Northport, NY, United States
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Zarrabi K.,State University of New York at Stony Brook | Fang C.,State University of New York at Stony Brook | Wu S.,State University of New York at Stony Brook | Wu S.,Northport Medical Center
Journal of Hematology and Oncology | Year: 2017

Angiogenesis is a critical process in the progression of advanced renal cell carcinoma. Agents targeting angiogenesis have played a primary role in the treatment of metastatic renal cell carcinoma. However, resistance to anti-angiogenesis therapy almost always occurs, and major progress has been made in understanding its underlying molecular mechanism. Axitinib and everolimus have been used extensively in patients whom have had disease progression after prior anti-angiogenesis therapy. Recently, several new agents have been shown to improve overall survival in comparison with everolimus. This review provides an in-depth summary of drugs employable in the clinical setting, the rationale to their use, and the studies conducted leading to their approval for use and provides perspective on the paradigm shift in the treatment of renal cell carcinoma. Highlighted are the newly approved agents cabozantinib, nivolumab, and lenvatinib for advanced renal cell carcinoma patients treated with prior anti-angiogenesis therapy. © 2017 The Author(s).


Jagroop S.,Northport Medical Center | Kumar A.,Northport Medical Center
World Journal of Gastroenterology | Year: 2012

Cameron lesions represent linear gastric erosions and ulcers on the crests of mucosal folds in the distal neck of a hiatal hernia (HH). Such lesions may be found in upto 50% of endoscopies performed for another indication. Though typically asymptomatic, these may rarely present as acute, severe upper gastrointestinal bleed (GIB). The aim is to report a case of a non-anemic 87-year-old female with history of HH and atrial fibrillation who presented with hematemesis and melena resulting in hypovolemic shock. Repeat esophagogastroduodenoscopy was required to identify multiple Cameron ulcers as the source. Endoscopy in a patient with HH should involve meticulous visualization of hernia neck and surrounding mucosa. Cameron ulcers should be considered in all patients with severe, acute GIB and especially in those with known HH with or without chronic anemia. © 2012 Baishideng.


Lu Z.,State University of New York at Stony Brook | Jiang Y.-P.,State University of New York at Stony Brook | Wu C.-Y.C.,State University of New York at Stony Brook | Ballou L.M.,State University of New York at Stony Brook | And 7 more authors.
Diabetes | Year: 2013

Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias. © 2013 by the American Diabetes Association.


Wu C.-Y.C.,State University of New York at Stony Brook | Carpenter E.S.,State University of New York at Stony Brook | Takeuchi K.K.,Mayo Clinic Florida | Halbrook C.J.,State University of New York at Stony Brook | And 10 more authors.
Gastroenterology | Year: 2014

BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis.METHODS: Tumorigenesis was measured in the KrasG12D/+;Ptf1aCre/+ mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110α and other PI3K pathway components.RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in KrasG12D/+;Ptf1aCre/+ mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110α but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from KrasG12D/+;Ptf1aCre/+ mice compared with controls. Loss of p110α reduced RAC1 activity and expression in these tissues. p110α was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110α and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata.CONCLUSIONS: KRAS signaling, via p110α to activate RAC1, is required for transformation in KrasG12D/+;Ptf1aCre/+ mice. © 2014 AGA Institute.


Ballou L.M.,State University of New York at Stony Brook | Lin R.Z.,State University of New York at Stony Brook | Lin R.Z.,Northport Medical Center | Cohen I.S.,State University of New York at Stony Brook
Circulation Research | Year: 2015

Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes mellitus also may result from changes in multiple currents because of decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the effect of PI3K and its downstream effectors, including Akt, on sodium, potassium, and calcium currents in cardiac myocytes. We also refer to some studies in noncardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility. © 2014 American Heart Association, Inc.


Gandy K.A.O.,Medical University of South Carolina | Canals D.,State University of New York at Stony Brook | Adada M.,State University of New York at Stony Brook | Wada M.,State University of New York at Stony Brook | And 5 more authors.
Biochemical Journal | Year: 2013

Previously we demonstrated that the sphingolipids ceramide and S1P (sphingosine 1-phosphate) regulate phosphorylation of the ERM (ezrin/radixin/moesin) family of cytoskeletal proteins [Canals, Jenkins, Roddy,Hernande-Corbacho, Obeid and Hannun (2010) J. Biol. Chem. 285, 32476-3285]. In the present article,we show that exogenously applied or endogenously generated S1P (in a sphingosine kinase-dependent manner) results in significant increases in phosphorylation of ERM proteins as well as filopodia formation. Using phosphomimetic and non-phosphorylatable ezrin mutants, we show that the S1P-induced cytoskeletal protrusions are dependent on ERM phosphorylation. Employing various pharmacological S1PR (S1P receptor) agonists and antagonists, along with siRNA(small interfering RNA) techniques and genetic knockout approaches, we identify the S1PR2 as the specific and necessary receptor to induce phosphorylation of ERM proteins and subsequent filopodia formation. Taken together, the results demonstrate a novel mechanism by which S1P regulates cellular architecture that requires S1PR2 and subsequent phosphorylation of ERM proteins. © The Authors Journal compilation © 2013 Biochemical Society.


Alexa Orr Gandy K.,Medical University of South Carolina | Obeid L.M.,Health Science University | Obeid L.M.,Northport Medical Center
Handbook of Experimental Pharmacology | Year: 2013

Sphingolipids have emerged as pleiotropic signaling molecules with roles in numerous cellular and biological functions. Defining the regulatory mechanisms governing sphingolipid metabolism is crucial in order to develop a complete understanding of the biological functions of sphingolipid metabolites. The sphingosine kinase/ sphingosine 1-phosphate pathway was originally thought to function in the irreversible breakdown of sphingoid bases; however, in the last few decades it has materialized as an extremely important signaling pathway involved in a plethora of cellular events contributing to both normal and pathophysiological events. Recognition of the SK/S1P pathway as a second messaging system has aided in the identification of many mechanisms of its regulation; however, a cohesive, global understanding of the regulatory mechanisms controlling the SK/S1P pathway is lacking. In this chapter, the role of the SK/S1P pathway as a second messenger is discussed, and its role in mediating TNF-?- and EGF-induced biologies is examined. This work provides a comprehensive look into the roles and regulation of the sphingosine kinase/ sphingosine 1-phosphate pathway and highlights the potential of the pathway as a therapeutic target. , © Springer-Verlag Wien 2013.


Orr Gandy K.A.,Medical University of South Carolina | Obeid L.M.,Health Science University | Obeid L.M.,Northport Medical Center
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2013

Sphingosine 1-phosphate (S1P) is an important bioactive sphingolipid metabolite that has been implicated in numerous physiological and cellular processes. Not only does S1P play a structural role in cells by defining the components of the plasma membrane, but in the last 20 years it has been implicated in various significant cell signaling pathways and physiological processes: for example, cell migration, survival and proliferation, cellular architecture, cell-cell contacts and adhesions, vascular development, atherosclerosis, acute pulmonary injury and respiratory distress, inflammation and immunity, and tumorogenesis and metastasis [1,2]. Given the wide variety of cellular and physiological processes in which S1P is involved, it is immediately obvious why the mechanisms governing S1P synthesis and degradation, and the manner in which these processes are regulated, are necessary to understand. In gaining more knowledge about regulation of the sphingosine kinase (SK)/S1P pathway, many potential therapeutic targets may be revealed. This review explores the roles of the SK/S1P pathway in disease, summarizes available SK enzyme inhibitors and examines their potential as therapeutic agents. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.


Adada M.,Health Science University | Canals D.,Health Science University | Hannun Y.A.,Health Science University | Obeid L.M.,Health Science University | Obeid L.M.,Northport Medical Center
FEBS Journal | Year: 2013

Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in cell proliferation, angiogenesis, inflammation and malignant transformation among other functions. S1P acts either directly on intracellular targets or activates G protein-coupled receptors, specifically five S1P receptors (S1PRs). The identified S1PRs differ in cellular and tissue distribution, and each is coupled to specific G proteins, which mediate unique functions. Here, we describe functional characteristics of all five receptors, emphasizing S1PR2, which is critical in the immune, nervous, metabolic, cardiovascular, musculoskeletal, and renal systems. This review also describes the role of this receptor in tumor growth and metastasis and suggests potential therapeutic avenues that exploit S1PR2. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in cell proliferation, angiogenesis, inflammation, and malignant transformation among other functions. S1P acts either directly on intracellular targets or activates G-protein coupled receptors, specifically five S1P receptors (S1PRs). Here, we describe functional characteristics of all five receptors, emphasizing S1PR2 and its role in tumor growth and metastasis. © 2013 FEBS.


Adada M.,Health Science University | Canals D.,Health Science University | Hannun Y.A.,Health Science University | Obeid L.M.,Health Science University | Obeid L.M.,Northport Medical Center
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014

A key but poorly studied domain of sphingolipid functions encompasses endocytosis, exocytosis, cellular trafficking, and cell movement. Recently, the ezrin, radixin and moesin (ERM) family of proteins emerged as novel potent targets regulated by sphingolipids. ERMs are structural proteins linking the actin cytoskeleton to the plasma membrane, also forming a scaffold for signaling pathways that are used for cell proliferation, migration and invasion, and cell division. Opposing functions of the bioactive sphingolipid ceramide and sphingosine-1-phosphate (S1P), contribute to ERM regulation. S1P robustly activates whereas ceramide potently deactivates ERM via phosphorylation/ dephosphorylation, respectively. This recent dimension of cytoskeletal regulation by sphingolipids opens up new avenues to target cell dynamics, and provides further understanding of some of the unexplained biological effects mediated by sphingolipids. In addition, these studies are providing novel inroads into defining basic mechanisms of regulation and action of bioactive sphingolipids. This review describes the current understanding of sphingolipid regulation of the cytoskeleton, it also describes the biologies in which ERM proteins have been involved, and finally how these two large fields have started to converge. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.

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