Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer

Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic–pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix-and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites. Moreover, uPAR activated by uPA regulates most cancer cell activities by interacting with a broad range of cell membrane receptors. These findings make uPA and uPAR not only promising diagnostic and prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure–function relationship as well as give an update on the molecules that interfere with or inhibit uPA/uPAR functions. Additionally, the possible clinical development of these compounds is discussed

. New ground-based lidar enables volcanic CO2 flux measurements

There have been substantial advances in the ability to monitor the activity of hazardous volcanoes in recent decades. However, obtaining early warning of eruptions remains challenging, because the patterns and consequences of volcanic unrests are both complex and nonlinear. Measuring volcanic gases has long been a key aspect of volcano monitoring since these mobile fluids should reach the surface long before the magma. There has been considerable progress in methods for remote and in-situ gas sensing, but measuring the flux of volcanic CO2—the most reliable gas precursor to an eruption—has remained a challenge. Here we report on the first direct quantitative measurements of the volcanic CO2 flux using a newly designed differential absorption lidar (DIAL), which were performed at the restless Campi Flegrei volcano. We show that DIAL makes it possible to remotely obtain volcanic CO2 flux time series with a high temporal resolution (tens of minutes) and accuracy (<30%). The ability of this lidar to remotely sense volcanic CO2 represents a major step forward in volcano monitoring, and will contribute improved volcanic CO2 flux inventories. Our results also demonstrate the unusually strong degassing behavior of Campi Flegrei fumaroles in the current ongoing state of unrest

Colorimetric Test for Fast Detection of SARS-CoV-2 in Nasal and Throat Swabs

Mass testing is fundamental to face the pandemic caused by the coronavirus SARS-CoV-2 discovered at the end of 2019. To this aim, it is necessary to establish reliable, fast, and cheap tools to detect viral particles in biological material so to identify the people capable of spreading the infection. We demonstrate that a colorimetric biosensor based on gold nanoparticle (AuNP) interaction induced by SARS-CoV-2 lends itself as an outstanding tool for detecting viral particles in nasal and throat swabs. The extinction spectrum of a colloidal solution of multiple viral-target gold nanoparticles-AuNPs functionalized with antibodies targeting three surface proteins of SARS-CoV-2 (spike, envelope, and membrane)-is red-shifted in few minutes when mixed with a solution containing the viral particle. The optical density of the mixed solution measured at 560 nm was compared to the threshold cycle (Ct) of a real-time PCR (gold standard for detecting the presence of viruses) finding that the colorimetric method is able to detect very low viral load with a detection limit approaching that of the real-time PCR. Since the method is sensitive to the infecting viral particle rather than to its RNA, the achievements reported here open a new perspective not only in the context of the current and possible future pandemics, but also in microbiology, as the biosensor proves itself to be a powerful though simple tool for measuring the viral particle concentration

Long term variations at Campi Flegrei (Italy) volcanic system highlighted by the monitoring of hydrothermal activity

Long time-series of chemical composition of fumaroles and of soil CO2 flux reveal that important variations in the activity of Solfatara fumarolic field, the most important hydrothermal site of Campi Flegrei, occurred in the 2000- 2008 period. A continuous increase of the CO2 concentration and a general decrease of the CH4 concentration are interpreted as the consequence of the increment of the relative amount of magmatic fluids, rich in CO2 and poor in CH4, hosted by the hydrothermal system. Contemporaneously the H2O-CO2-He-N2 gas system shows remarkable compositional variations in the samples collected after July 2000 with respect to the previous ones, indicating the progressive arrival at the surface of a magmatic component different from that involved in the 1983-84 bradyseism. The change starts in 2000 concurrently with the occurrence of relatively deep long periods seismic events which, in our interpretation, were the indicator of the opening of an easy pathway for the transfer of magmatic fluids towards the shallower, brittle domain hosting the hydrothermal system. Since 2000 this magmatic gas source is active and causes ground deformations, seismicity as well as the expansion of the area interested by diffuse soil degassing of deeply derived CO2

Inclusion of a degron reduces levelsof undesired inteins after AAV-mediated proteintrans-splicing in the retina

Split intein-mediated protein trans-splicing expands AAV transfer capacity, thus overcoming the limited AAV cargo. However, non-mammalian inteins persist as trans-splicing by-products, and this could raise safety concerns for AAV intein clinical applications. In this study, we tested the ability of several degrons to selectively decrease levels of inteins after protein trans-splicing and found that a version of E. coli dihydrofolate reductase, which we have shortened to better fit into the AAV vector, is the most effective. We show that subretinal administration of AAV intein armed with this short degron is both safe and effective in a mouse model of Stargardt disease (STGD1), which is the most common form of inherited macular degeneration in humans. This supports the use of optimized AAV intein for gene therapy of both STGD1 and other conditions that require transfer of large genes

Adverse pregnancy outcomes in women at increased risk of preterm pre-eclampsia on first-trimester combined screening.

OBJECTIVE: Uteroplacental dysfunction may not only result in pre-eclampsia (PE) but also in preterm birth (PTB), small-for-gestational-age (SGA) birth and stillbirth. The aim of this study is to evaluate the positive predictive value (PPV) of first-trimester combined PE screening for all of these placenta-mediated adverse pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Tertiary referral maternity unit. SAMPLE: A total of 13 211 singleton pregnancies. METHODS: First-trimester combined screening for preterm PE using the Fetal Medicine Foundation (FMF) algorithm. MAIN OUTCOMES MEASURES: Hypertensive disorders of pregnancy (HDP), PTB, SGA birth and stillbirth were combined to assess composite adverse and severe adverse pregnancy outcomes (CAPO and CAPO-S). The PPVs for CAPO and CAPO-S were calculated for women with a combined risk for preterm PE of ≥1 in 50 and ≥1 in 100. RESULTS: First-trimester combined screening identified 2215 women (16.8%) with a risk of ≥1 in 100 for preterm PE. The PPVs for a risk of ≥1 in 100 for CAPO and CAPO-S were 38.8% and 18.2%, respectively. The equivalent PPVs for a risk of ≥1 in 50 were 45.1% and 21.1%, respectively. CONCLUSIONS: Women identified at high risk of preterm PE are also at increased risk of other placenta-mediated adverse pregnancy outcomes, such as PTB, SGA birth and stillbirth. Women at high risk for preterm PE after first-trimester screening may benefit from a higher surveillance care pathway, with interventions to mitigate all the adverse outcomes associated with placental dysfunction

Level of carbon dioxide diffuse degassing from the ground of Vesuvio: comparison between extensive surveys and inferences on the gas source

An extensive campaign of diffuse CO2 soil flux was carried out at the cone of Vesuvio in October 2006 with two main objectives: 1) to provide an estimation of CO2 diffusely discharged through the soils in the summit area and 2) to evidence those sectors of the volcano where structural and morphological conditions could favour the gas output. The survey consisted of 502 measurements of soil CO2 flux homogenously distributed over an area of about 1.8 km2. Results of this survey were compared with those obtained during a similar campaign carried out by Frondini et al. in 2000, from which we have taken and reinterpreted a subset of data belonging to the common investigated area. Graphical statistical analysis showed three overlapping populations in both surveys, evidencing the contribution of three different sources feeding the soil CO2 degassing process. The overall CO2 emission pattern of 2006 is coherent with that observed in 2000 and suggests that a value between 120 and 140 t/day of CO2 is representative of the total CO2 discharged by diffuse degassing from the summit area of Vesuvio. The preferential exhaling area lies in the inner crater, whose contribution resulted in 45.3% of the total CO2 emission in 2006 (with 62.8 t/day) and in 57.4% (with 70.3 t/day) in 2000, although its extension is only 13% of the investigated area. This highly emissive area correlated closely with the structural discontinuities of Vesuvio cone, mainly suggesting that the NW-SE trending tectonic line is actually an active fault leaking deep gas to the bottom of the crater. The drainage action of the fault could be enhanced by the “aspiration” effect of the volcanic conduit

Prenatal prediction of adverse outcome using different charts and definitions of fetal growth restriction.

OBJECTIVE: Fetal growth assessment by ultrasound aims to identify small babies that are at higher risk of perinatal morbidity and mortality. The current study explores if the association between suboptimal fetal growth and adverse perinatal outcome varies with different definitions of fetal growth restriction and weight charts/standards. METHODS: This was a retrospective cohort study of 17261 singleton non-anomalous pregnancies from 24+0 weeks' gestation at a tertiary referral hospital. Estimated fetal weight (EFW) and Doppler indices were converted into gestational age specific centiles using a growth reference standard (Intergrowth-21) and various reference charts (Hadlock, Fetal Medicine Foundation [FMF] and Swedish). Test characteristics were assessed using definitions of FGR according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), Society of Maternal and Fetal Medicine (SMFM) and Swedish criteria. Adverse perinatal outcome was defined as perinatal death, admission to the neonatal intensive care (NICU) at term, 5' Apgar score < 7, and therapeutic cooling for neonatal encephalopathy. The association between FGR according to different definitions and adverse perinatal outcome was compared. Multivariate logistic regression was used to investigate the strength of the associations between ultrasound parameters and adverse perinatal outcome. Ultrasound parameters were also tested for correlation. RESULTS: Intergrowth-21 (IG-21), Hadlock and FMF fetal size references classified 1.47%, 3.55% and 4.5% fetuses respectively as FGR using the ISUOG definition and 2.87%, 8.82% and 10.6% fetuses respectively using the SMFM definition. The sensitivity of each of the definition/chart combinations for adverse perinatal outcome varied from 4.4% (ISUOG definition with IG-21 charts) to 13.2% (SMFM definition with FMF charts). The concomitant specificity also varied from 89.4% (SMFM definition with FMF charts) to 98.6% (ISUOG definition with IG-21 charts). ISUOG and Swedish criteria showed the highest specificity, positive predictive value, and positive likelihood ratio in detecting adverse outcomes irrespective of which fetal size reference charts/standards were used. Conversely, the SMFM definition had the highest sensitivity across all investigated growth charts. Low estimated fetal weight, elevated uterine artery mean PI, abnormal umbilical artery PI and abnormal cerebro-placental ratio were all significantly associated with adverse perinatal outcome and there was positive correlation between the covariates. Multivariate logistic regression showed that uterine artery Doppler mean PI and smallness (EFW below the 5th centile) were the only parameters to be consistently associated with adverse outcome irrespective of definitions or fetal size growth charts used. CONCLUSIONS: The prevalence of FGR is variable based on the specific definition as well as the fetal size reference chart used to diagnose FGR. Irrespective of the method of classification, the sensitivity for the identification of adverse perinatal outcome remains low. Estimated fetal weight, uterine artery and fetal Dopplers are all significant predictors of adverse perinatal outcome. As these indices are correlated to each other, a prediction algorithm is advocated to overcome the limitations of using them in isolation. This article is protected by copyright. All rights reserved

Maternal ethnicity and socioeconomic deprivation: influence on adverse pregnancy outcomes.

OBJECTIVES: To evaluate the relative importance of ethnicity and socioeconomic deprivation in determining the likelihood and the percentage of composite adverse pregnancy outcomes (CAPO) and composite of severe adverse pregnancy outcomes (CAPO-S) METHODS: This is a single centre retrospective cohort study conducted in a tertiary maternity unit. Data regarding the ethnicity and socioeconomic deprivation were collected for 13,165 singleton pregnant women routinely screened in the first trimester for preeclampsia using the Fetal Medicine Foundation combined algorithm. RESULTS: The prevalence or risk of CAPO was 16.3% for White women, 29.3% for Black women and 29.3% for South Asian women. However, half of all CAPO cases (51.7%) occurred in White women. There is a strong interaction between ethnicity and socioeconomic deprivation (as measured with indices of multiple deprivation). Both influence the prevalence of CAPO and CAPO-S, with the contribution of ethnicity being strongest. CONCLUSIONS: Black and Asian ethnicity as well as socioeconomic deprivation influence the prevalence of placentally-mediated adverse pregnancy outcomes. Despite this, most adverse pregnancy outcomes occur in White women, who represent the majority of the population and are also affected by socioeconomic deprivation. For these reasons, inclusion of socioeconomic deprivation should be considered in early pregnancy risk assessment for placentally-mediated CAPO. This article is protected by copyright. All rights reserved

Ultrasound prediction of adverse outcome and perinatal complications at diagnosis of late-onset fetal growth restriction: a cohort study

Background: Abnormal umbilical, cerebral and uterine artery Doppler findings and fetal biometry below the 3rd percentile have been proposed as risk factors for perinatal complications in late-onset fetal growth restriction (FGR). Recent evidence has allowed to reach a consensus on the clinical use of Doppler ultrasound for the monitoring and timing of delivery in early-onset FGR, however there is limited data on the relationship between abnormal Doppler and severity of the growth restriction and adverse outcome when a diagnosis of late-onset FGR is made. Objective: To evaluate the relationship between the ultrasound parameters measured at diagnosis and perinatal adverse outcome within a cohort of late-onset FGR fetuses. Methods: This is a multicentre retrospective study between 2014 and 2019 including non-anomalous singleton pregnancies complicated by late-onset FGR, which was defined either by abdominal circumference (AC), estimated fetal weight (EFW) &lt;10th percentile for the gestation or by a reduction of the longitudinal growth of the AC by over 50 percentiles compared to an ultrasound scan performed between 18 and 32 weeks of gestation. Sonographic findings at diagnosis were compared between fetuses with and without adverse outcomes including stillbirth, obstetric intervention due to intrapartum distress, neonatal acidaemia, transfer to neonatal intensive care unit (NICU) and composite adverse perinatal outcome (CAO), which was defined by either stillbirth or the combination of at least two adverse perinatal outcomes. Results: Overall, 468 cases with full biometry and umbilical, middle cerebral, and uterine artery (UtA) Doppler data were included, among whom CAO was recorded in 53 (11.3%). At logistic regression analysis, only the EFW percentile proved to be independently associated with CAO (p=0.01) and NICU admission (p&lt;0.01), while the mean UtA pulsatility index (PI) MoM &gt;95th percentile at diagnosis proved to be independently associated with obstetric intervention due to intrapartum distress (p&lt;0.01). The model including baseline pregnancy characteristics and the EFW percentile was associated with an area under the curve of 0.889, 95%CI (0.813-0.966), p&lt;0.001 for CAO. A cut-off value corresponding to the 3.95th percentile was found to better discriminate between cases with and without CAO yielding a 58.5% sensitivity [95% confidence interval (CI) (44.1-71.9)], a 69.6% specificity [95%CI (65.0-74.0)], a 19.8% positive predictive value [95%CI (13.8-26.8)], and a 92.9% negative predictive value [95%CI (89.5-95.5)]. Conclusions: Retrospective data on a large cohort of late-onset FGR fetuses shows that at diagnosis the EFW is the only sonographic parameter independently associated with the occurrence of adverse perinatal outcomes, while a mean UtA PI MoM &gt;95th percentile at diagnosis is independently associated with intrapartum distress leading to obstetric intervention. This article is protected by copyright. All rights reserved