Assessing the selectivity and efficacy of dihydroquinolinone inhibitors directly targeting the oncogene LSF

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second leading cause of cancer mortality. Despite the prevalence of HCC, there is only one FDA approved drug for the advanced disease, which extends lifespan by only 2-3 months and is associated with multiple side effects. Late SV40 Factor (LSF) has been shown to function as an oncogenic transcription factor in HCC, making it a promising protein target for HCC therapy. A library of dihydroquinolinones, termed FQIs, have been shown to inhibit LSF-DNA binding in in vitro and cellular assays. The lead compound FQI-1 causes dramatic mitotic defects in HCC cell lines, but has no or only limited growth effects on immortalized human hepatocytes or primary mouse hepatocytes. Additionally, FQI-1 has proven efficacious in in vivo HCC mouse models, with no evidence of associated toxicity. The dihydroquinolinones are promising compounds for a molecularly targeted therapy against HCC. Herein, the library of compounds was expanded and tested for potency in an aggressive HCC cell line, as well as for transactivation activity against the LSF and closely related family of transcription factors. Direct target engagement is shown for the first time with cellular thermal stability assays in HCC cell lysates. The lead compound is further shown to have a promising pharmacokinetic and tolerability profile in rats, supporting the development as a drug candidate. As a potential driver of mitosis, LSF may have a broader role in cancers beyond HCC. High-throughput screening identified hematopoietic cancer lineages as particularly sensitive to the dihydroquinolinones. As a proof-of-concept, the hematopoietic cell line U937 is shown to express high levels of LSF protein, and undergoes extensive apoptosis when treated with dihydroquinolinones or siRNA against the LSF subfamily.2019-11-03T00:00:00

An Observational Cohort Study on Delayed-Onset Infections after Mandibular Third-Molar Extractions.

OBJECTIVES: The purpose of the present study was to investigate the occurrence and clinical features of delayed-onset infections after mandibular third-molar extractions. METHOD AND MATERIALS: An observational cohort study was conducted on 179 patients undergoing mandibular third-molar extraction between January 2013 and December 2015, for a total of 217 extractions. Data were recorded at the time of extraction (T0), on suture removal seven days later (T1), and 30 days after the extraction, when patients were contacted and asked about their healing process (T2). The statistical analysis was performed with nonparametric tests. A p value lower than 0.05 was considered statistically significant. RESULTS: Eight delayed-onset infections were recorded, amounting to 3.7% of all extractions. The median time elapsing from the extraction to the delayed-onset infection was 35 days (IQR 28-40; min 24-max 49). Younger age and longer surgical procedures seemed to be more often associated with this complication. CONCLUSION: Delayed-onset infections after third-molar extractions are relatively rare postoperative complications characterized by a swelling, usually with a purulent discharge. Patients should be informed of this possibility, which might develop even several weeks after the extraction

Positioning with GNSS and 5G: Analysis of Geometric Accuracy in Urban Scenarios

GNSS positioning in urban scenarios suffers for the scarce visibility of satellites. Integration with 5G services for positioning could improve this situation. In this paper, the digital surface models (DSMs) relevant to different urban scenarios, namely residential streets and urban canyons, are simulated around one observer in northern Italy (Milano) for one day of the year chosen as an example. The time series of the number of in-view GNSS satellites, their geometry and the derived quality indexes (position dilution of precision (PDOP)) are computed and analyzed. As expected, in urban canyons, a significant number of epochs does not provide four satellites within view, and many more epochs present really mediocre PDOPs. In residential streets, the situation is always quite fair. Different geometric configurations of 5G base stations are simulated around the observer. The availability of 5G times of arrival (ToAs) and their differences (TDoAs) is hypothesized, and the integration of these observations with GNSS pseudoranges is analyzed, again in terms of the PDOPs. In residential streets, 5G availability improves the positioning. In urban canyons, the optimal configuration of 5G base stations (five base stations around the observer) completely solves the positioning problem for all the epochs of the day. Less favorable configurations (four and three base stations) improve epochs with poor PDOPs in a GNSS-only configuration. They allow the positioning of epochs with few satellites but cannot completely replace the GNSS

Influence of seismic activity on the atmospheric electric field in Lisbon (Portugal) from 1955 to 1991

In the present study, we considered the influence of seismic activity on the atmospheric electric field recorded at Portela meteorological station (Lisbon, Portugal) for the period from 1955 to 1991. To this end, an exploratory method was developed, which involved the selection of events for which the distance from the atmospheric electrical field sensor to the earthquake epicenter is smaller than the preparation radius of the event. This enabled the correlation of the atmospheric electric field variations with a quantity S, defined basically as the ratio of the earthquake preparation radius to the distance between the sensor and the event epicenter. The first results show promising perspectives, but clearly a more profound study is required, in which a careful analysis of the weather conditions and other variables, like atmospheric radon levels, must be considered

An Efficient Reliability-based Design Approach to Reduce Rockfall Risk Below a Target Threshold

Rockfalls are expected to increase due to global warming and extreme events induced by climate change. An accurate quantification of the risk is fundamental for Administrations to predispose effective risk mitigation plans. Risk value should account for all the possible events that can occur in a specific time, i.e. for a magnitude (block volume) frequency relationship. Among structural protective measures, rockfall barriers are widely selected. Despite their design method has been almost defined, even not standardized, the widely adopted safety factors approach with fixed factors does not allow obtaining a specific probability of failure. Moreover, the event magnitude-frequency relationship is not accounted. A novel time- independent reliability-based approach has been recently conceived by the Authors, allowing obtaining the design values for a specific failure probability. The method accounts for all the possible events, integrating them in time with their probability. In this way, an increase of rockfall events can been accurately considered. The obtained barrier failure probability can be used to compute the risk reduction in a given time or, conversely, to define the maximum failure probability of a barrier that could be accepted

A fixed combination of probiotics and herbal extracts attenuates intestinal barrier dysfunction from inflammatory stress in an in vitro model using Caco-2 cells.

Background: Inflammatory Bowel Diseases (IBD), are considered a growing global disease, with about ten million people being affected worldwide. Maintenance of intestinal barrier integrity is crucial for preventing IBD onset and exacerbations. Some recent patents regarding oily formulations containing probiotics (WO2010122107A1 and WO2010103374A9) and the use of probiotics for gastrointestinal complaints (US20110110905A1 and US9057112B2) exist, or are pending application. Objective: In this work, we studied the effect of a fixed combination of registered Lactobacillus reuteri and Lactobacillus acidophilus strains and herbal extracts in an in vitro inflammation experimental model. Methods: Caco-2 cell monolayer was exposed to INF-\u3b3+TNF-\u3b1 or to LPS; Trans Epithelial Electrical Resistance (TEER) and paracellular permeability were investigated. ZO-1 and occludin Tight Junctions (TJs) were also investigated by mean of immunofluorescence. Results: Pre-treatment with the fixed combination of probiotics and herbal extracts prevented the inflammation-induced TEER decrease, paracellular permeability increase and TJs translocation. Conclusions: In summary, the fixed combination of probiotics and herbal extracts investigated in this research was found to be an interesting candidate for targeting the re-establishment of intestinal barrier function in IBD conditions

SEISMO-ELECTROMAGNETIC PHENOMENA IN TECTONICALLY ACTIVE REGIONS

This work presents a research plan that aims to monitor seismo-electromagnetic signals in seismic active regions. Two effects will be considered: electromagnetic field emissions and radio broadcastings. Our study will be focused in the analysis of low magnitude earthquakes almost completely disregarded in literature. We aim to collect novel seismo-electromagnetic emission data emerging from seismic activity. We expect to address the time variation of electromagnetic properties of the crust in relation with the strain field and complement it with the development of proper models. Experimental studies based on the electrical properties of rocks will also be done aiming the understanding of pressure stimulated currents and voltages that produce detectable electromagnetic radiation and can be a cause for seismo-electromagnetic signals

Seismo-electromagnetic phenomena in the western part of the Eurasia-Nubia plate boundary

This paper presents a future research plan that aims to monitor Seismo-electromagnetic (SEM) phenomena in the western part of the Eurasia-Nubia plate boundary (WENP). This region has a significant tectonic activity [1] combined with relatively low electromagnetic noise levels and for that reason presents the possibility to perform high quality SEM measurements. Further, it is known that low-frequency [ultra (ULF), very (VLF), and low-frequencies (LF)] electromag- netic (EM) waves produce more convincing earthquake precursors (compared to higher frequencies) because of less contamination, large skin depth, and low attenuation [2]. Thus, two SEM effects will be considered: ULF electromagnetic field emissions [3], and VLF/LF radio broadcastings [4]. With respect to the ULF measurements, as a start, three ULF sensors are planned to be installed in the South of Iberian Peninsula supported by the existing networks of seismic research stations. Subsequent devel- opment of this initial plan could result in the implementation of a lager ULF monitoring network not only in the Iberian Peninsula, but also in the rest of Europe. Possible integration in the SEGMA array is now under consideration. Another perspective is to use a portable station to track seismic events. Regarding the VLF/LF radio broadcastings, a receiver is planned to be mounted in University of Évora. Radio signals from up to 10 transmitters (in these bands) of interest to study the seismic activity in the WENP region will be monitored. Actually, the radio path from the transmitter to the receiver should cross the epicentral area, therefore two possible transmitters are the ones installed in Monaco (France) and Sicily (Italy). Furthermore, the system will integrate the INFREP network and in this context it will not be restricted to WENP region. With the development of these research plans we aim to collect novel SEM data emerging from the seis- mic activity in the WENP region. We expect to address the time variations of EM properties of the crust/plate in relation with the strain field, and in space in relation with composition and temperature and stress fields. Further, the interplay between atmospheric (and solar) perturbations with crust perturbations will be monitored, to observe geomagnetic perturbations at different locations. Our study will be focused in the analyses of low magnitude earthquakes with M =< 4, these events are frequent in the WENP region, but have been almost completely disregarded in literature [5,6]. [1] J. Borges, A. J. S. Fitas, M. Bezzeghoud, and P. Teves-Costa, Tectonophysics 337, 373 (2001). [2] V. Chauhan, O.P. Singh, V. Kushwah, V. Singh, B. Singh, Journal of Geodynamics 48, 68 (2009). [3] L. Telesca, V. Lapenna, M. Macchiato, and K. Hattori, Earth and Planet. Science Lett. 268, 219 (2008)

Seismo-electromagnetic phenomena in the western part of the Eurasia-Nubia plate boundary

This paper presents a future research plan that aims to monitor Seismo-electromagnetic (SEM) phenomena in the western part of the Eurasia-Nubia plate boundary (WENP). This region has a significant tectonic activity [1] combined with relatively low electromagnetic noise levels and for that reason presents the possibility to perform high quality SEM measurements. Further, it is known that low-frequency [ultra (ULF), very (VLF), and low-frequencies (LF)] electromag- netic (EM) waves produce more convincing earthquake precursors (compared to higher frequencies) because of less contamination, large skin depth, and low attenuation [2]. Thus, two SEM effects will be considered: ULF electromagnetic field emissions [3], and VLF/LF radio broadcastings [4]. With respect to the ULF measurements, as a start, three ULF sensors are planned to be installed in the South of Iberian Peninsula supported by the existing networks of seismic research stations. Subsequent devel- opment of this initial plan could result in the implementation of a lager ULF monitoring network not only in the Iberian Peninsula, but also in the rest of Europe. Possible integration in the SEGMA array is now under consideration. Another perspective is to use a portable station to track seismic events. Regarding the VLF/LF radio broadcastings, a receiver is planned to be mounted in University of Évora. Radio signals from up to 10 transmitters (in these bands) of interest to study the seismic activity in the WENP region will be monitored. Actually, the radio path from the transmitter to the receiver should cross the epicentral area, therefore two possible transmitters are the ones installed in Monaco (France) and Sicily (Italy). Furthermore, the system will integrate the INFREP network and in this context it will not be restricted to WENP region. With the development of these research plans we aim to collect novel SEM data emerging from the seis- mic activity in the WENP region. We expect to address the time variations of EM properties of the crust/plate in relation with the strain field, and in space in relation with composition and temperature and stress fields. Further, the interplay between atmospheric (and solar) perturbations with crust perturbations will be monitored, to observe geomagnetic perturbations at different locations. Our study will be focused in the analyses of low magnitude earthquakes with M =< 4, these events are frequent in the WENP region, but have been almost completely disregarded in literature [5,6]. [1] J. Borges, A. J. S. Fitas, M. Bezzeghoud, and P. Teves-Costa, Tectonophysics 337, 373 (2001). [2] V. Chauhan, O.P. Singh, V. Kushwah, V. Singh, B. Singh, Journal of Geodynamics 48, 68 (2009). [3] L. Telesca, V. Lapenna, M. Macchiato, and K. Hattori, Earth and Planet. Science Lett. 268, 219 (2008)