tbuckley/cabot-search huggingface dataset:
Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma
Authors: Keith T. Flaherty
Journal: Clinical Cancer Research (2006)

Abstract For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only “standard” agent. With response rates of &amp;lt;10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion.
Proteomics by Mass Spectrometry: Approaches, Advances, and Applications
Authors: John R. Yates, Cristian I. Ruse, Aleksey Nakorchevsky
Journal: Annual Review of Biomedical Engineering (2009)

Mass spectrometry (MS) is the most comprehensive and versatile tool in large-scale proteomics. In this review, we dissect the overall framework of the MS experiment into its key components. We discuss the fundamentals of proteomic analyses as well as recent developments in the areas of separation methods, instrumentation, and overall experimental design. We highlight both the inherent strengths and limitations of protein MS and offer a rough guide for selecting an experimental design based on the goals of the analysis. We emphasize the versatility of the Orbitrap, a novel mass analyzer that features high resolution (up to 150,000), high mass accuracy (2-5 ppm), a mass-to-charge range of 6000, and a dynamic range greater than 10(3). High mass accuracy of the Orbitrap expands the arsenal of the data acquisition and analysis approaches compared with a low-resolution instrument. We discuss various chromatographic techniques, including multidimensional separation and ultra-performance liquid chromatography. Multidimensional protein identification technology (MudPIT) involves a continuum sample preparation, orthogonal separations, and MS and software solutions. We discuss several aspects of MudPIT applications to quantitative phosphoproteomics. MudPIT application to large-scale analysis of phosphoproteins includes (a) a fractionation procedure for motif-specific enrichment of phosphopeptides, (b) development of informatics tools for interrogation and validation of shotgun phosphopeptide data, and (c) in-depth data analysis for simultaneous determination of protein expression and phosphorylation levels, analog to western blot measurements. We illustrate MudPIT application to quantitative phosphoproteomics of the beta adrenergic pathway. We discuss several biological discoveries made via mass spectrometry pipelines with a focus on cell signaling proteomics.
A NOTE ON TYPE OF ONSET IN RELATION TO CLINICAL TYPE IN GENERAL PARALYSIS
Authors: Henry A. Bunker
Journal: American Journal of Psychiatry (1926)

1. In a series of 74 cases of general paralysis, the earliest onset of the disease was marked, in 57 (77 per cent), by abnormality in the emotional sphere of one of two forms: Irritability (in 29), or a seclusive and apathetic type of reaction (in 15); in 13 cases there occurred first the one and then the other as an early symptom. 2. Little correlation appears to exist between the type of onset, in this sense, and the clinical type of general paralysis which later develops, save with regard to the "manic" cases of the fully developed disease; for the patients with an "irritable" onset contributed 30 per cent of the "manic" cases as compared with 19 per cent of the latter in the group as a whole, while 100 per cent of these cases had an "irritable" rather than a "seclusive" type of onset when either of these forms of emotional alteration had a place among the earliest changes observed. In this respect the expansive cases did not differ from the group as a whole. On the part of the simple dementing cases there was, of the two, a slight tendency toward seclusiveness rather than irritability as an initial or early symptom. 3. Loss of weight, increased tendency to sleep, and perhaps also forgetfulness, when these appeared among the earliest symptoms noted, were without significance with regard to the clinical type of paresis which subsequently developed. 4. Of 11 patients who very early exhibited speech defect, all but one fell later into the category of simple dementing cases.
Simple First Aid Traction Splint for Cervical Spine Injuries
Authors: T. B. Quigley
Journal: JAMA (1962)

TWENTY YEARS AGO in Southern England, powerful vehicles and the blackout of war produced a steady stream of victims of mechanical trauma in the emergency rooms of civilian and military hospitals. Among the saddest of these were the quadriplegics, few of whom survived more than a few weeks. Often suspicion arose that injury to the cervical cord occurred<i>after</i>the accident, in transport to the hospital, but only rarely could this be proved. The then current manuals of first aid were reviewed with regard to injuries to the cervical spine. None had more to offer than the recommendation that the patient be moved with care, supine, and preferably with sandbags on the sides of the neck. A scheme of traction splinting was worked out which seemed better than sandbags, required no more equipment than that found in the average ambulance, and, if this were lacking, could be improvised from a
Relationship of burst‐forming‐unit‐erythroid progenitors and their DNA‐synthesis stage to fetal hemoglobin levels in hydroxyurea‐treated patients with sickle cell anemia
Authors: Vipul N. Mankad, Surendra Baliga, Karen Phillips, Arvind K. Shah, Yih‐Ming Yang
Journal: American Journal of Hematology (1994)

DNA-synthesis stage and total number of circulating burst-forming-units-erythroid (BFU-E) have been inversely correlated with hemoglobin F levels in the peripheral blood, as well as in the cells from the BFU-E-derived colonies obtained from homozygous sickle cell anemia (SS) patients during steady state. Similar studies in SS patients treated with cytotoxic agents have not been reported. However, regeneration of the erythroid marrow that follows the cytoreduction phase of chemotherapy has been suggested as one of the mechanisms of stimulation of fetal hemoglobin synthesis. Therefore, a longitudinal study of hemopoiesis in hydroxyurea-treated SS patients was conducted. Thirty-two sets of hemopoietic studies, including total circulating BFU-E and S-phase BFU-E, were obtained from three patients treated with hydroxyurea. A dose-dependent decrease in total BFU-E colonies occurred in peripheral blood of all three patients (r = -0.58, -0.85, and -0.97, respectively, with each P < 0.05). There was a strong positive correlation between hydroxyurea dose and fetal hemoglobin levels in two of the three patients who responded clinically (r = 0.89618 and 0.88632, respectively, with each P < 0.01). When data from all patients were combined (n = 32), there was a strong, inverse, linear relationship between total number of BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (r = -0.6649 and -0.7404, respectively, with each P < 0.0001). A stronger, curvilinear, multiple relationship was detected between total BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (R = 0.8351 and 0.8602 with each P < 0.0001).
Impact of heart rate on mechanical dyssynchrony and left ventricular contractility in patients with heart failure and normal QRS duration
Authors: Tairo Kurita, Katsuya Onishi, Kaoru Dohi, Masaki Tanabe, Naoki Fujimoto, Takashi Tanigawa, Morimichi Setsuda, Naoki Isaka, Tsutomu Nobori, Masaaki Ito
Journal: European Journal of Heart Failure (2007)
p53 Aerosol Formulation with Low Toxicity and High Efficiency for Early Lung Cancer Treatment
Authors: Yiyu Zou, Carmen Tornos, Xuan Qiu, Marie Lia, Roman Perez-Soler
Journal: Clinical Cancer Research (2007)

To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer.The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non-small-cell lung cancer (NSCLC) xenograft.After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P < 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 mum is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity.This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma.
Antibiotics for streptococcal endocarditis.
Authors: S W Newsom
Journal: Thorax (1980)

Antibiotics for streptococcal endocarditisTwo groups of bactericidal antibiotics are used to treat streptococcal endocarditis, the penicillins and the aminoglycosides.Vancomycin has a role for highly resistant bacteria or ithe patient allergic to penicillin.Bacteriostatic agents such as
Proteinuria, pancytopenia and hypoxaemic respiratory failure in a 28-year-old female
Authors: W. Berjaoui, N. Dean, N. Dahle
Journal: European Respiratory Journal (2006)

CASE REPORTA previously healthy 28-yr-old Caucasian female presented to the emergency department with a 1-week history of generalised body swelling that was followed by pleuritic chest pain radiating to the patient's back.She had mild shortness of breath, cough and palpitations, but no fever, chills, nausea, vomiting or diarrhoea.No medications were taken except oral contraceptives.She denied any history of tobacco or alcohol use, recent travel or sick contacts.The patient's vital signs were as follows: 1) blood pressure 135/94 mmHg; 2) body temperature 39.4uC; 3) respiratory rate 16 breaths?min - ; 4) pulse 105 beats?min -1 ; and 5) oxygen saturation 95%, while breathing room air.Her physical examination was remarkable for decreased breath sounds diffuse with minimal crackles, as well as facial swelling and pitting oedema of the lower extremities.Pertinent laboratory results of the blood tests performed on admission are shown in table 1.
Hospitalization Costs of Primary Stenting Versus Thrombolysis in Acute Myocardial Infarction
Authors: Michel R. Le May, Richard F. Davies, Marino Labinaz, Heather Sherrard, Jean-François Marquis, Louise A. Laramée, Edward R. O’Brien, William L. Williams, Rob S. Beanlands, Graham Nichol, Lyall A. Higginson
Journal: Circulation (2003)

We previously showed that primary stenting was more effective than accelerated tPA in reducing the 6-month composite of death, reinfarction, stroke, or repeat revascularization for ischemia. This study looks at the hospitalization costs of primary stenting compared with accelerated tPA.Initial and 6-month hospitalization costs were computed for all patients randomly assigned to primary stenting (n=62) or accelerated tPA (n=61) in the Stenting versus Thrombolysis in Acute myocardial infarction Trial (STAT). Costs and resource usage were collected in detail for each patient. Physician fees were obtained directly from billings to the Ontario Health Insurance Plan. The length of initial hospitalization was 6.7+/-11.3 days in the stent group and 8.7+/-6.7 days in the tPA group (P<0.001). Total hospitalization days at 6 months were 8.3+/-13 days in the stent group and 12.1+/-14.0 days in the tPA group (P=0.001). Hospitalization costs were less in the stent group for the initial hospitalization, 6354 dollars +/-6382 versus 7893 dollars +/-4429 (P=0.001), and at 6 months, 7100 dollars +/-7111 versus 9559 dollars +/-6933 (P=0.001).In centers in which facilities and experienced interventionists are available, primary stenting is less costly and more effective than thrombolysis.
Effects of Exercise and Respiration on Blood Flow in Total Cavopulmonary Connection
Authors: V.E. Hjortdal, K. Emmertsen, E. Stenbøg, T. Fründ, M. Rahbek Schmidt, O. Kromann, K. Sørensen, E.M. Pedersen
Journal: Circulation (2003)

Little is known about blood flow and its relationship to respiration during exercise in patients with total cavopulmonary connection (TCPC).We studied 11 patients 12.4+/-4.6 years (mean+/-SD) of age 5.9+/-2.8 years (mean+/-SD) after TCPC operation. Real-time MRI was used to measure blood flow in the superior vena cava (SVC), inferior vena cava (IVC), and ascending aorta under inspiration and expiration during supine lower-limb exercise (rest, 0.5 and 1.0 W/kg) on an ergometer bicycle. IVC and aortic flow increased from 1.60+/-0.52 and 2.99+/-0.83 L/min per m2 at rest to 2.58+/-0.71 and 3.97+/-1.20 L/min per m2 at 0.5 W/kg and to 3.25+/-1.23 and 4.62+/-1.49 L/min per m2 at 1.0 W/kg (P< or =0.05). SVC flow remained unchanged. Resting flow in the IVC was greater during inspiration (2.99+/-1.25 L/min per m2) than during expiration (0.83+/-0.44 L/min per m2) (inspiratory/mean flow ratio, 1.9+/-0.5), and retrograde flow was present during expiration (11+/-12% of mean flow). The predominance of inspiratory flow in IVC diminished with exercise to an inspiratory/mean flow ratio of 1.5+/-0.2 (P< or =0.05) and 1.4+/-0.3 at 0.5 and 1.0 W/kg, respectively.In the TCPC, circulation IVC and aortic but not SVC flows increase with supine leg exercise. Inspiration facilitates IVC flow at rest but less so during exercise, when the peripheral pump seems to be more important.
New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network
Authors: Yun Dai, Steven Grant
Journal: Clinical Cancer Research (2010)

The DNA damage response (DDR) represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous (metabolic) or environmental stresses. In cancer treatment, the DDR occurs in response to various genotoxic insults by diverse cytotoxic agents and radiation, representing an important mechanism limiting chemotherapeutic and radiotherapeutic efficacy. This has prompted the development of agents targeting DDR signaling pathways, particularly checkpoint kinase 1 (Chk1), which contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. Although numerous agents have been developed with the primary goal of enhancing the activity of DNA-damaging agents or radiation, the therapeutic outcome of this strategy remains to be determined. Recently, new insights into DDR signaling pathways support the notion that Chk1 represents a core component central to the entire DDR, including direct involvement in DNA repair and apoptotic events in addition to checkpoint regulation. Together, these new insights into the role of Chk1 in the DDR machinery could provide an opportunity for novel approaches to the development of Chk1 inhibitor strategies.
Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease
Authors: Patrick W. Serruys, Marie-Claude Morice, A. Pieter Kappetein, Antonio Colombo, David R. Holmes, Michael J. Mack, Elisabeth Ståhle, Ted E. Feldman, Marcel van den Brand, Eric J. Bass, Nic Van Dyck, Katrin Leadley, Keith D. Dawkins, Friedrich W. Mohr
Journal: New England Journal of Medicine (2009)

Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating patients with previously untreated three-vessel or left main coronary artery disease (or both).We randomly assigned 1800 patients with three-vessel or left main coronary artery disease to undergo CABG or PCI (in a 1:1 ratio). For all these patients, the local cardiac surgeon and interventional cardiologist determined that equivalent anatomical revascularization could be achieved with either treatment. A noninferiority comparison of the two groups was performed for the primary end point--a major adverse cardiac or cerebrovascular event (i.e., death from any cause, stroke, myocardial infarction, or repeat revascularization) during the 12-month period after randomization. Patients for whom only one of the two treatment options would be beneficial, because of anatomical features or clinical conditions, were entered into a parallel, nested CABG or PCI registry.Most of the preoperative characteristics were similar in the two groups. Rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization (13.5% vs. 5.9%, P<0.001); as a result, the criterion for noninferiority was not met. At 12 months, the rates of death and myocardial infarction were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2%, vs. 0.6% with PCI; P=0.003).CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year. (ClinicalTrials.gov number, NCT00114972.)
The Medical Liability Climate and Prospects for Reform
Authors: Michelle M. Mello, David M. Studdert, Allen Kachalia
Journal: JAMA (2014)

For many physicians, the prospect of being sued for medical malpractice is a singularly disturbing aspect of modern clinical practice. State legislatures have enacted tort reforms, such as caps on damages, in an effort to reduce the volume and costs of malpractice litigation. Attempts to introduce similar traditional reform measures at the federal level have so far failed. Much less prominent, but potentially more important, are proposed alternative approaches for resolving medical injuries; a number of these efforts are currently being tested in federally sponsored demonstration projects. These nontraditional reforms have considerable promise for addressing some of the system's most challenging issues, including high costs and barriers to accessing compensation. In this Special Communication, we review recent national trends in medical liability claims and costs, which indicate a sharp reduction in the rate of paid claims and flat or declining levels in compensation payments and liability insurance costs over the last 7 to 10 years. We discuss a number of nontraditional reform approaches--communication-and-resolution programs, presuit notification and apology laws, safe harbor legislation, judge-directed negotiation, and administrative compensation systems--and we conclude by describing several forces likely to shape change in the medical liability environment over the next decade.
Vitamin D and Asthma: Another Dimension
Authors: Anthony N. Gerber, E. Rand Sutherland
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

In this issue of the Journal, Gupta and colleagues (pp. 1342‐1349) add to the ever-enlarging body of literature reporting associations between vitamin D status (as reflected by serum 25(OH)D concentrations) and measures of asthma severity and control (1). In a well-characterized clinical cohort of children with either moderate or severe (treatment-resistant) asthma, they investigated associations between serum 25(OH)D and lung function, asthma control, exacerbations, and medication history. As might be expected in light of prior reports, the investigators found an inverse relationship between 25(OH)D and asthma severity, exacerbations, and inhaled glucocorticoid requirement, and a positive relationship between 25(OH)D and both lung function and asthma control. These findings validate, using data obtained directly from patients with severe asthma, other reports in which vitamin D status is associated with asthma severity in children (2‐4). The authors take their findings a step further, however, by also providing us with data regarding vita
Cardiac Side Population Cells
Authors: Kazumasa Unno, Mohit Jain, Ronglih Liao
Journal: Circulation Research (2012)

Over the past decade, extensive work in animal models and humans has identified the presence of adult cardiac progenitor cells, capable of cardiomyogenic differentiation and likely contributors to cardiomyocyte turnover during normal development and disease. Among cardiac progenitor cells, there is a distinct subpopulation, termed "side population" (SP) progenitor cells, identified by their unique ability to efflux DNA binding dyes through an ATP-binding cassette transporter. This review highlights the literature on the isolation, characterization, and functional relevance of cardiac SP cells. We review the initial discovery of cardiac SP cells in adult myocardium as well as their capacity for functional cardiomyogenic differentiation and role in cardiac regeneration after myocardial injury. Finally, we discuss recent advances in understanding the molecular regulators of cardiac SP cell proliferation and differentiation, as well as likely future areas of investigation required to realize the goal of effective cardiac regeneration.