A Collective Route to Head and Neck Cancer Metastasis

© 2018 The Author(s). Distant metastasis (DM) from head and neck cancers (HNC) portends a poor patient prognosis. Despite its important biological role, little is known about the cells which seed these DM. Circulating tumour cells (CTCs) represent a transient cancer cell population, which circulate in HNC patients' peripheral blood and seed at distant sites. Capture and analysis of CTCs offers insights into tumour metastasis and can facilitate treatment strategies. Whilst the data on singular CTCs have shown clinical significance, the role of CTC clusters in metastasis remains limited. In this pilot study, we assessed 60 treatment naïve HNC patients for CTCs with disease ranging from early to advanced stages, for CTC clusters utilizing spiral CTC enrichment technology. Single CTCs were isolated in 18/60-30% (Ranging from Stage I-IV), CTC clusters in 15/60-25% (exclusively Stage IV) with 3/15-20% of CTC clusters also containing leukocytes. The presence of CTC clusters associated with the development of distant metastatic disease(P = 0.0313). This study demonstrates that CTC clusters are found in locally advanced patients, and this may be an important prognostic marker. In vivo and in vitro studies are warranted to determine the role of these CTC clusters, in particular, whether leukocyte involvement in CTC clusters has clinical relevance

Longitudinal evaluation, acceptability and long-term retention of knowledge on a horizontally integrated organic and functional systems course

Undergraduate medical education is moving from traditional disciplinary basic science courses into more integrated curricula. Integration models based on organ systems originated in the 1950s, but few longitudinal studies have evaluated their effectiveness. This article outlines the development and implementation of the Organic and Functional Systems (OFS) courses at the University of Minho in Portugal, using evidence collected over 10 years. It describes the organization of content, student academic performance and acceptability of the courses, the evaluation of preparedness for future courses and the retention of knowledge on basic sciences. Students consistently rated the OFS courses highly. Physician tutors in subsequent clinical attachments considered that students were appropriately prepared. Performance in the International Foundations of Medicine examination of a self-selected sample of students revealed similar performances in basic science items after the last OFS course and 4 years later, at the moment of graduation. In conclusion, the organizational and pedagogical approaches of the OFS courses achieve high acceptability by students and result in positive outcomes in terms of preparedness for subsequent training and long-term retention of basic science knowledge

Ultra-Sensitive Hot-Electron Nanobolometers for Terahertz Astrophysics

The background-limited spectral imaging of the early Universe requires spaceborne terahertz (THz) detectors with the sensitivity 2-3 orders of magnitude better than that of the state-of-the-art bolometers. To realize this sensitivity without sacrificing operating speed, novel detector designs should combine an ultrasmall heat capacity of a sensor with its unique thermal isolation. Quantum effects in thermal transport at nanoscale put strong limitations on the further improvement of traditional membrane-supported bolometers. Here we demonstrate an innovative approach by developing superconducting hot-electron nanobolometers in which the electrons are cooled only due to a weak electron-phonon interaction. At T<0.1K, the electron-phonon thermal conductance in these nanodevices becomes less than one percent of the quantum of thermal conductance. The hot-electron nanobolometers, sufficiently sensitive for registering single THz photons, are very promising for submillimeter astronomy and other applications based on quantum calorimetry and photon counting.Comment: 19 pages, 3 color figure

Student and tutor perceptions on attributes of effective problems in problem-based learning

This study aimed to identify the attributes that students and tutors associated with effective PBL problems, and assess the extent to which these attributes related to the actual effectiveness of problems. To this end, students and tutors in focus groups were asked to discuss about possible attributes of effective problems. The same participants were then asked to individually and independently judge eight sample problems they had worked with. Text analysis of the focus group discussion transcripts identified eleven problem attributes. Participants' judgments of the sample problems were then frequency-scored on the eleven problem attributes. Relating the participants' judgments with the entire student cohort's grades yielded high and significant correlations, suggesting that the eleven problem attributes reflect aspects of problem effectiveness

The Railway Line Frequency and Size Setting Problem

[EN] The problem studied in this paper takes as input data a set of lines forming a railway network, and an origin¿destination (OD) matrix. The OD pairs may use either the railway network or an alternative transportation mode. The objective is to determine the frequency/headway of each line as well as its number of carriages, so that the net profit of the railway network is maximized. We propose a mixed integer non-linear programming formulation for this problem. Because of the computational intractability of this model, we develop four algorithms: a mixed integer linear programming (MIP) model, a MIP-based iterative algorithm, a shortest-path based algorithm, and a local search. These four algorithms are tested and compared over a set of randomly generated instances. An application over a case study shows that only the local search heuristic is capable of dealing with large instances.This research was partly funded by the Canadian Natural Sciences and Engineering Research Council under Grant 2015-06189, by the Ministerio de Economía y Competitividad (Spain)/FEDER under projects MTM2012-37048, MTM2015-67706-P and DPI2012-36243-C02-01, and by Junta de Andalucía (Spain)/FEDER under excellence project P10-FQM-5849. Part of this research was done while Federico Perea was enjoying a research visit to CIRRELT, funded by the Universitat Politècnica de València, under program PAID-00-15. This support is gratefully acknowledged. Thanks are due to the referees for their valuable comments.De-Los-Santos, A.; Laporte, G.; Mesa, JA.; Perea Rojas Marcos, F. (2017). The Railway Line Frequency and Size Setting Problem. Public Transport. 9(1-2):33-53. https://doi.org/10.1007/s12469-017-0154-2S335391-2Albrecht T (2009) Automated timetable design for demand-oriented service on suburban railways. Public Transport 1(1):5–20Caprara A, Kroon L, Monaci M, Peeters M, Toth P (2007) Passenger Railway optimization. In: Barnhart C, Laporte G (eds) Handbooks in operations research and management science, vol 14. Transportation, chapter 3. North-Holland, Amsterdam, pp 129–187De-Los-Santos A, Laporte G, Mesa J, Perea F (2014) Simultaneous frequency and capacity setting in uncapacitated metro lines in presence of a competing mode. Transp Res Proc 3:289–298Desaulniers G, Hickman M (2007) Public transport. In: Barnhart C, Laporte G (eds) Handbook in operations research and management science, vol 14, Transportation, chapter 2. North-Holland, Amsterdam, pp 69–127Gallo M, Montella B, D’Acierno L (2011) The transit network design problem with elastic demand and internalisation of external costs: An application to rail frequency optimisation. Transp Res Part C Emerg Technol 19(6):1276–1305Laporte G, Marín A, Mesa JA, Perea F (2011) Designing robust rapid transit networks with alternative routes. J Adv Transp 45(1):54–65Marín A, García-Ródenas R (2009) Location of infrastructure in urban railway networks. Comput Oper Res 36(5):1461–1477Michaelis M, Schöbel A (2009) Integrating line planning, timetable, and vehicle scheduling: a customer oriented heuristic. Public Transport 1(3):211–232Perea F, Mesa JA, Laporte G (2014) Adding a new station and a road link to a road-rail network in the presence of modal competition. Transp Res Part B Methodol 68:1–16Schmidt M, Schöbel A (2015) The complexity of integrating passenger routing decisions in public transportation models. Networks 65(3):228–243Schmidt ME (2014) Integrating routing decisions in public transportation problems. Springer, New YorkSchöbel A (2012) Line planning in public transportation. OR Spectrum 34:491–510van Oort N, van Nes R (2009) Regularity analysis for optimizing urban transit network design. Public Transport 1(2):155–168Vuchic VR (2005) Urban transit: operations, planning, and economics. Wiley, Hoboken, New Jerse

A semi-supervised large margin algorithm for white matter hyperintensity segmentation

Precise detection and quantification of white matter hyperintensities (WMH) is of great interest in studies of neurodegenerative diseases (NDs). In this work, we propose a novel semi-supervised large margin algorithm for the segmentation of WMH. The proposed algorithm optimizes a kernel based max-margin objective function which aims to maximize the margin averaged over inliers and outliers while exploiting a limited amount of available labelled data. We show that the learning problem can be formulated as a joint framework learning a classifier and a label assignment simultaneously, which can be solved efficiently by an iterative algorithm. We evaluate our method on a database of 280 brain Magnetic Resonance (MR) images from subjects that either suffered from subjective memory complaints or were diagnosed with NDs. The segmented WMH volumes correlate well with the standard clinical measurement (Fazekas score), and both the qualitative visualization results and quantitative correlation scores of the proposed algorithm outperform other well known methods for WMH segmentation

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection

Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions

Síntomas de pacientes antes de la primera hospitalización por Síndrome Coronario Agudo

Este estudo objetivou caracterizar os pacientes quanto ao relato da presença de sintomas de dor torácica, dispneia e limitação das atividades diárias uma semana antes da primeira hospitalização por Síndrome Coronariana Aguda, segundo a forma de apresentação clínica, e compará-las. Estudo transversal, descritivo e correlacional. Utilizou-se um instrumento de avaliação clínica que investigou a presença e a gravidade dos sintomas de dispneia, precordialgia e restrição física decorrentes da isquemia do miocárdio. Com relação à limitação para realização de atividades físicas, pacientes com diagnóstico de angina instável mostraram maior comprometimento na semana que antecedeu a internação, assim como relataram a presença de dispneia e precordialgia com maior frequência do que os pacientes infartados em situações que vão desde realizarem grandes esforços como, por exemplo, caminhar na subida ou muito rápido no plano, até situações de repouso ou de pequenos esforços.The objective of this study was to characterize and compare patients regarding their report of experiencing chest pain, dyspnea and limitation of the daily life activities one week before their first hospitalization due to Acute Coronary Syndrome, according to the clinical presentation form, and compare them. This is a cross-sectional, descriptive and correlational study. A clinical evaluation instrument was used to investigate the presence and severity of dyspnea, chest pain and physical restriction due to myocardial ischemia. Regarding the limitation to carry out physical activities, patients diagnosed with unstable angina showed lower capacity the week before hospitalization, and reported experiencing dyspnea and chest pain more frequently than patients who had an infarction in situations ranging from making strong efforts, such as walking uphill or on a flat surface but very quickly, to resting and in situations of little effort.Estudio que objetivó caracterizar a pacientes en cuanto al relato de presencia de síntomas de dolor torácico, disnea y limitación de actividades diarias una semana antes de la primera hospitalización por Síndrome Coronario Agudo, según la forma de presentación clínica, y compararlas. Estudio transversal, descriptivo y correlacional. Se utilizó un instrumento de evaluación clínica que investigó la presencia y gravedad de síntomas de disnea, precordialgia y restricción física derivadas de isquemia de miocardio. En relación a limitaciones para realización de actividades físicas, pacientes con diagnóstico de angina inestable mostraron mayor compromiso en la semana que antecedió a la internación, así como relataron la presencia de disnea y precordialgia con mayor frecuencia que en los pacientes infartados en situaciones tales como realizar grandes esfuerzos como, por ejemplo, caminar en pendiente ascendiente o muy rápido en el llano, hasta situaciones de reposo o pequeños esfuerzos