tbuckley/cabot-search huggingface dataset:
Functional consequences of detubulation of isolated rat ventricular myocytes
Authors: M FOWLER
Journal: Cardiovascular Research (2004)

Objective: Recent work has suggested that Na+/Ca2+ exchange (NCX) and L-type Ca2+ current (ICa) are located predominantly in the t-tubules of cardiac ventricular myocytes, which therefore represent a microdomain for the regulation of intracellular Na+ (Nai) and Ca2+ (Cai). The aim of this study was to investigate the role of the t-tubules in the response of Cai and contraction to interventions that alter the transsarcolemmal Na+gradient. Methods: Enzymatically isolated and detubulated Wistar rat ventricular myocytes were investigated using fluorescence microscopy and optical detection of cell length. Results: In unstimulated cells, spontaneous contractile activity increased when extracellular [Na+] was decreased or strophanthidin (100 μM) was added to the bathing solution, but the increase was significantly smaller in detubulated cells than in control cells. In electrically stimulated cells, strophanthidin increased Nai to a similar extent in normal and detubulated cells, although the associated increase in Ca2+ transient amplitude and contraction were significantly smaller in detubulated cells. Similarly, tetrodotoxin (TTX, 10 μM) attenuated the Ca2+ transient and contraction less in detubulated than in control cells. Increasing stimulation rate (0.05–1 Hz) caused little change or a small increase in contraction amplitude in control cells, but a significant decrease in contraction amplitude in detubulated cells, although the change of Nai caused by increasing stimulation rate from 0 to 1 Hz was not significantly different in the two cells types. Conclusion: It is concluded that although some Na/K ATPase, NCX and Na+channel activity is present on the surface membrane, the t-tubules play a major role in the modulation of contraction via NCX, allowing changes of the transsarcolemmal Na+gradient to be translated into changes of Cai.
Inhibition of <b> <i>MUC4</i> </b> Expression Suppresses Pancreatic Tumor Cell Growth and Metastasis
Authors: Ajay P. Singh, Nicolas Moniaux, Subhash C. Chauhan, Jane L. Meza, Surinder K. Batra
Journal: Cancer Research (2004)

Abstract The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.
Recommendations for Benchmarking Preclinical Studies of Nanomedicines
Authors: Charlene M. Dawidczyk, Luisa M. Russell, Peter C. Searson
Journal: Cancer Research (2015)

Abstract Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. Cancer Res; 75(19); 4016–20. ©2015 AACR.
Biweekly Chemotherapy With Oxaliplatin, Irinotecan, Infusional Fluorouracil, and Leucovorin: A Pilot Study in Patients With Metastatic Colorectal Cancer
Authors: Alfredo Falcone, Gianluca Masi, Giacomo Allegrini, Romano Danesi, Elisabetta Pfanner, Isa Maura Brunetti, Antonello Di Paolo, Samanta Cupini, Mario Del Tacca, Pierfranco Conte
Journal: Journal of Clinical Oncology (2002)

To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients.Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses.Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively.This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.
Treatment of rat gliosarcoma brain tumors by HSV-based multigene therapy combined with radiosurgery
Authors: Ajay Niranjan, Darren Wolfe, Masakazu Tamura, M Karina Soares, David M Krisky, L Dade Lunsford, Songhui Li, Wendy Fellows-Mayle, Neal A DeLuca, Justus B Cohen, Joseph C Glorioso
Journal: Molecular Therapy (2003)

Our laboratory has employed replication-defective herpes simplex virus type 1 gene transfer vectors for treatment of animal models of human malignant glioblastoma. The base vectors were defective for the immediate early (IE) genes ICP4, ICP27, and ICP22 but expressed the IE gene ICP0, which can arrest tumor cell division, and an IE thymidine kinase (α-tk) gene construct that mediates suicide gene therapy (SGT) in the presence of ganciclovir (GCV). Previously, we reported that SGT using ICP0/α-tk vectors in nude mouse models of glioblastoma was improved by coexpression of the gap-junction-forming protein connexin43 (Cx43) or human tumor necrosis factor α (TNFα). We also showed that further gains in therapeutic outcome could be achieved by combining TNFα-enhanced SGT with gamma-knife radiosurgery (GKR). To expand these observations, we have first repeated these studies in immunocompetent rats with brain tumors derived from implanted 9L gliosarcoma cells and second compared the most efficient vector from this study with a new recombinant vector, NUREL-C2, which expressed both TNFα and Cx43 along with ICP0 and α-tk. Results from the first part indicated that our ICP0/α-tk/TNFα vector in combination with GKR provides an effective therapy although this treatment was not statistically better than GKR combined with the ICP0/α-tk/Cx43 vector. Our observations in the second part suggested that NUREL-C2 may be more effective than the ICP0/α-tk/TNFα vector in combination treatments with GCV (P = 0.08) or GCV plus GKR (P = 0.10). GKR significantly enhanced the efficacy of NUREL-C2/GCV treatment (P = 0.02) as well as other virus/GCV treatments (P ≤ 0.05). Conversely, the efficacy of GKR was significantly improved by both the ICP0/α-tk/TNFα vector and NUREL-C2 in combination with GCV (P = 0.02 and P < 0.01, respectively). Together these results indicate that NUREL-C2 may be an attractive candidate for Phase I gene-therapy safety studies in patients with recurrent malignant glioblastoma.
Therapeutic Angiogenesis for Treating Cardiovascular Diseases
Authors: Lorenzo Deveza, Jeffrey Choi, Fan Yang
Journal: Theranostics (2012)

Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed.
Unpredictable results of laser assisted uvulopalatoplasty in the treatment of obstructive sleep apnoea
Authors: C F Ryan
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Laser assisted uvulopalatoplasty (LAUP) is increasingly offered for the treatment of obstructive sleep apnoea (OSA), although there is a lack of objective data to support its indications and efficacy. A study was undertaken to determine the treatment response to LAUP. <h3>METHODS</h3> Overnight polysomnography was performed before and at least three months after surgery in 44 consecutive patients with symptomatic mild to moderate OSA (apnoea + hypopnoea index (AHI) &gt;10/h). Pharyngeal dimensions were measured by videoendoscopy (n = 11) and disease-specific quality of life, sleepiness and snoring frequency (n = 16) before and after surgery were determined in subgroups of patients. LAUP was performed under local anaesthesia as a one stage resection of the uvula and soft palate by one of two experienced otolaryngologists. <h3>RESULTS</h3> Twelve patients (27%) had a good response (AHI ⩽10/h after LAUP); four (9%) had a partial response (AHI ⩽50% of pre-LAUP value); 15 (34%) had a poor response (AHI &gt;50% of pre-LAUP value); and 13 (30%) patients were worse (AHI &gt;100% of pre-LAUP value). The velopharyngeal cross sectional area and anteroposterior diameter increased following LAUP (p&lt;0.05). Quality of life indices improved significantly in all domains and sleepiness decreased. The snoring index did not decrease significantly. No preoperative anthropometric or videoendoscopic measures were predictive of a good response to LAUP. Patients who were worse after LAUP had milder baseline apnoea severity than those in the other response groups. <h3>CONCLUSIONS</h3> The treatment response to LAUP is variable and unpredictable, and only a few patients achieve a satisfactory response. There appears to be no relationship between subjective and objective measures of treatment efficacy.
Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage.
Authors: T Sacks, C F Moldow, P R Craddock, T K Bowers, H S Jacob
Journal: Journal of Clinical Investigation (1978)

During hemodialysis, alternative pathway complement activation leads to pulmonary sequestration of granulocytes, with loss of pulmonary vascular endothelial integrity and, at times, protein-rich pulmonary edema. An in vitro model of this phenomenon was constructed utilizing 51Cr-labeled human umbilical vein endothelial cell cultures. In this system, granulocytes, when exposed to activated complement (C), induce endothelial damage; this injury is mediated primarily by oxygen radicals produced by the granulocytes. C5a appears to be the C component responsible for granulocyte-induced cytotoxicity; studies with cytochalasin B-treated granulocytes suggest that close approximation of the granulocytes and endothelial cells is necessary for maximal cell injury.
Association of Electron-Dense Particles With Human Acute Leukemia
Authors: George H. Porter, Albert J. Dalton, John B. Moloney, Elisabeth Z. Mitchell
Journal: JNCI Journal of the National Cancer Institute (1964)

Electron-dense particles, bearing some morphologic similarities to viruses described in the avian and murine leukemias, have been identified by electron microscopy in peripheral blood from 8 of 56 patients with acute leukemia, from none of 51 random normal controls, and from 1 of 36 age- and sex-matched normal controls. The particles are spherical bodies with 1 or 2 concentric membranes and often a centrally located nucleoid. Their diameter is 800 to 900 A. When material was available, negative staining with phosphotungstic acid revealed a tail-like protrusion extending from an angular head. As the viral nature of these particles remains unproved and their relationship to the etiology of acute human leukemia is not established, the present significance of this observation must be limited to its use as one criterion for the selection of human leukemic materials to undergo biological testing.
Racial Differences in Waiting List Outcomes in Chronic Obstructive Pulmonary Disease
Authors: David J. Lederer, Emma K. T. Benn, R. Graham Barr, Jessie S. Wilt, Genevieve Reilly, Joshua R. Sonett, Selim M. Arcasoy, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Blacks with chronic illness have poorer outcomes than whites in the United States. The health outcomes of minorities with chronic obstructive pulmonary disease (COPD) on the lung transplant waiting list have not been studied.Objectives: To compare outcomes of black and white patients with COPD after listing for lung transplantation in the United States.Methods: Retrospective cohort study of all 280 non-Hispanic black and 5,272 non-Hispanic white adults 40 years and older with COPD listed for lung transplantation in the United States between 1995 and 2004.Measurements and Main Results: Blacks with COPD were more likely to have pulmonary hypertension, obesity, and diabetes; to lack private health insurance; and to live in poorer neighborhoods than whites. Blacks were less likely to undergo transplantation after listing compared with whites, despite adjustment for age, lung function, pulmonary hypertension, cardiovascular risk factors, insurance coverage, and poverty level (adjusted hazard ratio, 0.83; 95% confidence interval, 0.70–0.98; P = 0.03). This was accompanied by a greater risk of dying or being removed from the list among blacks (unadjusted hazard ratio, 1.31; 95% confidence interval, 1.05–1.63; P = 0.02).Conclusions: After listing for lung transplantation, black patients with COPD were less likely to undergo transplantation and more likely to die or be removed from the list compared with white patients. Unequal access to care may have contributed to these differences.
Prostaglandins Maintain Renal Vasodilation and Hyperfiltration During Chronic Nitric Oxide Synthase Blockade in Conscious Pregnant Rats
Authors: L.A. Danielson, K.P. Conrad
Journal: Circulation Research (1996)

Rats demonstrate renal vasodilation and hyperfiltration in pregnancy. Because both NO and cGMP biosynthesis are increased in gravid rats and because acute administration of NO synthase inhibitors abrogates renal vasodilation and hyperfiltration, NO most likely mediates the renal circulatory changes of gestation. In the present study, we tested the effect of chronic inhibition of NO synthase on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in chronically instrumented, conscious, gravid rats. Because gestation is a relatively long-term condition, we postulated that chronic withdrawal of NO would result in sustained inhibition of renal vasodilation and hyperfiltration. Contrary to our hypothesis, the renal circulatory changes of pregnancy were maintained during chronic blockade of NO synthase. That is, subcutaneous administration of 10 μg/min N ω-nitro- l -arginine methyl ester (NAME) for 48 hours did not significantly reduce GFR in either virgin or pregnant rats; thus, hyperfiltration persisted in the latter despite chronic NO synthase blockade. In contrast, ERPF was reduced and effective renal vascular resistance (ERVR) increased in both groups of rats during NAME administration but in a parallel fashion, such that renal vasodilation persisted in the gravid animals despite chronic inhibition of NO synthase. However, with superimposition of acute prostaglandin synthesis inhibition (meclofenamate, 10 mg/kg IV), renal vasodilation and hyperfiltration were abolished; ie, the combined treatments of chronic NO synthase blockade and acute prostaglandin synthesis inhibition led to the equalization of GFR, ERPF, and ERVR in conscious virgin and pregnant rats. Inhibition of prostaglandin synthesis alone had little affect on the renal circulation, as previously reported. In summary, prostaglandins are recruited to maintain renal vasodilation and hyperfiltration during chronic NO synthase blockade in conscious pregnant rats.
Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study
Authors: Ludwig Kappos, Mark S Freedman, Chris H Polman, Gilles Edan, Hans-Peter Hartung, David H Miller, Xavier Montalbán, Frederik Barkhof, Ernst-Wilhelm Radü, Lars Bauer, Susanne Dahms, Vivian Lanius, Christoph Pohl, Rupert Sandbrink
Journal: The Lancet (2007)
In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit
Authors: Amie S. Corbin, Shadmehr Demehri, Ian J. Griswold, Yihan Wang, Chester A. Metcalf, Raji Sundaramoorthi, William C. Shakespeare, Joseph Snodgrass, Scott Wardwell, David Dalgarno, John Iuliucci, Tomi K. Sawyer, Michael C. Heinrich, Brian J. Druker, Michael W. N. Deininger
Journal: Blood (2005)
Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates
Authors: Jerel K. Mueller, Erinn M. Grigsby, Vincent Prevosto, Frank W. Petraglia, Hrishikesh Rao, Zhi De Deng, Angel V. Peterchev, Marc A. Sommer, Tobias Egner, Michael L. Platt, Warren M. Grill
Journal: Nature Neuroscience (2014)
Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas
Authors: Sibille Everhard, Jörg Tost, Hafida El Abdalaoui, Emmanuelle Crinière, Florence Busato, Yannick Marie, Ivo G. Gut, Marc Sanson, Karima Mokhtari, Florence Laigle-Donadey, Khê Hoang-Xuan, Jean-Yves Delattre, Joëlle Thillet
Journal: Neuro-Oncology (2009)

The O(6)-methylguanine-DNA methyltransferase gene (MGMT) is methylated in several cancers, including gliomas. However, the functional role of cysteine-phosphate-guanine (CpG) island (CGI) methylation in MGMT silencing is still controversial. The aim of this study was to investigate whether MGMT CGI methylation correlates inversely with RNA expression of MGMT in glioblastomas and to determine the CpG region whose methylation best reflects the level of expression. The methylation level of CpG sites that are potentially related to expression was investigated in 54 glioblastomas by pyrosequencing, a highly quantitative method, and analyzed with respect to their MGMT mRNA expression status. Three groups of patients were identified according to the methylation pattern of all 52 analyzed CpG sites. Overall, an 85% rate of concordance was observed between methylation and expression (p < 0.0001). When analyzing each CpG separately, six CpG sites were highly correlated with expression (p < 0.0001), and two CpG regions could be used as surrogate markers for RNA expression in 81.5% of the patients. This study indicates that there is good statistical agreement between MGMT methylation and expression, and that some CpG regions better reflect MGMT expression than do others. However, if transcriptional repression is the key mechanism in explaining the higher chemosensitivity of MGMT-methylated tumors, a substantial rate of discordance should lead clinicians to be cautious when deciding on a therapeutic strategy based on MGMT methylation status alone.
Syphilis Then and Now
Authors: F. William Marlow
Journal: JAMA (1974)

THE conclusion of 40 years as chief of the Syphilis Clinic at the Peter Bent Brigham Hospital in Boston seems to justify a brief note on the changes in treatment as well as the change in the type of disease seen in this statesupported clinic. Also, a major alteration in the epidemiological viewpoint has developed during these years. Actually, with the addition of Peter Bent Brigham Hospital internship five years earlier and the intensive introduction to syphilography under Dr. Allan K. Poole while I was a resident in the New Haven Hospital, my experience really covers almost every form of therapy since the Middle Ages—from mercury and potassium iodide to oral antibiotics. Originally,<i>arsphenamine</i>was given by intravenous drip, each treatment requiring nearly an hour, with the intravenous courses alternated with<i>mercury</i>rubs, or by intramuscularly given<i>mercuric succinamide</i>. Mercury rubs were hated by the patients because of the inevitable