Putative role of circulating human papillomavirus DNA in the development of primary squamous cell carcinoma of the middle rectum: A case report

Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites

First and second order optimality conditions for optimal control problems of state constrained integral equations

This paper deals with optimal control problems of integral equations, with initial-final and running state constraints. The order of a running state constraint is defined in the setting of integral dynamics, and we work here with constraints of arbitrary high orders. First and second-order necessary conditions of optimality are obtained, as well as second-order sufficient conditions

Nonparametric Information Geometry

The differential-geometric structure of the set of positive densities on a given measure space has raised the interest of many mathematicians after the discovery by C.R. Rao of the geometric meaning of the Fisher information. Most of the research is focused on parametric statistical models. In series of papers by author and coworkers a particular version of the nonparametric case has been discussed. It consists of a minimalistic structure modeled according the theory of exponential families: given a reference density other densities are represented by the centered log likelihood which is an element of an Orlicz space. This mappings give a system of charts of a Banach manifold. It has been observed that, while the construction is natural, the practical applicability is limited by the technical difficulty to deal with such a class of Banach spaces. It has been suggested recently to replace the exponential function with other functions with similar behavior but polynomial growth at infinity in order to obtain more tractable Banach spaces, e.g. Hilbert spaces. We give first a review of our theory with special emphasis on the specific issues of the infinite dimensional setting. In a second part we discuss two specific topics, differential equations and the metric connection. The position of this line of research with respect to other approaches is briefly discussed.Comment: Submitted for publication in the Proceedings od GSI2013 Aug 28-30 2013 Pari

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in somatostatin analogue naive patients with acromegaly

ABSTRACT. Objective: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4-8 weeks in somatostatin analogue-na\uefve patients with acromegaly. Design: Open, non-comparative, phase III, multicenter clinical study. Methods: Fifty-one patients (28 women, aged 19-78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if !2.5 \u3bcg/l every 8 weeks (group A, 17patients); if 2.5-5 \u3bcg/l every 6 weeks (group B, 15 patients); and if >5 \u3bcg/l every 4 weeks (group C, 19 patients). Treatment duration was 48-52 weeks. The primary objective was to control GH and IGF-I levels (GH!2.5 \u3bcg/l and IGF-I normalized for age/gender). Secondary objectives were to assessGH, IGF-I, and acid-labile subunit (ALS) decrease, improvement of clinical symptoms and quality of life (QoL). Results:GH levels normalized in 32 patients (63%), similarly in de novo and post-op patients (72% vs 50%, p=0.48); in100% of group A, in 73% of group B and in 21% of group C(p<0.0001). IGF-I levels normalized in 19 patients (37%), similarly in the de novo and post-op patients (33% vs 50%,p=0.48): in 65% of group A, 33% of group B, and in 16% of group C. Circulating GH levels decreased by 80\ub117%, IGF I levels by 44\ub127%, and ALS by 30\ub117%. Symptoms (hyperhidrosis (68.6%), swelling (68.6%), asthenia (58.8%),spine arthralgia (54.9%), and paresthesias (52.9%) and QoL(from 9.1\ub17.9 to 6.1\ub16.6) significantly improved (p<0.001).No patient withdrew from the study because of adverse events (AE). The most frequent AE was diarrhea (76.2% of patients): at study end 16 mild and 1 moderate diarrhea were recorded. Gallstones developed in 12% of patients. Conclusion: ATG 120 mg in somatostatin-na\uefve patients with acromegaly controls GH secretion in 63% and IGF-I secretion in 37% during a 48-52 week period without any difference between de novo and post-op patients. The treatment was associated with improvement in clinical symptoms and QoL and with a good, safe profile. (J. Endocrinol. Invest. 32: 202-209, 2009

Search for Neutral Q-balls in Super-Kamiokande II

A search for Q-balls induced groups of successive contained events has been carried out in Super-Kamiokande II with 541.7 days of live time. Neutral Q-balls would emit pions when colliding with nuclei, generating a signal of successive contained pion events along a track. No candidate for successive contained event groups has been found in Super-Kamiokande II, so upper limits on the possible flux of such Q-balls have been obtained.Comment: 5 pages, 5 figures, Submitted to Phys. Lett.

Evidence for a mixed mass composition at the `ankle' in the cosmic-ray spectrum

We report a first measurement for ultra-high energy cosmic rays of the correlation between the depth of shower maximum and the signal in the water Cherenkov stations of air-showers registered simultaneously by the fluorescence and the surface detectors of the Pierre Auger Observatory. Such a correlation measurement is a unique feature of a hybrid air-shower observatory with sensitivity to both the electromagnetic and muonic components. It allows an accurate determination of the spread of primary masses in the cosmic-ray flux. Up till now, constraints on the spread of primary masses have been dominated by systematic uncertainties. The present correlation measurement is not affected by systematics in the measurement of the depth of shower maximum or the signal in the water Cherenkov stations. The analysis relies on general characteristics of air showers and is thus robust also with respect to uncertainties in hadronic event generators. The observed correlation in the energy range around the `ankle' at $\lg(E/{\rm eV})=18.5-19.0$ differs significantly from expectations for pure primary cosmic-ray compositions. A light composition made up of proton and helium only is equally inconsistent with observations. The data are explained well by a mixed composition including nuclei with mass $A > 4$. Scenarios such as the proton dip model, with almost pure compositions, are thus disfavoured as the sole explanation of the ultrahigh-energy cosmic-ray flux at Earth.Comment: Published version. Added journal reference and DOI. Added Report Numbe

The exposure of the hybrid detector of the Pierre Auger Observatory

The Pierre Auger Observatory is a detector for ultra-high energy cosmic rays. It consists of a surface array to measure secondary particles at ground level and a fluorescence detector to measure the development of air showers in the atmosphere above the array. The "hybrid" detection mode combines the information from the two subsystems. We describe the determination of the hybrid exposure for events observed by the fluorescence telescopes in coincidence with at least one water-Cherenkov detector of the surface array. A detailed knowledge of the time dependence of the detection operations is crucial for an accurate evaluation of the exposure. We discuss the relevance of monitoring data collected during operations, such as the status of the fluorescence detector, background light and atmospheric conditions, that are used in both simulation and reconstruction.Comment: Paper accepted by Astroparticle Physic

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs "radio-hybrid" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluoresence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request.Comment: accepted for publication in NIM A, 13 pages, minor corrections to author list and references in v

Search for First Harmonic Modulation in the Right Ascension Distribution of Cosmic Rays Detected at the Pierre Auger Observatory

We present the results of searches for dipolar-type anisotropies in different energy ranges above $2.5\times 10^{17}$ eV with the surface detector array of the Pierre Auger Observatory, reporting on both the phase and the amplitude measurements of the first harmonic modulation in the right-ascension distribution. Upper limits on the amplitudes are obtained, which provide the most stringent bounds at present, being below 2% at 99% $C.L.$ for EeV energies. We also compare our results to those of previous experiments as well as with some theoretical expectations.Comment: 28 pages, 11 figure

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio