tbuckley/cabot-search huggingface dataset:
IM-12 * RNA NANOPARTICLE VACCINES RE-PROGRAM HOST IMMUNITY IN FAVOR OF ENHANCED EFFECTOR RESPONSES AGAINST INTRACRANIAL MALIGNANCIES
Authors: E. Sayour, G. De Leon, C. Pham, C. Flores, L. Sanchez-Perez, D. Mitchell
Journal: Neuro-Oncology (2015)

BACKGROUND: Pediatric brain tumors are the number one cause of solid cancer death in children, and thus necessitate the development of novel targeted therapeutics. To enhance the feasibility of cancer immunotherapy, off-the-shelf vaccination strategies have been proposed, but have proven to be only weakly immunogenic. Consequently we have designed a novel, translatable nanoparticle (NP) vaccine that can be embedded with immunomodulatory modifications to generate robust anti-tumor responses against murine models for glioblastoma (GBM) and medulloblastoma (MB). OBJECTIVES: We sought to assess if RNA-NP vaccines would induce superior immune responses against GBM and MB by stimulating intracellular pathogen recognition receptors (PRRs) while simultaneously downregulating regulatory pathways. RESULTS: We screened commercially available and clinically translatable NP formulations and determined that the cationic liposome DOTAP was the most superior NP for delivery of RNA to antigen presenting cells (APCs) in vitro and in vivo. Afterwards, we verified that these particles preserve RNA stability over time, and induce in vivo gene expression. These RNA-NPs elicited potent T cell immunity, superior to peptide vaccines formulated in Complete Freund's Adjuvant (CFA) and induced anti-tumor efficacy in adoptive cellular therapy platforms in murine GBM and MB models. We showed dramatic upregulation of activation markers including CD80 and CD86 and demonstrated abrogation of regulatory markers such as programmed death-ligand1 (PD-L1) when RNA-NPs were administered in combination with anti-PD-L1 monoclonal antibodies. Finally, we demonstrated enhanced immune responses through incorporation of immunomodulatory RNAs encoding for pathogen associated molecular patterns (PAMPs) derived from hepatitis C. CONCLUSION: Since clinically translatable RNA-NP vaccines can deliver combinatorial therapies using a single delivery platform, they represent a novel platform for inducing potent nontoxic immunity against intracranial tumors that can be harnessed to provide a more effective and specific therapy critical in improving clinical outcomes for children affected by these malignancies.
Multimodal SPION-CREKA peptide based agents for molecular imaging of microthrombus in a rat myocardial ischemia-reperfusion model
Authors: Yanan Song, Zheyong Huang, Jianfeng Xu, Daoyuan Ren, Yu Wang, Xinde Zheng, Yunli Shen, Lili Wang, Hongxiang Gao, Jiayun Hou, Zhiqing Pang, Juying Qian, Junbo Ge
Journal: Biomaterials (2014)
Apparent pulse wave velocity in the canine superior vena cava
Authors: J. MINTEN, F. VAN DE WERF, A. E AUBERT, H. KESTELOOT, H. D. GEEST
Journal: Cardiovascular Research (1983)

In order to evaluate clinically recorded jugular vein pulses it is necessary to understand the transmission process of the right atrial pressure pulse through the caval veins up to the jugular veins. The transmission speed at distinct points of the venous pressure curve was studied in the superior vena cava of 20 anaesthetised dogs. Under control conditions the propagation velocities varied from 1.2±0.49 to 2.5±1.36 m·s−1. During increased preload of the heart propagation velocities rose significantly from 2.2 to 4.2 m·s−1 per kPa as a function of mean venous pressure and from 2.3 to 5.8 m·s−1 per kPa as a function of phasic pressures. Right atrial pacing (between 60 and 120 beats·min−1) did not influence the propagation velocity of the studied distinct points. It was found that the summits of the pressure pulse propagate at only a slightly higher speed than the nadirs.
Clinical trials update from the American Heart Association meeting: Ω‐3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE
Authors: John G.F. Cleland, Nick Freemantle, Gerry Kaye, Mansoor Nasir, Periaswamy Velavan, Krishna Lalukota, Telal Mudawi, Rhidian Shelton, Andrew L. Clark, Alison P. Coletta
Journal: European Journal of Heart Failure (2004)
Disposal of Low-Level Radioactive Waste
Authors: William R. Hendee
Journal: JAMA (1993)

RADIOACTIVE waste is categorized into high-level waste, including spent reactor fuel and waste from defense installations, and low-level waste generated principally by utilities, industry, clinical and research institutions, and government agencies. Low-level radioactive waste contains only small quantities of radioactivity. It includes items such as contaminated gloves and protective clothing; glass and plastic laboratory supplies; machine parts and tools; syringes, filters, and lightly radioactive equipment; and waste products from animal housing, radiopharmaceutical preparation facilities, and reactor coolingwater cleanup systems. It does not include transuranic elements, spent fuel from nuclear power plants, or high-level radioactive waste of any form. The disposal of low-level radioactive waste has been a controversial issue in the United States for more than two decades. Initial efforts to resolve this controversy for waste produced in the civilian sector led to congressional passage of the Low-Level Radioactive Waste Policy Act of 1980,<sup>1</sup>followed by a major amendment
Allopurinol attenuates caerulein induced acute pancreatitis in the rat.
Authors: J R Wisner, I G Renner
Journal: Gut (1988)

Oxygen derived free radicals have been implicated in the pathogenesis of acute pancreatitis in numerous animal models of the disease. The xanthine oxidase inhibitor allopurinol has been shown to attenuate pancreatic damage in canine and mouse models of acute pancreatitis presumably by preventing the generation of cytotoxic superoxide anions. We therefore examined whether allopurinol could attenuate pancreatic injury in conscious rats with caerulein induced acute pancreatitis. A continuous intravenous infusion of allopurinol (20 mg/kg/h) for six hours along with an acute pancreatitis producing dose of caerulein (10 micrograms/kg/h) reduced pancreas weights by approximately 45% and serum amylase concentrations by approximately 60% compared with rats intravenously infused with either caerulein alone or caerulein plus a lower dose (10 mg/kg/h) of allopurinol. We conclude that the generation of oxygen derived free radicals via pancreatic xanthine oxidase represents an early and perhaps pivotal mechanism in the pathogenesis of acute pancreatitis.
The public needs better understanding of drug regulation
Authors: Susan Mayor
Journal: BMJ (2006)

Healthcare professionals and patients should be given more information on how new drugs are licensed, to avoid confusion like that surrounding access to trastuzumab (Herceptin) for women with early breast cancer, medicines policy experts have suggested.

Trastuzumab is currently licensed only in New Zealand for early breast cancer that is HER2 receptive, with licence applications for this indication currently being considered by European, US, and Australian drug regulators.

However, an investor …
Neurological and Electroencephalographic Correlative Studies in Infancy
Authors: Jerome K. Merlis
Journal: JAMA (1965)

This volume presents the proceedings of a conference and symposium held in Houston in October, 1963. The theme is the immature brain, and there is a wide range of subject matter in the 20 papers presented. About half the papers are devoted to morphologic and physiological studies in young animals, with emphasis on the development of electrical activity of the brain, the maturation of evoked potentials, and the relationship of morphologic and physiological characteristics of the developing brain to seizure susceptibility. Electroclinical correlations in the child occupy the other half, with greatest attention being given to seizures and hypoxia. Some of the data have been published elsewhere, but there are significant new studies and the conference format has given the opportunity for integration and coherence not available in the usual journal publication. This volume is not for the general pediatrician, but will be of interest to workers in many fields,
Traffic Safety Experts Prescribe Treatment, Sanctions to Improve Driving
Authors: Thomas B. Cole
Journal: JAMA (1995)

DO CARS kill people, or is it people who do the killing? Both, say the physicians, epidemiologists, engineers, and others who attended the 39th Annual Conference of the Association for the Advancement of Automotive Medicine (AAAM), held in Chicago, Ill. The guiding philosophy of the AAAM is that both vehicle construction and personal behavior can be modified to reduce morbidity and mortality on the nation's roadways. Behavioral modification has proved to be the more difficult task. Advances are both helped and hindered by the interdependence of man and machine. "Intelligent" safety restraint systems can sense when to deploy, slacken, and hold fast, but fewer than three fourths of drivers and passengers buckle up. Trauma systems can triage, transport, and treat injured patients so effectively that preventable mortality is reduced by as much as 30%, but the same patients may be injured again and again as a result of alcoholism. Ultimately,
Spontaneous awakening trials added to spontaneous breathing trials improved weaning from mechanical ventilation
Authors: Randolph J. Lipchik
Journal: Annals of Internal Medicine (2008)

Source Citation Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126-34. 18191684
Abstract 769: Restoration of c-Cbl function, by inhibiting Cdc42, confers tamoxifen sensitivity on basal-like (triple negative) breast cancer cells
Authors: Hsing-Yu Chen, Yin Yang, Mark D. Noble
Journal: Cancer Research (2012)

Abstract Our present work offers a new means by which cancer cells become resistant to anti-cancer treatments and mechanism-driven approaches for overcoming such resistance. Specifically, here we demonstrate a previously unrecognized mechanism of tamoxifen (TMX) resistance distinct from loss of estrogen receptor on basal-like (triple negative) breast cancer cells, which are among the most challenging tumors to treat with current therapies. Our present finding emerged from trying to understand the puzzling differences in regulation of receptor tyrosine kinase (RTK) degradation in normal progenitor cells and in breast cancer cells. When glial progenitor cells become slightly more (15-20%) oxidized, such as by exposing them to TMX, we find sequential activation of Fyn (a member of the Src-family of kinases) and c-Cbl (an E3 ubiquitin ligase) is activated. Phosphorylation of c-Cbl causes ubiquitylation of its target proteins and thus increases the degradation of its target proteins, such as particular RTKs, including the epidermal growth factor receptor (EGFR, our specific target in this study). In contrast to normal progenitor cells, basal-like breast cancer cells exposed to TMX show increased Fyn activation but no increase in c-Cbl phosphorylation. We now have found that oxidation-induced activation of c-Cbl in basal-like breast cancer cells is inhibited due to expression of Cdc42. Cdc42 sequestered c-Cbl, prevented its activation and prevented EGFR from being degraded. Restoration of c-Cbl function, by genetically or pharmacologically inhibiting Cdc42 activation, reduced EGFR levels in these cells. More critically, restoring c-Cbl function sensitized these cells to TMX both in vitro and in vivo. Analysis of tumor growth in vivo showed that reducing the levels of Cdc42 both reduced the size of tumors and made them more sensitive to TMX. The results provide a novel defense mechanism that basal-like breast cancer cells utilize to prevent EGFR degradation which may have high relevance to treatment of these tumors. Of particular importance is the ability of Cdc42 knockdown to confer TMX sensitivity on these otherwise resistant tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 769. doi:1538-7445.AM2012-769
More Evidence on Low Vitamin D Levels Fuels Push to Revise Recommended Intake
Authors: Mike Mitka
Journal: JAMA (2009)

A RECENT SPATE OF PUBLISHED studies adds to the drumbeat of those researchers who argue that vitamin D deficiency and insufficiency are tied to poor health outcomes for a variety of conditions in a large proportion of the US population. But the nature of these studies, mainly retrospective analyses, makes it difficult for regulatory bodies or specialty societies to develop specific recommendations for raising the established levels for minimum vitamin D intake. These circumstances have left some physicians reluctant to aggressively diagnose and treat their patients for vitamin D insufficiency. More rigorous studies could clarify recent findings associating vitamin D insufficiency with such health problems as osteoporosis and bone fracture, muscle weakness, cancer, autoimmune disease, diabetes, schizophrenia, depression, lung dysfunction, kidney disease, and cardiovascular disease. “We know vitamin D can prevent rickets in children, but there are all these other health outcomes thought to be affected by vitamin D,” said Michal L. Melamed, MD, MHS, an assistant professor of medicine and epidemiology at Albert Einstein College of Medicine, Bronx, NY. “We need randomized clinical trials to see if supplementing vitamin D has an effect on the nontraditional outcomes.”
Selecting and supporting contented doctors
Authors: Ed Peile, Yvonne Carter
Journal: BMJ (2005)

Medical students must receive regular, structured, and constructive appraisal 

Unhappy doctors often underperform,1 and by depressing morale in the workplace, they exert a negative influence on recruitment and retention, which are pressing problems in the NHS.2 Everything we can do to promote contentedness at work is therefore a worthwhile endeavour in the interest of patients.

Much of the difference in the ways that doctors approach work and perceive the climate at the workplace is a reflection of stable long term individual differences in the doctors themselves.3 In a comprehensive questionnaire study, which included measures of approaches to work, workplace climate, stress (general health questionnaire), burnout (Maslach burnout inventory), and satisfaction with medicine as a career as well as the Big Five personality inventories, McManus et al obtained data on 1668 medical graduates, 12 years after they had entered medical school. They were able to relate doctors' present perceptions of the workplace climate to differences in measures of personality and learning style, which were already evident at medical school entry, and remained fairly stable when measured again in the final year at medical school and five years later in working doctors. Stress, burnout, and satisfaction also correlate with trait measures of personality taken five years earlier. Neuroticism …
A lag in intracellular degradation of mutant alpha1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha1-antitrypsin deficiency Wu Y, Whitman I, Molmenti E, Moore K, Hippenmeyer P, Perlmutter DH. Proc Natl Acad Sci U S A 1994; 91: 9014?9018
Authors: F ASKARI
Journal: Hepatology (1995)

Liver injury in PiZZ α1-antitrypsin (α1-AT) deficiency probably results from toxic effects of the abnormal α1-AT molecule accumulating within the ER of liver cells. However, only 12–15% of individuals with this same genotype develops liver disease. Therefore, we predicted that other genetic traits that determine the net intracellular accumulation of the mutant α1-AT molecule would also determine susceptibility to liver disease. To address this prediction, we transduced skin fibroblasts from PiZZ individuals with liver disease or without liver disease with amphotropic recombinant retroviral particles designed for constitutive expression of the mutant α1-AT Z gene. Human skin fibroblasts do not express the endogenous α1-AT gene but presumably express other genes involved in postsynthetic processing of secretory proteins. The results show that expression of human α1-AT gene was conferred on each fibroblast cell line. Compared to the same cell line transduced with the wild-type α1-AT M gene, there was selective intracellular accumulation of the mutant α1-AT Z protein in each case. However, there was a marked delay in degradation of the mutant α1-AT Z protein after it accumulated in the fibroblasts from ZZ individuals with liver disease (“susceptible hosts”) as compared to those without liver disease (“protected hosts”). Appropriate disease controls showed that the lag in degradation in susceptible hosts is specific for the combination of PiZZ phenotype and liver disease. Biochemical characteristics of α1-AT Z degradation in the protected hosts were found to be similar to those of a common ER degradation pathway previously described in model experimental cell systems for T-cell receptor a subunits and asialoglycoprotein receptor subunits, therefore, raising the possibility that the lag in degradation in the susceptible host is a defect in this common ER degradation pathway. Thus, these data provide evidence that other genetic traits that affect the fate of the abnormal α1-AT Z molecule, at least in part, determine susceptibility to liver disease. These data also validate a system for elucidating the biochemical/genetic characteristics of these traits and for examining the relevance to human disease of pathways for protein degradation in the ER.
Road safety plan aims to save five million lives in next 10 years
Authors: J. Zarocostas
Journal: BMJ (2011)

<h3>Background</h3> Dutch policy makers needed a knowledge base for prioritising control of different indoor air pollutants. Several burden of disease (BoD) estimates were available, but it was not known if they could be applied to The Netherlands. <h3>Objectives</h3> To quantify the BoD related to indoor air in The Netherlands, and to compare the outcomes with a previous study (EnVIE), which used a different BoD methodology. <h3>Results</h3> The largest BoD was attributable to environmental tobacco smoke. The next most important indoor air pollutants were radon and thoron from soils and building materials, followed by dampness and carbon monoxide (CO). Formaldehyde exposure did not contribute to the total BoD, according to our estimates. The EnVIE estimate was three times higher, and the most important indoor air pollutants by BoD were combustion products from outdoor sources, bioaerosols due to dampness and by outdoor sources, volatile organic compounds, radon from soils, pathogens and CO. The differences in estimates were primarily caused by the different selection or definition of substances in indoor air, rather than the differing BoD methodology. <h3>Conclusions</h3> Indoor air exposure is associated with a considerable BoD in The Netherlands; approximately 1500 healthy life years per 1 million inhabitants are lost due to 1 year of exposure. The results from the different BoD studies examined here are difficult to compare—even the relative order of most important pollutants depends on choices and assumptions in the assessment. A careful evaluation of BoD estimates is required before they can be used in policy making.
Abstract P5-01-12: Over- and Undergrading of Breast Cancer on Core Biopsies in Comparison to Surgical Specimens
Authors: T Decker, CM Focke, D Gläser, K Finsterbusch
Journal: Cancer Research (2012)

Abstract Background: In numerous studies histological grade (HG) remained an independent prognostic factor for ER positive tumours even after the inclusion of gene signatures in the multivariate models. Moreover, grade 3 is judged as clear argument in favour of chemotherapy. Therefore, there are many reasons to provide patients and doctors with HG as important prognostic and predictive information already preoperatively. To evaluate the relevance of histological grading (HG) based on core biopsies (CB) for clinical decision making in breast cancer (BC) we evaluated the concordance with HG from surgical specimen (SSP) and the reasons for under- or overgrading. Methods: CB and related SSP of 398 BCs were prospectively graded according to the Nottingham grading system (SSP: 65 G1, 162 G2 and 171 G3). CB/SSP agreement rates and positive predictive values (PPV) of CB based HG were calculated. Rates of over- and underestimation of glandular differentiation (GD), nuclear pleomorphism (NP) and mitotic activity (MA) were calculated. Results: CB/SSP agreement rates came out with 95% for G1, 73% for G2, and 56 % for G3. The PPVs of CB based HG were 56% for G1, 61% for G2 and 100% for G3. The overgrading and undergrading rates on CB were 1% and 37%, respectively. Main causes for undergrading in CB were underestimated MA (40%) and a combination of underestimated NP and MA (32%). Conclusions: Whereas overgrading on CB is an exception, undergrading derives largely from underestimation of proliferation. G3 assessed on CB came out with the highest PPV, providing a reliable base for preoperative decisions i.e. about primary chemotherapy. Reversely, because of the relative low PPV of G1 on CB one has to be aware of potential upgrading on surgical specimen later on. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-12.
Endogenous α<sub>2</sub>-Antiplasmin Is Protective during Severe Gram-Negative Sepsis (Melioidosis)
Authors: Liesbeth M. Kager, Tassili A. Weehuizen, W. Joost Wiersinga, Joris J. T. H. Roelofs, Joost C. M. Meijers, Arjen M. Dondorp, Cornelis van ’t Veer, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

α2-Antiplasmin (A2AP) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit plasmin. Although the fibrinolytic system is strongly affected by infection, the functional role of A2AP in the host response to sepsis is unknown.To study the role of A2AP in melioidosis, a common form of community-acquired sepsis in Southeast Asia and Northern Australia caused by the gram-negative bacterium Burkholderia pseudomallei.In a single-center observational study A2AP was measured in patients with culture-proven septic melioidosis. Wild-type and A2AP-deficient (A2AP(-/-)) mice were intranasally infected with B. pseudomallei to induce severe pneumosepsis (melioidosis). Parameters of inflammation and coagulation were measured, and survival studies were performed.Patients with melioidosis showed elevated A2AP plasma levels. Likewise, A2AP levels in plasma and lung homogenates were elevated in mice infected with B. pseudomallei. A2AP-deficient (A2AP(-/-)) mice had a strongly disturbed host response during experimental melioidosis as reflected by enhanced bacterial growth at the primary site of infection accompanied by increased dissemination to distant organs. In addition, A2AP(-/-) mice showed more severe lung pathology and injury together with an increased accumulation of neutrophils and higher cytokine levels in lung tissue. A2AP deficiency further was associated with exaggerated systemic inflammation and coagulation, increased distant organ injury, and enhanced lethality.This study is the first to identify A2AP as a protective mediator during gram-negative (pneumo)sepsis by limiting bacterial growth, inflammation, tissue injury, and coagulation.