AB012. Transcriptional and chromatin profiling reveals the molecular architecture and druggable vulnerabilities of thymic epithelial tumors (TETs)

Thymic epithelial tumors (TETs) have been profiled to the present moment mainly through several analyses of FFPE samples. Despite the leap forward brought by the TCGA, several questions remain still unsolved. Among these, TETs are characterized by a strong component of immune infiltrate which makes the transcriptomic analyses conducted so far scarcely interpretable to profile stromal subpopulations constitutive of the tumor. Furthermore, rarely correspondent healthy tissue is available due to the lipomatous atrophy of aged thymi. Therefore, the recent report of (I) isolation, (II) propagation (III) and characterization of human thymic epithelial cells (TECs) and their capacity to reconstitute the functional organ ex vivo and in vivo, represents a novel approach to study the biology of both healthy and neoplastic thymi. Human thymic biopsies (both healthy and neoplastic) were digested and plated on a lethally irradiated murine feeder layer. Both RNA-Seq and CUTANDTAG were performed on cultivated TECs at different passages. Cultured TECs were injected with human thymic interstitial cells into rat decellularized scaffolds and cultivated for 10–12 days. sc-RNA Seq is currently being performed on both healthy and neoplastic thymic mini-organs and their correspondent primary tissues. Here show that we successfully cultivated a cohort of 21 clonogenic TECs in vitro including adult neoplastic TECs, their non-tumoral counterpart and pediatric TECs. We show that at the transcriptome level each class of TECs clusters independently and that neoplastic TECs belong to the same cloud independently from thymoma histotype. Around 1,400 differentially expressed genes (DEGs) can be found when comparing adult neoplastic and non-neoplastic counterpart, among which around 70 are transcription factors. Importantly, we prove for the first time that clonogenic TECs derived from TETs can repopulate a decellularized rat scaffold and recreate a 3D architecture mimicking the primary tumor. This work demonstrates that this culture system allows the expansion of clonogenic TECs from both tumor samples and their non-tumoral counterpart. Those cells, when transplanted into decellularized thymi, reproduce the architecture of the primary tissue, showing that TETs contain progenitor/stem epithelial cells. We are currently characterizing TECs at the transcriptomic and epigenomic level with aim of identifying new druggable targets prior to clinical trials

Sistema Integrato Multicentrico di Indicatori. Rapporto 2005. Provincia di Potenza

The SIMI (Integrated System of Indicators multicenter) Project contributes to the development of an integrated management of informative data streams related to drug addicted persons. This report analyzes the phenomenon of addiction on the territory of Potenza province through a description of the network services that provide care and rehabilitation of those addicted. Besides the characteristics of users of local services for addictions, has been developed the analysis of the subjects reported to the prefectures for use of illegal drugs and any action taken. Standard methods of estimation were also applied to quantify the proportion of users of substances that do not relate to services and to identify certain characteristics.Il Progetto SIMI (Sistema Integrato Multicentrico di Indicatori) intende contribuire allo sviluppo di una gestione integrata e sinergica dei flussi informativi relativi ai consumatori di sostanze stupefacenti afferenti alle diverse amministrazioni dello Stato. In linea con quanto proposto dall\u27Osservatorio europeo di Lisbona, per la descrizione e analisi del fenomeno connesso all\u27uso/abuso di sostanze, risulta di fondamentale importanza la possibilit? di ottenere informazioni esaustive e comparabili sulle persone che usano e/o abusano di sostanze psicotrope. Il presente rapporto analizza il fenomeno delle dipendenze sul territorio della provincia di Potenza attraverso la descrizione della rete dei servizi preposti alla cura e riabilitazione dei soggetti tossicodipendenti. Accanto alle caratteristiche degli utenti dei servizi territoriali per le dipendenze, ? stata sviluppata l\u27analisi dei soggetti segnalati alle Prefetture per uso di sostanze illegali e degli eventuali provvedimenti adottati. Sono state inoltre applicate metodologie standard di stima per quantificare la quota parte di utilizzatori di sostanze che non afferiscono ai servizi e per identificarne alcune caratteristiche

INAF Raggruppamento Scientifico Nazionale 5 - Forum delle Tecnologie 2022

Il CSN5, rispondendo alle esigenze di creare maggiori occasioni di dialogo e di networking e di mettere a fattor comune le esperienze maturate in settori strategici del nostro Ente, ha organizzato il primo “Forum della Ricerca Sperimentale e Tecnologica INAF” che si è svolto presso l’area di ricerca di Bologna nei giorni 22, 23 e 24 giugno 2022. L'evento aveva diversi obiettivi: - incrementare la reciproca conoscenza delle attività tecnologiche condotte nelle diverse strutture INAF; - favorire discussioni, scambi, sinergie; - promuovere il senso di appartenenza alla comunità INAF; - introdurre e coinvolgere il personale assunto negli ultimi anni, che non dispone di una visione di insieme di tutte le attività svolte dall’INAF; - stimolare le collaborazioni, anche al di fuori dei rapporti già esistenti; - far emergere eventuali problematiche, discuterne insieme ed individuare possibili soluzioni; - in generale, migliorare la capacità dell’Ente nel realizzare strumentazione sempre più sofisticata e complessa

European achievements in soil remediation and brownfield redevelopment

With the aim of sharing best practices of soil restoration and management of contaminated sites among European countries and to raise awareness of the enormous efforts made to succeed in such difficult commitment, the experts of the EIONET Soil working group on contaminated sites and brownfields agreed to gather their country's interesting cases and successful stories of recovery of contaminated areas. This second edition of the monograph presents seventeen new cases from eight European countries and its Regions of how polluted sites and brownfields have been remediated like new methodologies of sustainable restoration of the subsoil, development of innovative technologies, and funding mechanisms etc. These stories have been compiled to present what national, regional or local governments are doing to improve the quality of the environment and the living conditions of their population. A second aim is the promotion of best practices among industry, consultancies and business operators.JRC.D.3-Land Resource

Cohort profile: the Turin prostate cancer prognostication (TPCP) cohort

IntroductionProstate cancer (PCa) is the most frequent tumor among men in Europe and has both indolent and aggressive forms. There are several treatment options, the choice of which depends on multiple factors. To further improve current prognostication models, we established the Turin Prostate Cancer Prognostication (TPCP) cohort, an Italian retrospective biopsy cohort of patients with PCa and long-term follow-up. This work presents this new cohort with its main characteristics and the distributions of some of its core variables, along with its potential contributions to PCa research.MethodsThe TPCP cohort includes consecutive non-metastatic patients with first positive biopsy for PCa performed between 2008 and 2013 at the main hospital in Turin, Italy. The follow-up ended on December 31st 2021. The primary outcome is the occurrence of metastasis; death from PCa and overall mortality are the secondary outcomes. In addition to numerous clinical variables, the study’s prognostic variables include histopathologic information assigned by a centralized uropathology review using a digital pathology software system specialized for the study of PCa, tumor DNA methylation in candidate genes, and features extracted from digitized slide images via Deep Neural Networks.ResultsThe cohort includes 891 patients followed-up for a median time of 10 years. During this period, 97 patients had progression to metastatic disease and 301 died; of these, 56 died from PCa. In total, 65.3% of the cohort has a Gleason score less than or equal to 3 + 4, and 44.5% has a clinical stage cT1. Consistent with previous studies, age and clinical stage at diagnosis are important prognostic factors: the crude cumulative incidence of metastatic disease during the 14-years of follow-up increases from 9.1% among patients younger than 64 to 16.2% for patients in the age group of 75-84, and from 6.1% for cT1 stage to 27.9% in cT3 stage.DiscussionThis study stands to be an important resource for updating existing prognostic models for PCa on an Italian cohort. In addition, the integrated collection of multi-modal data will allow development and/or validation of new models including new histopathological, digital, and molecular markers, with the goal of better directing clinical decisions to manage patients with PCa

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

One-trocar-assisted nephrectomy (OTAN): Initial experience and codification of a technique

Background Laparoscopic nephrectomy in children has gradually become a reasonable alternative to open nephrectomy and, besides, a retroperitoneal approach seems more logical than transperitoneal approach to perform nephroureterectomy for benign disease, as in open surgery. To further reduce the access-related complications, we propose a retroperitoneal one trocar-assisted nephrectomy (OTAN). We report our experience with minimally invasive OTAN for the treatment of benign renal disease. Methods A total of 27 OTANs were performed at our institution between 2003 and 2009. The median patient age was 7.6 (range, 2-32 months). Indications for unilateral nephrectomy were multicystic dysplastic kidney (MCDK) in 23 cases (85.2%), dysplastic kidney in 3 cases (11.1%), and reflux nephropathy in 1 case (3.7%). Results The median operative time from the initial incision to skin closure was 60 min. Perioperative transfusion was not required in any cases. No major perioperative complications developed. Conversion to open surgery was necessary in four cases (14.8%): in three cases for a small working space arising from a peritoneal perforation, and in one case for a difficult visualization of the parenchyma (renal fusion not detected by preoperative ultrasound evaluation). Most patients were allowed oral intake on postoperative day 1. The median hospital stay was 2 (range, 2-3) days; the cosmetic results were excellent. Convalescence was uneventful in all patients. Conclusions Although the indications for a nephrectomy in case of benign disease remain limited, when a little child has small, poorly functioning kidneys that must be removed, a one trocar-assisted approach for nephrectomy is usefully a safe and effective treatment choice. The procedure can be easily performed through a small incision with minimal morbidity, comparable operative time, and excellent cosmesis without excessive postoperative pain issues, allowing early discharge home. © Springer Science+Business Media, LLC 2011

A muscle cell line from dystrophic mice expressing an altered phenotype in vitro

The isolation and characterization of a myogenic cell line from C57BL/6J/dydy mice is described. This line (DyA4) maintains the morphological, biochemical and electrophysiological characteristics of the primary cultured cells, at least for 20 passages. The cells actively divide as long as they are subcultured in media supplemented with horse serum and embryo extract. If the cells are not subcultured for a few days, they fuse into multinucleated contracting myotubes, which readily synthesize specific muscle products such as acetylcholinesterase and acetylcholine receptor. This dystrophic cell line expresses in vitro the same altered phenotype that is characteristic of dystrophic muscle cells in primary cultures, namely reduced acetylcholine sensitivity and reduced acetylcholine receptor expression. Because they can be grown in large amounts, and represent a pure muscle cell population which express an altered phenotype in an in vitro aneural avascular environment, DyA4 cells provide a very useful model system for investigating the pathogenesis of murine muscular dystrophy