Defining the critical hurdles in cancer immunotherapy.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

Parameter estimation for the distribution of single cell lag times.

In Quantitative Microbial Risk Assessment, it is vital to understand how lag times of individual cells are distributed over a bacterial population. Such identified distributions can be used to predict the time by which, in a growth-supporting environment, a few pathogenic cells can multiply to a poisoning concentration level. We model the lag time of a single cell, inoculated into a new environment, by the delay of the growth function characterizing the generated subpopulation. We introduce an easy-to-implement procedure, based on the method of moments, to estimate the parameters of the distribution of single cell lag times. The advantage of the method is especially apparent for cases where the initial number of cells is small and random, and the culture is detectable only in the exponential growth phase.

ILS-ESP An efficient, simple, and parameter-free algorithm for solving the permutation flow-shop problem

From a managerial point of view, the more effcient, simple, and parameter-free (ESP) an algorithm is, the more likely it will be used in practice for solving real-life problems. Following this principle, an ESP algorithm for solving the Permutation Flowshop Sequencing Problem (PFSP) is proposed in this article. Using an Iterated Local Search (ILS) framework, the so-called ILS-ESP algorithm is able to compete in performance with other well-known ILS-based approaches, which are considered among the most effcient algorithms for the PFSP. However, while other similar approaches still employ several parameters that can affect their performance if not properly chosen, our algorithm does not require any particular fine-tuning process since it uses basic "common sense" rules for the local search, perturbation, and acceptance criterion stages of the ILS metaheuristic. Our approach defines a new operator for the ILS perturbation process, a new acceptance criterion based on extremely simple and transparent rules, and a biased randomization process of the initial solution to randomly generate different alternative initial solutions of similar quality -which is attained by applying a biased randomization to a classical PFSP heuristic. This diversification of the initial solution aims at avoiding poorly designed starting points and, thus, allows the methodology to take advantage of current trends in parallel and distributed computing. A set of extensive tests, based on literature benchmarks, has been carried out in order to validate our algorithm and compare it against other approaches. These tests show that our parameter-free algorithm is able to compete with state-of-the-art metaheuristics for the PFSP. Also, the experiments show that, when using parallel computing, it is possible to improve the top ILS-based metaheuristic by just incorporating to it our biased randomization process with a high-quality pseudo-random number generator.

Interhuman transmission as a potential key parameter for geographical variation in the prevalence of Pneumocystis jirovecii dihydropteroate synthase mutations.

BACKGROUND: Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations are associated with failure of prophylaxis with sulfa drugs. This retrospective study sought to better understand the geographical variation in the prevalence of these mutations. METHODS: DHPS polymorphisms in 394 clinical specimens from immunosuppressed patients who received a diagnosis of P. jirovecii pneumonia and who were hospitalized in 3 European cities were examined using polymerase chain reaction (PCR) single-strand conformation polymorphism. Demographic and clinical characteristics were obtained from patients' medical charts. RESULTS: Of the 394 patients, 79 (20%) were infected with a P. jirovecii strain harboring one or both of the previously reported DHPS mutations. The prevalence of DHPS mutations was significantly higher in Lyon than in Switzerland (33.0% vs 7.5%; P < .001). The proportion of patients with no evidence of sulfa exposure who harbored a mutant P. jirovecii DHPS genotype was significantly higher in Lyon than in Switzerland (29.7% vs 3.0%; P < .001). During the study period in Lyon, in contrast to the Swiss hospitals, measures to prevent dissemination of P. jirovecii from patients with P. jirovecii pneumonia were generally not implemented, and most patients received suboptimal prophylaxis, the failure of which was strictly associated with mutated P. jirovecii. Thus, nosocomial interhuman transmission of mutated strains directly or indirectly from other individuals in whom selection of mutants occurred may explain the high proportion of mutations without sulfa exposure in Lyon. CONCLUSIONS: Interhuman transmission of P. jirovecii, rather than selection pressure by sulfa prophylaxis, may play a predominant role in the geographical variation in the prevalence in the P. jirovecii DHPS mutations.

Detection of Optimal Models in Parameter Space with Support Vector Machines

The paper proposes an approach aimed at detecting optimal model parameter combinations to achieve the most representative description of uncertainty in the model performance. A classification problem is posed to find the regions of good fitting models according to the values of a cost function. Support Vector Machine (SVM) classification in the parameter space is applied to decide if a forward model simulation is to be computed for a particular generated model. SVM is particularly designed to tackle classification problems in high-dimensional space in a non-parametric and non-linear way. SVM decision boundaries determine the regions that are subject to the largest uncertainty in the cost function classification, and, therefore, provide guidelines for further iterative exploration of the model space. The proposed approach is illustrated by a synthetic example of fluid flow through porous media, which features highly variable response due to the parameter values' combination.

Measurements of three-dimensional glenoid erosion when planning the prosthetic replacement of osteoarthritic shoulders.

The three-dimensional (3D) correction of glenoid erosion is critical to the long-term success of total shoulder replacement (TSR). In order to characterise the 3D morphology of eroded glenoid surfaces, we looked for a set of morphological parameters useful for TSR planning. We defined a scapular coordinates system based on non-eroded bony landmarks. The maximum glenoid version was measured and specified in 3D by its orientation angle. Medialisation was considered relative to the spino-glenoid notch. We analysed regular CT scans of 19 normal (N) and 86 osteoarthritic (OA) scapulae. When the maximum version of OA shoulders was higher than 10°, the orientation was not only posterior, but extended in postero-superior (35%), postero-inferior (6%) and anterior sectors (4%). The medialisation of the glenoid was higher in OA than normal shoulders. The orientation angle of maximum version appeared as a critical parameter to specify the glenoid shape in 3D. It will be very useful in planning the best position for the glenoid in TSR.

Sweet sixteen for ANLS.

Since its introduction 16 years ago, the astrocyte-neuron lactate shuttle (ANLS) model has profoundly modified our understanding of neuroenergetics by bringing a cellular and molecular resolution. Praised or disputed, the concept has never ceased to attract attention, leading to critical advances and unexpected insights. Here, we summarize recent experimental evidence further supporting the main tenets of the model. Thus, evidence for distinct metabolic phenotypes between neurons (mainly oxidative) and astrocytes (mainly glycolytic) have been provided by genomics and classical metabolic approaches. Moreover, it has become clear that astrocytes act as a syncytium to distribute energy substrates such as lactate to active neurones. Glycogen, the main energy reserve located in astrocytes, is used as a lactate source to sustain glutamatergic neurotransmission and synaptic plasticity. Lactate is also emerging as a neuroprotective agent as well as a key signal to regulate blood flow. Characterization of monocarboxylate transporter regulation indicates a possible involvement in synaptic plasticity and memory. Finally, several modeling studies captured the implications of such findings for many brain functions. The ANLS model now represents a useful, experimentally based framework to better understand the coupling between neuronal activity and energetics as it relates to neuronal plasticity, neurodegeneration, and functional brain imaging.

Stress, coping and presenteeism in nurses assisting critical and potentially critical patients

Objective to verify the associations between stress, Coping and Presenteeism in nurses operating on direct assistance to critical and potentially critical patients. Method this is a descriptive, cross-sectional and quantitative study, conducted between March and April 2010 with 129 hospital nurses. The Inventory of stress in nurses, Occupational and Coping Questionnaire Range of Limitations at Work were used. For the analysis, the Kolmogorov-Smirnov test, correlation coefficient of Pearson and Spearman, Chi-square and T-test were applied. Results it was observed that 66.7% of the nurses showed low stress, 87.6% use control strategies for coping stress and 4.84% had decrease in productivity. Direct and meaningful relationships between stress and lost productivity were found. Conclusion stress interferes with the daily life of nurses and impacts on productivity. Although the inability to test associations, the control strategy can minimize the stress, which consequently contributes to better productivity of nurses in the care of critical patients and potentially critical.


Report of Task Force into Critical Incidents within the Iowa Prison System, 2004

Report #02-04 Concerns about the death of two Iowa inmates at the Anamosa State Penitentiary, asked the Ombudsman Office to review the incidents and provide an assessment of each incident. The Governor also asked the Ombudsman Office to propose a set of recommendations for improving inmate and staff safety within Anamosa State Penitentiary.

Seismic attenuation in heterogeneous partially saturated rocks

We study wave-induced fluid flow effects in porous rocks partially saturated with gas and water, where the saturation patterns are governed by mesoscopic heterogeneities associated with the dry frame properties. The link between the dry frame properties and the gas saturation is defined by the assumption of capillary pressure equilibrium, which in the presence of heterogeneity implies that neighboring regions can exhibit different levels of saturation. In order to determine the equivalent attenuation and phase velocity of the synthetic rock samples considered in this study, we apply a numerical upscaling procedure, which permits to take into account mesoscopic heterogeneities associated with the dry frame properties as well as spatially continuous variations of the pore fluid properties. We consider numerical experiments to analyze such effects in heterogeneous partially saturated porous media, where the saturation field is determined by realistic variations in porosity. Our results indicate that the spatially continuous nature of gas saturation inherent to this study is a critical parameter controlling the seismic response of these environments, which in turn suggests that the physical mechanisms governing partial saturation should be accounted for when analyzing seismic data in a poro-elastic context.

Mécanismes cellulaires du métabolisme énergétique cérébral: implications pour l'imagerie fonctionnelle

Signals detected with functional brain imaging techniques are based on the coupling of neuronal activity with energy metabolism. Techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) allow the visualization of brain areas that are activated by a variety of sensory, motor or cognitive tasks. Despite the technological sophistication of these brain imaging techniques, the precise mechanisms and cell types involved in coupling and in generating metabolic signals are still debated. Recent experimental data on the cellular and molecular mechanisms that underlie the fluorodeoxyglucose (FDG) - based PET imaging point to a critical role of a particular brain cell type, the astrocytes, in coupling neuronal activity to glucose utilization. Indeed, astrocytes possess receptors and re-uptake sites for a variety of neurotransmitters, including glutamate, the predominant excitatory neurotransmitter in the brain, In addition, astrocytic end-feet, which surround capillaries, are enriched in the specific glucose transporter GLUT-1. These features allow astrocytes to "sense" synaptic activity and to couple it with energy metabolism. In vivo and in vitro data support the following functional model: in response to glutamate released by active neurons, glucose is predominantly taken up by astrocytic end-feet; glucose is then metabolized to lactate which provides a preferred energy substrate for neurons. These data support the notion that astrocytes markedly contribute to the FDG-PET signal.

Wheat germ cell-free expression: Two detergents with a low critical micelle concentration allow for production of soluble HCV membrane proteins.

Membrane proteins are notoriously difficult to express in a soluble form. Here, we use wheat germ cell-free expression in the presence of various detergents to produce the non-structural membrane proteins 2, 4B and 5A of the hepatitis C virus (HCV). We show that lauryl maltose neopentyl glycol (MNG-3) and dodecyl octaethylene glycol ether (C12E8) detergents can yield essentially soluble membrane proteins at detergent concentrations that do not inhibit the cell-free reaction. This finding can be explained by the low critical micelle concentration (CMC) of these detergents, which keeps the monomer concentrations low while at the same time providing the necessary excess of detergent concentration above CMC required for full target protein solubilization. We estimate that a tenfold excess of detergent micelles with respect to the protein concentration is sufficient for solubilization, a number that we propose as a guideline for detergent screening assays.