Retrovirus-induced target cell activation in the early phases of infection: the mouse mammary tumor virus model.

Mouse mammary tumor virus (MMTV) infects B lymphocytes and expresses a superantigen on the cell surface after integration of its reverse-transcribed genome. Superantigen-dependent B- and T-cell activation becomes detectable 2 to 3 days after infection. We show here that before this event, B cells undergo a polyclonal activation which does not involve massive proliferation. This first phase of B-cell activation is T cell independent. Moreover, during the first phase of activation, when only a small fraction of B cells is infected by MMTV(SW), viral DNA is detected only in activated B cells. Such a B-cell activation is also seen after injection of murine leukemia virus but not after injection of vaccinia virus, despite the very similar kinetics and intensity of the immune response. Since retroviruses require activated target cells to induce efficient infection, these data suggest that the early polyclonal retrovirus-induced target cell activation might play an important role in the establishment of retroviral infections.

Physical considerations on discrepancies in target volume delineation.

BACKGROUND AND PURPOSE: To compare the delineations and interpretations of target volumes by physicians in different radio-oncology centers. MATERIALS AND METHODS: Eleven Swiss radio-oncology centers delineated volumes according to ICRU 50 recommendations for one prostate and one head and neck case. In order to evaluate the consistency of the volume delineations, the following parameters were determined: 1) the target volumes (GTV, CTV and manually expanded PTV) and their extensions in the three main axes and 2) the correlation of the volume delineated by each pair of centers using the ratio of the intersection to the union (called proximity index). RESULTS: The delineated prostate volume was 105+/-55cm(3) for the CTV and 218+/-44cm(3) for the PTV. The delineated head and neck volume was 46+/-15cm(3) for the GTV, 327+/-154cm(3) for the CTV and 528+/-106cm(3) for the PTV. The mean proximity index for the prostate case was 0.50+/-0.13 for the CTV and 0.57+/-0.11 for the PTV. The proximity index for the head and neck case was 0.45+/-0.09 for the GTV, 0.42+/-0.13 for the CTV and 0.59+/-0.06 for the PTV. CONCLUSIONS: Large discrepancies between all the delineated target volumes were observed. There was an inverse relationship between the CTV volume and the margin between CTV and PTV, leading to less discrepancies in the PTV than is the CTV delineations. There was more spread in the sagittal and frontal planes due to CT pixel anisotropy, which suggests that radiation oncologists should delineate the target volumes not only in the transverse plane, but also in the sagittal and frontal planes to improve the delineation by allowing a consistency check.

Location of hubs in a competitive environment

We offer a formulation that locates hubs on a network in a competitiveenvironment; that is, customer capture is sought, which happenswhenever the location of a new hub results in a reduction of thecurrent cost (time, distance) needed by the traffic that goes from thespecified origin to the specified destination.The formulation presented here reduces the number of variables andconstraints as compared to existing covering models. This model issuited for both air passenger and cargo transportation.In this model, each origin-destination flow can go through either oneor two hubs, and each demand point can be assigned to more than a hub,depending on the different destinations of its traffic. Links(``spokes'' have no capacity limit. Computational experience is provided.

EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach.

PURPOSE: The Gastro-Intestinal Working Party of the EORTC Radiation Oncology Group (GIWP-ROG) developed guidelines for target volume definition in neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction (GEJ) and the stomach. METHODS AND MATERIALS: Guidelines about the definition of the clinical target volume (CTV) are based on a systematic literature review of the location and frequency of local recurrences and lymph node involvement in adenocarcinomas of the GEJ and the stomach. Therefore, MEDLINE was searched up to August 2008. Guidelines concerning prescription, planning and treatment delivery are based on a consensus between the members of the GIWP-ROG. RESULTS: In order to support a curative resection of GEJ and gastric cancer, an individualized preoperative treatment volume based on tumour location has to include the primary tumour and the draining regional lymph nodes area. Therefore we recommend to use the 2nd English Edition of the Japanese Classification of Gastric Carcinoma of the Japanese Gastric Cancer Association which developed the concept of assigning tumours of the GEJ and the stomach to anatomically defined sub-sites corresponding respectively to a distinct lymphatic spread pattern. CONCLUSION: The GIWP-ROG defined guidelines for preoperative irradiation of adenocarcinomas of the GEJ and the stomach to reduce variability in the framework of future clinical trials.

Locating emergency services with different priorities: The priority queuing covering location problem

Previous covering models for emergency service consider all the calls to be of the sameimportance and impose the same waiting time constraints independently of the service's priority.This type of constraint is clearly inappropriate in many contexts. For example, in urban medicalemergency services, calls that involve danger to human life deserve higher priority over calls formore routine incidents. A realistic model in such a context should allow prioritizing the calls forservice.In this paper a covering model which considers different priority levels is formulated andsolved. The model heritages its formulation from previous research on Maximum CoverageModels and incorporates results from Queuing Theory, in particular Priority Queuing. Theadditional complexity incorporated in the model justifies the use of a heuristic procedure.

Probabilistic maximal covering location-allocation models with constrained waiting time or queue length for congested systems

When dealing with the design of service networks, such as healthand EMS services, banking or distributed ticket selling services, thelocation of service centers has a strong influence on the congestion ateach of them, and consequently, on the quality of service. In this paper,several models are presented to consider service congestion. The firstmodel addresses the issue of the location of the least number of single--servercenters such that all the population is served within a standard distance,and nobody stands in line for a time longer than a given time--limit, or withmore than a predetermined number of other clients. We then formulateseveral maximal coverage models, with one or more servers per service center.A new heuristic is developed to solve the models and tested in a 30--nodesnetwork.

Location models in the public sector

The past four decades have witnessed an explosive growth in the field of networkbased facilitylocation modeling. This is not at all surprising since location policy is one of the mostprofitable areas of applied systems analysis in regional science and ample theoretical andapplied challenges are offered. Location-allocation models seek the location of facilitiesand/or services (e.g., schools, hospitals, and warehouses) so as to optimize one or severalobjectives generally related to the efficiency of the system or to the allocation of resources.This paper concerns the location of facilities or services in discrete space or networks, thatare related to the public sector, such as emergency services (ambulances, fire stations, andpolice units), school systems and postal facilities. The paper is structured as follows: first,we will focus on public facility location models that use some type of coverage criterion,with special emphasis in emergency services. The second section will examine models based onthe P-Median problem and some of the issues faced by planners when implementing thisformulation in real world locational decisions. Finally, the last section will examine newtrends in public sector facility location modeling.

A new chance-constrained maximum capture location problem

The paper presents a new model based on the basic Maximum Capture model,MAXCAP. The New Chance Constrained Maximum Capture modelintroduces astochastic threshold constraint, which recognises the fact that a facilitycan be open only if a minimum level of demand is captured. A metaheuristicbased on MAX MIN ANT system and TABU search procedure is presented tosolve the model. This is the first time that the MAX MIN ANT system isadapted to solve a location problem. Computational experience and anapplication to 55 node network are also presented.

Consumer choice in competitive location models: Formulations and heuristics

A new direction of research in Competitive Location theory incorporatestheories of Consumer Choice Behavior in its models. Following thisdirection, this paper studies the importance of consumer behavior withrespect to distance or transportation costs in the optimality oflocations obtained by traditional Competitive Location models. To dothis, it considers different ways of defining a key parameter in thebasic Maximum Capture model (MAXCAP). This parameter will reflectvarious ways of taking into account distance based on several ConsumerChoice Behavior theories. The optimal locations and the deviation indemand captured when the optimal locations of the other models are usedinstead of the true ones, are computed for each model. A metaheuristicbased on GRASP and Tabu search procedure is presented to solve all themodels. Computational experience and an application to 55-node networkare also presented.

Treating high blood pressure: is reaching the target more important than the means? No, the means are important.

All major antihypertensive drug classes i.e. diuretics, beta-blockers, calcium antagonists and blockers of the renin-angiotensin system have been shown to effectively lower blood pressure and hence to reduce cardiovascular outcomes in hypertensive patients. These drugs decrease cardiovascular complications in hypertension essentially because they reduce systemic blood pressure. Nevertheless, there is growing evidence that the extent of the benefits differed between drug classes suggesting that the various classes of antihypertensive agents are not equivalent in their ability to protect against target organ damages and cardiovascular and renal endpoints. More recently, evidence has also accumulated to demonstrate that even combination therapies are not equally effective in reducing the occurrence of cardiovascular complications in hypertension. These recent observations suggest that the means to lower blood pressure are as important as the achieved target blood pressure in the management of hypertensive patients.

Incorporating waiting time in competitive location models: Formulations and heuristics

In this paper we propose a metaheuristic to solve a new version of the Maximum CaptureProblem. In the original MCP, market capture is obtained by lower traveling distances or lowertraveling time, in this new version not only the traveling time but also the waiting time willaffect the market share. This problem is hard to solve using standard optimization techniques.Metaheuristics are shown to offer accurate results within acceptable computing times.

Location models for ceding market share and shrinking services

New location models are presented here for exploring the reduction of facilities in aregion. The first of these models considers firms ceding market share to competitorsunder situations of financial exigency. The goal of this model is to cede the leastmarket share, i.e., retain as much of the customer base as possible while sheddingcostly outlets. The second model considers a firm essentially without competition thatmust shrink it services for economic reasons. This firm is assumed to close outlets sothat the degradation of service is limited. An example is offered within a competitiveenvironment to demonstrate the usefulness of this modeling approach.

The p63 target HBP1 is required for skin differentiation and stratification.

Genetic experiments established that p63 is crucial for the development and maintenance of pluristratified epithelia. In the RNA interference (RNAi) screening for targets of p63 in keratinocytes, we identified the transcription factor, High Mobility Group (HMG) box protein 1 (HBP1). HBP1 is an HMG-containing repressor transiently induced during differentiation of several cell lineages. We investigated the relationship between the two factors: using RNAi, overexpression, chromatin immunoprecipitations and transient transfections with reporter constructs, we established that HBP1 is directly repressed by p63. This was further confirmed in vivo by evaluating expression in p63 knockout mice and in transgenics expressing p63 in basal keratinocytes. Consistent with these findings, expression of HBP1 increases upon differentiation of primary keratinocytes and HaCaT cells in culture, and it is higher in the upper layers of human skin. Inactivation of HBP1 by RNAi prevents differentiation of keratinocytes and stratification of organotypic skin cultures. Finally, we analyzed the keratinocyte transcriptomes after HBP1 RNAi; in addition to repression of growth-promoting genes, unexpected activation of differentiation genes was uncovered, coexisting with repression of other genes involved in epithelial cornification. Our data indicate that suppression of HBP1 is part of the growth-promoting strategy of p63 in the lower layers of epidermis and that HBP1 temporally coordinates expression of genes involved in stratification, leading to the formation of the skin barrier.

Improved HIV-1 RNA quantitation by COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0 using a novel dual-target approach.

BACKGROUND: HIV-1 RNA viral load is a key parameter for reliable treatment monitoring of HIV-1 infection. Accurate HIV-1 RNA quantitation can be impaired by primer and probe sequence polymorphisms as a result of tremendous genetic diversity and ongoing evolution of HIV-1. A novel dual HIV-1 target amplification approach was realized in the quantitative COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0 (HIV-1 TaqMan test v2.0) to cope with the high genetic diversity of the virus. OBJECTIVES AND STUDY DESIGN: The performance of the new assay was evaluated for sensitivity, dynamic range, precision, subtype inclusivity, diagnostic and analytical specificity, interfering substances, and correlation with the COBAS AmpliPrep/COBAS TaqMan HIV-1 (HIV-1 TaqMan test v1.0) predecessor test in patients specimens. RESULTS: The new assay demonstrated a sensitivity of 20 copies/mL, a linear measuring range of 20-10,000,000 copies/mL, with a lower limit of quantitation of 20 copies/mL. HIV-1 Group M subtypes and HIV-1 Group O were quantified within +/-0.3 log(10) of the assigned titers. Specificity was 100% in 660 tested specimens, no cross reactivity was found for 15 pathogens nor any interference for endogenous substances or 29 drugs. Good comparability with the predecessor assay was demonstrated in 82 positive patient samples. In selected clinical samples 35/66 specimens were found underquantitated in the predecessor assay; all were quantitated correctly in the new assay. CONCLUSIONS: The dual-target approach for the HIV-1 TaqMan test v2.0 enables superior HIV-1 Group M subtype coverage including HIV-1 Group O detection. Correct quantitation of specimens underquantitated in the HIV-1 TaqMan test v1.0 test was demonstrated.

Location models for airline hubs behaving as M/D/c queues

Models are presented for the optimal location of hubs in airline networks, that take into consideration the congestion effects. Hubs, which are the most congested airports, are modeled as M/D/c queuing systems, that is, Poisson arrivals, deterministic service time, and {\em c} servers. A formula is derived for the probability of a number of customers in the system, which is later used to propose a probabilistic constraint. This constraint limits the probability of {\em b} airplanes in queue, to be lesser than a value $\alpha$. Due to the computational complexity of the formulation. The model is solved using a meta-heuristic based on tabu search. Computational experience is presented.