tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor Receptor (EGFR) Ubiquitination as a Mechanism of Acquired Resistance Escaping Treatment by the Anti-EGFR Monoclonal Antibody Cetuximab
Authors: Yang Lu, Xinqun Li, Ke Liang, Rodney Luwor, Zahid H. Siddik, Gordon B. Mills, John Mendelsohn, Zhen Fan
Journal: Cancer Research (2007)

Abstract Cetuximab is an epidermal growth factor receptor (EGFR)–blocking antibody that has been approved for treatment of patients with metastatic colorectal cancer. In this study, we investigated biochemical changes in signaling pathways of a cetuximab-resistant subline of DiFi colorectal cancer cells (DiFi5) that was developed by exposing the parental sensitive cells to subeffective doses of cetuximab over an extended period of time. Compared with parental DiFi cells that express high levels of EGFR and in which cetuximab induces apoptosis, the cetuximab-resistant DiFi5 cells showed markedly lower protein levels of EGFR, an increased association of EGFR with Cbl, and an increased ubiquitination of EGFR. DiFi5 cells also had a markedly higher level of Src-Y416 phosphorylation both at baseline and on EGF stimulation. Although EGFR levels were low, DiFi5 cells responded to EGF stimulation with robust phosphorylation of EGFR on Y845 and strong phosphorylation of Akt and extracellular signal–regulated kinase, comparable to those of parental cells. Most importantly, inhibition of Src kinase activity with PP2 reversed the resistance of DiFi5 cells to cetuximab-induced apoptosis without affecting the levels of EGFR in the cells. Our results indicate that colorectal cancer cells may develop acquired resistance to cetuximab via altering EGFR levels through promotion of EGFR ubiquitination and degradation and using Src kinase-mediated cell signaling to bypass their dependency on EGFR for cell growth and survival. [Cancer Res 2007;67(17):8240–7]
Baseline characteristics of idiopathic PAH patients with severely reduced diffusion capacity
Authors: Pia Trip, Esther Nossent, Anco Boonstra, Harm Jan Bogaard, Frances de Man, Nico Westerhof, Katrien Grunberg, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2012)

Introduction:  Pulmonary arterial hypertension (PAH) is a disease affecting the vasculature of the lung and is known to decrease carbon monoxide diffusion capacity (DLCO). Although most patients have a moderately decreased DLCO, a group of patients has severely reduced DLCO. The reason for this low DLCO is unclear. Therefore, the aim of this study is to describe baseline characteristics of idiopathic PAH patients with a low DLCO and compare this group with a group of idiopathic PAH patients with moderate low or normal DLCO.   Methods:  Patients with idiopathic or familial PAH were included. Patients were grouped based on the finding of a bimodal distribution in DLCO-values.   Results:  A total of 170 patients were included. DLCO groups were DLCO    Conclusions:  Compared with IPAH patients with moderate low or normal DLCO, IPAH patients with a severely reduced DLCO were characterized at baseline by a higher age, increased number of males, more often a history of smoking and coronary disease, and a lower exercise performance. No differences however were found in hemodynamic parameters.
Wireless capsule endoscopy: a comparison with push enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding
Authors: M Mylonaki
Journal: Gut (2003)

<b>Background:</b> The development of wireless capsule endoscopy allows painless imaging of the small intestine. Its clinical use is not yet defined. The aim of this study was to compare the clinical efficacy and technical performance of capsule endoscopy and push enteroscopy in a series of 50 patients with colonoscopy and gastroscopy negative gastrointestinal bleeding. <b>Methods:</b> A wireless capsule endoscope was used containing a CMOS colour video imager, transmitter, and batteries. Approximately 50 000 transmitted images are received by eight abdominal aerials and stored on a portable solid state recorder, which is carried on a belt. Push enteroscopy was performed using a 240 cm Olympus video enteroscope. <b>Results:</b> Studies in 14 healthy volunteers gave information on normal anatomical appearances and preparation. In 50 patients with gastrointestinal bleeding and negative colonoscopy and gastroscopy, push enteroscopy was compared with capsule endoscopy. A bleeding source was discovered in the small intestine in 34 of 50 patients (68%). These included angiodysplasia (16), focal fresh bleeding (eight), apthous ulceration suggestive of Crohn's disease (three), tumour (two), Meckel's diverticulum (two), ileal ulcer (one), jejunitis (one), and ulcer due to intussusception (one). One additional intestinal diagnosis was made by enteroscopy. The yield of push enteroscopy in evaluating obscure bleeding was 32% (16/50). The capsule identified significantly more small intestinal bleeding sources than push enteroscopy (p&lt;0.05). Patients preferred capsule endoscopy to push enteroscopy (p&lt;0.001). <b>Conclusions:</b> In this study capsule endoscopy was superior to push enteroscopy in the diagnosis of recurrent bleeding in patients who had a negative gastroscopy and colonoscopy. It was safe and well tolerated.
Risk of Hospitalization According to Chemotherapy Regimen in Early-Stage Breast Cancer
Authors: Carlos H. Barcenas, Jiangong Niu, Ning Zhang, Yufeng Zhang, Thomas A. Buchholz, Linda S. Elting, Gabriel N. Hortobagyi, Benjamin D. Smith, Sharon H. Giordano
Journal: Journal of Clinical Oncology (2014)

Purpose To compare the risk of hospitalization between patients with early-stage breast cancer who received different chemotherapy regimens. Patient and Methods We identified 3,567 patients older than age 65 years from the SEER/Texas Cancer Registry-Medicare database and 9,327 patients younger than age 65 years from the MarketScan database who were diagnosed with early-stage breast cancer between 2003 and 2007. The selection was nonrandomized and nonprospectively collected. We categorized patients according to the regimens they received: docetaxel (T) and cyclophosphamide (C), doxorubicin (A) and C, TAC, AC + T, dose-dense AC + paclitaxel (P) or AC + weekly P. We compared the rates of chemotherapy-related hospitalizations that occurred within 6 months of chemotherapy initiation and used multivariable logistic regression analysis to identify the factors associated with these hospitalizations. Results Among patients younger than age 65 years, the hospitalization rates ranged from 6.2% (dose-dense AC + P) to 10.0% (TAC), and those who received TAC and AC + T had significantly higher rates of hospitalization than did patients who received TC. Among patients older than age 65 years, these rates ranged from 12.7% (TC) to 24.2% (TAC) and the rates of hospitalization of patients who received TAC, AC + T, AC, or AC + weekly P were higher than those of patients who received TC. Conclusion TAC and AC + T were associated with the highest risk of hospitalization in patients younger than age 65 years. Among patients older than age 65 years, all regimens (aside from dose-dense AC + P) were associated with a higher risk of hospitalization than TC. Results may be affected by selection biases where less aggressive regimens are offered to frailer patients.
Unexpected Bronchial Anatomy Lesson
Authors: Manuel L. Ribeiro Neto, Steve Hoffman, Francisco A. Almeida
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

A 73-year-old woman presented with hemoptysis. Significant past medical history included paroxysmal atrial fibrillation, deep vein thrombosis of lower extremities, and recently diagnosed segmental pulmonary embolism on right upper lobe. The patient was being treated with warfarin. Her initial physical examination was unremarkable. Admission laboratory data showed an international normalized ratio of 3.9, which rapidly decreased to 1.5 after fresh frozen plasma administration. Chest radiograph showed no lung infiltrates or mass. Bronchoscopy was performed, and surprisingly, a large organized blood clot was visualized completely occluding the right main stem bronchi. No active bleed was noted. The blood clot was removed with a cryotherapy probe in a single attempt, providing us with an unexpected bronchial anatomy lesson (Figure 1). Further airway exam immediately after the clot removal Figure 1. (A) Blood clot removed in one piece from patient’s right bronchial tree. (B) Some form of tracheobronchial tree variation or anomaly has been reported to be found in 1 to 12% of patients (up to 70% in four more recent series) (1, 2). Therefore, the anatomy seen in these pictures cannot be generalized to all patients.
Francis Leslie Jackson
Authors: W. J. L. Jackson
Journal: BMJ (2013)

After work as resident pathologist at Guy’s and postgraduate study at the London School of Hygiene and Tropical Medicine, Francis Leslie Jackson obtained the Dip Bact in 1949. He worked at the Lister Institute and the National Institute for Medical Research in Mill Hill until 1953, when he moved to King’s College Hospital Medical School, London, as research fellow and later senior lecturer in bacteriology. His publications included papers in Nature on …
Palliation of allograft vasculopathy with transluminal angioplasty
Authors: Raymond L. Benza, Gilbert J. Zoghbi, Jose Tallaj, Robert Brown, James K. Kirklin, Meloneysa Hubbard, Barry Rayburn, Brian Foley, David C. McGiffin, Laura J. Pinderski, Vijay Misra, Robert C. Bourge
Journal: Journal of the American College of Cardiology (2004)
miR-15 Family Regulates Postnatal Mitotic Arrest of Cardiomyocytes
Authors: Enzo R. Porrello, Brett A. Johnson, Arin B. Aurora, Emma Simpson, Young-Jae Nam, Scot J. Matkovich, Gerald W. Dorn, Eva van Rooij, Eric N. Olson
Journal: Circulation Research (2011)

Mammalian cardiomyocytes withdraw from the cell cycle during early postnatal development, which significantly limits the capacity of the adult mammalian heart to regenerate after injury. The regulatory mechanisms that govern cardiomyocyte cell cycle withdrawal and binucleation are poorly understood.Given the potential of microRNAs (miRNAs) to influence large gene networks and modify complex developmental and disease phenotypes, we searched for miRNAs that were regulated during the postnatal switch to terminal differentiation.Microarray analysis revealed subsets of miRNAs that were upregulated or downregulated in cardiac ventricles from mice at 1 and 10 days of age (P1 and P10). Interestingly, miR-195 (a member of the miR-15 family) was the most highly upregulated miRNA during this period, with expression levels almost 6-fold higher in P10 ventricles relative to P1. Precocious overexpression of miR-195 in the embryonic heart was associated with ventricular hypoplasia and ventricular septal defects in β-myosin heavy chain-miR-195 transgenic mice. Using global gene profiling and argonaute-2 immunoprecipitation approaches, we showed that miR-195 regulates the expression of a number of cell cycle genes, including checkpoint kinase 1 (Chek1), which we identified as a highly conserved direct target of miR-195. Finally, we demonstrated that knockdown of the miR-15 family in neonatal mice with locked nucleic acid-modified anti-miRNAs was associated with an increased number of mitotic cardiomyocytes and derepression of Chek1.These findings suggest that upregulation of the miR-15 family during the neonatal period may be an important regulatory mechanism governing cardiomyocyte cell cycle withdrawal and binucleation.
Load-dependent relaxation with late systolic volume steps: servo-pump studies in the intact canine heart.
Authors: Y Ariel, W H Gaasch, D K Bogen, T A McMahon
Journal: Circulation (1987)

In isolated heart muscle preparations an abrupt increase in load during the latter portion of contraction (at a time when there is little if any potential to develop additional force) causes a premature and more rapid relaxation; this load-dependent relaxation characterizes relaxation in myocardium with normal sarcoplasmic reticulum. The purpose of our study was to assess whether or not the phenomenon of load-dependent relaxation is present in the intact heart and to describe the left ventricular response to abrupt load increments (volume steps) throughout the cardiac cycle. Using a microcomputer-controlled servo-pump attached to the apex of an intact canine heart, we studied the effects of 6 ml steps on left ventricular pressure transients during relaxation. Each volume step was carried out in a single beat with 20 stabilization beats separating the intervention beats; thus, at a heart rate of 120 beats/min, a sequence of 10 intervention beats could be carried out in less than 2 min. By performing the experiments on a single-beat basis (control vs intervention beat), we were able to minimize reflex and other physiologic feedback mechanisms that might alter the results. Studies were performed in five anesthetized dogs. In ejecting beats, an early step (immediately after aortic valve opening) caused an increase (3%) in the duration of systole (the time from the onset of pressure rise to the instant at which left ventricular pressure had declined to one-half its maximal value); in contrast, a late step (just before aortic value closure) caused a decrease (7%) in the duration of systole.(ABSTRACT TRUNCATED AT 250 WORDS)
Current Evidence and Future Directions for Targeting HIV Entry
Authors: M. Patricia D'Souza, J. Scott Cairns, Susan F. Plaeger
Journal: JAMA (2000)

Great strides have been made in developing potent antiretroviral regimens that block human immunodeficiency virus (HIV) transcription and assembly. Despite these therapeutic advances, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. One promising approach involves blocking HIV entry into human cells, a complex process that involves multiple protein interactions. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of several chemokine receptors and ends with fusion of viral and cell membranes. Conceptually, there are 3 steps in the HIV entry process that could serve as therapeutic targets: binding of the viral envelope glycoprotein with the CD4 receptor, binding of the envelope-CD4 complex to chemokine receptors, and fusion of the viral and cell membranes. Preclinical and clinical assessment of these entry inhibitors is ongoing and will determine if they possess properties required for drug licensure. Moreover, the worldwide epidemic is largely occurring in developing countries that cannot afford these drugs: a prophylactic vaccine is necessary and urgent. New knowledge of the HIV-envelope glycoprotein has also provided insight into possibilities for the design of novel HIV vaccines.
Urokinase-Type Plasminogen Activator System in Breast Cancer
Authors: Marion E. Meijer-van Gelder, Maxime P. Look, Harry A. Peters, Manfred Schmitt, Nils Brünner, Nadia Harbeck, Jan G. M. Klijn, John A. Foekens
Journal: Cancer Research (2004)

Abstract The prognostic value of components of the urokinase-type plasminogen activator (uPA) system, its receptor uPAR (CD87), and plasminogen activator inhibitors PAI-1 and PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their tumor expression level and the efficacy of tamoxifen therapy in patients with recurrent breast cancer. The antigen levels of the four factors were determined by ELISA in cytosols prepared from estrogen receptor-positive primary breast tumors of 691 hormone-naive breast cancer patients with recurrent disease and treated with tamoxifen as first-line systemic therapy. High tumor levels of uPA (P &amp;lt; 0.001), uPAR (P &amp;lt; 0.01), and PAI-1 (P = 0.01) were associated with a lower efficacy of tamoxifen therapy. In the multivariable analysis, uPA (P &amp;lt; 0.001) provided additional information independent of the traditional predictive factors to predict benefit from tamoxifen therapy. High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy. However in the analysis during the total follow-up period, high PAI-2 levels (P = 0.01) showed a longer response to tamoxifen. In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer. Knowledge of their tumor expression levels might be helpful for future individualized therapy protocols, including possible new-targeted therapies based on the interference in the urokinase system.
Twelve-Year Experience With Two Courses of Adjuvant Single-Agent Carboplatin Therapy for Clinical Stage I Seminoma
Authors: Werner J. Reiter, Thomas Brodowicz, Saeid Alavi, Christoph C. Zielinski, Walter Kozak, Ulrich Maier, Gerald Nöst, Herbert Lipsky, Michael Marberger, Christian Kratzik
Journal: Journal of Clinical Oncology (2001)

During the past 30 years, radiation therapy with 28 to 30 Gy for para-aortic and ipsilateral iliac node areas was the standard adjuvant treatment for clinical stage I seminoma after orchiectomy. However, late effects of radiotherapy prompted a search for alternative adjuvant treatment approaches, including surveillance and application of carboplatin. In this retrospective analysis, we evaluated the efficacy and toxicity of two adjuvant single-agent carboplatin courses in 107 patients who were diagnosed with clinical stage I seminoma at our study centers between 1988 and 1999.All 107 patients (median age, 39 years; range, 24 to 63 years) received two postoperative adjuvant cycles of carboplatin (400 mg/m(2)). The pathologic tumor stage was pT1 in 84 patients, pT2 in 18 patients, and pT3 in five patients. Whole blood count and serum chemistry were evaluated weekly during treatment to assess hematologic and nonhematologic toxicity.Six patients died from tumor-unrelated causes. The remaining 101 patients are currently alive and free of disease after a median follow-up of 74 months (range, 5 to 145 months). A detailed analysis of hematologic toxicity showed only World Health Organization (WHO) grade 1 leukocytopenia in 10.7% of all cycles and WHO grade 2 leukocytopenia in 2.1% of all cycles.Regarding the absence of tumor recurrences in our retrospective analysis and the favorable toxicity profile with no episodes of long-term toxicity, we suggest that two adjuvant courses of single-agent carboplatin for clinical stage I seminoma patients might be equivalent to radiotherapy.
Corrigendum to: Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor
Authors: J.-S. Lee, S.-H. Song, J.-M. Kim, I.-S. Shin, K. L. Kim, Y.-L. Suh, H.-Z. Kim, G. Y. Koh, J. Byun, E.-S. Jeon, W. Suh, D.-K. Kim
Journal: Cardiovascular Research (2008)
Carrageenan-induced ulceration of the large intestine in the guinea pig
Authors: J. Watt, R. Marcus
Journal: Gut (1971)

A 5% aqueous solution of degraded carrageenan derived from the red seaweed Eucheuma spinosum was fed to guinea pigs in their drinking water over a period of 20-45 days. Occult blood in the faeces and multiple ulcers in the caecum, colon and rectum occurred in 100% of animals by the 30th day. The clinical and pathological features bear a close resemblance to human ulcerative colitis. The method provides a simple experimental model for the study of various aspects of the pathology of ulcerative lesions in the large intestine as well as the effects of therapeutic agents.
Neutrophil primary granule proteins HBP and HNP1–3 boost bacterial phagocytosis by human and murine macrophages
Authors: Oliver Soehnlein, Ylva Kai-Larsen, Robert Frithiof, Ole E. Sorensen, Ellinor Kenne, Karin Scharffetter-Kochanek, Einar E. Eriksson, Heiko Herwald, Birgitta Agerberth, Lennart Lindbom
Journal: Journal of Clinical Investigation (2008)

In acute inflammation, infiltrating polymorphonuclear leukocytes (also known as PMNs) release preformed granule proteins having multitudinous effects on the surrounding environment. Here we present what we believe to be a novel role for PMN-derived proteins in bacterial phagocytosis by both human and murine macrophages. Exposure of macrophages to PMN secretion markedly enhanced phagocytosis of IgG-opsonized Staphylococcus aureus both in vitro and in murine models in vivo. PMN secretion activated macrophages, resulting in upregulation of the Fcγ receptors CD32 and CD64, which then mediated the enhanced phagocytosis of IgG-opsonized bacteria. The phagocytosis-stimulating activity within the PMN secretion was found to be due to proteins released from PMN primary granules; thorough investigation revealed heparin-binding protein (HBP) and human neutrophil peptides 1–3 (HNP1–3) as the mediators of the macrophage response to PMN secretion. The use of blocking antibodies and knockout mice revealed that HBP acts via β2 integrins, but the receptor for HNP1–3 remained unclear. Mechanistically, HBP and HNP1–3 triggered macrophage release of TNF-α and IFN-γ, which acted in an autocrine loop to enhance expression of CD32 and CD64 and thereby enhance phagocytosis. Thus, we attribute what may be a novel role for PMN granule proteins in regulating the immune response to bacterial infections.
Early Surgery Versus Conventional Treatment for Asymptomatic Severe Mitral Regurgitation
Authors: Duk-Hyun Kang, Sung-Ji Park, Byung Joo Sun, Eun Jeong Cho, Dae-Hee Kim, Sung-Cheol Yun, Jong-Min Song, Seung Woo Park, Cheol-Hyun Chung, Jae-Kwan Song, Jae-Won Lee, Pyo-Won Park
Journal: Journal of the American College of Cardiology (2014)
Hemodynamic Evaluation of the Heart With a Nonfluoroscopic Electromechanical Mapping Technique
Authors: Lior Gepstein, Gal Hayam, Shlomo Shpun, Shlomo A. Ben-Haim
Journal: Circulation (1997)

Background Clinical cardiac volumetric measurement techniques are essential for assessing cardiac performance but produce significant inaccuracies in extrapolation of the volume of a three-dimensional (3D) object from two-dimensional images and lack the ability to associate cardiac electrical and mechanical activities. In this study, we tested the accuracy of cardiac volumetric measurements using a new catheter-based system. Methods and Results The system uses magnetic technology to accurately locate a special catheter at a frequency of 125 Hz and is currently used in the field of electrophysiology, in which activation maps are superimposed on the 3D geometry of the cardiac chamber. The mapping procedure is based on sequentially acquiring the location of the tip and local electrogram while in contact with the endocardium. The 3D geometry of the chamber is reconstructed in real time, and its volume could be calculated at every time step (8 ms). The volumetric measurements of the system were found to be highly accurate for simple phantoms (mean±SEM deviation, 2.3±1.1%), left ventricular casts (9.6±1.3%), and a dynamic test jig. In addition, left ventricular volumes of 12 swine were measured. Intraobserver and interobserver variabilities were found to be minimal (ejection fraction, 6.5±1.9% and 7.1±2.0%; stroke volume, 4.5±1.0% and 11.3±2.4%). Comparison with the thermodilution method for measuring stroke volume showed an average deviation of 8.1±2.2%. Typical pressure-volume loops were also obtained. Conclusions The new mapping image provides, for the first time, simultaneous information regarding cardiac mechanics, hemodynamics, and electrical properties. Furthermore, all this information is achieved without the use of fluoroscopy, contrast medium, or complicated image processing.