tbuckley/cabot-search huggingface dataset:
Temporally Tunable, Enzymatically Responsive Delivery of Proangiogenic Peptides from Poly(ethylene glycol) Hydrogels
Authors: Amy H. Van Hove, Erin Antonienko, Kathleen Burke, Edward Brown, Danielle S. W. Benoit
Journal: Advanced Healthcare Materials (2015)

Proangiogenic drugs hold great potential to promote reperfusion of ischemic tissues and in tissue engineering applications, but efficacy is limited by poor targeting and short half‐lives. Methods to control release duration or provide enzymatically responsive drug delivery have independently improved drug efficacy. However, no material has been developed to temporally control the rate of enzymatically responsive drug release. To address this void, hydrogels are developed to provide sustained, tunable release of Qk, a proangiogenic peptide mimic of vascular endothelial growth factor, via tissue‐specific enzymatic activity. After confirmation that sustained delivery of Qk is necessary for proangiogenic effects, a variety of previously identified matrix metalloproteinase (MMP)‐degradable linkers are used to tether Qk to hydrogels. Of these, three (IPES↓LRAG, GPQG↓IWGQ, and VPLS↓LYSG) show MMP‐responsive peptide release. These linkers provide tunable Qk release kinetics, with rates ranging from 1.64 to 19.9 × 10 −3 h −1 in vitro and 4.82 to 8.94 × 10 −3 h −1 in vivo. While Qk is confirmed to be bioactive as released, hydrogels releasing Qk fail to induce significant vascularization in vivo after one week, likely due to the use of nonenzymatically degradable hydrogels. While Qk is the focus of this study, the approach could easily be adapted to control the delivery of a variety of therapeutic molecules.
Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus
Authors: Tom M. McCaughtry, Ruth Etzensperger, Amala Alag, Xuguang Tai, Sema Kurtulus, Jung-Hyun Park, Alex Grinberg, Paul Love, Lionel Feigenbaum, Batu Erman, Alfred Singer
Journal: The Journal of Experimental Medicine (2012)

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γc) genes were deleted in thymocytes just before positive selection. We found that γc expression was required to signal the differentiation of MHC class I (MHC-I)–specific thymocytes into CD8+ cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)–specific thymocytes into CD4+ T cells, even into regulatory Foxp3+CD4+ T cells which require γc signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8+ cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8+ T cells expressing Runx3d could arise without γc signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γc-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I–selected thymocytes into functionally mature T cells.
The Effect of Primary Graft Dysfunction on Survival after Lung Transplantation
Authors: Jason D. Christie, Robert M. Kotloff, Vivek N. Ahya, Gregory Tino, Alberto Pochettino, Christina Gaughan, Ejigayehu DeMissie, Stephen E. Kimmel
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Primary graft dysfunction is a severe acute lung injury syndrome after lung transplantation. Long-term outcomes of subjects with primary graft dysfunction have not been studied.We sought to test the relationship of primary graft dysfunction with both short- and long-term mortality using a large registry.We used data collected on 5,262 patients in the United Network for Organ Sharing/International Society of Heart and Lung Transplantation registry between 1994 and 2000. We assessed outcomes in all subjects; to assess potential bias from the effects of early mortality, we also evaluated subjects who survived at least 1 year, using Cox proportional hazards models with time-varying covariates.The overall incidence of primary graft dysfunction was 10.2% (95% confidence intervals [CI], 9.2, 10.9). The incidence did not vary by year over the period of observation (p = 0.22). All-cause mortality at 30 days was 42.1% for primary graft dysfunction versus 6.1% in patients without graft dysfunction (relative risk = 6.95; 95% CI, 5.98, 8.08; p < 0.001); among subjects who died by 30 days, 43.6% had primary graft dysfunction. Among patients surviving at least 1 year, those who had primary graft dysfunction had significantly worse survival over ensuing years (hazard ratio, 1.35; 95% CI, 1.07, 1.70; p = 0.011). Adjustment for clinical variables including bronchiolitis obliterans syndrome did not change this relationship.Primary graft dysfunction contributes to nearly half of the short-term mortality after lung transplantation. Survivors of primary graft dysfunction have increased risk of death extending beyond the first post-transplant year.
Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial
Authors: Aimée R Kreimer, Paula González, Hormuzd A Katki, Carolina Porras, Mark Schiffman, Ana Cecilia Rodriguez, Diane Solomon, Silvia Jiménez, John T Schiller, Douglas R Lowy, Leen-Jan van Doorn, Linda Struijk, Wim Quint, Sabrina Chen, Sholom Wacholder, Allan Hildesheim, Rolando Herrero
Journal: The Lancet Oncology (2011)
Insulin Pump Risks and Benefits: A Clinical Appraisal of Pump Safety Standards, Adverse Event Reporting, and Research Needs
Authors: Lutz Heinemann, G. Alexander Fleming, John R. Petrie, Reinhard W. Holl, Richard M. Bergenstal, Anne L. Peters
Journal: Diabetes Care (2015)

Insulin pump therapy, also known as continuous subcutaneous insulin infusion (CSII), is an important and evolving form of insulin delivery, which is mainly used for people with type 1 diabetes. However, even with modern insulin pumps, errors of insulin infusion can occur due to pump failure, insulin infusion set (IIS) blockage, infusion site problems, insulin stability issues, user error, or a combination of these. Users are therefore exposed to significant and potentially fatal hazards: interruption of insulin infusion can result in hyperglycemia and ketoacidosis; conversely, delivery of excessive insulin can cause severe hypoglycemia. Nevertheless, the available evidence on the safety and efficacy of CSII remains limited. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have therefore joined forces to review the systems in place for evaluating the safety of pumps from a clinical perspective. We found that useful information held by the manufacturing companies is not currently shared in a sufficiently transparent manner. Public availability of adverse event (AE) reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is potentially a rich source of safety information but is insufficiently utilized due to the current configuration of the system; the comparable database in Europe (European Databank on Medical Devices [EUDAMED]) is not publicly accessible. Many AEs appear to be attributable to human factors and/or user error, but the extent to which manufacturing companies are required by regulators to consider the interactions of users with the technical features of their products is limited. The clinical studies required by regulators prior to marketing are small and over-reliant on bench testing in relation to "predicate" products. Once a pump is available on the market, insufficient data are made publicly available on its long-term use in a real-world setting; such data could provide vital information to help health care teams to educate and support users and thereby prevent AEs. As well as requiring more from the manufacturing companies, we call for public funding of more research addressing clinically important questions in relation to pump therapy: both observational studies and clinical trials. At present, there are significant differences in the regulatory systems between the US and European Union at both pre- and postmarketing stages; improvements in the European system are more urgently required. This statement concludes with a series of recommended specific actions for "meknovigilance" (i.e., a standardized safety approach to technology) that could be implemented to address the shortcomings we highlight.
Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD
Authors: George P. Canellos, James R. Anderson, Kathleen J. Propert, Nis Nissen, M. Robert Cooper, Edward S. Henderson, Mark R. Green, Arlan Gottlieb, Bruce A. Peterson
Journal: New England Journal of Medicine (1992)

MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkin's disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkin's disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen.Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose.In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.
Technique for the management of anterior flail chest.
Authors: N Guernelli, R B Bragaglia, A Briccoli, M Mastrorilli, R Vecchi
Journal: Thorax (1979)

A technique for the management of anterior flail chest consisting of osteosynthesis and the positioning of two long Kirschner wires behind the sternum in the form of a St Andrew's cross is described. The procedure is easy to perform, the patient is ambulant early, and the results are good.
Effect of amiloride and saline on nasal mucociliary clearance and potential difference in cystic fibrosis and normal subjects.
Authors: P G Middleton, D M Geddes, E W Alton
Journal: Thorax (1993)

Mucociliary clearance is an important component of pulmonary defence. Maximum clearance is thought to depend on an optimal depth of the sol layer, allowing the most efficient interaction between the cilia and the overlying mucus layer. Sodium absorption, the major ion transport in human airways, is thought to be important in the regulation of the depth of the sol layer. In the airways of patients with cystic fibrosis sodium absorption is increased and mucociliary clearance decreased. Amiloride, a sodium channel blocker, has been shown to improve pulmonary mucociliary clearance in patients with cystic fibrosis. However, its effects on nasal mucociliary clearance in either normal subjects or those with cystic fibrosis are unknown. A study was therefore performed to investigate whether nebulised amiloride improves nasal mucociliary clearance in normal or cystic fibrosis subjects.Nasal mucociliary clearance was measured by the saccharin clearance technique in 12 normal subjects and 12 with cystic fibrosis. For the control study measurements were made on two consecutive days and the mean time for each subject averaged. For the drug study measurements were also made on two consecutive days, after administration of nasally nebulised amiloride or placebo (saline) in a double blind manner. Nasal potential difference was measured in eight patients with cystic fibrosis after the administration of amiloride or placebo to assess the efficacy of deposition and duration of action.Baseline values of mucociliary clearance were significantly faster in the normal subjects than in those with cystic fibrosis. In both groups mucociliary clearance was increased after both saline and amiloride, with no significant difference between either treatment. As previously reported, baseline nasal potential difference was significantly more negative in the subjects with cystic fibrosis. Amiloride significantly reduced the potential difference for at least 60 minutes in these subjects.Nebulised saline significantly improves nasal mucociliary clearance in both normal subjects and those with cystic fibrosis. Amiloride did not appear to exert any additional effects in either group of subjects, despite evidence of its efficacy of deposition.
Influence of experience on performance of individual surgeons in thyroid surgery: prospective cross sectional multicentre study
Authors: A. Duclos, J.-L. Peix, C. Colin, J.-L. Kraimps, F. Menegaux, F. Pattou, F. Sebag, S. Touzet, S. Bourdy, N. Voirin, J.-C. Lifante
Journal: BMJ (2012)

<b>Objective</b> To determine the association between surgeons’ experience and postoperative complications in thyroid surgery. <b>Design</b> Prospective cross sectional multicentre study. <b>Setting</b> High volume referral centres in five academic hospitals in France. <b>Participants</b> All patients who underwent a thyroidectomy undertaken by every surgeon in these hospitals from 1 April 2008 to 31 December 2009. <b>Main outcome measures</b> Presence of two permanent major complications (recurrent laryngeal nerve palsy or hypoparathyroidism), six months after thyroid surgery. We used mixed effects logistic regression to determine the association between length of experience and postoperative complications. <b>Results</b> 28 surgeons completed 3574 thyroid procedures during a one year period. Overall rates of recurrent laryngeal nerve palsy and hypoparathyroidism were 2.08% (95% confidence interval 1.53% to 2.67%) and 2.69% (2.10% to 3.31%), respectively. In a multivariate analysis, 20 years or more of practice was associated with increased probability of both recurrent laryngeal nerve palsy (odds ratio 3.06 (1.07 to 8.80), P=0.04) and hypoparathyroidism (7.56 (1.79 to 31.99), P=0.01). Surgeons’ performance had a concave association with their length of experience (P=0.036) and age (P=0.035); surgeons aged 35 to 50 years had better outcomes than their younger and older colleagues. <b>Conclusions</b> Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further.
COMPARISON OF THE YIELD OF INFECTIOUS VIRUS FROM CLONES OF HUMAN AND SIMIAN LYMPHOBLASTOID LINES TRANSFORMED BY EPSTEIN-BARR VIRUS
Authors: George Miller, Muriel Lipman
Journal: The Journal of Experimental Medicine (1973)

Three lymphoblastoid cell lines, of human, squirrel monkey, and marmoset origin, all transformed by the same strain of Epstein-Barr virus (EBV), differed markedly in their content of infectious virus. Single cell clones were obtained from each line to learn whether these differences were dependent upon factors shared by all cells in each line or upon factors present only in a proportion of the total cell population. A total of 17 primary clones were examined: 6 human, 6 squirrel monkey, and 5 marmoset. Cloning efficiency on human placental cell feeder layers varied from 16 to 24%. EBV antiserum, present in the cloning suspension, was shown to neutralize all extracellular virus. 15 of the 17 clones released EBV as measured by the transformation assay. Titers of infectious virus released by daughter clones paralleled titers of virus in the parent line. The median virus titers from human, squirrel monkey, and marmoset clones were respectively 10(1.5), 10(3.0), and 10(4.3) 50% transforming doses per 0.2 ml. The median yield of virus from clones of the three species was, respectively, 4, 96, and 786 transforming units per 1,000 cells containing viral capsid antigen. Two nonproducer clones (one human and one squirrel monkey) did not release infectious virus after treatment with 5'-bromodeoxyuridine, or with X ray followed by co-cultivation with marmoset leukocytes. The nonproducer clones could not be superinfected by biologically active EBV. These results show that differences in production of infectious EBV among the lines tested are reflected in the majority of cells of these lines. The data imply that the mechanism for regulation of the expression of the EBV genome is cellular rather than viral in origin. There are presumably genetic differences among primate species in this regulatory process.
The Action of SKF 688A (Phenoxyethyl Derivative of Dibenamine) upon Certain Functions of the Sympathetic Nervous System in Man
Authors: WALTER REDISCH, E. CLINTON TEXTER, ROYAL M. HOWARD, PAUL H. STILLMAN, J. MURRAY STEELE, LEONARD SASLAW
Journal: Circulation (1952)

A Dibenamine analogue was administered orally to five hypertensive and 10 normotensive subjects over periods from 14 to 21 days. Its adrenergic blocking effect was studied by observing blood pressure, pulse rate, skin temperature of the toes and the pupillary mechanism. Nasal congestion, weakness, listlessness, dizziness, drowsiness and palpitation were persistent sequelae of adrenergic blocking. The drug was found valuable for investigation of autonomous nervous system functions and may hold promise as a therapeutic agent for the treatment of arterial insufficiency and some types of hypertensive subjects.
Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells
Authors: Mingmei Liao, Jinfeng Zhao, Ton Wang, Jinghua Duan, Yangde Zhang, Xingming Deng
Journal: Molecular Cancer (2011)

Abstract Background Glycochenodeoxycholate (GCDA) is one of the major human bile salts. Bile salts stimulate cell survival and proliferation through the mitogen-activated protein kinase, but the downstream signaling mechanism(s) remains enigmatic. Mcl-1 is an antiapoptotic molecule of the Bcl2 family that is extensively overexpressed in tumor tissues of patients with hepatocellular carcinoma (HCC). Results Here we found that exposure of HepG2 cells to GCDA results in activation of ERK1 and ERK2 and phosphorylation of Mcl-1 in a PD98059 (MEK inhibitor)-sensitive manner. GCDA stimulates Mcl-1 phosphorylation in cells expressing WT but not T163A Mcl-1 mutant, indicating that GCDA-induced Mcl-1 phosphorylation occurs exclusively at the T163 site in its PEST region. GCDA-induced Mcl-1 phosphorylation at T163 enhances the half-life of Mcl-1. Treatment of HepG2 cells with GCDA facilitates Mcl-1 dissociation from Mule (a physiological Mcl-1 ubiquitin E3 ligase). Specific depletion of Mcl-1 from HepG2 cells by RNA interference increases sensitivity of HepG2 cells to chemotherapeutic drugs ( i.e . cisplatin and irinotecan). In addition to activation of the ERK/Mcl-1 survival pathway, GCDA can also induce dose-dependent apurinic/apyrimidinic (AP) sites of DNA lesions, which may partially neutralize its survival activity. Conclusion Our findings suggest that bile salt may function as a survival agonist and/or potential carcinogen in the development of HCC. Molecular approaches that inactivate Mcl-1 by blocking its T163 phosphorylation may represent new strategies for treatment of HCC.
The pulmonary physician in critical care * 11: Critical care management of respiratory failure resulting from COPD
Authors: A C Davidson
Journal: Thorax (2002)

It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model. Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance. The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients. The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients.