish the immunoreactivity, a percentage of union to cells was obtained (B lymphocytes) bigger to 30%. The biodistribution in mice balb/c one hour after their administration, it shows that there is not high reception in mucous neither kidneys, what indicates that the complex is stable in vivo. In conclusion, the radiopharmaceutical {sup 131} I-anti-CD20 was obtained in sterile injectable solution and free of pyrogens with a radiochemical purity bigger to 98% and a specific activity of 296 MBq. The radiolabelled molecule maintains its biological recognition for the receiving CD20

HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.

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Yorifumi Satou

2011-02-01

Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL, and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (T(reg. Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ, which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ T(reg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

Cutaneous double-hit B-cell lymphoma: an aggressive form of B-cell lymphoma with a propensity for cutaneous dissemination.

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Magro, Cynthia M; Wang, Xuan; Subramaniyam, Shivakumar; Darras, Natasha; Mathew, Susan

2014-04-01

Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center cell lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 3 patients with an aggressive form of B-cell lymphoma secondarily involving the skin. Two of the patients were in the ninth decade of life, whereas 1 patient was 34 years of age. In the elderly patients, there was an antecedent and/or concurrent history of follicular lymphoma, whereas in the younger patient, the tumor was a de novo presentation of this aggressive form of lymphoma. The elderly patients succumbed to their disease within less than a year from the time of diagnosis, whereas 1 patient is alive but with persistent and progressive disease despite chemotherapeutic intervention. The infiltrates in all 3 cases were diffuse and composed of large malignant hematopoietic cells that exhibited a round nucleus with a finely dispersed chromatin. Phenotypically, the tumor cells were Bcl-2 and CD10 positive, whereas Bcl-6 and Mum-1 showed variable positivity. One case showed combined Mum-1 positivity along with an acute lymphoblastic lymphoma phenotype, including the absence of CD20 expression. In each case, there was a c-MYC and BCL2/IGH rearrangement diagnostic of double-hit lymphoma. In one case, there was an additional BCL6 rearrangement, defining what is in essence triple-hit lymphoma. In conclusion, double-hit lymphoma is an aggressive form of B-cell neoplasia resistant to standard chemotherapy regimens, which in many but not all cases represents tumor progression in the setting of a lower grade B-cell malignancy.

Lymphoma of the Eyelid

DEFF Research Database (Denmark)

Svendsen, Frederik Holm; Rasmussen, Peter Kristian; Coupland, Sarah E.

2017-01-01

Purpose To document subtype-specific clinical features of lymphoma of the eyelid, and their effect on patient outcome. Design Retrospective observational case series. Methods Patient data were collected from 7 international eye cancer centers from January 1, 1980 through December 31, 2015....... The cases included primary and secondary lymphomas affecting the eyelid. Overall survival, disease-specific survival (DSS), and progression-free survival were the primary endpoints. Results Eighty-six patients were included. Mean age was 63 years and 47 (55%) were male. Non-Hodgkin B-cell lymphomas...... constituted 83% (n = 71) and T-cell lymphomas constituted 17% (n = 15). The most common subtypes were extranodal marginal-zone lymphoma (EMZL) (37% [n = 32]), follicular lymphoma (FL) (23% [n = 20]), diffuse large B-cell lymphoma (DLBCL) (10% [n = 9]), mantle cell lymphoma (MCL) (8% [n = 7]), and mycosis...

MRI findings of pancreatic lymphoma and autoimmune pancreatitis: A comparative study

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Ishigami, Kousei, E-mail: Ishigamikousei@aol.co [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Tajima, Tsuyoshi; Nishie, Akihiro; Ushijima, Yasuhiro [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Fujita, Nobuhiro [Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University (Japan); Asayama, Yoshiki; Kakihara, Daisuke; Irie, Hiroyuki [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Ito, Tetsuhide; Igarashi, Hisato [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University (Japan); Nakamura, Masafumi [Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University (Japan); Honda, Hiroshi [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan)

2010-06-15

Purpose: To clarify whether there are differences in MRI findings between pancreatic lymphomas and autoimmune pancreatitis (AIP). Materials and methods: MRI of 8 patients with pancreatic lymphomas and 21 patients with AIP were retrospectively reviewed. For multifocal pancreatic lymphomas (n = 2) and AIP (n = 4), the largest 2 lesions were evaluated. Ten pancreatic lymphomas and 25 AIP were compared on three bases: the signal intensity on T2-weighted images, internal homogeneity, and presence or absence of capsule-like rim. In 8 lymphomas and 19 AIP, the enhancement pattern on dynamic MRI was compared, as well. Results: On T2-weighted images, pancreatic lymphomas comprised 5, 5 and 4 lesions with low (iso), slightly high, and moderately high intensity, respectively, while the numbers for AIP were 14, 10, and 1 (P < 0.01). Nine of 10 (90%) lymphomas appeared homogenous, and 11 of 25 (44%) AIP were homogenous (P < 0.05). A capsule-like rim was present in 9 of 25 (36%) AIP, but was not seen in lymphomas (P < 0.05). On dynamic MRI, 18 of 19 (94.7%) AIP showed persistent (n = 5) or delayed enhancement (n = 13), and 6 of 8 (75%) lymphomas showed low intensity without delayed enhancement (P < 0.001). Conclusion: MRI findings for pancreatic lymphomas and AIP were significantly different, which may be helpful for the differential diagnosis of these two diseases.

Mantle-cell lymphoma.

Science.gov (United States)

Barista, I; Romaguera, J E; Cabanillas, F

2001-03-01

During the past decade, mantle-cell lymphoma has been established as a new disease entity. The normal counterparts of the cells forming this malignant lymphoma are found in the mantle zone of the lymph node, a thin layer surrounding the germinal follicles. These cells have small to medium-sized nuclei, are commonly indented or cleaved, and stain positively with CD5, CD20, cyclin D1, and FMC7 antibodies. Because of its morphological appearance and a resemblance to other low-grade lymphomas, many of which grow slowly, this lymphoma was initially thought to be an indolent tumour, but its natural course was not thoroughly investigated until the 1990s, when the BCL1 oncogene was identified as a marker for this disease. Mantle-cell lymphoma is a discrete entity, unrelated to small lymphocytic or small-cleaved-cell lymphomas.

Transformation of marginal zone lymphoma (and association with other lymphomas).

Science.gov (United States)

Casulo, Carla; Friedberg, Jonathan

Marginal zone lymphomas (MZL) are a diverse group of indolent lymphoproliferative disorders that comprise three subtypes: nodal, splenic and mucosal associated marginal zone lymphomas (MALT). Histologic transformation (HT) to an aggressive lymphoma is a rare event that can occur in any subtype, and at lower frequency compared to other indolent non Hodgkin lymphomas (NHL) like follicular lymphoma. There are few data directly associated with risk and prognosis of transformation in MZL. However, recent advances in the understanding of molecular and genetic features of MALT have contributed to an evolving appreciation of HT in this disease. Optimal treatment of HT of MZL remains unknown. Much of the approach to managing transformed MZL is extrapolated from other indolent NHLs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Adult T-Cell Leukemia/Lymphoma

Science.gov (United States)

... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

Muscular involvement by malignant lymphoma: CT and MR findings

International Nuclear Information System (INIS)

Kim, Baek Hyun

2000-01-01

To investigate the CT and MR findings of muscular involvement by malignant lymphoma. Thirteen patients with biopsy-proved muscular involvement by malignant lymphoma were included in this study. Two patients were primary muscle lymphoma and 11 patients were muscle lymphoma by secondary involvement of malignant lymphoma. CT of 10 patients (6 pre-contrast CT and 9 postcontrast CT) and MRI of 6 patients (all with pre a nd post-contrast studies) were retrospectively analyzed. In the majority of patients (84.6%, 11/13), the appearance of muscular involvement was the diffuse enlargement of several muscles as like as a group. The muscles involved by malignant lymphoma showed iso-attenuation (5/6) and homogeneity (6/6) on pre-contrast CT scan, and high attenuation (5/9) or iso-attenuation (4/9) and homogeneity (7/9) on post-contrast CT scan. The signal intensity of involved muscle showed slightly hyper- (4/6) or iso-intense (2/6) and homogeneous (6/6) on T1-weighted images, and hyper-intense (6/6) and homogeneous (4/6) on T2- and Gadolinium-enhanced T1-weighted images. Adjacent bone change was demonstrated in 69.2% (9/13), subcutaneous fat change in 61.5% (8/13), and neurovascular encasement within involved muscle in 53.8% (7/13). The CT and MR findings of muscular involvement by malignant lymphoma were diffuse enlargement of several muscles with homogeneous attenuation or signal intensity, and frequent changes in adjacent bones and subcutaneous fat, or neurovascular encasement. (author)

Is an increase in CD4/CD8 T-cell ratio in lymph node fine needle aspiration helpful for diagnosing Hodgkin lymphoma? A study of 85 lymph node FNAs with increased CD4/CD8 ratio

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Hernandez Osvaldo

2005-01-01

Full Text Available Abstract Background An elevated CD4/CD8 T-cell ratio on flow cytometry (FCM analysis has been reported in the literature to be associated with Hodgkin lymphoma (HL. The purpose of our study was to determine the diagnostic significance of an elevated CD4/CD8 ratio in lymph node fine needle aspiration (FNA specimens. Design Between 1996 and 2002, out of 837 lymph node FNAs submitted for flow cytometry analysis, 85 cases showed an elevated CD4/CD8 ratio, defined as greater than or equal to 4, without definitive evidence of a lymphoproliferative disorder. The cytologic diagnoses of these 85 cases were grouped into four categories: reactive, atypical, Hodgkin lymphoma (HL, and non-Hodgkin lymphoma (NHL. Histologic follow-up was available in 17/85 (20% of the cases. Results 5 of the 64 cases in which FCM and cytology did not reveal evidence of a lymphoproliferative disease had tissue follow-up because of persistent lymphadenopathy and high clinical suspicion. 3/5 (60% confirmed the diagnosis of reactive lymphadenopathy. The two remaining cases (40% were positive for lymphoma (1HL, 1NHL. 8/15 cases called atypical on cytology had histologic follow-up. 7/8 (87.5% cases were positive for lymphoma (3HL, 4NHL. 3/4 cases called HL on cytology had tissue follow-up and all 3 (100% confirmed the diagnosis of HL. One case diagnosed as NHL on cytology was found to be a diffuse large B-cell lymphoma. In summary, out of 17 cases with histologic follow-up 4/17 (24% were reactive with CD4/CD8 T-cell ratio of 4.1–29, 7/17 (41% were HLs with CD4/CD8 T-cell ratio of 5.3 – 11, and 6/17 (35% were NHLs with CD4/CD8 T-cell ratio of 4.2 – 14. Conclusion An elevated CD4/CD8 ratio on FCM is a nonspecific finding which may be seen in both reactive and lymphoproliferative disorders. The cytomorphologic features of the smear are more relevant than the sole flow cytometric finding of an elevated CD4/CD8 ratio.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

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Ritika Prasad

2014-01-01

Full Text Available Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton’s lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton’s lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton’s lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton’s lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

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Prasad, Ritika; Koch, Biplob

2014-01-01

Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton's lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton's lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton's lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton's lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved. PMID:24959588

Abdominal lymphadenopathy in tuberculosis and lymphoma: Differentiation with CT

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Shin, Yong Moon; Choi, Byung Ihn; Han, Joon Koo; Han, Man Chung; Song, Chi Sung; Yang, Seoung Oh

1993-01-01

Tuberculosis and lymphoma, these 2 dieases can present with lymphadenopathy in anywhere of the body. Therefore differentiation of tuberculosis from lymphoma is often difficult. CT scans of 17 patients with tuberculosis and 23 patients with lymphoma were retrospectively reviewed to evaluate the efficacy of CT scans in differentating adenopathy between tuberculosis and lymphoma. All the patients underwent abdominal CT scans with contrast enhancement before treatment. The size, internal architecture, distribution of lymph nodes, and associated findings on CT scans were analyzed. As compared with lymphoma, tuberculous lymphadenopathy showed 1) female preponderance (65%), 2) predilection for percolative lymph nodes (47%), 3) internal low attenuation in lymph nodes (82%), 4) cold abscess formation (24%). Characteristics of lymphoma on CT scans include 1) male preponderance (78%), 2) conglomeration of lymph nodes (39%), 3) homogeneous internal lymph node structure (83%). These results suggest that evaluation of the cahracteristics of lymphadenopathy on CT scans is helpful for differentiating between tuberculousis and lymphoma

Gastric Lymphoma with Secondary Trigeminal Nerve Lymphoma: A Case Report

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Warissara Rongthong

2017-05-01

Full Text Available Data supporting the role of radiotherapy in secondary trigeminal nerve lymphoma is scarce. Here, I report the case of 64-year-old Thai male diagnosed as gastric diffuse large B cell lymphoma with secondary trigeminal nerve lymphoma. He had previously received one cycle of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, followed by five cycles of rituximab plus CHOP (R-CHOP with intrathecal methotrexate (MTX and cytarabine (Ara-C. One month after the last cycle of R-CHOP, he developed a headache and numbness on the left side of his face. MRI revealed thickening of the left trigeminal nerve. He received one intrathecal injection of MTX and Ara-C, followed by systemic chemotherapy. After receiving intrathecal chemotherapy, his symptoms disappeared. Clinical response and MRI studies suggested secondary trigeminal nerve lymphoma. Two months later, our patient’s secondary trigeminal nerve lymphoma had progressed. Salvage whole brain irradiation (36 Gy with boost dose (50 Gy along the left trigeminal nerve was given. Unfortunately, our patient developed heart failure and expired during the radiotherapy session. In conclusion and specific to secondary central nervous system lymphoma (SCNSL, radiotherapy may benefit patients who fail to respond to systemic chemotherapy and palliative treatment. The results this report fail to support the role of radiotherapy in secondary trigeminal nerve lymphoma.

Synergistic action of radiation and chemical carcinogen in induction of leukemia in mice, 3

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Kajitani, Takashi

1982-01-01

1. There was no synergistic interaction of radiation and N-nitrosoethylurea (NEU) in induction of leukemia if irradiation was confined to the thymic region. 2. Cell kinetics in the thymus and bone marrow of young-adult mice were studied following whole-body X-irradiation or local X-irradiation over the thymus. It was found that whole-body X-irradiation caused drastic injuries, followed by a vigorous regeneration in both thymus and bone marrow, whereas local X-irradiation caused much milder changes in the thymus than whole-body X-irradiation, and caused no apparent changes in the bone marrow. 3. A single dose of 5 mg of NEU force administered by gastric intubation was found to be moderately leukemogenic, inducing thymic lymphomas in 37% of young adult female C57BL/6N mice. 4. Whole-body X-irradiation with 400R enhanced the incidence of thymic lymphoma when mice were irradiated 5 days prior to a single dose of NEU force administered by gastric intubation. In contrast, no enhancing effect was observed when the mice were irradiated 30 days prior to a single dose of NEU. 5. The results indicate that whole-body X-irradiation right before NEU administration plays a role in providing a cell population either in the thymus or bone marrow susceptible to NEU during postirradiation repair-period. (author)

Absence of Wip1 partially rescues Atm deficiency phenotypes in mice

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Darlington, Yolanda; Nguyen, Thuy-Ai; Moon, Sung-Hwan; Herron, Alan; Rao, Pulivarthi; Zhu, Chengming; Lu, Xiongbin; Donehower, Lawrence A.

2011-01-01

Wildtype p53-Induced Phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may play a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared to Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared to their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared to Atm null mice. Finally, doubly null mice were partially rescued from infertility defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular. PMID:21765465

[Secondary orbital lymphoma].

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Basanta, I; Sevillano, C; Álvarez, M D

2015-09-01

A case is presented of an 85 year-old Caucasian female with lymphoma that recurred in the orbit (secondary ocular adnexal lymphoma). The orbital tumour was a diffuse large B-cell lymphoma according to the REAL classification (Revised European-American Lymphoma Classification). Orbital lymphomas are predominantly B-cell proliferations of a variety of histological types, and most are low-grade tumours. Patients are usually middle-aged or elderly, and it is slightly more common in women. A palpable mass, proptosis and blepharoptosis are the most common signs of presentation. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Lymphoma Research Foundation

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Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.

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Kim, Byung Hak; Min, Yun Sook; Choi, Jung Sook; Baeg, Gyeong Hun; Kim, Young Soo; Shin, Jong Wook; Kim, Tae Yoon; Ye, Sang Kyu

2011-05-31

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.

Radiation therapy for primary orbital lymphoma

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Chao, Cliff K.S.; Lin Hsiusan; Rao Devineni, V.; Smith, Morton

1995-01-01

Purpose: The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. Methods and Materials: Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). Results: Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder, however, no corneal ulceration occurred. Conclusions: Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local

Radiation therapy for primary orbital lymphoma

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Chao, Cliff K.S.; Hsiusan, Lin; Rao Devineni, V; Smith, Morton

1995-02-15

Purpose: The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. Methods and Materials: Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). Results: Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder, however, no corneal ulceration occurred. Conclusions: Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local

Molecular diagnosis of Burkitt's lymphoma

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Dave, SS; Fu, K; Wright, GW; Lam, LT; Kluin, P; Boerma, EJ; Greiner, TC; Weisenburger, DD; Rosenwald, A; Ott, G; Muller-Hermelink, H; Gascoyne, RD; Delabie, J; Rimsza, LM; Braziel, RM; Grogan, TM; Campo, E; Jaffe, ES; Dave, BJ; Sanger, W; Bast, M; Vose, JM; Armitage, JO; Connors, JM; Smeland, EB; Kvaloy, S; Holte, H; Fisher, RI; Miller, TP; Montserrat, E; Wilson, WH; Bahl, M; Zhao, H; Yang, LM; Powell, J; Simon, R; Chan, WC; Staudt, LM

2006-01-01

Background: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

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Yuya Yoshimoto

Full Text Available PURPOSE: There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL activity. METHODS AND MATERIALS: C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD was defined as the time (in days for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. RESULTS: In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days and prolonged median survival time (MST to 59 days (versus 28 days in the non-irradiated group. CD8(+ cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days. Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days, while anti-FR4 and anti-GITR antibodies did not affect efficacy. CONCLUSIONS: Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4

Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model

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Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

2014-01-01

Purpose There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. Methods and Materials C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. Results In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Conclusions Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a

Transformation of follicular lymphoma to plasmablastic lymphoma with c-myc gene rearrangement.

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Ouansafi, Ihsane; He, Bing; Fraser, Cory; Nie, Kui; Mathew, Susan; Bhanji, Rumina; Hoda, Rana; Arabadjief, Melissa; Knowles, Daniel; Cerutti, Andrea; Orazi, Attilio; Tam, Wayne

2010-12-01

Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/ BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.

The CD4+CD26-T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

NARCIS (Netherlands)

Ma, Yue; Visser, Lydia; Blokzijl, Tjasso; Harms, Geert; Atayar, Cigdem; Poppema, Sibrand; van den Berg, Anke

Little is known about the gene expression profile and significance of the rosetting CD4+CD26- T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4+CD26- and CD4+CD26+ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL)

Therapy of non-Hodgkin's lymphoma

International Nuclear Information System (INIS)

Coffey, J.; Hodgson, D.C.; Gospodarowicz, M.K.

2003-01-01

Non-Hodgkin's lymphomas are a heterogeneous group of malignancies of the lymphoid system. The exact etiology for most lymphomas has not been determined, but both viral and bacterial infections have been shown to be important etiologic factors. The WHO classification of hematopoietic and lymphoid tumours classifies lymphomas into B-cell and T-cell neoplasms. B-cell lymphomas account for more than 85% of all lymphomas. The Ann Arbor staging classification has been adopted by the AJCC and UICC as a standard for classifying extent of anatomic disease. The two most common histologic disease entities are follicular lymphomas and diffuse large B-cell lymphomas. The management of follicular lymphomas is used as a paradigm for the management of all indolent lymphomas. Radiation therapy is used for stage I and II disease, while alkylating agent chemotherapy, immunotherapy and radioimmunotherapy are most frequently used in stage III and IV disease that requires treatment. Most patients with follicular lymphoma enjoy prolonged survival, but at present there is no evidence that those with stage III and IV follicular lymphoma can be cured. Diffuse large B-cell lymphomas serve as a paradigm for treating aggressive lymphomas. Stage I and II diffuse large cell lymphomas are generally treated with combined modality therapy with doxorubicin-based chemotherapy followed by involved field radiation therapy, while those with stage III and IV disease are treated with chemotherapy alone. Patients who fail initial management are treated with further chemotherapy. High-dose chemotherapy with stem cell rescue has been shown to be particularly effective as salvage treatment for diffuse large cell lymphomas. The management of a heterogeneous group of primary extranodal lymphomas in general follows the above treatment principles, with additional treatment being required for those with a high risk of CNS failures, or involvement of contralateral paired organs. The management of MALT lymphomas

Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma

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Jianyun Liu

2018-01-01

Full Text Available Neurofibromin 1 (NF1 is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/− mice. Nf1+/− mice were found to have similar levels of NKT cells as wildtype (WT littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/− mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/− mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/− mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/− mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.

Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging.

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Ghosh, Amiya K; O'Brien, Martin; Mau, Theresa; Yung, Raymond

2017-09-07

Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

Clinicopathological Analysis of Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma with IgG4-Positive Cells

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Lee, Min Joung; Kim, Namju; Choe, Ji-Young; Khwarg, Sang In; Jeon, Yoon Kyung

2015-01-01

This study aims to analyze clinical and pathological characteristics of ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL) accompanying IgG4-positive cells. Fifty patients with a diagnosis of primary non-conjunctival ocular adnexal EMZL were enrolled in this study. The number of IgG4-positive cells and the ratio of IgG/IgG4 were evaluated by immunohistochemistry in the biopsy specimens. The patients were divided into two groups based on the absolute number and the ratio of IgG4-positive cells (IgG4-posivite vs IgG4-negative groups). The demographic data, clinical staging at diagnosis, histopathological characteristics, and response to initial treatment were comparatively analyzed between the 2 groups. Five (10%) of 50 patients were defined as IgG4-positive group, and all the cases showed characteristic histological features such as extensive plasma cell infiltration and dense fibrosis. Most of these patients (4 of 5 patients) had lymphoma of the lacrimal gland. The patients from the IgG4-positive group showed a lower response rate to initial treatment (87.5 vs 33%, p = 0.03) than IgG4-negative group with a median follow-up period of 38 months. A part of the ocular adnexal EMZLs were accompanied with IgG4-positive cells. Significantly, most IgG4-positive ocular adnexal EMZLs occurred in the lacrimal gland, and can be related with a more frequent treatment failure. PMID:26111022

Imaging of MALT lymphomas

International Nuclear Information System (INIS)

Rodallec, M.; Guermazi, A.; Attal, P.; Zagdanski, A.M.; Frija, J.; De Kerviler, E.; Brice, P.

2002-01-01

The broad category of non-Hodgkin's lymphoma includes a large variety of different diseases including indolent as well as aggressive lymphomas. Mucosa-associated lymphoid tissue (MALT) lymphoma arises in the extranodal mucosal lymphoid tissue and has only been recognised as a distinct entity in recent years. It affects one or several extranodal structures such as the stomach, the lung, the eye and salivary glands. The lymphoma is generally of low grade and has indolent course. The aim of this article is to exemplify the most common radiological patterns of MALT lymphoma. (orig.)

Radiation carcinogenesis in scid mice

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Ishii, Hiroko; Nishimura, Mayumi; Kobayashi, Shigeru; Tsuji, Hideo; Shimada, Yoshiya; Ogiu, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan); Suzuki, Fumio; Sado, Toshihiko

1999-06-01

Scid mice which have the defect of DNA-dependent protein kinase catalitic subunit, exhibit the limited activities of repair from DNA double strand breaks, and are sensitive to ionizing radiation. In order to study the relationship between repair capacity for DNA double strand breaks and carcinogenesis, the effects of ionizing radiation were studied using scid homozygotes (scid/scid), scid heterozygotes (scid/+) and CB-17 (+/+) mice. Both the Scid bone marrow cells and fibroblast cell lines from Scid embryos were highly sensitivity to acute effects of ionizing radiation. Carcinogenesis experiments showed the high incidence of thymic lymphomas (80 to 90%) in 1 to 3 Gy {sup 137}Cs-{gamma}-ray-irradiated Scid mice. (author)

Immunohistochemical Characterization of Canine Lymphomas

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Roxana CORA

2017-11-01

Full Text Available Lymphomas occur by clonal expansion of lymphoid cells and have distinctive morphological and immunophenotypic features. Determination of canine lymphoma immunophenotype is useful for accurate prognosis and further therapy. In the suggested study, we performed an immunohistochemical evaluation of some cases with canine lymphoma diagnosed in the Department of Pathology (Faculty of Veterinary Medicine, Cluj-Napoca, Romania, in order to characterize them. The investigation included 39 dogs diagnosed with different anatomical forms of lymphoma, following necropsy analysis or assessment of biopsies. The diagnosis of lymphoma was confirmed by necropsy and histopathology (Hematoxylin-eosin stain examinations. The collected specimens were analyzed by immunohistochemistry technique (automatic method using the following antibodies: CD3, CD20, CD21 and CD79a. The analyzed neoplasms were characterized as follows: about 64.10% of cases were diagnosed as B-cell lymphomas, 33.34% of cases as T-cell lymphomas, whereas 2.56% of cases were null cell type lymphomas (neither B nor T. Most of multicentric (80%, mediastinal (60% and primary central nervous system lymphomas (100% had B immunophenotype, while the majority of cutaneous (80% and digestive (100% lymphomas had T immunophenotype. Immunohistochemical description of canine lymphomas can deliver some major details concerning their behavior and malignancy. Additionally, vital prognosis and efficacy of some therapeutic protocols are relying on the immunohistochemical features of canine lymphoma.

Lym-1 Chimeric Antigen Receptor T Cells Exhibit Potent Anti-Tumor Effects against B-Cell Lymphoma

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Long Zheng

2017-12-01

Full Text Available T cells expressing chimeric antigen receptors (CARs recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies.

The Danish National Lymphoma Registry

DEFF Research Database (Denmark)

Arboe, Bente; El-Galaly, Tarec Christoffer; Clausen, Michael Roost

2016-01-01

BACKGROUND: The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information in the LYFO has never been systematically assessed. AIM: To test the coverage and data...... of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000-2012 were included. The positive predictive...... was good with high PPVs (87% to 100%), and high completeness (92% to 100%). CONCLUSION: The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research....

Hodgkin lymphoma

Science.gov (United States)

Lymphoma - Hodgkin; Hodgkin disease; Cancer - Hodgkin lymphoma ... to 70 years old. Past infection with the Epstein-Barr virus ( EBV ) is thought to contribute to some cases. People with HIV infection are at increased risk compared to the general population.

Maturation Stage Enamel Malformations in Amtn and Klk4 Null Mice

Science.gov (United States)

Nunez, Stephanie M.; Chun, Yong-Hee P.; Ganss, Bernhard; Hu, Yuanyuan; Richardson, Amelia S; Schmitz, James E.; Fajardo, Roberto; Yang, Jie; Hu, Jan C-C.; Simmer, James P.

2015-01-01

Amelotin (AMTN) and kallikrein-4 (KLK4) are secreted proteins specialized for enamel biomineralization. We characterized enamel from wild-type, Amtn−/−, Klk4−/−, Amtn+/−Klk4+/− and Amtn−/−Klk4−/− mice to gain insights into AMTN and KLK4 functions during amelogenesis. All of the null mice were healthy and fertile. The mandibular incisors in Amtn−/−, Klk4−/− and Amtn−/−Klk4−/− mice were chalky-white and chipped. No abnormalities except in enamel were observed, and no significant differences were detected in enamel thickness or volume, or in rod decussation. Micro-computed tomography (µCT) maximum intensity projections localized the onset of enamel maturation in wild-type incisors distal to the first molar, but mesial to this position in Amtn−/−, Klk4−/− and Amtn−/−Klk4−/− mice, demonstrating a delay in enamel maturation in Amtn−/− incisors. Micro-CT detected significantly reduced enamel mineral density (2.5 and 2.4 gHA/cm3) in the Klk4−/− and Amtn−/−Klk4−/− mice respectively, compared with wild-type enamel (3.1 gHA/cm3). Backscatter scanning electron microscopy showed that mineral density progressively diminished with enamel depth in the Klk4−/− and Amtn−/−Klk4−/− mice. Knoop hardness of Amtn−/− outer enamel was significantly reduced relative to the wild-type and was not as hard as the middle or inner enamel. Klk4−/− enamel hardness was significantly reduced at all levels, but the outer enamel was significantly harder than the inner and middle enamel. Thus the hardness patterns of the Amtn−/− and Klk4−/− mice were distinctly different, while the Amtn−/−Klk4−/− outer enamel was not as hard as in the Amtn−/− and Klk4−/− mice. We conclude that AMTN and KLK4 function independently, but are both necessary for proper enamel maturation. PMID:26620968

Preparation of the radiopharmaceutical {sup 131}I-Anti-CD20 for the treatment of lymphomas; Preparacion del radiofarmaco {sup 131}I-Anti-CD20 para el tratamiento de linfomas

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Pantoja H, I.E

2004-07-01

At the present time they are considered to the lymphomas like a problem of first magnitude since has happened it is necessary to be the fifth cancer cause in the world. Different treatments focused to the lymphoma like the chemotherapy and the radiotherapy, have been employees to counteract the No-Hodgkin lymphoma, without these they don't exclude the healthy tissue of the toxicity. It is for it that is taking a new direction with the employment of the directed radioimmunotherapy since this it allows to kill wicked cells selectively with radiation dose joined to the apoptosis and cytotoxicity induced by the own one bio molecule. The radioimmunotherapy with radiolabelled antibodies directed to the surface antigen CD20 represents a new modality for the treatment of No-Hodgkin lymphoma and potentially other illnesses. In this work the parameters of optimization are presented for the preparation, control of quality and evaluation of the stability in vitro and in vivo of the monoclonal antibody anti-CD20 labelled with {sup 131} I for the treatment of No-Hodgkin lymphoma. The anti-CD20 labelled by the chloramine-T method with high radiochemical purity (>98%), it is stable in solution for but of a half life of the radionuclide (8.04 days) The {sup 131} I-anti-CD20 doesn't present dehalogenation in vitro (human serum) during 24 h of incubation at 37 C. According to the tests carried out to establish the immunoreactivity, a percentage of union to cells was obtained (B lymphocytes) bigger to 30%. The biodistribution in mice balb/c one hour after their administration, it shows that there is not high reception in mucous neither kidneys, what indicates that the complex is stable in vivo. In conclusion, the radiopharmaceutical {sup 131} I-anti-CD20 was obtained in sterile injectable solution and free of pyrogens with a radiochemical purity bigger to 98% and a specific activity of 296 MBq. The radiolabelled molecule maintains its biological recognition for the receiving

Stimulation of anti-tumor effect by low-dose irradiation. Pt. 2. The prolongation of life span in AKR mice

International Nuclear Information System (INIS)

Ishii, Keiichiro; Misonoh, Jun; Hosoi, Yoshio; Ono, Tetsuya; Sakamoto, Kiyohiko.

1994-01-01

To elucidate the antileukemic effect of low-dose X-irradiation, we studied the influence of periodical low-dose X-irradiation on survival and tumor incidence of thymus using AKR mice. The findings of the experiments were as follows; (1) The median survival time of control AKR mice was 283±3 days. It of irradiation group of 15 cGy/week and 30cGy was 309±14 days and 316±10 days respectively. The life span was significantly prolonged (p < 0.05 and p < 0.01 respectively by Wilcoxon test) by periodical low-dose X-irradiation in term of breeding. (2) The incidence of thymus tumor which is observed remarkably in control AKR mice was 48.8%. It of irradiation group of 15 cGy/week and 30 cGy/week was 40% and 20% respectively. Inversely, the non-tumor incidence of tymus in control AKR mice was 19.5%. It of irradiation group of 15 cGy/week and 30 cGy/week was 32.5% and 51.4% respectively. The thymic tumor incidence was significantly decreased (p < 0.01 by chi-square test) in irradiation group of 30 cGy/week. (3) The incidence of thymic lymphoma as a death cause in control AKR mice was 80.4%. It of irradiation group of 15 cGy/week and 30cGy/week was 67.5% and 48.6% respectively. The incidence of thymic lymphoma was significantly decreased (p < 0.05 by chi-square test) in irradiation group of 30 cGy/week. (author)

Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

KAUST Repository

Zibellini, S.

2010-05-29

Antigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) SMZL-specific subsets (n=5), composed only of 12 SMZL (9 HCV- from our series); ii) Non-Hodgkin\\'s lymphoma-like subsets (n=5), comprising 5 SMZL (4 from our series) clustering with other indolent lymphomas; iii) "CLL-like subsets" (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV unrelated epitopes or an antigenic trigger common to other indolent lymphomas. ©2010 Ferrata Storti Foundation.

Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

KAUST Repository

Zibellini, S.; Capello, D.; Forconi, F.; Marcatili, P.; Rossi, D.; Rattotti, S.; Franceschetti, S.; Sozzi, E.; Cencini, E.; Marasca, R.; Baldini, L.; Tucci, A.; Bertoni, F.; Passamonti, F.; Orlandi, E.; Varettoni, M.; Merli, M.; Rizzi, S.; Gattei, V.; Tramontano, A.; Paulli, M.; Gaidano, G.; Arcaini, L.

2010-01-01

Antigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) SMZL-specific subsets (n=5), composed only of 12 SMZL (9 HCV- from our series); ii) Non-Hodgkin's lymphoma-like subsets (n=5), comprising 5 SMZL (4 from our series) clustering with other indolent lymphomas; iii) "CLL-like subsets" (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV unrelated epitopes or an antigenic trigger common to other indolent lymphomas. ©2010 Ferrata Storti Foundation.

Primary cervical and uterine corpus lymphoma; a case report and literature review

Czech Academy of Sciences Publication Activity Database

Anagnostopoulos, A.; Mouzakiti, N.; Ruthven, S.; Herod, J.; Kotsyfakis, Michalis

2013-01-01

Roč. 6, č. 4 (2013), s. 298-306 ISSN 1940-5901 R&D Projects: GA ČR GAP502/12/2409 Institutional support: RVO:60077344 Keywords : Non-Hodgkin's lymphoma * extra-nodal lymphoma * uterine/cervical lymphoma Subject RIV: EC - Immunology Impact factor: 1.422, year: 2013

Toxicity of Parasporin-4 and Health Effects of Pro-parasporin-4 Diet in Mice

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Shiro Okumura

2014-07-01

Full Text Available Parasporin-4 (PS4 is an aerolysin-type β-pore-forming toxin produced by Bacillus thuringiensis strain A1470. It exhibits specific cytotoxicity against human cancer cell lines; therefore, it is expected to be useful for the diagnosis and treatment of particular types of cancer cells. We examined the acute toxicity of PS4 on ICR mice. The LD50 value was 160 μg/kg by a subcutaneous route. Potassium, ammonium, magnesium ion, creatinine, and urea nitrogen decreased in urine by the injection of PS4. Simultaneously, creatinine and urea nitrogen in mice serum increased. These results imply that PS4 impairs kidney function in mice. PS4 is obtained from Pro-parasporin-4 (ProPS4 by processing, and ProPS4 is produced by recombinant Escherichia coli as the inclusion body. The inclusion body of ProPS4 can be solubilized in a weak acid solution and activated by pepsin, implying that it would be solubilized and activated in the stomach of mammals after oral administration. Thus, the influence of the oral administration of it by C57BL/6J mice was examined. Although ProPS4 was activated to PS4 in the mouse digestive tract, any serious health hazard was not observed and there was no significant difference in body weight change.

Radiolabeling and Preclinical Evaluation of 131I-anti-CD20 for Non-Hodgkin's Lymphomas Therapy

International Nuclear Information System (INIS)

Kullaprawittaya, Usa; Khongpetch, Pranom; Ngamprayad, Tippanan; Nuanchuen, Suphatphong

2007-08-01

Full text: In this study, a monoclonal anti-CD20 was developed for radioimmunotherapy of non-Hodgkin's B-cell lymphoma by reacting anti-CD20 with iodine-131 using iodogen procedure. It was found that radiochemical yield was > 95 % independently of incubation time and the antibody could be conjugated with iodine-131 up to 10 mCi/mg. The radiolabeled antibody exhibited excellent retention of immunoreactivity with radio incorporations >95% for 6 hr at 4 o C. In vitro stability tests showed minimal loss of iodine-131 from the conjugate in the presence of cysteine and in human serum at 37 o C. Biodistribution study in normal ICR mice showed higher uptake by the liver, kidney and intestines but lower thyroid uptake compared to 131 I -MIBG. Biodistribution studies confirmed the in vitro stability of 131 I -anti-CD20. In particular, excellent in vivo retention of iodine-131 was demonstrated by lower thyroid accumulation over 48 hr. A favorable biological distribution of 131 I -anti-CD20 suggests this radiopharmaceutical may be effectively used in the therapy of non-Hodgkin's lymphoma

Discordant lymphoma consisting of splenic mantle cell lymphoma and marginal zone lymphoma involving the bone marrow and peripheral blood: a case report

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Caracciolo Francesco

2011-09-01

Full Text Available Abstract Introduction Discordant lymphomas are rare entities characterized by the simultaneous presence of two distinct types of lymphomas in different anatomic sites. We describe a very rare case of simultaneous occurrence of splenic mantle cell lymphoma and marginal zone lymphoma involving the bone marrow and peripheral blood. Case presentation We report the case of a 60-year-old asymptomatic Caucasian woman in whom discordant lymphomas were discovered when a slight lymphocytosis and a conspicuous splenomegaly were observed. The different morphological, immunophenotypical and immunohistochemical features found in the different pathologic samples obtained from peripheral blood, bone marrow and spleen sections made it possible to differentiate two types of non-Hodgkin B-cell lymphomas: a mantle cell lymphoma infiltrating the spleen and a marginal zone lymphoma involving both the bone marrow and peripheral blood. Since a similar IgH gene rearrangement was found both in the bone marrow and in the spleen, the hypothesis of a common origin, followed by a different clonal selection of the neoplastic lymphocytes may be taken into consideration. Conclusion Our case emphasizes the usefulness of investigating simultaneous specimens from different anatomic sites from the same patient and the relevant diagnostic role of splenectomy.

Lymphomas or leukemia presenting as ovarian tumors. An analysis of 42 cases.

Science.gov (United States)

Osborne, B M; Robboy, S J

1983-11-15

Forty cases of ovarian lymphoma and two of extramedullary leukemia were examined with emphasis on histologic types correlated with age, modes of presentation, operative findings, including frequency of bilaterality and omental spread, clinical course following therapy, and problems in differential diagnosis. Although most cases were referred with diagnoses other than lymphoma (granulosa cell tumor or dysgerminoma, occasionally anaplastic tumor, Krukenberg tumor, or metastatic breast carcinoma), utilization of sections cut at 4 mu and stained with hematoxylin and eosin, or sections stained by the methyl green pyronine (MGP), naphthol-ASD esterase (NASD) or periodic acid-Schiff (PAS) methods helped bring out the lymphoid or hematopoietic nature of the cells. Sixteen patients were under 20 years of age. They had small noncleaved cell lymphoma (undifferentiated Burkitt's and non-Burkitt's, 10 cases), diffuse immunoblastic large cell lymphoma (4 cases), or acute granulocytic leukemia (2 cases). Twenty-six patients were 29 to 74 years of age and had diffuse large cell lymphoma (10 cases), diffuse immunoblastic large cell lymphoma (9 cases), follicular (nodular) lymphoma (6 cases) or small noncleaved cell lymphoma (1 case). Pain with an abdominal or pelvic mass was the most common presentation. Nine tumors were discovered during investigation of other gynecologic complaints. At laparotomy, the tumors in 55% of cases involved both ovaries, and in 64% also involved extragonadal sites (usually omentum, fallopian tubes, or lymph nodes). Seventeen patients had tumor affecting one ovary, seven of these without any evidence of extragonadal spread. Forty-two percent (15) of 37 patients with follow-up were alive after 2 years. Only nine patients survived more than 5 years; two subsequently died of lymphoma. Favorable prognostic features included: (1) FIGO stage IA; (2) unilateral ovarian involvement; (3) focal involvement of one ovary; and (4) follicular (nodular) lymphoma.

Orbital and conunctival lymphoma treatment and prognosis

International Nuclear Information System (INIS)

Bessell, E.M.; Henk, J.M.; Whitelocke, R.A.F.; Wright, J.E.

1988-01-01

115 patients with lymphoid tumours presenting in the orbit were seen between 1970 and 1984. The histological types were high-grade malignant lymphoma - 18, low-grade malignant lymphoma - 43, and indeterminate lymphocytic lesions - 54. Eighteen patients were found to have disseminated lymphoma at presentation. The majority of the patients received radiotherapy to the orbit; local control was achieved in all cases and the ocular morbidity from radiotherapy was low with 11 patients developing lens opacities and 5 a dry eye. Survival of patients with stage I low-grade lymphoma adn indeterminate lymphocytic lesions was similar to that of a normal population of the same age distribution. The clinic features and dissemination pattern of the low-grade malignant lymphomata and the indeterminate lymphocytic lesions were identical, suggesting that most, if not all, lymphoid masses presenting in the orbit are neoplastic rather than reactive in nature. 28 refs.; 4 figs.; 5 tabs

Orbital and conunctival lymphoma treatment and prognosis

Energy Technology Data Exchange (ETDEWEB)

Bessell, E M; Henk, J M; Whitelocke, R A.F.; Wright, J E

1988-12-01

115 patients with lymphoid tumours presenting in the orbit were seen between 1970 and 1984. The histological types were high-grade malignant lymphoma - 18, low-grade malignant lymphoma - 43, and indeterminate lymphocytic lesions - 54. Eighteen patients were found to have disseminated lymphoma at presentation. The majority of the patients received radiotherapy to the orbit; local control was achieved in all cases and the ocular morbidity from radiotherapy was low with 11 patients developing lens opacities and 5 a dry eye. Survival of patients with stage I low-grade lymphoma adn indeterminate lymphocytic lesions was similar to that of a normal population of the same age distribution. The clinic features and dissemination pattern of the low-grade malignant lymphomata and the indeterminate lymphocytic lesions were identical, suggesting that most, if not all, lymphoid masses presenting in the orbit are neoplastic rather than reactive in nature. 28 refs.; 4 figs.; 5 tabs.

Linfomas de la órbita y anexos oculares: Correlación clínico patológica de 25 casos Orbital and ocular adnexal lymphomas: Clinico-pathological correlation in 25 cases

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Erica A. Rojas Bilbao

2010-08-01

Full Text Available Se evaluaron las características clínicas, histológicas y la evolución de una cohorte de pacientes con linfomas de la órbita y anexos oculares. Entre 1995 y 2008 se estudiaron 25 casos de linfomas de la órbita y anexos oculares en un centro oncológico de referencia. En cada caso se analizó el inmunofenotipo usando un panel de anticuerpos monoclonales (CD45, CD20, CD3, CD5, CD23, BCL2, BCL6, BCL10, Ki67, CD30, CD15, BCL1, Kappa, Lambda, CD138. Las lesiones fueron evaluadas utilizando el sistema de clasificación de linfomas (OMS, 2008. Se analizaron 23 linfomas primarios y dos secundarios. Los subtipos histológicos fueron: 16 linfomas B de la zona marginal asociados a las mucosas (MALT, cuatro linfomas difusos de células grandes B, dos linfomas foliculares y un paciente con linfoma Hodgkin. De los 25 casos estudiados, 22 presentaron estadios localizados. El linfoma MALT fue el subtipo más frecuente. En este estudio se observó enfermedad localizada en la mayoría de los casos y con baja progresión a distancia.Clinical, histological features and outcome of a cohort of patients with orbital and adnexal lymphoproliferative tumors were evaluated. Twenty-five cases in an oncologic referral center from 1995 to 2008, were included in the study. Each case had detailed immunophenotypic analysis using a panel of monoclonal antibodies (CD45, CD20, CD3, CD5, CD23, BCL2, BCL6, BCL10, Ki67, CD30, CD15, BCL1, Kappa, Lambda, CD138. Lesions were classified by using WHO (2008 lymphomas classification. Twenty-three patients were found to have primary and two secondary lymphomas. Histological subtypes were: 16 patients with marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma, four diffuse large B cell lymphomas, two mantle cell lymphomas, two follicular lymphomas, and one Hodgkin lymphoma. Among the 25 patients studied, 22 had localized stage. Extranodal marginal zone lymphoma was the most frequent type of primary orbital

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Burkitt's lymphoma: A case report and review

OpenAIRE

Chettiankandy, Tabita Joy; Tupkari, Jagdish Vishnu; Kumar, Keshav; Ahire, Manisha Sandeep

2016-01-01

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Burkitt's lymphoma (BL), is a diagnostic provisional category in the World Health Organization 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typica...

Life-shortening and carcinogenesis in mice irradiated neonatally with x rays

International Nuclear Information System (INIS)

Sasaki, S.; Kasuga, T.

1981-01-01

The characteristics of life-shortening and carcinogenesis were investigated in x-irradiated neonatal B6WFr mice. Animals were irradiated with 24 hr after birth and allowed to complete their normal life span. Mean life span was shortened linearly with doses at a rate of 9.1% per 100 R for females and 9.8% for males. The spectrum of neoplastic diseases was apparently modulated by x irradiation, showing neonatal B6WFr mice to be highly susceptible to the induction of thymic lymphoma, liver tumor, and pituitary tumor. The dose-response relationship for thymice lymphoma could be described by a linear-quadratic model, and linearity could be rejected. Thymic lymphoma developed after a short latent period, resulting in death between 100 and 450 days of age. Liver and pituitary tumors increased with increasing dose up to 400 R and decreased thereafter. The latent period for liver tumor development was apparently shortened with increasing doses. Pituitary tumor developed in excess only in females after a long latent period

Linfoma tipo MALT de la glándula parótida Lymphoma type MALT of the parotid gland

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Carlos Frómeta Neira

2010-09-01

Full Text Available Los linfomas tipo MALT (tejido linfoideo asociado a mucosa, constituyen la variedad más recientemente descubierta de los linfomas no Hodgkin, tienen lugar fundamentalmente en la mucosa gástrica asociados a infección por Helycobacter pylori, y en la glándula tiroides en relación con la tiroiditis de Hashimoto. Sin embargo, internacionalmente se han descrito casos en glándulas salivales asociados a linfoadenitis. La naturaleza de la lesión a menudo no puede ser determinada solo por el estudio citológico; se hace necesario el análisis histopatológico para el diagnóstico definitivo en la mayoría de los casos. El presente estudio muestra un paciente masculino con aumento de volumen bilateral de ambas glándulas parótidas y diagnóstico citohistopatológico de un proceso linfoepitelial benigno, el cual desarrolló un linfoma tipo MALT en relación con la glándula parótida derecha.The lymphomas type MALT or the mucosa-associated lymphoid tissue, are the most recent variety of non-Hodgkin lymphomas present mainly in the gastric mucosa associated with Helycobacter pylori infection and in the thyroid gland in relation to Hashimoto's thyroiditis. Frequently the origin of this lesion can't be determined only by cytology study, thus it is necessary the histopathology analysis for a definitive diagnosis in most cases. Present paper includes the case of male patient with bilateral volume increase of both parotid glands and a diagnosis cytopathological of a benign lymphoepithelial process and the development of a type MALT lymphoma in relation to the right parotid gland.

How I treat double-hit lymphoma.

Science.gov (United States)

Friedberg, Jonathan W

2017-08-03

The 2016 revision of the World Health Organization (WHO) classification for lymphoma has included a new category of lymphoma, separate from diffuse large B-cell lymphoma, termed high-grade B-cell lymphoma with translocations involving myc and bcl-2 or bcl-6 . These lymphomas, which occur in hit lymphomas (or triple-hit lymphomas if all 3 rearrangements are present). It is important to differentiate these lymphomas from the larger group of double-expressor lymphomas, which have increased expression of MYC and BCL-2 and/or BCL-6 by immunohistochemistry, by using variable cutoff percentages to define positivity. Patients with double-hit lymphomas have a poor prognosis when treated with standard chemoimmunotherapy and have increased risk of central nervous system involvement and progression. Double-hit lymphomas may arise as a consequence of the transformation of the underlying indolent lymphoma. There are no published prospective trials in double-hit lymphoma, however retrospective studies strongly suggest that aggressive induction regimens may confer a superior outcome. In this article, I review my approach to the evaluation and treatment of double-hit lymphoma, with an eye toward future clinical trials incorporating rational targeted agents into the therapeutic armamentarium. © 2017 by The American Society of Hematology.

Tumor microvessel density–associated mast cells in canine nodal lymphoma

Science.gov (United States)

Mann, Elizabeth; Whittington, Lisa

2014-01-01

Objective: Mast cells are associated in angiogenesis in various human and animal neoplasms. However, association of mast cells with tumor microvessel density in canine lymphoma was not previously documented. The objective of the study is to determine if mast cells are increased in canine nodal lymphomas and to evaluate their correlation with tumor microvessel density and grading of lymphomas. Methods: Nodal lymphomas from 33 dogs were studied and compared with nonneoplastic lymph nodes from 6 dogs as control. Mast cell count was made on Toluidine blue stained sections. Immunohistochemistry using antibody against Factor VIII was employed to visualize and determine microvessel density. Results: The mast cell count in lymphoma (2.95 ± 2.4) was significantly higher (p < 0.05) than that in the control (0.83 ± 0.3) and was positively correlated with tumor microvessel density (r = 0.44, p = 0.009). Significant difference was not observed in mast cell count and tumor microvessel density among different gradings of lymphomas. Conclusions: Mast cells are associated with tumor microvessel density in canine nodal lymphoma with no significant difference among gradings of lymphomas. Mast cells may play an important role in development of canine nodal lymphomas. Further detailed investigation on the role of mast cells as important part of tumor microenvironment in canine nodal lymphomas is recommended. PMID:26770752

Tumor microvessel density–associated mast cells in canine nodal lymphoma

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Moges Woldemeskel

2014-11-01

Full Text Available Objective: Mast cells are associated in angiogenesis in various human and animal neoplasms. However, association of mast cells with tumor microvessel density in canine lymphoma was not previously documented. The objective of the study is to determine if mast cells are increased in canine nodal lymphomas and to evaluate their correlation with tumor microvessel density and grading of lymphomas. Methods: Nodal lymphomas from 33 dogs were studied and compared with nonneoplastic lymph nodes from 6 dogs as control. Mast cell count was made on Toluidine blue stained sections. Immunohistochemistry using antibody against Factor VIII was employed to visualize and determine microvessel density. Results: The mast cell count in lymphoma (2.95 ± 2.4 was significantly higher (p < 0.05 than that in the control (0.83 ± 0.3 and was positively correlated with tumor microvessel density (r = 0.44, p = 0.009. Significant difference was not observed in mast cell count and tumor microvessel density among different gradings of lymphomas. Conclusions: Mast cells are associated with tumor microvessel density in canine nodal lymphoma with no significant difference among gradings of lymphomas. Mast cells may play an important role in development of canine nodal lymphomas. Further detailed investigation on the role of mast cells as important part of tumor microenvironment in canine nodal lymphomas is recommended.

Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice

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Veronica S. Gil

2016-12-01

Full Text Available Histone deacetylase 9 (HDAC9 is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL. We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL. To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH enhancer (Eμ. Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.

Application of 99Tcm-HL-91 in the hypoxia study of malignant lymphoma

International Nuclear Information System (INIS)

Li Li; Han Peizhen; Yan Yujun; Wang Yueying; Wang Junqi; Li Meijia

2002-01-01

Objective: 99 Tc m -HL91 is a putative hypoxic tracer probing hypoxia in solid tumors. This study was aimed at investigating the property of the spontaneous IRM-2-ML malignant lymphoma in homozygotic IRM-2 mice, and at testing the applicability of 99 Tc m -HL91 to the imaging of hypoxia in tumors. Methods: Biodistribution of 99 Tc m -HL91 after intravenously injection into normal and tumor-bearing IRM-2 mice was studied by determining blood and tissue levels of radioactivity from 20 to 360 min after injection. Nicotinamide was used to reduce the extent of hypoxia in the tumors. Planar SPECT imaging on normal and tumor-bearing IRM-2 mice was also performed. Results: Tumor load did not significantly influence the retention of 99 Tc m -HL91 in normal organs. 99 Tc m -HL91 was metabolized mainly via the liver and kidney, and was cleared fast from the blood. The tumor-to-blood ratio and tumor-to-muscle ratio continued to increase until 360 min (2.63 +- 0.25 and 3.37 +- 0.22 at 120 min, 3.51 +- 0.17 and 6.44 +- 0.29 at 360 min, respectively). The retention of 99 Tc m -HL91 in the tumor was reduced in mice by treatment with nicotinamide. Planar SPECT imaging showed that tumor could be observed clearly. Conclusion: These results confirm that IRM-2-ML malignant lymphoma possesses the common property of solid tumors,and also indicate that 99 Tc m -HL91 could be used to detect tumor hypoxia

Type distribution of lymphomas in Lebanon: five-year single institution experience.

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Sader-Ghorra, Claude; Rassy, Marc; Naderi, Samah; Kourie, Hampig Raphael; Kattan, Joseph

2014-01-01

Lymphomas represent the fifth most frequent cancer in Lebanon. However, little is known concerning epidemiologic characteristics and distribution of lymphoid neoplasms according to the 2008 WHO classification. We conducted a retrospective study of lymphoma cases diagnosed from 2008 till 2012 at Hotel-Dieu de France University Hospital. A total of 502 new cases of lymphoma were diagnosed at our institution during a five year period: 119 cases (24%) were Hodgkin lymphomas (HL) and 383 cases (76%) were non-Hodgkin lymphomas (NHL). HLs were equally distributed in both sexes with a mean age at diagnosis of 30 years. Among NHL, 87% (332 cases) were B cell lymphomas, 9% (34 cases) were T cell lymphomas and 4%(17 cases) were classified as precursor lymphoid neoplasms. Among B cell lymphomas, 44% (147 cases) were diffuse large B cell lymphomas (DLBCL), 20% (65 cases) follicular lymphomas and 8% (27 cases) mantle cell lymphomas. DLBCL were equally distributed in both sexes with a mean age of 58 years. Follicular lymphomas were characterized by a male predominance (57%) and a mean age of 60 years. Mantle cell lymphomas showed a pronounced male predominance (85%) with a mean age of 60 years in men and 70 years in women. Some 72% of patients having T cell lymphomas were men, with a mean age of 57 years in men and 45 years in women, while 65% of patients having precursor lymphoid neoplasms were women with a mean age of 22 years in women and 30 years in men. The lymphoma subtype distribution in Lebanon is unique when compared to other countries from around the world. In fact, Hodgkin and follicular lymphomas are more frequent than in most Far Eastern, European and American countries, while T-cell lymphomas and DLBCL are less frequent.

Radiation therapy planning for early-stage Hodgkin lymphoma

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Maraldo, Maja V; Dabaja, Bouthaina S; Filippi, Andrea R

2015-01-01

PURPOSE: Early-stage Hodgkin lymphoma (HL) is a rare disease, and the location of lymphoma varies considerably between patients. Here, we evaluate the variability of radiation therapy (RT) plans among 5 International Lymphoma Radiation Oncology Group (ILROG) centers with regard to beam arrangements...... axillary disease, and 1 had disease in the neck only. The median age at diagnosis was 34 years (range, 21-74 years), and 5 patients were male. Of the resulting 50 treatment plans, 15 were planned with volumetric modulated arc therapy (1-4 arcs), 16 with intensity modulated RT (3-9 fields), and 19 with 3...

[Gastric perforation by MALT lymphoma. Case report].

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López-Zamudio, José; Ramírez-González, Luis Ricardo; Núñez-Márquez, Julia; Fuentes Orozco, Clotilde; González Ojeda, Alejandro; Leonher-Ruezga, Karla Lisseth

2015-01-01

Gastric non-Hodgkin lymphoma is a rare tumour that represents approximately 7% of all stomach cancers and 2% of all lymphomas. The most frequent location of gastric MALT (mucosa associated lymphoid tissue) lymphomas is in the antrum in 41% of the cases, and 33% can be multifocal. The risk of spontaneous perforation of a gastric MALT lymphoma is 4-10%. 24 year old male patient carrying the Human Immunodeficiency Virus, who began with signs and symptoms of acute abdomen and fever 72 hours before arriving in the emergency room. A computed tomography was performed that showed free fluid in the cavity, and gastric wall thickening. The patient underwent a laparotomy, finding absence of the anterior wall of the stomach, sealed with the left lobe of the liver, colon and omentum. Total gastrectomy, with oesophagosty and jejunostomy tube, was performed. Gastric perforation secondary to a MALT lymphoma is rare, with high mortality. There is limited information reported of this complication and should be highly suspected in order to provide appropriate treatment for a complication of this type. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

The enhancing effect of fractionated whole-body x-irradiation on replication of endogenous leukemia viruses in BALB/c mice

International Nuclear Information System (INIS)

Takamori, Yasuhiko; Okumoto, Masaaki; Iwai, Mineko; Iwai, Yoshiaki

1976-01-01

The incidence of leukemia, changes in the tissue weight of spleen and thymus, and the expression of endogenous viruses were examined with BALB/c mice following 4 weekly fractionated whole-body x-irradiation of 170 R each, starting at 4 weeks of age. The leukemia incidence was quite low for the unirradiated controls, while 60% of the irradiated male mice developed thymic lymphoma. The virus-positive cells appeared earlier in the spleen than in the thymus and bone marrow, and increased with aging. The time of appearance of virus-positive cells in these tissues was remarkably promoted by the fractionated x-irradiation, and its frequency was also enhanced. (auth.)

Imaging of non-hodgkin lymphomas

DEFF Research Database (Denmark)

El-Galaly, Tarec Christoffer; Hutchings, Martin

2015-01-01

Optimal lymphoma management requires accurate pretreatment staging and reliable assessment of response, both during and after therapy. Positron emission tomography with computerized tomography (PET/CT) combines functional and anatomical imaging and provides the most sensitive and accurate methods...... for lymphoma imaging. New guidelines for lymphoma imaging and recently revised criteria for lymphoma staging and response assessment recommend PET/CT staging, treatment monitoring, and response evaluation in all FDG-avid lymphomas, while CT remains the method of choice for non-FDG-avid histologies. Since...... interim PET imaging has high prognostic value in lymphoma, a number of trials investigate PET-based, response-adapted therapy for non-Hodgkin lymphomas (NHL). PET response is the main determinant of response according to the new response criteria, but PET/CT has little or no role in routine surveillance...

Human CD4 restores normal T cell development and function in mice deficient in murine CD4

OpenAIRE

1994-01-01

The ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4-/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V beta T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positiv...

The molecular biology of radiation-induced carcinogenesis: thymic lymphoma, myeloid leukaemia and osteosarcoma

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Janowski, M [Centre d' Etude de l' Energie Nucleaire, Mol (Belgium); Cox, R [Medical Research Council, Harwell (UK). Radiobiological Research Unit; Strauss, P G [GSF, Neuherberg (Germany, F.R.). Abt. fuer Molekulare Zellpathologie

1990-04-01

In mice, external X- or {gamma}-irradiation may induce thymic lymphomas or myeloid leukaemias, while bone-seeking {alpha}-emitters may induce osteosarcomas, and to a lesser extent acute myeloid leukaemia. The paper reviews briefly some experimental data in respect to molecular mechanisms underlying these radio-carcinogenic processes. Thymic lymphomagenesis proceeds by an indirect mechanism in which recombinant proviruses could be involved. Myeloid leukaemogenesis is characterized by a very early putative initiating event, consisting of non-random rearrangements and/or deletions of chromosome 2. Osteosarcomagenesis in mice is often associated with the expression of proviruses, and the tumors often contain somatically acquired proviruses. (UK).

Distinct patterns of HIV-1 evolution within metastatic tissues in patients with non-Hodgkins lymphoma.

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Marco Salemi

2009-12-01

Full Text Available Despite highly active antiretroviral therapy (HAART, AIDS related lymphoma (ARL occurs at a significantly higher rate in patients infected with the Human Immunodeficiency Virus (HIV than in the general population. HIV-infected macrophages are a known viral reservoir and have been shown to have lymphomagenic potential in SCID mice; therefore, there is an interest in determining if a viral component to lymphomagenesis also exists. We sequenced HIV-1 envelope gp120 clones obtained post mortem from several tumor and non-tumor tissues of two patients who died with AIDS-related Non-Hodgkin's lymphoma (ARL-NH. Similar results were found in both patients: 1 high-resolution phylogenetic analysis showed a significant degree of compartmentalization between lymphoma and non-lymphoma viral sub-populations while viral sub-populations from lymph nodes appeared to be intermixed within sequences from tumor and non-tumor tissues, 2 a 100-fold increase in the effective HIV population size in tumor versus non-tumor tissues was associated with the emergence of lymphadenopathy and aggressive metastatic ARL, and 3 HIV gene flow among lymph nodes, normal and metastatic tissues was non-random. The different population dynamics between the viruses found in tumors versus the non-tumor associated viruses suggest that there is a significant relationship between HIV evolution and lymphoma pathogenesis. Moreover, the study indicates that HIV could be used as an effective marker to study the origin and dissemination of lymphomas in vivo.

Immunoexpression of CD95 in chronic gastritis and gastric mucosa-associated lymphomas

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Vassallo J.

2004-01-01

Full Text Available CD95 (Fas/APO-1-mediated apoptosis plays an important role in immunological regulation and is related to the pathogenesis of autoimmune diseases. Immunoexpression of CD95 has been reported to frequently occur in low grade non-Hodgkin lymphomas, especially of post-germinal center histogenesis, among which those originating in mucosa-associated lymphoid tissue (MALT lymphomas. However, there is no report comparing in situ immunoexpression of this marker in lymphomas and the hyperplastic lymphoid reaction (chronic gastritis related to Helicobacter pylori infection. The purpose of the present research was to compare the intensity of lymphoid CD95 immunoexpression in 15 cases of H. pylori-related chronic gastritis and 15 gastric MALT lymphomas. CD95 (anti-CD95 was detected by an immunoperoxidase technique in paraffin sections using the catalyzed amplification system. Graduation of reaction intensity (percentage of CD95-positive cells was semiquantitative, from 1+ to 4+. Nine cases of chronic gastritis were 4+, five 2+ and one 1+. Three lymphomas were 4+, three 3+, four 2+, four 1+, and one was negative. Although 14 of 15 lymphomas were positive for CD95, the intensity of the reaction was significantly weaker compared to that obtained with gastric tissue for patients with gastritis (P = 0.03. The difference in CD95 immunoexpression does not seem to be useful as an isolated criterion in the differential diagnosis between chronic gastritis and MALT lymphomas since there was overlapping of immunostaining patterns. However, it suggests the possibility of a pathogenetic role of this apoptosis-regulating protein in MALT lymphomas.

Multimodality imaging of cardiothoracic lymphoma

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Carter, Brett W., E-mail: bcarter2@mdanderson.org [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Section of Thoracic Imaging, 1515 Holcombe Blvd., Unit 1478, Houston, TX 77030 (United States); Wu, Carol C. [Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, FND-202, Boston, MA 02114 (United States); Khorashadi, Leila [Department of Radiology, Mount Auburn Hospital, Cambridge, MA 02138 (United States); Godoy, Myrna C.B.; Groot, Patricia M. de [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Section of Thoracic Imaging, 1515 Holcombe Blvd., Unit 1478, Houston, TX 77030 (United States); Abbott, Gerald F. [Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, FND-202, Boston, MA 02114 (United States); Lichtenberger III, John P. [Department of Radiology, David Grant Medical Center, Travis AFB, CA 94535 (United States)

2014-08-15

Lymphoma is the most common hematologic malignancy and represents approximately 5.3% of all cancers. The World Health Organization published a revised classification scheme in 2008 that groups lymphomas by cell type and molecular, cytogenetic, and phenotypic characteristics. Most lymphomas affect the thorax at some stage during the course of the disease. Affected structures within the chest may include the lungs, mediastinum, pleura, and chest wall, and lymphomas may originate from these sites as primary malignancies or secondarily involve these structures after arising from other intrathoracic or extrathoracic sources. Pulmonary lymphomas are classified into one of four types: primary pulmonary lymphoma, secondary pulmonary lymphoma, acquired immunodeficiency syndrome-related lymphoma, and post-transplantation lymphoproliferative disorders. Although pulmonary lymphomas may produce a myriad of diverse findings within the lungs, specific individual features or combinations of features can be used, in combination with secondary manifestations of the disease such as involvement of the mediastinum, pleura, and chest wall, to narrow the differential diagnosis. While findings of thoracic lymphoma may be evident on chest radiography, computed tomography has traditionally been the imaging modality used to evaluate the disease and effectively demonstrates the extent of intrathoracic involvement and the presence and extent of extrathoracic spread. However, additional modalities such as magnetic resonance imaging of the thorax and {sup 18}F-FDG PET/CT have emerged in recent years and are complementary to CT in the evaluation of patients with lymphoma. Thoracic MRI is useful in assessing vascular, cardiac, and chest wall involvement, and PET/CT is more accurate in the overall staging of lymphoma than CT and can be used to evaluate treatment response.

Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy.

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Pavlova, Elena V; Archer, Joy; Wang, Susan; Dekker, Nick; Aerts, Johannes Mfg; Karlsson, Stefan; Cox, Timothy M

2015-01-01

Clonal B-cell proliferation is a frequent manifestation of Gaucher disease - a sphingolipidosis associated with a high risk of multiple myeloma and non-Hodgkin lymphoma. Gaucher disease is caused by genetic deficiency of acid β-glucosidase, the natural substrates of which (β-d-glucosylceramide and β-d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of β-glucosidase [Gba(tm1Karl/tm1Karl)Tg(MX1-cre)1Cgn/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B-cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B-cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (GENZ 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty-two Gaucher mice received 300 mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of β-d-glucosylceramide and the unacylated glycosphingolipid, β-d-glucosylsphingosine, declined. After administration of GENZ 112638 to Gaucher mice for 3-10 months, serum paraproteins were not detected and there was a striking reduction in the malignant lymphoproliferation: neither lymphomas nor plasmacytomas were found in animals that had received the investigational agent. In contrast, 14 out of 60 Gaucher mice without GENZ 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age-matched mice with Gaucher disease that had not received GENZ 112638. Long-term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B-cell lymphoma and myeloma in Gaucher mice. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

G2M arrest and apoptosis in murine T lymphoma cells following exposure to 212Bi alpha particle irradiation

International Nuclear Information System (INIS)

Palayoor, S.T.; Humm, J.L.; Macklis, R.M.

1993-01-01

Asynchronous exponentially growing EL4 murine T lymphoma cells were exposed either to high LET α-radiation from 212 Bi-DTPA or to γ-radiation from a 137 Cs source. Radiation-induced cell cycle perturbation was studied by flow cytometry. Alpha irradiation, like γ, transiently arrested cells in the G2M phase in a dose-dependent manner. The maximum percentages of cells accumulated in G2M 18 h after α- and γ-irradiation were comparable, though the dose-response relationships differed. The ''RBE'' value for G2M block for α- versus γ-radiation was approx. 4. (author)

Diagnostic imagings of malignant lymphoma of the pancreas with obstructive jaundice

International Nuclear Information System (INIS)

Shirahase, Isao; Kobayashi, Nobuaki; Tanimura, Hiroshi; Yamaoka, Yoshio; Ozawa, Kazue; Hayashi, Nobushige; Itoh, Kyo; Nakajima, Yasuaki

1987-01-01

We performed pancreatoduodenectomy in a 41-year-old man with pancreatic malignant lymphoma, who began to have obstructive jaundice and in whom imaging showed a tumor of the head of the pancreas with extrapancreatic growth. The tumor was 8 x 8.5 x 4 cm in size. The histopathological findings of the tumor indicated a malignant lymphoma, non-Hodgkin, diffuse large cell type. The patient was discharged after receiving nine courses of postoperative chemotherapy with VEPA. It is very important in determing the surgical indication to preoperatively differentiate malignant lymphoma from pancreatic cancer, since malignant lymphoma originating from the gastrointestinal organs can, in some cases, be almost completely repaired if the tumor is removed in the early stage. Thus, it is possible to achieve effective multidisciplinary treatment for malignant lymphoma by performing closer preoperative examinations and taking into consideration the possibility of the existence of malignant lymphoma. This paper discusses the details of the imaging necessary to differentiate pancreatic malignant lymphoma. (author)

President's categorical course on lymphoma

International Nuclear Information System (INIS)

Hoppe, Richard T.

1997-01-01

Improvements in the classification, staging, and treatment of the lymphomas, complemented by an improved understanding of the biology of these diseases, has led to an improved outcome of therapy for both Hodgkin's disease and many of the non-Hodgkin's lymphomas. The rapid changes that have occurred in this field in the last decade make it timely to review this subject for radiation oncologists in a comprehensive fashion. This course is designed to meet broad educational needs required for understanding these diseases and providing effective care for patients with lymphoma. The faculty includes many leaders from both laboratory and clinical disciplines dealing with lymphomas, who will address a variety of scientific and clinical topics. The morning session will be devoted to Hodgkin's disease, including new concepts in its biology, a review of clinical trials for early stage disease, a discussion of the role of high dose therapy, and description of long term complications of treatment. The afternoon sessions will be devoted to the non-Hodgkin's lymphomas, including new concepts in pathology and biology, a description of specific entities including the low grade lymphomas, MALT lymphomas, extranodal lymphomas, intermediate grade lymphomas, mantle cell lymphomas, and summary discussions of the role of radioimmuno-therapy and high dose therapy. Although the role of radiation therapy in the management of patients with lymphoma has changed dramatically in the past two decades, radiation remains the most effective single agent for the treatment of these diseases and it is especially important for radiation onologists to keep abreast of these new concepts. This course has been designed to achieve that goal

Extranodal diffuse non hodgkin lymphoma in the thigh

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Bölke E

2010-08-01

Full Text Available Abstract Diffuse large B-cell lymphoma usually starts as a rapidly growing mass in an internal lymph node and can grow in other areas such as the bone or intestines. About 1/3 of these lymphomas are confined to one part of the body when they are localized. In the case of a 78-year-old man, an extensive tumour was located on the right thigh. Biopsies of the tumour revealed diffuse proliferation of large lymphoid cells which have totally affected the normal architecture of striated muscle. The patient received multimodality treatment including chemotherapy of the CHOP regimen and adjuvant radiotherapy. Despite this being a fast growing lymphoma, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy.

Renal and perirenal non-Hodgkin's lymphoma: CT findings

International Nuclear Information System (INIS)

Lee, Seon Kyu; Kim, Seung Hyup; Lee, Goo; Choi, Byeung In; Han, Man Chung

1992-01-01

CT findings of 19 kidneys in 12 patients with renal and perirenal non-Hodgkin's lymphoma were retrospectively reviewed to determine distinguishing characteristic and specific findings. CT manifestation of the renal and perirenal lymphoma included multiple nodules in five kidneys(26.3%), trans-capsular infiltration in three kidneys(15.8%), trans-sinus infiltration in nine kidneys(47.4%) and diffuse infiltration in two kidneys(10.5%). Perirenal changes were thickening of the renal fascia in ten kidneys(52.6%) and crescent lesion of low attenuation in the subcapsular area in five kidneys(26.3%) Retroperitoneal lymphadenopathy was evident in eleven patient(57.9%). Renal calyceal dilatation without renal pelvic dilatation(selective calycelal dilatation) was noted in three kidneys. Familiarity with these CT findings of renal and perirenal lymphoma may be helpful in the diagnosis and management of patient with non-Hodgkin's lymphoma

CARDIAC LYMPHOMA IN DOG

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G. D. Cruz

2016-11-01

Full Text Available Lymphoma is a lymphoid tumor that originates in hematopoietic organs such as lymph node, spleen or liver. In dogs, the overall prevalence of cardiac tumors was estimated to be only 0.19% based on the results of the survey of a large database, and lymphomas accounts for approximately 2% of all cardiac tumors. In general, the involvement of the myocardium is rarely described in canine lymphoma. Currently, there is no evidence of a viral association with primary cardiac lymphoma in dogs, but other types of immunosuppression may contribute to abnormal events, such as involvement primary cardiac. The aim of this study was to analyze a case of sudden death of a bitch, SRD, aged 10, who had the final diagnosis of cardiac lymphoma.

CT appearances of mucosa-associated lymphoid tissue (MALT) lymphoma

International Nuclear Information System (INIS)

Kessar, P.; Norton, A.; Rohatiner, A.Z.S.; Lister, T.A.; Reznek, R.H.

1999-01-01

Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade lymphoma that differs from high-grade non-Hodgkin lymphoma both clinically and histologically. The CT appearances of MALT lymphoma are described. Of 40 patients referred with biopsy-proven MALT lymphoma, only seven had not had gastrectomy or chemotherapy prior to CT examination. The CT scans of these seven cases were analysed for the degree and extent of gastric wall thickening, enlargement of abdominal and extra-abdominal lymph nodes, and presence of extranodal disease. In all patients the stomach was distended with oral contrast medium and scans performed at narrow collimation, after intravenous administration of 20 mg hyoscine butylbromide. In six patients focal thickening of the gastric wall was 1 cm or less. One patient had thickening of over 4 cm. There was no enlargement of abdominal or extra-abdominal lymph nodes or extension to adjacent organs. Thus on CT, at presentation, MALT lymphoma results in minimal gastric wall thickening, unlike high-grade non-Hodgkin lymphoma, which typically causes bulky gastric disease, nodal enlargement and extension into adjacent organs. CT is therefore of limited value in monitoring response to treatment. With disease greater than minimal thickening, transformation to a higher grade should be considered. (orig.)

Primary bone lymphoma: A report of two cases and review of the literature

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Singh Tejinder

2010-01-01

Full Text Available Primary bone lymphoma (PBL is an uncommon tumor accounting for approximately 4-5% of extra nodal lymphoma and less than 1% of all non-Hodgkin′s lymphoma. Disease may be complicated at presentation by pathological fracture or spinal cord compression. Diffuse large-B-cell lymphoma (DLBCL accounts for the majority of cases of PBL. Owing to its rarity, only a few retrospective studies have been published addressing the prognosis and treatment of primary bone lymphoma. In this paper, we report our experience with two cases of PBL treated with chemotherapy and radiotherapy and review literature to elucidate the optimal treatment of primary bone lymphoma.

Characterization and clonality of prelymphoma cells of B10 mice treated with fractionated X-irradiation (FX)

International Nuclear Information System (INIS)

Muto, M.; Kubo, E.; Sado, T.; Shimizu, T.; Yamagishi, H.

1992-01-01

With a combined use of cell separation by cell sorter and intrathymic injection assay, it was shown that prelymphoma cells existed in the subpopulation of thymocytes expressing TL-2 antigen which is not expressed on normal thymocytes of B10. Thy 1.2 or B10. Thy 1.1 mice. We then addressed a question whether all TL-2 + cells undergo neoplastic initiation or pre-neoplastic cells develop infrequently from TL-2 + cells. To investigate this problem and to examine the clonality of prelymphoma cells, thymocytes from individual B10. Thy 1.1 mice at various times after FX were stained with anti TL-2 mAb and the content of TL-2 + cells was evaluated. A graded amount of TL-2 + thymocytes from individual mice was injected into the thymuses of B10. Thy 1.2 mice. Although various numbers of TL-2 + cells appeared in the thymus of individual mice 14 - 28 days after FX, the donor type T cell lymphomas developed when 10 2 - 10 5 of TL-2 + cells from 7 individuals out of 20 mice were injected into the recipient mice. On the other hand, injection of TL-2 + cells from other mice (13 out of 20) did not develop donor type T cell lymphoma in spite of TL-2 + cells appearing in the thymus. These results indicate that all TL-2 + cells did not always undergo neoplastic initiation, and prelymphoma cells might develop infrequently from TL-2 + cells. To evaluate the clonality of prelymphoma cells, high molecular weight DNAs were isolated from the donor-derived T cell lymphomas and the rearrangement of T cell receptors examined by Southern blot analysis. The nucleotide sequences of V-J junctions were also determined by polymerase chain reaction techniques. The results indicated that after irradiation neoplastic initiation might occur oligoclonally in some of the TL-2 + cells. (author)

Primary immunodeficiencies and B-cell lymphomas.

Science.gov (United States)

Martín-Mateos, María Anunciación; Piquer Gibert, Mónica

In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were<18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Isolated orbital mass as the primary presentation of a triple-hit lymphoma transformed from a systemic follicular lymphoma

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Xiao Yi Zhou

2018-06-01

Full Text Available Purpose: Triple-hit lymphoma is a highly aggressive B-cell lymphoma. We report a case of triple-hit lymphoma transformed from systemic follicular lymphoma (FL after 9-year remission and presented primarily as an isolated orbital mass without systemic symptoms or lymphadenopathy. Observations: A 58-year-old female presented with intermittent vertical binocular diplopia, left upper eyelid swelling and pain and was found to have a 2.9 cm orbital mass. Histological section revealed a CD10-positive large B-cell lymphoma, consistent with transformation of FL. Fluorescent in situ hybridization (FISH analysis demonstrated rearrangements involving C-MYC, BCL-2 and BCL-6 genes, indicating a high grade, triple-hit lymphoma. Conclusions and importance: Triple-hit lymphoma transformed from a low-grade lymphoma may initially present as an isolated orbital mass without systemic evidence of transformation. Early recognition of double or triple-hit lymphomas is important since these patients require aggressive chemotherapy. Keywords: Lymphoma, Triple-hit lymphoma, Orbital mass

MRI features of lymphoma in spinal area

International Nuclear Information System (INIS)

Zhou Liangping; Peng Weijun; Yang Wentao; Tang Feng

2008-01-01

Objective: To analyze MR imaging manifestations of spinal area lymphoma in order to improve the recognition and understanding of the disease. Methods: A group of 45 patients with pathologically or clinically proven spinal area lymphoma were reviewed. Five cases were primary NHL, 40 cases were secondary with 9 HL and 31 NHL (27 B-cell type NHL and 4 T-cell type NHL). MR Imaging findings were analyzed and correlated with clinical and pathologic findings. Results: (1) Location of lesions: 13 cases were focal type and 32 cases were multifocal type. All of the 5 patients with primary lymphoma were focal type, while 32 of 40 eases of secondary lymphoma were multifocal type. (2)Type of lesions: (1) Vertebral destruction: 27 cases manifested as bone destruction with 23 of them had soft tissue mass and the extent of soft tissue masses were larger than that of bone destruction in 18 eases. (2) Soft tissue masses: 6 cases manifested as soft masses without obvious bone destruction, of which 5 cases had soft tissue masses imbedded vertebrae and communicated paravertebral and epidural spaces through intervertebral foramen. (3) Bone marrow infiltration: 9 cases of secondary spinal lymphoma had signal intensity changes of bone marrow without obvious cortical bone destruction and soft tissue mass. (4) Spinal cord infiltration: 3 cases of secondary spinal lymphoma had spinal cord swelling and signal intensity changes. (3) MRI findings: all lesions of bone destruction and marrow infiltration manifested as hypointense on T 1 -weighted images, hypointense, isointense or hyperintense on T 2 -weighted images and hyperintense on T 2 -weighted images with fat-suppression technique. All soft tissue masses were homogeneous hypointense on T 1 -weighted images and hyperintense on T 2 -weighted images. After intravenous injection of contrast media, the lesions of the bone and the soft tissue showed mild or moderate enhancement without remarkable cystic degeneration and necrosis. Conclusions

Effect of bovine pellucid zone 3 monoclonal antibodies on B cell lymphoma 2 expressions of granulosa cell and mice (Mus musculus follicle diameter

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Heti Ira Ayue

2017-01-01

Full Text Available Objective: To evaluate the effects of pellucid zone 3 monoclonal antibodies against B-cell lymphoma 2 (BCL-2 expression and mice follicle diameter at various time periods.Methods: The animal model of this study was 36 Balb/c mice (Mus musculus. A true experimental design was used with a post-test only control group approach. BCL-2 expression was observed using immunohistochemistry, while the follicle diameter was observed by haematoxylin-eosin staining. The data was analyzed using nested ANOVA to compare the results of the mean expression of BCL-2 on the 5th and 20th day of observation in the pre-antral and antral follicle between the control and treatment groups.Results: No significant differences were found in BCL-2 gene expression. There were also no significant differences in BCL-2 expression on the 10th day of pre-antral follicle analysis. Moreover, there were no significant differences between the mean follicle diameter on the 5th, 10th, and 20th day of pre-antral and antral follicle development between the control and treatment groups. The addition of bovine pellucid zone 3 (bZP3 monoclonal antibodies on the 5th and 20th day of observation did not decrease the expression of BCL-2 gene in the pre-antral and antral follicle of mice. Administering bZP3 monoclonal antibodies on the 10th day of observation did not affect BCL-2 expression in the pre-antral follicle but did decrease BCL-2 expression in the antral follicle. Supplying bZP3 monoclonal antibodies on the 5th, 10th and 20th day did not affect the diameter of pre-antral and antral follicles of the mice.Conclusion: The monoclonal antibodies bovine zona pelusida 3 has the potential to be developed as a safe immunocontraception preparation.

Central nervous system complications in non-Hodgkin-lymphomas and radiotherapy

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Liffers, R.

1981-01-01

261 case historys of malignant non-Hodgkin-lymphomas were analysed in the years from 1969 until 1978 in the 'Radiologische Universitaetsklinik Kiel'/West-Germany. 18 Patients got a central nervous complication of Non Hodgkin-Lymphoma earlier or later, a percentage of about 7. There were 7 cases of lymphoblastic lymphoma (LB), a percentage of 10 for this entity. In the group of immunoblastic lymphoma (IB) 6 cases of central nervous infiltration were detected, that is a ratio of 7.7 percent. 4 case histories M. Brill-Symmers (CC/CB) were complicated by central nervous dissemination, a percentage of 5.3. Patients with lymphoblastic lymphoma have the highest risk of central nervous complication. The beginning of central nervous dissemination in the single case histories is very different between the histological groups. Patients with lymphoblastic lymphoma suffered from central nervous complication in an early phase of history, in cases of M. Brill-Symmers central nervous infiltration can occur also in a late phase. The results may determine the discussion about stratifying of radiotherapy. Early radiotherapy including central nervous system may be discussed and investigated in special histological entities of malignant non-Hodgkin-lymphoma. (orig.) [de

Deletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection.

Directory of Open Access Journals (Sweden)

Magdalena Radwanska

2007-05-01

Full Text Available Effector responses induced by polarized CD4+ T helper 2 (Th2 cells drive nonhealing responses in BALB/c mice infected with Leishmania major. Th2 cytokines IL-4 and IL-13 are known susceptibility factors for L. major infection in BALB/c mice and induce their biological functions through a common receptor, the IL-4 receptor alpha chain (IL-4Ralpha. IL-4Ralpha-deficient BALB/c mice, however, remain susceptible to L. major infection, indicating that IL-4/IL-13 may induce protective responses. Therefore, the roles of polarized Th2 CD4+ T cells and IL-4/IL-13 responsiveness of non-CD4+ T cells in inducing non-healer or healer responses have yet to be elucidated. CD4+ T cell-specific IL-4Ralpha (Lck(creIL-4Ralpha(-/lox deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Ralpha signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4+ T cells. Efficient deletion was confirmed by loss of IL-4Ralpha expression on CD4+ T cells and impaired IL-4-induced CD4+ T cell proliferation and Th2 differentiation. CD8+, gammadelta+, and NK-T cells expressed residual IL-4Ralpha, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Ralpha(-/lox BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(creIL-4Ralpha(-/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(creIL-4Ralpha(-/lox mice correlated with reduced numbers of IL-10-secreting cells and early IL-12p35 mRNA induction, leading to increased delayed type hypersensitivity responses, interferon-gamma production, and elevated ratios of inducible nitric oxide synthase mRNA/parasite, similar to C57BL/6 mice. These data demonstrate that abrogation of IL-4 signaling in CD4+ T cells is required to transform non-healer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Ralpha signaling in L

Characterization of the myeloid-derived suppressor cell subset regulated by NK cells in malignant lymphoma.

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Sato, Yusuke; Shimizu, Kanako; Shinga, Jun; Hidaka, Michihiro; Kawano, Fumio; Kakimi, Kazuhiro; Yamasaki, Satoru; Asakura, Miki; Fujii, Shin-Ichiro

2015-03-01

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population with the ability to suppress immune responses and are currently classified into three distinct MDSC subsets: monocytic, granulocytic and non-monocytic, and non-granulocytic MDSCs. Although NK cells provide an important first-line defense against newly transformed cancer cells, it is unknown whether NK cells can regulate MDSC populations in the context of cancer. In this study, we initially found that the frequency of MDSCs in non-Hodgkin lymphoma (NHL) patients was increased and inversely correlated with that of NK cells, but not that of T cells. To investigate the regulation of MDSC subsets by NK cells, we used an EL4 murine lymphoma model and found the non-monocytic and non-granulocytic MDSC subset, i.e., Gr1 + CD11b + Ly6G med Ly6C med MDSC, is increased after NK cell depletion. The MDSC population that expresses MHC class II, CD80, CD124, and CCR2 is regulated mainly by CD27 + CD11b + NK cells. In addition, this MDSC subset produces some immunosuppressive cytokines, including IL-10 but not nitric oxide (NO) or arginase. We also examined two subsets of MDSCs (CD14 + HLA-DR - and CD14 - HLA-DR - MDSC) in NHL patients and found that higher IL-10-producing CD14 + HLA-DR - MDSC subset can be seen in lymphoma patients with reduced NK cell frequency in peripheral blood. Our analyses of MDSCs in this study may enable a better understanding of how MDSCs manipulate the tumor microenvironment and are regulated by NK cells in patients with lymphoma.

The First Year of the AEVD Primary Cutaneous Lymphoma Registry.

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Peñate, Y; Servitje, O; Machan, S; Fernández-de-Misa, R; Estrach, M T; Acebo, E; Mitxelena, J; Ramón, M D; Flórez, A; Blanes, M; Morillo, M; Medina, S; Bassas, J; Zayas, A; Espinosa, P; Pérez, A; Gónzalez-Romero, N; Domínguez, J D; Muniesa, C; López Robles, J; Combalia, A; Yanguas, I; Suh, H; Polo-Rodríguez, I; Bielsa, I; Mateu, A; Ferrer, B; Descalzo, M A; García-Doval, I; Ortiz-Romero, P L

2018-04-18

Primary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. Disease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. In December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30 + T-cell lymphoproliferative disorder (CD30 + CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical corticosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30 + CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). The characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate

Computational diagnosis of canine lymphoma

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Mirkes, E. M.; Alexandrakis, I.; Slater, K.; Tuli, R.; Gorban, A. N.

2014-03-01

One out of four dogs will develop cancer in their lifetime and 20% of those will be lymphoma cases. PetScreen developed a lymphoma blood test using serum samples collected from several veterinary practices. The samples were fractionated and analysed by mass spectrometry. Two protein peaks, with the highest diagnostic power, were selected and further identified as acute phase proteins, C-Reactive Protein and Haptoglobin. Data mining methods were then applied to the collected data for the development of an online computer-assisted veterinary diagnostic tool. The generated software can be used as a diagnostic, monitoring and screening tool. Initially, the diagnosis of lymphoma was formulated as a classification problem and then later refined as a lymphoma risk estimation. Three methods, decision trees, kNN and probability density evaluation, were used for classification and risk estimation and several preprocessing approaches were implemented to create the diagnostic system. For the differential diagnosis the best solution gave a sensitivity and specificity of 83.5% and 77%, respectively (using three input features, CRP, Haptoglobin and standard clinical symptom). For the screening task, the decision tree method provided the best result, with sensitivity and specificity of 81.4% and >99%, respectively (using the same input features). Furthermore, the development and application of new techniques for the generation of risk maps allowed their user-friendly visualization.

Abdominal Burkitt lymphoma

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Alvarez, Romina J.; Villavicencio, Roberto L.; Oxilia, Hector G.

2004-01-01

Purpose: As scarce information is available, in this research we have tried to describe the imaging findings of the Burkitt's lymphoma. Retrospective analysis of the clinical and imaging presentation of a 4 years old boy, is given. Biopsy confirmed the BL. Different imaging techniques were combined. The X-rays were negative. The US revealed a moderate hepatomegaly with multiple hypoechoic nodules and free fluid in the abdominal cavity. The CT showed the hepatomegaly as well as solid nodules in great number and different sizes(due to the densitometric behaviour and to post contrast enhancement), a scarce amount of ascites and a density increase of the mesentery fat. The MRI characterized and revealed in detail the US and the CT findings. The Burkitt's lymphoma is a rare entity; several methods are needed to approach the diagnosis. It represents a great clinical and imaging challenge. (author)

Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4

DEFF Research Database (Denmark)

Holm, Anne Trommelholt; Wulf-Johansson, Helle; Hvidsten, Svend

2015-01-01

to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4-deficient (Mfap4(-/-)) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4(-/-) mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated...... were both significantly decreased in Mfap4(-/-) mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4(-/-) mice. However, Mfap4(-/-) mice developed a spontaneous loss...... of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes....

Identification of Candidate B-Lymphoma Genes by Cross-Species Gene Expression Profiling

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Tompkins, Van S.; Han, Seong-Su; Olivier, Alicia; Syrbu, Sergei; Bair, Thomas; Button, Anna; Jacobus, Laura; Wang, Zebin; Lifton, Samuel; Raychaudhuri, Pradip; Morse, Herbert C.; Weiner, George; Link, Brian; Smith, Brian J.; Janz, Siegfried

2013-01-01

Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the “mouse filter” for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists. PMID:24130802

Dose-Effect Relationship of Alkylating Agents on Testicular Function in Male Survivors of Childhood Lymphoma.

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Servitzoglou, Marina; De Vathaire, Florent; Oberlin, Odile; Patte, Catherine; Thomas-Teinturier, Cécile

2015-01-01

The purpose of our study was to assess the gonadal function in male survivors of childhood lymphoma. We studied 171 male survivors of childhood lymphoma (83 with B-cell non-Hodgkin lymphoma [B-NHL], 32 with T-cell non-Hodgkin lymphoma [T-NHL], 50 with Hodgkin lymphoma [HL], and 6 with anaplastic large-cell lymphoma [ALCL]), measuring follicle-stimulating hormone [FSH] and luteinizing hormone [LH] levels at a median age of 21.1 (17-30.4) years after a median delay of 9.3 (2-22.4) years from treatment. FSH levels were above normal range (≥10 IU/L) in 42.1% and LH levels ≥8 IU/L in only 8.9% of survivors. In multivariate analysis, only the following chemotherapeutic agents were associated with higher FSH or LH levels: cyclophosphamide (P alkylating agents on childhood lymphoma survivors is dose dependent and not correlated to diagnosis, age, or pubertal status at diagnosis.

Nodular breast lymphoma

International Nuclear Information System (INIS)

Rodriguez, M.; Sahagun, E.; Pena, J.; Mendez, J.

1996-01-01

We attempt to correlate the histological types [in three cases of B-cell non-Hodgkin's lymphoma (NHL), one case of T-cell NHL and one of Hodgkin's disease] with the radiological presentation and compare our findings with the literature reviewed. Among the mammographic studies, performed over and 18-month period, we have assessed five patients (four women and one man, aged as having lymphoma. the man presented bilateral involvement. Both mammography and a broader study with ultrasound and chest and abdominal CT scan were performed in every case. Four patients underwent breast ultrasound. The definitive diagnosis was based on biopsy in all cases. Three of the five cases involved primary lymphomas and the other two were secondary. Four patients presented NHL and the remaining patient had Hodgkin's disease. In mammography, the nodules showed different degrees of margin definition. In ultrasound, all the lesion were hypoechoic. The radiological diagnosis of breast lymphoma is difficult in the absence of a previous diagnosis of lymphoma. This lesion should be included in the differential diagnosis in the presence of a breast nodule associated with axillary lymph nodes, especially when the latter are bilateral. (Author)

Clinicopathological study of primary gastric lymphoma

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Al-Shehabi, Zubeir A.; Saleh, Rana S.; Zezafon, Hassan B.

2007-01-01

Objective was to present a histopathologic and immunohistochemical analysis of primary gastric lymphomas that was reclassified according to the new World Health Organization classification of lymphoid neoplasms. We reviewed the morphological and immunohistochemical features of 28 patients with gastric lymphomas, diagnosed in the Department of pathology at the University Hospital of Tishreen University, Lattakia, Syria, during the period 1994-2003. Specimens were obtained from endoscopic and surgical biopsies. The immunohistochemical study was performed to analyze the immunophenotype of these lymphomas. Patients were aged 17-71 years. There was a slight predominance of females (male to female ratio, 13:15). Seventeen of the patients had tumors mainly located in the gastric antrum. Histologically, the most common lymphoma was of mucosa-associated lymphoid tissue (MALT) type (20 patients), also with diffuse large B-cell lymphoma (7 patients) and anaplastic large cell lymphoma (one patient). Our study demonstrates the different patterns of gastric lymphomas in Lattakia, Syria during a 10-year period in 28 Syrian patients, and reveals that the most primary gastric lymphomas are B-cell MALT lymphomas. (author)

Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc−/+ mice

International Nuclear Information System (INIS)

Karim, Baktiar O; Rhee, Ki-Jong; Liu, Guosheng; Zheng, Dongfeng; Huso, David L

2013-01-01

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Colorectal cancers have a prolonged latency following initiation that may span decades providing ample time for implementing a chemoprevention strategy that could block or reverse the progression to CRC. Cdk4 pathway alterations have been linked to a number of cancers including CRC. In these experiments we focused on the Cdk4 pathway and its role in intestinal tumorigenesis as a possible target in chemoprevention strategies. We evaluated the effect of Cdk4 blockade on the prevention of intestinal tumor formation by crossing Cdk4 −/− mice to Apc −/+ mice. In addition, we tested the effect of the dietary compound silibinin on the Cdk4 pathway in Apc −/+ mice and HT-29 colon cancer cells in culture. Cdk4 −/− mice backcrossed to Apc −/+ mice reduced intestinal adenoma formation compared to Apc −/+ controls. Silibinin effectively targeted the Cdk4 pathway causing hypophosphorylation of the retinoblastoma protein, inhibited cell growth, and induced apoptosis. As a result silibinin blocked the development of intestinal adenomas by 52% in this genetic model (Apc −/+ mice) of early events in colorectal cancer formation. No toxic abnormalities were detected in mice which received silibinin. Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas

Role of IL-4 in aversion induced by food allergy in mice.

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Dourado, Luana Pereira Antunes; Saldanha, Janaína Cláudia da Silva; Gargiulo, Daniela Longo; Noviello, Maria de Lourdes Meirelles; Brant, Cláudia Caldeira; Reis, Maria Letícia Costa; Souza, Raphaela Mendes Fernandes de; Faria, Ana Maria Caetano; Souza, Danielle da Glória de; Cara, Denise Carmona

2010-01-01

To ascertain the role of IL-4 in aversion to antigen induced by food allergy, wild type and IL-4 deficient BALB/c mice were sensitized with ovalbumin and challenged orally with egg white. Sensitized wild type mice had increased production of IL-4 by spleen and mesenteric lymph node cells in vitro, higher levels of serum anti-ovalbumin IgE and IgG1, aversion to ingestion of the antigen and loss of body weight after continuous oral challenge. Intestinal changes in wild type sensitized mice included eosinophil infiltration and increased mucus production. The IL-4 deficiency impaired the development of food allergy and the aversion to antigen, suggesting the involvement of the antigen specific antibodies. When IL-4 deficient mice received serum from sensitized wild type donors, the aversion was restored. These results indicate that production of IL-4 and specific IgE/IgG1 antibodies correlate with aversion to antigen induced by food allergy in mice. Copyright 2009 Elsevier Inc. All rights reserved.

Effects on normal tissues during radiosensitization of Dalton's Lymphoma by the DNA ligand Hoechst 33342 in Balb/c mice

International Nuclear Information System (INIS)

Kalra, Namita; Sampath, Swapna; Adhikari, J.S.; Dwarakanath, B.S.

2014-01-01

Hoechst 33342 is a bisbenzimidazole derivative with AT specific minor groove DNA binding ability. Scavenging of free radicals and stabilization of macromolecular structure resulting in reduced induction of DNA damage contributes to radioprotection afforded by the ligand. Their ability to inhibit topoisomerases I and II, which play important roles in damage response pathways including DNA repair has been shown to sensitize tumor cells in vitro and in vivo. Due to its mutagenic and clastogenic potentials, damage to vital normal tissues are a matter of concern in deploying the ligand as adjuvant in radiotherapy. Therefore, we investigated the effects of the ligand in Dalton's Lymphoma (DL) bearing Balb/c mice by studying the local tumor control and animal survival, besides damage to normal tissues like bone marrow, kidney and testis. Hoechst 33342 (10 mg/kg b wt) was administered (i.v.) 1 h before focal irradiation (10 Gy) of the tumor (∼ 500 mm 3 ) grown on the hind leg of the mice. Partial response with a growth delay of 16 days (3 x initial volume) was seen following irradiation, while a complete response (cure; tumor-free survival) was observed in 88% mice following the combined treatment (Hoechst 33342+radiation); ligand alone had no significant effect. Although the ligand induced marginal degree of chromosomal aberrations in the bone marrow, it did not enhance aberrations induced by radiation further. In testes, the proportions of diploid, haploid and hypo-haploid cells as well as resting primary spermatocytes (RPS) were not significantly altered by either. In kidney, Hoechst 33342 alone or in combination with radiation did not cause significant damage to the proximal tubules and glomeruli. These observations suggest that radiosensitization of tumor by the DNA ligand Hoechst 33342 may not be associated with enhanced toxicity to bone marrow as well as proximal normal tissues. (author)

CD3+, CD56+, CD4−, CD8−, CD20−, CD30− Peripheral T-Cell Non-Hodgkin's Lymphoma: A Rare Case Report

Directory of Open Access Journals (Sweden)

Ashish Jagati

2017-01-01

Full Text Available Cutaneous T-cell lymphoma (CTCL commonly presents as mycosis fungoides or Sezary syndrome, both having CD4 positivity. A subset of CTCL which lacks CD4 surface marker is classified as cutaneous g and d–T-cell lymphoma (CGD-TCL. Because of its rarity and inability to study large number of patients, the impact of immunophenotype on the clinical outcome of primary CTCL in patients is limited. We report a case of primary CGD-TCL in a 71-year-old male because of this rarity and to emphasize its aggressive nature.

Treatment results of localized gastric lymphoma

International Nuclear Information System (INIS)

Abe, Tatsuyuki; Gomi, Hiromichi; Sakaino, Shinjiro; Nakajima, Yasuo

2008-01-01

Between 2000 and 2007, 17 patients with localized gastric lymphoma (10 mucosa-associated lymphoid tissue lymphomas and 7 diffuse large B-cell lymphomas) were treated with radiotherapy alone or doxorubicin-based chemotherapy followed by radiotherapy. Radiation dose of mucosa-associated lymphoid tissue (MALT) lymphoma was 30 Gy with a daily fraction size of 1.5 Gy. Sixteen patients achieved complete remission and the 5-year overall survival of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) were 100% and 87%, respectively. No gastric perforation and hemorrhage were noticed. Using AP/LR 2-port radiotherapy markedly decreased the liver dose. (author)

[Effects of aquaporin-4 gene knockout on behavior changes and cerebral morphology during aging in mice].

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Su, Shengan; Lu, Yunbi; Zhang, Weiping

2013-05-01

To investigate the effects of aquaporin-4 (AQP4) gene knockout on the behavior changes and cerebral morphology during aging in mice,and to compare that of young and aged mice between AQP4 knockout mice (AQP4(-/-)) and wild type mice (AQP4(+/+)). Fifty-eight CD-1 mice were divided into four groups: young (2-3 months old) AQP4(-/-), aged (17-19 months old) AQP4(-/-), young AQP4(+/+) and aged AQP4(+/+). The activity levels and exploring behavior of mice were tested in open field. The neurons were stained with toluidine blue and NeuN, the astrocytes and microglia were stained with GFAP and Iba-1, respectively. The morphological changes of neuron, astrocyte and microglia were then analyzed. Compared with young mice, the total walking distance in open field of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 41.2% and 44.1%, respectively (Ptime in the central area of open field. The density of neuron in cortex of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 19.6% and 15.8%, respectively (P<0.05), while there was no difference in the thickness of neuron cell body in hippocampus CA1 region. The density of astrocyte in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 57.7% and 64.3%, respectively (P<0.001), while there was no difference in the area of astrocyte. The area of microglia in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 46.9% and 52.0%, respectively (P<0.01), while there was no difference in the density of microglia. Compared with AQP4(+/+) mice, the young and aged AQP4(-/-) mice showed smaller area of astrocyte in hippocampus CA3 region, reduced 18.0% in young mice and 23.6% in aged mice. There was no difference between AQP4(+/+) mice and AQP4(-/-) mice for other observed indexes. AQP4 may be involved in change of astrocyte and astrocyte-related behaviors during aging. AQP4 gene knockout may have limited effects on the change of neuron, microglia and most neuronal behaviors in aging