tbuckley/cabot-search huggingface dataset:
Concomitant BRAF and PI3K/mTOR Blockade Is Required for Effective Treatment of <i>BRAFV600E</i> Colorectal Cancer
Authors: Erin M. Coffee, Anthony C. Faber, Jatin Roper, Mark J. Sinnamon, Gautam Goel, Lily Keung, Wei Vivian Wang, Loredana Vecchione, Veerle de Vriendt, Barbara J. Weinstein, Roderick T. Bronson, Sabine Tejpar, Ramnik J. Xavier, Jeffrey A. Engelman, Eric S. Martin, Kenneth E. Hung
Journal: Clinical Cancer Research (2013)

BRAF(V600E) mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF(V600E) CRC.We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF(V600E) CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF(V600E) CRC.Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF(V600E) GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.We have established a novel GEMM to interrogate BRAF(V600E) CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.
Serious infections with antirheumatic therapy: are biologicals worse?
Authors: K L Winthrop
Journal: Annals of the Rheumatic Diseases (2006)

This paper reviews the current evidence for the role of antirheumatic therapy in the development of serious infections in patients with rheumatoid arthritis (RA). Prednisone is clearly associated with increased infectious risk, but no definitive data link methotrexate to infection. Emerging data suggest that biological agents also pose increase infectious risk, particularly when used in combination with corticosteroids or methotrexate. Further research is needed in this important aspect of RA treatment. In the meantime, the author recommends that physicians should remain vigilant for serious infections in their patients with RA and use appropriate vaccines and screening procedures to mitigate their risk.
Supersensitivity to light: possible trait marker for manic-depressive illness
Authors: A. J. Lewy, John Nurnberger, T. A. Wehr, D. Pack, L. E. Becker, R. L. Powell, D. A. Newsome
Journal: American Journal of Psychiatry (1985)

Exposure to light during the night reduces plasma melatonin levels. A previous study showed that, in response to light, nighttime plasma melatonin levels fell twice as much in a group of acutely ill manic-depressive patients as in a group of normal subjects. The present study compares 11 euthymic manic-depressive patients not taking medications with 24 age- and sex-matched normal subjects. Melatonin levels in these patients also fell twice as much as the levels of the normal subjects, suggesting that supersensitivity to light may be a trait marker for bipolar affective disorder.
Effects of pH on Blood Flow and Peripheral Resistance in Muscular and Cutaneous Vascular Beds in the Hind Limb of the Pentobarbitalized Dog
Authors: C. P. DEAL, HAROLD D. GREEN
Journal: Circulation Research (1954)

The responses of the vascular beds in skeletal muscle and skin to changes in blood pH on the acid and alkaline sides of the physiologic range were compared. Dilatation occurred in both cutaneous and muscular beds when the blood pH was shifted to the acid range. Dilatation also occurred in the muscle beds when the blood pH was shifted to the alkaline range but such change in blood pH caused vasoconstriction in skin.
ENVELOPE GENE-DERIVED RECOMBINANT PEPTIDE IN THE SERODIAGNOSIS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Authors: T.F. Schulz, J.M. Aschauer, P. Hengster, C. Larcher, H. Wachter, B. Fleckenstein, M.P. Dierich
Journal: The Lancet (1986)
Isolated ventricular systolic interaction during transient reductions in left ventricular pressure.
Authors: J C Woodard, E Chow, D J Farrar
Journal: Circulation Research (1992)

The volume and pressure of one ventricle have been demonstrated to modulate the volume and pressure in the contralateral chamber during systole and diastole. To quantitate the isolated systolic effects of left ventricular (LV) pressure on right ventricular (RV) mechanics, we rapidly withdrew blood from the LV immediately after diastole via an apex cannula during a single cardiac cycle in eight open-chest, open-pericardium anesthetized pigs (45 kg) and studied the effects on the RV. Reductions in LV pressure of up to 75 mm Hg were achieved in midsystolic without changing LV or RV diastolic volume or pressure. Resultant changes in RV flow and pressure development during these single unloaded beats may therefore be considered to result from pure systolic interaction. The instantaneous left-to-right systolic pressure gain [G(t)] was determined as the ratio of RV pressure change to LV pressure change as a function of time during systole, and the mean LV-to-RV systolic pressure gain was determined as the ratio of changes in mean systolic RV pressure to changes in mean systolic LV pressure. During LV unloading, there was an average reduction of 62.6 +/- 12.3% in the mean systolic LV pressure, which resulted in decreases of 13.6 +/- 6.4% in mean RV systolic pressure, 17.9 +/- 10.4% in RV stroke volume, and 27.0 +/- 11.3% in RV stroke work. G(t) was found to vary significantly within systole, reaching a minimum of 0.042 +/- 0.014 mm Hg/mm Hg at normalized time 0.70 of the systolic duration and a maximum of 0.079 +/- 0.029 at the end of RV ejection.(ABSTRACT TRUNCATED AT 250 WORDS)
Regional Differences in Ventricular Fibrillation in the Open-Chest Porcine Left Ventricle
Authors: Kumaraswamy Nanthakumar, Jian Huang, Jack M. Rogers, Philip L. Johnson, Jonathan C. Newton, Greg P. Walcott, Robert K. Justice, Dennis L. Rollins, William M. Smith, Raymond E. Ideker
Journal: Circulation Research (2002)

It has been hypothesized that during ventricular fibrillation (VF), the fastest activating region, the dominant domain, contains a stable reentrant circuit called a mother rotor. This hypothesis postulates that the mother rotor spawns wavefronts that propagate to maintain VF elsewhere and implies that the ratio of wavefronts propagating off a region to those propagating onto it (propoff/propon) should be &gt;1 for the dominant domain but &lt;1 elsewhere. To test this prediction in the left ventricular (LV) epicardium of a large animal, most of the LV free wall was mapped with 1008 electrodes in 7 pigs. VF activation rate was faster in the posterior than in the anterior LV (10.0±1.3Hz versus 9.3±1.3Hz; P &lt;0.001). The anterior LV had a higher fraction of wavefronts that blocked than did the posterior LV and had a propoff/propon ratio &lt;1 ( P &lt;0.001). The mean conduction velocity vectors of the VF wavefronts pointed in the direction from the posterior to the anterior LV. Although these findings favor a dominant domain in the posterior LV, the facts that the anterior LV had a higher incidence of reentry than did the posterior LV and that the posterior LV did not have propoff/propon significantly different from 1 do not. Thus, quantitative regional differences are present over the porcine LV epicardium during VF. Although these differences are not totally consistent with the presence of a dominant domain within the LV free wall, the mean conduction velocity vector is consistent with one in the septum.
Prion disease tempo determined by host-dependent substrate reduction
Authors: Charles E. Mays, Chae Kim, Tracy Haldiman, Jacques van der Merwe, Agnes Lau, Jing Yang, Jennifer Grams, Michele A. Di Bari, Romolo Nonno, Glenn C. Telling, Qingzhong Kong, Jan Langeveld, Debbie McKenzie, David Westaway, Jiri G. Safar
Journal: Journal of Clinical Investigation (2014)

The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains.
Lack of Association Between SMAD7 Gene Polymorphism and Risk of Colorectal Cancer in an Iranian Population
Authors: Akbari Zahra, Safari-Alighiarloo Nahid, Yaghoob Taleghani Mohammad, Vahedi Mohsen, Montazer Haghighi Mahdi, Nazemalhosseini Mojarad Ehsan, Asadzadeh Aghdaee Hamid, Zali Mohammad Reza
Journal: Annals of Oncology (2014)
Severe acute respiratory syndrome in Taiwan: analysis of epidemiological characteristics in 29 cases
Authors: T.-N Jang, D.Y Yeh, S.-H Shen, C.-H Huang, J.-S Jiang, S.-J Kao
Journal: Journal of Infection (2003)

To describe the clinical characteristics and outcomes of patients with severe acute respiratory syndrome (SARS).Between March 28 and June 30 '2003, 29 patients with probable SARS seen at Shin Kong Wu Ho-Su Memorial Hospital, Taipei, were analysed.Presenting symptoms included fever (100%), cough (69.0%), chills or rigor (62.1%), and shortness of breath (41.4%). Mean days to defervescence were 6.8+/-2.9 days, but fever recurred in 15 patients (51.7%) at 10.9+/-3.4 days. Common laboratory features included lymphopenia (72.4%), thrombocytopenia (34.5%) and elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) (93.1, 62.1, 44.8%, respectively). All patients except one had initial abnormal chest radiographs and 20 (69.0%) had radiological worsening at 7.5+/-2.6 days. Nine patients (31.0%) subsequently required mechanical ventilation with four deaths (13.8%). Most patients with clinical deterioration responded to pulse corticosteroid therapy (14 out of 17) but six complicated with nosocomial infections. The risk factors associated with severe disease were presence of diarrhoea, high peak LDH and CRP, high AST and creatine kinase on admission and high peak values.Prudent corticosteroid use, vigilant microbiological surveillance and appropriate antibiotics coverage are the key to successful treatment.
SeaView Version 4: A Multiplatform Graphical User Interface for Sequence Alignment and Phylogenetic Tree Building
Authors: M. Gouy, S. Guindon, O. Gascuel
Journal: Molecular Biology and Evolution (2009)

We present SeaView version 4, a multiplatform program designed to facilitate multiple alignment and phylogenetic tree building from molecular sequence data through the use of a graphical user interface. SeaView version 4 combines all the functions of the widely used programs SeaView (in its previous versions) and Phylo_win, and expands them by adding network access to sequence databases, alignment with arbitrary algorithm, maximum-likelihood tree building with PhyML, and display, printing, and copy-to-clipboard of rooted or unrooted, binary or multifurcating phylogenetic trees. In relation to the wide present offer of tools and algorithms for phylogenetic analyses, SeaView is especially useful for teaching and for occasional users of such software. SeaView is freely available at http://pbil.univ-lyon1.fr/software/seaview.
Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV
Authors: Katja Deterding, Björn Tegtmeyer, Markus Cornberg, Johannes Hadem, Andrej Potthoff, Klaus H.W. Böker, Hans L. Tillmann, Michael P. Manns, Heiner Wedemeyer
Journal: Journal of Hepatology (2006)
Impact of Changes in Transportation and Commuting Behaviors During the 1996 Summer Olympic Games in Atlanta on Air Quality and Childhood Asthma
Authors: Michael S. Friedman
Journal: JAMA (2001)

Vehicle exhaust is a major source of ozone and other air pollutants. Although high ground-level ozone pollution is associated with transient increases in asthma morbidity, the impact of citywide transportation changes on air quality and childhood asthma has not been studied. The alternative transportation strategy implemented during the 1996 Summer Olympic Games in Atlanta, Ga, provided such an opportunity.To describe traffic changes in Atlanta, Ga, during the 1996 Summer Olympic Games and concomitant changes in air quality and childhood asthma events.Ecological study comparing the 17 days of the Olympic Games (July 19-August 4, 1996) to a baseline period consisting of the 4 weeks before and 4 weeks after the Olympic Games.Children aged 1 to 16 years who resided in the 5 central counties of metropolitan Atlanta and whose data were captured in 1 of 4 databases.Citywide acute care visits and hospitalizations for asthma (asthma events) and nonasthma events, concentrations of major air pollutants, meteorological variables, and traffic counts.During the Olympic Games, the number of asthma acute care events decreased 41.6% (4.23 vs 2.47 daily events) in the Georgia Medicaid claims file, 44.1% (1.36 vs 0.76 daily events) in a health maintenance organization database, 11.1% (4.77 vs 4.24 daily events) in 2 pediatric emergency departments, and 19.1% (2.04 vs 1.65 daily hospitalizations) in the Georgia Hospital Discharge Database. The number of nonasthma acute care events in the 4 databases changed -3.1%, +1.3%, -2.1%, and +1.0%, respectively. In multivariate regression analysis, only the reduction in asthma events recorded in the Medicaid database was significant (relative risk, 0.48; 95% confidence interval, 0.44-0.86). Peak daily ozone concentrations decreased 27.9%, from 81.3 ppb during the baseline period to 58.6 ppb during the Olympic Games (P<.001). Peak weekday morning traffic counts dropped 22.5% (P<.001). Traffic counts were significantly correlated with that day's peak ozone concentration (average r = 0.36 for all 4 roads examined). Meteorological conditions during the Olympic Games did not differ substantially from the baseline period.Efforts to reduce downtown traffic congestion in Atlanta during the Olympic Games resulted in decreased traffic density, especially during the critical morning period. This was associated with a prolonged reduction in ozone pollution and significantly lower rates of childhood asthma events. These data provide support for efforts to reduce air pollution and improve health via reductions in motor vehicle traffic.
Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis
Authors: Rachel A Harry, Amy E Anderson, John D Isaacs, Catharien M U Hilkens
Journal: Annals of the Rheumatic Diseases (2010)

Objectives Tolerogenic dendritic cells (tolDCs) constitute a promising experimental treatment for targeting autoreactive T cells in autoimmune diseases, including rheumatoid arthritis (RA). The authors' goal is to bring tolDC therapy for RA to the clinic. Here the authors address key translational issues related to the manufacturing of tolDCs from RA patients with current good manufacturing practice (cGMP)-compliant reagents, the stability of tolDCs, and the selection of suitable quality control markers. Methods Human monocyte-derived tolDCs were established from RA patients and healthy controls (HCs) using the immunosuppressive drugs dexamethasone and vitamin D 3 , and the cGMP-grade immunomodulator, monophosphoryl lipid A, in the cGMP-compliant medium, CellGroDC. The functionality of tolDCs and tolDC-modulated autologous CD4 T cells was determined by flow cytometry, [ 3 H]thymidine incorporation and ELISA. Results Clinical-grade tolDCs established from patients with RA exhibit a typical tolerogenic phenotype of reduced costimulatory molecules, low production of proinflammatory cytokines and impaired stimulation of autologous antigen-specific T cells, comparable to HC tolDCs. Toll-like receptor 2 (TLR-2) was highly expressed by tolDCs but not mature DCs. Furthermore, tolDCs suppressed mature DC-induced T cell proliferation, interferon γ and interleukin 17 production, and rendered T cells hyporesponsive to further stimulation. Importantly, tolDCs were phenotypically stable in the absence of immunosuppressive drugs and were refractory to further challenge with proinflammatory mediators. Conclusions tolDCs established from patients with RA are comparable to those derived from healthy donors. TLR-2 was identified as an ideal marker for quality control of tolDCs. Potently tolerogenic and highly stable, these tolDCs are a promising cellular therapeutic for tailored immunomodulation in the treatment of RA.
IgG4 subclass antibodies impair antitumor immunity in melanoma
Authors: Panagiotis Karagiannis, Amy E. Gilbert, Debra H. Josephs, Niwa Ali, Tihomir Dodev, Louise Saul, Isabel Correa, Luke Roberts, Emma Beddowes, Alexander Koers, Carl Hobbs, Silvia Ferreira, Jenny L.C. Geh, Ciaran Healy, Mark Harries, Katharine M. Acland, Philip J. Blower, Tracey Mitchell, David J. Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis
Journal: Journal of Clinical Investigation (2013)

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell–mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.
Systematic Review: Repair of Unruptured Abdominal Aortic Aneurysm
Authors: Frank A. Lederle, Robert L. Kane, Roderick MacDonald, Timothy J. Wilt
Journal: Annals of Internal Medicine (2007)

Background: Recent recommendations to screen for abdominal aortic aneurysm (AAA) in high-risk populations and the rapidly increasing use of endovascular repair have led to increased interest in evaluating the effectiveness of treatment options for patients with AAA. Purpose: To compare the effectiveness of treatment options, including active surveillance, open repair, and endovascular repair, for unruptured AAAs. Data Sources: The authors searched MEDLINE, the Cochrane Library, and www.ClinicalTrials.gov through December 2006 with no language restrictions, searched reference lists, and queried experts and study authors. Study Selection: Randomized trials that compared open or endovascular AAA repair with another treatment strategy and published clinical outcomes. Data Extraction: Data were extracted onto standardized, piloted forms and were confirmed. Data Synthesis: Two trials compared open repair with surveillance for small AAAs (n = 2226). Repair did not improve all-cause mortality (relative risk, 1.01 [95% CI, 0.77 to 1.32]) or AAA-related mortality (relative risk, 0.78 [CI, 0.56 to 1.10]). Four trials compared open repair with endovascular repair (n = 1532). Endovascular repair reduced 30-day mortality (relative risk, 0.33 [CI, 0.17 to 0.64]) but not mid-term (up to 4 years) mortality (relative risk, 0.95 [CI, 0.76 to 1.19]). One trial compared endovascular repair with observation in 338 patients who were unfit for open repair. Endovascular repair did not reduce all-cause mortality or AAA-related mortality, but high crossover and procedural mortality rates complicate interpretation of results. Limitations: Few trials have been published. Those published were of small to moderate size and were not U.S. trials of endovascular repair. Conclusions: Repairing AAAs smaller than 5.5 cm has not been shown to improve survival. Endovascular repair is associated with lower operative mortality than open repair, similar mid-term mortality, and unknown long-term mortality and has not been shown to improve survival in patients unfit for open repair. Long-term trial data comparing endovascular repair with open repair are needed, as is another trial comparing endovascular repair with observation in high-risk patients.
HEALTH DISPARITIES AND HEALTH EQUITY: Concepts and Measurement
Authors: Paula Braveman
Journal: Annual Review of Public Health (2005)

▪ Abstract There is little consensus about the meaning of the terms “health disparities,” “health inequalities,” or “health equity.” The definitions can have important practical consequences, determining the measurements that are monitored by governments and international agencies and the activities that will be supported by resources earmarked to address health disparities/inequalities or health equity. This paper aims to clarify the concepts of health disparities/inequalities (used interchangeably here) and health equity, focusing on the implications of different definitions for measurement and hence for accountability. Health disparities/inequalities do not refer to all differences in health. A health disparity/inequality is a particular type of difference in health (or in the most important influences on health that could potentially be shaped by policies); it is a difference in which disadvantaged social groups—such as the poor, racial/ethnic minorities, women, or other groups who have persistently experienced social disadvantage or discrimination—systematically experience worse health or greater health risks than more advantaged social groups. (“Social advantage” refers to one's relative position in a social hierarchy determined by wealth, power, and/or prestige.) Health disparities/inequalities include differences between the most advantaged group in a given category—e.g., the wealthiest, the most powerful racial/ethnic group—and all others, not only between the best- and worst-off groups. Pursuing health equity means pursuing the elimination of such health disparities/inequalities.