tbuckley/cabot-search huggingface dataset:
Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF- expression and improves cardiac function during endotoxemia
Authors: T. Zhang, X. Lu, P. Arnold, Y. Liu, R. Baliga, H. Huang, J. A. Bauer, Y. Liu, Q. Feng
Journal: Cardiovascular Research (2011)

Myocardial tumour necrosis factor-α (TNF-α) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-α expression and cardiac function during endotoxemia. Lipopolysaccharide (LPS) increased MKP1 expression in the myocardium in vivo and in cultured neonatal cardiomyocytes in vitro. LPS-induced extracellular signal-regulated kinase (ERK) 1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1−/− mice. Myocardial TNF-α mRNA and protein levels were enhanced in MKP1−/− compared with wild-type (WT) mice in endotoxemia, leading to a further decrease in cardiac function. To study if Rac1/p21-activated kinase 1 (PAK1) signalling regulates MKP1 expression, cardiomyocytes were treated with LPS. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad-Rac1N17) and PAK1 siRNA, respectively, blocked LPS-induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c-Jun N-terminal kinase (JNK) activation, and TNF-α expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. LPS activates the Rac1/PAK1 pathway, which increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF-α expression, and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro-inflammatory response in the heart during sepsis.
Gene Expression Profiling Uncovers Molecular Classifiers for the Recognition of Anaplastic Large-Cell Lymphoma Within Peripheral T-Cell Neoplasms
Authors: Roberto Piva, Luca Agnelli, Elisa Pellegrino, Katia Todoerti, Valentina Grosso, Ilaria Tamagno, Alessandro Fornari, Barbara Martinoglio, Enzo Medico, Alberto Zamò, Fabio Facchetti, Maurilio Ponzoni, Eva Geissinger, Andreas Rosenwald, Hans Konrad Müller-Hermelink, Christiane De Wolf-Peeters, Pier Paolo Piccaluga, Stefano Pileri, Antonino Neri, Giorgio Inghirami
Journal: Journal of Clinical Oncology (2010)

To unravel the regulatory network underlying nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) -mediated lymphomagenesis of anaplastic large-cell lymphoma (ALCL) and to discover diagnostic genomic classifiers for the recognition of patients with ALK-positive and ALK-negative ALCL among T-cell non-Hodgkin's lymphoma (T-NHL).The transcriptome of NPM-ALK-positive ALCL cell lines was characterized by silencing the expression of ALK or STAT3, a major effector of ALK oncogenic activity. Gene expression profiling (GEP) was performed in a series of systemic primary T-NHL (n = 70), including a set of ALK-positive and ALK-negative ALCL (n = 36). Genomic classifiers for ALK-positive and ALK-negative ALCL were generated by prediction analyses and validated by quantitative reverse-transcriptase polymerase chain reaction and/or immunohistochemistry.In ALCL cell lines, two thirds of ALK-regulated genes were concordantly dependent on STAT3 expression. GEP of systemic primary T-NHL significantly clustered ALK-positive ALCL samples in a separate subgroup, underscoring the relevance of in vitro ALK/STAT3 signatures. A set of genomic classifiers for ALK-positive ALCL and for ALCL were identified by prediction analyses. These gene clusters were instrumental for the distinction of ALK-negative ALCL from peripheral T-cell lymphomas not otherwise specified (PTCLs-NOS) and angioimmunoblastic lymphomas.We proved that experimentally controlled GEP in ALCL cell lines represents a powerful tool to identify meaningful signaling networks for the recognition of systemic primary T-NHL. The identification of a molecular signature specific for ALCL suggests that these T-NHLs may represent a unique entity discernible from other PTCLs, and that a restricted number of genes can be instrumental for clinical stratification and, possibly, therapy of T-NHL.
Standardized evaluation methodology and reference database for evaluating coronary artery centerline extraction algorithms
Authors: Michiel Schaap, Coert T. Metz, Theo van Walsum, Alina G. van der Giessen, Annick C. Weustink, Nico R. Mollet, Christian Bauer, Hrvoje Bogunović, Carlos Castro, Xiang Deng, Engin Dikici, Thomas O’Donnell, Michel Frenay, Ola Friman, Marcela Hernández Hoyos, Pieter H. Kitslaar, Karl Krissian, Caroline Kühnel, Miguel A. Luengo-Oroz, Maciej Orkisz, Örjan Smedby, Martin Styner, Andrzej Szymczak, Hüseyin Tek, Chunliang Wang, Simon K. Warfield, Sebastian Zambal, Yong Zhang, Gabriel P. Krestin, Wiro J. Niessen
Journal: Medical Image Analysis (2009)
Regulation and properties of extracellular signal-regulated protein kinases 1, 2, and 3.
Authors: D J Robbins, E Zhen, M Cheng, S Xu, C A Vanderbilt, D Ebert, C Garcia, A Dang, M H Cobb
Journal: Journal of the American Society of Nephrology (1993)

The extracellular signal-regulated kinases ERK1 and ERK2 are 43- and 41-kd enzymes activated by many extracellular cues. They lie within a protein kinase cascade that is used to achieve many cellular responses. In addition to the wide variety of regulatory contexts in which they are activated, they phosphorylate important regulatory proteins, including receptors, transcription factors, cytoskeletal proteins, and other protein kinases. Thus, the stimulation of this kinase cascade is thought to have a pleiotropic action. ERK1 and ERK2 are controlled by phosphorylation on threonine and tyrosine. To understand the regulatory mechanisms, wild-type and mutant ERKs were expressed in bacteria and phosphorylated with MEK, the enzyme that is upstream of ERKs. Wild-type proteins could be activated 500- to 1,000-fold in vitro by MEK. ERK3, an enzyme of 62 kd and only 50% identical to ERK1 and ERK2 in the catalytic core, was also phosphorylated by MEK in vitro. This suggests that all three of these enzymes are targets of common signaling pathways.
Peritoneal Changes after Exposure to Sterile Solutions by Catheter
Authors: Michael F Flessner, Kimberly Credit, Karla Henderson, Heather M Vanpelt, Rebecca Potter, Zhi He, Jeffrey Henegar, Barry Robert
Journal: Journal of the American Society of Nephrology (2007)

Most current animal models that are used to study effects of long-term peritoneal exposure to dialysis solutions use an indwelling catheter for daily injections. It was hypothesized that the presence of a foreign body in the peritoneal cavity (PC) might alter the inflammatory response to the solutions and that the response would depend on exposure duration. For addressing these, long-term injections were carried out for 2 to 8 wk in 90 Sprague-Dawley rats: 40 via a subcutaneous port connected to a silicone catheter tunneled to the PC, 40 via direct needle injection, and 10 noninjected, age-control rats. Daily volumes were 30 to 40 ml of filter-sterilized, bicarbonate-buffered solutions that contained 4% dextrose. After 2, 4, 6, and 8 wk, anesthetized rats underwent transport experiments with a chamber affixed to the abdominal wall to determine mass transfer coefficients of mannitol (MTC(mannitol)) and albumin (MTC(BSA)), osmotic filtration flux (J(osm)), and hydrostatic pressure-driven flux. After the rats were killed, tissues were collected for measurement of peritoneal thickness, vascular density, and immunohistochemical staining. ANOVA demonstrated significant (P < 0.01) differences in thickness, vessel density, MTC(mannitol), and MTC(BSA) among the groups at the various time intervals and in overall means. Differences among the groups were less pronounced for hydrostatic pressure-driven flux and J(osm). Vessel density, MTC(mannitol), MTC(BSA), and J(osm) were dependent on injection duration (P < 0.01). There were marked differences between the needle injection and catheter injection groups at various intervals in the expression of three cytokines. It is concluded that the histologic and functional response depends on the duration of injection with animals that are exposed for as little as 2 wk demonstrating alterations. These findings confirm the hypothesis that the presence of a PC catheter increases inflammatory response to sterile solutions as evidenced by the structural and functional changes in the peritoneal barrier.
Genetic Basis of Intellectual Disability
Authors: Jay W. Ellison, Jill A. Rosenfeld, Lisa G. Shaffer
Journal: Annual Review of Medicine (2012)

In the past decade, we have witnessed a flood of reports about mutations that cause or contribute to intellectual disability (ID). This rapid progress has been driven in large part by the implementation of chromosomal microarray analysis and next-generation sequencing methods. The findings have revealed extensive genetic heterogeneity for ID, as well as examples of a common genetic etiology for ID and other neurobehavioral/psychiatric phenotypes. Clinical diagnostic application of these new findings is already well under way, despite incomplete understanding of non-Mendelian transmission patterns that are sometimes observed.
Circulating levels of sialic acid and glycosaminoglycans: a diagnostic test for ankylosing spondylitis.
Authors: A K Susheela, T K Das, J S Khurana, A Jayaswal, P K Dave
Journal: Annals of the Rheumatic Diseases (1988)

The circulating levels of sialic acid (N-acetylneuraminic acid) and glycosaminoglycans (GAGs) were measured in 69 patients with spinal disorders of orthopaedic interest (ankylosing spondylitis 17, osteofluorosis 6, idiopathic backache 10, osteoarthrosis 16, osteoporosis 20). The serum GAG levels showed no statistically significant change from control values in the five disorders investigated in the present study. Although osteoporosis and osteoarthrosis showed a decrease in serum sialic acid (SA) levels, the mean ratio (SA/GAG) demonstrated no change from control values. Idiopathic backache showed no difference in any of the parameters studied when compared with control values. Ankylosing spondylitis and osteofluorosis had a remarkable similarity in their clinical and radiological features, but a divergent mean value of ratio was noted. The mean ratio of both the conditions also showed a statistically significant difference from the control value. This suggests that the SA/GAG ratio can be used as a diagnostic test in ankylosing spondylitis.
THE EFFECT OF SKIN HOMOGRAFT REJECTION ON RECIPIENT AND DONOR MIXED LEUKOCYTE CULTURES
Authors: Joost J. Oppenheim, Jacqueline Whang, Emil Frei
Journal: The Journal of Experimental Medicine (1965)

The lymphocyte proliferation in repeatedly studied mixed leukocyte cultures of peripheral white blood cells from a skin graft donor and 2 recipients was significantly increased at the time of graft rejection. This was determined from the increased proportions of mononuclear cells labeling with tritiated thymidine, increased mitotic indices, and the appearance of increased numbers of transformed lymphocytes after rejection of 1st and 2nd skin grafts. The temporarily enhanced response occurred sooner and was of shorter duration after the second than after the first graft, but was quantitatively similar each time. The cell proliferation in the mixed leukocyte cultures of the two recipients was similarly affected by the homograft rejections. The cultures containing three cell populations usually manifested a greater lymphocyte response than corresponding cultures of leukocytes from only two unrelated subjects. An increase in the ratio of female recipient to male graft donor metaphases in the cultures at the time of enhanced lymphocyte transformation indicated that proliferation of the graft recipient lymphocytes was responsible for the above findings. Unmixed, unstimulated control cultures grown in autologous, the other subjects plasma, or heterologous calf serum failed to support significant lymphocyte transformation. The role of humoral factors and relationship of the in vitro cellular responses to the in vivo homograft reaction are discussed.
A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis
Authors: M.E. Hodson, C.G. Gallagher, J.R.W. Govan
Journal: European Respiratory Journal (2002)

Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis (CF) patients. The purpose of this trial was to assess the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients chronically infected with P. aeruginosa . One-hundred and fifteen patients, aged ≥6 yrs, were randomised to receive either TNS or colistin, twice daily for 4 weeks. The primary end point was an evaluation of the relative change in lung function from baseline, as measured by forced expiratory volume in one second % predicted. Secondary end points included changes in sputum P. aeruginosa density, tobramycin/colistin minimum inhibitory concentrations and safety assessments. TNS produced a mean 6.7% improvement in lung function (p=0.006), whilst there was no significant improvement in the colistin-treated patients (mean change 0.37%). Both nebulised antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density, and there was no development of highly resistant strains over the course of the study. The safety profile for both nebulised antibiotics was good. Tobramycin nebuliser solution significantly improved lung function of patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa , but colistin did not, in this study of 1-month's duration. Both treatments reduced the bacterial load.
Endothelial nitric oxide synthase uncoupling: Is it a physiological mechanism of endothelium-dependent relaxation in cerebral artery?
Authors: M YOKOYAMA, K HIRATA
Journal: Cardiovascular Research (2006)

See article by Drouin et al.  [8]  (pages 73–81) in this issue. 

Nitric oxide (NO) is generated from the conversion of l -arginine to l-citrulline by endothelial nitric oxide synthase (eNOS), which requires Ca2+/calmodulin, FAD, FMN, and tetrahydrobiopterin (BH4) as cofactors. Chemical studies in vitro demonstrated that the catalytic mechanisms of NOS involve flavin-mediated electron transport from a flavin-containing reductase domain to a heme-containing oxygenase domain. Here, oxygen is reduced and incorporated into the guanidine group of l-arginine, giving rise to NO and l-citrulline. Calcium/calmodulin binding to NOS increases the rate of reduction of both flavins and the heme iron. Reduction of iron (III) to iron (II) facilitates oxygen binding to the heme group to form a transient ferrous–dioxygen complex. NOS can also produce superoxide under certain conditions. Superoxide is generated from the oxygenase domain by dissociation of the ferrous–dioxygen complex [1,2]. This state is referred to as the “uncoupled state of eNOS” (eNOS uncoupling). BH4 couples l-arginine oxidation to NADPH consumption and prevents dissociation of the ferrous–dioxygen complex. Although in vitro data using purified eNOS demonstrate that modulation of the BH4 concentration may regulate the ratio of superoxide to NO … 

*Corresponding author. Tel.: +81 78 382 5840; fax: +81 78 382 5858. Email address: yokoyama{at}med.kobe-u.ac.jp
Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA-induced fluorescence
Authors: K. Takahashi, N. Ikeda, N. Nonoguchi, Y. Kajimoto, S.-I. Miyatake, Y. Hagiya, S.-I. Ogura, H. Nakagawa, T. Ishikawa, T. Kuroiwa
Journal: Neuro-Oncology (2011)

In photodynamic diagnosis, 5-aminolevulinic acid (5-ALA) is widely used for the fluorescence-guided resection of malignant brain tumors, where 5-ALA is converted to protoporphyrin IX, which exhibits strong fluorescence. Little is known, however, about the detailed molecular mechanisms underlying 5-ALA–induced fluorescence. To resolve this issue, we analyzed transcriptome profiles for the genes encoding enzymes, transporters, and a transcription factor involved in the porphyrin-biosynthesis pathway. By quantitative real-time (qRT)-PCR, we measured the mRNA levels of those genes in a total of 20 tumor samples that had been surgically resected from brain tumor patients at the Department of Neurosurgery of Osaka Medical College from 2008 to 2009. We selected 10 tumor samples with no 5-ALA–induced fluorescence, among which 2 were glioblastomas and 8 were metastatic brain tumors. Another 10 tumor samples were selected with strong fluorescence, among which 7 were glioblastomas and 3 were metastatic brain tumors. The qRT-PCR analysis study of these latter 10 samples revealed predominantly high levels of the mRNA of the coproporphyrinogen oxidase (CPOX) gene. The high mRNA level of CPOX expression was significantly well correlated with the phenotype of strong 5-ALA–induced fluorescence (P = .0003). These findings were further confirmed by immunohistochemical studies with a CPOX-specific antibody. It is concluded that induction of CPOX gene expression is one of the key molecular mechanisms underlying the 5-ALA–induced fluorescence of malignant brain tumors. The induction mechanism for the CPOX gene in brain tumors remains to be elucidated.
Changes in Content of Purine Nucleoside in Canine Myocardium during Coronary Occlusion
Authors: R. A. OLSSON
Journal: Circulation Research (1970)

The use of a sensitive double-beam spectrophotometer and modifications in enzymatic assay techniques permitted the measurement of adenine nucleosides in extracts of canine left ventricle. In hearts not subjected to left coronary occlusion, adenosine content averaged 0.32 ± 0.04 ( SE ) nmole/g, increasing to an average of 1.82 ± 0.21 ( SE ) nmole/g after 15 seconds of coronary occlusion. The myocardial content of inosine plus hypoxanthine was 1.07 ± 0.21 ( SE ) nmole/g without coronary occlusion, rising to 1.98 ± 0.24 ( SE ) nmole/g after 15 seconds of coronary occlusion. Unlike the myocardial content of adenosine and inosine, the myocardial content of hypoxanthine did not appear to change during coronary occlusion.
Concentric myocardial hypertrophy after one year of increased training volume in experienced distance runners
Authors: T Venckunas, A Stasiulis, R Raugaliene
Journal: British Journal of Sports Medicine (2006)

As evidence on the predominant type of cardiac hypertrophy due to endurance running training is inconsistent, the aim of this study was to investigate the effect of increased training volume on echocardiographic variables of distance runners.Twenty three adult, experienced, male distance runners underwent standard two dimensionally guided M mode and Doppler echocardiography before and after a one year period during which they were randomly allocated to either control (n = 11) or intervention (n = 12) groups. The intervention group increased their training volume from (mean (SD)) 8.0 (3.0) to 12.5 (3.9) hours/week without increasing the intensity, and the controls changed neither training parameter.In the intervention group, training induced an increase in left ventricular (LV) mass (from 240.4 (53.8) to 279.5 (60.6) g, p<0.001) and LV mass index (from 126.7 (28.2) to 147.6 (32.3) g/m2, p<0.001) mainly due to an increase in end diastolic interventricular septum (from 10.4 (1.8) to 11.5 (1.7) mm, p<0.01) and LV posterior wall thickness (from 10.4 (1.6) to 11.5 (1.6) mm, p<0.001). No significant changes in LV internal diameter or measured indices of LV function occurred (p>0.05). The sum of the right ventricular diameter and wall thickness was greater after the increased volume training (p<0.05). None of the variables changed significantly in the control group (p>0.05).In experienced, subelite distance runners, further increasing the training volume results in concentric cardiac hypertrophy.
Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells
Authors: Sheng Cao, Usman Yaqoob, Amitava Das, Uday Shergill, Kumaravelu Jagavelu, Robert C. Huebert, Chittaranjan Routray, Soha Abdelmoneim, Meher Vasdev, Edward Leof, Michael Charlton, Ryan J. Watts, Debabrata Mukhopadhyay, Vijay H. Shah
Journal: Journal of Clinical Investigation (2010)

PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor β (PDGFRβ) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-β–dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFRβ-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.
Opioids in chronic non-malignant pain
Authors: H. McQuay
Journal: BMJ (2001)

Primary care p 1154 

The use of opioids in chronic non-malignant pain is profoundly messy. A simple start is to say that if somebody has severe pain which responds to opioids and for which there is no other effective remedy then why should they not receive opioids? Two judgments are then implicit: that opioids are effective and that other remedies are not. How well do these judgments hold up? And if they do, how do we work out which opioid and formulation? A paper in this week's issue addresses, but doesn't answer, the second question (p 1154).1

Opioids are often withheld to protect society or to protect the patient. The society argument is that the medical availability of opioid increases street addiction. There has never been any strong evidence that medical use increases street problems, and the introduction of oral morphine in Sweden in the early 1980s was shown not to increase addiction.2

Withholding the opioid to protect the individual might be done for physical or psychological reasons. Many notables across the centuries used opioids long term without deterioration in physical health: Florence Nightingale, …
A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma
Authors: Ghassan K. Abou-Alfa, Marinela Capanu, Eileen M. O’Reilly, Jennifer Ma, Joanne F. Chou, Bolorsukh Gansukh, Jinru Shia, Marcia Kalin, Seth Katz, Leslie Abad, Diane L. Reidy-Lagunes, David P. Kelsen, Helen X. Chen, Leonard B. Saltz
Journal: Journal of Hepatology (2013)