tbuckley/cabot-search huggingface dataset:
Effects of sildenafil on cardiac repolarization
Authors: C Chiang
Journal: Cardiovascular Research (2002)

Objectives: Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. Methods: We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. Results: Action potential duration at 90% repolarization (APD90) was not affected by sildenafil in the therapeutic ranges (≤1 μM), but shortened by higher concentration (≥10 μM) in both guinea pig papillary muscles and canine Purkinje fibers. d-Sotalol prolonged APD90 in the same preparations with concentrations ≥1 μM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 μM) abolished the APD-prolonging effects of d-sotalol (30 μM) and amiodarone (100 μM). Sildenafil, with concentrations up to 30 μM, had no significant effect on both the rapid (IKr) and the slow (IKs) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca2+ current (ICa,L), but had no effect on persistent Na+ current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by d,l-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). Conclusions: Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on ICa,L.
The Efficacy of Dual Time Point F-18 FDG PET Imaging for Grading of Brain Tumors
Authors: Dae-Weung Kim, Sang-Ah Jung, Chang-Guhn Kim, Soon-Ah Park
Journal: Clinical Nuclear Medicine (2010)

Several studies have explored the usefulness of dual time point F-18 FDG positron emission tomography imaging (DTPI) in improving detection of brain metastases and tumors outside the brain, distinguishing malignant from benign. In the same manner, DTPI may show better performance to grade of brain tumors.Twenty-two lesions of 18 consecutive patients with primary or metastatic brain tumor were included prospectively. DTPI was performed and analyzed using maximum standardized uptake values (SUVmax), mean standardized uptake values within isocontour at 70% of maximum pixel values (SUViso), and retention index (RI) for each lesion.SUVmax and SUViso of the delayed image were more efficient than those of early images to classify lesions by the grade of tumors. The RI of SUVmax and SUViso were not significant to classify lesions.DTPI may be a better imaging method to grade the brain tumor than early imaging only.
Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions
Authors: Avi Ashkenazi
Journal: Journal of Clinical Investigation (2015)

Apoptosis is a metazoan process of controlled cell elimination that plays critical roles in embryonic development and adult tissue homeostasis. Apoptosis dysregulation contributes to several important diseases, including cancer. Two distinct yet interconnected signaling pathways control apoptosis by activating a core intracellular machinery of death proteases called caspases. The intrinsic apoptotic pathway engages caspases via members of the BCL-2 protein family and the mitochondria in reaction to severe cellular damage or stress. The extrinsic pathway activates caspases via cell-surface death receptors, which respond to cognate death ligands expressed on immune-effector cells. Tumor cells can acquire various apoptosis-evasion mechanisms; nevertheless, the transformed state of these cells makes them uniquely susceptible to apoptosis reactivation if resistance is circumvented. Molecular approaches to reengage the apoptotic pathways in cancer have been underway for over two decades. Gratifyingly, BCL-2 antagonists — which drive the intrinsic pathway — are beginning to bear clinical fruit. In contrast, clinical attempts to stimulate the extrinsic pathway with proapoptotic receptor agonists (PARAs) have been disappointing, despite compelling preclinical efficacy with this class of agents. Here, I discuss some of the possible reasons for this translational discrepancy and suggest strategies to overcome it with the next generation of PARAs.
The Promise of Antibody–Drug Conjugates
Authors: Beverly A. Teicher, James H. Doroshow
Journal: New England Journal of Medicine (2012)

The promise of antibody–drug conjugates (ADCs) is the specific targeting of highly potent cytotoxic agents to malignant disease without adversely affecting normal tissues. We may be on the verge of fulfilling that promise. This moment has been more than 25 years in the making and has required technology development in every facet of the conception and execution of ADCs. In this issue of the Journal, Verma et al.1 describe the positive results of their phase 3 trial comparing the ADC trastuzumab emtansine to the combination of lapatinib and capecitabine in women with advanced breast cancers that are strongly positive for . . .
The Doctor's PDA and Smartphone Handbook The task list
Authors: C. Paton
Journal: Journal of the Royal Society of Medicine (2006)

A good house officer is an organized house officer; and keeping track of the jobs to be done for each patient is arguably the most important skill for doctors beginning their career. Your handheld computer's task list will not make you organized, but it will provide you with the tools you need to be organized.

Like the diary and address book, the task list's importance means that most handheld computers include a button that takes you straight to the program. This is usually in the bottom right-hand corner, second from the right. Alternatively, on Palm Powered machines, tap on the HOME icon and then the icon labeled To Do List. On Pocket PCs, tap on the START icon and then Tasks.

The tasks are given in a list, with a tick box next to each task (Figures ​(Figures11 and ​and2).2). Tap on a tick box if you have completed its task, and tap again to remove the tick from the box. Tapping on a task allows you to look at the task's related text, priority and due date. The priority and due date are what you really need to manage your tasks for the day.



Figure 1

Pocket PC's Tasks





Figure 2

Palm Powered device's To Do list
Surface engineering of stainless steel materials by covalent collagen immobilization to improve implant biocompatibility
Authors: Rainer Müller, Jochen Abke, Edith Schnell, Frank Macionczyk, Uwe Gbureck, Robert Mehrl, Zbigniev Ruszczak, Richard Kujat, Carsten Englert, Michael Nerlich, Peter Angele
Journal: Biomaterials (2005)
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1
Authors: Immacolata Andolfo, Seth L. Alper, Lucia De Franceschi, Carla Auriemma, Roberta Russo, Luigia De Falco, Fara Vallefuoco, Maria Rosaria Esposito, David H. Vandorpe, Boris E. Shmukler, Rupa Narayan, Donatella Montanaro, Maria D’Armiento, Annalisa Vetro, Ivan Limongelli, Orsetta Zuffardi, Bertil E. Glader, Stanley L. Schrier, Carlo Brugnara, Gordon W. Stewart, Jean Delaunay, Achille Iolascon
Journal: Blood (2013)
Access to Universal Grammar: The real issues
Authors: Hagit Borer
Journal: Behavioral and Brain Sciences (1996)

Abstract Issues concerning UG access for L2 acquisition as formulated by Epstein et al. are misleading as well as poorly discussed. UG accessibility can only be fully evaluated with respect to the steady state gram mar reached by the learner. The steady state for LI learners is self evidently the adult grammar in the speech community. For L2 learners, however, the steady state is not obvious. Yet, without its clear characterization, debates concerning stages of L2 acquisition and direct and indirect UG accessibility cannot be resolved.
Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
Authors: Genglin Jin, Zachary J. Reitman, Christopher G. Duncan, Ivan Spasojevic, David M. Gooden, B. Ahmed Rasheed, Rui Yang, Giselle Y. Lopez, Yiping He, Roger E. McLendon, Darell D. Bigner, Hai Yan
Journal: Cancer Research (2012)

Abstract Point mutations at Arg132 of the cytoplasmic NADP+-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the “oncometabolite” D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers. Cancer Res; 73(2); 496–501. ©2012 AACR.
Bcl-2 Antisense Oligonucleotide Overcomes Resistance to <i>E1A</i> Gene Therapy in a Low HER2-Expressing Ovarian Cancer Xenograft Model
Authors: Chandra Bartholomeusz, Hiroaki Itamochi, Linda X.H. Yuan, Francisco J. Esteva, Christopher G. Wood, Naoki Terakawa, Mien-Chie Hung, Naoto T. Ueno
Journal: Cancer Research (2005)

Abstract We are currently conducting clinical trials of E1A gene therapy for patients with ovarian cancer. The adenovirus type 5 E1A gene suppresses growth of ovarian cancer cells that overexpress HER-2/neu (HER2) and growth of some—but not all—that express low HER2. In HER2-overexpressing cells, suppression by E1A is predominantly by down-regulation of HER2, but the mechanism in low HER2-expressing cells is not fully understood. The adenoviral E1B protein has sequential and functional homology to Bcl-2 and prolongs the viability of adenovirus host cells by inhibiting E1A-induced apoptosis. Bcl-2 is overexpressed in ovarian cancer and participates in chemoresistance; we hypothesized that Bcl-2 inhibits E1A-induced apoptosis leading to resistance to E1A gene therapy. E1A suppressed colony formation of ovarian cancer cells that express low levels of Bcl-2 and HER2 (OVCAR-3 and OVCA 433), but enhanced colony formation in low HER2-, high Bcl-2–expressing ovarian cancer cells (2774 and HEY). Treating 2774 or HEY cells with antisense oligonucleotide Bcl-2 (Bcl-2-ASO) did not reduce cell viability. E1A combined with Bcl-2-ASO led to significant decreases in cell viability resulting from increased apoptosis relative to cells treated with E1A alone (P &amp;lt; 0.05). The increase in apoptosis was partly due to cytochrome c release and subsequently caspase-9 activation by Bcl-2-ASO. Finally, in an ovarian cancer xenograft model, treatment with Bcl-2-ASO did not prolong survival, but E1A plus Bcl-2-ASO did (P &amp;lt; 0.001). In conclusion, ovarian tumors overexpressing Bcl-2 may not respond well to E1A gene therapy, but treatment with a combination of E1A and Bcl-2-ASO may overcome this resistance.
The Trypanosoma cruzi neuraminidase contains sequences similar to bacterial neuraminidases, YWTD repeats of the low density lipoprotein receptor, and type III modules of fibronectin.
Authors: M E Pereira, J S Mejia, E Ortega-Barria, D Matzilevich, R P Prioli
Journal: The Journal of Experimental Medicine (1991)

Trypanosoma cruzi expresses a developmentally regulated neuraminidase (TCNA) implicated in parasite invasion of cells. We isolated full-length DNA clones encoding TCNA. Sequence analysis demonstrated an open reading frame coding for a polypeptide of 1,162 amino acids. In the N-terminus there is a cysteine-rich domain containing a stretch of 332 amino acids nearly 30% identical to the Clostridium perfringens neuraminidase, three repeat motifs highly conserved in bacterial and viral neuraminidases, and two segments with similarity to the YWTD repeats found in the low density lipoprotein (LDL) receptor and in other vertebrate and invertebrate proteins. This domain is connected by a structure characteristic of type III modules of fibronectin to a long terminal repeat (LTR) consisting of 44 full length copies of twelve amino acids rich (75%) in serine, threonine, and proline. LTR is unusual in that it contains at least 117 potential phosphorylation sites. At the extreme C-terminus is a hydrophobic segment of 35 amino acids, which could mediate anchorage of TCNA to membranes via a glycosylphosphatidylinositol linkage. This is the first time a protozoan protein has been found to contain a YWTD repeat and a fibronectin type III module. The domain structure of TCNA suggests that the enzyme may have functions additional to its catalytic activity such as in protein-protein interaction, which could play a role in T. cruzi binding to host cells.
Action of Thymoxamine on Mydriasis induced by Levodopa and Dopamine
Authors: A. S. D. Spiers, D. B. Calne, S. D. Vakil, T. M. French
Journal: BMJ (1971)

Eye-drops of levodopa and dopamine induce pupillary dilatation which is inhibited by thymoxamine, an alpha-adrenergic blocking drug. This indicates that the mydriatic action of levodopa and dopamine involves excitation of alpha-adrenergic receptors of the dilator pupillae muscle. Such a conclusion is in accord with the previously expressed suggestion that levodopa is rapidly converted to dopamine, which displaces noradrenaline from adrenergic nerve endings.The findings that dopamine exerts alpha-adrenergic effects at the periphery may be construed as evidence in support of the view that the hypotensive action of levodopa is mediated via the central nervous system.
NTP Talks Transgenics
Authors: Brandy E. Fisher
Journal: Environmental Health Perspectives (1998)

NIEHS and National Toxicology Program (NTP) researchers recently shared with the public their research on transgenic mouse models aimed at evaluating how they can be used for testing the carcinogenicity ofchemicals and drugs.Research suggests that some of these models have the potential to identify carcinogens more quickly and at a fraction of the cost of the standard two-year rodent bioassay for carcinogenicity testing.Promising research on three specific transgenic mouse models prompted a meet- ing of the NTP's Board of Scientific Counselors (BSC) at the NIEHS on 5-6 February 1998.The purpose of the meeting was to review the NTP/NIEHS efforts to evaluate these models and to discuss incor-
ACTIVITY OF DISSOCIATED AND REASSOCIATED 19S ANTI-γ-GLOBULINS
Authors: Ralph E. Schrohenloher, Henry G. Kunkel, Thomas B. Tomasi
Journal: The Journal of Experimental Medicine (1964)

19S anti-gamma-globulins were isolated in a high state of purity from the sera of two patients with rheumatoid arthritis. Following reduction with ethyl mercaptan and alkylation by iodoacetamide, fragments were produced which retained the capacity to combine with 7S gamma-globulin. The fragments from one of the 19S anti-gamma-globulins agglutinated red cells coated with incomplete anti-Rh antibodies. This activity was shown by density gradient ultracentrifugation to be associated with low molecular weight fractions. The agglutination of the coated red cells by the fragments was strongly inhibited by normal and myeloma 7S gamma-globulins and showed a greater specificity than the parent 19S material. Analytical ultracentrifuge experiments demonstrated that the fragments from either of the 19S anti-gamma-globulins formed complexes with 7S gamma-globulin. Reassociation of the dissociated fragments through reformation of disulfide bonds resulted in the formation of fast sedimenting molecules having properties similar to those of the untreated 19S material in respect to precipitation with aggregated gamma-globulin and agglutination of coated red cells.
SALMON IN A DIET FOR THE PROPHYLAXIS OF GOITER
Authors: NORMAN D. JARVIS
Journal: JAMA (1926)

The researches of Chatin<sup>1</sup>on the distribution of iodine in nature, and his conclusion that goiter was due to a deficiency of this element, have been the subject of much discussion. It is now generally believed that iodine deficiency is the immediate cause of simple goiter, and that this disease is readily combated by a prophylactic treatment that supplies the amount of iodine necessary for the normal functioning of the thyroid. This may be accomplished by increasing the iodine in the diet by use of the proper foods, or by the administration of compounds of iodine. Fellenberg<sup>2</sup>made a comprehensive study of the distribution of iodine in foods, beverages, soil and air. He found that the intake and excretion of iodine were approximately equal on a low iodine diet, but that, by the addition of iodine in such forms as cod liver oil, sardines, butter or potassium iodide,
Phytophotodermatitis and Limes
Authors: Miriam Keltz Pomeranz, Julie K Karen
Journal: New England Journal of Medicine (2007)

This 23-year-old woman presented to the emergency department with a painful, erythematous, blistering rash on sun-exposed skin. At the beach, she had prepared cocktails of rum and limes. A burning erythema developed and later blistered.
S151 TRAIL deficiency is protective in experimental pulmonary arterial hypertension
Authors: A. G. Hameed, J. Chamberlain, N. D. Arnold, S. E. Francis, C. M. H. Newman, D. C. Crossman, A. Lawrie
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Despite advances in the overall management of Pulmonary Arterial Hypertension (PAH) significant morbidity and poor prognosis remain a major clinical problem. Identifying key pathways in the pathogenesis of this disease will allow development of more targeted therapies aimed at treating PAH. There is emerging evidence to support that Tumour Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) plays an important role in vascular biology. We have recently reported expression of TRAIL from lesions of patients with advanced Idiopathic PAH. To further determine the role of TRAIL in the pathogenesis of PAH we used a diet-induced murine model of PAH. <h3>Methods</h3> ApoE<sup>−/−</sup>, TRAIL<sup>−/−</sup> and ApoE<sup>−/−</sup>/TRAIL<sup>−/−</sup> double null mice were fed chow or Paigen (high fat, cholate-containing diet) for 8 weeks. They underwent echocardiographic assessment prior to right heart catheterisation using the internal jugular venous route. The heart and right lung were perfusion fixed with 10% formalin for subsequent determination of right ventricular mass and Immunohistochemistry of pulmonary vascular lesions. The left lung was immediately frozen in liquid nitrogen for subsequent determination of protein and RNA by western Immunoblotting and quantitative PCR. Identical to above ApoE<sup>−/−</sup>/TRAIL<sup>−/−</sup> double null mice were also treated with recombinant murine TRAIL, or saline (4 week infusion via an osmotic mini pump) at the time of commencing the diet for 8 weeks. <h3>Results</h3> Compared to control chow fed mice, ApoE<sup>−/−</sup> mice fed the Paigen diet developed significant elevation of Right Ventricular Systolic Pressure (RVSP) (23 mm Hg vs 50 mm Hg n=7 p&lt;0.001), pulmonary vascular resistance and arteriolar remodelling. ApoE<sup>−/−</sup>/TRAIL<sup>−/−</sup> double null mice fed the Paigen diet, were protected from these haemodynamic (RVSP 27 mm Hg n=6 p&lt;0.05) and pulmonary vascular remodelling changes. Moreover, the PAH phenotype was re-established in the ApoE<sup>−/−</sup>/TRAIL<sup>−/−</sup> double null mice by the administration of exogenous recombinant TRAIL. <h3>Conclusions</h3> TRAIL is a critical mediator in disease pathogenesis of PAH in the diet-induced murine model of PAH. Targeting TRAIL could provide a novel therapeutic approach to the treatment of PAH. Work is ongoing to determine if this approach can stabilise or reverse established disease, in both this, and rat, experimental models of PAH.
BAG3 and Hsc70 Interact With Actin Capping Protein CapZ to Maintain Myofibrillar Integrity Under Mechanical Stress
Authors: Akinori Hishiya, Toshio Kitazawa, Shinichi Takayama
Journal: Circulation Research (2010)

A homozygous disruption or genetic mutation of the bag3 gene, a member of the Bcl-2-associated athanogene (BAG) family proteins, causes cardiomyopathy and myofibrillar myopathy that is characterized by myofibril and Z-disc disruption. However, the detailed disease mechanism is not yet fully understood.bag3(-/-) mice exhibit differences in the extent of muscle degeneration between muscle groups with muscles experiencing the most usage degenerating at an accelerated rate. Usage-dependent muscle degeneration suggests a role for BAG3 in supporting cytoskeletal connections between the Z-disc and myofibrils under mechanical stress. The mechanism by which myofibrillar structure is maintained under mechanical stress remains unclear. The purpose of the study is to clarify the detailed molecular mechanism of BAG3-mediated muscle maintenance under mechanical stress.To address the question of whether bag3 gene knockdown induces myofibrillar disorganization caused by mechanical stress, in vitro mechanical stretch experiments using rat neonatal cardiomyocytes and a short hairpin RNA-mediated gene knockdown system of the bag3 gene were performed. As expected, mechanical stretch rapidly disrupts myofibril structures in bag3 knockdown cardiomyocytes. BAG3 regulates the structural stability of F-actin through the actin capping protein, CapZβ1, by promoting association between Hsc70 and CapZβ1. BAG3 facilitates the distribution of CapZβ1 to the proper location, and dysfunction of BAG3 induces CapZ ubiquitin-proteasome-mediated degradation. Inhibition of CapZβ1 function by overexpressing CapZβ2 increased myofibril vulnerability and fragmentation under mechanical stress. On the other hand, overexpression of CapZβ1 inhibits myofibrillar disruption in bag3 knockdown cells under mechanical stress. As a result, heart muscle isolated from bag3(-/-) mice exhibited myofibrillar degeneration and lost contractile activity after caffeine contraction.These results suggest novel roles for BAG3 and Hsc70 in stabilizing myofibril structure and inhibiting myofibrillar degeneration in response to mechanical stress. These proteins are possible targets for further research to identify therapies for myofibrillar myopathy or other degenerative diseases.