Fox Chase Cancer Center and Wistar Institute | Date: 2014-03-10
A high-throughput method for identifying a compound or biomolecule that modulates cell senescence involves simultaneously measuring in a cell population exposed to the test compound or biomolecule, the expression of a senescence marker and cell number, wherein each well contains a single test compound; and determining from said simultaneous measurements whether the test compound increases or decreases cell senescence. In various embodiments, the method is useful is identifying compounds that delay the aging process of normal healthy cells, or identifying a compound useful as a tumor suppressor or identifying a compound useful in the treatment of cancer.
Seeger-Nukpezah T.,Fox Chase Cancer Center |
Golemis E.A.,Fox Chase Cancer Center
Current Opinion in Cell Biology | Year: 2012
The primary cilium protrudes like an antenna from the cell surface, sensing mechanical and chemical cues provided in the cellular environment. In some tissue types, ciliary orientation to lumens allows response to fluid flow; in others, such as bone, ciliary protrusion into the extracellular matrix allows response to compression forces. The ciliary membrane contains receptors for Hedgehog, Wnt, Notch, and other potent growth factors, and in some instances also harbors integrin and cadherin family members, allowing receipt of a robust range of signals. A growing list of ciliopathies, arising from deficient formation or function of cilia, includes both developmental defects and chronic, progressive disorders such as polycystic kidney disease (PKD); changes in ciliary function have been proposed to support cancer progression. Recent findings have revealed extensive signaling dialog between cilia and extracellular matrix (ECM), with defects in cilia associated with fibrosis in multiple contexts. Further, a growing number of proteins have been determined to possess multiple roles in control of cilia and focal adhesion interactions with the ECM, further coordinating functionality. We summarize and discuss these recent findings. © 2012 Elsevier Ltd.
Taylor J.M.,Fox Chase Cancer Center
Cold Spring Harbor Perspectives in Medicine | Year: 2015
This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still-unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
Taylor J.M.,Fox Chase Cancer Center
Seminars in Liver Disease | Year: 2012
Although much of the current understanding of the replication of hepatitis D virus (HDV) has been gained from ex vivo rather than in vivo studies, many seemingly unique aspects have been discovered. These include the ultra-small size and circular conformation of the RNA genome, the presence on the viral RNAs of two ribozymes, the role of RNA-directed RNA transcription by redirection of host enzymes, the requirement of site-specific, posttranscriptional RNA-editing, and more. This review addresses recent insights, remaining controversies, and just plain deficits in our understanding of HDV replication. ©Copyright 2012 by Thieme MedicalPublishers, Inc.
Olszanski A.J.,Fox Chase Cancer Center
Journal of Managed Care Pharmacy | Year: 2014
Background: Melanoma is an aggressive disease that accounts for approximately 75% of skin cancer-related deaths. Historically, treatment options for patients with advanced stage melanoma have been limited by modest response rates and failure to improve overall survival. The treatment landscape for advanced stage melanoma was revolutionized in 2011 with the approval of ipilimumab and vemurafenib, both of which improved overall survival in phase III clinical trials. More recently, the targeted inhibitors dabrafenib and trametinib have demonstrated similar therapeutic profiles. Objectives: To (a) discuss emerging treatment options for advanced melanoma, specifically ilpilimumab, vemurafenib, dabrafenib, and trametinib, in the context of their mechanisms of action and their potential for longterm improvement in patient outcome, and (b) to consider the impact of these agents on the current treatment landscape. METHODS: A literature search was conducted to collect data from clinical trials involving ipilimumab, vemurafenib, dabrafenib, and trametinib. Emphasis was placed on outcome measures related to long-term clinical benefit. Results: Ipilimumab, a fully human monoclonal antibody, exploits the natural ability of the immune system to eradicate primary cancer cells. It inhibits the binding of cytotoxic T-lymphocyte antigen-4 to its ligands, thereby potentiating T-cell response and antitumor immunity. In a phase III clinical trial, ipilimumab at 3 mg/kg improved overall survival in previously treated patients with metastatic melanoma. Components of the mitogenactivated protein kinase (MAPK) pathway are particularly relevant in melanoma and have been targeted by small molecular inhibitors. Vemurafenib and dabrafenib inhibit the BRAF V600 mutation, which prevents oncogenic activities such as uncheck proliferation and evasion of immune response. Data from phase III clinical trials suggest that both vemurafenib and dabrafenib improve patient outcomes, with vemurafenib showing an overall survival benefit and dabrafenib showing improved median progression-free survival. The targeted-therapy approach in melanoma continued to gain momentum with the development of trametinib, which inhibits the MEK protein, the only known substrate of the BRAF V600 protein. Inhibition of MEK leads to decreased cell signaling and proliferation in cancer cells. In phase III trials, trametinib demonstrated significant improvement in median progression-free survival and median overall survival compared with chemotherapy treatment, making this treatment a valuable addition to the current armamentarium. The adverse events associated with these new treatments are generally tolerable and mild to moderate in severity; however, care should be taken when selecting a therapy, since the specific adverse events associated with these treatments are unique, and serious events have been reported. Conclusions: The immunotherapy ipilimumab and the MAPK-targeted inhibitors vemurafenib, dabrafenib, and trametinib have forever changed the treatment landscape for melanoma. Indeed, these new therapies have demonstrated long-term improvement in patient outcome, a benefit not afforded by traditional therapeutics. Important research continues on the molecular basis of melanoma, and new targets are likely to emerge. Other areas of work include optimization of sequencing and/or combination of current treatments, which may increase the number of patients who experience clinical benefit. © 2014, Academy of Managed Care Pharmacy. All rights reserved.
Grivennikov S.I.,Fox Chase Cancer Center
Seminars in Immunopathology | Year: 2013
Connection between inflammation and cancer is a rapidly developing field. Epidemiological data suggests that inflammation along with distinct arms of host immune system plays a very important role in the development and progression of many different cancers. Inflammatory bowel disease (IBD) is an important risk factor for the development of colon cancer, namely, colitis-associated cancer (CAC). The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and may differ between CAC and other forms of colorectal cancer. Recent work has shed light on the role of distinct immune cells, cytokines, and other immune mediators in virtually all of the steps of colonic tumorigenesis, including tumor initiation and promotion as well as progression and metastasis. The close proximity of colonic tumors to the myriad of intestinal microbes, as well as instrumental role of microbiota in IBD, introduces microbes as new players capable of triggering inflammation and possibly promoting tumorigenesis. Various mechanisms of CAC tumorigenesis as well as new possible hints for the future approaches for prevention and therapy are discussed in this review. © 2012 Springer-Verlag Berlin Heidelberg.
Fox Chase Cancer Center | Date: 2015-09-23
The invention provides a natural killer cell, NK-92, modified to express an Fc receptor on the surface of the cell, such as CD 16 (FcRIII-A), or other Fc or Fc receptors. The modified NK-92 cell can be further modified to concurrently express an associated accessory signaling protein, such as FcRI-,TCR-, or to concurrently express interleukin-2 (IL-2) or other cytokines. Additional methods are disclosed for various assays, assessments, and therapeutic treatments with the modified NK-92 cell.
Fox Chase Cancer Center | Date: 2016-06-02
Fox Chase Cancer Center | Date: 2015-08-26
The invention provides a natural killer cell, NK-92, modified to express an Fc receptor on the surface of the cell, such as CD 16 (FcRIII-A), or other Fc or Fc receptors. The modified NK-92 cell can be further modified to concurrently express an associated accessory signaling protein, such as FcRI-,TCR-, or to concurrently express interleukin-2 (IL-2) or other cytokines. Additional methods are disclosed for various assays, assessments, and therapeutic treatments with the modified NK-92 cells.
Fox Chase Cancer Center | Date: 2016-03-10
Compositions and methods which indicate an increased risk for pancreatic carcinoma in a test subject are disclosed.