tbuckley/cabot-search huggingface dataset:
Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522
Authors: K. Kian Ang, Qiang Zhang, David I. Rosenthal, Phuc Felix Nguyen-Tan, Eric J. Sherman, Randal S. Weber, James M. Galvin, James A. Bonner, Jonathan Harris, Adel K. El-Naggar, Maura L. Gillison, Richard C. Jordan, Andre A. Konski, Wade L. Thorstad, Andy Trotti, Jonathan J. Beitler, Adam S. Garden, William J. Spanos, Sue S. Yom, Rita S. Axelrod
Journal: Journal of Clinical Oncology (2014)

Purpose Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). Patients and Methods Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. Results Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m 2 v 191.1 mg/m 2 , respectively); and more grade 3 to 4 radiation mucositis (43.2% v 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v 2.0%, respectively; P = .81), 3-year PFS (61.2% v 58.9%, respectively; P = .76), 3-year OS (72.9% v 75.8%, respectively; P = .32), locoregional failure (19.9% v 25.9%, respectively; P = .97), or distant metastasis (13.0% v 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v 49.2%, respectively; P &lt; .001) and OS (85.6% v 60.1%, respectively; P &lt; .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome. Conclusion Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.
Microbial Translocation Across the GI Tract
Authors: Jason M. Brenchley, Daniel C. Douek
Journal: Annual Review of Immunology (2012)

The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.
Acute severe acne in a female patient (acne fulminans?)
Authors: T. Jansen, R. Romiti, G. Plewig
Journal: British Journal of Dermatology (1999)

Journal Article Acute severe acne in a female patient (acne fulminans?) Get access T. Jansen, T. Jansen Department of Dermatology and Allergology, Ludwig‐Maximilians‐University of Munich, Frauenlobstrasse 9–11, D‐80337 Munich, Germany Search for other works by this author on: Oxford Academic Google Scholar R. Romiti, R. Romiti Department of Dermatology and Allergology, Ludwig‐Maximilians‐University of Munich, Frauenlobstrasse 9–11, D‐80337 Munich, Germany Search for other works by this author on: Oxford Academic Google Scholar G. Plewig G. Plewig Department of Dermatology and Allergology, Ludwig‐Maximilians‐University of Munich, Frauenlobstrasse 9–11, D‐80337 Munich, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 141, Issue 5, 1 November 1999, Pages 945–947, https://doi.org/10.1046/j.1365-2133.1999.03187.x Published: 01 November 1999
Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects
Authors: Marieke F. Fransen, Tetje C. van der Sluis, Ferry Ossendorp, Ramon Arens, Cornelis J.M. Melief
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy. Experimental Design: We use different preclinical mouse models of cancer to investigate the local administration of CTLA-4 blocking antibody and its effect on cancer progression and the antitumor T-cell response. Results: By injecting the antibodies in a subcutaneous slow-release delivery formulation in the tumor area, we show that an eight-fold lower dose of antibody is as effective in inducing tumor eradication as systemic delivery. A lower dose and slow release of the antibody results in thousand-fold decreased levels of antibody in the serum, reducing adverse events and the risk of autoimmunity. The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8+ T cells that are capable of eradicating also distant tumors, whereas CD4+ T cells do not play a prominent role in the antibody-mediated tumor eradication. Conclusions: Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings. Clin Cancer Res; 19(19); 5381–9. ©2013 AACR.
An Angiotensin II Type 1 Receptor Mutant Lacking Epidermal Growth Factor Receptor Transactivation Does Not Induce Angiotensin II–Mediated Cardiac Hypertrophy
Authors: Peiyong Zhai, Jonathan Galeotti, Jing Liu, Eric Holle, Xianzhong Yu, Thomas Wagner, Junichi Sadoshima
Journal: Circulation Research (2006)

We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT 1 Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein–coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT 1 R (Tg-WT) and an AT 1 R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of Gαq/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice. In conclusion, overexpression of AT 1 -Y319F in cardiac myocytes diminished EGFR transactivation and inhibited a pathological form of cardiac hypertrophy. The YIPP motif in the AT 1 R plays an important role in mediating cardiac hypertrophy in vivo.
Increased airway responsiveness to acetaldehyde in asthmatic subjects with alcohol-induced bronchoconstriction
Authors: M Fujimura, S Myou, Y Kamio, Y Ishiura, K Iwasa, T Hashimoto, T Matsuda
Journal: European Respiratory Journal (1999)

Bronchial responsiveness to acetaldehyde, a main factor in alcohol-induced bronchoconstriction, and methacholine were compared between 10 subjects with alcohol-induced bronchoconstriction and 16 asthmatic subjects without alcohol sensitivity. In the alcohol-sensitive group, the geometric mean (geometric SEM (GSEM)) of the provocative concentration of methacholine (PC20,meth) and acetaldehyde (PC20,acet) causing a 20% fall in forced expiratory volume in one second were 0.947 mg x mL(-1) (GSEM 0.139) and 21.0 mg x mL(-1) (GSEM 0.112), respectively, which were not significantly different from those in the nonalcohol-sensitive group, which were 0.634 mg x mL(-1) (GSEM 0.115) and 31.7 mg x mL(-1) (GSEM 0.077), respectively. The ratio of airway responsiveness to acetaldehyde relative to methacholine (log PC20,acet/PC20,meth) was 1.345+/-0.093 (mean+/-SEM) in the alcohol-sensitive group, which was significantly different from the value of 1.699+/-0.059 in the nonalcohol-sensitive group (p=0.0025). A significant correlation was observed between PC20,meth and PC20,acet in both the alcohol-sensitive group (r=-0.742, p=0.0115) and nonsensitive group (r=0.882, p&lt;0.0001). In conclusion, the airways of asthmatic subjects with alcohol-induced bronchoconstriction have a selective hyperresponsiveness to acetaldehyde.
Low levels of air pollution induce changes of lung function in a panel of schoolchildren
Authors: H. Moshammer, H-P. Hutter, H. Hauck, M. Neuberger
Journal: European Respiratory Journal (2006)

In search of sensitive screening parameters for assessing acute effects of ambient air pollutants in young schoolchildren, the impact of 8-h average air pollution before lung function testing was investigated by oscillatory measurements of resistance and spirometry with flow–volume loops. At a central elementary school in Linz, the capital of Upper Austria, 163 children aged 7–10 yrs underwent repeated examinations at the same time of day during 1 school year, yielding a total of 11–12 lung function tests per child. Associations to mass concentrations of particulate matter and nitrogen dioxide (NO 2 ) measured continuously at a nearby monitoring station were tested, applying the Generalised Estimating Equations model. Reductions per 10 µg·m −3 (both for particles and for NO 2 ) were in the magnitude of 1% for most lung function parameters. The most sensitive indicator for acute effects of combustion-related pollutants was a change in maximal expiratory flow in small airways. NO 2 at concentrations below current standards reduced (in the multipollutant model) the forced expiratory volume in one second by 1.01%, maximal instantaneous forced flow when 50% of the forced vital capacity remains to be exhaled (MEF 50% ) by 1.99% and MEF 25% by 1.96%. Peripheral resistance increased by 1.03% per 10 µg·m −3 of particulate matter with a 50% cut-off aerodynamic diameter of 2.5 μm (PM 2.5 ). Resistance is less influenced by the child's cooperation and should be utilised more often in environmental epidemiology when screening for early signs of small airway dysfunction from urban air pollution, but cannot replace the measurement of MEF 50% and MEF 25% . In the basic model, the reduction of these parameters per 10 µg·m −3 was highest for NO 2 , followed by PM 1 , PM 2.5 and PM 10 , while exposure to coarse dust (PM 10 –PM 2.5 ) did not change end-expiratory flow significantly. All acute effects of urban air pollution found on the lung function of healthy pupils were evident at levels below current European limit values for nitrogen dioxide. Thus, planned reduction of nitrogen dioxide emission (Euro 5; vehicles that comply with the emission limits as defined in Directive 99/96/EC) of 20% in 2010 would seem to be insufficient.
NO kidding: exhaled nitric oxide fraction in preschool children
Authors: Mariëlle W. Pijnenburg, Peter J. Merkus
Journal: European Respiratory Journal (2014)

Wheeze is one of the most prevalent symptoms in preschool children with huge impacts on children and their families, on healthcare utilisation and hence costs [1]. While most children will become asymptomatic by 5–6 years of age, some will develop asthma or, even more importantly, severe problematic asthma and/or will experience an accelerated decline in lung function. Several studies have shown that lung function in asthmatic children at 6 years of age is already reduced compared with nonasthmatic children, in particular among children with allergic asthma [2]. This impaired lung function seems to be present soon after birth in children who are at risk of asthma [3]. Hence, the preschool years and the prenatal period seem of the utmost importance if we are looking for a window of opportunity to prevent asthma or to identify those children who are at risk for severe disease. F eNO may be helpful in predicting future asthma in preschool wheezing children, but more longitudinal data are needed <http://ow.ly/DXKxR>
From disorder to coherence in social psychology
Authors: Todd K. Shackelford, Robin R. Vallacher
Journal: Behavioral and Brain Sciences (2004)

Krueger &amp; Funder (K&amp;F) presuppose that the base rate for social cognition is more rational than is indicated by research, and that a focus on cognitive errors and behavioral shortcomings is responsible for the fragmented nature of social psychology. Insight concerning both issues is forthcoming from advances in evolutionary psychology and the adaptation of dynamical systems theory to social psychology.
A Recombinant Reporter System for Monitoring Reactivation of an Endogenously DNA Hypermethylated Gene
Authors: Ying Cui, Frederick Hausheer, Robert Beaty, Cynthia Zahnow, Jean Pierre Issa, Frederick Bunz, Stephen B. Baylin
Journal: Cancer Research (2014)

Reversing abnormal gene silencing in cancer cells due to DNA hypermethylation of promoter CpG islands may offer new cancer prevention or therapeutic approaches. Moreover, such approaches may be broadly applicable to enhance the efficacy of radiotherapy, chemotherapy, or immunotherapy. Here, we demonstrate the powerful utility of a novel gene reporter system to permit studies of the dynamics, mechanisms, and translational relevance of candidate therapies of this type in human colon cancer cells. The reporter system is based on in situ modification of the endogenous locus of the tumor-suppressor gene SFRP1, a pivotal regulator of the Wnt pathway that is silenced by DNA hypermethylation in many colon cancers. The modified SFRP1-GFP reporter allele used remained basally silent, like the unaltered allele, and it was activated only by drug treatments that derepress gene silencing by reversing DNA hypermethylation. We used the established DNA methyltransferase inhibitor (DNMTi) 5-aza-deoxycitidine (DAC) to show how this system can be used to address key questions in the clinical development of epigenetic cancer therapies. First, we defined conditions for which clinically relevant dosing could induce sustained induction of RNA and protein. Second, we found that, in vivo, a more prolonged drug exposure than anticipated was essential to derepress gene silencing in significant cell numbers, and this has implications for generating effective anticancer responses in patients with hematopoietic or solid tumors. Finally, we discovered how histone deacetylase inhibitors (HDACi) alone, when administered to cells actively replicating DNA, can robustly reexpress the silenced gene with no change in promoter methylation status. Taken together, our findings offer a new tool and insights for devising optimal clinical experiments to evaluate DNMTi and HDACi, alone or in combination, and with other cancer treatments, as agents for the epigenetic management and prevention of cancer.
Doubts about the BMA's policy on bicycle helmets
Authors: S. J. Watkins, J. Mindell
Journal: BMJ (2013)

For many years the BMA opposed compulsory cycle helmets on the basis that helmets would reduce rates of cycling. It changed this policy only because of the Ontario study. Apart from this single study in unusual circumstances (high rates of voluntary wearing and the law not enforced) all studies of helmet legislation show that cycling rates fall. The serious doubts about the study described in this new work raise questions about whether the BMA should continue …
Monitoring procalcitonin is of value in acute pancreatitis
Authors: David Bihari
Journal: BMJ (2004)

Firm foundation for senior house officers Five years is long enoughEditor-The editorial by Gallen and Peile signals anything but a firm foundation for training junior doctors. 1 The first foundation year will essentially be an extension of undergraduate training, its doctors allowed only to observe medical practice.And doctors in foundation year 2 will be "career tourists," spending too little time in each specialty to be able to offer much service in return.Medical educationalists should realise that nurses and other paramedical groups are encroaching on traditional medical practice and do not seem to need the sort of extended training we demand of medical students.For example, a six week course apparently enables paramedics to administer safely almost all drugs used in emergency practice.By contrast we seem intent on postponing the time at which our bright and enthusiastic young doctors can start treating patients.Five years is quite long enough to learn the theory of medicine.After that, the sooner young doctors are allowed to start treating patients, in a supervised setting, the better.
Organization of Ventricular Fibrillation in the Human Heart
Authors: Kirsten H.W.J. Ten Tusscher, Rok Hren, Alexander V. Panfilov
Journal: Circulation Research (2007)

Sudden cardiac death is a major cause of death in the industrialized world, claiming approximately 300,000 victims annually in the United States alone. In most cases, sudden cardiac death is caused by ventricular fibrillation (VF). Experimental studies in large animal hearts have shown that the uncoordinated contractions during VF are caused by large numbers of chaotically wandering reentrant waves of electrical activity. However, recent clinical data on VF in the human heart seem to suggest that human VF may have a markedly different organization. Here, we use a detailed model of the human ventricles, including a detailed description of cell electrophysiology, ventricular anatomy, and fiber direction anisotropy, to study the organization of human VF. We show that characteristics of our simulated VF are qualitatively similar to the clinical data. Furthermore, we find that human VF is driven by only approximately 10 reentrant sources and thus is much more organized than VF in animal hearts of comparable size, where VF is driven by approximately 50 sources. We investigate the influence of anisotropy ratio, tissue excitability, and restitution properties on the number of reentrant sources driving VF. We find that the number of rotors depends strongest on minimum action potential duration, a property that differs significantly between human and large animal hearts. Based on these findings, we suggest that the simpler spatial organization of human VF relative to VF in large animal hearts may be caused by differences in minimum action potential duration. Both the simpler spatial organization of human VF and its suggested cause may have important implications for treating and preventing this dangerous arrhythmia in humans.
Imaging Features of Extramedullary, Relapsed, and Refractory Multiple Myeloma involving the Liver Across Treatment With Cyclophosphamide, Lenalidomide, Bortezomib, and Dexamethasone
Authors: Sachin S. Saboo, Fiona Fennessy, Lina Benajiba, Jacob Laubach, Kenneth C. Anderson, Paul G. Richardson
Journal: Journal of Clinical Oncology (2012)

A 55-year-old white woman presented in June 2003 with stage IIIA Durie-Salmon immunoglobulin (Ig) G κ multiple myeloma (MM) and was initially treated with thalidomide and dexamethasone followed by cyclophosphamide, with concurrent bisphosphonate (zoledronic acid), and intensified by autologous stem-cell transplant (ASCT) after high-dose melphalan conditioning. She remained in complete remission until December 2008, when she experienced relapse with occipital plasmacytoma and symptomatic extramedullary disease (EMD) arising from her skeleton. She was treated with an experimental second-generation proteasome inhibitor (NPI-0052, 0.7 mg/m2 administered intravenously [IV]), combined with low-dose weekly oral dexamethasone. She had evidence of clinical response (disease stabilization and symptomatic improvement). Treatment was completed after 6 months, and she declined maintenance options other than bisphosphonate.
Complement activation and regulation in early and advanced stage osteoarthritis
Authors: J. L. Scott, C. R. Scanzello, C. Dragomir, M. K. Crow
Journal: Annals of the Rheumatic Diseases (2010)

Objective Although not considered a classical infl ammatory arthropathy, osteoarthritis (OA) is often associated with lowgrade synovitis.The stimuli required to establish infl ammation in OA synovium are as yet unclear, but there is emerging evidence to suggest activation of the complement pathway may have a role in this process.The aim of this study is to better describe the role that complement activation may play in the establishment or perpetuation of synovial infl ammation in early and advanced OA. Methods Gene expression of complement regulatory proteins was determined in RNA extracted from the synovium of 14 early and 28 advanced stage OA patients using real-time PCR.Immunohistochemistry was used to assess the level of C3 and membrane attack complex (MAC) C5b-9 protein deposition as well as expression of the MAC inhibitor CD59 in early and advanced stage OA synovium.In order to investigate the effect of oxidative stress, OA fi broblast-like synoviocytes (FLS) were treated with H 2 O 2 and subsequently exposed to normal human serum.CD59 expression was then assessed by fl uorescent immunocytochemistry and the level of intact C3 in the supernatant determined by western blot. ResultsThe expression of properdin, a positive regulator of the alternative complement pathway, and CD59, an inhibitor of MAC formation, were signifi cantly upregulated in early OA synovium compared with advanced stage OA synovium by 2.2-fold (p=0.03) and 2.1-fold (p=0.02),respectively.Evidence of C3 and C5b-9 deposition and CD59 protein expression was observed in both early and advanced stage OA, predominantly localised to the synovial membrane.Treatment of OA FLS with H 2 O 2 led to decreased CD59 expression on the cell surface and a reduction in the amount of intact C3 present in the supernatant.Conclusions Increased synovial expression of properdin mRNA and C3 and C5b-9 protein deposition suggests local activation of the alternative complement pathway in early OA.While increased CD59 gene expression at an early stage of disease may protect the tissue from associated damage, the authors hypothesise that complement activation in the setting of oxidative stress might contribute to impaired expression of complement regulatory proteins and uncontrolled infl ammation, resulting in progression to chronic joint damage.Characterisation of the regulation of CD59 and other complement regulatory proteins in the OA synovial membrane may suggest novel approaches to interrupt OA progression and reduce joint damage.