bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non–Small Cell Lung Cancer
Authors: Bahcall Magda , Awad Mark M. , Sholl Lynette M. , Wilson Frederick H. , Xu Man , Wang Stephen , Palakurthi Sangeetha , Choi Jihyun , Ivanova Elena V. , Leonardi Giulia C. , Ulrich Bryan C. , Paweletz Cloud P. , Kirschmeier Paul T. , Watanabe Masayuki , Baba Hideo , Nishino Mizuki , Nagy Rebecca J. , Lanman Richard B. , Capelletti Marzia , Chambers Emily S. , Redig Amanda J. , VanderLaan Paul A. , Costa Daniel B. , Imamura Yu , Jänne Pasi A. 
Published: August 2018

Abstract

Purpose:
MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non–small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14-mutant NSCLC and propose a combination therapy to target it.

Experimental Design:
The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14-mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays.

Results:
KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition.

Conclusions:
Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
Bonhoeffer and Reformation Ecclesiology
Authors: Garcia Javier 
Published: August 2018

AbstractThis article offers a threefold engagement with Dietrich Bonhoeffer’s ecumenically oriented ecclesiology. First, it proposes a new avenue of understanding Bonhoeffer’s ecclesiology in relation to the Reformed tradition by comparing him with John Calvin instead of with Karl Barth, which is the common route of Bonhoeffer scholarship. Second, it identifies points of convergence between Bonhoeffer and Calvin that have been neglected in the literature, notably in the areas of ecclesial participation and sanctification. Third, it calls for a return to Bonhoeffer’s primary goal in ecumenism—to discern God’s concrete commandment to the churches in history—in the Trump era.
Do the Different Sensory Areas Within the Cat Anterior Ectosylvian Sulcal Cortex Collectively Represent a Network Multisensory Hub?
Authors: Meredith M. Alex , Wallace Mark T. , Clemo H. Ruth 
Published: August 2018

AbstractCurrent theory supports that the numerous functional areas of the cerebral cortex are organized and function as a network. Using connectional databases and computational approaches, the cerebral network has been demonstrated to exhibit a hierarchical structure composed of areas, clusters and, ultimately, hubs. Hubs are highly connected, higher-order regions that also facilitate communication between different sensory modalities. One computationally identified network hub is the visual area of the Anterior Ectosylvian Sulcal cortex (AESc) of the cat. The Anterior Ectosylvian Visual area (AEV) is but one component of the AESc since the latter also includes the auditory (Field of the Anterior Ectosylvian Sulcus — FAES) and somatosensory (Fourth somatosensory representation — SIV) areas. To better understand the nature of cortical network hubs, the present report reviews the biological features of the AESc. Within the AESc, each area has extensive external cortical connections as well as among one another. Each of these core representations is separated by a transition zone characterized by bimodal neurons that share sensory properties of both adjoining core areas. Finally, core and transition zones are underlain by a continuous sheet of layer 5 neurons that project to common output structures. Altogether, these shared properties suggest that the collective AESc region represents a multiple sensory/multisensory cortical network hub. Ultimately, such an interconnected, composite structure adds complexity and biological detail to the understanding of cortical network hubs and their function in cortical processing.
Erythropoietin response to anaemia in heart failure
Authors: Montero David , Haider Thomas , Flammer Andreas J 
Published: August 2018

BackgroundDespite multiple factors correlating with the high prevalence of anaemia in heart failure, the prevailing mechanisms have yet to be established. The purpose of this study is to systematically review the literature and determine whether low circulating haemoglobin is primarily underlain by erythropoietin resistance or defective production in heart failure.Design and methodsWe conducted a systematic search of MEDLINE since its inception until May 2017 for articles reporting erythropoietin and haemoglobin concentrations in heart failure patients not treated with erythropoietin-stimulating agents. The primary outcome was the mean difference in observed/predicted (O/P) erythropoietin ratio between heart failure patients and normal reference values. Meta-regression analyses assessed the influence of potential moderating factors.ResultsForty-one studies were included after systematic review, comprising a total of 3137 stable heart failure patients with mean age and left ventricular ejection fraction ranging from 52 years to 80 years and 21% to 59%. The O/P erythropoietin ratio was below reference values in 24 of 25 studies in anaemic heart failure patients ( n = 1094, range = 0.49–1.05), whereas only one out of 16 studies in non-anaemic heart failure patients presented a low O/P erythropoietin ratio ( n = 2043, range = 0.91–1.97). In studies comparing anaemic versus non-anaemic heart failure patients ( n = 1531), the mean O/P erythropoietin ratio was consistently reduced in anaemic heart failure patients (mean difference = –0.68, 95% confidence interval = −0.78, −0.57; p < 0.001). In meta-regression, the O/P erythropoietin ratio was negatively associated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.ConclusionAnaemia in heart failure is overwhelmingly characterized by impaired erythropoietin production, which is exacerbated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.
Pay for Delay Agreements: Antitrust Watch Intensifies
Authors: Chawla Twinkle , Verma Ruchi 
Published: August 2018

The pharmaceutical sector has constantly endeavoured to balance its dual objectives of promoting state-of-art innovation and achieving affordable healthcare for all. The contrasting aims are also germane to the inevitable conflict between the competition law and the patent law with respect to this sector. Reverse payment settlement is one such concept that lies at the cross-section of these two legislations and strangely offers an uncanny mechanism where extreme partisans (i.e., innovator and generics) become comrades, thereby prodding genuine concerns and exposing legal vulnerabilities of such agreements. Against this backdrop, this article seeks to examine the growing undercurrent re reverse payment settlement agreements from a competition law perspective. In an attempt to harmonize the conflicting policy objectives, it will study the interplay between patent law and competition law by placing reliance on the approach followed by other jurisdictions. Further, this article will also assess whether reverse payment settlement agreements fall within the statutory construct of the Competition Act, 2002 and whether the Competition Commission of India (“CCI”) can assert its jurisdiction over such agreements. An attempt is also made to outline the approach which the CCI could adopt, bearing in mind the importance of ensuring exclusivity as an incentive for innovation.
Nivolumab-induced cold agglutinin syndrome successfully treated with rituximab
Authors: Hasanov Merve , Konoplev Sergej N. , Hernandez Cristhiam M. Rojas 
Published: August 2018

Key Points
Cold agglutinin syndrome is one of the rare immune-related adverse events of nivolumab. Rituximab should be considered for treatment of nivolumab-induced cold agglutinin syndrome.
The effect of religiosity during childhood and adolescence on drug consumption patterns in adults addicted to crack cocaine
Authors: Rezende-Pinto Alexandre , Moreira-Almeida Alexander , Ribeiro Marcelo , Laranjeira Ronaldo , Vallada Homero 
Published: August 2018

BackgroundAlthough many studies suggest that religiosity is a protective factor against drug use, there is little information on its effect on drug consumption patterns of those who do use drugs.AimsWe aimed to examine if there is any relationship between religiosity during childhood and adolescence, and drug consumption in adult crack users.MethodWe performed a cross-sectional study of adults addicted to crack cocaine. Logistic regression analysis was used to estimate the odds ratio for the association between religious history in the age groups 8–11, 12–14 and 15–17 years and outcome variables.ResultsFrom a total of 531 respondents, religious involvement during childhood and adolescence was correlated to less frequent onset of drug consumption before 18 years (odds ratio 0.95, 95% CI 0.92–0.98) and less craving (odds ratio 0.95, 95% CI 0.91–0.99), mainly between the ages of 15 and 17 years.ConclusionsReligiosity provides some protection against drug consumption patterns in crack cocaine addicts.Declaration of interestNone.
Impact of detecting potentially serious incidental findings during multi-modal imaging
Authors: Gibson Lorna M , Littlejohns Thomas J , Adamska Ligia , Garratt Steve , Doherty Nicola ,   UK Biobank Imaging Working Group, Wardlaw Joanna M , Maskell Giles , Parker Michael , Brownsword Roger , Matthews Paul M , Collins Rory , Allen Naomi E , Sellors Jonathan , Sudlow Cathie LM 
Published: August 2018

Background: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank’s protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer ‘flagging’ with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers of non-serious final diagnoses (158/179) (i.e., false positives). Almost all (90%) participants had further clinical assessment (including invasive procedures in similar numbers with serious and non-serious final diagnoses [11 and 12 respectively]), with additional impact on emotional wellbeing (16.9%), finances (8.9%), and work or activities (5.6%). Conclusions: Compared with systematic radiologist review, radiographer flagging missed some serious diagnoses, but avoided adverse impacts for many participants with non-serious diagnoses. While systematic radiologist review may benefit some participants, UK Biobank’s responsibility to avoid both unnecessary harm to larger numbers of participants and burdening of publicly-funded health services suggests that radiographer flagging is a justifiable approach in the UK Biobank imaging study. The potential scale of non-serious final diagnoses raises questions relating to handling IFs in other settings, such as commercial and public health screening.
Modifying Intestinal Integrity and MicroBiome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial
Authors: Walsh Kevin , Calder Nuala , Olupot-Olupot Peter , Ssenyondo Tonny , Okiror William , Okalebo Charles Bernard , Muhindo Rita , Mpoya Ayub , Holmes Elaine , Marchesi Julian , Delamare de  la Villenaise de Chenevarin Gael , Frost Gary , Maitland Kathryn 
Published: August 2018

Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outcome by reducing lactose intolerance-related diarrhoea, improving mucosal integrity and enhancing immunity, and limiting the risk of systemic infection and associated broad-spectrum antibiotic resistance. Registration: ISRCTN 10309022.
Closing the medical mortality gap in patients with major psychiatric conditions
Authors: de Silva Prasanna N 
Published: August 2018

This article discusses options for closing the mortality gap between the general population and people with major psychiatric conditions such as psychosis, autism, learning disability and dementia. Most of the mortality (85%) involves physical disease, with most deaths occurring in general hospitals or care homes, so is relevant to all doctors. The main focus of psychiatric treatments has been to reduce suicide, although there is no evidence that they achieve this. This article calls for psychiatrists to collaborate with medical colleagues to help reduce excess deaths from physical causes. The practicalities of combined physical and mental health monitoring and prescribing clinics are discussed, based on experience in Whitby. Potential national solutions are summarized including options for smoking cessation, sugar restriction, nutritional supplementation and flu vaccination.
Phosphoglycolipid Profiling of Bacterial Endotoxins
Authors: Kilár Anikό , Dornyel Ágnes , Sándor Viktor , Kilár Ferenc , Kocsis Béla 
Published: August 2018

Abstract
Much interest is at present focused on bacterial endotoxins, also known as lipopolysaccharides (LPS), as they are responsible for the development of clinical symptoms of Gram-negative sepsis which is the leading cause of death in intensive care units. Endotoxicity is associated with the special phosphoglycolipid part of LPS, termed lipid A. Main challenges in the structural elucidation of lipid A arise from its amphiphilic character and inherent heterogeneity. A mass spectrometrybased de novo method combined with reversed-phase liquid chromatography for the detailed structural characterization of complex lipid A mixtures (obtained by mild acid hydrolysis of LPS) from different bacterial sources has been developed. Tandem mass spectrometric measurements were performed with an electrospray-ionisation quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer in both negative- and positive-ionization modes in order to explore fragmentation pathways. It was found that characteristic product ions in the positive-ion mode could be used for the unambiguous assignment of the phosphorylation site, whereas the use of both ionization modes provided consistent and/or complementary information about the fatty acyl distribution between the two glucosamine moieties of lipid A. Since the immunostimulatory (advantageous) vs. proinflammatory (endotoxic) effect of the lipid A is closely related to the fine chemical structure, our relatively simple structural elucidation strategy could offer great potential in the bioanalysis of native lipid A samples and lipid A-based vaccines
Study of Various Parameters that Influence the Content of Exhaled Breath Condensate Used in the Diagnosis of Gastroesophageal Reflux Disease
Authors: Greguš Michal , Ďurč Pavlo , Lačná Julia , Foreti František , Kubáň Peter 
Published: August 2018

Abstract
In this work, various parameters that influence the ionic content and pH of exhaled breath condensate in of the noninvasive diagnosis of gastroesophageal reflux disease were studied. Exhaled breath condensate samples were collected using a miniature and inexpensive sampling device. Capillary electrophoresis with contactless conductometric detection was used to monitor the ionic content of exhaled breath condensate. Background electrolyte composed of 20 mM of 2-(N-Morpholino)ethanesulfonic acid, 20 mM of L-Histidine, 2 mM of 18-Crown-6 and 30 M of cetyltrimethylammonium bromide facilitated the rapid separation of anions and cations, both in less than 2 minutes. The possibility of contamination of the exhaled breath condensate by saliva is discussed in detail. The day-to-day repeatability (n=5) of the ionic content and pH of the exhaled breath condensate was studied and was satisfactory, reflecting mainly the physiological variability
Ein Atavismus der Hochmoderne? Die Sommerzeit als „social engineering“ (1907–1980)
Authors: Kuchenbuch David 
Published: August 2018

Zusammenfassung
Vor rund hundert Jahren – im Ersten Weltkrieg – zum ersten Mal erprobt, ist die Sommerzeit heute umstrittener denn je: Wird der energiepolitische Nutzen der periodischen Zeitumstellung schon lange bezweifelt, mehren sich die Hinweise auf ihre medizinischen Nachteile. Dabei waren es gerade „biopolitische“ Argumente gewesen, mit denen der britische Bauunternehmer William Willett schon 1907 in seinem Pamphlet „The Waste of Daylight“ die Maßnahme zur verbesserten gesellschaftlichen Ausnutzung der Solarenergie öffentlichkeitswirksam propagiert hatte. Das legt es nahe, die Sommerzeit als Phänomen des „hochmodernen“ social engineering zu analysieren. Wie der Aufsatz am deutschen und britischen Beispiel zeigt, macht die Sommerzeit dann sowohl die sich im späten 19. Jahrhundert immer stärker ausprägenden innergesellschaftlichen (Zeit-)Interdependenzen sichtbar als auch die sozialtechnologische Machbarkeitsgewissheit bürgerlicher Eliten und den Aufschwung des Staates als Hüter der temporalen Ordnung. Die wechselhafte politische Geschichte der Sommerzeit im Deutschland des 20. Jahrhunderts verdeutlicht aber auch, dass sich die Handlungsspielräume der „Ingenieure der Sozialen Zeit“ im Zuge transnationaler Verflechtungsprozesse ebenso stark veränderten wie angesichts der wachsenden Bedeutung der Meinungsforschung. Beide Entwicklungen werfen ein Licht auf die sozial- wie kulturhistorischen Rahmenbedingungen des staatlichen „Zeitens“ (Norbert Elias) im vergangenen Jahrhundert, aus denen sich wiederum theoretische Anregungen für die Untersuchung von Zeitregimes der Moderne ziehen lassen.
Antioxidant activity of plant extracts and their effect on methane fermentation in bioreactors
Authors: Oleszek Marta , Kozachok Solomiia 
Published: August 2018

Abstract
Extracts of Solidago virgaurea L. (European goldenrod), Lavandula angustifolia Mill. (lavender) and Arnica chamissonis Less. (arnica) were tested as potential additives for methane fermentation in bioreactors, as it was hypothesized that their antioxidant properties may improve biogas production efficiency. Hence, methane fermentation of maize silage with the addition of tested extracts was performed in eudiometers, and both the biogas volume and methane content in biogas were measured. In addition, antioxidant properties, such as reducing power and 1,1-diphenyl-2-picrylhydrazyl free radical-scavenging activity, were determined spectrophotometrically. The results showed that only the addition of a goldenrod crude extract caused a significant increase in biogas yield, despite the fact that it presented the lowest antioxidant activity of the three tested species. No significant differences in biogas yield were found between the other two additives and the control. Biogas production efficiency was not correlated with the antioxidant activity of the crude extracts. Hence, the increase in methane fermentation efficiency in the case of goldenrod supplementation might have resulted from some other non-antioxidant compounds occurring in this species.