tbuckley/cabot-search huggingface dataset:
Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice
Authors: Y LIAO, M ASAKURA, S TAKASHIMA, A OGAI, Y ASANO, H ASANUMA, T MINAMINO, H TOMOIKE, M HORI, M KITAKAZE
Journal: Cardiovascular Research (2004)

Objective: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling.
A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors
Authors: Archie N. Tse, David S. Klimstra, Mithat Gonen, Manish Shah, Tahir Sheikh, Rachel Sikorski, Richard Carvajal, Janet Mui, Caroll Tipian, Eileen O'Reilly, Ki Chung, Robert Maki, Robert Lefkowitz, Karen Brown, Katia Manova-Todorova, Nian Wu, Merrill J. Egorin, David Kelsen, Gary K. Schwartz
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. Experimental Design: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity. Results: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD. Conclusions: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.
Re: You Say Tomato and I Say Tomahto: Getting a Handle on Pronouncing Apoptosis
Authors: D. L. LONGO
Journal: JNCI Journal of the National Cancer Institute (1997)

You Say Tomato and I Say Tomahto: Getting a Handle on Pronouncing ApoptosisI am writing about the item in the News section (1) in which Bob Kuska attempted to lay to rest the controversy over the pronunciation of ''apoptosis.''Although it is true that a proper name can be pronounced any way at all (e.g., Tagliaferro is often pronounced ''Tolliv-er''), there are rules for Greek pronunciation and they do not include silencing the ''p'' in ''pt'' when it occurs in the middle of the word.Following the author's recommendation, helicopter would be ''hel-i-cot-er,'' proptosis would be ''prot-osis,'' and lepidoptera would be ''lep-i-dot-era.''With all due respect to Kerr et al. ( 2), it would not seem necessary to change the rules of Greek pronunciation simply to accommodate the process they observed.By the way, pathologists have been recognizing this process for many years on light microscopic examination, but they called it ''karyorrhexis'' from karyon for nucleus or nut and rhexis, a breaking.A new word to describe the process may not have been necessary in the first place; making up new rules for pronouncing it seems even less justified.
Lesson of the week: The painful red foot---inflammation or ischaemia?
Authors: W. Humphreys
Journal: BMJ (1999)

Although a recent history of a painful foot may indicate gout or cellulitis, a diagnosis of severe ischaemia should always be suspected, even when the foot is erythematous. Failure to recognise severe foot ischaemia can have an adverse impact on the outcome for the patient —and may have legal consequences for the doctor— as the three cases discussed below illustrate.

Case 1 —A 72 year old woman presented with a three day history of pain in her left foot. The pain was worse at night and was described as “throbbing.” The family doctor, who visited the woman, diagnosed cellulitis and prescribed antibiotics. Three days later the condition had not improved. The woman was eventually admitted to hospital by another general practitioner, who believed that she might have ischaemia as he had difficulty detecting a pulse. Physical examination showed that the foot was erythematous while dependent but cool to the touch and pale when it was raised. The patient was investigated by Doppler ultrasonography and arteriography, and ischaemia was confirmed. Femoropopliteal artery bypass surgery was carried out, and this relieved the pain.

Case 2 —A 52 year old man presented to his general practitioner with a three day history of pain in his left foot. At that time the forefoot looked red and inflamed. The man was treated with oral antibiotics, but after four days there was no improvement and his toes had become blue and lacked sensation. The patient …
Small airway obstruction in severe pulmonary arterial hypertension correlates with increased airway CD8+ T-cells and fractalkine expression
Authors: C. Ars, P. Thurion, M. Delos, Y. Sibille, C. Pilette
Journal: European Respiratory Journal (2009)

To the Editors: 

Pulmonary arterial hypertension (PAH) is primarily a disease of lung small arteries. However, several studies have documented mild-to-moderate peripheral airflow obstruction in most adults 1–3 and children 4 with PAH, which could be significantly reversed with β2-agonist administration 5. Although peribronchial infiltrates have been scarcely reported in PAH 1, it is still unclear whether airway dysfunction occurs as a result of lung vascular disease or from a direct impairment of the airways.

In lung specimens from six patients with severe group I PAH 6 undergoing lung transplantation (and who did not display signs of cardiopulmonary decompensation at that time), we assessed airway inflammatory cell infiltration and PAH-related chemokine expression in comparison with specimens from nine nonsmoking controls (sampled as far as possible from the tumour) and correlated findings to lung function data. Patient's characteristics and lung function tests are summarised in table 1⇓.

View this table:

Table 1— 
Patients' characteristics with hemodynamic and lung function tests



No impairment of routine lung function tests was observed in PAH patients, except a trend for lower forced expiratory volume in 1 s and increased residual volume. However, among indices of small airway …
Signal Transformations Required for the Generation of Saccadic Eye Movements
Authors: D L Sparks, L E Mays
Journal: Annual Review of Neuroscience (1990)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery
Authors: Jean L. Rouleau, Wayne J. Warnica, Richard Baillot, Pierre J. Block, Sidney Chocron, David Johnstone, Martin G. Myers, Cristina-Dana Calciu, Sonia Dalle-Ave, Pierre Martineau, Christine Mormont, Wiek H. van Gilst
Journal: Circulation (2007)

Background— Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. Methods and Results— The Ischemia Management with Accupril post–bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (≤7 days) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction ≥40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio 1.15, 95% confidence interval 0.92 to 1.42, P =0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P =0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG. Conclusions— In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk.
UK becomes first country to allow mitochondrial donation
Authors: Z. Kmietowicz
Journal: BMJ (2015)

Britain has become the first country in the world to allow mitochondrial donation to prevent serious genetic inherited diseases, after the House of Lords voted in favour of a change in the law to permit new in vitro fertilisation (IVF) techniques.

Peers voted by 280 to 48 in favour of new regulations on 24 February, three weeks after MPs in the House of Commons approved the techniques by 382 votes to 128.1 The vote has been hailed as “wonderful news for patients and families” and a “great day for UK science” by leading scientists.

The regulations governing the techniques will come into force at the end …
Metacognition is prior
Authors: Justin J. Couchman, Mariana V. C. Coutinho, Michael J. Beran, J. David Smith
Journal: Behavioral and Brain Sciences (2009)

Abstract We agree with Carruthers that evidence for metacognition in species lacking mindreading provides dramatic evidence in favor of the metacognition-is-prior account and against the mindreading-is-prior account. We discuss this existing evidence and explain why an evolutionary perspective favors the former account and poses serious problems for the latter account.
Decreased FOXP3 expression in small airways of smokers with COPD
Authors: S. Isajevs, I. Taivans, G. Strazda, U. Kopeika, M. Bukovskis, V. Gordjusina, A. Kratovska
Journal: European Respiratory Journal (2008)

CD4+CD25+ FOXP3-positive T-regulatory cells have an important role in controlling immune and inflammatory reactions. The present authors hypothesise that these cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of the present study was to characterise the expression of FOXP3 in large and small airways of nonsmokers, smokers with normal lung function and COPD patients. A total of 19 nonsmokers, 20 smokers with normal lung function and 20 smokers with moderate COPD, undergoing lung resection for a solitary peripheral nonsmall cell carcinoma, were enrolled in the study. Immunohistochemical methods were used to evaluate FOXP3 expression in large and small airways. Smokers with normal lung function and COPD patients had increased numbers of FOXP3-positive cells in large airways compared with nonsmokers. A positive correlation was observed between FOXP3 expression in large airways and smoked pack-yrs. In small airways, COPD patients had decreased numbers of FOXP3-positive cells, compared with asymptomatic smokers and nonsmokers, that negatively correlated with airflow obstruction. To conclude, chronic obstructive pulmonary disease is characterised by upregulation of FOXP3-positive cells in large airways but a downregulation in small airways that correlated with airflow limitation. The results of the present study contribute to a better understanding of the pathogenesis of chronic obstructive pulmonary disease.
Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors
Authors: Euan C. Ramsay, Malathi Anantha, Jason Zastre, Marieke Meijs, Jet Zonderhuis, Dita Strutt, Murray S. Webb, Dawn Waterhouse, Marcel B. Bally
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C, a novel liposomal formulation of irinotecan (CPT-11). Experimental Design: The plasma lactone/carboxy levels of CPT-11 and SN-38 were determined in mice after a single i.v. dose of irinotecan (Camptosar), or Irinophore C, and the plasma t1/2, plasma area under the curve, plasma Cmax, and plasma clearance were calculated. Further, plasma and tumor drug levels were also measured in tumor-bearing mice following Irinophore C treatment. The efficacy of Irinophore C was compared with that of Camptosar in five s.c. human tumor xenografts using single-dose treatment (LS 180), a total of three doses administered at 4-day intervals (H460), or a total of three doses administered at 7-day intervals (Capan-1, PC-3, and HT-29). Results: Compared with Camptosar, Irinophore C mediated an 8-fold increase in t1/2, a 100-fold increase in Cmax, a 1,000-fold increase in area under the curve, and a 1,000-fold decrease in clearance for the active lactone form of CPT-11. Further, the plasma and tumor SN-38 lactone levels were consistent for at least 48 h post-Irinophore C injection. Camptosar treatment (40 mg/kg) mediated a delay in the time required for tumors to increase to four times their pretreatment size compared with controls (T-C). T-Cs ranged from 2 days (LS 180 model) to 18 days (PC-3 model). Irinophore C (40 mg/kg) engendered T-Cs ranging from 14 days (LS 180 model) to 87 days (Capan-1 model). Conclusion: Irinophore C improved CPT-11/SN-38 pharmacokinetics, promoted tumor drug accumulation, and increased therapeutic efficacy in a panel of five distinct human tumor xenografts.
Willful Modulation of Brain Activity in Disorders of Consciousness
Authors: Martin M. Monti, Audrey Vanhaudenhuyse, Martin R. Coleman, Melanie Boly, John D. Pickard, Luaba Tshibanda, Adrian M. Owen, Steven Laureys
Journal: New England Journal of Medicine (2010)

The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patient's capacity to show behavioral signs of awareness is diminished.At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patient's ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions.Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside.These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive.
The Possible Role of EWS-Fli1 in Evasion of Senescence in Ewing Family Tumors
Authors: Tomoya Matsunobu, Kazuhiro Tanaka, Tomoyuki Nakamura, Fumihiko Nakatani, Riku Sakimura, Masuo Hanada, Xu Li, Takamitsu Okada, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto
Journal: Cancer Research (2006)

Abstract The chromosomal translocation t(11;22) yields the EWS-Fli1 fusion gene and is associated with oncogenesis of Ewing family tumors (EFT). In this study, using the RNA interference method, we show that EWS-Fli1–targeting small interfering RNAs (siRNA) depleted EWS-Fli1 protein and caused growth inhibition in EFT cells with the accumulation of p27 protein and the down-regulation of Skp2 protein in dose-dependent, time-dependent, and sequence-specific manners. Depletion of EWS-Fli1 subacutely elicited a senescence-like phenotype, but not apoptosis, in EFT cells. Furthermore, not only the knockdown of p27, but also the forced expression of Skp2, reduced the expression levels of p27 protein and partially rescued senescence-like phenotype caused by EWS-Fli1–targeting siRNAs. The accumulation of p27 protein in EWS-Fli1–depleted cells inhibited cdk2 kinase activity and was related to the stability of p27 protein, which resulted from a decrease in Skp2 protein. Immunohistochemical analysis of p27 and Skp2 proteins in EFT samples revealed that there was an inverse relationship between the expression profiles of p27 and Skp2 proteins. These findings indicate an important role of EWS-Fli1 in the prevention of senescence, leading to the unlimited growth and oncogenesis of EFT cells through a decrease in the stability of p27 protein due to increased action of Skp2-mediated 26S proteasome degradation. (Cancer Res 2006; 66(2): 803-11)
Real-time analysis of T cell receptors in naive cells in vitro and in vivo reveals flexibility in synapse and signaling dynamics
Authors: Rachel S. Friedman, Peter Beemiller, Caitlin M. Sorensen, Jordan Jacobelli, Matthew F. Krummel
Journal: The Journal of Experimental Medicine (2010)

The real-time dynamics of the T cell receptor (TCR) reflect antigen detection and T cell signaling, providing valuable insight into the evolving events of the immune response. Despite considerable advances in studying TCR dynamics in simplified systems in vitro, live imaging of subcellular signaling complexes expressed at physiological densities in intact tissues has been challenging. In this study, we generated a transgenic mouse with a TCR fused to green fluorescent protein to provide insight into the early signaling events of the immune response. To enable imaging of TCR dynamics in naive T cells in the lymph node, we enhanced signal detection of the fluorescent TCR fusion protein and used volumetric masking with a second fluorophore to mark the T cells expressing the fluorescent TCR. These in vivo analyses and parallel experiments in vitro show minimal and transient incorporation of TCRs into a stable central supramolecular activating cluster (cSMAC) structure but strong evidence for rapid, antigen-dependent TCR internalization that was not contingent on T cell motility arrest or cSMAC formation. Short-lived antigen-independent TCR clustering was also occasionally observed. These in vivo observations demonstrate that varied TCR trafficking and cell arrest dynamics occur during early T cell activation.
Hemodynamic and Metabolic Effects of Hemorrhage in Man, with Particular Reference to the Splanchnic Circulation
Authors: Henry L. Price, Stanley Deutsch, Bryan E. Marshall, George W. Stephen, Marjam G. Behar, Gordon R. Neufeld
Journal: Circulation Research (1966)

1. Eleven normal subjects were studied before and after removal of 15 to 20% of their blood volume within 35 minutes. 2. This amount of blood loss did not produce conspicuous effects upon any of the usually measured circulatory or metabolic parameters. 3. The results suggest that the splanchnic circulation functions as an important blood reservoir in man, that it can be preferentially depleted of blood by a mechanism which does not automatically increase vascular resistance, and that the ability of our subjects to tolerate blood loss was attributable in large part to this response.
Influence of Balloon Pressure During Stent Placement in Native Coronary Arteries on Early and Late Angiographic and Clinical Outcome
Authors: Josef Dirschinger, Adnan Kastrati, Franz-Josef Neumann, Peter Boekstegers, Shpend Elezi, Julinda Mehilli, Helmut Schühlen, Jürgen Pache, Eckhard Alt, Rudolf Blasini, Gerhard Steinbeck, Albert Schömig
Journal: Circulation (1999)

Background —High-pressure dilatation is considered a better stent placement strategy, but this has not yet been proved by appropriately designed studies. The objective of this randomized trial was to assess the role of high-pressure dilatation in the early and late outcome of patients undergoing coronary stent placement. Methods and Results —Consecutive patients with coronary stent placement were randomly assigned to high- (15 to 20 atm, 468 patients) or low- (8 to 13 atm, 466 patients) balloon-pressure dilatation. The primary end point of the study was the event-free survival at 1 year. Secondary end points were the incidence of stent thrombosis at 30 days and angiographic restenosis (≥50% diameter stenosis) at 6 months. The incidence of stent thrombosis was 1.7% in the high-pressure and 1.9% in the low-pressure group (relative risk 0.89; 95% CI 0.30 to 2.56). During the first 30 days, although there was no significant difference in the incidence of Q-wave myocardial infarction, the incidence of non–Q-wave infarction was 6.4% in the high-pressure and 3.4% in the low-pressure group (relative risk 1.87; 95% CI 1.02 to 3.42). The restenosis rate was 30.4% in the high-pressure and 31.4% in the low-pressure group (relative risk 0.97; 95% CI 0.75 to 1.26). Event-free survival at 1 year was not significantly different between the groups, with 78.8% in high-pressure patients and 75.5% in patients assigned to low-pressure dilatation (hazard ratio 0.85; 95% CI 0.65 to 1.11). Conclusions —The systematic use of high-balloon-pressure inflation (15 to 20 atm) during coronary stent placement is not associated with any significant influence on the 1-year outcome of patients undergoing this intervention.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study: 30th Anniversary Presentations
Authors: Bernard Zinman, Saul Genuth, David M. Nathan
Journal: Diabetes Care (2013)

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) both recognized the seminal contributions of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, by scheduling a dedicated DCCT/EDIC symposium in their respective programs “The DCCT/EDIC study: 30 years of progress and contributions.”

We are very grateful that both organizations provided the DCCT/EDIC Research Group this important opportunity to highlight our advances and contributions to improving the health and quality of life of people with type 1 diabetes (T1D). What …