mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein–Barr Virus–Associated T and Natural Killer Cell Lymphoma Cells

Kawada, Junji; Ito, Yoshinori; Iwata, Seiko; Suzuki, Michio; Kawano, Yoshihiko; Kanazawa, Tetsuhiro; Siddiquey, Mohammed Nure Alam; Kimura, Hiroshi

doi:10.1158/1078-0432.ccr-13-3172

Cited by 46 publications

(31 citation statements)

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“…Mammalian target of rapamycin (mTOR) inhibitors may be risk-neutral or potentially reduce risk by inhibiting growth signals in PTLD-associated EBV+ B-cell lymphomas [27]. There is evidence that mTOR inhibition blocks the replication of EBV-positive B-cells, T-cells and natural killer (NK) cells [28,29]. Treatment of rejection with high-dose steroids can adversely affect risk for PTLD [30].…”

Section: The Role Of Immunosuppressive Therapiesmentioning

confidence: 99%

Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update

Hertig

Zuckermann

2015

Transplant Immunology

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The most modifiable risk factor for post-transplant lymphoproliferative disease (PTLD) is the type and dose of induction and maintenance immunosuppressive therapy. It is challenging to identify the contribution of a single agent such as rabbit antithymocyte globulin (rATG) in the setting of multidrug therapy. Registry analyses can be helpful but are limited by methodological restrictions and inclusion of historical patient cohorts. These are typically from eras when rATG dosing was markedly higher than current dosing (e.g. total dose 14 mg/kg versus 6 mg/kg now), accompanied by higher exposure to maintenance therapies, and often an absence of antiviral prophylaxis. The largest registry analysis to assess rATG specifically found no risk of PTLD after kidney transplantation, but conflicting results have been reported, highlighting the difficulty of interpreting this type of analysis. The relative rarity of PTLD means that individually controlled trials are underpowered to assess its occurrence, but the available data do not suggest an effect of rATG. A pooled analysis of data from studies of rATG induction in kidney and heart transplantation found the incidence of PTLD to be comparable to published reports in the overall transplant population. Data on the effect of rATG dose are inconclusive, but in patients receiving antiviral prophylaxis it does not appear to be influential. Nevertheless, it would seem reasonable to employ the lowest dose of rATG compatible with effective induction, particularly in EBV-seronegative recipients and other high-risk groups such as heart-lung transplant recipients. Overall, the risk of PTLD following rATG induction therapy with modern dosing regimens and under current management conditions appears unlikely to make an important contribution to the risk:benefit balance.

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Section: The Role Of Immunosuppressive Therapiesmentioning

confidence: 99%

Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update

Hertig

Zuckermann

2015

Transplant Immunology

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“…On the other hand, even if the models are established successfully, they remain not stable in passages, or never have been passaged. So far, only some Japanese established SNK6‐which is a NK/T cell lymphoma cell line‐mouse model in NOG mice, which is a similar species to NSG . It is known that using NSG and NOG mice to establish models costs too much, meanwhile because of the patent problem, many enthusiastic researchers have not the opportunity to use them.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 These mice to NSG. 24,25 It is known that using NSG and NOG mice to establish models costs too much, meanwhile because of the patent problem, many enthusiastic researchers have not the opportunity to use them.…”

Section: Discussionmentioning

confidence: 99%

One method to establish Epstein‐Barr virus‐associated NK/T cell lymphoma mouse models

Xue

Shang

et al. 2018

J Cellular Molecular Medi

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Novel nude mice model of human NK/T cell lymphoma were established by subcutaneously injecting two NK/T cell lymphoma cell lines into the right axillary region of mice and successful passages were completed by injecting cell suspension which was obtained through a 70‐μm cell strainer. These mice models and corresponding cell clones have been successfully developed for more than 8 generations. The survival rates of both resuscitation and transplantation in NKYS and YT models were 90% and 70% correspondingly. Pathologically, the tumour cells in all passages of the lymphoma‐bearing mice and cell lines obtained from tumours were parallel to initial cell lines. Immunologically, the tumour cells expressed the characteristics of the primary and essential NK/T lymphomas. The novel mice models maintained the essential features of human NK/T cell lymphoma, and they would be ideal tools in vivo for further research of human NK/T cell lymphoma.

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“…[17][18][19] This can be attributed to the limited replication of viruses in biological systems via several pathways and cellular alterations. 20 The NS5A protein was linked to an increased replication of the hepatitis C virus through p70S6K phosphopeptides.…”

Section: Discussionmentioning

confidence: 99%

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients

et al. 2018

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Efeitos da conversão de inibidores da calcineurina para everolimo na viremia por hepatite C em receptores adultos de transplantes renais Introdução: Atualmente não há um protocolo imunossupressor específico para os receptores de transplantes renais portadores de hepatite C (HCV). Assim, o objetivo deste estudo foi avaliar o efeito da conversão a Everolimo (EVR) na HCV em receptores adultos de transplantes renais. Método: Trata-se de um estudo unicêntrico, prospectivo, randomizado, exploratório, controlado, aberto em receptores de aloenxertos renais com sorologia positiva para HCV. Os participantes foram randomizados para conversão a EVR ou manutenção dos inibidores da calcineurina. Resultados: Trinta pacientes foram randomizados e 28 foram acompanhados por um período de 12 meses (grupo de conversão, Grupo 1 = 15 e grupo controle, Grupo 2 = 13). Níveis de RT-PCR HCV descritos em valores logarítmicos foram compará-veis entre os grupos e entre pacientes em um mesmo grupo. A análise estatística não mostrou efeitos de interação entre tempo e grupo (valor p G*M = 0,852), ao longo do tempo em cada grupo (valor p M = 0,889) e entre grupos (valor p G = 0,286). O Grupo 1 apresentou uma maior incidência de eventos de dislipidemia (p = 0,03) e proteinúria (p = 0,01); não houve diferença na incidência de anemia (p = 0,17), diabetes mellitus de início pós-transplante (p = 1,00) ou infecção do trato urinário (p = 0,60). A TFGe média foi semelhante nos dois grupos. Conclusão: Nosso estudo não mostrou redução da carga viral após conversão a EVR com manutenção do tratamento antiproliferativo. ResumoPalavras-chave: Imunossupressão; Hepatite C; Transplante Renal; Carga Viral. Introduction:Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. Method: This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Results: Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 = 15 and control group, Group 2 = 13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M = 0.852), overtime intra-groups (p-value M =0.889) and between group (p-value G = 0.286). Group 1 showed a higher incidence of dyslipidemia (p = 0.03) and proteinuria events (p = 0.01), while no difference was observed in the incidence of anemia (p = 0.17), new onset of post-transplant diabetes mellitus (p = 1.00) or urinary tract infection (p = 0.60). The mean eGFR was similar in both groups. Conclusion: Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy. AbstRAct

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mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein–Barr Virus–Associated T and Natural Killer Cell Lymphoma Cells

Cited by 46 publications

References 50 publications

Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update

Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update

One method to establish Epstein‐Barr virus‐associated NK/T cell lymphoma mouse models

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients

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