Research Institute of Fox Chase Cancer Center

Philadelphia, PA, United States

Research Institute of Fox Chase Cancer Center

Philadelphia, PA, United States
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Davies M.L.,Pennsylvania State University | Sei J.J.,Pennsylvania State University | Siciliano N.A.,Thomas Jefferson University | Xu R.-H.,Research Institute of Fox Chase Cancer Center | And 4 more authors.
Journal of Virology | Year: 2014

Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. © 2014, American Society for Microbiology.


Rubio D.,Research Institute of Fox Chase Cancer Center | Rubio D.,Autonomous University of Madrid | Xu R.-H.,Research Institute of Fox Chase Cancer Center | Remakus S.,Research Institute of Fox Chase Cancer Center | And 7 more authors.
Cell Host and Microbe | Year: 2013

Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-κB inhibitor activates NF-κB more effectively in vivo, resulting in increased proinflammatory molecule transcription in uninfected cells and organs and decreased viral replication. Unexpectedly, NF-κB activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-κB pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease. © 2013 Elsevier Inc.


PubMed | Philadelphia University, University of Ferrara, Research Institute of Fox Chase Cancer Center, University of Queensland and 2 more.
Type: Journal Article | Journal: Experimental cell research | Year: 2015

Satellite cells are muscle resident stem cells and are responsible for muscle regeneration. In this study we investigate the involvement of PKC during muscle stem cell differentiation in vitro and in vivo. Here, we describe the identification of a previously unrecognized role for the PKC-HMGA1 signaling axis in myoblast differentiation and regeneration processes.PKC expression was modulated in the C2C12 cell line and primary murine satellite cells in vitro, as well as in an in vivo model of muscle regeneration. Immunohistochemistry and immunofluorescence, RT-PCR and shRNA silencing techniques were used to determine the role of PKC and HMGA1 in myogenic differentiation.PKC expression increases and subsequently re-localizes to the nucleus during skeletal muscle cell differentiation. In the nucleus, PKC blocks Hmga1 expression to promote Myogenin and Mrf4 accumulation and myoblast formation. Following in vivo muscle injury, PKC accumulates in regenerating, centrally-nucleated myofibers. Pharmacological inhibition of PKC impairs the expression of two crucial markers of muscle differentiation, namely MyoD and Myogenin, during injury induced muscle regeneration.This work identifies the PKC-HMGA1 signaling axis as a positive regulator of skeletal muscle differentiation.


Choi H.J.,University of Kansas Medical Center | Lui A.,University of Kansas Medical Center | Ogony J.,University of Kansas Medical Center | Jan R.,Research Institute of Fox Chase Cancer Center | And 2 more authors.
Breast Cancer Research | Year: 2015

Introduction: Estrogen deprivation using aromatase inhibitors (AIs) is currently the standard of care for postmenopausal women with hormone receptor-positive breast cancer. Unfortunately, the majority of patients treated with AIs eventually develop resistance, inevitably resulting in patient relapse and, ultimately, death. The mechanism by which resistance occurs is still not completely known, however, recent studies suggest that impaired/defective interferon signaling might play a role. In the present study, we assessed the functional role of IFITM1 and PLSCR1; two well-known interferon response genes in AI resistance. Methods: Real-time PCR and Western blot analyses were used to assess mRNA and protein levels of IFITM1, PLSCR1, STAT1, STAT2, and IRF-7 in AI-resistant MCF-7:5C breast cancer cells and AI-sensitive MCF-7 and T47D cells. Immunohistochemistry (IHC) staining was performed on tissue microarrays consisting of normal breast tissues, primary breast tumors, and AI-resistant recurrence tumors. Enzyme-linked immunosorbent assay was used to quantitate intracellular IFNaα level. Neutralizing antibody was used to block type 1 interferon receptor IFNAR1 signaling. Small interference RNA (siRNA) was used to knockdown IFITM1, PLSCR1, STAT1, STAT2, IRF-7, and IFNaα expression. Results: We found that IFITM1 and PLSCR1 were constitutively overexpressed in AI-resistant MCF-7:5C breast cancer cells and AI-resistant tumors and that siRNA knockdown of IFITM1 significantly inhibited the ability of the resistant cells to proliferate, migrate, and invade. Interestingly, suppression of IFITM1 significantly enhanced estradiol-induced cell death in AI-resistant MCF-7:5C cells and markedly increased expression of p21, Bax, and Noxa in these cells. Significantly elevated level of IFNaα was detected in AI-resistant MCF-7:5C cells compared to parental MCF-7 cells and suppression of IFNaα dramatically reduced IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells. Lastly, neutralizing antibody against IFNAR1/2 and knockdown of STAT1/STAT2 completely suppressed IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells, thus confirming the involvement of the canonical IFNaα signaling pathway in driving the overexpression of IFITM1 and other interferon-stimulated genes (ISGs) in the resistant cells. Conclusion: Overall, these results demonstrate that constitutive overexpression of ISGs enhances the progression of AI-resistant breast cancer and that suppression of IFITM1 and other ISGs sensitizes AI-resistant cells to estrogen-induced cell death. © 2015 Choi et al.; licensee BioMed Central.


Sykes S.M.,Research Institute of Fox Chase Cancer Center | Scadden D.T.,Harvard Stem Cell Institute
Seminars in Hematology | Year: 2013

Hematopoietic stem cells (HSCs) have the immense task of supplying an organism with enough blood to sustain a lifespan. Much of what is known about how this scant population of cells can meet the varying demand of producing more than 1011 cells per day comes from studies conducted in an animal that is a fraction of our size and lives roughly 1/30th of our lifespan. The differences in longevity can be expected to impose different demands on a cell essential for existence. It is therefore unsurprising that while the mouse has proven invaluable in defining the organizing principals of how hematopoiesis is governed, mediators of cell localization as well as a range of experimental methods, the differences in cell cycling, DNA repair and specific molecular features of HSCs in humans are evident and important. Here, the utility and drawbacks of the mouse as an experimental model for human HSC biology are discussed. © 2013 Elsevier Inc.


Lev A.,Research Institute of Fox Chase Cancer Center | Sigal L.,Research Institute of Fox Chase Cancer Center
Cell Host and Microbe | Year: 2013

How immune cells collaborate to clear a virus from the skin is not well understood. In this issue of Cell Host & Microbe, Hickman et al. (2013) show that spatially segregated Ly6G+ monocytes and CD8+ T cells act synergistically to clear vaccinia virus from a primary skin infection. © 2013 Elsevier Inc.


Remakus S.,Research Institute of Fox Chase Cancer Center | Sigal L.J.,Research Institute of Fox Chase Cancer Center
Advances in Experimental Medicine and Biology | Year: 2013

Memory CD8+ T cells play an essential role in controlling pathogenic infections. Therefore generating protective memory CD8+ T cells by vaccination is an attractive strategy for preventing and treating a variety of human diseases. Understanding what comprises a protective memory CD8+ T cell response will help optimize vaccine-induced CD8 + T cell immunity. Here we discuss essential antiviral effector functions and highlight how recall expansion of memory CD8+ T cells may affect the primary response. © Springer Science+Business Media New York 2013.


PubMed | Research Institute of Fox Chase Cancer Center
Type: Journal Article | Journal: Seminars in hematology | Year: 2013

Hematopoietic stem cells (HSCs) have the immense task of supplying an organism with enough blood to sustain a lifespan. Much of what is known about how this scant population of cells can meet the varying demand of producing more than 10(11) cells per day comes from studies conducted in an animal that is a fraction of our size and lives roughly 1/30th of our lifespan. The differences in longevity can be expected to impose different demands on a cell essential for existence. It is therefore unsurprising that while the mouse has proven invaluable in defining the organizing principals of how hematopoiesis is governed, mediators of cell localization as well as a range of experimental methods, the differences in cell cycling, DNA repair and specific molecular features of HSCs in humans are evident and important. Here, the utility and drawbacks of the mouse as an experimental model for human HSC biology are discussed.


PubMed | Research Institute of Fox Chase Cancer Center
Type: Journal Article | Journal: Journal of virology | Year: 2012

The orthopoxvirus (OPV) vaccinia virus (VACV) requires an intact F13L gene to produce enveloped virions (EV) and to form plaques in cell monolayers. Simultaneous introduction of an exogenous gene and F13L into F13L-deficient VACV results in expression of the foreign gene and restoration of plaque size. This is used as a method to rapidly generate VACV recombinants without the need for drug selection. However, whether other OPVs require the orthologs of F13L to generate EV and form plaques, whether F13L orthologs and EV are important for OPV pathogenesis in natural hosts, and whether a system based on F13L ortholog deficiency can be used to generate recombinant OPVs other than VACV have not been reported. The F13L ortholog in ectromelia virus (ECTV), the agent of mousepox, is EVM036. We show that ECTV lacking EVM036 formed small plaques and was highly attenuated in vivo but still induced strong antibody responses. Reintroduction of EVM036 in tandem with the DsRed gene resulted in a virus that expressed DsRed in infected cells but was indistinguishable from wild-type ECTV in terms of plaque size and in vivo virulence. Thus, our data show that, like F13L in VACV, EVM036 is required for ECTV plaque formation and that EVM036 and EV are important for ECTV virulence. Our experiments also suggest that OPVs deficient in F13L orthologs could serve as safer anti-OPV vaccines. Further, our results demonstrate that ECTV deficient in EVM036 can be exploited for the rapid generation of fully virulent ECTV expressing foreign genes of interest.


PubMed | Research Institute of Fox Chase Cancer Center
Type: Journal Article | Journal: Cell host & microbe | Year: 2013

Nuclear factor kappa B (NF-B) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-B and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-B is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-B inhibitor activates NF-B more effectively invivo, resulting in increased proinflammatorymolecule transcription in uninfected cells and organsand decreased viral replication. Unexpectedly, NF-B activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-B pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease.

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