tbuckley/cabot-search huggingface dataset:
CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells
Authors: David Krige, Lindsey A. Needham, Lindsay J. Bawden, Nicolas Flores, Hannah Farmer, Lauren E.C. Miles, Erica Stone, Juliana Callaghan, Stephen Chandler, Vanessa L. Clark, Patricia Kirwin-Jones, Valérie Legris, Jo Owen, Thakor Patel, Steve Wood, Gary Box, David Laber, Rajesh Odedra, Annette Wright, L. Michael Wood, Suzanne A. Eccles, Elisabeth A. Bone, Andrew Ayscough, Alan H. Drummond
Journal: Cancer Research (2008)

Abstract CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia. [Cancer Res 2008;68(16):6669–79]
Clinical review of sports medicine. : 2nd ed. Eds P Brukner, K Khan. (A$ 108.99.) Sydney: McGraw-Hill, 2001. ISBN 0-074-70651-9.
Authors: Tom Crisp
Journal: British Journal of Sports Medicine (2001)

This, the second edition, has been thoroughly updated and revamped (see the section on Achilles tendons!). It is a superb book for the clinician working with athletes, outlining the treatment of injuries in a straightforward and clear way. It is such a change to read a book written by physicians rather than surgeons, with consequently a much more …
Physical activity in patients with asthma referred to a pulmonologist, a pilot-study
Authors: Alex van 't Hul, Hans In 't Veen, Arjen Roos, Simone van der Sluys, Alie van Bruggen
Journal: European Respiratory Journal (2013)

Introduction 

Physical activity (PA) in daily life has been reported to be low in patients with COPD. In patients with asthma the evaluation of PA has rarely been topic of research. Therefore, the aim of the present pilot-study was to evaluate PA in daily life in patients with asthma newly referred to a pulmonologist.

Methods and materials 

In 20 patients with asthma, PA was meaured over 7 consecutive days using the Dynaport® Activity Monitor (McRoberts, The netherlands). The dynaport is a well validated instrument to measure PA in patients with obstructive lung disease. The average number of steps per day, physical activity level (PAL), the time spent at exercise intensity > 3 MET and lying time were selected as parameters of interest. Outcomes were related to accepted PA recommendations for maintaning fitness.

Results 

Patient characteristics are presented in Table 1. Three patients (25%) had asthma in control (ACQ 1.5). Results with respect to PA are shown in Table 2. Only 2 patients (10%) had >10.000 of the recommended steps/day and only 4 patients (20%) were > 2 hours/day engaged in exercise with an intensity > 3 MET.

Conclusion 

Numerous patients with asthma referred to secondary care, do not meet the recommendations of PA necessary to maintan physical fitness.

View this table:

Table 1. Patient Characteristics





View this table:

Table 2. Physical activity
Application of High Amplitude Alternating Magnetic Fields for Heat Induction of Nanoparticles Localized in Cancer
Authors: Robert Ivkov, Sally J. DeNardo, Wolfgang Daum, Allan R. Foreman, Robert C. Goldstein, Valentin S. Nemkov, Gerald L. DeNardo
Journal: Clinical Cancer Research (2005)

Abstract Objective: Magnetic nanoparticles conjugated to a monoclonal antibody can be i.v. injected to target cancer tissue and will rapidly heat when activated by an external alternating magnetic field (AMF). The result is necrosis of the microenvironment provided the concentration of particles and AMF amplitude are sufficient. High-amplitude AMF causes nonspecific heating in tissues through induced eddy currents, which must be minimized. In this study, application of high-amplitude, confined, pulsed AMF to a mouse model is explored with the goal to provide data for a concomitant efficacy study of heating i.v. injected magnetic nanoparticles. Methods: Thirty-seven female BALB/c athymic nude mice (5-8 weeks) were exposed to an AMF with frequency of 153 kHz, and amplitude (400-1,300 Oe), duration (1-20 minutes), duty (15-100%), and pulse ON time (2-1,200 seconds). Mice were placed in a water-cooled four-turn helical induction coil. Two additional mice, used as controls, were placed in the coil but received no AMF exposure. Tissue and core temperatures as the response were measured in situ and recorded at 1-second intervals. Results: No adverse effects were observed for AMF amplitudes of ≤700 Oe, even at continuous power application (100% duty) for up to 20 minutes. Mice exposed to AMF amplitudes in excess of 950 Oe experienced morbidity and injury when the duty exceeded 50%. Conclusion: High-amplitude AMF (up to 1,300 Oe) was well tolerated provided the duty was adjusted to dissipate heat. Results presented suggest that further tissue temperature regulation can be achieved with suitable variations of pulse width for a given amplitude and duty combination. These results suggest that it is possible to apply high-amplitude AMF (&amp;gt;500 Oe) with pulsing for a time sufficient to treat cancer tissue in which magnetic nanoparticles have been embedded.
Role of nitric oxide and endothelin-1 in monocrotaline-induced pulmonary hypertension in rats
Authors: R. Mathew, G. A. Zeballos, H. Tun, M. H. Gewitz
Journal: Cardiovascular Research (1995)

Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH.Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C).One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups.These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.
Genome sequence of the hot pepper provides insights into the evolution of pungency in Capsicum species
Authors: Seungill Kim, Minkyu Park, Seon-In Yeom, Yong-Min Kim, Je Min Lee, Hyun-Ah Lee, Eunyoung Seo, Jaeyoung Choi, Kyeongchae Cheong, Ki-Tae Kim, Kyongyong Jung, Gir-Won Lee, Sang-Keun Oh, Chungyun Bae, Saet-Byul Kim, Hye-Young Lee, Shin-Young Kim, Myung-Shin Kim, Byoung-Cheorl Kang, Yeong Deuk Jo, Hee-Bum Yang, Hee-Jin Jeong, Won-Hee Kang, Jin-Kyung Kwon, Chanseok Shin, Jae Yun Lim, June Hyun Park, Jin Hoe Huh, June-Sik Kim, Byung-Dong Kim, Oded Cohen, Ilan Paran, Mi Chung Suh, Saet Buyl Lee, Yeon-Ki Kim, Younhee Shin, Seung-Jae Noh, Junhyung Park, Young Sam Seo, Suk-Yoon Kwon, Hyun A Kim, Jeong Mee Park, Hyun-Jin Kim, Sang-Bong Choi, Paul W Bosland, Gregory Reeves, Sung-Hwan Jo, Bong-Woo Lee, Hyung-Taeg Cho, Hee-Seung Choi, Min-Soo Lee, Yeisoo Yu, Yang Do Choi, Beom-Seok Park, Allen van Deynze, Hamid Ashrafi, Theresa Hill, Woo Taek Kim, Hyun-Sook Pai, Hee Kyung Ahn, Inhwa Yeam, James J Giovannoni, Jocelyn K C Rose, Iben Sørensen, Sang-Jik Lee, Ryan W Kim, Ik-Young Choi, Beom-Soon Choi, Jong-Sung Lim, Yong-Hwan Lee, Doil Choi
Journal: Nature Genetics (2014)

Doil Choi and colleagues report the genome sequence of the hot pepper, Capsicum annuum, as well as the resequencing of two cultivated peppers and a wild species, Capsicum chinense. Comparative genomic analysis across Solanaceae provides insights into genome expansion, pungency, ripening and disease resistance in hot peppers. Hot pepper (Capsicum annuum), one of the oldest domesticated crops in the Americas, is the most widely grown spice crop in the world. We report whole-genome sequencing and assembly of the hot pepper (Mexican landrace of Capsicum annuum cv. CM334) at 186.6× coverage. We also report resequencing of two cultivated peppers and de novo sequencing of the wild species Capsicum chinense. The genome size of the hot pepper was approximately fourfold larger than that of its close relative tomato, and the genome showed an accumulation of Gypsy and Caulimoviridae family elements. Integrative genomic and transcriptomic analyses suggested that change in gene expression and neofunctionalization of capsaicin synthase have shaped capsaicinoid biosynthesis. We found differential molecular patterns of ripening regulators and ethylene synthesis in hot pepper and tomato. The reference genome will serve as a platform for improving the nutritional and medicinal values of Capsicum species.
Should doctors be the judges of medical orthodoxy? The Barker case of 1920
Authors: M. Bishop
Journal: Journal of the Royal Society of Medicine (2002)

The continuing rise of complementary medicine, with a sympathetic report from the House of Lords1, provides an incentive for revisiting an incident in the early twentieth century when the issues of empirical and orthodox medical treatment exploded into the public arena.

Empirical treatment was represented by Mr Herbert Barker, a bonesetter, and the extent to which his activities had penetrated to the core of public life is illustrated by the transcript of the discussion of the Parliamentary Standing Committee dealing with the Dentists Bill in June 19212. Colonel Wedgwood (Newcastle-under-Lyme), who throughout the discussion was vocal in defence of liberty, pointed out that the Bill as it stood made dentists different from doctors, for they would not be permitted to practise even without fee or reward unless registered. He said:


‘We know that in the case of the medical profession, men like Barker, the bone-setter, can continue to practise without being fined, so long as they have no legal right to claim payment of fees. I believe Barker does bone-setting rather better than some of the registered practitioners. Does this mean that if a Barker springs up in the dental profession and cures people of the tooth-ache without the usual paraphernalia of pincers, and so forth, he will be fined £100, or will he be able to practise as long as he has not the legal right to recover fees? In other words, are you making a distinction between the dental profession and the medical profession?’


In reply Sir Kingsley Wood (Woolwich, West), said, ‘Future practitioners must comply with the regulations and examinations of the Board, but I hope that if a Barker does arise he will be just as successful with the Dental Association as he has been in the medical world.’

So who was Barker, and just how successful was he with the medical world? The account that follows of the extraordinary events that surrounded Herbert Atkinson Barker (Figure 1) in 1920 and 1921, and which led to his name being so familiar that he could be used as the stereotype empiricist, is gleaned mainly from a press cuttings file at Lambeth Palace (Davidson Papers Vol. 404) and from Barker's autobiography3.



Figure 1

Herbert Atkinson Barker. Augustus John. 1916 [By courtesy of the National Portrait Gallery, London]
MUNC-ing around with insulin action
Authors: David E. James
Journal: Journal of Clinical Investigation (2005)

Defective uptake of glucose into muscle and fat cells, or insulin resistance, is a central feature of obesity and type 2 diabetes. As we brace ourselves for the diabetes epidemic, it is reassuring to know that real progress is being made in defining the molecular biology of how insulin stimulates glucose uptake and what goes awry in obesity and type 2 diabetes. An understanding of the molecular determinants of insulin-stimulated glucose transport has been one of the holy grails of hormone action research. A major breakthrough was the discovery that insulin stimulates the translocation of a specific glucose transport protein, GLUT4, from intracellular vesicles to the cell surface. Elucidating how this process is regulated has remained a challenge because it represents a convergence of 2 disparate and complex fields of research--namely, vesicle transport and signal transduction. A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle-trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling/trafficking intersection that controls insulin-stimulated GLUT4 movement.
New insights into β2-adrenoceptor signaling in the adult rat heart
Authors: S Bartel
Journal: Cardiovascular Research (2003)

The role of cAMP in beta(2)-adrenoceptor signaling and its functional relevance in adult rat heart has been the subject of considerable controversy. Therefore, we investigated the beta(2)-adrenoceptor pathways in both adult cardiomyocytes and in the intact hearts of Wistar rats with respect to protein kinase A (at Ser16)-, the key event in shortening of relaxation time, and CaM kinase II (at Thr17)-dependent phospholamban phosphorylation.Contractile and cellular beta(1)/beta(2)-adrenergic responses were studied in parallel on the same perfused rat heart. (-)Isoproterenol and the beta(2)-adrenergic agonists zinterol and procaterol were used to discriminate the beta-adrenoceptor subtype-related actions.Beta(2)-adrenoceptor stimulation induces protein kinase A-dependent phospholamban phosphorylation in both adult cardiomyocytes and in adult hearts of rats. The beta(2)-adrenoceptor-mediated shortening of relaxation time in the heart correlates with Ser16 phosphorylation. Adenosine elicited antiadrenergic action on both beta(1)- and beta(2)-adrenergic signaling cascades by reducing the phosphorylation status of phospholamban. Only beta(1)-adrenoceptor stimulation produced significant CaM kinase II-related Thr17 phosphorylation, troponin I phosphorylation and activation of phosphorylase a.Our findings clearly show that beta(2)-adrenoceptor signaling is coupled to phospholamban phosphorylation and shortening of relaxation time in the adult rat heart.
Positional cloning of the gene for Nijmegen breakage syndrome
Authors: Shinya Matsuura, Hiroshi Tauchi, Asako Nakamura, Noriko Kondo, Shuichi Sakamoto, Satoru Endo, Dominique Smeets, Brigitte Solder, Bernd H. Belohradsky, Vazken M. Der Kaloustian, Mitsuo Oshimura, Minoru Isomura, Yusuke Nakamura, Kenshi Komatsu
Journal: Nature Genetics (1998)
Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial
Authors: H C Gerstein, S Yusuf, J Bosch, J Pogue, P Sheridan, N Dinccag, M Hanefeld, B Hoogwerf, M Laakso, V Mohan, J Shaw, B Zinman, R R Holman
Journal: The Lancet (2006)
Comparison of Right and Left Ventricular Responses to Left Ventricular Assist Device Support in Patients With Severe Heart Failure
Authors: Alessandro Barbone, Jeff W. Holmes, Paul M. Heerdt, Andrew H.S. The’, Yoshifumni Naka, Neel Joshi, Michael Daines, Andrew R. Marks, Mehmet C. Oz, Daniel Burkhoff
Journal: Circulation (2001)

Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown.Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for >/=30 days had higher central venous pressures (11+/-6 versus 8+/-5 mm Hg, P=0.04), lower pulmonary artery diastolic pressures (14+/-9 versus 21+/-9 mm Hg, P=0.01), and higher cardiac outputs (5.1+/-1.6 versus 3.7+/-1.0 L/min, P<0.001). In LVAD versus transplantation hearts, V(30) (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179+/-75 versus 261+/-118 mL, P=0.005) but not in the right ventricle (RV) (140+/-59 versus 148+/-52 mL, P=NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P=0.05) than in the RV (11%, P=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51+/-0.26 versus 1.04+/-0.34, P<0.001) but not in the RV (0.48+/-34 versus 0.67+/-0.55, P=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (P=0.01) but not RV trabeculae.Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.
Regulatory mechanisms in cell-mediated immune responses. III. I-region control of suppressor cell interaction with responder cells in mixed lymphocyte reactions.
Authors: S S Rich, R R Rich
Journal: The Journal of Experimental Medicine (1976)

Active suppression of mixed lymphocyte reaction (MLR) response is mediated by a soluble factor released by alloantigen-activated murine suppressor cells. Genetic restrictions controlling suppressor factor interaction with MLR responder cells were elucidated in this study. Non-H-2 genetic background was irrelevant to effective interaction. Using congenic strains and strains with intra-H-2 recombinants the genetic locus controlling suppressor T-cell-responder cell interaction was mapped in the I-C or S regions of the H-2 complex. Similarly, recombinant strains were used to exclude the presence of another suppressor cell-responder cell interaction locus in K,I-A, and I-B regions. It thus appears that the I-C subregion of the H-2 complex controls suppressive cell interactions in this T-cell-mediated immune response.
High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study
Authors: S W Syversen, P I Gaarder, G L Goll, S Ødegård, E A Haavardsholm, P Mowinckel, D van der Heijde, R Landewé, T K Kvien
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> New effective therapies with particularly good effect on joint destruction have highlighted the need for reliable predictors of radiographic progression in rheumatoid arthritis (RA). Our objective was to assess the combined predictive role of a set of laboratory markers with regard to 10-year radiographic progression, and to examine the effect of anti-cyclic citrullinated peptide (anti-CCP) level. <h3>Methods:</h3> A cohort of 238 patients with RA was followed longitudinally for 10 years with the collection of clinical data and serum samples. 125 patients with radiographs of the hands available at both baseline and after 10 years were included in this study. Radiographs were scored according to the van der Heijde modified Sharp score. Baseline sera were analysed for C-reactive protein, erythrocyte sedimentation rate (ESR), anti-CCP, IgA rheumatoid factor (RF) and IgM RF. Logistic regression analyses were used to identify predictors of radiographic progression and to examine the effect of anti-CCP level. <h3>Results:</h3> Anti-CCP (OR 4.0; 95% CI 1.6 to 10.0) was the strongest independent predictor of radiographic progression. Female gender (OR 3.3; 95% CI 1.3 to 7.6), high ESR (OR 3.2; 95% CI 1.2 to 7.6) and a positive IgM RF (OR 3.1; 95% CI 1.2 to 7.9) were also independent predictors. Compared with the anti-CCP-negative patients, patients with low to moderate levels of anti-CCP (OR 2.6; 95% CI 0.9 to 7.2) and patients with high levels of anti-CCP (OR 9.9; 95% CI 2.7 to 36.7) were more likely to develop radiographic progression. <h3>Conclusions:</h3> Anti-CCP, IgM RF, ESR and female gender were independent predictors of radiographic progression and could be combined into an algorithm for better prediction. Patients with high levels of anti-CCP were especially prone to radiographic progression, indicating that the anti-CCP level may add prognostic information.