Luo L.G.,Roger Williams Hospital |
Luo J.Z.Q.,Brown Alpert Medical School |
Jackson I.,Roger Williams Hospital
Current Aging Science | Year: 2013
A very small tripeptide amide L-pyroglutamyl-L-histidyl-L-prolineamide (L-PHP, Thyrotropin-Releasing Hormone, TRH), was first identified in the brain hypothalamus area. Further studies found that L-PHP was expressed in pancreas. The biological role of pancreatic L-PHP is still not clear. Growing evidence indicates that L-PHP expression in the pancreas may play a pivotal role for pancreatic development in the early prenatal period. However, the role of L-PHP in adult pancreas still needs to be explored. L-PHP activation of pancreatic β cell Ca2+ flow and stimulation of β-cell insulin synthesis and release suggest that L-PHP involved in glucose metabolism may directly act on the β cell separate from any effects via the central nervous system (CNS). Knockout L-PHP animal models have shown that loss of L-PHP expression causes hyperglycemia, which cannot be reversed by administration of thyroid hormone, suggesting that the absence of L-PHP itself is the cause. L-PHP receptor type-1 has been identified in pancreas which provides a possibility for L-PHP autocrine and paracrine regulation in pancreatic function. During pancreatic damage in adult pancreas, L-PHP may protect beta cell from apoptosis and initiate its regeneration through signal pathways of growth hormone in β cells. L-PHP has recently been discovered to affect a broad array of gene expression in the pancreas including growth factor genes. Signal pathways linked between L-PHP and EGF receptor phosphorylation suggest that L-PHP may be an important factor for adult β - cell regeneration, which could involve adult stem cell differentiation. These effects suggest that L-PHP may benefit pancreatic β cells and diabetic therapy in clinic.© 2013 Bentham Science Publishers.
Bond D.S.,The Miriam Hospital |
Wing R.R.,The Miriam Hospital |
Vithiananthan S.,The Miriam Hospital |
Sax H.C.,Brown University |
And 4 more authors.
Surgery for Obesity and Related Diseases | Year: 2011
Background: We have previously reported that most women seeking bariatric surgery have had female sexual dysfunction (FSD) as defined by the validated Female Sexual Function Index (FSFI). The present study examined whether FSD resolves after bariatric surgery. Methods: A total of 54 reportedly sexually active women (43.3 ± 9.5 years) completed the FSFI preoperatively and 6 months postoperatively after a mean percentage of excess weight loss of 42.3% (laparoscopic adjustable gastric banding [n = 38], percentage of excess weight loss, 34.6% ± 15.7%; Roux-en-Y gastric bypass [n = 16], percentage of excess weight loss 60.0% ± 21.2%). The FSFI assesses sexual function across 6 domains, with higher scores indicating better sexual function. The summing of these scores yields a FSFI total score (range 236, with a score of ≤26.55 indicating FSD). Results: Before surgery, 34 women (63%) had scores indicative of FSD. By 6 months postoperatively, the FSD had resolved in 23 (68%) of these 34 women, and only 1 woman had developed FSD postoperatively. In the entire sample, significant (P < .05) improvements occurred from before to after surgery on all FSFI domains. The FSFI total scores improved after laparoscopic adjustable gastric banding (from 24.2 ± 5.9 to 29.1 ± 4.1, P < .001) and Roux-en-Y gastric bypass (from 23.7 ± 7.7 to 30.0 ± 4.7, P < .001). In regression analyses, being married, younger age, and worse preoperative sexual function were related to greater sexual function improvements. Postoperatively, the participants' FSFI total scores were indistinguishable from those of published normative controls (29.4 ± 4.3 versus 30.5 ± 5.3, P = .18). Conclusion: FSD resolved in a large percentage of women after bariatric surgery. Sexual functioning in the entire sample improved to levels consistent with those of normative controls. This improvement in sexual function did not depend on surgery type or weight loss amount and appears to be an additional benefit for women undergoing bariatric surgery. © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved. All rights reserved.
Bond D.S.,The Miriam Hospital |
Jakicic J.M.,University of Pittsburgh |
Unick J.L.,The Miriam Hospital |
Vithiananthan S.,The Miriam Hospital |
And 5 more authors.
Obesity | Year: 2010
Bariatric surgery patients report significant pre- to postoperative increases in physical activity (PA). However, it is unclear whether objective measures would corroborate these changes. The present study compared self-reported and accelerometer-based estimates of changes in moderate-to-vigorous intensity PA (MVPA) from pre- (pre-op) to 6 months postsurgery (post-op). Twenty bariatric surgery (65% laparoscopic-adjustable gastric banding, 35% gastric bypass) patients (46.2± 9.8 years, 88% female, pre-op BMI = 50.8 9.7kg/m 2) wore RT3 accelerometers as an objective measure of MVPA and completed the Paffenbarger Physical Activity Questionnaire (PPAQ) as a subjective measure before and 6 months after bariatric surgery. Time (min/week) spent in MVPA was calculated for the PPAQ and RT3 (1-min and 10-min bouts) at pre-op and post-op. Self-reported MVPA increased fivefold from pre-op to post-op (44.6 ±80.8 to 212.3± 212.4min/week; P< 0.005). By contrast, the RT3 showed nonsignificant decreases in MVPA for both 1-min (186.0 ±169.0 to 151.2 118.3min/week) and 10-min (41.3 ±109.3 to 39.8 71.3min/week) bouts. At pre-op, the percentage of participants who accumulated 150-min/week of MVPA in bouts 10-min according to the PPAQ and RT3 was identical (10%). However, at post-op, 55% of participants reported compliance with the recommendation compared to 5% based on RT3 measurement (P = 0.002). Objectively-measured changes in MVPA from pre-op to 6 months post-op appear to be much smaller than self-reported changes. Further research involving larger samples is needed to confirm these findings and to determine whether self-report and objective PA measures are differentially associated with surgical weight loss outcomes. © 2010 The Obesity Society.
Gross I.,Eastern Maine Medical Center |
Shander A.,Englewood Hospital and Medical Center |
Shander A.,Mount Sinai School of Medicine |
Sweeney J.,Roger Williams Hospital |
Sweeney J.,Brown University
Best Practice and Research: Clinical Anaesthesiology | Year: 2013
Patient blood management (PBM) seeks to improve the clinical outcomes of patients through the application of evidence-based medical and surgical concepts designed to maintain haemoglobin concentration, optimise haemostasis and minimise blood loss. Hence, assessment of the outcomes of patients is essential in evaluating the success of PBM programmes. Clinical outcomes measure the meaningful impact of interventions on patients in terms of living longer or healthier or experiencing fewer complications. The assessment of these outcomes can often be complicated and laborious and, therefore, alternative approaches are sometimes explored. Use of surrogate endpoints such as transfusion rates or volume and haemoglobin level, and creating composite outcomes (to achieve higher frequency for relatively rare clinical events such as mortality and major morbidity) are among the common strategies but their use and interpretation have limitations and need careful consideration. Creating registries of patients managed under PBM can be an effective and feasible approach to provide safety and effectiveness data on various clinical outcomes. While outcome data on PBM programmes are limited, the emerging studies support that PBM can be effective in reducing transfusion and, more importantly, improving the outcomes of the patients. Continued and further research in this field is imperative. © 2012 Elsevier Ltd. All rights reserved.
Lum L.G.,Barbara Ann Karmanos Cancer Institute |
Thakur A.,Barbara Ann Karmanos Cancer Institute |
Al-Kadhimi Z.,Barbara Ann Karmanos Cancer Institute |
Colvin G.A.,South County Hospital |
And 8 more authors.
Clinical Cancer Research | Year: 2015
Purpose: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). Experimental Design: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 109 armed ATC (aATC) per infusion. Results: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 109 ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 02+ patients. Conclusions: Targeting HER2+ and HER2- tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials. © 2015 American Association for Cancer Research.
Weber L.L.,Roger Williams Hospital |
Roberts L.D.,Rhode Island Hospital |
Sweeney J.D.,Roger Williams Hospital |
Sweeney J.D.,Rhode Island Hospital
Transfusion | Year: 2014
Background Transfusion-related acute lung injury (TRALI) is the most common cause of death from blood transfusion and red blood cells (RBCs) now account for approximately 50% of these fatalities. RBCs from female donors have been implicated in large series and HLA Class II antibodies to cognate recipient antigens identified in small series and case reports. The absolute volume of residual plasma in these RBCs is unknown.Study Design and Methods Two confirmed cases of RBC-associated TRALI in which the implicated donors had Class II antibodies were investigated, and the antibody strength against recipient cognate antigens was assessed using a fluorescent bead assay. RBCs in additive solution (AS) were studied on Day 42 of liquid storage to calculate residual anticoagulated plasma.Results Both RBC units were stored in AS-1 and were from female donors who had anti-HLA Class II antibodies of high strength against cognate antigens in the recipients. Anti-DR4 was identified in both cases. Nineteen AS-1 RBC units manufactured from whole blood donations using a hard spin had a mean (±1SD) residual plasma content of 38 ± 8 mL, and 26 AS-3 RBC units manufactured using a soft spin had 66 ± 13 mL (p < 0.01).Conclusion RBCs continue to be manufactured from female donors of unknown or even known anti-HLA status. The residual plasma content of these RBCs may approach 100 mL. A combination of a high-strength antibody and large residual plasma volume could explain severe or even fatal RBC-associated TRALI. © 2014 AABB.
Tavares M.M.,Roger Williams Hospital |
Diquattro P.J.,Roger Williams Hospital |
Sweeney J.D.,Roger Williams Hospital
Transfusion | Year: 2014
Background Data on red blood cell (RBC) transfusion in the United States show variation in practice and overprescribing or overdosing is considered to be prevalent. Education or restrictive interventions could modify practice.Study Design and Methods RBC transfusion and mortality rates were recorded in a single institution over a 15-year period. The first 3 years were used as a baseline. Education measures were used to influence practice for 3 years followed by a 9-year period when questionable RBC orders in nonbleeding inpatients resulted in prospective physician notification for potential modification. Physician notification was done by blood bank technologists with transfusion medicine physician support, if needed. Pretransfusion hemoglobin levels of more than 9 g/dL were recommended for cancellation and levels between 8 and 9 g/dL advised for a single unit, if 2 or more units were requested. RBC transfusion rates were described as inpatient units per 1000 discharges to allow for interyear comparison.Results A downward trend in RBC transfusion was noted for the intervention period. Comparison of the baseline period with the past 3 years of the intervention period showed an approximate 33% decrease, which was highly significant (508 ± 66 vs. 341 ± 32, p < 0.01). Inpatient mortality rates declined over this period.Conclusion Physician education in appropriate transfusion practice is desirable but may not greatly impact RBC use. Engagement of physicians who prescribe RBCs that appear inappropriate for indication or dose was associated with a significant decline in RBC use without evidence of a change in mortality. © 2014 AABB.
Meehan R.,Roger Williams Hospital |
Tavares M.,Roger Williams Hospital |
Sweeney J.,Roger Williams Hospital
Transfusion | Year: 2013
Background: Reversal of warfarin with plasma accounts for a large amount of fresh-frozen plasma transfused in the United States. The use of vitamin K is an alternate strategy. Study Desing and Methods: Records of vitamin K prescriptions for warfarin reversal were examined and recipients identified where data were available on dosage, route of administration (oral [PO] and intravenous [IV]) and the availability of both pre- and postadministration international normalized ratio(s) (INRs). Results: A total of 135 administration events were evaluated: 81 PO and 54 IV. The median (range) preadministration INRs were 5.8 (1.9-16.5) versus 5.0 (1.4-16.5; p = 0.61) and the median (range) for the postadministration INRs were 2.4 (1.0-10.4) and 2.1 (1.2-8.2; p < 0.01) for the PO and IV routes, respectively. The median (range) doses were 2.5 (1-10) and 2.0 (1-10) mg for PO and IV, respectively (p < 0.01). A total of 44% of the IV vitamin K group achieved an INR of 2 or less within 12 hours versus 14% for the PO route (p < 0.01). In multilinear regression the preadministration INR (r = 0.14, p < 0.01) and time after administration (r = -0.05, p < 0.01) were independent variables influencing the postadministration INR but the dose administered (r = 0.09, p = 0.07) was not. Conclusion: Vitamin K needs to be given IV if urgent partial correction (<12 hr) of warfarin is required. No influence of dose administered in the range 1 to 10 mg on the postadministration INR was observed. © 2012 American Association of Blood Banks.
Roger Williams Hospital | Date: 2015-12-04
The present invention relates to compositions and methods for creation of vector nucleic acid sequences (e.g., retroviral nucleic acid sequences) that comprise two or more exogenous nucleic acid sequences that encode highly homologous (e.g., identical) polypeptide sequences, yet wherein at least one of the exogenous nucleic acid sequences has been mutated using degenerate codons for purpose of reducing homology between the two or more exogenous nucleic acid sequences while maintaining the encoded polypeptide sequence. Preferred nucleic acid sequences include those encoding multi-chimeric immune receptor (CIR) genes. Specific nucleic acid sequences of such CIR genes are also disclosed.
Roger Williams Hospital | Date: 2015-12-01
Described are compositions and methods relating to immune cells which express both a chimeric antigen receptor which binds to the IL13 receptor -2 (IL13R2) and a O^(6)-methylguanine DNA methyltransferase (MGMT) protein. Viral particles containing an IL13 chimeric antigen receptor (IL13CAR) or variant thereof and an MGMT protein or variant thereof are used to transfect immune cells such as T cells, imparting to the transfected cells both IL13R2-targeting activity and resistance to the chemotherapeutic agent temozolomide (TMZ). The compositions and methods described are useful for cancer therapy such as the treatment of a high-grade malignant glioma.