tbuckley/cabot-search huggingface dataset:
B-Raf Inhibition in the Clinic: Present and Future
Authors: Warren Fiskus, Nicholas Mitsiades
Journal: Annual Review of Medicine (2016)

Somatic activating mutations in the B-Raf kinase (BRAF mutations) are present in hairy-cell leukemia, cutaneous melanoma, thyroid carcinomas and, less commonly, in ovarian, colon, lung, and other malignancies. These mutations—in particular the most common substitution, V600E—are oncogenic drivers and important therapeutic targets. The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic. In BRAF-mutant melanomas, orally bioavailable B-Raf inhibitors, such as vemurafenib, achieve dramatic responses initially, but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches. In tumors with wild-type B-Raf, vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated, highlighting again the importance of genotype-based clinical decision making. These advances were greatly facilitated by the study of biopsied tumor tissue, especially at the time of drug resistance. Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future.
Elastase and cathepsin G activities are present in immature bone marrow neutrophils and absent in late marrow and circulating neutrophils of beige (Chediak-Higashi) mice.
Authors: K H Takeuchi, M P McGarry, R T Swank
Journal: The Journal of Experimental Medicine (1987)

Elicited peritoneal neutrophils of beige (Chediak-Higashi) mice essentially lack activities of the neutral serine proteinases elastase and cathepsin G, which may explain the increased susceptibility to infection of beige mice and Chediak-Higashi patients. We have examined neutrophils of beige mice at earlier points in their development to determine if the proteinase genes are never expressed or whether they are expressed and then lost during neutrophil maturation. Surprisingly, bone marrow of beige mice had significant elastase and cathepsin G activity (approximately 60% of normal). The results of several experiments indicate that neutrophils were the sole source of elastase and cathepsin G in bone marrow. Neutral proteinase activity was readily demonstrable by histochemical procedures in beige marrow neutrophil precursors up to and including the metamyelocyte stage. However, mature neutrophils of beige marrow had greatly decreased activity. Also mature neutrophils (PMNs) of the peripheral circulation, like peritoneal neutrophils, had very low elastase and cathepsin C activities. Thus we conclude that beige neutrophil precursors express neutral proteinase activity, which is largely and irreversibly depleted by the time they fully mature in marrow.
Surveillance des activités de dépistage et contrôle de dépistage de l’hépatite C au sein du réseau de laboratoires RENA-VHC, France, 2000-2001
Authors: Christine Meffre, Christine Larsen, Annie Périn, Laurence Bouraoui, Elisabeth Delarocque-Astagneau
Journal: Eurosurveillance (2003)

Durant les annees 2000-2001, 189 laboratoires prives et hospitaliers, repartis sur toute la France, ont participe au reseau sentinelle RENA-VHC. Au total, 759 591 serologies (depistage et controle de depistage) ont ete effectuees avec une augmentation de 10% entre 2000 et 2001. Le rapport entre le total des tests positifs de controle de depistage et le total des tests realises etait de 1,2% en 2000 et 1,0% en 2001, suggerant que le depistage a plus souvent concerne des personnes peu ou pas a risque. Les personnes confirmees positives etaient en majorite des hommes (sex ratio 1,5) et 31% d'entre eux etaient âges de 30 a 39ans.
Re: Diagnostic Testing Following Screening Mammography in the Elderly
Authors: R. Clark
Journal: JNCI Journal of the National Cancer Institute (1999)

Re: Diagnostic Testing Following Screening Mammography in the ElderlyI enjoyed the excellent report by Welch and Fisher (1), describing the screening and subsequent diagnostic experience of women in the Medicare population.These authors report a screening-incurred work-up rate of 8.5% and positive predictive values of 0.08-0.14 in women more than 65 years of age.They conclude that the general practice of mammography in the United States may involve lower thresholds (and higher rates) for subsequent testing than have been expected or previously reported.My own interpretation of their data was somewhat different.Published guidelines for the practice of screening mammography in this country state the expectations for quality mammography practice, including an incurred work-up rate of less than 10% and positive predictive values of 0.05-0.10(2,3).One would expect, because of the higher prevalence of cancer in older women, that the biopsy rates and positive predictive values in older women would be greater than in younger women.Moreover, there is evidence that reducing the incurred work-up rate substantially below 8%-10% reduces the sensitivity of mammography and the number of cancers detected per 1000 women screened (4).To analyze rates of incurred workup and positive predictive values without including related outcome data is looking at only a small part of the picture.
Single-chamber cardiac pacing with activity-initiated chronotropic response: evaluation by cardiopulmonary exercise testing.
Authors: D G Benditt, M Mianulli, J Fetter, D W Benson, A Dunnigan, E Molina, C C Gornick, A Almquist
Journal: Circulation (1987)

In this study, sequential cardiopulmonary exercise testing was used to assess the physiologic benefits of a single-chamber ventricular pacing system that utilizes a piezoceramic sensor to adjust heart rate by detecting "physical activity." An initial exercise test was conducted with the pacemaker programmed (based on a randomization table) to either the fixed rate (VVI, 70 beats/min) or rate-variable (VVI-Act) mode, and the results were compared with those obtained during a second exercise test in which the pacemaker was programmed to the alternate pacing mode. A 1.5 to 2 hr rest period was permitted between exercise tests, each of which consisted of a symptom-limited constant speed (3.0 mph) Balke protocol with 2 min stages commencing at 0.0% grade with increments of 2.5% at end of each stage. Compared with findings during fixed-rate VVI pacing, VVI-Act pacing was associated with greater exercise-induced positive chronotropic response (mean maximum heart rate VVI-Act 128 +/- 15.3 beats/min vs VVI 90 +/- 28.4 beats/min; p less than .01), prolongation of exercise duration (VVI-Act 10.2 +/- 3.8 min vs VVI 7.7 +/- 2.5 min; p less than .01), increased peak oxygen consumption (VVI-Act 1617 +/- 656 ml O2/min vs VVI 1325 +/- 451 ml O2/min; p less than .01), and onset of anaerobic threshold at a higher oxygen consumption (VVI-Act 1208 +/- 343 ml O2/min vs VVI 1064 +/- 377 ml O2/min: p less than .01). Additionally, of 44 comparable exercise stages tested in the two pacing modes, perceived exertion (assessed by a numerical grading system) was lower in 38 of 44 instances during VVI-Act compared with VVI pacing.(ABSTRACT TRUNCATED AT 250 WORDS)
Modified epithelial cell distribution in chronic airways inflammation
Authors: C Chapelin, A Coste, L Gilain, F Poron, F Verra, E Escudier
Journal: European Respiratory Journal (1996)

Although airway epithelium is known to be modified during chronic respiratory diseases, epithelial cells have rarely been precisely quantified. We therefore intended to evaluate epithelial cell distribution in inflammatory airways, using a cytological approach. Nasal airway cells in 12 patients with nonallergic chronic rhinitis were sampled by brushing, quantified after cytocentrifugation and compared to those from eight controls. Cell populations were quantified after May-Grünwald Giemsa staining and alpha-tubulin immunolabelling to demonstrate ciliary differentiation. When compared to controls, rhinitis patients exhibited lower percentages of ciliated cells (59 +/- 4 versus 32 +/- 2%, respectively), and higher percentages of goblet (24 +/- 3 versus 37 +/- 2%) and basal cells (9 +/- 1 versus 18 +/- 2%). After tubulin immunolabelling, positive staining was specifically detected in cells with cilia (LC+), and in the cytoplasm of some small round cells without obvious cilia (LC-). Fewer immunolabelled cells were detected in rhinitis patients than in controls (with significantly lower percentages of LC+ and higher percentages of LC-). Nasal brushing is an effective technique for quantification of airway epithelial cells. Tubulin immunolabelling is useful to detect ciliated cells and distinguishes another cell population, possibly preciliated cells. These cytological findings suggest the presence of modifications of epithelial differentiation and proliferation, possibly related to local chronic inflammation.
Enhancement of Fibrinolysis With 40-kHz Ultrasound
Authors: Valentina Suchkova, Farhan N. Siddiqi, Edwin L. Carstensen, Diane Dalecki, Sally Child, Charles W. Francis
Journal: Circulation (1998)

Background —Ultrasound at frequencies of 0.5 to 1 MHz and intensities of ≥0.5 W/cm 2 accelerates enzymatic fibrinolysis in vitro and in some animal models, but unacceptable tissue heating can occur, and limited penetration would restrict application to superficial vessels. Tissue heating is less and penetration better at lower frequencies, but little information is available regarding the effect of lower-frequency ultrasound on enzymatic fibrinolysis. We therefore examined the effect of 40-kHz ultrasound on fibrinolysis, tissue penetration, and heating. Methods and Results — 125 I-fibrin–radiolabeled plasma clots in thin-walled tubes were overlaid with plasma containing tissue plasminogen activator (tPA) and exposed to ultrasound. Enzymatic fibrinolysis was measured as solubilization of radiolabel. Tissue attenuation and heating were examined in samples of porcine rib cage. Fibrinolysis was increased significantly in the presence of 40-kHz ultrasound at 0.25 W/cm 2 , reaching 39±7% and 93±11% at 60 minutes and 120 minutes, compared with 13±8% and 37±4% in the absence of ultrasound ( P &lt;0.0001). The acceleration of fibrinolysis increased at higher intensities. Attenuation of the ultrasound field was only 1.7±0.5 dB/cm through the intercostal space and 3.4±0.9 dB/cm through rib. Temperature increments in rib were &lt;1°C/(W/cm 2 ). Conclusions —These findings indicate that 40-kHz ultrasound significantly accelerates enzymatic fibrinolysis at intensities of ≥0.25 W/cm 2 with excellent tissue penetration and minimal heating. Externally applied 40-kHz ultrasound at low intensities is a potentially useful therapeutic adjunct to enzymatic fibrinolysis with sufficient tissue penetration for both peripheral vascular and coronary applications.
Regulation of megakaryocyte colony forming cell numbers and ploidy by dideoxynucleosides in immunodeficient mice
Authors: Fung‐Phing R. Chow, José V. Ordóñez, Patricia A. Sutton, Anne W. Hamburger
Journal: American Journal of Hematology (1993)

Abstract We have recently demonstrated that azidothymidine (AZT) elevates the levels of circulating platelets in mice made immune deficient by infection with LP‐BM5 murine leukemia virus (MAIDS mice). In an attempt to elucidate the mechanisms of the AZT platelet elevating effect, we examined the number of splenic and bone marrow megakaryocyte colony‐forming cells (CFU‐mk) and the ploidy of megakaryocytes derived from CFU‐mk using fluorescence cytophotometric methods. Two other dideoxynucleosides (ddN) 2′3′‐dideoxyinosine (ddL) and 2′3′‐dideoxycytidine (ddC) were assessed to determine the specificity of the effect of AZT. MAIDS mice were given ddN in drinking water for 15 days. AZT was the only ddN that significantly increased circulating platelet levels in MAIDS mice. AZT significantly increased splenic CFU‐mk in MAIDS mice, but bone marrow CFU‐mk were not affected. ddL and ddC failed to change either platelet levels or the numbers of splenic or bone marrow CFU‐mk. The ploidy of megakaryocytes derived from splenic and bone marrow CFU‐mk were examined by first identifying CFU‐mk by staining for acetylcholinesterase, followed by nuclear staining with propidium iodide. The fluorescence of individual cells was then measured using a Perceptics image analysis system. Modal ploidy of CFU‐mk megakaryocytes derived from spleen cells of AZT‐treated immunodeficient mice was shifted upwards from 16N to 32N. Similarly, AZT treatment changed the modal ploidy number of colony megakaryocytes derived from bone marrows of immunodeficient mice from 16N to 32N. The ploidy distribution was also significantly shifted. ddL and ddC failed to significantly alter either modal ploidy number or distribution of megakaryocytes derived from splenic or bone marrow CFU‐mk. These findings suggest that AZT may affect physiological processes that lead to platelet formation. © 1993 Wiley‐Liss, Inc.
Predicting response to peginterferon -2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B
Authors: F Bonino, P Marcellin, G K K Lau, S Hadziyannis, R Jin, T Piratvisuth, G Germanidis, C Yurdaydin, M Diago, S Gurel, M-Y Lai, M R Brunetto, P Farci, M Popescu, P McCloud
Journal: Gut (2006)

In a trial of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B, 24 week post-treatment biochemical and virological response rates with peginterferon alpha-2a with or without lamivudine were significantly higher than with lamivudine alone. The effect of pre-treatment factors on post-treatment responses was investigated.Multivariate analyses were performed using available data from 518 patients treated with peginterferon alpha-2a with or without lamivudine, or with lamivudine alone. A post-treatment response was defined as alanine aminotransferase (ALT) normalisation and hepatitis B virus (HBV) DNA level of <20,000 copies/ml.In logistic regression analyses across all treatment arms, peginterferon alpha-2a (with or without lamivudine) therapy, younger age, female gender, high baseline ALT, low baseline HBV DNA and HBV genotype were identified as significant predictors of combined response at 24 weeks post-treatment. In the peginterferon alpha-2a and lamivudine monotherapy arms, patients with genotypes B or C had a higher chance of response than genotype D infected patients (p<0.001), the latter responding better to the combination than to peginterferon alpha-2a monotherapy (p = 0.015). At 1 year post-treatment, response rates by intention-to-treat analysis were 19.2% for the peginterferon alpha-2a, 19.0% for the combination, and 10.0% for the lamivudine groups, with genotypes B or C associated with a sustained combined response to peginterferon alpha-2a with or without lamivudine therapy.Baseline ALT and HBV DNA levels, patient age, gender, and infecting HBV genotype significantly influenced combined response at 24 weeks post-treatment, in patients treated with peginterferon alpha-2a and/or lamivudine. At 1 year post-treatment HBV genotype was significantly predictive of efficacy for patients treated with peginterferon alpha-2a with or without lamivudine.
Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas
Authors: A. Larghi, N. Panic, G. Capurso, E. Leoncini, D. Arzani, R. Salvia, M. Del Chiaro, L. Frulloni, P.G. Arcidiacono, A. Zerbi, R. Manta, C. Fabbri, M. Ventrucci, I. Tarantino, M. Piciucchi, A. Carnuccio, U. Boggi, G. Costamagna, G. Delle Fave, R. Pezzilli, C. Bassi, M. Bulajic, W. Ricciardi, S. Boccia
Journal: Annals of Oncology (2013)
Efficacy of bath psoralen plus ultraviolet A (PUVA) vs. system PUVA in psoriasis: a prospective, open, randomized, multicentre study
Authors: M. Berneburg, T. Herzinger, J. Rampf, W. Hoetzenecker, E. Guenova, C. Meisner, J. Maetzke, T. Schaefer, B. Eberlein, K. Scharffetter-Kochanek, M. Rocken
Journal: British Journal of Dermatology (2013)

Plaque psoriasis is an inflammatory disease affecting approximately 2% of the population. The clinical hallmarks of psoriasis are sharply demarcated, erythematous plaques with thick scales. Photochemotherapy (psoralen plus ultraviolet A, PUVA) is one of the most effective therapies of psoriasis. The photosensitizer 8-methoxypsoralen (8-MOP) can be applied either orally (system PUVA) or topically in a warm water bath (bath PUVA).To compare bath PUVA and system PUVA in the treatment of plaque psoriasis.This was a randomized, open, prospective, multicentre trial. We included 74 patients with moderate-to-severe plaque psoriasis during a 6-week treatment and a 4-week follow-up period. Of the patients enrolled in the study, 38 received bath PUVA and 36 system PUVA.Both treatment modalities significantly reduced the median Psoriasis Area and Severity Index (PASI) score in the intention-to-treat population. Within 6 weeks bath PUVA reduced the median PASI by 74% (16·4 to 4·2) while system PUVA did so by 62% (15·3 to 5·8). The difference between the two modalities was not significant with regard to treatment efficacy (P = 0·389).There is no difference between bath PUVA and system PUVA in the treatment of psoriasis.
Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension
Authors: Reda E. Girgis, Hunter C. Champion, Gregory B. Diette, Roger A. Johns, Solbert Permutt, J. T. Sylvester
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Decreased nitric oxide (NO) is considered an important pathogenetic mechanism in pulmonary arterial hypertension (PAH), but clear evidence is lacking. Objectives: We used multiple techniques to assess endogenous NO in 10 patients with untreated PAH (8 idiopathic and 2 anorexigen-associated PAH) and 12 control subjects. Methods: After a nitrite/nitrate-restricted diet, NO metabolites (NOx) were assayed in 24-hour urine collections and exhaled NO (FENO) determined at multiple expiratory flows. Analysis of the relation between FENO and flow allowed derivation of three flow-independent parameters: airway wall concentration (CW), diffusing capacity (DNO), and alveolar concentration (CA). Seven patients underwent follow-up testing after 3 months of bosentan treatment. Results: At baseline, FENO was markedly decreased at the two lowest expiratory flows in PAH: 21 ± 4 versus 36 ± 4 ppb at 18 ml/second and 11 ± 2 versus 17 ± 2 ppb at 50 ml/second, for subjects with PAH and control subjects, respectively (p < 0.05). CW was 33 ± 11 ppb in subjects with PAH versus 104 ± 34 in control subjects (p = 0.04). Urinary NOx was also reduced in PAH (42 ± 6 μM NOx/mM creatinine versus 62 ± 7 in control subjects; p = 0.04). After bosentan, FENO, CW, and urine NOx increased to control values (p < 0.05). Exclusion of the two anorexigen cases did not alter these results. Conclusions: FENO at low expiratory flows was decreased in PAH due to reduced CW. Bosentan reversed these abnormalities, suggesting that suppression of NO in PAH may have been caused by endothelin.
Activity and Regulation of Low Density Lipoprotein Receptors in a Human Hepatoblastoma Cell Line
Authors: George Y. Wu, Catherine H. Wu, Vincent A. Rifici, Richard J. Stockert
Journal: Hepatology (1984)

The responsiveness of low density lipoprotein (LDL) binding and uptake was measured in a human hepatoblastoma cell line, Hep G2. These cells exhibited both saturable, high-affinity and nonsaturable low-affinity components similar to that described for LDL binding in other mammalian cells. In addition, receptor-mediated uptake of [125I]LDL was dependent on the presence of Ca++ and required intact lysine residues in LDL as evidenced by abolition of binding following reductive methylation of LDL. The receptor activity was rapidly responsive to changes made in LDL concentrations in the medium, up-regulating by 200% in the absence of LDL, and down-regulating by 56% in the presence of LDL, both changes occurring within 2 hr. Cholesterol synthesis was estimated by measuring 3-hydroxymethylglutaryl coenzyme A reductase activity. The activity of this enzyme was also found to increase rapidly in the absence of LDL and decrease rapidly in the presence of LDL in the media. The human cell line Hep G2 possesses an active and responsive receptor for LDL and provides a useful model for the study of lipoprotein uptake and metabolism in intact human liver.
New Insights into the Nature and Phylogeny of Prasinophyte Antenna Proteins: Ostreococcus tauri, a Case Study
Authors: Christophe Six, Alexandra Z. Worden, Francisco Rodríguez, Hervé Moreau, Frédéric Partensky
Journal: Molecular Biology and Evolution (2005)

The basal position of the Mamiellales (Prasinophyceae) within the green lineage makes these unicellular organisms key to elucidating early stages in the evolution of chlorophyll a/b–binding light-harvesting complexes (LHCs). Here, we unveil the complete and unexpected diversity of Lhc proteins in Ostreococcus tauri, a member of the Mamiellales order, based on results from complete genome sequencing. Like Mantoniella squamata, O. tauri possesses a number of genes encoding an unusual prasinophyte-specific Lhc protein type herein designated "Lhcp". Biochemical characterization of the complexes revealed that these polypeptides, which bind chlorophylls a, b, and a chlorophyll c–like pigment (Mg-2,4-divinyl-phaeoporphyrin a5 monomethyl ester) as well as a number of unusual carotenoids, are likely predominant. They are retrieved to some extent in both reaction center I (RCI)– and RCII-enriched fractions, suggesting a possible association to both photosystems. However, in sharp contrast to previous reports on LHCs of M. squamata, O. tauri also possesses other LHC subpopulations, including LHCI proteins (encoded by five distinct Lhca genes) and the minor LHCII polypeptides, CP26 and CP29. Using an antibody against plant Lhca2, we unambiguously show that LHCI proteins are present not only in O. tauri, in which they are likely associated to RCI, but also in other Mamiellales, including M. squamata. With the exception of Lhcp genes, all the identified Lhc genes are present in single copy only. Overall, the discovery of LHCI proteins in these prasinophytes, combined with the lack of the major LHCII polypeptides found in higher plants or other green algae, supports the hypothesis that the latter proteins appeared subsequent to LHCI proteins. The major LHC of prasinophytes might have arisen prior to the LHCII of other chlorophyll a/b–containing organisms, possibly by divergence of a LHCI gene precursor. However, the discovery in O. tauri of CP26-like proteins, phylogenetically placed at the base of the major LHCII protein clades, yields new insight to the origin of these antenna proteins, which have evolved separately in higher plants and green algae. Its diverse but numerically limited suite of Lhc genes renders O. tauri an exceptional model system for future research on the evolution and function of LHC components.
Radiographic bilateral cavitary lesions in lipoid pneumonia
Authors: J Casademont, A Xaubet, J López-Guillermo, C Agusti, J Ramirez
Journal: European Respiratory Journal (1988)

We report a case of lipoid pneumonia with pulmonary bilateral cavitated lesions. The diagnosis was based on the finding of abundant lipid-laden alveolar macrophages in bronchoalveolar lavage and the presence of histologic changes indicative of lipoid pneumonia in transbronchial lung biopsy.
Two-Dimensional Intravascular Near-Infrared Fluorescence Molecular Imaging of Inflammation in Atherosclerosis and Stent-Induced Vascular Injury
Authors: Farouc A. Jaffer, Marcella A. Calfon, Amir Rosenthal, Georgios Mallas, R. Nika Razansky, Adam Mauskapf, Ralph Weissleder, Peter Libby, Vasilis Ntziachristos
Journal: Journal of the American College of Cardiology (2011)