tbuckley/cabot-search huggingface dataset:
Dynamic Interactions of Cortactin and Membrane Type 1 Matrix Metalloproteinase at Invadopodia: Defining the Stages of Invadopodia Formation and Function
Authors: Vira V. Artym, Ying Zhang, Françoise Seillier-Moiseiwitsch, Kenneth M. Yamada, Susette C. Mueller
Journal: Cancer Research (2006)

Metastatic tumor cells that actively migrate and invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers. Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little is known about the formation, function, and regulation of invadopodia. Here, we show that invadopodia have two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membrane protrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA (siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereas protease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the key invadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell line MDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a block of matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMP siRNA depletion moderately decreased the formation of invadopodial structures that were identified as actin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia that were able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but were unable to degrade matrix. Examination of cells at different time points as well as live-cell imaging revealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent to matrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at the invadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMP accumulation associated with foci of degraded matrix. Based on these results, we propose a stepwise model of invadopodia formation and function.
EFFECTS OF CONCANAVALIN A ON MOUSE PERITONEAL MACROPHAGES
Authors: Paul J. Edelson, Zanvil A. Cohn
Journal: The Journal of Experimental Medicine (1974)

Concanavalin A (Con A) binds to saccharide residues on the mouse peritoneal macrophage plasma membrane and stimulates extensive pinocytic interiorization of the membrane. The overall pinocytic rate is increased 3.5–4.5 times by the addition of Con A, and the surface marker enzyme adenosine triphosphatase can be identified histochemically in association with the cytoplasmic vesicles generated after exposure of the cells to Con A. Once formed, these pinocytic vesicles may persist for several days and fail to show morphologic evidence of fusion with primary or preformed secondary lysosomes. There is no apparent effect on the capacity of the macrophage to ingest either latex particles or IgG-coated SRBC administered either simultaneously with or subsequent to the Con A.
A multicentre comparison of the efficacy of terbutaline Turbuhaler and salbutamol pressurized metered dose inhaler in hot, humid regions
Authors: DA Lindsay, NL Russell, JE Thompson, TH Warnock, ID Shellshear, PR Buchanan
Journal: European Respiratory Journal (1994)

Twenty seven adults and 20 children with previously diagnosed stable asthma, using a salbutamol pressurized metered dose inhaler (P-MDI) and living in Cairns, Townsville and Southport, Queensland, Australia participated in a randomized, open-label cross-over comparison of terbutaline administered via Turbuhaler and salbutamol administered via P-MDI. The aim of the study was to compare the clinical effectiveness and patient acceptance of the two treatments in hot, humid regions. Terbutaline was administered via Turbuhaler and salbutamol via P-MDI on at least two occasions per day during each four week treatment period. Spirometry was performed at the start of the study, after the two week run-in and at the end of each treatment period. Patients used diary cards to record morning and evening peak expiratory flows, daily symptom scores and daily intake of beta 2 agonist medication. At the end of the study, patients answered a treatment preference question. Forty six patients completed the study. No statistically significant differences were observed between the two treatments in peak expiratory flow, change in morning peak expiratory flow pre- and post-beta-agonist, daily symptom scores, diurnal variability and spirometry. Forty four percent of patients preferred the terbutaline Turbuhaler and 39% preferred salbutamol P-MDI. Both agents were similarly tolerated. Terbutaline delivered by Turbuhaler is as clinically effective as salbutamol delivered by P-MDI in patients with asthma living in hot, humid regions.
Focal Pharmacological Modulation of Atrioventricular Nodal Conduction via Implantable Catheter
Authors: Daniel C. Sigg, Prasanga Hiniduma-Lokuge, James A. Coles, Phillip Falkner, Rebecca Rose, Jon F. Urban, Michael R. Ujhelyi
Journal: Circulation (2006)

Pharmacological ventricular rate control is an acceptable atrial fibrillation (AF) therapy limited by systemic toxicity. We postulate that focal catheter-based drug delivery into the atrioventricular nodal (AVN) region may effectively control ventricular rate during AF without systemic toxicity. This study evaluated the effects of focally administered acetylcholine on AVN conduction and refractoriness during sinus rhythm and AF.Canines (n=7) were anesthetized and instrumented to assess cardiac electrophysiology and blood pressure. A custom drug delivery catheter was implanted in the AVN region. Incremental doses of acetylcholine starting at 10 microg/min were infused until complete AV block was achieved. Acetylcholine induced dose-dependent AV block. AF induction and electrophysiology measurements were performed during baseline and acetylcholine-induced first-degree and third-degree AV block. During AF, infusion of acetylcholine decreased ventricular rates from 182+/-32 to 77+/-28 and 28+/-8 bpm (first-degree and third-degree AV block, respectively; P<0.05). At the first-degree AV block dose, AVN effective refractory period increased from 186+/-37 to 282+/-33 ms, and Wenckebach cycle length increased from 271+/-29 to 378+/-58 ms (P<0.05). The first-degree AV block dose prolonged AV and AH intervals by 26% and 23% (P<0.05), whereas AA intervals and blood pressure remained unchanged, demonstrating a local effect. All effects were reversed 20 minutes after infusion was stopped.Focal acetylcholine delivery into the AVN increased AVN refractoriness and significantly decreased ventricular rate response during induced AF in a dose-related, reversible manner without systemic side effects. This may represent a novel therapy for AF whereby ventricular rate is controlled with the use of an implantable drug delivery system.
Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors
Authors: Harma Feitsma, Raoul V. Kuiper, Jeroen Korving, Isaac J. Nijman, Edwin Cuppen
Journal: Cancer Research (2008)

Abstract Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neurofibromas/malignant peripheral nerve sheath tumors were observed; however, a range of other tumor types was also observed. Our findings indicate that zebrafish mimic distinct features of the human disease and are complementary to mouse models. [Cancer Res 2008;68(13):5059–66]
Etoposide, ifosfamide, and methotrexate with or without bleomycin in refractory or recurrent lymphomas
Authors: Mohammad R. Nowrousian, Christof H. Anders, Norbert Niederle, Marianne Nagel-Hiemke, Thomas Moritz, Siegfried Seeber, Carl G. Schmidt
Journal: Annals of Oncology (1991)
Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C
Authors: M Colombo, I Fernández, D Abdurakhmanov, P A Ferreira, S I Strasser, P Urbanek, C Moreno, A Streinu-Cercel, A Verheyen, W Iraqi, R DeMasi, A Hill, J M Läuffer, I Lonjon-Domanec, H Wedemeyer
Journal: Gut (2013)

<h3>Background and aim</h3> Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). <h3>Methods</h3> 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. <h3>Results</h3> 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1–4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). <h3>Conclusions</h3> In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.
Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis
Authors: Gerwin Huls, André B. Mulder, Stefano Rosati, Arjan A. van de Loosdrecht, Edo Vellenga, Joost T. M. de Wolf
Journal: Blood (2010)
Protective effects of repeated short sprints in exercise-induced asthma.
Authors: R P Schnall, L I Landau
Journal: Thorax (1980)

Many asthmatic patients demonstrate bronchial lability with a six-minute period of exercise, which is characterised by an initial bronchodilatation followed by bronchoconstriction. This early bronchodilatation response has been further analysed by investigation of the effects of repeated 30-second sprints before and after a six-minute run. It was found that these repeated short sprints did not induce bronchoconstriction, resulted in less bronchoconstriction after a subsequent six-minute run, and caused bronchodilatation if exercise-induced bronchoconstriction was present. It is postulated that this effect may be related to an increase in circulating catecholamines or altered vagal-sympathetic balance.
Actions of cADP-Ribose and Its Antagonists on Contraction in Guinea Pig Isolated Ventricular Myocytes
Authors: Shigeo Iino, Yi Cui, Antony Galione, Derek A. Terrar
Journal: Circulation Research (1997)

Abstract Although it is becoming widely accepted that cADP-ribose (cADPR) can regulate calcium release from the endoplasmic reticulum in sea urchin eggs and in a variety of mammalian cell types, it remains controversial whether this substance might influence calcium release during excitation-contraction coupling in cardiac muscle. We have investigated possible actions of cADPR in intact cells isolated from guinea pig ventricle, paying particular attention to the possible influence of temperature. At 36°C, myocyte contraction was influenced by cytosolic application of cADPR in a concentration-dependent manner (showing an ≈30% increase in contraction with 5 μmol/L cADPR applied via a patch pipette in myocytes stimulated to fire action potentials at 1 Hz). Calcium transients measured with fura 2 were also increased by 5 μmol/L cADPR. Antagonists of cADPR reduced contraction at 36°C (by ≈35% with either 50 μmol/L 8-Br-cADPR or 5 μmol/L 8-amino-cADPR applied via the patch pipette). At room temperature (≈20°C to 24°C), no significant effects on contraction were detected with either cADPR or its antagonists. At 36°C, treatment of the cells with a mixture of 2 μmol/L ryanodine and 1 μmol/L thapsigargin to suppress function of the sarcoplasmic reticulum stores of calcium prevented the action of 5 μmol/L cADPR applied via a patch pipette. These observations are consistent with an action of cytosolic cADPR to enhance calcium-induced calcium release from the sarcoplasmic reticulum in guinea pig ventricular myocytes at 36°C. The observed influence of temperature under the conditions of our experiments is one factor that might help to account for failure to detect actions of cADPR and its analogues in some previous studies.
The combined effect of smoking and coffee drinking on LDL and HDL cholesterol.
Authors: S Heyden, G Heiss, C Manegold, H A Tyroler, C G Hames, A G Bartel, G Cooper
Journal: Circulation (1979)

Conflicting reports on the effect of smoking and coffee drinking on lipoproteins prompted us to study the combined effect of these two associated, widely prevalent habits in 361 persons randomly sampled from the Evans County cohort. Low-density lipoprotein (LDL) cholesterol levels were significantly higher among persons who smoked cigarettes and consumed five or more cups of coffee per day than among nonsmokers who abstained from coffee. Conversely, high-density lipoprotein (HDL) cholesterol was higher in persons who did not smoke or drink coffee than in coffee-consuming smokers. However, this trend was not statistically significant. Triglycerides and very low-density lipoprotein (VLDL) cholesterol were highest among smokers who drank five or more cups of coffee per day, but these differences did not reach statistical significance. Lipoprotein cholesterol levels were adjusted for age, sex and body mass. Smoking and coffee drinking interact in affecting LDL and total cholesterol, but coffee drinking alone did not appear to affect blood lipids.
Improvement in Spirometry following Lung Volume Reduction Surgery
Authors: HENRY E. FESSLER, STEVEN M. SCHARF, SOLBERT PERMUTT
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

According to a previously published theoretical model of emphysema, the ratio of RV to TLC (RV/TLC) reflects the size mismatch between the hyperinflated lungs in the disease and the surrounding chest. The model suggests that RV/TLC is an important predictor of improvement in FVC and that increased FVC is an important determinant of increased FEV1 after lung volume reduction surgery (LVRS). We tested these predictions in 13 patients undergoing LVRS, in whom we made detailed measurements of lung mechanics. Using stepwise regression, we found that RV/TLC was the only preoperative independent predictor of the increase in FVC. Seventy percent of the increase in FEV1 was attributable to increased FVC, with the remainder due to increased FEV1/FVC. In a separate group of 78 LVRS patients evaluated with standard preoperative pulmonary function tests, RV/TLC again was found to correlate with the increase in FVC, and changes in FEV1 were also due largely to changes in FVC. However, RV/TLC was not predictive of the increase in FEV1 among the group of 78 patients, because FEV1/FVC in patients with a low preoperative RV/TLC often increased despite little change in FVC. These findings support the proposed mechanism for increased FVC following LVRS. They also illustrate the limitations of the model, and suggest further hypotheses for selecting patients who may benefit from surgery.
Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission
Authors: Heather A. Hirsch, Dimitrios Iliopoulos, Philip N. Tsichlis, Kevin Struhl
Journal: Cancer Research (2009)

The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non-stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers.
Tinea barbae due to Trichophyton rubrum with possible involvement of autoinoculation
Authors: A. Kawada, Y. Aragane, A. Maeda, T. Yudate, T. Tezuka, M. Hiruma
Journal: British Journal of Dermatology (2000)

Journal Article Tinea barbae due to Trichophyton rubrum with possible involvement of autoinoculation Get access A. Kawada, A. Kawada Department of Dermatology, Kinki University School of Medicine, Ohno‐Higashi 377–2, Osaka‐Sayama‐si, Osaka 589–8511, Japan Search for other works by this author on: Oxford Academic Google Scholar Y. Aragane, Y. Aragane Department of Dermatology, Kinki University School of Medicine, Ohno‐Higashi 377–2, Osaka‐Sayama‐si, Osaka 589–8511, Japan Search for other works by this author on: Oxford Academic Google Scholar A. Maeda, A. Maeda Department of Dermatology, Kinki University School of Medicine, Ohno‐Higashi 377–2, Osaka‐Sayama‐si, Osaka 589–8511, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Yudate, T. Yudate Department of Dermatology, Kinki University School of Medicine, Ohno‐Higashi 377–2, Osaka‐Sayama‐si, Osaka 589–8511, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Tezuka, T. Tezuka Department of Dermatology, Kinki University School of Medicine, Ohno‐Higashi 377–2, Osaka‐Sayama‐si, Osaka 589–8511, Japan Search for other works by this author on: Oxford Academic Google Scholar M. Hiruma M. Hiruma Department of Dermatology, Juntendo University School of Medicine, Hongo 2–1–1, Bunkyo‐ku, Tokyo 113–8421, Japan E‐mail: kawada@med.kindai.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 5, 1 May 2000, Pages 1064–1065, https://doi.org/10.1046/j.1365-2133.2000.03510.x Published: 01 May 2000
Consequences of inflammatory arthritis for workplace productivity loss and sick leave: a systematic review
Authors: Marie-Louise B Lenssinck, Alex Burdorf, Annelies Boonen, Monique A Gignac, Johanna M W Hazes, Jolanda J Luime
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To review the occurrence and magnitude of workplace productivity loss and sick leave in inflammatory arthritis (IA) patients and to identify determinants. <h3>Methods</h3> PubMed, EMbase, PsycINFO and CINAHL articles to July 2012 on IA and workplace productivity loss or sick leave were reviewed. Methodological quality was assessed by a criteria list developed by the authors. <h3>Results</h3> 47 original studies were identified. The occurrence of sick leave in IA patients varied from 3.7% in the past 4 days to 84% in the past 2.5 years. Total duration of sick leave ranged from 0.1 to 11 days over 1 month. Pain and functional disability were associated with sick leave and workplace productivity loss. About 17%–88% of IA patients experienced workplace productivity loss, four studies investigated determinants. Tumour necrosis factor inhibitors were associated with reduced workplace productivity loss and sick leave. <h3>Conclusions</h3> IA impacts worker productivity, but its estimated magnitude varies. Higher levels of sick leave and workplace productivity loss were reported for increased levels of pain and decreased levels of functional ability.
Impact of Drug Transporter Studies on Drug Discovery and Development
Authors: Naomi Mizuno, Takuro Niwa, Yoshihisa Yotsumoto, Yuichi Sugiyama
Journal: Pharmacological Reviews (2003)

Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.
How to identify when a performance indicator has run its course
Authors: D. Reeves, T. Doran, J. M. Valderas, E. Kontopantelis, P. Trueman, M. Sutton, S. Campbell, H. Lester
Journal: BMJ (2010)

In April 2011 eight clinical indicators will be removed from the UK Quality and Outcomes Framework. <b>David Reeves and colleagues</b> explain why they were chosen and suggest a rationale for future decisions