tbuckley/cabot-search huggingface dataset:
Darinaparsin: Solid Tumor Hypoxic Cytotoxin and Radiosensitizer
Authors: Junqiang Tian, Hongjuan Zhao, Rosalie Nolley, Stephen W. Reese, Sarah R. Young, Xuejun Li, Donna M. Peehl, Susan J. Knox
Journal: Clinical Cancer Research (2012)

Hypoxia is an important characteristic of the solid tumor microenvironment and constitutes a barrier for effective radiotherapy. Here, we studied the effects of darinaparsin (an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues.The cytotoxicity and radiosensitization of darinaparsin were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of darinaparsin effects, including reactive oxygen species (ROS) generation, cellular damage, and changes in global gene expression, were also investigated.In comparison with ATO, darinaparsin had significantly higher in vitro cytotoxic and radiosensitizing activities against solid tumor cells under both normoxia and hypoxia. In vivo experiments confirmed these activities at doses that had no systemic toxicities. Importantly, darinaparsin did not radiosensitize normal bone marrow and actually radioprotected normal intestinal crypts. The darinaparsin-mediated antitumor effects under hypoxia were not dependent on ROS generation and oxidative damage, but were associated with inhibition of oncogene (RAS and MYC)-dependent gene expression.Darinaparsin has significant and preferential cytotoxic and radiosensitizing effects on solid tumors as compared with normal cells. Darinaparsin may therefore increase the therapeutic index of radiation therapy and has near term translational potential.
Sodium Thiosulfate Administered Six Hours after Cisplatin Does Not Compromise Antineuroblastoma Activity
Authors: Theresa M. Harned, Ondrej Kalous, Alexander Neuwelt, Jason Loera, Lingyun Ji, Peter Iovine, Richard Sposto, Edward A. Neuwelt, C. Patrick Reynolds
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We determined if the potentially otoprotective agent sodium thiosulfate (STS) could be given 6 h after cisplatin without diminishing the antineuroblastoma activity of cisplatin in human neuroblastoma cell lines in vitro (including cisplatin-resistant cell lines) and in neuroblastoma xenografts in vivo. Experimental Design: We determined the antineuroblastoma activity of cisplatin with or without the addition of STS at 0 or 6 h after cisplatin in six neuroblastoma cell lines, both in standard cell culture conditions (20% O2) and in physiologic hypoxia (2% O2). Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay. In vivo studies of cisplatin combined with STS used a human neuroblastoma subcutaneous xenograft model (SMS-SAN) in athymic nu/nu mice. Results: A significant protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were exposed to cisplatin directly combined with STS. However, when cisplatin was given first and STS exposure occurred 6 h later, no effect on cisplatin cytotoxicity was observed. In a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin + STS at 6 h had significantly better progression-free survival rates (P &amp;lt; 0.03) compared with controls or mice treated with cisplatin + STS concurrently. There was no statistically significant difference in outcomes between mice treated with cisplatin alone and the group treated with cisplatin followed by STS 6 h later (P = 0.9). Conclusion: These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.
Nothing but natural: targeting natural IgM in ischaemia/reperfusion injury
Authors: U. Hofmann, J. Bauersachs, S. Frantz
Journal: Cardiovascular Research (2010)

This editorial refers to ‘Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction’ by M.S. Haas et al. , doi:10.1093/cvr/cvq141 

Ischaemic heart disease and stroke are major causes of morbidity and mortality in the western world. In both clinical entities, reperfusion within several hours is the only established therapy to limit infarct size. However, therapeutic or spontaneous reperfusion itself may contribute to tissue injury. Reoxygenation often aggravates hypoxic cellular changes including mitochondrial alterations, reactive oxygen species generation, intracellular ion imbalance, and damage of membrane constituents. Furthermore, ischaemia induces a sterile inflammatory response, which mainly involves innate immune cells, especially neutrophils.1,2

With the seminal finding that so-called natural antibodies can recognize self-antigens during ischaemia,3 Michael Carroll's group introduced the model of ‘innate autoimmunity’ for ischaemia/reperfusion injury. This concept integrates mechanisms of both intrinsic ischaemic cell injury and initiation of an extrinsic innate immune response.4 According to their hypothesis, ischaemia/reperfusion induces intracellular damage, rendering cells susceptible to a second phase of injury that is initiated by natural antibody-mediated complement activation. Early evidence for the involvement of the complement system in ischaemia/reperfusion injury came from a study from Weisman … 

*Corresponding author. Tel: +49 931 201 43542; fax: +49 931 201 61633, Email: frantz_s{at}medizin.uni-wuerzburg.de
PET imaging with [11C]PBR28 and [18F]FDG distinguishes macrophage from neutrophil lung inflammation
Authors: Delphine Chen, Eugene Agapov, Kiran Solingapuram, Jacquelyn Engle, Elizabeth Griffin, Steven Brody, Jason Woods, Robert Mach, Richard Pierce, Michael Holtzman
Journal: European Respiratory Journal (2012)

Introduction: Noninvasive methods for quantifying macrophage and neutrophil activation and recruitment in chronic obstructive pulmonary disease (COPD) would be highly useful in assessing the efficacy of anti-inflammatory therapies.

Objective: To test whether positron emission tomography (PET) imaging with [11C]PBR28 and [18F]fluorodeoxyglucose ([18F]FDG) could distinguish macrophage-dominant from neutrophilic inflammation in a mouse model of COPD.

Methods: C57BL/6J mice inoculated with PBS or Sendai virus were imaged by microPET (Inveon or Focus 220, Siemens/CTI) with both [11C]PBR28 and [18F]FDG at Days 3 and 84 post-inoculation (p.i.). Regions of interest placed over the lungs determined the % injected dose per cc (%ID/cc) at 60 min. Lung sections were stained for TSPO ([11C]PBR28 ligand), Ly6G (neutrophil marker) and CD68 (macrophage marker).

Results: Only [18F]FDG uptake increased significantly during acute illness at p.i. Day 3. Both [11C]PBR28 and [18F]FDG uptake increased significantly during chronic disease at p.i. Day 84. The [11C]PBR28:[18F]FDG ratio, calculated for each mouse, was no different between infected (1.9 ± 0.3) and uninfected mice (2.0 ± 0.4) at p.i. Day 3. This ratio increased significantly at p.i. Day 84 (3.1 ± 0.9) in infected mice compared to controls (1.7 ± 0.5). Lung sections showed macrophages with intense TSPO staining at p.i. Day 84.

Conclusion: PET imaging with [11C]PBR28 and [18F]FDG quantitatively distinguishes macrophage-dominant from neutrophilic inflammation in a mouse model of COPD. This approach may be useful for monitoring the pulmonary macrophage burden in humans with COPD, thereby guiding emerging targeted anti-inflammatory therapies.
PKC Phosphorylation of Titin’s PEVK Element
Authors: Carlos Hidalgo, Bryan Hudson, Julius Bogomolovas, Yi Zhu, Brian Anderson, Marion Greaser, Siegfried Labeit, Henk Granzier
Journal: Circulation Research (2009)

Rationale : Protein kinase C (PKC) regulates contractility of cardiac muscle cells by phosphorylating thin- and thick- filament-based proteins. Myocardial sarcomeres also contain a third myofilament, titin, and it is unknown whether titin can be phosphorylated by PKC and whether it affects passive tension. Objective : The purpose of this study was to examine the effect of PKC on titin phosphorylation and titin-based passive tension. Methods and Results : Phosphorylation assays with PKCα revealed that titin is phosphorylated in skinned myocardial tissues; this effect is exacerbated by pretreating with protein phosphatase 1. In vitro phosphorylation of recombinant protein representing titin’s spring elements showed that PKCα targets the proline – glutamate – valine – lysine (PEVK) spring element. Furthermore, mass spectrometry in combination with site-directed mutagenesis identified 2 highly conserved sites in the PEVK region that are phosphorylated by PKCα (S11878 and S12022); when these 2 sites are mutated to alanine, phosphorylation is effectively abolished. Mechanical experiments with skinned left ventricular myocardium revealed that PKCα significantly increases titin-based passive tension, an effect that is reversed by protein phosphatase 1. Single molecule force-extension curves show that PKCα decreases the PEVK persistence length (from 1.20 nm to 0.55 nm), without altering the contour length, and using a serially-linked wormlike chain model we show that this increases titin-based passive force with a sarcomere length dependence that is similar to that measured in skinned myocardium after PKCα phosphorylation. Conclusions : PKC phosphorylation of titin is a novel and conserved pathway that links myocardial signaling and myocardial stiffness.
Erratum. Combination of Empagliflozin and Linagliptin as Second-Line Therapy in Subjects With Type 2 Diabetes Inadequately Controlled on Metformin. Diabetes Care 2015;38:384–393
Authors: Ralph A. DeFronzo, Andrew Lewin, Sanjay Patel, Dacheng Liu, Renee Kaste, Hans J. Woerle, Uli C. Broedl
Journal: Diabetes Care (2015)

In the print version of the article cited above, mean (SD) body weight for empagliflozin 10 …
STUDIES ON THE PNEUMONIC EXUDATE
Authors: Frederick T. Lord, Robert N. Nye
Journal: The Journal of Experimental Medicine (1921)

Specific agglutinins for the homologous pneumococcus are lacking or present only in small amount in the pneumonic exudates due to the fixed types of pneumococci. Suspensions of fixed types of pneumococci in the supernatant fluid obtained after centrifuging the mash of the pneumonic lung give positive agglutination tests in dilutions not higher than equal parts of suspension and supernatant fluid (1:2). The pneumonic lung contains a soluble substance inhibiting agglutination of the fixed types of pneumococci by the homologous antipneumococcus serum.
Lymphocyte-macrophage co-operation during induction of T-suppressor cell activity in rats with adjuvant arthritis.
Authors: L Binderup
Journal: Annals of the Rheumatic Diseases (1983)

The role of macrophages and of macrophage-lymphocyte co-operation in the induction of T-suppressor cell activity in rats with adjuvant arthritis was investigated. Macrophages from arthritic rats had no direct effect on the induction of T-suppressor cells, but, in the presence of arthritic rats9 lymphocytes or supernatants from such lymphocytes, macrophages inhibited the induction of T-suppressor cell activity. Addition of indomethacin during the induction of T-suppressor cells reduced the inhibitory effects, suggesting that prostaglandins released from lymphocyte-activated macrophages might be involved in the defective induction of T-suppressor cell activity in rats with adjuvant arthritis.
The development of tuberculosis in Bucharest in the last ten years
Authors: Emilia Tabacu, Elmira Ibraim, Cristian Didilescu
Journal: European Respiratory Journal (2011)

Bucharest, capitale of Romania, with a population of 1 944 500 inhabitants, constitutes an important problem of epidemiological surveillance of tuberculosis due to a high percent of floating population, numerous overcrowds of persons in locations that are deteriorating (8528 inhabitants/km 2 ), existence of vulnerable groups (homeless, roma population, poor, immigrants) with a lower social, economic and educational level, increasing number of the unemployed, etc.   Objective:  The study of the main indicators of the TB endemic in Bucharest in the last nine years.   Material and method:  We used the information existing in the official documents of the information system within the National Program of Tuberculosis Control.   Results:  A tendency of incidence increase has been installed, reaching from 65,9%ooo in 1985 to 154,1%000 in 2001, after which a decrease occurred yearly, reaching 68,3%ooo in 2010. A decrease of the incidence with 52% was recorded during 2001 – 2010. The incidence for new cases decrease from 135,8%ooo in 2001 to 57,5%ooo in 2010 and the incidence for relapses decrease from 18,3%ooo in 2001 to 10,9%ooo in 2010. The tuberculosis incidence in the 0-14 year children population decrease from 60,8%ooo in 2001 to 22,6%ooo in 2010. The source density was reduced from 12 sources/Km 2  in 2001 to 5 sources/Km 2  in 2009. The rate of the therapeutic success of the new source cases with pulmonary TB (M+) increased from 82,2% in the patient cohort from 2001 to 85,23% in those from 2009.   Conclusions:  Tuberculosis control in Bucharest benefits from a rather complex material basis which should be improved according to the present day epidemiological conditions.
The Ethics of Advertising for Health Care Services
Authors: Yael Schenker, Robert M. Arnold, Alex John London
Journal: The American Journal of Bioethics (2014)

Advertising by health care institutions has increased steadily in recent years. While direct-to-consumer prescription drug advertising is subject to unique oversight by the Federal Drug Administration, advertisements for health care services are regulated by the Federal Trade Commission and treated no differently from advertisements for consumer goods. In this article, we argue that decisions about pursuing health care services are distinguished by informational asymmetries, high stakes, and patient vulnerabilities, grounding fiduciary responsibilities on the part of health care providers and health care institutions. Using examples, we illustrate how common advertising techniques may mislead patients and compromise fiduciary relationships, thereby posing ethical risks to patients, providers, health care institutions, and society. We conclude by proposing that these risks justify new standards for advertising when considered as part of the moral obligation of health care institutions and suggest that mechanisms currently in place to regulate advertising for prescription pharmaceuticals should be applied to advertising for health care services more broadly.
EMF AND HEALTH
Authors: Maria Feychting, Anders Ahlbom, Leeka Kheifets
Journal: Annual Review of Public Health (2004)

Electric and magnetic fields are ubiquitous in the modern society, and concerns have been expressed regarding possible adverse effects of these exposures. This review covers epidemiologic research on health effects of exposures to static, extremely low-frequency (ELF), and radio frequency (RF) fields. Research on ELF fields has been performed for more than two decades, and the methodology and quality of studies have improved over time. Studies have consistently shown increased risk for childhood leukemia associated with ELF magnetic fields, whereas ELF fields most likely are not a risk factor for breast cancer and cardiovascular disease. There are still inadequate data for other outcomes. More recently, focus has shifted toward RF exposures from mobile telephony. There are no persuasive data suggesting a health risk, but this research field is still immature with regard to the quantity and quality of available data. This technology is constantly changing and there is a need for continued research on this issue. Almost no epidemiologic data are available for static fields.
Adaptive Immunity to Nontypeable<i>Haemophilus influenzae</i>
Authors: Paul T. King, Paul E. Hutchinson, Paul D. Johnson, Peter W. Holmes, Nicholas J. Freezer, Stephen R. Holdsworth
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Nontypeable Haemophilus influenzae (NTHi) colonizes the upper respiratory tract of most healthy people and is also a major cause of infection in chronic obstructive lung disease. The immune response to this bacterium has not been well characterized. We tested the hypothesis that recurrent airway infection with NTHi may be associated with nonclearing adaptive immunity. Study subjects were healthy control subjects and patients with idiopathic bronchiectasis who had severe chronic infection with H. influenzae. We established that all subjects in both groups had detectable antibody to NTHi, suggesting that most normal people have developed an adaptive immune response. To characterize the nature of the immune response, we measured antigen-specific production of T helper cell cytokines and CD40 ligand by flow cytometry and immunoglobulin subclass levels in peripheral blood. We found that normal control subjects made Th1 response to NTHi with distinct CD40 ligand production. In contrast, subjects with bronchiectasis had predominant production of Th2 cytokines, decreased expression of CD40 ligand, and different immunoglobulin G subclass production. Therefore, chronic infection with NTHi in bronchiectasis is associated with a change in adaptive immunity that may be important in the pathogenesis of bronchial infection.
Epigenomics of human embryonic stem cells and induced pluripotent stem cells: insights into pluripotency and implications for disease
Authors: Alvaro Rada-Iglesias, Joanna Wysocka
Journal: Genome Medicine (2011)

Human pluripotent cells such as human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) and their in vitro differentiation models hold great promise for regenerative medicine as they provide both a model for investigating mechanisms underlying human development and disease and a potential source of replacement cells in cellular transplantation approaches. The remarkable developmental plasticity of pluripotent cells is reflected in their unique chromatin marking and organization patterns, or epigenomes. Pluripotent cell epigenomes must organize genetic information in a way that is compatible with both the maintenance of self-renewal programs and the retention of multilineage differentiation potential. In this review, we give a brief overview of the recent technological advances in genomics that are allowing scientists to characterize and compare epigenomes of different cell types at an unprecedented scale and resolution. We then discuss how utilizing these technologies for studies of hESCs has demonstrated that certain chromatin features, including bivalent promoters, poised enhancers, and unique DNA modification patterns, are particularly pervasive in hESCs compared with differentiated cell types. We outline these unique characteristics and discuss the extent to which they are recapitulated in iPSCs. Finally, we envision broad applications of epigenomics in characterizing the quality and differentiation potential of individual pluripotent lines, and we discuss how epigenomic profiling of regulatory elements in hESCs, iPSCs and their derivatives can improve our understanding of complex human diseases and their underlying genetic variants.
Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications
Authors: David S. Schrump
Journal: Clinical Cancer Research (2009)

Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacologic agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clinical implications of HDAC inhibition as a strategy for cancer therapy.
Distinct ACPA fine specificities, formed under the influence of HLA shared epitope alleles, have no effect on radiographic joint damage in rheumatoid arthritis
Authors: H. U. Scherer, D. van der Woude, A. Willemze, L. A. Trouw, R. Knevel, S. W. Syversen, M. P. van der Linden, B. Lie, T. W. Huizinga, D. M. van der Heijde, A. H. van der Helm-van Mil, T. K. Kvien, R. E. Toes
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> Human leucocyte antigen shared epitope (SE) alleles are associated with joint destruction, the presence of anticitrullinated protein antibodies (ACPA) and the ACPA fine specificity repertoire in rheumatoid arthritis (RA). A large variation in joint destruction is seen within the ACPA-positive patient population, and it is conceivable that certain ACPA reactivities contribute to radiological damage. The authors investigated whether ACPA fine specificities, which are formed under the influence of SE alleles, associate with the extent of radiographic joint damage. <h3>Methods</h3> Antibodies recognising six citrullinated epitopes were determined in sera of 330 ACPA-positive RA patients genotyped for SE alleles. The association between SE alleles, ACPA fine specificity and radiographic joint damage was assessed using radiographic follow-up data. A second cohort of 154 RA patients with 5 and 10-year radiographic follow-up was used for replication. <h3>Results</h3> SE alleles predisposed to the recognition of certain citrullinated epitopes. However, none of the ACPA fine specificities studied influenced radiographic joint damage. Importantly, although SE alleles associated with radiographic damage in the total RA population, this association was no longer detectable after stratification for the presence of ACPA. <h3>Conclusions</h3> SE alleles are instrumental in shaping the ACPA repertoire. However, ACPA fine specificities formed under the influence of SE alleles do not seem to affect joint destruction.
Pedalling up the Amazon
Authors: James Owen Drife
Journal: BMJ (2004)

I have been subscribing to a local fitness centre for years but have not lost any weight at all. Sometimes my wife suggests that I ought to go and at least look at the place. She says it is delightful, full of slim people of both genders.

That's the trouble. What I want to kick-start my personal struggle against cuddliness is a gymnasium where I don't stick out. I resemble the “before” part of the advertisements and …