Rational treatment of metastatic colorectal cancer: A reverse tale of men, mice, and culture dishes

Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance

Experimental determination of the frequency and field dependence of Specific Loss Power in Magnetic Fluid Hyperthermia

Magnetic nanoparticles are promising systems for biomedical applications and in particular for Magnetic Fluid Hyperthermia, a promising therapy that utilizes the heat released by such systems to damage tumor cells. We present an experimental study of the physical properties that influences the capability of heat release, i.e. the Specific Loss Power, SLP, of three biocompatible ferrofluid samples having a magnetic core of maghemite with different core diameter d= 10.2, 14.6 and 19.7 nm. The SLP was measured as a function of frequency f and intensity of the applied alternating magnetic field H, and it turned out to depend on the core diameter, as expected. The results allowed us to highlight experimentally that the physical mechanism responsible for the heating is size-dependent and to establish, at applied constant frequency, the phenomenological functional relationship SLP=cH^x, with 2<x<3 for all samples. The x-value depends on sample size and field frequency/ intensity, here chosen in the typical range of operating magnetic hyperthermia devices. For the smallest sample, the effective relaxation time Teff=19.5 ns obtained from SLP data is in agreement with the value estimated from magnetization data, thus confirming the validity of the Linear Response Theory model for this system at properly chosen field intensity and frequency

Cellular-Automata model for dense-snow avalanches

This paper introduces a three-dimensional model for simulating dense-snow avalanches, based on the numerical method of cellular automata. This method allows one to study the complex behavior of the avalanche by dividing it into small elements, whose interaction is described by simple laws, obtaining a reduction of the computational power needed to perform a three-dimensional simulation. Similar models by several authors have been used to model rock avalanches, mud and lava flows, and debris avalanches. A peculiar aspect of avalanche dynamics, i.e., the mechanisms of erosion of the snowpack and deposition of material from the avalanche is taken into account in the model. The capability of the proposed approach has been illustrated by modeling three documented avalanches that occurred in Susa Valley (Western Italian Alps). Despite the qualitative observations used for calibration, the proposed method is able to reproduce the correct three-dimensional avalanche path, using a digital terrain model, and the order of magnitude of the avalanche deposit volume

Access Control Design and Implementations in the ATLAS Experiment

The ATLAS experiment operates with a significant number of hardware and software resources. Their protection against misuse is an essential task to ensure a safe and optimal operation. To achieve this goal, the Role Based Access Control (RBAC) model has been chosen for its scalability, flexibility, ease of administration and usability from the lowest operating system level to the highest software application level. This paper presents the overall design of RBAC implementation in the ATLAS experiment and the enforcement solutions in different areas such as the system administration, control room desktops and the data acquisition software. The users and the roles are centrally managed using a directory service based on Lightweight Directory Access Protocol which is kept in synchronization with the human resources and IT data

Climate tolerances and trait choices shape continental patterns of urban tree biodiversity

Aim: We propose and test a climate tolerance and trait choice hypothesis of urban macroecological variation in which strong filtering associated with low winter temperatures restricts urban biodiversity while weak filtering associated with warmer temperatures and irrigation allows dispersal of species from a global source pool, thereby increasing urban biodiversity. Location: Twenty cities across the USA and Canada. Methods: We examined variation in tree community taxonomic diversity, origins and production of an aesthetic ecosystem service trait in a cross-section of urban field surveys. We correlated urban tree community composition indicators with a key climate restriction, namely mean minimum winter temperature, and evaluated alternative possible drivers: precipitation, summer maximum temperature, population size and the percentage of adults with a college education. Results: Species accumulation curves differed substantially among cities, with observed richness varying from 22 to 122 species. Similarities in tree communities decreased exponentially with increases in climatic differences. Ordination of tree communities showed strong separation among cities with component axes correlated with minimum winter temperature and annual precipitation. Variation among urban tree communities in richness, origins and the provisioning of an aesthetic ecosystem service were all correlated with minimum winter temperature. Main conclusions: The urban climate tolerance and trait choice hypothesis provides a coherent mechanism to explain the large variation among urban tree communities resulting from an interacting environment, species and human decisions. Reconciling the feedbacks between human decision making and biophysical limitations provides a foundation for an urban ecological theory that can better understand and predict the dynamics of other linked biotic communities, associated ecosystem dynamics and resulting services provided to urban residents

The Process Manager in the ATLAS DAQ System

The Process Manager is the component responsible for launching and controlling processes in the ATLAS DAQ system. The tasks of the Process Manager can be coarsely grouped into three categories: process creation, control and monitoring. Process creation implies the creation of the actual process on behalf of different users and the preparation of all the resources and data needed to actually start the process. Process control includes mostly process termination and UNIX signal dispatching. Process monitoring implies both giving state information on request and initiating call-backs to notify clients that processes have changed states. This paper describes the design and implementation of the DAQ Process Manager for the ATLAS experiment. Since the Process Manager is at the basis of the DAQ control system it must be extremely robust and tolerate the failure of any other DAQ service. Particular emphasis will be given to the testing and quality assurance procedures carried out to validate this component

The impact of positivity and transparency on trust in leaders and their perceived effectiveness

A critical challenge facing today’s organizational leaders is gaining their followers’ trust and having them view leaders as effective in addressing turmoil and change. Using a downsizing scenario as the context, this field experiment examined how a leader’s positivity and transparency impacted followers’ perceived trust, defined in terms of willingness to be vulnerable, and effectiveness of their leader. To test the hypotheses, 304 participants were randomly assigned to one of the four conditions of high (low) leader positivity × high (low) leader transparency. Results of our mixed methods study indicated both the leader’s level of positivity and transparency impacted followers’ perceived trust and evaluations of leader effectiveness. Besides limitations and suggestions for future research, we conclude with the practical implications that positive, transparent leaders may have on building trust and perceived effectiveness among their followers

The meteorological model RAMS at Crati Scrl

International audienceAt Crati Scrl an operational version of RAMS 4.3 (Regional Atmospheric Modeling System) was implemented in January 2001. This paper aims to give a first assessment of model performances for quantitative precipitation forecast (QPF). In essence, the effects of enhanced horizontal grid resolution over Calabria, using a 6km spacing domain nested in a 30km resolution parent grid, is studied. To cope with this problem two integrations sets are discussed using two model resolutions. Integrations are performed daily for six months. ECMWF 12:00UTC forecast cycle is used for initial and dynamic boundary conditions. Performances are evaluated by scores computed from model outputs and raingauge measurements coming from Calabrian regional network

The impact of positivity and transparency on trust in leaders and their perceived effectiveness

A critical challenge facing today’s organizational leaders is gaining their followers’ trust and having them view leaders as effective in addressing turmoil and change. Using a downsizing scenario as the context, this field experiment examined how a leader’s positivity and transparency impacted followers’ perceived trust, defined in terms of willingness to be vulnerable, and effectiveness of their leader. To test the hypotheses, 304 participants were randomly assigned to one of the four conditions of high (low) leader positivity × high (low) leader transparency. Results of our mixed methods study indicated both the leader’s level of positivity and transparency impacted followers’ perceived trust and evaluations of leader effectiveness. Besides limitations and suggestions for future research, we conclude with the practical implications that positive, transparent leaders may have on building trust and perceived effectiveness among their followers

The application of LEPS technique for Quantitative Precipitation Forecast (QPF) in Southern Italy

International audienceThis paper reports preliminary results of a Limited area model Ensemble Prediction System (LEPS), based on RAMS, for eight case studies of moderate-intense precipitation over Calabria, the southernmost tip of the Italian peninsula. LEPS aims to transfer the benefits of a probabilistic forecast from global to regional scales in countries where local orographic forcing is a key factor to force convection. To accomplish this task and to limit computational time, in order to implement LEPS operational, we perform a cluster analysis of ECMWF-EPS runs. Starting from the 51 members that forms the ECMWF-EPS we generate five clusters. For each cluster a representative member is selected and used to provide initial and dynamic boundary conditions to RAMS, whose integrations generate LEPS. RAMS runs have 12 km horizontal resolution. Hereafter this ensemble will be referred also as LEPS_12L30. To analyze the impact of enhanced horizontal resolution on quantitative precipitation forecast, LEPS_12L30 forecasts are compared to a lower resolution ensemble, based on RAMS that has 50 km horizontal resolution and 51 members, nested in each ECMWF-EPS member. Hereafter this ensemble will be also referred as LEPS_50L30. LEPS_12L30 and LEPS_50L30 results were compared subjectively for all case studies but, for brevity, results are reported for two "representative" cases only. Subjective analysis is based on ensemble-mean precipitation and probability maps. Moreover, a short summary of objective scores. Maps and scores are evaluated against reports of Calabria regional raingauges network. Results show better LEPS_12L30 performance compared to LEPS_50L30. This is obtained for all case studies selected and strongly suggests the importance of the enhanced horizontal resolution, compared to ensemble population, for Calabria, at least for set-ups and case studies selected in this work