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New Brunswick, NJ, United States

Schlesinger N.,UMDNJ RWJMS
Expert Opinion on Biological Therapy

Introduction: Gout is a painful inflammatory arthritis with a prevalence of approximately 4% in the United States, affecting an estimated 8.3 million adults. The past 20 years have shown significant increases in the number of patients with gout and its incidence may still be increasing. Current treatment options to control the pain and inflammation of acute gout include nonsteroidal anti-inflammatory drugs, colchicine and corticosteroids, although patients are often unresponsive to, intolerant of, or have contraindications for, these therapies. Additional treatment options are therefore needed for this population with difficult-to-treat gout.Areas covered: Currently available and investigational anti-inflammatory agents for acute and chronic gout will briefly be reviewed. Canakinumab, a fully human monoclonal anti-interleukin (IL)-1β antibody that selectively blocks IL-1β and that is being investigated for the treatment of gout, will be discussed in greater detail.Expert opinion: Canakinumab has been found to be superior to triamcinolone acetonide in acute gout and to colchicine in gout attack prophylaxis in reducing pain and risk of new gout attacks. Canakinumab's long half-life contributes to its prolonged anti-inflammatory effects. © 2012 Informa UK, Ltd. Source

Su B.,Yale University | Jacinto E.,UMDNJ RWJMS
Critical Reviews in Biochemistry and Molecular Biology

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR. © 2011 Informa Healthcare USA, Inc. Source

Schlesinger N.,UMDNJ RWJMS
Seminars in Arthritis and Rheumatism

Objectives: The management of gouty arthritis is focused on treating pain and inflammation associated with acute flares and preventing further acute flares and urate crystal deposition. A challenge associated with the successful management of gouty arthritis is an increased risk of acute flares during the first months after initiation of urate-lowering therapy (ULT). This increase in flare frequency can occur regardless of the choice of ULT and is linked to suboptimal patient adherence to ULT. Current treatment recommendations for the use of prophylaxis are limited. There are no definitive recommendations as to which agents should be used or for how long therapy is beneficial after starting ULT. This article aims to improve awareness of the importance of gouty arthritis flare prophylaxis when initiating ULTand to summarize current recommendations and clinical findings related to the efficacy and safety of currently available and investigational new therapies. Methods: This review discusses the pathophysiology of acute gouty arthritis flares during initiation of ULT and examines the literature on the use of anti-inflammatory prophylaxis for reduction of these flares. Results: It has recently become clear that, even when the patient is asymptomatic, chronic inflammation is often present in patients with chronic gouty arthritis. Chronic anti-inflammatory therapy should therefore be added to chronic ULT. Prophylaxis with colchicine as well as with nonsteroidal antiinflammatory drugs (NSAIDs) during ULT initiation can reduce the incidence and severity of gouty arthritis flares substantially; however, safety concerns associated with colchicine and NSAIDs may limit their use. Conclusion: When colchicine and NSAIDs are contraindicated or poorly tolerated, rilonacept and canakinumab, interleukin-1 inhibitors in trials, may prove to be useful alternatives for flare prevention. (Of note, although both inhibit the IL-1β pathway, rilonacept also binds to IL-1α and IL-1RA, in contrast to canakinumab, which binds selectively to IL-1β). © 2012 Elsevier Inc. Source

Yip D.,UMDNJ RWJMS | Drachtman R.,Cancer Institute of New Jersey | Amorosa L.,Metabolism and Nutrition | Trooskin S.,UMDNJ RWJMS
Pediatric Blood and Cancer

Thyroid carcinomas are an uncommon entity in childhood. We report a case of papillary thyroid cancer presenting as Horner syndrome in a 14 year-old child, which is the only reported such case in the pediatric population. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc. Source

Kaul M.,UMDNJ RWJMS | Zhang Y.,TAXIS Pharmaceuticals Inc. | Parhi A.K.,TAXIS Pharmaceuticals Inc. | Lavoie E.J.,Rutgers University | And 4 more authors.

New antibiotics with novel mechanisms of action are urgently needed to overcome the growing bacterial resistance problem faced by clinicians today. PC190723 and related compounds represent a promising new class of antibacterial compounds that target the essential bacterial cell division protein FtsZ. While this family of compounds exhibits potent antistaphylococcal activity, they have poor activity against enterococci and streptococci. The studies described herein are aimed at investigating the molecular basis of the enterococcal and streptococcal resistance to this family of compounds. We show that the poor activity of the compounds against enterococci and streptococci correlates with a correspondingly weak impact of the compounds on the self-polymerization of the FtsZ proteins from those bacteria. In addition, computational and mutational studies identify two key FtsZ residues (E34 and R308) as being important determinants of enterococcal and streptococcal resistance to the PC190723-type class of compounds. © 2013 Elsevier Masson SAS. All rights reserved. Source

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