tbuckley/cabot-search huggingface dataset:
Fibrin-targeted recombinant hirudin inhibits fibrin deposition on experimental clots more efficiently than recombinant hirudin.
Authors: C Bode, M Hudelmayer, P Mehwald, S Bauer, M Freitag, E von Hodenberg, J B Newell, W Kübler, E Haber, M S Runge
Journal: Circulation (1994)

Although the indirect thrombin inhibitor heparin and the more potent direct inhibitor hirudin are useful in preventing thrombosis, a substantial opportunity remains for improving the thrombus selectivity of thrombin inhibitors.To explore the effect of targeting an antithrombin to the surface of a clot, we covalently linked recombinant hirudin to the Fab' (or IgG) of a monoclonal antibody (59D8) that selectively binds to an epitope on fibrin that becomes exposed only after thrombin cleaves fibrinopeptide B. Antibody-coupled hirudin bound to an immobilized peptide of the fibrin beta-chain amino-terminal sequence and inhibited the peptidolytic activity of thrombin more efficiently than free hirudin. Thrombin inhibition dependent on binding to immobilized fibrin monomer was enhanced 1100-fold (P < .0001). Hirudin-59D8 Fab' was 10 times more effective than hirudin in inhibiting fibrin deposition on experimental clot surfaces in fibrinogen solution (P < .0001) and human plasma (P < .0001). The more effective inhibition of thrombin by the conjugate was supported by significantly diminished concentrations of fibrinopeptide A in the plasma supernatant of the clot (P = .0001). Inhibition of clotting by an uncoupled mixture of hirudin and 59D8 Fab' was indistinguishable from that by hirudin alone, indicating that the conjugate's greater inhibitory activity was due to the covalent linkage between antibody and hirudin.Fibrin-targeted hirudin (in comparison with unmodified hirudin) significantly reduces fibrin deposition on the surface of experimental clots.
Pulmonary Alveolar Microlithiasis
Authors: Nishant Gupta, Francis X. McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

A 59-year-old Middle Eastern female with a history of pulmonary alveolar microlithiasis (PAM) was referred to our clinic for second opinion.The patient had been diagnosed in her childhood but was asymptomatic until she developed exertional dyspnea at the age of 54 years.Chest examination revealed bibasilar crackles.Pulmonary function tests revealed mild restriction and reduced diffusing capacity.Six-minute-walk test revealed normal exercise capacity (distance walked, 1,800 ft) with mild exertional desaturation to 88%.Chest X-ray (Figure 1) showed remarkable, fine nodular lower lung zone opacities, and computed tomography of the chest (Figures 234) showed symmetrical lower lobe predominant micronodular calcifications along bronchovascular bundles and interlobular septal thickening, findings pathognomonic for PAM (1).PAM is caused by inactivating mutations in the SCL34A2 gene (2, 3).The mutation leads to reduced phosphate reuptake by type IIb sodium phosphate transporter in the apical membrane of type II alveolar cells, resulting in calcium phosphate chelation and microlith formation in alveolar air spaces.PAM is associated with consanguinity, and the incidence is higher in Turkey, Japan, India, and Italy.PAM can be diagnosed on the basis of characteristic radiological findings (4), and biopsy is not usually required.The clinical course of PAM is highly variable, with some patients developing pulmonary fibrosis and others remaining asymptomatic for decades.Etidronate, a bisphosphonate, reduces the formation of calcium hydroxyapatite crystals and has led to clinical and radiological improvement in few cases of PAM (5).The patient was started on treatment with etidronate.
Cellular Copper Transport and Metabolism
Authors: Edward D. Harris
Journal: Annual Review of Nutrition (2000)

The transport and cellular metabolism of Cu depends on a series of membrane proteins and smaller soluble peptides that comprise a functionally integrated system for maintaining cellular Cu homeostasis. Inward transport across the plasma membrane appears to be a function of integral membrane proteins that form the channels that select Cu ions for passage. Two membrane-bound Cu-transporting ATPase enzymes, ATP7A and ATP7B, the products of the Menkes and Wilson disease genes, respectively, catalyze an ATP-dependent transfer of Cu to intracellular compartments or expel Cu from the cell. ATP7A and ATP7B work in concert with a series of smaller peptides, the copper chaperones, that exchange Cu at the ATPase sites or incorporate the Cu directly into the structure of Cu-dependent enzymes such as cytochrome c oxidase and Cu, Zn superoxide dismutase. These mechanisms come into play in response to a high influx of Cu or during the course of normal Cu metabolism.
Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial
Authors: W. Scheithauer, J. McKendrick, S. Begbie, M. Borner, W.I. Burns, H.A. Burris, J. Cassidy, D. Jodrell, P. Koralewski, E.L. Levine, N. Marschner, J. Maroun, P. Garcia-Alfonso, J. Tujakowski, G. Van Hazel, A. Wong, J. Zaluski, C. Twelves
Journal: Annals of Oncology (2003)
A RED LINE ON THE GUMS
Authors: G. A. Stephens
Journal: BMJ (1910)

_ZIA.Tu-A X -the solid organs swollen and purple with excess of blood content, and, when cut, running out like overfull sponges.The splanchnic nerves, it will be remembered, run down within the thorax.If paroxysmal tachyeardia can be really determined by dilatation of the splanchnic area and the consequent greatly diminished supply of blood to the left ventricle, it is easier to understand the usually sudden manner of its inception and termination.
Duration of Chemotherapy for Metastatic Non–Small-Cell Lung Cancer: More May Be Not Better
Authors: Andre D. Sasse, Joao P. Lima, Emma C. Sasse, Lucas V. Santos
Journal: Journal of Clinical Oncology (2009)

pared to best supportive care alone. 2 Trials fully published presented no gain in OS (hazard ratio [HR], 0.98; 95% CI, 0.90 to 1.07) while those presented in abstract format stated relevant gain in OS (HR, 0.79; 95% CI 0.69 to 0.91). The difference among these two groups (fully and partially published trials) cannot be overlooked (interaction P .01). Nevertheless, the main source of concern in this meta-analysis is the assumption that different therapeutic approaches were similar and could be polled. Seven trials continued all drugs used in first-line therapy, three maintained a single drug already used in first-line therapy (maintenance therapies) and three switched to a new single drug before progression (sequential therapy) in the longer therapy arms. Even though there was no relevant statistical heterogeneity, pooling all these types of trials caused an inconsistency beyond numbers. Is the use of docetaxel or pemetrexed after four cycles of platinum-based chemotherapy similar to maintaining a platinum-doublet up to six cycles? Can continuing vinorelbine after platinum doublet be considered equal to docetaxel after platinum doublets? Are six or more courses of platinum doublets better than four cycles? It is hardly believable that such specifics question could be answered by a single broad meta-analysis. Ideally, a systematic review must point to a specific direction, and this was not the case with the Soon et al metaanalysis. An appropriated answer to the optimal duration of first-line chemotherapy must be better defined. The meta-analysis presented by Soon et al 1 did not perform a straightforward comparison of duration of first-line therapy alone, it is confounded by major differences in treatment. The OS benefit identified (HR, 0.92; 95% CI 0.86 to 0.99) when all types of trials were combined merits a deeper discussion. We could speculate that not all therapeutic approaches (maintenance and sequential) contribute equally to this result. In fact, the inclusion of one large sequential trial 3 seemed to be capital for achieving this survival gain as the robust analysis pointed out. These consideration were all taken into account in other systematic review recently published. 4 This review had more restricts inclusion criteria: trials comparing early introduction of a different drug (sequential trials) were excluded to avoid confounding bias. These narrow inclusion criteria of the meta-analysis diminished the number of included trials and patients but provided an interesting clinical uniformity among trials. Prolonged use of third-generation doublets increased progressionfree survival (HR, 0.75; 95% CI, 0.65 to 0.85) but not OS (HR, 1.08; 95% CI 0.90 to 1.28). The conclusion was that three to four cycles of platinum-based doublets would provide similar benefit of longer platinum-doublets therapies with less toxicity.
Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment
Authors: Brent A. Hanks, Alisha Holtzhausen, Katherine S. Evans, Rebekah Jamieson, Petra Gimpel, Olivia M. Campbell, Melissa Hector-Greene, Lihong Sun, Alok Tewari, Amanda George, Mark Starr, Andrew Nixon, Christi Augustine, Georgia Beasley, Douglas S. Tyler, Takayu Osada, Michael A. Morse, Leona Ling, H. Kim Lyerly, Gerard C. Blobe
Journal: Journal of Clinical Investigation (2013)

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.
No Change in Serotonin Type 1A Receptor Binding in Patients With Posttraumatic Stress Disorder
Authors: Omer Bonne, Earle Bain, Alexander Neumeister, Allison C Nugent, Meena Vythilingam, Richard E Carson, David A Luckenbaugh, William Eckelman, Peter Herscovitch, Wayne C Drevets, Dennis S Charney
Journal: American Journal of Psychiatry (2005)

Serotonin type 1A receptors (5HT1ARs) have been shown to be affected by stress in experimental animals and related to anxiety and depression in humans. In the present study, the authors sought an association between 5HT1AR binding and posttraumatic stress disorder (PTSD).Using positron emission tomography and the radioligand [18F]FCWAY, the authors compared 5HT1AR binding between patients with PTSD and healthy subjects.No significant differences in 5HT1AR distribution volume, binding potential, or tracer delivery were found.5HT1AR expression may not be altered in patients with PTSD.
Pharmacology of cardiac potassium channels
Authors: J Tamargo
Journal: Cardiovascular Research (2004)

Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potential under physiological and pathological conditions.
Shoulder pain after stroke: case report and review
Authors: G E GAMBLE, A K P JONES, P J TYRRELL
Journal: Annals of the Rheumatic Diseases (1999)

A 65 year old man with multiple vascular risk factors was admitted after a stroke. Five days later, he complained of left shoulder pain. This was a dull ache, worse on movement and on touching the shoulder. He also voluntarily described a second different pain, as a “clawing at the flesh” that was constant. Abnormalities on examination were a global decrease in the range of left shoulder movement, dysarthria, left pyramidal weakness, left hemisensory diminished pinprick sensation and decreased sensation to touch and temperature in the left upper limb. “Referred” allodynic pain was experienced in the shoulder joint, when the skin over the left scapula was touched. A left shoulder radiograph was normal. Central post stroke pain (CPSP) was diagnosed and amitriptyline 25 mg nightly was …
Postoperative Chemoradiotherapy or Surgery Alone for Gastric Cancer: The Plausibility of the Question and Pertinence of the Answer
Authors: Francesco Sclafani, Giuseppe Gullo, Armando Santoro
Journal: Journal of Clinical Oncology (2010)

TO THEEDITOR:WereadwithgreatinterestthereportbyDikken etal 1 ontheroleofpostoperativechemoradiotherapy(CRT)ingastric cancer.Inthisretrospectivestudy,theauthorscomparedtheoutcome of patients treated with surgery only with that of patients treated with surgeryandadjuvantCRT.Althoughastatisticallysignificantdecrease in the rate of 2-year local recurrence was found in the CRT group (5% v17%), this difference did not translate into a significant benefit in progression-free survival or overall survival (OS). These disappointing results were confirmed in the subgroup analysis, in which— despite a better local control—no survival advantage could be detected for patients with CRT compared with patients who received surgery only, according to the extent of lymph node dissection (D1 v D2)andMaruyamaIndex.Onlythepresenceofmicroscopicresidual diseaseaftersurgerywasfoundtobeapredictorofsurvivaladvantage in CRT, with the significant decrease in rate of local recurrence observed in R1 patients translating into significant improvement in 2-year OS (66% v 29%). Although this study raises the controversial issue of the optimal strategy to use in resectable gastric cancer, we think that it has some important conceptual and methodologic limits that affect its appeal and strength. Thesignificantimprovementinprogression-freesurvivalandOS in resectable gastric cancer deriving from the addition of a multimodalitystrategy,includingpostoperativeCRTandperioperativechemo
Time for change: a roadmap to guide the implementation of the World Anti-Doping Code 2015
Authors: Jiri Dvorak, Norbert Baume, Francesco Botré, Julian Broséus, Richard Budgett, Walter O Frey, Hans Geyer, Peter Rex Harcourt, Dave Ho, David Howman, Victor Isola, Carsten Lundby, François Marclay, Annie Peytavin, Andrew Pipe, Yannis P Pitsiladis, Christian Reichel, Neil Robinson, Grigory Rodchenkov, Martial Saugy, Souheil Sayegh, Jordi Segura, Mario Thevis, Alan Vernec, Marjolaine Viret, Marc Vouillamoz, Mario Zorzoli
Journal: British Journal of Sports Medicine (2014)

A medical and scientific multidisciplinary consensus meeting was held from 29 to 30 November 2013 on Anti-Doping in Sport at the Home of FIFA in Zurich, Switzerland, to create a roadmap for the implementation of the 2015 World Anti-Doping Code. The consensus statement and accompanying papers set out the priorities for the antidoping community in research, science and medicine. The participants achieved consensus on a strategy for the implementation of the 2015 World Anti-Doping Code. Key components of this strategy include: (1) sport-specific risk assessment, (2) prevalence measurement, (3) sport-specific test distribution plans, (4) storage and reanalysis, (5) analytical challenges, (6) forensic intelligence, (7) psychological approach to optimise the most deterrent effect, (8) the Athlete Biological Passport (ABP) and confounding factors, (9) data management system (Anti-Doping Administration & Management System (ADAMS), (10) education, (11) research needs and necessary advances, (12) inadvertent doping and (13) management and ethics: biological data. True implementation of the 2015 World Anti-Doping Code will depend largely on the ability to align thinking around these core concepts and strategies. FIFA, jointly with all other engaged International Federations of sports (Ifs), the International Olympic Committee (IOC) and World Anti-Doping Agency (WADA), are ideally placed to lead transformational change with the unwavering support of the wider antidoping community. The outcome of the consensus meeting was the creation of the ad hoc Working Group charged with the responsibility of moving this agenda forward.
Dispersion of monophasic action potential durations and activation times during atrial pacing, ventricular pacing, and ventricular premature stimulation in canine ventricles
Authors: C.-S. KUO, J. P. AMLIE, K. MUNAKATA, C P. REDDY, B. SURAWICZ
Journal: Cardiovascular Research (1983)

We studied dispersion of repolarisation and the components of dispersion during atrial pacing (AP), ventricular pacing (VP), and programmed ventricular premature stimulation (VPS) using six simultaneously recorded monophasic action potentials (MAP's) from ventricular surface in nine open-chest dogs. Varitions in MAP duration (MAPD) caused no changes in the configuration of strength-interval curves. During AP, maximum dispersion (MD) between any two of six sites averaged 32± 10 ms, consisting of 27 ± 10 ms MAPD and 4±9 ms activation time (AT) differences; during VP, MD averaged 77± 16 ms, consisting of 7± 15 ms MAPD and 70± 13 ms AT differences. Maximum dispersion in the earliest ventricular premature complexes (VPC) averaged 97 ± 16 ms: the difference between this value and the MD during VP was due to an increase in MAPD difference without significant change in AT difference. Dispersion during VPS exceeded dispersion during AP by 5 to 70 ms at 61 of 68 pairs of adjacent sites separated by 1.5 to 2.0 cm; the greatest increases were due to added contributions of MAPD and AT differences. Greatest dispersion between any two of six sites during VPS occurred in the early VPC, ie, at coupling intervals (CI) ≤30 ms following effective refractory period (ERP), but at the adjacent sites the timing of greatest dispersion during VPS varied, occurring at about one half of the sites at CI within 40 to 220 ms following ERP. Our results show that the MD during AP is due predominantly to MAPD difference, during VP predominantly to AT difference, and that prematurity increases the contribution of MAPD differences to dispersion from an average of 9% during VP to an average of 25%. No spontaneous repetitive activity occurred during VPS on the surface of the left ventricle using 2 ms stimuli of strength up to 40 mA.
γδT17 Cells Promote the Accumulation and Expansion of Myeloid-Derived Suppressor Cells in Human Colorectal Cancer
Authors: Pin Wu, Dang Wu, Chao Ni, Jun Ye, Wuzhen Chen, Guoming Hu, Zhen Wang, Changrong Wang, Zhigang Zhang, Wenjie Xia, Zhigang Chen, Ke Wang, Tao Zhang, Jinghong Xu, Yuehua Han, Ting Zhang, Xianguo Wu, Jianwei Wang, Weihua Gong, Shu Zheng, Fuming Qiu, Jun Yan, Jian Huang
Journal: Immunity (2014)
Effect of preoperative hyperinflation on static lung volumes after lung transplantation
Authors: C Pinet, M Estenne
Journal: European Respiratory Journal (2000)

It is still not known whether persistent increases in functional residual capacity (FRC) and residual volume (RV) after lung transplantation are due to preexisting hyperinflation. Therefore, the aim of this study was to determine the effects of chronic lung hyperinflation on static lung volumes after heart/lung (HLT) and bilateral lung transplantation (BLT). Static lung volumes were measured in 33 patients before and at 6 month intervals for up to 3 yrs after HLT (n=25) or BLT (n=8). The preoperative diagnosis was cystic fibrosis in 25 patients and other chronic hyperinflated lung diseases in eight patients. After surgery, total lung capacity returned to predicted normal values but FRC and RV remained greater than expected for either the recipient or the donor. At 1 yr after surgery, mean+/-SD FRC and RV were 130+/-18% and 151+/-34% of the predicted values for the recipient (p<0.001), and these figures did not change significantly over time. Similar abnormalities were found in patients with and without cystic fibrosis. After transplantation for lung diseases producing chronic hyperinflation, there is a persistent increase in functional residual capacity and residual volume. This alteration is present in patients operated on for diseases developed in both childhood and adulthood and is not recovered over time. It may be due to irreversible changes in the structure of the ribcage.
Incidence and risk factors for myelofibrotic transformation among 272 Chinese patients with JAK2-mutated polycythemia vera
Authors: Jie Bai, Limei Ai, Lei Zhang, Feng‐Chun Yang, Yuan Zhou, Yanping Xue
Journal: American Journal of Hematology (2015)

Post-polycythemia vera myelofibrosis (post-PV MF) is a critical hematologic evolution of polycythemia vera (PV). The main purpose of the present study was to identify the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. A cohort of 272 Chinese PV patients with JAK2(V617F) or exon12 mutation was retrospectively analyzed. Of the 272 patients with PV, 63 developed post-PV MF. Platelet count >550 × 10(9) /L and splenomegaly were identified as independent risk factors for post-PV MF. The median duration of survival for post-PV MF patients was 8 years. Anemia and age >65 years at diagnosis of post-PV MF were identified as significant predictors for the poor prognosis of post-PV MF. In conclusion, platelet counts and splenomegaly were significant predictors for the transformation to post-PV MF, while anemia (hemoglobin levels <100 g/L) and age>65 years were significant predictors for poor prognosis of post-PV MF in Chinese PV patients with JAK2(V617F) or exon12 mutation.