Brown K.,The New School |
Heller D.S.,The New School |
Zamudio S.,Hackensack University |
Illsley N.P.,The New School
Placenta | Year: 2011
Conflicting information regarding expression of GLUT3 protein in the human placenta has been reported and the localization and pattern of expression of GLUT3 protein across gestation has not been clearly defined. The objective of this study was characterization of syncytial GLUT3 protein expression across gestation. We hypothesized that GLUT3 protein is present in the syncytial microvillous membrane and that its expression decreases over gestation. GLUT3 protein was measured in samples from a range of gestational ages (first to third trimester), with human brain and human bowel used as a positive and negative control respectively. As an additional measure of specificity, we transfected BeWo choriocarcinoma cells, a trophoblast cell line expressing GLUT3, with siRNA directed against GLUT3 and analyzed expression by Western blotting. GLUT3 was detected in the syncytiotrophoblast at all gestational ages by immunohistochemistry. Using Western blotting GLUT3 was detected as an integral membrane protein at a molecular weight of ∼50 kDa in microvillous membranes from all trimesters but not in syncytial basal membranes. The identity of the primary antibody target was confirmed by demonstrating that expression of the immunoblotting signal in GLUT3 siRNA-treated BeWo was decreased to 18 ± 6% (mean ± SEM) of that seen in cells transfected with a non-targeting siRNA. GLUT3 expression in microvillous membranes detected by Western blot decreased through the trimesters such that expression in the second trimester (wks 14-26) was 48 ± 7% of that in the first trimester and by the third trimester (wks 31-40) only 34 ± 10% of first trimester expression. In addition, glucose uptake into BeWo cells treated with GLUT3 siRNA was reduced to 60% of that measured in cells treated with the nontargeting siRNA. This suggests that GLUT3-mediated uptake comprises approximately 50% of glucose uptake into BeWo cells. These results confirm the hypothesis that GLUT3 is present in the syncytial microvillous membrane early in gestation and decreases thereafter, supporting the idea that GLUT3 is of greater importance for glucose uptake early in gestation. © 2011 Elsevier Ltd. All rights reserved.
Ye W.,New York University |
Ye W.,Hackensack University |
Blain S.W.,New York University
Apoptosis | Year: 2011
Neuronal death in the central nervous system contributes to the development of age-related neurodegeneration. The ATR/Chk1 pathway appears to function neuroprotectively to prevent DNA damage induced by cytotoxic agents. Here, we examine the function of Chk1 on cell viability of cortical neurons in the absence of additional DNA damaging stimuli. The Chk1-specific inhibitor, UCN-01, and the ATR inhibitor, Caffeine, cause neuronal apoptosis in differentiated neurons in the absence of additional treatment, whereas inhibition of ATM or Chk2, does not. UCN-01 treatment increased the detection of γ-H2AX phosphorylation, DNA strand breaks, and an activated p53-dependent DNA damage response (DDR), suggesting that Chk1 normally helps to maintain genomic stability. UCN-01 treatment also enhanced the apoptosis seen in neurons treated with DNA damaging agents, such as camptothecin (CPT). Our results indicate that Chk1 is essential for neuronal survival, and perturbation of this pathway increases a cell's sensitivity to naturally accumulating DNA damage. © 2011 Springer Science+Business Media, LLC.
Niesvizky R.,Cornell College |
Martin III T.G.,University of California at San Francisco |
Bensinger W.I.,Fred Hutchinson Cancer Research Center |
Alsina M.,H. Lee Moffitt Cancer Center and Research Institute |
And 5 more authors.
Clinical Cancer Research | Year: 2013
Purpose: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. Experimental Design: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. Results: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%);20%and36%were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. Conclusion: The maximum planned CRd dose, carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. ©2013 AACR.
Park B.J.,Hackensack University |
Melfi F.,University of Pisa |
Mussi A.,University of Pisa |
Maisonneuve P.,Italian National Cancer Institute |
And 3 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2012
Objective(s): We evaluated a large series of patients undergoing robotic lobectomy for the treatment of early-stage non-small cell lung cancer (NSCLC) to assess long-term oncologic efficacy. Methods: A multi-institutional retrospective review of patients undergoing robotic lobectomy for NSCLC was performed. Robotic lobectomy was performed in a manner consistent with the Cancer and Leukemia Group B (CALGB) consensus video-assisted thoracic surgery (VATS) lobectomy technique using a robotic surgical system. Perioperative outcomes and long-term follow-up were recorded prospectively, and survival was calculated from the date of surgery to last follow-up. Results: From November 2002 through May 2010, a total of 325 consecutive patients underwent robotic lobectomy for early-stage NSCLC at 3 institutions. The median age of patients was 66 years (range, 30-87 years), and 37% (120) were female. The majority were in clinical stage I (IA, 247; IB, 63). Conversion rate to thoracotomy was 8% (27/325). Overall morbidity rate was 25.2% (82/325), and major complication rate was 3.7% (12/325). There was 1 in-hospital death (0.3%), and the median length of stay was 5 days (range, 2-28 days). Pathologic stage distribution was 54% (176) IA, 22% (72) IB, 13% (41) IIA, 5% (15) IIB, and 6% (21) IIIA. With a median follow-up of 27 months, overall 5-year survival was 80% (95% confidence intervals [CI] = 73-88), and by pathologic stage, 91% (CI = 83-99) for stage IA, 88% (CI = 77-98) for stage IB, and 49% (CI = 24-74) for all patients with stage II disease. Overall 3-year survival for patients with stage IIIA disease was 43% (CI = 16-69). Conclusions: Robotic lobectomy for early-stage NSCLC can be performed with low morbidity and mortality. Long-term stage-specific survival is acceptable and consistent with prior results for VATS and thoracotomy. © 2012 by The American Association for Thoracic Surgery.
Mu L.,Hackensack University Medical Center |
Sobotka S.,Hackensack University Medical Center |
Sobotka S.,Mount Sinai School of Medicine |
Chen J.,Hackensack University Medical Center |
And 8 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013
Parkinson disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor manifestations and CNS pathology. Current drug therapies can often stabilize these cardinal motor symptoms, and attention has shifted to the other motor and nonmotor symptoms of PD that are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug-resistant symptom because it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. We examined the cervical vagal nerve (cranial nerve X), pharyngeal branch of nerve X, and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, that is, from 10 patients with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. Alpha-synuclein aggregates were revealed in nerve X and the pharyngeal branch of nerve X, and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all of the PD patients but in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathologic process of PD. Notably, PD patients who have had dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves than those without dysphagia. These findings indicate that motor involvement of the pharynx in PD is one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients. © 2013 by the American Association of Neuropathologists, Inc.