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Danville, PA, United States
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Zhang S.,00 North Academy Avenue | Chen H.,00 North Academy Avenue | Gerhard G.S.,00 North Academy Avenue
Chemico-Biological Interactions | Year: 2010

Artemisinin (ART) is a sesquiterpene lactone natural product that is widely used to treat multi-drug resistant strains of malaria. Artemisinin and its derivatives are also selectively cytotoxic to cancer cells, which can be modulated by altering heme synthesis. Cytotoxicity to cancer cells is thought to involve generation of oxidative stress, although conflicting data exist. We have analyzed reactive oxygen species (ROS) generation using the fluorescent probes 2',7'-dichlorodihydrofluorescein diacetate (DCF) and dihydroethidine (HET) upon exposure to dihydroartemisinin (DHA) in Molt-4 leukemia cells. HET fluorescence correlated with dose-dependent DHA-induced cytotoxicity, increased within 30. min of DHA exposure, and was significantly enhanced by increasing heme synthesis. Protein levels of copper,zinc-superoxide dismutase (CuZnSOD), manganese-superoxide dismutase (MnSOD), catalase, and glutathione peroxidases 1/2 were also found to increase with DHA exposure. 4-hydroxy-tempol (TEMPOL) and DF-Mn, MnSOD mimetics, could significantly inhibit ROS generation and reduce cell death. Production of superoxide appears to be a central mediator of cytotoxicity from DHA. © 2010 Elsevier Ireland Ltd.

Chang A.R.,00 North Academy Avenue | Chang A.R.,University of Baltimore | Lazo M.,University of Baltimore | Appel L.J.,University of Baltimore | And 3 more authors.
American Journal of Clinical Nutrition | Year: 2014

Background: Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake. Objective: We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998-1994). Design: Study participants were 9686 nonpregnant adults aged 20-80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006. Results: Median phosphorus intake was 1166 mg/d (IQR: 823- 1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48- 0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed .1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At ,1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount .0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At ,0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at .0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes. Conclusions: High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications. © 2014 American Society for Nutrition.

Strony R.,00 North Academy Avenue
Critical Care Clinics | Year: 2010

The use of ultrasound to mark landmarks for diagnostic lumbar puncture has been described in emergency medicine as well as in the anesthesia literature. One of the most difficult scenarios arises when obese patients with a body mass index (BMI) of greater than 30 present to an acute care setting, such as the emergency department or intensive care unit and require diagnostic LP. This article discusses lumbar puncture in patients with a high BMI. © 2010 Elsevier Inc.

Bieniek J.M.,00 North Academy Avenue | Meade P.G.,Geisinger Medical Center
Journal of Endourology | Year: 2012

In an attempt to reduce iatrogenic ureteral injury, urologists are frequently called on for placement of prophylactic ureteral catheters in difficult pelvic surgeries. Reflux anuria, which may be more appropriately termed catheter-induced obstructive anuria, has been reported as a complication of ureteral catheter placement and is characterized by the absence of urine output after ureteral manipulation because of edema and obstruction. We report a case of obstructive anuria after bilateral ureteral catheter removal and review the literature regarding this rare complication. Medline was searched for all relevant case reports, case series, and trials that included prophylactic ureteral catheters and described complications of their use. Published series report varying incidence of obstructive anuria after prophylactic ureteral catheter removal from 0% to 7.6%. There are no proven strategies for prevention of obstructive anuria after prophylactic ureteral catheter removal, but staged removal has shown a trend toward reduced incidence. When encountered, most cases of anuria after catheter removal resolved with medical management alone; however, indwelling stent placement has been advocated while ureteral edema resolves. © 2012, Mary Ann Liebert, Inc.

Grant M.P.,00 North Academy Avenue | Stepanchick A.,00 North Academy Avenue | Cavanaugh A.,00 North Academy Avenue | Breitwieser G.E.,00 North Academy Avenue
Science Signaling | Year: 2011

Calcium-sensing receptors (CaSRs) regulate systemic calcium homeostasis in the parathyroid gland, kidney, intestine, and bone and translate fluctuations in serum calcium into peptide hormone secretion, cell signaling, and regulation of gene expression. The CaSR is a G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor that operates in the constant presence of agonist, sensing small changes with high cooperativity and minimal functional desensitization. Here, we used multiwavelength total internal reflection fluorescence microscopy to demonstrate that the signaling properties of the CaSR result from agonist-driven maturation and insertion of CaSRs into the plasma membrane. Plasma membrane CaSRs underwent constitutive endocytosis without substantial recycling, indicating that signaling was determined by the rate of insertion of CaSRs into the plasma membrane. Intracellular CaSRs colocalized with calnexin in the perinuclear endoplasmic reticulum and formed complexes with 14-3-3 proteins. Ongoing CaSR signaling resulted from agonist-driven trafficking of CaSR through the secretory pathway. The intracellular reservoir of CaSRs that were mobilized by agonist was depleted when glycosylation of newly synthesized receptors was blocked, suggesting that receptor biosynthesis was coupled to signaling. The continuous, signaling-dependent insertion of CaSRs into the plasma membrane ensured a rapid response to alterations in the concentrations of extracellular calcium or allosteric agonist despite ongoing desensitization and endocytosis. Regulation of CaSR plasma membrane abundance represents a previously unknown mechanism of regulation that may be relevant to other receptors that operate in the chronic presence of agonist.

Karosas A.O.,00 North Academy Avenue
American Journal of Health-System Pharmacy | Year: 2010

Purpose. The current treatments of and new therapeutic options for the management of Ewing's sarcoma (ES) are reviewed. Summary. ES is the second most common primary bone malignancy in pediatric patients and is numbered among the cancers that result in the greatest risk of mortality and morbidity in children and young adults. Much progress has been made in the treatment of ES since the disease was first described in the 1920s. With current multimodality treatment including chemotherapy, radiation, and surgery, patients with localized disease have a long-term survival rate of approximately 50%. Survival rates for patients with metastatic disease or those with early relapse remain poor. New combinations of cytotoxic agents such as cyclophosphamide, topotecan, irinotecan, and temozolomide have shown efficacy and tolerability in patients with relapsed or refractory disease. To date, the role of high-dose chemotherapy supported by stem cell rescue as a consolidation therapy for high-risk ES tumors has yet to be conclusively determined. Much effort is being invested in treating cancer with targeted therapies, and the EWS-ETS fusion gene would likely provide an important tumor-specific target. Tyrosine kinases (TKs) are overexpressed in human sarcoma tumors, and cell lines may serve as potential targets for new therapies. One TK receptor that is a promising therapeutic target is insulinlike growth factor-1 receptor. Conclusion. Treatments for ES include surgery, radiation, and cytotoxic regimens, many of which include vincristine. Treatment for recurrent ES has included topotecan, cyclophosphamide, temozolomide, and irinotecan. Angiogenesis inhibitors, TK inhibitors, and bisphosphonates have also been studied. Copyright © 2010, American Society of Health-System Pharmacists, Inc. All rights reserved.

The calcium-sensing receptor (CaSR) regulates organismal Ca2+ homeostasis. Dysregulation of CaSR expression or mutations in the CASR gene cause disorders of Ca2+ homeostasis and contribute to the progression or severity of cancers and cardiovascular disease. This brief review highlights recent findings that define the CaSR life cycle, which controls the cellular abundance of CaSR and CaSR signaling. A novel mechanism, termed agonist-driven insertional signaling (ADIS), contributes to the unique hallmarks of CaSR signaling, including the high degree of cooperativity and the lack of functional desensitization. Agonist-mediated activation of plasma membrane-localized CaSR increases the rate of insertion of CaSR at the plasma membrane without altering the constitutive endocytosis rate, thereby acutely increasing the maximum signaling response. Prolonged CaSR signaling requires a large intracellular ADIS-mobilizable pool of CaSR, which is maintained by signaling-mediated increases in biosynthesis. This model provides a rational framework for characterizing the defects caused by CaSR mutations and the altered functional expression of wild-type CaSR in disease states. Mechanistic dissection of ADIS of CaSR should lead to optimized pharmacological approaches to normalize CaSR signaling in disorders of Ca2+ homeostasis. © 2012 by The Endocrine Society.

Sudol M.,00 North Academy Avenue | Sudol M.,Mount Sinai School of Medicine
Structure | Year: 2012

WW domains are small modules that mediate protein/protein interactions. In this issue of Structure, Aragón and colleagues show that a WW domain of YAP can mediate complexes with either the canonical PY motif in an inhibitory Smad or engage in phosphorylation-dependent complexes with one of the activated Smads. The propensity of YAP WW to recognize a pSP motif is a surprising find with a number of far-reaching ramifications. © 2012 Elsevier Ltd.

Argyropoulos G.,00 North Academy Avenue
Current Diabetes Reports | Year: 2015

Type 2 diabetes is a chronic disease that can be treated with pharmacologic and/or lifestyle interventions, but in most cases it does not get cured. One of the few interventions, however, that can remit diabetes is the Roux-en-Y gastric bypass (RYGB) surgery. Approximately 63 % of patients undergoing RYGB surgery experience diabetes remission, but the underlying mechanisms are poorly understood. Some studies implicate enterohepatic pathways with bile acids, fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) being the primary components. Here, we discuss these enterohepatic changes and highlight the roles of bile acids, FGF19, and GLP-1 in diabetes remission. We also describe how we can now actually predict, prior to surgery, the probability for remitting diabetes after RYGB surgery by using the DiaRem score. Deeper understanding of the mechanisms of diabetes remission by RYGB surgery could provide the basis for developing more effective interventions for curing the disease. © 2015, Springer Science+Business Media New York.

Williams B.A.,00 North Academy Avenue | Merhige M.E.,Coronary Disease Reversal and Prevention
Heart and Lung: Journal of Acute and Critical Care | Year: 2013

Objective: To determine whether an elevated neutrophil-lymphocyte ratio (NLR) is associated with chronically impaired myocardial perfusion in patients with known or suspected coronary disease. Background: Elevated NLRs are positively associated with cardiac events, anatomic coronary disease, and myocardial infarct size. However, no study has evaluated the association between NLR and chronically impaired myocardial perfusion. Methods: This study included 683 patients undergoing cardiac positron emission tomography (PET) with a calculable NLR within 90 days of PET. The primary outcome was myocardial perfusion defect size measured in percent of left ventricular mass (%LV60). Results: NLR was independently associated with %LV60 when analyzed as both a continuous and binary outcome ( p<0.001). Individuals with NLR above the 90th percentile had a 5-fold increased likelihood of significant perfusion defects compared to individuals with NLR between the 10th and 25th percentiles (Odds ratio=4.7, p<0.001). Conclusion: An elevated NLR demonstrated strong associations with myocardial perfusion. © 2013 Elsevier Inc.

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