tbuckley/cabot-search huggingface dataset:
Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects
Authors: Christophe Borg, Magali Terme, Julien Taïeb, Cédric Ménard, Caroline Flament, Caroline Robert, Koji Maruyama, Hiro Wakasugi, Eric Angevin, Kris Thielemans, Axel Le Cesne, Véronique Chung-Scott, Vladimir Lazar, Isabelle Tchou, Florent Crépineau, François Lemoine, Jacky Bernard, Jonhantan A. Fletcher, Ali Turhan, Jean-Yves Blay, Alain Spatz, Jean-François Emile, Michael C. Heinrich, Salah Mécheri, Thomas Tursz, Laurence Zitvogel
Journal: Journal of Clinical Investigation (2004)

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell–dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
Allemande l'Asthmatique and Etude Asthmatique
Authors: D. O'Neill
Journal: BMJ (2010)

At the heart of narrative medicine is the search for a better understanding of how illness is experienced. Some of these experiences are universal and have remained constant through time; others have been alleviated by modern medicine. Our relatively ready access to effective bronchodilators and diuretics can lead us to forget how challenging asthma (and cardiac asthma) must have been in earlier times, without hope of effective succour.

Two of the most flexible, virtuosic, and humorous composers have left us unique musical insights into “asthma” in the 18th and 19th centuries. Marin Marais (1656-1728) clearly relished the challenge of programme music. His works for viola da …
Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study
Authors: Gregg W Stone, Bernhard Witzenbichler, Giora Weisz, Michael J Rinaldi, Franz-Josef Neumann, D Christopher Metzger, Timothy D Henry, David A Cox, Peter L Duffy, Ernest Mazzaferri, Paul A Gurbel, Ke Xu, Helen Parise, Ajay J Kirtane, Bruce R Brodie, Roxana Mehran, Thomas D Stuckey
Journal: The Lancet (2013)
Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study
Authors: C. Ulrich, J.S. Jürgensen, A. Degen, M. Hackethal, M. Ulrich, M.J. Patel, J. Eberle, D. Terhorst, W. Sterry, E. Stockfleth
Journal: British Journal of Dermatology (2009)

Skin cancers represent a major challenge within the ever growing group of long time surviving organ transplant recipients (OTR) world wide. Especially UV-induced non-melanoma skin cancers (NMSC) like invasive squamous cell carcinomas (SCC) and actinic keratoses (AK), and basal cell carcinoma (BCC), outnumber every other form of cancer in organ transplant recipients. Despite encouraging reports of protective effects of broad-spectrum sunscreens in immunocompetent patients, evidence for the prevention of NMSC in immunocompromised patients is still missing.To assess preventive effects of regular sun-screen use on AK, SCC and BCC in chronically immunocompromised organ transplant recipients.Hundred and twenty matched (age, sex, skin type, graft, transplant duration, previous post-transplant skin malignancies) organ transplant recipients (40 heart, 40 kidney, 40 liver grafted) were recruited for this prospective, single-center study. Both groups received equally written and oral information on sun protection measures. Sixty patients were provided with a free broad spectrum study-sunscreen (SPF>50, high-UVA absorption) for daily application of 2 mg cm(-2) to the head, neck, forearms, and hands.All 120 patients completed the 24 months study. Within this 24 month study interval 42 of the 120 patients developed 82 new AK (-102 sunscreen group vs. +82 control; P<0.01), 8 new invasive SCC (0 vs. 8; P<0.01) and 11 BCC (2 vs. 9; ns). In spite of equal numbers of AK at baseline, a marked difference in favor of the intent-to-treat sunscreen group was recorded after 24 months (89 vs. 273; P<0.01, mean difference 3.07 [1.76-4.36]) and the lesion count was significantly lower as compared to the initial visit (89 vs. 191; P<0.01, mean difference 1.7 [0.68-2.72]). With an average of 5.6 applications per week throughout the 24 months the study sunscreen was generally well tolerated. Serum 25-hydroxy vitamin D levels as marker for vitamin D status were decreased in all patients without adequate substitution and 25(OH)D was found to be lower in the sunscreen-group as compared to the control group (mean value 53 ng mL(-1) vs. 60 ng mL(-1)).Regular use of sunscreens, as part of a consequent UV-protection strategy, may prevent the development of further AK and invasive SCC and, to a lesser degree, BCC in immune-compromised organ transplant recipients.
The Micromachinery of Mechanotransduction in Hair Cells
Authors: Melissa A. Vollrath, Kelvin Y. Kwan, David P. Corey
Journal: Annual Review of Neuroscience (2007)

Mechanical stimuli generated by head movements and changes in sound pressure are detected by hair cells with amazing speed and sensitivity. The mechanosensitive organelle, the hair bundle, is a highly elaborated structure of actin-based stereocilia arranged in precise rows of increasing height. Extracellular linkages contribute to its cohesion and convey forces to mechanically gated channels. Channel opening is nearly instantaneous and is followed by a process of sensory adaptation that keeps the channels poised in their most sensitive range. This process is served by motors, scaffolds, and homeostatic mechanisms. The molecular constituents of this process are rapidly being elucidated, especially by the discovery of deafness genes and antibody targets.
The Demographic and Biomedical Case for Late-Life Interventions in Aging
Authors: Michael J. Rae, Robert N. Butler, Judith Campisi, Aubrey D. N. J. de Grey, Caleb E. Finch, Michael Gough, George M. Martin, Jan Vijg, Kevin M. Perrott, Barbara J. Logan
Journal: Science Translational Medicine (2010)

A global research agenda to slow or arrest the effects of biological aging has the potential to avert enormous economic, social, and human costs.
A telecare programme for self-management of COPD exacerbations and promotion of an active lifestyle
Authors: Monique Tabak, Marjolein Brusse-Keizer, Clara Ommeren, Hayke Kotte, Paul Weltevreden, Hermanus J. Hermens, Miriam Marie Rosé Vollenbroek-Hutten
Journal: European Respiratory Journal (2013)

Objective: The Condition Coach (CoCo) is a technology-supported care programme for self-management of COPD exacerbations and for promotion of an active lifestyle. The objective is to investigate the added value of the telecare programme in terms of clinical changes compared to usual care, and in addition, to evaluate its use and acceptance.

Intervention: CoCo consists of four modules:
1) activity coach for ambulant activity registration and real-time feedback to improve daily activity behaviour,
2) web-based exercise programme set up by the patient’s primary care physiotherapist,
3) self-treatment of COPD exacerbations via a triage diary on the webportal that provides advice to start medication when necessary, and 
4) teleconsultation via the webportal. The latter is accessible for the patient and the involved primary and secondary care professionals. 

Methods: Twenty-nine COPD patients with ≥3 exacerbations or 1 hospitalization in the past 2 years are randomly assigned to either the intervention group (CoCo programme for 9 months) or the control group (usual care). Exacerbations, activity level, exercise capacity, symptom levels, health status and quality of life are assessed to evaluate clinical changes. Page hits on the webportal show the use of the programme, and the Unified Theory of Acceptance & Use of Technology explains usage behaviour.

Results: Preliminary findings show that the webportal is highly accessed by the patients (90% of the days) with good usability (median 5.8, 7-point Likert). Remaining data will be collected in the upcoming months.

Conclusions: The CoCo programme has potential as the intervention is highly used and accepted. Final results are expected in July 2013.
Identification of enterotoxigenic Escherichia coli (ETEC) clades with long-term global distribution
Authors: Astrid von Mentzer, Thomas R Connor, Lothar H Wieler, Torsten Semmler, Atsushi Iguchi, Nicholas R Thomson, David A Rasko, Enrique Joffre, Jukka Corander, Derek Pickard, Gudrun Wiklund, Ann-Mari Svennerholm, Åsa Sjöling, Gordon Dougan
Journal: Nature Genetics (2014)
Rise in emergency admissions is multifactorial
Authors: L. S. Lewis
Journal: BMJ (2013)

Currently I have “no competing interests,” but I will have if this draconian proposal to fine me if more of my patients become “avoidable emergency admissions” is implemented. Nagpaul makes it clear that the proposal is ethically questionable and legally suspect.1 Despite the headline, McShane does not favour fining GPs but suggests “Financial incentives …
The intrinsic innervation of the canine heart: a functional study.
Authors: D V Priola, H A Spurgeon, W P Geis
Journal: Circulation Research (1977)

The intrinsic innervation of the heart has been described anatomically but seldom, functionally. These experiments were designed to verify and to evaluate the influence of intrinsic neural activation on the contractility of the atria and ventricles. Nine mongrel dogs underwent total cardiac denervation using the Geis two-stage technique. Following recovery, they were placed on total cardiopulmonary bypass. Balloons were inserted into each cardiac chamber, filled with saline, and used to record atrial and ventricular isovolumic pressures in response to intracoronary drug injections. The hearts were paced to avoid rate changes. Acetylcholine (ACh) (0.05-1.0 mug) was given to assess direct effects on the myocardium; nicotine (NIC) (25-200 mug) was used to produce indirect inotropic effects. d-Tubocurare (dTC) (1.0-2.5 mg) and tetrodotoxin (TTX) (10-30 mug) were used to differentiate the direct and the indirect effects. Both ACh and NIC produced qualitatively similar negative inotropic responses in both atria and ventricles. dTC usually produced a significantly greater blockade of responses to NIC than toACh. TTX administered to 12 other denervated dogs to differentiate direct and neurally mediated responses, completely blocked NIC-induced negative inotropy but did not change responses to ACh. The data show that (1) the intrinsic cardiac innervation can exert significant negative inotropic effects on atria and ventricles (10 to greater than 30%); (2) there is no functional evidence of participation by chromaffin cells in the inotropic responses to intrinsic nerve activation; (3) the negative inotropy produced by NIC is sensitive to dTC and, especially, TTX blockade. This is consistent with the mechanism of action being intrinsic neural stimulation.
β-Cryptoxanthin Synergistically Enhances the Antitumoral Activity of Oxaliplatin through Δ<i>NP73</i> Negative Regulation in Colon Cancer
Authors: Coral San Millán, Beatriz Soldevilla, Paloma Martín, Beatriz Gil-Calderón, Marta Compte, Belén Pérez-Sacristán, Encarnación Donoso, Cristina Peña, Jesús Romero, Fernando Granado-Lorencio, Félix Bonilla, Gemma Domínguez
Journal: Clinical Cancer Research (2015)

The acquired resistance to chemotherapy represents the major limitation in the treatment of cancer. New strategies to solve this failure and improve patients' outcomes are necessary. The cancer preventive effect of β-cryptoxanthin has been widely described in population studies. Few reports support its putative use as an antitumoral compound. Here we focus on the therapeutic potential of β-cryptoxanthin individually or in combination with oxaliplatin in colon cancer and try to decipher the molecular basis underlying its effect.Apoptosis, viability and proliferation assays, mouse models, and an intervention study in 20 healthy subjects were performed. A PCR array was carried out to unravel the molecular putative basis of the β-cryptoxanthin effect, and further signaling experiments were conducted. Comet Assay was completed to evaluate the genotoxicity of the treatments.β-Cryptoxanthin differentially regulates the expression of the P73 variants in vitro, in vivo, and in a human intervention study. This carotenoid decreases the proliferation of cancer cells and cooperates with oxaliplatin to induce apoptosis through the negative regulation of ΔNP73. The antitumoral concentrations of oxaliplatin decrease in the presence of β-cryptoxanthin to achieve same percentage of growth inhibition. The genotoxicity in peripheral blood mononuclear cells of mice decreased in the combined treatment.We propose a putative novel therapeutic strategy for the treatment of colon cancer based on the combination of β-cryptoxanthin and oxaliplatin. The combined regimen produced more benefit than either individual modality without increasing side effects. In addition, the concentration-limiting toxicity of oxaliplatin is reduced in the presence of the carotenoid.
Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter.
Authors: A E Goldfeld, P G McCaffrey, J L Strominger, A Rao
Journal: The Journal of Experimental Medicine (1993)

Tumor necrosis factor alpha (TNF-alpha), a cytokine with pleiotropic biological effects, is produced by a variety of cell types in response to induction by diverse stimuli. In this paper, TNF-alpha mRNA is shown to be highly induced in a murine T cell clone by stimulation with T cell receptor (TCR) ligands or by calcium ionophores alone. Induction is rapid, does not require de novo protein synthesis, and is completely blocked by the immunosuppressant cyclosporin A (CsA). We have identified a human TNF-alpha promoter element, kappa 3, which plays a key role in the calcium-mediated inducibility and CsA sensitivity of the gene. In electrophoretic mobility shift assays, an oligonucleotide containing kappa 3 forms two DNA protein complexes with proteins that are present in extracts from unstimulated T cells. These complexes appear in nuclear extracts only after T cell stimulation. Induction of the inducible nuclear complexes is rapid, independent of protein synthesis, and blocked by CsA, and thus, exactly parallels the induction of TNF-alpha mRNA by TCR ligands or by calcium ionophore. Our studies indicate that the kappa 3 binding factor resembles the preexisting component of nuclear factor of activated T cells. Thus, the TNF-alpha gene is an immediate early gene in activated T cells and provides a new model system in which to study CsA-sensitive gene induction in activated T cells.
ANTINUCLEAR ANTIBODIES IN RABBIT ANTISERA
Authors: Eugene V. Barnett, John H. Vaughan
Journal: The Journal of Experimental Medicine (1966)

Antinuclear antibodies were detected by immunofluorescence in most sera from rabbits immunized with whole human serum emulsified in Freund's complete adjuvant. Four of 14 sera from rabbits immunized with Cohn fractions III, IV-1, or IV-4 also gave positive nuclear fluorescence with human leukocyte nuclei. Other human and animal nuclei gave negative results with these rabbit antisera. Three rabbit anti-whole human sera had complement-fixing antibody against DNA in sufficient titer for study in quantitative complement fixation tests. Antibody with greatest reactivity with human single strand DNA was detected in the 3 rabbit antisera. Reactivity with rabbit, calf thymus, and B. natto DNA was also detected. In each case reactivity was greater with single strand than with native DNA. Antibodies against human histone and purine-6-oly BSA were also detected. No correlation was found between the titers of rheumatoidlike factors and antinuclear antibodies present in the rabbit antisera. The induction of antinuclear antibodies in these rabbits was not associated with disease attributable to the antibodies. The induction of antinuclear antibody by immunization with whole human serum was interpreted as indicating the presence of antigenic nuclear material in whole human serum.
Electrical Induction of Ventricular Fibrillation for Resuscitation From Postcountershock Pulseless and Asystolic Cardiac Arrests
Authors: Charles T. Leng, Ronald D. Berger, Hugh Calkins, Albert C. Lardo, Norman A. Paradis, Henry R. Halperin
Journal: Circulation (2001)

There is increasing evidence that defibrillation from prolonged ventricular fibrillation (VF) before CPR decreases survival. It remains unclear, however, whether harmful effects are due primarily to initial countershock of ischemic myocardium or to resultant postdefibrillation rhythms (ie, pulseless electrical activity [PEA] or asystole).We induced 15 dogs into 12 minutes of VF and randomized them to 3 groups. Group 1 was defibrillated at 12 minutes and then administered advanced cardiac life support (ACLS); group 2 was allowed to remain in VF and was subsequently defibrillated after 4 minutes of ACLS; group 3 was defibrillated at 12 minutes, electrically refibrillated, and then defibrillated after 4 minutes of ACLS. All group 1 and 3 animals were defibrillated into PEA/asystole at 12 minutes. After 4 minutes of ACLS, group 2 and 3 animals were effectively defibrillated into sinus rhythm. The extension of VF in group 2 and 3 subjects paradoxically resulted in shorter mean resuscitation times (251+/-15 and 245+/-7 seconds, respectively, versus 459+/-66 seconds for group 1; P<0.05) and improved 1-hour survival (10 of 10 group 2 and 3 dogs versus 1 of 5 group 1 dogs; Fisher's exact, P<0.005) compared with more conservatively managed group 1 subjects.Precountershock CPR during VF appears more conducive to resuscitation than CPR during postcountershock PEA or asystole. The intentional induction of VF may prove useful in the management of PEA and asystolic arrests.
Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep.
Authors: J P Wiener-Kronish, V C Broaddus, K H Albertine, M A Gropper, M A Matthay, N C Staub
Journal: Journal of Clinical Investigation (1988)

We studied anesthetized sheep to determine the relationship between increased permeability pulmonary edema and the development and mechanism of pleural effusion formation. In 12 sheep with intact, closed thoraces, we studied the time course of pleural liquid formation after 0.12 ml/kg i.v. oleic acid. After 1 h, there were no pleural effusions, even though extravascular lung water increased 50% to 6.0 +/- 0.7 g/g dry lung. By 3 h pleural effusions had formed, they reached a maximum at 5 h (48.5 +/- 16.9 ml/thorax), and at 8 h there was no additional accumulation of pleural liquid (45.5 +/- 16.9 ml). Morphologic studies by light and electron microscopy demonstrated subpleural edema but no detectable injury to the visceral pleura, suggesting that the pleural liquid originated from the lung and not the pleura. In nine sheep, we quantified the rate of formation of pleural liquid by enclosing one lung in a plastic bag. By comparing in the same sheep the volume of pleural liquid collected from the enclosed lung to the volume found in the opposite intact chest, we estimated the rate of liquid absorption from the intact chest to be 0.32 ml/(kg.h); we had previously reported a liquid absorption rate of 0.28 ml/(kg.h) in normal sheep. These studies also supported the conclusion that the majority of the pleural liquid originated from the lung because we could account for all of the pleural liquid that was formed and cleared. The volume of pleural liquid collected from the enclosed lungs was equal to 21% of the excess lung liquid that formed after oleic acid-induced lung injury. Thus, the pleural space and parietal pleural lymphatic pathways are important pathways for the clearance of pulmonary edema liquid after experimentally induced increased permeability pulmonary edema.
Peptide hydrolases in the brush border and soluble fractions of small intestinal mucosa of rat and man
Authors: Y. S. Kim, W. Birtwhistle, Y. W. Kim
Journal: Journal of Clinical Investigation (1972)

Peptide hydrolases, catalyzing the hydrolysis of 13 dipeptides and 5 tripeptides into their respective amino acids, were studied in small intestinal mucosa and other tissues, in man and in the rat. Studies on the subcellular distribution of these enzymes showed enzyme activities in both the soluble and brush border fractions of the rat small intestinal mucosa, the former constituting 80-90% and the latter 10-15% of the total activity. Zymogram studies of peptide hydrolases, in both fractions, yielded multiple bands indicating multiple zones of enzyme activity. With most substrates a rather broad range of enzyme activities was observed in the soluble fraction differing only slightly from substrate to substrate, the exception being when L-leucyl-L-proline was used: this latter led to a zymogram pattern which was quite distinct. The synthetic substrates, L-leucyl-beta-naphthylamide and L-leucinamide appeared to be hydrolyzed by two electrophoretically distinct enzymes, different from those hydrolyzing other leucyl-containing peptide substrates. Zymogram patterns of the brush border membrane fraction were quite different from those of the soluble fraction of rat small intestine indicating that enzymes from the two sources may be different. No comparable human data were obtained.Peptide hydrolases in the soluble fractions of various organs from the same species gave similar zymogram patterns, while those from the plasma membrane-bound fractions of different organs in the same species were peculiar to each organ. From these data, it is suggested that peptide hydrolases in the brush border and the soluble fractions of small intestine are distinct enzymes and may play different roles in cellular function.
The effects on offspring of premature parturition
Authors: A Cano, F Fons, J Brines
Journal: Human Reproduction Update (2001)

The time of parturition defines the length of the intrauterine period of fetal life, a requisite to achieve adequate adaptation to the external environment. Immaturity, a condition whose severity is inversely related to the length of pregnancy, is the main determinant of the increased morbidity and mortality associated with preterm birth. Despite great advances in medical technology and expertise, mainly after the introduction of the neonatal intensive care units, only one- to two-thirds of infants from the subsets with lower birthweight/gestational age reach survival at discharge. Distinct major neurological and sensorial sequelae, including cerebral palsy, retinopathy of prematurity, and hearing loss, as well as reduced neuropsychological abilities, leading to deficient academic achievement and deterioration of several aspects of health status, are still highly prevalent among the most immature children. Interestingly, decreasing mortality rates, which are not followed by detectable increases of disability, are being observed in recent years. Future advances may be expected from clinical and basic research on uterine contractility and cervical softening. Also, changes in reproductive technology procedures, a main factor in the incidence of multiple pregnancies, and a more refined approach to obstetric care, compose some of the clinical interventions which may reduce the problem.