Functional sphere profiling reveals the complexity of neuroblastoma tumor-initiating cell model.

Neuroblastoma (NB) is a neural crest-derived childhood tumor characterized by a remarkable phenotypic diversity, ranging from spontaneous regression to fatal metastatic disease. Although the cancer stem cell (CSC) model provides a trail to characterize the cells responsible for tumor onset, the NB tumor-initiating cell (TIC) has not been identified. In this study, the relevance of the CSC model in NB was investigated by taking advantage of typical functional stem cell characteristics. A predictive association was established between self-renewal, as assessed by serial sphere formation, and clinical aggressiveness in primary tumors. Moreover, cell subsets gradually selected during serial sphere culture harbored increased in vivo tumorigenicity, only highlighted in an orthotopic microenvironment. A microarray time course analysis of serial spheres passages from metastatic cells allowed us to specifically "profile" the NB stem cell-like phenotype and to identify CD133, ABC transporter, and WNT and NOTCH genes as spheres markers. On the basis of combined sphere markers expression, at least two distinct tumorigenic cell subpopulations were identified, also shown to preexist in primary NB. However, sphere markers-mediated cell sorting of parental tumor failed to recapitulate the TIC phenotype in the orthotopic model, highlighting the complexity of the CSC model. Our data support the NB stem-like cells as a dynamic and heterogeneous cell population strongly dependent on microenvironmental signals and add novel candidate genes as potential therapeutic targets in the control of high-risk NB.

On uniform conjugators in torsion-free hyperbolic groups

"Vegeu el resum a l'inici del document del fitxer adjunt."

Solidarity and uniform rules in bankruptcy problems

The idea of ensuring a guarantee (a minimum amount of the resources) to each agent has recently acquired great relevance, in both social and politi- cal terms. Furthermore, the notion of Solidarity has been treated frequently in redistribution problems to establish that any increment of the resources should be equally distributed taking into account some relevant characteris- tics. In this paper, we combine these two general concepts, guarantee and solidarity, to characterize the uniform rules in bankruptcy problems (Con- strained Equal Awards and Constrained Equal Losses rules). Keywords: Constrained Equal Awards, Constrained Equal Losses, Lower bounds, Bankruptcy problems, Solidarity. JEL classification: C71, D63, D71.

Which European Public Sphere? Normative Standards and Empirical Insights from Multilingual Switzerland

Since the beginning of the 1990s, the EU has been increasingly criticised for its democratic deficit, which is intrinsically linked to the absence of a public sphere at the European level. Whereas scholars consider the emergence of such a public sphere as a necessary requirement for the democratisation of the EU, they disagree on the conceptualisation and normative requirements for a meaningful public sphere at the European level. This article takes an empirical perspective and draws on the nation-state context of multilingual Switzerland to get insights into what a European public sphere might realistically look like. Based on a content analysis of the leading quality paper from each German- and French-speaking Switzerland by means of political claims analysis, it shows that three of the most often cited criteria for a European public sphere - horizontal openness and interconnectedness, shared meaning structures, and inclusiveness - are hardly met in the Swiss context. On this basis, it concludes that the normative barrier for finding a European public sphere might be unrealistically high and should be reconsidered.

Characterization of myelomonocytoid progenitor cells with mesenchymal differentiation potential obtained by outgrowth from pancreas explants.

Progenitor cells can be obtained by outgrowth from tissue explants during primary ex vivo tissue culture. We have isolated and characterized cells outgrown from neonatal mouse pancreatic explants. A relatively uniform population of cells showing a distinctive morphology emerged over time in culture. This population expressed monocyte/macrophage and hematopoietic markers (CD11b(+) and CD45(+)), and some stromal-related markers (CD44(+) and CD29(+)), but not mesenchymal stem cell (MSC)-defining markers (CD90(-) and CD105(-)) nor endothelial (CD31(-)) or stem cell-associated markers (CD133(-) and stem cell antigen-1; Sca-1(-)). Cells could be maintained in culture as a plastic-adherent monolayer in culture medium (MesenCult MSC) for more than 1 year. Cells spontaneously formed sphere clusters "pancreatospheres" which, however, were nonclonal. When cultured in appropriate media, cells differentiated into multiple mesenchymal lineages (fat, cartilage, and bone). Positive dithizone staining suggested that a subset of cells differentiated into insulin-producing cells. However, further studies are needed to characterize the endocrine potential of these cells. These findings indicate that a myelomonocytoid population from pancreatic explant outgrowths has mesenchymal differentiation potential. These results are in line with recent data onmonocyte-derivedmesenchymal progenitors (MOMPs).

A clinical trial for uniform multidrug therapy for leprosy patients in Brazil: rationale and design

Leprosy will continue to be a public health problem for several decades. The World Health Organization (WHO) recommends that, for treatment purposes, leprosy cases be classified as either paucibacillary or multibacillary (MB). A uniform leprosy treatment regimen would simplify treatment and halve the treatment duration for MB patients. The clinical trial for uniform multidrug therapy (U-MDT) for leprosy patients (LPs) in Brazil is a randomised, open-label clinical trial to evaluate if the effectiveness of U-MDT for leprosy equals the regular regimen, to determine the acceptability of the U-MDT regimen and to identify the prognostic factors. This paper details the clinical trial methodology and patient enrolment data. The study enrolled 858 patients at two centres and 78.4% of participants were classified as MB according to the WHO criteria. The main difficulty in evaluating a new leprosy treatment regimen is that no reliable data are available for the current treatment regimen. Relapse, reaction and impaired nerve function rates have never been systematically determined, although reaction and impaired nerve function are the two major causes of nerve damage that lead to impairments and disabilities in LPs. Our study was designed to overcome the need for reliable data about the current treatment and to compare its efficacy with that of a uniform regimen.

Brazilian clinical trial of uniform multidrug therapy for leprosy patients: the correlation between clinical disease types and adverse effects

This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.

Iowa Uniform Crime Report, Iowa Department of Public Safety, 1997

In 1974, the 65th Iowa General Assembly enacted a provision of Chapter 749 B of the Code of Iowa requiring law enforcement agencies to submit reports of crime and arrests to the Bureau of Criminal Investigation. The following language now is contained in section 692.15 Code of Iowa concerning Uniform Crime Reports: If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

Iowa Uniform Crime Report, Iowa Department of Public Safety, 1998

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

Iowa Uniform Crime Report, Iowa Department of Public Safety, 1999

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

Iowa Uniform Crime Report, Iowa Department of Public Safety, 2000

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

Iowa Uniform Crime Report, Iowa Department of Public Safety, 2002

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

1995 Iowa Uniform Crime Report

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

Iowa Uniform Crime Report, 2001

If it comes to the attention of a sheriff, police department or other law enforcement agency that a public offense has been committed in its jurisdiction, the law enforcement agency shall report information concerning such a public offense to the department on a form to be furnished by the department not more than thirty-five days from the time the public offense first comes to the attention of the law enforcement agency. The reports shall be used to generate crime statistics. The department shall submit statistics to the governor, the general assembly, and the division of criminal and juvenile justice planning of the department of human rights on a quarterly and yearly basis.

A model of cellular dosimetry for macroscopic tumors in radiopharmaceutical therapy.

PURPOSE: In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment's ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably. METHODS: Ten homogenous spheres representing tumors of different sizes were constructed in GEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, N(r): 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to Nr-1/2. From dose volume histograms the surviving fraction of cells, equivalent uniform dose (EUD), and TCP for the different scenarios were calculated. Comparably sized spherical models containing individual spherical cells (15 microm diameter) in hexagonal lattices were constructed, and Monte Carlo simulations were executed for all the same previous scenarios. The dosimetric quantities were calculated and compared to the adjusted simple sphere model results. The model was then applied to the Bortezomib-induced enzyme-targeted radiotherapy (BETR) strategy of targeting Epstein-Barr virus (EBV)-expressing cancers. RESULTS: The TCP values were comparable to within 2% between the adjusted simple sphere and full cellular models. Additionally, models were generated for a nonuniform distribution of activity, and results were compared between the adjusted spherical and cellular models with similar comparability. The TCP values from the experimental macroscopic tumor results were consistent with the experimental observations for BETR-treated 1 g EBV-expressing lymphoma tumors in mice. CONCLUSIONS: The adjusted spherical model presented here provides more accurate TCP values than simple spheres, on par with full cellular Monte Carlo simulations while maintaining the simplicity of the simple sphere model. This model provides a basis for complementing and understanding laboratory and clinical results pertaining to radiopharmaceutical therapy.