White E.,Cancer Institute of New Jersey |
White E.,Johnson University |
White E.,Rutgers University
Nature Reviews Cancer | Year: 2012
Autophagy (also known as macroautophagy) captures intracellular components in autophagosomes and delivers them to lysosomes, where they are degraded and recycled. Autophagy can have two functions in cancer. It can be tumour suppressive through the elimination of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Alternatively, it can be tumour promoting in established cancers through autophagy-mediated intracellular recycling that provides substrates for metabolism and that maintains the functional pool of mitochondria. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention. © 2012 Macmillan Publishers Limited. All rights reserved.
Silverstein S.M.,Rutgers University |
Silverstein S.M.,Johnson University |
Keane B.P.,Rutgers University
Schizophrenia Bulletin | Year: 2011
Perceptual organization (PO) refers to the processes by which visual information is structured into coherent patterns such as groups, contours, perceptual wholes, and object representations. Impairments in PO have been demonstrated in schizophrenia since the 1960s and have been linked to several illness-related factors including poor premorbid functioning, poor prognosis, and disorganized symptoms. This literature was last reviewed in 2005. Since then, electrophysiological (electroencephalographic, event-related potential, and magnetoencephalographic) and fMRI studies in both patient and nonpatient samples have clarified brain mechanisms involved in the impairment, and additional behavioral studies in patients and nonpatients have clarified the computational mechanisms. In addition, data now exist on the functional consequences of PO impairments, in terms of secondary difficulties in face processing, selective attention, working memory, and social cognition. Preliminary data on drug effects on PO and on changes in response to treatment suggest that anomalies in PO may furnish a biomarker for the integrity of its associated biological mechanisms. All of this recent evidence allows for a clearer picture of the nature of the impairment and how it relates to broader aspects of brain and behavioral functioning in schizophrenia. © The Author 2011. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
Phadtare S.,Johnson University
RNA Biology | Year: 2011
Temperature downshift from 37°C to 15°C results in the exertion of cold shock response in Escherichia coli, which induces cold shock proteins, such as CsdA. Previously, we showed that the helicase activity of CsdA is critical for its function in the cold acclimation of cells and its primary role is mRNA degradation. Only RhlE (helicase), CspA (RNA chaperone) and RNase R (exoribonuclease) were found to complement the cold shock function of CsdA. RNase R has two independent activities, helicase and ribonuclease, only helicase being essential for the functional complementation of CsdA. Here, we discuss the significance of above findings as these emphasize the importance of the unwinding activity of cold-shock-inducible proteins in the RNA metabolism at low temperature, which may be different than that at 37°C. It requires assistance of proteins to destabilize the secondary structures in mRNAs that are stabilized upon temperature downshift, hindering the activity of ribonucleases. © 2011 Landes Bioscience.
Sesti F.,Johnson University |
Liu S.,Johnson University |
Cai S.-Q.,Johnson University
Trends in Cell Biology | Year: 2010
A wealth of evidence underscores the tight link between oxidative stress, neurodegeneration and aging. When the level of excess reactive oxygen species (ROS) increases in the cell, a phenomenon characteristic of aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. Recently we showed that in the nematode, Caenorhabditis elegans, oxidation of K+ channels by ROS is a major mechanism underlying the loss of neuronal function. The C. elegans results support an argument that K+ channels controlling neuronal excitability and survival might provide a common, functionally important substrate for ROS in aging mammals. Here we discuss the implications that oxidation of K+ channels by ROS might have for the mammalian brain during normal aging, as well as in neurodegenerative diseases such as Alzheimer's and Parkinson's. We argue that oxidation of K+ channels by ROS is a common theme in the aging brain and suggest directions for future experimentation.
Zhang Y.,Johnson University |
Zheng X.F.S.,Johnson University
Cell Cycle | Year: 2012
ATP -competitive mTO R kinase inhibitors (mTorKIs) are a new generation of mTO R-targeted agents with more potent anticancer activity than rapamycin in several tumor models. However, the sensitivity and resistance of cancer cells to mTorKIs remain poorly understood. In this study, we tested mTorKIs against a large panel of colorectal cancer (CRC) cell lines, and found that mTorKIs displayed broader anti-CRC activity than rapamycin, including CRC cells with K-Ras or B-Raf mutations, suggesting that these mTorKIs are particularly useful for CRCs resistant to EGFR inhibitors. Unexpectedly, we found that 40% CRC cell lines were intrinsically drug resistant. Moreover, we discovered an mTO R-independent 4E-BP1 phosphorylation that was correlated with mTorKI resistance. Altogether, our findings provide compelling preclinical support for testing mTorKIs in human CRC clinical trials. They further reveal the existence of significant intrinsic mTorKI drug resistance in cancer cells and suggest that 4E-BP1 phosphorylation is a predictive biomarker for mTorKI sensitivity and resistance. © 2012 Landes Bioscience.
Lee H.-L.R.,Johnson University |
Dougherty J.P.,Johnson University
Pharmacology and Therapeutics | Year: 2012
Nonsense codons, generated from nonsense mutations or frameshifts, contribute significantly to the spectrum of inherited human diseases such as cystic fibrosis, Duchenne muscular dystrophy, hemophilia, spinal muscular atrophy, and many forms of cancer. The presence of a mutant nonsense codon results in premature termination to preclude the synthesis of a full-length protein and leads to aberrations in gene expression. Suppression therapy to recode a premature termination codon with an amino acid allowing readthrough to rescue the production of a full-length protein presents a promising strategy for treatment of patients suffering from debilitating nonsense-mediated disorders. Suppression therapy using aminoglycosides to promote readthrough in vitro have been known since the sixties. Recent progress in the field of recoding via pharmaceuticals has led to the continuous discovery and development of several pharmacological agents with nonsense suppression activities. Here, we review the mechanisms that are involved in discriminating normal versus premature termination codons, the factors involved in readthrough efficiency, the epidemiology of several well-known nonsense-mediated diseases, and the various pharmacological agents (aminoglycoside and non-aminoglycoside compounds) that are currently being employed in nonsense suppression therapy studies. We also discuss how these therapeutic agents can be used to regulate gene expression for gene therapy applications. © 2012 Elsevier Inc.
Matise M.P.,Johnson University
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2013
The generation of neuronal diversity in the ventral spinal cord during development is a multistep process that occurs with precise and reproducible spatiotemporal order. The proper functioning of the central nervous system requires that this be carried out with extraordinary precision from the outset. Extrinsic influences such as the secreted Sonic hedgehog (SHH) protein provide positional cues that are read out genetically as specific patterns of gene expression in subsets of dividing progenitors, which is the first overt indication that they have begun to embark upon cell-type-specific differentiation programs. Cells generated from these segregated domains will ultimately share similar properties and functions. Recent work illustrates that SHH, which regulates target genes via the GLI transcription factors, directly controls a subset of progenitor fate determinant genes and that both derepression and activation play a role in shaping the differential response to this morphogen. © 2012 Wiley Periodicals, Inc.
Hollenberg S.M.,Johnson University
American Journal of Respiratory and Critical Care Medicine | Year: 2011
Shock occurs when failure of the cardiovascular systemcompromises tissue perfusion. When fluid administration fails to restore adequate arterial pressure and organ perfusion in patients with shock, therapy with vasoactive agents should be initiated. The key to selecting among vasoactive agents is to make the choice in the context of the goals of therapy. The ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. The clinician needs to consider ways of achieving those goals and the mechanisms of action of potential therapies. Armed with this knowledge, it becomes easier to match the mechanism of action of a particular agent to the goals of therapy. When this is done, differences among various agents are seen primarily as differences in mechanisms of action, and discussions about which agent is "best" are transformed into consideration of which agent is best suited to implement the therapeutic strategy that has been selected in a given clinical context. Despite the complex pathophysiology of shock, use of vasoactive agents for hemodynamic support of patients with shock can be guided by an underlying approach in which clinicians define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis. Copyright © 2011 American Thoracic Society.
Karantza V.,Johnson University |
Karantza V.,Cancer Institute of New Jersey
Oncogene | Year: 2011
Keratins are the intermediate filament (IF)-forming proteins of epithelial cells. Since their initial characterization almost 30 years ago, the total number of mammalian keratins has increased to 54, including 28 type I and 26 type II keratins. Keratins are obligate heteropolymers and, similarly to other IFs, they contain a dimeric central α-helical rod domain that is flanked by non-helical head and tail domains. The 10-nm keratin filaments participate in the formation of a proteinaceous structural framework within the cellular cytoplasm and, as such, serve an important role in epithelial cell protection from mechanical and non-mechanical stressors, a property extensively substantiated by the discovery of human keratin mutations predisposing to tissue-specific injury and by studies in keratin knockout and transgenic mice. More recently, keratins have also been recognized as regulators of other cellular properties and functions, including apico-basal polarization, motility, cell size, protein synthesis and membrane traffic and signaling. In cancer, keratins are extensively used as diagnostic tumor markers, as epithelial malignancies largely maintain the specific keratin patterns associated with their respective cells of origin, and, in many occasions, full-length or cleaved keratin expression (or lack there of) in tumors and/or peripheral blood carries prognostic significance for cancer patients. Quite intriguingly, several studies have provided evidence for active keratin involvement in cancer cell invasion and metastasis, as well as in treatment responsiveness, and have set the foundation for further exploration of the role of keratins as multifunctional regulators of epithelial tumorigenesis. © 2011 Macmillan Publishers Limited All rights reserved.
Check J.H.,Johnson University
American Journal of Reproductive Immunology | Year: 2012
Recommendations for the use of heparin for preventing miscarriage are recently rapidly changing based on evidenced based prospective studies. At present either heparin or low molecular weight heparin (LMWH) is recommended for the antiphospholipid syndrome (APS). However criteria for diagnosing APS have become much stricter. The exact timing of the heparin is still being evaluated since it is not clear if the main therapeutic effect is in inhibition of thrombosis when the heparin could be started at the time in the first trimester when the platelets become thrombophilic or does its main role in improving implantation in which it would be started shortly before or shortly after ovulation. Possibly heparin is superior to LMWH in improving the implantation process though more studies are needed to corroborate or refute this suggestion. At present inherited thrombophilias are not considered a cause of first trimester miscarriage and thus measuring these factors are not recommended. There is no evidence that heparin has any benefit in preventing miscarriage from unexplained causes. Heparin is effective alone and there does not appear to be any extra benefit from adding aspirin (or even aspirin may negate some of its benefits). © 2012 John Wiley & Sons A/S.