In-room test results at CNAO of an innovative PT treatments online monitor (Dose Profiler)

The use of C, He and O ions as projectiles in Particle Therapy (PT) treatments is getting more and more widespread as a consequence of their enhanced relative biological effectiveness and oxygen enhancement ratio, when compared to the protons one. The advantages related to the incoming radiation improved efficacy are requiring an accurate online monitor of the dose release spatial distribution. Such monitor is necessary to prevent unwanted damage to the tissues surrounding the tumour that can arise, for example, due to morphological changes occurred in the patient during the treatment with respect to the initial CT scan. PT treatments with ions can be monitored by detecting the secondary radiation produced by the primary beam interactions with the patient body along the path towards the target volume. Charged fragments produced in the nuclear process of projectile fragmentation can be emitted at large angles with respect to the incoming beam direction and can be detected with high efficiency in a nearly background-free environment. The Dose Profiler (DP) detector, developed within the INSIDE project, is a scintillating fibre tracker that allows an online reconstruction and backtracking of such secondary charged fragments. The construction and preliminary in-room tests performed on the DP, carried out using the 12C ions beam of the CNAO treatment centre using an anthropomorphic phantom as a target, will be reviewed in this contribution. The impact of the secondary fragments interactions with the patient body will be discussed in view of a clinical application. Furthermore, the results implications for a pre-clinical trial on CNAO patients, foreseen in 2019, will be discussed

Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases

Scintillating fiber devices for particle therapy applications

Particle Therapy (PT) is a radiation therapy technique in which solid tumors are treated with charged ions and exploits the achievable highly localized dose delivery, allowing to spare healthy tissues and organs at risk. The development of a range monitoring technique to be used on-line, during the treatment, capable to reach millimetric precision is considered one of the important steps towards an optimization of the PT efficacy and of the treatment quality. To this aim, charged secondary particles produced in the nuclear interactions between the beam particles and the patient tissues can be exploited. Besides charged secondaries, also neutrons are produced in nuclear interactions. The secondary neutron component might cause an undesired and not negligible dose deposition far away from the tumor region, enhancing the risk of secondary malignant neoplasms that can develop even years after the treatment. An accurate neutron characterization (flux, energy and emission profile) is hence needed for a better evaluation of long-term complications. In this contribution two tracker detectors, both based on scintillating fibers, are presented. The first one, named Dose Profiler (DP), is planned to be used as a beam range monitor in PT treatments with heavy ion beams, exploiting the charged secondary fragments production. The DP is currently under development within the INSIDE (Innovative Solutions for In-beam DosimEtry in hadrontherapy) project. The second one is dedicated to the measurement of the fast and ultrafast neutron component produced in PT treatments, in the framework of the MONDO (MOnitor for Neutron Dose in hadrOntherapy) project. Results of the first calibration tests performed at the Trento Protontherapy center and at CNAO (Italy) are reported, as well as simulation studies

An exact self-consistent gravitational shock wave in semiclassical gravity

We find a self-consistent pp-gravitational shock wave solution to the semiclassical Einstein equations resulting from the $1/N$ approach to the effective action. We model the renormalized matter stress-energy-momentum tensor by $N$ massless scalar fields in the Minkowski vacuum plus a classical particle. We show that quantum effects generate a milder singularity at the position of the particle than the classical solution, but the singularity does not disappear. At large distances from the particle, the quantum correction decreases slowly, as $1/\rho^2$ ($\rho$ being the distance to the particle in the shock wave plane). We argue that this large distance correction is a necessary consequence of quantum gravity.Comment: 13 pages, REVTEX, 4 PS figures. Revised version contains a derivation of the solution compatible with its distributional character. The final results, though, are the sam

Castration-induced downregulation of SPARC in stromal cells drives neuroendocrine differentiation of prostate cancer

Fatal neuroendocrine differentiation (NED) of castration-resistant prostate cancer is a recurrent mechanism of resistance to androgen deprivation therapies (ADT) and antiandrogen receptor pathway inhibitors (ARPI) in patients. The design of effective therapies for neuroendocrine prostate cancer (NEPC) is complicated by limited knowledge of the molecular mechanisms governing NED. The paucity of acquired genomic alterations and the deregulation of epigenetic and transcription factors suggest a potential contribution from the microenvironment. In this context, whether ADT/ARPI induces stromal cells to release NED-promoting molecules and the underlying molecular networks are unestablished. Here, we utilized transgenic and transplantable mouse models and coculture experiments to unveil a novel tumor-stroma cross-talk that is able to induce NED under the pressure of androgen deprivation. Castration induced upregulation of GRP78 in tumor cells, which triggers miR29-b-mediated downregulation of the matricellular protein SPARC in the nearby stroma. SPARC downregulation enabled stromal cells to release IL6, a known inducer of NED. A drug that targets GRP78 blocked NED in castrated mice. A public, human NEPC gene expression dataset showed that Hspa5 (encoding for GRP78) positively correlates with hallmarks of NED. Finally, prostate cancer specimens from patients developing local NED after ADT showed GRP78 upregulation in tumor cells and SPARC downregulation in the stroma. These results point to GRP78 as a potential therapeutic target and to SPARC downregulation in stromal cells as a potential early biomarker of tumors undergoing NED

Artificial intelligence for renal cancer: From imaging to histology and beyond

Artificial intelligence (AI) has made considerable progress within the last decade and is the subject of contemporary literature. This trend is driven by improved computational abilities and increasing amounts of complex data that allow for new approaches in analysis and interpretation. Renal cell carcinoma (RCC) has a rising incidence since most tumors are now detected at an earlier stage due to improved imaging. This creates considerable challenges as approximately 10%–17% of kidney tumors are designated as benign in histopathological evaluation; however, certain co-morbid populations (the obese and elderly) have an increased peri-interventional risk. AI offers an alternative solution by helping to optimize precision and guidance for diagnostic and therapeutic decisions. The narrative review introduced basic principles and provide a comprehensive overview of current AI techniques for RCC. Currently, AI applications can be found in any aspect of RCC management including diagnostics, perioperative care, pathology, and follow-up. Most commonly applied models include neural networks, random forest, support vector machines, and regression. However, for implementation in daily practice, health care providers need to develop a basic understanding and establish interdisciplinary collaborations in order to standardize datasets, define meaningful endpoints, and unify interpretation

Anchoring of proteins to lactic acid bacteria

The anchoring of proteins to the cell surface of lactic acid bacteria (LAB) using genetic techniques is an exciting and emerging research area that holds great promise for a wide variety of biotechnological applications. This paper reviews five different types of anchoring domains that have been explored for their efficiency in attaching hybrid proteins to the cell membrane or cell wall of LAB. The most exploited anchoring regions are those with the LPXTG box that bind the proteins in a covalent way to the cell wall. In recent years, two new modes of cell wall protein anchoring have been studied and these may provide new approaches in surface display. The important progress that is being made with cell surface display of chimaeric proteins in the areas of vaccine development and enzyme- or whole-cell immobilisation is highlighted.

Renormalization-Group Improved Effective Potential for Interacting Theories with Several Mass Scales in Curved Spacetime

The renormalization group (RG) is used in order to obtain the RG improved effective potential in curved spacetime. This potential is explicitly calculated for the Yukawa model and for scalar electrodynamics, i.e. theories with several (namely, more than one) mass scales, in a space of constant curvature. Using the $\lambda \varphi^4$-theory on a general curved spacetime as an example, we show how it is possible to find the RG improved effective Lagrangian in curved spacetime. As specific applications, we discuss the possibility of curvature induced phase transitions in the Yukawa model and the effective equations (back-reaction problem) for the $\lambda \varphi^4$-theory on a De Sitter background.Comment: 18 pages, LaTeX file, UB-ECM-PF 93/2

Stochastic semiclassical cosmological models

We consider the classical stochastic fluctuations of spacetime geometry induced by quantum fluctuations of massless non-conformal matter fields in the Early Universe. To this end, we supplement the stress-energy tensor of these fields with a stochastic part, which is computed along the lines of the Feynman-Vernon and Schwinger-Keldysh techniques; the Einstein equation is therefore upgraded to a so called Einstein-Langevin equation. We consider in some detail the conformal fluctuations of flat spacetime and the fluctuations of the scale factor in a simple cosmological modelintroduced by Hartle, which consists of a spatially flat isotropic cosmology driven by radiation and dust.Comment: 29 pages, no figures, ReVTeX fil

Algorithm Engineering in Robust Optimization

Robust optimization is a young and emerging field of research having received a considerable increase of interest over the last decade. In this paper, we argue that the the algorithm engineering methodology fits very well to the field of robust optimization and yields a rewarding new perspective on both the current state of research and open research directions. To this end we go through the algorithm engineering cycle of design and analysis of concepts, development and implementation of algorithms, and theoretical and experimental evaluation. We show that many ideas of algorithm engineering have already been applied in publications on robust optimization. Most work on robust optimization is devoted to analysis of the concepts and the development of algorithms, some papers deal with the evaluation of a particular concept in case studies, and work on comparison of concepts just starts. What is still a drawback in many papers on robustness is the missing link to include the results of the experiments again in the design