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Supplementary Data from Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

A transcriptional signature of the pan–cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors. Mol Cancer Ther; 9(5); 1265–73. ©2010 AACR.

The COVID-19 pandemic exacerbates the difficulties of psychology support in the domain of pediatric oncology, given the risks of infecting children who present a defect in their immune response. Adopting the right precautionary measures, the play-based intervention can be a powerful tool for the child, affected by oncological and onco-hematological pathologies, to understand the medical environment and counteract isolation through socialization and distraction. The present study explores quantitatively and qualitatively the experience of six psychologists that conducted play-based interventions to support children with cancer during the COVID-19 pandemic in Italy. Descriptive data about the stress levels and emotional states experienced by the psychologists will be presented. Psychologists' focus group outcomes are also discussed in the form of three thematic categories: (1) fear of infecting patients, (2) adultization of children related to precautionary behaviors, and (3) parental defense mechanisms.

to analyse the trade flow of pigs to Lombardy (Northern Italy) to single out the farms more involved in animal movements to identify the holdings and areas most exposed to the risk of introducing pathogens into the region and to plan proper mitigation measures. Indeed, the movement of live animals and of the means of transport is one of the main risk factors in the spread of diseases and this is particularly relevant in areas with high stocking density.statistical analysis on movements of pigs entering Lombardy was carried out. Data on pigs' movements and farm characteristics were collected from the National and Regional databases. Social Network Analysis (SNA) was used to analyse the flows of pigs to Lombardy, to identify the holdings and geographical areas that are central in the trading network and that could have a role in the introduction of swine pathogens into the region.data on pigs' movements introduced into Lombardy in 2016 were analysed. Lombardy is a region of Northern Italy with intensive livestock husbandry. The pig sector is of particular economic relevance also in view of the processing industry, suited to the production of high quality pork products. Annually about 1.8 million pigs are introduced into the region also to satisfy the request of the processing industry for the production of pork products.in this study, the farms that buy pigs from outside the region were identified as well as the territories where the largest number of pigs are introduced. The analysis was carried out also considering certain factors related to the movement of animals, which can be relevant for the transmission of pathogens, such as number of commercial partners, number of exchanged animals, and number of shipments.in 2016, 1,782,568 pigs were introduced into Lombardy; by using SNA, it was possible to highlight a complex trade network of pigs, mainly involving the Northern regions. Indeed, the pigs were mostly purchased from Emilia Romagna (33.4%), followed by Veneto and Piedmont. These regions have been the most closely analysed in this study. SNA was also used to identify Lombardy territories (provinces and municipalities) which, based on the number of introduced pigs, are potentially most exposed to the introduction of pathogens from outside the region. Mantua and Brescia provinces resulted the most exposed area.Italy is one of most important European producers of pigs and about 50% of national pig assets is present in Lombardy; furthermore, about 1.8 million pigs are introduced yearly into the region. Currently, the region is free from the main diseases of pigs and the introduction of an epidemic disease into the pig population could adversely affect the entire productive sector. For this reason, an analysis of the movements of pigs entering the region was carried out to identify the areas (provinces, municipalities) and holdings most exposed to the risk of introduction of pathogens. This information is relevant for the veterinary authorities to plan appropriate control activities (official controls, surveillance, biosecurity, and vaccination, where possible) in order to enhance disease prevention and promote early detection.

An accurate non-invasive evaluation of the mechanical properties of the vessel wall is important for a variety of screening protocols and surgical treatments. In this work, we focused on a section of the Pulmonary Artery (PA), and developed a patient-specific approach to estimate its stiffness in terms of the Young's modulus along the circumferential direction (E). First, we developed a patient-specific semi-automatic approach to estimate its expected value and standard deviation. To this end, pressure-length curves were derived from magnetic resonance images acquired during the cardiac cycle and information on vessel pressure obtained by catheterization. Then, the estimates of E were derived through a maximum likelihood estimation approach based on a vessel constitutive law. In particular, we analyzed the entire PA boundary and an arc free from surrounding organs. Second, we applied the approach to the study of pulmonary endarterectomy (PEA) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). We observed a decrease in the circumferential E after PEA for the whole boundary, while no clear trend was observed for the free arc. The low standard deviations associated with the estimates showed high accuracy when considering the entire boundary, while greater variability was observed for the free arc, which was however limited. Finally, reliable hysteretic behavior was obtained from the reconstructed pressure-length curves.

Variation in cancer incidence between countries and groups of countries has been well studied. However cancer incidence is linked to risk factors that may vary within countries, and may subsist in localized geographic areas. In this study we investigated between- and within-country variation in the incidence of all cancers combined for countries belonging to the Group for Cancer Epidemiology and Registration in Latin Language Countries (GRELL). We hypothesized that investigation at the micro-level (circumscribed regions and local cancer registry areas) would reveal incidence variations not evident at the macro level and allow identification of cancer incidence hotspots for research, public health, and to fight social inequalities. Data for all cancers diagnosed in 2008–2012 were extracted from Cancer Incidence in Five Continents, Vol XI. Incidence variation within a country or region was quantified as r/R, defined as the difference between the highest and lowest incidence rates for cancer registries within a country/region (r), divided by the incidence rate for the entire country/region × 100. We found that the area with the highest male incidence had an ASRw 4.3 times higher than the area with the lowest incidence. The area with the highest female incidence had an ASRw 3.3 times higher than the area with the lowest incidence. Areas with the highest male ASRws were Azores (Portugal), Florianopolis (Brazil), Metropolitan France, north Spain, Belgium, and north-west and north-east Italy. Areas with the highest female ASRws were Florianopolis (Brazil), Belgium, north-west Italy, north-east Italy, central Italy, Switzerland and Metropolitan France. Our analysis has shown that cancer incidence varies markedly across GRELL countries but also within several countries: the presence of several areas with high cancer incidence suggests the presence of area-specific risk factors that deserve further investigation.

The first events of bee decline in Italy were reported during 1999. Since then, population decline has frequently been reported in Lombardy. In this study, the association between bee decline and the type of land surrounding the apiary was evaluated. A risk map was developed to identify areas with the highest risk of decline. Apiaries in Lombardy were selected from the national beekeeping database (BDA). The study period was from 2014 to 2016. Apiaries were deemed “declined” if they reported at least one event of decline or tested positive for plant protection products, apiaries were “not declined” if they did not report any events of bee decline during the study period. Out of 14,188 apiaries extracted from the BDA, 80 were considered declined. The probability of an apiary being declined increases by 10% in orchards and by 2% in arable land for each additional km2 of land occupied by these crops. The study showed an association between bee decline and the type of territory surrounding the apiaries, and the areas at the greatest risk of decline in Lombardy were identified. This information can be used by Veterinary Services as a predictive parameter for planning prevention and control activities.

Atmospheric particulate matter (PM) has multiple adverse effects on human health, high temperatures are also associated with adverse health outcomes, and the frequency of cardiovascular events (CVEs) varies with season. We investigated a hypothesized increase in PM-related accident and emergency (A&amp, E) presentations for CVE with high temperature, warm season, days of high influenza incidence, and in people with a cancer diagnosis, using a time-stratified case-crossover study design. Outcomes were associations of A&amp, E presentation for CVE with atmospheric PM &le, 10 &mu, m (PM10), season, and air temperature. PM10 levels in the municipality of residence (exposure variable) were estimated by modeling data from local monitoring stations. Conditional logistic regression models estimated odds ratios (OR) with 95% confidence intervals (CI) for presentations in relation to supposed influencers, adjusting for confounders. Study participants were all who presented at the A&amp, E of a large hospital near Milan, Italy, for a CVE (ICD-9: 390&ndash, 459) from 1st January 2014 to 31st December 2015. There were 1349 A&amp, E presentations for CVE in 2014&ndash, 2015 and 5390 control days. Risk of A&amp, E presentation was significantly increased on hot days with OR 1.34 (95%CI 1.05&ndash, 1.71) per 10 &mu, g/m3 PM10 increment (as mean PM10 on day of presentation, and 1 and 2 days before (lags 0&ndash, 2)), and (for lag 0) in autumn (OR 1.23, 95%CI 1.09&ndash, 1.37) and winter (OR 1.18, 95%CI 1.01&ndash, 1.38). Risks were also significantly increased when PM10 was on lag 1, in people with a cancer diagnosis in the spring and summer months (1.88, 95%CI 1.05&ndash, 3.37), and on days (lags 0&ndash, 2) of high influenza incidence (OR 2.34, 95%CI 1.01&ndash, 5.43). PM10 levels exceeded the 50 &mu, g/m3 &ldquo, safe&rdquo, threshold recommended by the WHO and Italian legislation for only 3.8% of days during the warm periods of 2014&ndash, 2015. Greater risk of A&amp, E presentation for CVE in periods of high PM10 and high temperature suggests that &ldquo, thresholds for PM10 should be temperature-dependent and that the adverse effects of PM10 will increase as temperatures increase due to climate change.

ABSTRACT Background: Atmospheric particulate matter (PM) has multiple adverse effects on human health; high temperatures are also associated with adverse health outcomes; and the frequency of cardiovascular events (CVEs) varies with season. We investigated a hypothesized increase in PM-related accident and emergency (A&E) presentations for CVE with temperature, season, days of high influenza incidence, and in persons with a cancer diagnosis. Methods: This was a time-stratified case-crossover study in which patients served as their own controls on days without A&E presentation. Outcomes were associations of A&E presentation for CVE with atmospheric PM ≤10μm (PM10), season, air temperature and influenza incidence. PM10 in municipality of residence (exposure variable) were estimated by modelling data from local monitoring stations. Conditional logistic regression models estimated odds ratios (OR) with 95% confidence intervals (CI) for presentations in relation to supposed influencers, adjusting for confounders. Separate analyses were performed on persons with a cancer diagnosis. Study participants were all who presented at the A&E of a large hospital near Milan, Italy, for a CVE (ICD-9: 390-459) from 1st January 2014 to 31st December 2015. Results: There were 1349 A&E presentations for CVE in 2014-2015 and 5390 control days. Risk of A&E presentation was significantly increased (OR 1.34, 95%CI 1.05-1.71) when PM10 was high (as mean PM10 on day of presentation, and 1 and 2 days before [lags 0-2]) on hot days and (for lag 0) in autumn (OR 1.23, 95%CI 1.09-1.37) and winter (OR 1.18, 95%CI 1.01-1.38). Risks were also significantly increased when PM10 was on lag 1, in people with a cancer diagnosis in the spring and summer months (1.88, 95%CI 1.05-3.37), and on days (lags 0-2) of high influenza incidence (OR 2.34, 95%CI 1.01-5.43). Conclusions: Greater risk of A&E presentation for CVE in periods of high PM10 and high temperature suggests that “safe” thresholds for PM10 should be temperature dependent and that the adverse effects of PM10 will increase as temperatures increase due to climate change.

In 2019, the area of the European Union (EU) affected by African swine fever (ASF) expanded progressively in a southwestern direction from Baltic and eastern countries. The disease can severely affect and disrupt regional and international trade of pigs and pork products with serious socioeconomic damages to the pig industry. Lombardy is one of the most important European pig producers and the introduction of ASF into the pig population could adversely affect the entire sector. A study was carried out to identify the farms and territories in the region most at risk of ASF introduction to plan preventive measures. The pig holdings were identified through a descriptive analysis of pig movements and Social Network Analysis (SNA), while, for the identification of the most exposed municipalities, an assessment of risk factors was carried out using the ranking of summed scores attributed to the Z-score. From the analysis, it was found that 109 municipalities and 297 pig holdings of the region were potentially more at risk, and these holdings were selected for target surveillance. This information was provided to veterinary authority to target surveillance in pig farms, in order to early detect a possible incursion of ASF and prevent its spread.

The spread of electronic cigarettes (e-cigs) and of the so-called heat-not-burn (HnB), also known as heated tobacco products, presented as a less harmful alternative to traditional cigarettes, required further in-depth studies to demonstrate the real benefits or possible risks linked to this type of habit among smokers and possible new smokers. There are numerous harmful substances produced by these devices, such as metals, organic compounds, and aldehydes. The presence of formaldehyde is particularly worrying: its indoor concentration is 2.7, 1.2, and 40 µg/m3 for HnB, e-cigs, and traditional cigarettes, respectively. The evidence of this substance, which numerous epidemiological studies have already shown to be harmful to health (in particular, the International Agency for Research on Cancer classified it as a group 1 carcinogen), would lead to the need to modify the legislation with more restrictive rules on the use of these devices in public environment and in particular in the presence of more susceptible subjects, such as minors and pregnant women.

Background The role of occupational exposures in breast cancer development is still uncertain and, to our knowledge, no studies have been recently carried out in Italy to provide a comprehensive estimation of this possible risk. Methods Based on administrative data, a case-control study was carried out recruiting all incident cases of female breast cancer in the period 2002–2009, aged between 35 and 69 years, residing in Lombardy, Italy. Controls were randomly sampled from all women residing in Lombardy as of December 31, 2005. Occupational histories, including blue-collar status, were available from 1974 through record linkage with a social security pension database, and were obtained for 11,188 cases and 25,329 controls. Adjusted odds ratios (ORs) and corresponding 90% confidence intervals (CIs) were calculated using multiple unconditional logistic regression models, including terms for sectors of longest employment and for duration of employment. Multiple comparisons were accounted for according to the Benjamini–Hochberg method. Results The ORs for female breast cancer were modestly but significantly increased for employment in electrical manufacturing (OR 1.12, 90%CI 1.04–1.21), textile (OR 1.08, 90%CI 1.02–1.15), paper (OR 1.25, 90%CI 1.06–1.46) and rubber (OR 1.26, 90%CI 1.03–1.54) industries. Analysis by duration of employment within sectors showed significantly increased ORs for electrical manufacturing and rubber industries. After adjustment for multiple comparisons no estimates remained statistically significant. Conclusions Although with several limitations, our results point to a possible role of exposures in electrical manufacturing, textile, paper and rubber industries in the process leading to breast cancer. An in-dept study for the electrical manufacturing industry has been already planned. Am. J. Ind. Med. 56:1051–1062, 2013. © 2013 Wiley Periodicals, Inc.

Objectives Atmospheric fine particulate matter (PM2.5) has multiple adverse effects on human health. Global atmospheric levels of PM2.5 increased by 0.55 μg/m3/year (2.1%/year) from 1998 through 2012. There is evidence of a causal relationship between atmospheric PM2.5 and breast cancer (BC) incidence, but few studies have investigated BC mortality and atmospheric PM2.5. We investigated BC mortality in relation to atmospheric PM2.5 levels among patients living in Varese Province, northern Italy. Methods We selected female BC cases, archived in the local population-based cancer registry, diagnosed at age 50–69 years, between 2003 and 2009. The geographic coordinates of each woman9s place of residence were identified, and individual PM2.5 exposures were assessed from satellite data. Grade, stage, age at diagnosis, period of diagnosis and participation in BC screening were potential confounders. Kaplan-Meir and Nelson-Aalen methods were used to test for mortality differences in relation to PM2.5 quartiles. Multivariable Cox proportional hazards modelling estimated HRs and 95% CIs of BC death in relation to PM2.5 exposure. Results Of 2021 BC cases, 325 died during follow-up to 31 December 2013, 246 for BC. Risk of BC death was significantly higher for all three upper quartiles of PM2.5 exposure compared to the lowest, with HRs of death: 1.82 (95% CI 1.15 to 2.89), 1.73 (95% CI 1.12 to 2.67) and 1.72 (95% CI 1.08 to 2.75). Conclusions Our study indicates that the risk of BC mortality increases with PM2.5 exposure. Although additional research is required to confirm these findings, they are further evidence that PM2.5 exposure is harmful and indicate an urgent need to improve global air quality.

A global minima search weighted and non-weighted least squares algorithm has been employed for a comparative study of various possible models to describe electrical properties of high dose Al implanted 4H-SiC. A wide range of experimental data has been taken from literature to demonstrate validation of the model. It was found that a single activation energy level, a temperature dependent Hall scattering factor and a degeneracy factor equal to 4 lead to a satisfactory fitting of experimental Hall data up to an Al substitutional density of 1020cm 3 in 4H SiC.

PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887.Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity.Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated.PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.