Novel regulators of prostate cancer stem cells and tumor aggressiveness

In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications.Printing of this thesis was kindly sponsored by Astellas, Sanofi-Aventis and Boehringer Ingelheim.LUMC / Geneeskund

Hardware-Software Co-Design of BIKE with HLS-Generated Accelerators

In order to mitigate the security threat of quantum computers, NIST is undertaking a process to standardize post-quantum cryptosystems, aiming to assess their security and speed up their adoption in production scenarios. Several hardware and software implementations have been proposed for each candidate, while only a few target heterogeneous platforms featuring CPUs and FPGAs. This work presents a HW/SW co-design of BIKE for embedded platforms featuring both CPUs and small FPGAs and employs high-level synthesis (HLS) to timely deliver the hardware accelerators. In contrast to state-of-the-art solutions targeting performance-optimized HLS accelerators, the proposed solution targets the small FPGAs implemented in the heterogeneous platforms for embedded systems. Compared to the software- only execution of BIKE, the experimental results collected on the systems-on-chip of the entire Xilinx Zynq-7000 family highlight a performance speedup ranging from 1.37x, on Z-7010, to 2.78x, on Z-7020

Investigation on virucidal activity of chlorine dioxide. Experimental data on Feline calicivirus, HAV and Coxsackie B5

Introduction. The aim of this study was to evaluate the efficacy of ClO2 with regard to viruses which show a particular resistance to oxidizing agent such as HAV and Norwalk and Norwalk-like viruses, and which play an important role in the epidemiology of viral foodborne diseases. In the food industry, disinfection of processing systems and equipment is a very important instrument to prevent secondary contamination and to guarantee food safety. Among disinfectants, chlorine dioxide (ClO2) presents a good efficacy at wide range of pH values, its action is rapid and generates few reaction byproducts if compared to hypoclorite. Experimental studies have highlighted that ClO2 shows a good bactericidal activity and it is also active towards viruses. Furthermore, the low concentrations and low contact times required to obtain microbial load reduction are favourable elements for the application of this compound in the industrial sanitizing practices. Methods. As it is impossible to cultivate the Norwalk virus in vitro, we tested the resistance of Feline calicivirus (F9 strain) vs. ClO2, in comparison with HAV (strain HM-175) and CoxsackieB5. Chlorine dioxide was used at concentrations ranging from 0.2 to 0.8 mg/l in water solution, at pH 7 and at +20 °C. Viral suspensions were added to disinfecting solution and, at pre-set times, were sampled to undergo to titration after blocking the disinfectant action with thiosulphate 0.05 M. On the basis of the data obtained, for each virus and in relation to different concentrations, mean reduction times were calculated for 99%, 99.9% and 99.99% using the regression analysis model. Results. As regards Feline calicivirus, at a concentration of 0.8 mg/l of ClO2, we obtained the complete elimination of the viral titre in 2 min while 30 min were required at concentrations of 0.2 mg/l. Coxackie B5 showed a similar behaviour, being completely inactivated in 4 min with 0.4 mg/l of ClO2 and after 30 min at a concentration of 0.2 mg/l. Inactivation was quicker for HAV, which was eliminated after only 30 sec at a concentration of 0.8 mg/l and after 5 min at 0.4 mg/l. Conclusion. Our data show that for complete inactivation of HAV and Feline calicivirus, concentrations ? 0.6 mg/l are required. This observation is true for Coxsackie B5 too, but this virus has shown a good sensitivity at all concentration tested according to regression analysis results. For Feline calicivirus and HAV, at low concentrations of disinfectant, prolonged contact times were needed to obtain a 99.99% reduction of viral titres (about 16 and 20 minutes respectively)

Reorganization of Active Surveillance of Acute Flaccid Paralysis (AFP) in Emilia-Romagna, Italy: a two-step Public Health intervention

BACKGROUND AND AIM OF THE WORK: The International Health Regulations Emergency Committee declared in 2014 that poliovirus circulation is a public health emergency of international concern. In 2017 and 2018 Italy was classified at intermediate risk of poliovirus reintroduction based on suboptimal poliovirus surveillance. Acute flaccid paralysis active surveillance is the gold standard in the polio eradication process. The aims of this study were to investigate the causes of reduced acute flaccid paralysis case reporting in Emilia-Romagna in the last few years (step 1) and to study a public health intervention to restore an adequate level of acute flaccid paralysis surveillance in that region (step 2). METHODS: In the first step a context analysis was performed by analysing the 2015-2017 Hospital Discharge Registers in Emilia-Romagna with the ICD-9-CM differential diagnosis codes for acute flaccid paralysis. Data from context analysis was then used to plan a new regional collaborative network of acute flaccid paralysis active surveillance. RESULTS: The active surveillance network was, at the end of the study, composed by 49 doctors from both hospital administrations and clinical wards from 4 University Hospitals and 7 Local Health Authorities throughout the Region. In 15 months, 7 acute flaccid paralysis cases have been reported; 85,7% received a full clinical and virological investigation and 83,3% completed the 60 day's follow-up. The mean response to each e-mail was 48,5% (SD 7,5%). CONCLUSIONS: In 2019, the Emilia-Romagna's active surveillance system reached the sensitivity, completeness of case investigation and follow-up required to achieve the minimum levels for certification standard surveillance

Virological surveillance of SARS-CoV-2 in an Italian northern area: Comparison of real time RT PCR cycle threshold (CT) values in three epidemic periods

Aim of the study was to investigate the differences in Ct values in nasopharingeal swabs collected in three SARS-CoV-2 epidemic periods: first one from February 23 to March 25 (14 days from lockdown started on March 11); the second one from March 26 to May 18 (14 days from the end of strict lockdown on May 4) and the third one from May 19 until June 15. Viral RNA was detected in nasopharyngeal swabs obtained both from inpatients and outpatients. COVID-19 infection was confirmed according to the Ct values for N1 and N2 genes ascertained by Real-Time RT-PCR assay as described by the CDC. We calculated the prevalence of nasopharyngeal swabs tested positive for SARS-CoV-2, the mean and median of the Cts and the percentage of samples equal or below the Ct value of 25 in the 3 periods considered. The average value of Ct increased, going from 24.80 in the first epidemic period to 26.64 in the second period to 28.50 in the third period (p <0.001). The percentage of samples with Ct lower than or equal to 25 also decreased sharply from 54.7% to 20.0%. These findings need to be integrated with epidemiological and clinical data. (www.actabiomedica.it)

From Compact Plasma Particle Sources to Advanced Accelerators with Modeling at Exascale

Developing complex, reliable advanced accelerators requires a coordinated, extensible, and comprehensive approach in modeling, from source to the end of beam lifetime. We present highlights in Exascale Computing to scale accelerator modeling software to the requirements set for contemporary science drivers. In particular, we present the first laser-plasma modeling on an exaflop supercomputer using the US DOE Exascale Computing Project WarpX. Leveraging developments for Exascale, the new DOE SCIDAC-5 Consortium for Advanced Modeling of Particle Accelerators (CAMPA) will advance numerical algorithms and accelerate community modeling codes in a cohesive manner: from beam source, over energy boost, transport, injection, storage, to application or interaction. Such start-to-end modeling will enable the exploration of hybrid accelerators, with conventional and advanced elements, as the next step for advanced accelerator modeling. Following open community standards, we seed an open ecosystem of codes that can be readily combined with each other and machine learning frameworks. These will cover ultrafast to ultraprecise modeling for future hybrid accelerator design, even enabling virtual test stands and twins of accelerators that can be used in operations.Comment: 4 pages, 3 figures, submitted to the 20th Advanced Accelerator Concepts Workshop (AAC22

The prevention of doping and the improper use of drugs and food supplements in sports and physical activities: a survey on the activity of the prevention departments of Italian local health authorities

Doping is an important public health problem widespread not only among elite athletes, but also among amateur and recreational athletes and the general population. In Italy the introduction of doping prevention within the Essential Levels of Care (LEA) with the DPCM 12/1/2017 represents a crucial step towards the implementation of education and health promotion interventions. In this context, the Departments of Prevention (DP) of the Local Health Authorities (LHA) have to play a fundamental role, becoming the cultural and operational reference on this issue. As part of the "Doping prevention: development of a permanent educational tool coordinated by the National Health Service Prevention Departments" project, funded by the Italian Ministry of Health, a survey was conducted on the activities carried out by the DP regarding doping prevention and improper use and abuse of drugs and food supplements in sports and physical activities, as a basis for the harmonization of organizational structures and prevention programs and the creation of a collaboration network at a regional and national level

CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.Oncogene advance online publication, 10 April 2017; doi:10.1038/onc.2017.87