tbuckley/cabot-search huggingface dataset:
Lesion-to-lesion independence of restenosis after treatment by conventional angioplasty, stenting, or directional atherectomy. Validation of lesion-based restenosis analysis.
Authors: C M Gibson, R E Kuntz, M Nobuyoshi, B Rosner, D S Baim
Journal: Circulation (1993)

Since many restenosis trials include patients in whom more than one lesion is treated, analysis of the angiographic data on a "per lesion" basis might be confounded by potential correlations of restenosis among multiple treated lesions within each patient. The goals of this study were: 1) to determine whether there was any correlation in the rate of restenosis among multiple lesions that underwent conventional angioplasty, stenting, or directional atherectomy within the same patient and 2) to determine whether lesions treated in a multilesion intervention experience a different magnitude of restenosis than lesions undergoing single-lesion procedures.Of 441 patients treated by Palmaz-Schatz stenting (n = 114), directional atherectomy (n = 100), or conventional balloon angioplasty (n = 227), 67 underwent multilesion procedures involving treatment of 146 lesions. A general linear model with intraclass correlation (GLIMIC) was used to calculate the coefficient of correlation (rho) of the change in the measured minimum luminal diameter (late loss) from the time of the initial procedure to 6-month angiogram among the multiple lesions within the same patient for all 441 patients. This showed no correlation among multiple lesions within the same patient for the late loss in minimum luminal diameter (rho = -0.12 [95% CI: -0.40, 0.12]), among lesions in the same vessel (rho = 0.14 [95% CI: -0.34, 0.62]), or among different vessels (rho = -0.18 [95% CI: -0.52, 0.16]), suggesting that the magnitude of late loss is independent among multiple lesions within the same patient. There was no difference (p = 0.96) between the observed incidence of zero-, one-, and two-vessel restenosis (> or = 50% diameter stenosis at follow-up) for patients with multiple-lesion treatment and that predicted assuming lesion-to-lesion independence. Similarly, there was no difference in late loss or in the overall binary restenosis rate when single-lesion procedures were compared with multilesion procedures. Multivariable analysis of the late loss in lumen diameter (which adjusted for the effects of the acute result and the device used) demonstrated no independent effect (p = 0.20) of single-lesion versus multilesion status.Luminal encroachment appears to occur at independent rates among multiple lesions treated in a single patient. The observed incidence of restenosis for patients with multiple treated lesions is accurately predicted assuming independent probabilities of restenosis. Lesion-based analysis, even when including multiple treated lesions within the same patient, is thus valid for evaluating conventional angioplasty, stenting, or directional atherectomy.
Significance of an Atrial Gallop Sound in Mitral Regurgitation
Authors: LAWRENCE S. COHEN, DEAN T. MASON, EUGENE BRAUNWALD
Journal: Circulation (1967)

The incidence of atrial gallop sounds was studied in 51 patients with pure mitral regurgitation of sufficient severity to require operative treatment. Seventeen patients were in sinus rhythm. Nine of them had atrial gallop sounds and mitral regurgitation secondary to ruptured chordae tendineae, while six without atrial gallop sounds had primary valvular disease. The degrees of disability or the hemodynamic findings did not differ among the patients with ruptured chordae tendineae and those with primary valvular disease and sinus rhythm. However, the duration of symptoms and the history of a heart murmur were much shorter and the left atrium tended to be smaller in patients with ruptured chordae tendineae than in those with primary valvular disease. Sinus rhythm in a symptomatic patient with severe mitral regurgitation, therefore, should suggest the diagnosis of ruptured chordae tendineae. If, in addition, an atrial gallop sound is found the diagnosis of ruptured chordae tendineae is even more likely.
Chemical risks associated with consumption of shellfish harvested on the north shore of the St. Lawrence River's lower estuary.
Authors: Fabien Gagnon, Thierry Tremblay, Justine Rouette, Jacques-François Cartier
Journal: Environmental Health Perspectives (2004)

Shellfish have the capacity to accumulate chemical contaminants found in their biotope and therefore present a potential risk for consumers. This study was conducted to assess the chemical risks associated with consumption of shellfish harvested on the north shore of the St. Lawrence River's lower estuary. A survey was carried out on 162 recreational harvesters, and shellfish were sampled for chemical contaminant analysis. We quantified 10 metals, 22 polycyclic aromatic hydrocarbons (PAHs), 14 polychlorinated biphenyls (PCBs), and 10 chlorinated pesticides. We subsequently evaluated cancer and noncancer risks for four consumption scenarios based on our survey results and published results. Soft-shell clams (Mya arenaria) were by far the most consumed shellfish species. Of the 56 selected contaminants, 36 were detected in the 23 homogenates of soft-shell clam meat. None of the contaminants found in the soft-shell clams were associated with intakes that exceed the main exposure limit recommendations proposed to prevent noncancer effects. However, several limits must be considered before drawing conclusions about the relative safety of shellfish consumption regarding this end point. Furthermore, inorganic arsenic and PCBs were present in sufficient concentrations to lead to cancer risks exceeding the level often considered acceptable for environmental exposure (1 x 10 (-4) to 1 x 10(-6)) in each of the four scenarios, even for the lowest observed scenario of 15 meals of soft-shell clams per year.
The statistics of targets
Authors: L Elli
Journal: Gut (2006)

a survival advantage from 5-FU chemotherapy or have extremely good survival when treated with 5-FU. 9-11There are several possible reasons for these discordances, including the methods used to evaluate MSI status and the small sample size and short follow up time of most studies.The Jover et al study examined only 19 MSI+ patients with a median follow up time of just two years.Another potentially important issue that has been widely overlooked is the fact that MSI+ tumours show different molecular profiles according to patient age and genetic background.For example, both BRAF mutation and tumour suppressor gene methylation are rare in MSI+ tumours from young patients and HNPCC patients, but frequent in sporadic MSI+ tumours from older patients. 12 13This observation may not be relevant if the MSI+ phenotype itself is directly involved in the response to 5-FU.However, it becomes a critical issue if BRAF mutations, DNA methylation, or other related phenotypic features are more important for 5-FU response than MSI.Evidence that DNA methylation is a predictive marker for good survival benefit in 5-FU treated colorectal cancer patients has already been published. 14 15 It is therefore reasonable to hypothesise that non-methylated MSI+ tumours from younger or HNPCC patients do not respond to 5-FU whereas the heavily methylated MSI+ tumours typically seen in older sporadic patients do respond.In support of this, the only study on the predictive value of MSI+ carried out exclusively on HNPCC patients found no survival benefit from the use of 5-FU. 16None of the other published studies on the predictive significance of MSI has taken into account the molecular heterogeneity of this phenotype in relation to patient age and genetic background (HNPCC or sporadic), particularly with respect to DNA methylation.Until this issue is addressed, we believe it is premature and potentially irresponsible to herald the arrival of MSI+ as a predictive marker to guide the use of 5-FU in colorectal cancer.
JAM-A regulates permeability and inflammation in the intestine in vivo
Authors: Mike G. Laukoetter, Porfirio Nava, Winston Y. Lee, Eric A. Severson, Christopher T. Capaldo, Brian A. Babbin, Ifor R. Williams, Michael Koval, Eric Peatman, Jacquelyn A. Campbell, Terence S. Dermody, Asma Nusrat, Charles A. Parkos
Journal: The Journal of Experimental Medicine (2007)

Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A–deficient (JAM-A−/−) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A−/− mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A−/− mice. The in vivo observations were epithelial specific, because monolayers of JAM-A−/− epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A−/− mice and in JAM-A small interfering RNA–treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A−/− mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A−/− animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.
Sigma Receptors and Cancer
Authors: Ebru Aydar, Christopher P. Palmer, Mustafa B. A. Djamgoz
Journal: Cancer Research (2004)

Abstract The sigma (σ) receptor and its agonists have been implicated in a myriad of cellular functions, biological processes and diseases. Whereas the precise molecular mechanism(s) of σ receptors and their involvement in cancer cell biology have not been elucidated, recent work has started to shed some light on these issues. A molecular model has been proposed for the cloned σ1 receptor; the precise molecular nature of the σ2 receptor remains unknown. σ receptors have been found to be frequently up-regulated in human cancer cells and tissues. σ2 receptor drugs particularly have been shown to have antiproliferative effects. An interesting possibility is that σ and/or σ1 drugs could produce anticancerous effects by modulating ion channels. As well as proliferation, a variety of other metastatic cellular behaviors such as adhesion, motility, and secretion may also be affected. Other mechanisms of σ receptor action may involve interaction with ankyrin and modulation of intracellular Ca2+ and sphingolipid levels. Although more research is needed to further define the molecular physiology of σ receptors, their involvement in the cellular pathophysiology of cancer raises the possibility that σ drugs could be useful as novel therapeutic agents.
Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study
Authors: Aki Morikawa, David M. Peereboom, Helen R. Thorsheim, Ramakrishna Samala, Rajiv Balyan, Conleth G. Murphy, Paul R. Lockman, Ahkeem Simmons, Robert J. Weil, Viviane Tabar, Patricia S. Steeg, Quentin R. Smith, Andrew D. Seidman
Journal: Neuro-Oncology (2014)

Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood–tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m2) 2–3 h before surgery or 2–5 doses of lapatinib (1250 mg) daily, the last dose 2–3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19–9.8) was noted for lapatinib BCBM-to-serum ratio. This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.
Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors
Authors: Marlene L. Hauck, Susan M. LaRue, William P. Petros, Jean M. Poulson, Daohai Yu, Ivan Spasojevic, Amy F. Pruitt, Allison Klein, Beth Case, Donald E. Thrall, David Needham, Mark W. Dewhirst
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received ≥2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 ± 6.17 ng/mg tissue. Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.
Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes
Authors: Rury R. Holman, Sanjoy K. Paul, M. Angelyn Bethel, H. Andrew W. Neil, David R. Matthews
Journal: New England Journal of Medicine (2008)

Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained.Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories.Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02).The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.)
Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial
Authors: Werner H Poewe, Olivier Rascol, Niall Quinn, Eduardo Tolosa, Wolfgang H Oertel, Emilia Martignoni, Markus Rupp, Babak Boroojerdi
Journal: The Lancet Neurology (2007)
Elevated Levels of cAMP Inhibit Protein Kinase C– Independent Mechanisms of Endothelial Platelet-Derived Growth Factor–B Chain and Intercellular Adhesion Molecule-1 Gene Induction by Lysophosphatidylcholine
Authors: Hiroshi Ochi, Noriaki Kume, Eiichiro Nishi, Toru Kita
Journal: Circulation Research (1995)

Lysophosphatidylcholine (lyso-PC), a polar phospholipid product increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to differentially induce functional intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 and mRNA for platelet-derived growth factor (PDGF)-A and -B chains and heparin-binding epidermal growth factor-like growth factor in various cultured endothelial cells. In this study, we have demonstrated increased expression of cell- and matrix-associated forms of PDGF-B chain (PDGF-B) protein elicited by lyso-PC and further characterized potential signal transduction mechanisms responsible for lyso-PC-induced gene expression, focusing on PDGF-B and ICAM-1 genes in cultured human umbilical vein endothelial cell models. Cycloheximide almost completely inhibited PDGF-B but not ICAM-1 mRNA induction elicited by lyso-PC, suggesting that dependence on de novo protein synthesis for PDGF-B is different from that for ICAM-1. Prolonged exposure to phorbol myristate acetate (PMA), which depletes protein kinase C (PKC), or staurosporine, a PKC inhibitor, did not block lyso-PC-induced increases in PDGF-B or ICAM-1 mRNA. Forskolin and dibutyryl cAMP, which elevate intracellular cAMP levels, blocked both PDGF-B and ICAM-1 upregulation elicited by lyso-PC; however, these cAMP-elevating agents did not suppress ICAM-1 upregulation by PMA. Taken together, PDGF-B and ICAM-1 gene induction by lyso-PC may involve different signaling mechanisms; however, both appear to be independent of PMA-regulatable PKC activation but are suppressed by increased levels of intracellular cAMP.
Alteration of amino acid 101 within capsid protein VP-1 changes the pathogenicity of Theiler's murine encephalomyelitis virus.
Authors: A Zurbriggen, J M Hogle, R S Fujinami
Journal: The Journal of Experimental Medicine (1989)

Chronic Theiler's murine encephalomyelitis virus infection of susceptible mice is an animal model for human demyelinating diseases. Previously we described an altered and diminished pattern of central nervous system disease in immunocompetent SJL/J mice infected with a variant virus. This variant virus H7A6-2 was selected with a neutralizing mAb recognizing the capsid protein VP-1 of Theiler's virus. Here we characterize the variant virus by ELISA and neutralization assays and by sequencing selected regions of the viral RNA genome and relate the alteration to disease. The variant virus contains one single point mutation within a neutralizing epitope of VP-1. This nucleotide change lead to an amino acid replacement at amino acid 101 of VP-1, a threonine (wild type) to an isoleucine (variant). Model building based on sequence alignments and the known structure of the related Mengo virus indicates that the altered amino acid is located in an exposed loop on the surface of the virus at the periphery of a site that has been proposed to be the receptor binding site. The results of ELISA, neutralization assay, and direct RNA sequencing provide for the first time an opportunity to precisely map an important structural determinant of neurovirulence.
Communicating Quality of Life Information to Cancer Patients: A Study of Six Presentation Formats
Authors: M. Brundage, D. Feldman-Stewart, A. Leis, A. Bezjak, L. Degner, K. Velji, L. Zetes-Zanatta, D. Tu, P. Ritvo, J. Pater
Journal: Journal of Clinical Oncology (2005)

To determine which formats for presenting health-related quality of life (HRQL) data are interpreted most accurately and are most preferred by cancer patients. Patients often want a great deal of information about cancer treatments, including information relevant to HRQL. Clinical trials provide methodologically sound HRQL data that may be useful to patients.In a multicenter study, 198 patients with previously treated cancer participated in a structured interview. Participants judged HRQL information presented in one textual and five graphical formats. Outcome measures included the accuracy of patients' interpretations and ease-of-use and helpfulness ratings for each format.Correct interpretations ranged from 85% to 98% across formats (F = 10.3, P < .0001) with line graphs of mean HRQL scores over time being interpreted correctly most often. Older patients and less-educated patients were less likely to interpret graphs accurately (F = 7.3, P = .008; and F = 10.6, P = .001, respectively), but all groups were most accurate on simple line graphs. Multivariate analysis revealed that format type, participant age and education were independent predictors of accuracy rates. Patients' ratings also varied across formats both for ease of understanding scores (F = 12.1, P < .0001) and for helpfulness scores (F = 13.2, P < .0001), with line graphs being rated highest on both outcomes.Patients generally prefer a simple linear representation of group mean HRQL scores, and can accurately interpret data presented in this format more than 98% of the time irrespective of their age group and educational level. The findings have important implications for the communication of clinical trial HRQL results.