Many pathogens that cause human disease infect only humans. To identify the mechanisms of immune protection against these pathogens and also to evaluate promising vaccine candidates, a small animal model would be desirable. We demonstrate that primary T cell responses in mice with reconstituted human immune system components control infection with the oncogenic and persistent Epstein-Barr virus (EBV). These cytotoxic and interferon-γ–producing T cell responses were human leukocyte antigen (HLA) restricted and specific for EBV-derived peptides. In HLA-A2 transgenic animals and similar to human EBV carriers, T cell responses against lytic EBV antigens dominated over recognition of latent EBV antigens. T cell depletion resulted in elevated viral loads and emergence of EBV-associated lymphoproliferative disease. Both loss of CD4+ and CD8+ T cells abolished immune control. Therefore, this mouse model recapitulates features of symptomatic primary EBV infection and generates T cell–mediated immune control that resists oncogenic transformation.

https://rupress.org/jem/article-pdf/206/6/1423/1200140/jem_20081720.pdf

Priming of protective T cell responses against virus-induced tumors in mice with human immune system components.

Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States

Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia

This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.

Phytochemicals As Chemosensitizers: From Molecular Mechanism to Clinical Significance

Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.

/pdf/outlook-on-pi3k-akt-mtor-inhibition-in-acute-leukemia-32t86wdfbo.pdf

Outlook on PI3K/AKT/mTOR inhibition in acute leukemia

Background

Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL.



Procedure

We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs.



Results

P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance.



Conclusion

These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

/pdf/activation-of-akt-is-associated-with-poor-prognosis-and-4kwgcb6w1r.pdf

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

CAEBV is a high mortality and morbidity disease with life-threatening complications. Nevertheless, the treatment regimens for CAEBV have not yet been established. Although some reports have described CAEBV therapy involving treatments such as antiviral drugs, immunomodulatory agents, and immunochemotherapy, none of these treatments have been demonstrated to be effective. The only treatment reported to be effective is allogeneic SCT. However, the complications of SCT are severe, so treatment results have been poor. Recently, immunotherapy has been devised, but this is still in the developmental stage. In this report, two cases of CAEBV in which allogeneic SCT was performed soon after diagnosis are reported. In both cases, a high EBV genome titer in the peripheral blood was detected at onset. After SCT, the EBV genome titer decreased as CTL activity gradually increased. This fact suggested that not only high-dose chemotherapy as a preconditioning treatment of SCT but also increased CTL activity which could eliminate virus-infected cells might be effective, although additional cases should be studied in order to establish effective treatments.

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation.

Miyamura T, Yoshida R, Yagi T, Matsukawa H, Chayama K, Ishida T, Washio K, Morishita N, Oda M, Morishima T. Successful treatment of unresectable advanced hepatoblastoma: Living liver transplantation after surgical removal of lung metastasis. Pediatr Transplantation 2011: 15: E87–E91. © 2010 John Wiley & Sons A/S.



Abstract:  Hepatoblastoma is a rare malignant tumor of the liver in children. Intensive combination chemotherapy has increased the number of surgically resectable cases and improved prognosis markedly. However, unresectable cases and cases with residual metastasis, including lung metastases, have a poor prognosis. In these refractory cases, treatment strategy has not been established. On the other hand, living liver transplantation has been shown to be effective in cases of advanced hepatoblastoma, but its effectiveness in cases with residual distant metastases after chemotherapy remains unclear. We report one successful case of advanced unresectable hepatoblastoma with multiple lung metastases. Intensive chemotherapy consisting of high-dose chemotherapy with autologous hematopoietic stem cell transplantation was not effective. We performed living liver transplantation after surgical resection of residual lung metastases, which were histologically viable. After liver transplantation, the level of tumor marker decreased gradually. The patient experienced no severe complications. This case suggested that living liver transplantation could be effective in cases of advanced refractory hepatoblastoma after control of distant metastases.

Naoto Morishita

Papers

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation.

Successful treatment of unresectable advanced hepatoblastoma: living liver transplantation after surgical removal of lung metastasis.