tbuckley/cabot-search huggingface dataset:
Platelet-released phospholipids link haemostasis and angiogenesis
Authors: D English
Journal: Cardiovascular Research (2001)

Considerable attention has focused on identifying mediators of neovascularization at sites of growth and abnormal tissue development. By contrast, mediators of angiogenesis at sites of injury and wound repair are not well defined but factors generated during blood coagulation (haemostasis) are attractive candidates. In addition to proteins generated, activated and released during the activation of clotting cascades, platelet-derived lipid mediators are now known to play a key role in many aspects of the angiogenic response. The first indication of lipid mediator involvement in angiogenesis was the discovery that lysophosphatidate (LPA), phosphatidic acid (PA) and sphingosine 1-phosphate (SPP) are high affinity agonists for G-protein coupled EDG (endothelial differentiation gene) receptors. The prototype for this family, EDG-1, was cloned from genes expressed when endothelial cells were activated to assume an angiogenic phenotype in vitro. The subsequent finding that SPP is a high affinity ligand for EDG-1 led Spiegel, Hla and associates (Lee et al., Science 1998;279:1552–1555) to hypothesize that platelet-released phospholipids play an important role in angiogenesis. These investigators and others demonstrated that SPP, LPA and phosphatidate (PA) induce many important endothelial cell responses associated with angiogenesis, including liberation of endothelial cells from established monolayers, chemotactic migration, proliferation, adherens junction assembly and morphogenesis into capillary-like structures. Although these studies indicated the potential involvement of platelet-derived phospholipids in angiogenesis, their physiological importance was not established. However, recent work demonstrates that <80% of the potent endothelial cell chemoattractive activity generated in human serum during clotting — an activity necessary for optimal angiogenesis — results from platelet-derived SPP. Other factors released from platelets during clotting, including LPA and PA, exert profound effects on endothelial cells that contribute unique aspects to the angiogenic response. These combined studies establish that SPP and other platelet-derived lipid mediators provide a novel link between haemostasis and angiogenesis.
Targeted Expression of a Dominant-Negative K <sub>v</sub> 4.2 K <sup>+</sup> Channel Subunit in the Mouse Heart
Authors: Alan D. Wickenden, Paul Lee, Rajan Sah, Qian Huang, Glenn I. Fishman, Peter H. Backx
Journal: Circulation Research (1999)

Abstract —Action potential duration is prolonged in many forms of heart disease, often as a result of reductions in Ca 2+ -independent transient outward K + currents (ie, I to ). To examine the effects of a primary reduction in I to current in the heart, transgenic mice were generated that express a dominant-negative N-terminal fragment of the K v 4.2 pore-forming potassium channel subunit under the control of the mouse α-myosin heavy chain promoter. Two of 6 founders died suddenly, and only 1 mouse successfully transmitted the transgene in mendelian fashion. Electrophysiological analysis at 2 to 4 weeks of age demonstrated that I to density was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction in I to was accompanied by significant prolongation of monophasic action potentials. In vivo hemodynamic studies at this age revealed significant elevations in the mean arterial pressure, peak systolic ventricular pressures, and ±dP/dt, indicative of enhanced contractility. Surprisingly, by 10 to 12 weeks of age, transgenic mice developed clinical and hemodynamic evidence of congestive heart failure. Failing transgenic hearts displayed molecular and cellular remodeling, with evidence of hypertrophy, chamber dilatation, and interstitial fibrosis, and individual myocytes showed sharp reductions in I to and I K1 densities, action potential duration prolongation, and increased cell capacitance. Our results confirm that K v 4.2 subunits contribute to I to in the mouse and demonstrate that manipulation of cardiac excitability may secondarily influence contractile performance.
Role of Endoscopic Ultrasonography in the Staging and Follow-Up of Esophageal Cancer
Authors: Charles J. Lightdale, Ketan G. Kulkarni
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate the role of endoscopic ultrasonography (EUS) in the initial staging and follow-up of esophageal cancer on the basis of a review of the published literature. Methods Articles published from 1985 to 2005 were searched and reviewed using the following keywords: “esophageal cancer staging,” “endoscopic ultrasound,” and “endoscopic ultrasonography.” Results For initial anatomic staging, EUS results have consistently shown more than 80% accuracy compared with surgical pathology for depth of tumor invasion (T). Accuracy increased with higher stage, and was &gt;90% for T3 cancer. EUS results have shown accuracy in the range of 75% for initial staging of regional lymph nodes (N). EUS has been invariably more accurate than computed tomography for T and N staging. EUS is limited for staging distant metastases (M), and therefore EUS is usually performed after a body imaging modality such as computed tomography or positron emission tomography. Pathologic staging can be achieved at EUS using fine-needle aspiration (FNA) to obtain cytology from suspect Ns. FNA has had greatest efficacy in confirming celiac axis lymph node metastases with more than 90% accuracy. EUS is inaccurate for staging after radiation and chemotherapy because of inability to distinguish inflammation and fibrosis from residual cancer, but a more than 50% decrease in tumor cross-sectional area or diameter has been found to correlate with treatment response. Conclusion EUS has a central role in the initial anatomic staging of esophageal cancer because of its high accuracy in determining the extent of locoregional disease. EUS is inaccurate for staging after radiation therapy and chemotherapy, but can be useful in assessing treatment response.
Cross-species cluster co-conservation: a new method for generating protein interaction networks
Authors: Anis Karimpour-Fard, Corrella S Detweiler, Kimberly D Erickson, Lawrence Hunter, Ryan T Gill
Journal: Genome biology (2007)

Abstract Co-conservation (phylogenetic profiles) is a well-established method for predicting functional relationships between proteins. Several publicly available databases use this method and additional clustering strategies to develop networks of protein interactions (cluster co-conservation (CCC)). CCC has previously been limited to interactions within a single target species. We have extended CCC to develop protein interaction networks based on co-conservation between protein pairs across multiple species, cross-species cluster co-conservation.
C-Jun Nh2-Terminal Kinase (Jnk)1 and Jnk2 Have Similar and Stage-Dependent Roles in Regulating T Cell Apoptosis and Proliferation
Authors: Kanaga Sabapathy, Tuula Kallunki, Jean-Pierre David, Isabella Graef, Michael Karin, Erwin F. Wagner
Journal: The Journal of Experimental Medicine (2001)

Apoptotic and mitogenic stimuli activate c-Jun NH2-terminal kinases (JNKs) in T cells. Although T cells express both JNK1 and JNK2 isozymes, the absence of JNK2 alone can result in resistance to anti-CD3–induced thymocyte apoptosis and defective mature T cell proliferation. Similar defects in thymocyte apoptosis and mature T cell proliferation, the latter due to reduced interleukin 2 production, are also caused by JNK1 deficiency. Importantly, T cell function was compromised in Jnk1+/−Jnk2+/− double heterozygous mice, indicating that JNK1 and JNK2 play similar roles in regulating T cell function. The reduced JNK dose results in defective c-Jun NH2-terminal phosphorylation in thymocytes but not in peripheral T cells, in which nuclear factors of activated T cells (NK-ATs)–DNA binding activity is affected. Thus, JNK1 and JNK2 control similar functions during T cell maturation through differential targeting of distinct substrates.
Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study
Authors: M. Fralick, E. M. Macdonald, T. Gomes, T. Antoniou, S. Hollands, M. M. Mamdani, D. N. Juurlink
Journal: BMJ (2014)

<b>Objective:</b> To compare the analgesic efficacy of single and multiple doses of ibuprofen with that of paracetamol in patients with knee or hip osteoarthritis (IPSO study). <b>Method:</b> 222 patients were randomised in a double blind, multicentre study—156 (70%) had a painful knee joint and 66 (30%) a painful hip joint. The main efficacy criterion was pain intensity assessment after a single dose (ibuprofen 400 mg, paracetamol 1000 mg). Functional disability assessment and patient global assessment were carried out over 14 days. <b>Results:</b> The sum of the pain intensity difference over 6 hours after the first administration was significantly higher (p = 0.046) in the ibuprofen group than in the paracetamol group. Over 14 days pain intensity decreased from the first day and was significantly lower in the ibuprofen group than in the paracetamol group (p&lt;0.05). The functional disability of the patient was assessed using the WOMAC; the ibuprofen group improved significantly over 2 weeks compared with the paracetamol group for each of the subscales: stiffness (p&lt;0.002), pain (p&lt;0.001), physical function (p&lt;0.002). The drugs were equally safe. <b>Conclusion:</b> The IPSO study shows that for the treatment of osteoarthritic pain, ibuprofen 400 mg at a single and multiple dose (1200 mg/day) for 14 days is more effective than paracetamol, either as a single dose of 1000 mg or a multiple dose (3000 mg/day). Because ibuprofen and paracetamol have similar tolerability, this study indicates that the efficacy/tolerability ratio of ibuprofen is better than that of paracetamol in this indication over 14 days.
Predictors of weaning outcome in chronic obstructive pulmonary disease patients
Authors: R. Alvisi, C.A. Volta, E.R. Righini, M. Capuzzo, R. Ragazzi, M. Verri, G. Candini, G. Gritti, J. Milic-Emili
Journal: European Respiratory Journal (2000)

Several threshold values for predicting weaning outcome from mechanical ventilation have been proposed. These values, however, have been obtained in nonhomogeneous patient populations. The aim of the present study was to determine the threshold values in chronic obstructive pulmonary disease (COPD) patients and compare them to those reported for nonhomogeneous patient populations. The initial weaning trial included 81 COPD patients. Fifty-three of them underwent a successful weaning trial, whereas 28 failed it. The latter were enrolled into the present investigation, and were restudied during a subsequent successful trial. The weaning indices used were those reported in the literature. The threshold values obtained were within 10% of those reported for a nonhomogeneous patients population only for tidal volume and effective compliance. The classification error was &lt;20% for maximal inspiratory pressure (MIP), occluded inspiratory pressure swing (deltaPI)/MIP, rapid and shallow breathing (respiratory frequency/tidal volume), and compliance, rate, oxygenation, pressure index (CROP), whereas the area under the receiver operating characteristic curves was &gt;0.9 only for deltaPI/MIP and CROP. In conclusion, the threshold values obtained in chronic obstructive pulmonary disease patients who failed the first weaning attempt differed from those previously reported. Although a gold standard weaning index is not available for chronic obstructive pulmonary disease patients, the occluded inspiratory pressure swing/ maximal inspiratory pressure and compliance, rate, oxygenation, pressure index may be candidates for such a role.
Results of a Phase II Trial of Gemcitabine Plus Doxorubicin in Patients with Recurrent Head and Neck Cancers: Serum C18-Ceramide as a Novel Biomarker for Monitoring Response
Authors: Sahar A. Saddoughi, Elizabeth Garrett-Mayer, Uzair Chaudhary, Paul E. O'Brien, Larry B. Afrin, Terry A. Day, M. Boyd Gillespie, Anand K. Sharma, Christina S. Wilhoit, Robin Bostick, Can E. Senkal, Yusuf A. Hannun, Jacek Bielawski, George R. Simon, Keisuke Shirai, Besim Ogretmen
Journal: Clinical Cancer Research (2011)

Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C(18)-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed.Patients received GEM (1,000 mg/m²) and DOX (25 mg/m²) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements.We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4-4.2) with a median survival of 5.6 months (95% CI: 3.8-18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C₁₈-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment.Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C₁₈-ceramide elevation might be a novel serum biomarker of chemotherapy response.
THE RESPONSE OF CULTURED MAMMALIAN CELLS TO DIPHTHERIA TOXIN
Authors: Thomas J. Moehring, Joan M. Moehring, Robert J. Kuchler, Morris Solotorovsky
Journal: The Journal of Experimental Medicine (1967)

The response to diphtheria toxin of two sensitive cell lines, KB and HeLa, was investigated. Inhibition of the incorporation of radioactively labeled amino acids into protein was the earliest detectable effect of diphtheria toxin. It was observed that, during the period of intoxication, the cell membrane was morphologically intact and retained its semi-permeable character, although it was rendered fragile and more easily disrupted by mechanical manipulations than the normal cell. The transport of amino acids continued even after intoxicated cells had ceased to synthesize protein, and the levels accumulated were equal to those of control cells. It was observed that cultural conditions, age, and handling of cells affected their response to toxin. In early log phase cells subjected to a minimum of handling before application of the toxin, the normally observed latent period preceding detectable effects was reduced to 15 min for KB cells and 30 min for HeLa cells, shorter times than previously reported. The data are consistent with the hypothesis that diphtheria toxin enters susceptible cells, possibly by pinocytosis, and there acts upon cytoplasmic sites of protein synthesis.
European Practices of Genetic Information and Insurance
Authors: Ine Van Hoyweghen, Klasien Horstman
Journal: JAMA (2008)

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Granulocyte/macrophage colony-stimulating factor and accessory cells modulate radioprotection by purified hematopoietic cells
Authors: Tamiko R. Katsumoto, Jennifer Duda, Andrew Kim, Zabihullah Wardak, Glenn Dranoff, D. Wade Clapp, Kevin Shannon
Journal: The Journal of Experimental Medicine (2005)

Granulocyte/macrophage colony-stimulating factor (GM-CSF) promotes the survival, proliferation, and differentiation of myeloid lineage cells and regulates chemotaxis and adhesion. However, mice in which the genes encoding GM-CSF (Gmcsf) or the β common subunit of the GM-CSF receptor (βc) are inactivated display normal steady-state hematopoiesis. Here, we show that host GM-CSF signaling strongly modulates the ability of donor hematopoietic cells to radioprotect lethally irradiated mice. Although bone marrow mononuclear cells efficiently rescue Gmcsf mutant recipients, fetal liver cells and Sca1+ lin−/dim marrow cells are markedly impaired. This defect is partially attributable to accessory cells that are more prevalent in bone marrow. In contrast, Gmcsf-deficient hematopoietic stem cells demonstrate normal proliferative potentials. Short-term survival is also impaired in irradiated βc mutant recipients transplanted with fetal liver or bone marrow. These data demonstrate a nonredundant function of GM-CSF in radioprotection by donor hematopoietic cells that may prove relevant in clinical transplantation.
Estrogen Therapy Increases Benign Breast Disease
Authors: L. Savage
Journal: JNCI Journal of the National Cancer Institute (2008)

Estrogen Therapy Increases Benign Breast DiseaseWomen who took conjugated equine estrogen, a commonly prescribed form of estrogen, had more than twice the risk of developing specifi c types of benign breast disease as women who took a placebo, according to a randomized controlled trial
Amygdala Hyperactivity at Rest in Paranoid Individuals With Schizophrenia
Authors: Amy E. Pinkham, Peiying Liu, Hanzhang Lu, Michael Kriegsman, Claire Simpson, Carol Tamminga
Journal: American Journal of Psychiatry (2015)

The amygdala's role in threat perception suggests that increased activation of this region may be related to paranoid ideation. However, investigations of amygdala function in paranoid individuals with schizophrenia, compared with both healthy individuals and nonparanoid individuals with schizophrenia, have consistently reported reduced task-related activation. The reliance of blood-oxygen-level-dependent functional MRI on a contrast between events and baseline, and the inability to quantitatively measure this baseline, may account for these counterintuitive findings. The present study tested for differences in baseline levels of amygdala activity in paranoid and nonparanoid individuals with schizophrenia using arterial spin labeling perfusion MRI.Resting cerebral blood flow (CBF) and task-related activation of the amygdala were measured in 25 healthy individuals, 16 individuals with schizophrenia who were actively paranoid at the time of scanning, and 16 individuals with schizophrenia who were not paranoid.Analysis of relative CBF values extracted from the amygdala bilaterally revealed significantly increased activity in the left amygdala in paranoid patient volunteers compared with healthy comparison subjects and nonparanoid patient volunteers. Increased CBF was also evident in the right amygdala but did not reach the level of statistical significance. Paranoid volunteers also showed significantly decreased task-related activation of the amygdala compared with the two other groups.These findings suggest that amygdala hyperactivation may underlie paranoia in schizophrenia. Additionally, the reported differences between paranoid and nonparanoid patient volunteers emphasize the importance of considering symptom-based subgroups and baseline levels of activity in future investigations of neural activation in schizophrenia.
Diacetylmorphine versus Methadone for the Treatment of Opioid Addiction
Authors: Eugenia Oviedo-Joekes, Suzanne Brissette, David C. Marsh, Pierre Lauzon, Daphne Guh, Aslam Anis, Martin T. Schechter
Journal: New England Journal of Medicine (2009)

Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.
Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Yang-Min Ning, James L. Gulley, Philip M. Arlen, Sukyung Woo, Seth M. Steinberg, John J. Wright, Howard L. Parnes, Jane B. Trepel, Min-Jung Lee, Yeong Sang Kim, Haihao Sun, Ravi A. Madan, Lea Latham, Elizabeth Jones, Clara C. Chen, William D. Figg, William L. Dahut
Journal: Journal of Clinical Oncology (2010)

PURPOSE We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients. PATIENTS AND METHODS Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of > or = 50%. Secondary end points included time to progression, overall survival, and safety. Results In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of > or = 50%, and 88% achieved a PSA decline of > or = 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. CONCLUSION The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.