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Summary: Cancer cells undergoing immunogenic cell death (ICD) can initiate adaptive immune responses against dead cell‐associated antigens, provided that (1) said antigens are not perfectly covered by central tolerance (antigenicity), (2) cell death occurs along with the emission of immunostimulatory cytokines and damage‐associated molecular patterns (DAMPs) that actively engage immune effector mechanisms (adjuvanticity), and (3) the microenvironment of dying cells is permissive for the initiation of adaptive immunity. Finally, ICD‐driven immune responses can only operate and exert cytotoxic effector functions if the microenvironment of target cancer cells enables immune cell infiltration and activity. Multiple forms of radiation, including non‐ionizing (ultraviolet) and ionizing radiation, elicit bona fide ICD as they increase both the antigenicity and adjuvanticity of dying cancer cells. Here, we review the molecular determinants of ICD as elicited by radiation as we critically discuss strategies to reinforce the immunogenicity of cancer cells succumbing to clinically available radiation strategies. [ABSTRACT FROM AUTHOR]

Newly formed malignant cells must escape immunosurveillance to generate progressing neoplastic lesions of clinical relevance. Recent data indicate that the immunogenicity of nascent cancer cells, at least in some settings, is dictated by inherent epigenetic mechanisms rather than by immunoediting and the consequent Darwinian selection of poorly immunogenic phenotypes. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are known for their superior tumor-initiating and tumor-repopulating potential, partly reflecting their pronounced ability to evade immune recognition. Liu and colleagues recently identified a new aldehyde dehydrogenase (ALDH)-dependent mechanism whereby triple-negative breast CSCs evade immunosurveillance upon recruitment of myeloid-derived suppressor cells. [ABSTRACT FROM AUTHOR]

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance. [ABSTRACT FROM AUTHOR]

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance. [ABSTRACT FROM AUTHOR]

Background: Evidence on the effect of maternal complications in pregnancy on wheezing in offspring is still insufficient.Methods: A pooled analysis was performed on individual participant data from fourteen European birth cohorts to assess the relationship between several maternal pregnancy complications and wheezing symptoms in the offspring.Exposures of interest included hypertension and preeclampsia, diabetes, as well as pre-pregnancy overweight (body mass index between 25 and 29.9) and obesity (body mass index ≥30) compared with normal weight (body mass index between 18.5 and 24.9). Outcomes included both ever and recurrent wheezing from birth up to 12–24 months of age.Cohort-specific crude and adjusted risk ratios (RR) were calculated using log-binomial regression models and then pooled using a random effects model.Results: The study included 85 509 subjects. Cohort-specific prevalence of ever wheezing varied from 20.0% to 47.3%, and of recurrent wheezing from 3.0% to 14.3%. Adjusted pooled RR for ever and recurrent wheezing were: 1.02 (95% CI: 0.98–1.06) and 1.20 (95% CI: 0.98–1.47) for hypertensive disorders; 1.09 (95% CI: 1.01–1.18) and 1.23 (95% CI: 1.07–1.43) for preeclampsia; 1.04 (95% CI: 0.97–1.13) and 1.24 (95% CI: 0.86–1.79) for diabetes; 1.08 (95% CI: 1.05–1.11) and 1.19 (95% CI: 1.12–1.26) for overweight; 1.12 (95% CI: 1.08–1.17) and 1.16 (95% CI: 0.97–1.39) for obesity. No heterogeneity was found in RR estimates among the cohorts, except for diabetes and recurrent wheezing (P = 0.027).Conclusions: Preeclampsia, maternal pre-pregnancy overweight and obesity are associated with an increase risk of wheezing in the offspring. [ABSTRACT FROM AUTHOR]

Simple Summary: The crucial immune stimulatory functions exerted by Type I Interferons (IFNs) in cancer settings have been not only widely demonstrated during the last fifty years but also recently harnessed for therapy. However, depending on the dose and timing, and the downstream induced signatures, Type I IFNs can and do foster cancer progression and immune evasion. Dysregulations of Type I IFN signaling cascade are more and more frequently found in the tumor microenvironment, representing critical determinants of therapeutic innate and adaptive resistance to several anticancer treatments. Understanding when and through which genetic signatures Type I IFNs control or promote cancer growth is extremely urgent in order to prevent and by-pass the deleterious clinical effects and develop optimized innovative (combinatorial) strategies for an effective cancer management. Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune"logical" way to exploit these cytokines for anticancer therapy. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs. [ABSTRACT FROM AUTHOR]

In most (if not all) solid tumors, malignant cells are outnumbered by their non-malignant counterparts, including immune, endothelial and stromal cells. However, while the mechanisms whereby cancer cells adapt to microenvironmental perturbations have been studied in great detail, relatively little is known on stress responses in non-malignant compartments of the tumor microenvironment. Here, we discuss the mechanisms whereby cancer-associated fibroblasts and other cellular components of the tumor stroma react to stress in the context of an intimate crosstalk with malignant, endothelial and immune cells, and how such crosstalk influences disease progression and response to treatment. [ABSTRACT FROM AUTHOR]

Host genetic variability contributes to susceptibility to SARS‐CoV‐2 infection and COVID‐19 evolution and the role of HLA system has not clearly emerged, suggesting the involvement of other factors. Studying response to vaccination with Spyke protein mRNA represents an ideal model to highlight whether the humoral or cellular responses are influenced by HLA. Four hundred and sixteen workers, vaccinated with Comirnaty beginning 2021, were selected within the Azienda Ospedaliera Universitaria "Città della Salute e della Scienza di Torino." The humoral response was determined with the LIAISON® kit, while the analysis of the cellular response was performed with the Quantiferon SARS‐CoV‐2 assay, for the S1 (receptor‐binding domain; Ag1) and S1 and S2 (Ag2) subunits of the Spyke protein. Six HLA loci were typed by next‐generation sequencing. Associations between HLA and vaccine response were performed with univariate and multivariate analyses. An association was found between A*03:01, B*40:02 and DPB1*06:01 and high antibody concentration and between A*24:02, B*08:01 and C*07:01 and low humoral responses. The haplotype HLA‐A*01:01 ~ B1*08:01 ~ C*07:01 ~ DRB1*03:01 ~ DQB1*02:01 conferred an increased risk of low humoral response. Considering cellular responses, 50% of the vaccinated subjects responded against Ag1 and 59% against Ag2. Carriers of DRB1*15:01 displayed a higher cellular response both to Ag1 and Ag2 compared to the rest of the cohort. Similarly, DRB1*13:02 predisposed to a robust cellular response to Ag1 and Ag2, while DRB1*11:04 showed an opposite trend. Cellular and humoral responses to Comirnaty are influenced by HLA. Humoral response is mainly associated to class I alleles, with A*03:01, previously associated to protection against severe COVID‐19, and response to vaccination, standing out. Cellular response predominantly involves class II alleles, with DRB1*15:01 and DPB1*13:01 prevailing. Affinity analysis for Spyke peptides is generally in line with the association results. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients who leave Emergency Department before physician’s visit (LWBS) or during treatment (LDT) represent a useful indicator of the emergency care's quality. The profile of patients LWBS was described: they are generally males, young, with lower urgency triage allocation and longer waiting time. They have a greater risk of ED re-admission compared to discharged patients, but effect on hospitalization and mortality are more controversial. The aims of this study are to identify determinants and adverse short term outcomes for LWBS and LDT patients. Methods: This is a retrospective cohort study that include all ED visits of LWBS, LDT and discharged patients in 2015 in the Lazio region, Central Italy. Determinants of LWBS or LDT were selected from gender, age, citizenship, residence area, triage category, chronic comorbidities, number of uncompleted ED visit in the previous year, mode of arrival in ED, time-band, day of the week, waiting time and ED crowding, using a multi-level logistic regression. A multivariate logistic regression was used to test if LWBS or LDT have a greater risk of short term adverse outcome compared to discharged patients. Results: The cohort consists in 835,440 visits in ED, 86.8% subjects visited and discharged, 8.9% subjects are LWBS patients and 4.3% LDT. LWBS and LDT patients are mainly young, males, with a less severe triage, with long waiting times in ED. Moreover, ED crowding and leaving ED before physician’s visit in the previous year are risk factors of self-discharging. LWBS and LDT patients have a higher risk of readmission (LWBS: OR = 4.63, 95%CI 4.5–4.7; OR = 2.89, 95%CI 2.8–2.9; LDT: OR = 3.12, 95%CI 3–3.2; OR = 2.25, 95%CI2.2–2.3 for readmissions within 2 and 7 days respectively) and hospitalization (LWBS: OR = 3.65, 95%CI 3.4–3.9; OR = 2.25, 95%CI 2.1–2.4; LDT: OR = 3.96, 95%CI 3.6–4.3; OR = 2.62, 95%CI 2.4–2.8 for hospitalization within 2 and 7 days respectively). Furthermore, we find a mortality excess of risk for LWBS patients compared to the reference group (OR = 2.56, 95%CI1.6–4.2; OR = 1.7, 95%CI 1.3–2.2 within 2 and 7 days respectively). Conclusions: Determinants of LWBS confirmed what already known, but LDT patients should be further investigated. There could be adverse health effects for people with LWBS and LDT behaviour. This could be an issue that the Regional Health System should deal with. [ABSTRACT FROM AUTHOR]

Background: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies.Methods: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle.Results: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively.Conclusions: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020. [ABSTRACT FROM AUTHOR]

Background: Several studies have reported an increased risk of wheezing in the children of mothers who used paracetamol during pregnancy. We evaluated to what extent this association is explained by confounding. Methods: We investigated the association between maternal paracetamol use in the first and third trimester of pregnancy and ever wheezing or recurrent wheezing/asthma in infants in the NINFEA cohort study. Risks ratios (RR) and 95% confidence intervals (CI) were estimated after adjustment for confounders, including maternal infections and antibiotic use during pregnancy. Results: The prevalence of maternal paracetamol use was 30.6% during the first and 36.7% during the third trimester of pregnancy. The prevalence of ever wheezing and recurrent wheezing/asthma was 16.9% and 5.6%, respectively. After full adjustment, the RR for ever wheezing decreased from 1.25 [1.07–1.47] to 1.10 [0.94–1.30] in the first, and from 1.26 [1.08–1.47] to 1.10 [0.93–1.29] in the third trimester. A similar pattern was observed for recurrent wheezing/asthma. Duration of maternal paracetamol use was not associated with either outcome. Further analyses on paracetamol use for three non-infectious disorders (sciatica, migraine, and headache) revealed no increased risk of wheezing in children. Conclusion: The association between maternal paracetamol use during pregnancy and infant wheezing is mainly, if not completely explained by confounding. [ABSTRACT FROM AUTHOR]

Abstract Introduction Previous analysis from the large European multicentre ESCAPE study showed an association of ambient particulate matter <2.5 μm (PM 2.5) air pollution exposure at residence with the incidence of gastric cancer. It is unclear which components of PM are most relevant for gastric and also upper aerodigestive tract (UADT) cancer and some of them may not be strongly correlated with PM mass. We evaluated the association between long-term exposure to elemental components of PM 2.5 and PM 10 and gastric and UADT cancer incidence in European adults. Methods Baseline addresses of individuals were geocoded and exposure was assessed by land-use regression models for copper (Cu), iron (Fe) and zinc (Zn) representing non-tailpipe traffic emissions; sulphur (S) indicating long-range transport; nickel (Ni) and vanadium (V) for mixed oil-burning and industry; silicon (Si) for crustal material and potassium (K) for biomass burning. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. Results Ten cohorts in six countries contributed data on 227,044 individuals with an average follow-up of 14.9 years with 633 incident cases of gastric cancer and 763 of UADT cancer. The combined hazard ratio (HR) for an increase of 200 ng/m3 of PM 2.5 _S was 1.92 (95%-confidence interval (95%-CI) 1.13;3.27) for gastric cancer, with no indication of heterogeneity between cohorts (I2 = 0%), and 1.63 (95%-CI 0.88;3.01) for PM 2.5 _Zn (I2 = 70%). For the other elements in PM 2.5 and all elements in PM 10 including PM 10 _S, non-significant HRs between 0.78 and 1.21 with mostly wide CIs were seen. No association was found between any of the elements and UADT cancer. The HR for PM 2.5 _S and gastric cancer was robust to adjustment for additional factors, including diet, and restriction to study participants with stable addresses over follow-up resulted in slightly higher effect estimates with a decrease in precision. In a two-pollutant model, the effect estimate for total PM 2.5 decreased whereas that for PM 2.5 _S was robust. Conclusion This large multicentre cohort study shows a robust association between gastric cancer and long-term exposure to PM 2.5 _S but not PM 10 _S, suggesting that S in PM 2.5 or correlated air pollutants may contribute to the risk of gastric cancer. Highlights • Population-based cohorts from 6 European countries (227,044 participants) • Copper, iron, zinc, sulphur, nickel, vanadium, silicon and potassium in PM 2.5 and PM 10 were studied. • Statistically significant strong association of gastric cancer with sulphur in PM 2.5 , but not in PM 10 • No association of gastric cancer with any of the other 7 elements tested • No association with upper aerodigestive tract cancer [ABSTRACT FROM AUTHOR]

Abstract Background Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratory and cardiovascular diseases, suggesting the involvement of common altered molecular pathways. Objectives The goal was to find intermediate metabolites or metabolic pathways that could be associated with both air pollutants and health outcomes (“meeting-in-the-middle”), thus shedding light on mechanisms and reinforcing causality. Methods We applied a statistical approach named ‘meet-in-the-middle’ to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio-cerebrovascular diseases (CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways. Results A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26, 2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentially mediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolism pathway was associated with air pollution exposure, AOA and CCVD. Conclusions Our results suggest common pathway perturbations may occur as a consequence of chronic exposure to air pollution leading to increased risk for both AOA and CCVD. Highlights • Strong association of long-term ultrafine particle exposure with adult-onset asthma • Linoleate metabolism and carnitine shuttle as “meeting-in-the-middle” pathways. • Metabolic pathways mediate the air pollution effects on health outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study evaluates associations of maternal eating disorders (bulimia nervosa, anorexia nervosa, and purging behaviors) with infant wheezing and examines the effects of eating disorders on several wheezing determinants. Method: We studied 5,150 singletons from the NINFEA birth cohort. Maternal bulimia nervosa and anorexia nervosa diagnoses were ascertained from the questionnaires completed in pregnancy and 6 months after delivery, and were analyzed as: ever diagnosis, only before pregnancy, and during pregnancy. Purging behaviors were assessed for 12 months before or during pregnancy. The associations with wheezing between 6 and 18 months of age were assessed in models adjusted for a priori selected confounders. Results: Children born to mothers with lifetime eating disorders were at an increased risk of developing wheezing (adjusted OR 1.68; [95% CI: 1.08, 2.60]), and this risk further increased when the disorders were active during pregnancy (2.52 [1.23, 5.19]). Increased risk of offspring wheezing was observed also for purging behaviors without history of eating disorder diagnosis (1.50 [1.10, 2.04]). The observed associations were not explained by comorbid depression and/or anxiety. Bulimia nervosa and/or anorexia nervosa during pregnancy were also associated with several risk factors for wheezing, including maternal smoking, adverse pregnancy outcomes, shorter breastfeeding duration, and day‐care attendance. Discussion: The associations of maternal eating disorders with offspring wheezing suggest long‐term adverse respiratory outcomes in children of mothers with eating disorders. A better understanding of mechanisms implicated is necessary to help reduce the respiratory disease burden in these children. [ABSTRACT FROM AUTHOR]

Oxidative potential (OP) of particulate matter (PM) is proposed as a biologically-relevant exposure metric for studies of air pollution and health. We aimed to evaluate the spatial variability of the OP of measured PM 2.5 using ascorbate (AA) and (reduced) glutathione (GSH), and develop land use regression (LUR) models to explain this spatial variability. We estimated annual average values (m −3 ) of OP AA and OP GSH for five areas (Basel, CH; Catalonia, ES; London-Oxford, UK (no OP GSH ); the Netherlands; and Turin, IT) using PM 2.5 filters. OP AA and OP GSH LUR models were developed using all monitoring sites, separately for each area and combined-areas. The same variables were then used in repeated sub-sampling of monitoring sites to test sensitivity of variable selection; new variables were offered where variables were excluded (p > .1). On average, measurements of OP AA and OP GSH were moderately correlated (maximum Pearson's maximum Pearson's R = = .7) with PM 2.5 and other metrics (PM 2.5 absorbance, NO 2 , Cu, Fe). HOV (hold-out validation) R 2 for OP AA models was .21, .58, .45, .53, and .13 for Basel, Catalonia, London-Oxford, the Netherlands and Turin respectively. For OP GSH , the only model achieving at least moderate performance was for the Netherlands (R 2 = .31). Combined models for OP AA and OP GSH were largely explained by study area with weak local predictors of intra-area contrasts; we therefore do not endorse them for use in epidemiologic studies. Given the moderate correlation of OP AA with other pollutants, the three reasonably performing LUR models for OP AA could be used independently of other pollutant metrics in epidemiological studies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological evidence on the association between ambient air pollution and breast cancer risk is inconsistent. OBJECTIVE: We examined the association between long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in European women. METHODS: In 15 cohorts from nine European countries, individual estimates of air pollution levels at the residence were estimated by standardized land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE) and Transport related Air Pollution and Health impacts - Integrated Methodologies for Assessing Particulate Matter (TRANSPHORM) projects: particulate matter (PM) ≤2:5 μm, ≤10 μm, and 2:5-10 μm in diameter (PM2.5, PM10, and PMcoarse, respectively); PM2.5 absorbance; nitrogen oxides (NO2 and NOx); traffic intensity; and elemental composition of PM. We estimated cohort-specific associations between breast cancer and air pollutants using Cox regression models, adjusting for major lifestyle risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. RESULTS: Of 74,750 postmenopausal women included in the study, 3,612 developed breast cancer during 991,353 person-years of follow-up. We found positive and statistically insignificant associations between breast cancer and PM2.5 {hazard ratio (HR)=1:08 [95% confidence interval (CI): 0.77, 1.51] per 5 μg = m3}, PM10 [1.07 (95% CI: 0.89, 1.30) per 10 μg = m3], PMcoarse [1.20 (95% CI: 0.96, 1.49 per 5 μg = m3], and NO2 [1.02 (95% CI: 0.98, 1.07 per 10 μg = m3], and a statistically significant association with NOx [1.04 (95% CI: 1.00, 1.08) per 20 μg = m3, p = 0:04]. CONCLUSIONS: We found suggestive evidence of an association between ambient air pollution and incidence of postmenopausal breast cancer in European women. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Large-cell neuroendocrine carcinoma (LCNC) is a rare tumour characterized by aggressive biological behaviour and poor prognosis. Due to its rarity and the lack of randomized clinical trials, the best treatment is still under debate. Some recent reports indicate that adjuvant chemotherapy (CT) may have a beneficial effect on survival. Our goal was to evaluate this finding using a large series of patients with neuroendocrine tumours obtained from the European Society of Thoracic Surgeons database. METHODS: Data for 400 patients with LCNC operated on in 14 thoracic surgery institutions worldwide between 1992 and 2014 were collected retrospectively. Overall survival was the primary endpoint; we used a multivariable Cox regression model to evaluate which clinical variables may influence patient outcomes; we also focused on the possible prognostic role of adjuvant CT. A propensity score (PS) analysis using the inverse probability of treatment weighting was also carried out. RESULTS: The 3- and 5-year survival rates were 54.1% and 45%, respectively. With the multivariable model, we found that increasing age, Eastern Cooperative Oncology Group Performance Status >2 and advanced TNM stage were indicators of poor prognosis. Weak evidence of a higher overall survival in patients receiving adjuvant CT (adjusted hazard ratio 0.73; 95% confidence interval: 0.56–0.96, P = 0.022) was observed. CONCLUSIONS: A trend towards benefit from adjuvant CT has been observed in patients with LCNC. Although surgical procedures remain the mainstay of curative options, combination with other treatments (e.g. neoadjuvant CT/radiotherapy) should be evaluated by future studies. [ABSTRACT FROM AUTHOR]

Background Tobacco smoke exposure increases the risk of cancer in the liver, but little is known about the possible risk associated with exposure to ambient air pollution. Objectives We evaluated the association between residential exposure to air pollution and primary liver cancer incidence. Methods We obtained data from four cohorts with enrolment during 1985–2005 in Denmark, Austria and Italy. Exposure to nitrogen oxides (NO 2 and NO X ), particulate matter (PM) with diameter of less than 10 µm (PM 10 ), less than 2.5 µm (PM 2.5 ), between 2.5 and 10 µm (PM 2.5–10 ) and PM 2.5 absorbance (soot) at baseline home addresses were estimated using land-use regression models from the ESCAPE project. We also investigated traffic density on the nearest road. We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and random-effects meta-analyses to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs). Results Out of 174,770 included participants, 279 liver cancer cases were diagnosed during a mean follow-up of 17 years. In each cohort, HRs above one were observed for all exposures with exception of PM 2.5 absorbance and traffic density. In the meta-analysis, all exposures were associated with elevated HRs, but none of the associations reached statistical significance. The summary HR associated with a 10-μg/m 3 increase in NO 2 was 1.10 (95% confidence interval (CI): 0.93, 1.30) and 1.34 (95% CI: 0.76, 2.35) for a 5-μg/m 3 increase in PM 2.5 . Conclusions The results provide suggestive evidence that ambient air pollution may increase the risk of liver cancer. Confidence intervals for associations with NO 2 and NO X were narrower than for the other exposures. [ABSTRACT FROM AUTHOR]

Long-term ultrafine particle (UFP) exposure estimates at a fine spatial scale are needed for epidemiological studies. Land use regression (LUR) models were developed and evaluated for six European areas based on repeated 30 min monitoring following standardized protocols. In each area; Basel (Switzerland), Heraklion (Greece), Amsterdam, Maastricht, and Utrecht ("The Netherlands"), Norwich (United Kingdom), Sabadell (Spain), and Turin (Italy), 160-240 sites were monitored to develop LUR models by supervised stepwise selection of GIS predictors. For each area and all areas combined, 10 models were developed in stratified random selections of 90% of sites. UFP prediction robustness was evaluated with the intraclass correlation coefficient (ICC) at 31-50 external sites per area. Models from Basel and The Netherlands were validated against repeated 24 h outdoor measurements. Structure and model R² of local models were similar within, but varied between areas (e.g., 38-43% Turin; 25-31% Sabadell). Robustness of predictions within areas was high (ICC 0.73- 0.98). External validation R² was 53% in Basel and 50% in The Netherlands. Combined area models were robust (ICC 0.93-1.00) and explained UFP variation almost equally well as local models. In conclusion, robust UFP LUR models could be developed on short-term monitoring, explaining around 50% of spatial variance in longer-term measurements. [ABSTRACT FROM AUTHOR]

Satellite-derived (SAT) and chemical transport model (CTM) estimates of PM 2.5 and NO 2 are increasingly used in combination with Land Use Regression (LUR) models. We aimed to compare the contribution of SAT and CTM data to the performance of LUR PM 2.5 and NO 2 models for Europe. Four sets of models, all including local traffic and land use variables, were compared (LUR without SAT or CTM, with SAT only, with CTM only, and with both SAT and CTM). LUR models were developed using two monitoring data sets: PM 2.5 and NO 2 ground level measurements from the European Study of Cohorts for Air Pollution Effects (ESCAPE) and from the European AIRBASE network. LUR PM 2.5 models including SAT and SAT+CTM explained ~60% of spatial variation in measured PM 2.5 concentrations, substantially more than the LUR model without SAT and CTM (adjR 2 : 0.33–0.38). For NO 2 CTM improved prediction modestly (adjR 2 : 0.58) compared to models without SAT and CTM (adjR 2 : 0.47–0.51). Both monitoring networks are capable of producing models explaining the spatial variance over a large study area. SAT and CTM estimates of PM 2.5 and NO 2 significantly improved the performance of high spatial resolution LUR models at the European scale for use in large epidemiological studies. [ABSTRACT FROM AUTHOR]

An increasing number of epidemiological studies suggest that adverse health effects of air pollution may be related to particulate matter (PM) composition, particularly trace metals. However, we lack comprehensive data on the spatial distribution of these elements. We measured PM 2.5 and PM 10 in twenty study areas across Europe in three seasonal two-week periods over a year using Harvard impactors and standardized protocols. In each area, we selected street (ST), urban (UB) and regional background (RB) sites (totaling 20) to characterize local spatial variability. Elemental composition was determined by energy-dispersive X-ray fluorescence analysis of all PM 2.5 and PM 10 filters. We selected a priori eight (Cu, Fe, K, Ni, S, Si, V, Zn) well-detected elements of health interest, which also roughly represented different sources including traffic, industry, ports, and wood burning. PM elemental composition varied greatly across Europe, indicating different regional influences. Average street to urban background ratios ranged from 0.90 (V) to 1.60 (Cu) for PM 2.5 and from 0.93 (V) to 2.28 (Cu) for PM 10 . Our selected PM elements were variably correlated with the main pollutants (PM 2.5 , PM 10 , PM 2.5 absorbance, NO 2 and NO x ) across Europe: in general, Cu and Fe in all size fractions were highly correlated (Pearson correlations above 0.75); Si and Zn in the coarse fractions were modestly correlated (between 0.5 and 0.75); and the remaining elements in the various size fractions had lower correlations (around 0.5 or below). This variability in correlation demonstrated the distinctly different spatial distributions of most of the elements. Variability of PM 10 _Cu and Fe was mostly due to within-study area differences (67% and 64% of overall variance, respectively) versus between-study area and exceeded that of most other traffic-related pollutants, including NO 2 and soot, signaling the importance of non-tailpipe (e.g., brake wear) emissions in PM. [ABSTRACT FROM AUTHOR]

Background: Aetiology of childhood leukaemia and childhood neoplasm is poorly understood. Information on the prevalence of risk factors in the childhood population is limited. SETIL is a population based case?control study on childhood leukaemia, conducted with two companion studies on non-Hodgkin Lymphoma (NHL) and neuroblastoma. The study relies on questionnaire interviews and 50 Hz magnetic field (ELF-MF) indoor measurements. This paper discusses the SETIL study design and includes descriptive information. Methods: The study was carried out in 14 Italian regions (78.3% of Italian population aged 0?10). It included leukaemia, NHL and neuroblastoma cases incident in 0?10 year olds in 1998?2001, registered by the Italian Association of Paediatric Haematology and Oncology (AIEOP) (accrual over 95% of estimated incidence). Two controls for each leukaemia case were randomly sampled from the Local Health Authorities rolls, matched by gender, birthdate and residence. The same controls were used in NHL and neuroblastoma studies. Parents were interviewed at home on: physical agents (ELF-MF and ionizing radiation), chemicals (smoking, solvents, traffic, insecticides), occupation, medical and personal history of children and parents, infectious diseases, immunizations and associated factors. Occupational exposure was collected using job specific modules. ELF-MF was measured in the main rooms (spot measurement) and close to child?s bed (48 hours measurement). Results: The study included: 683 leukaemia cases (87% ALL, 13% AnLL), 97 NHL, 155 neuroblastomas, and 1044 controls. ELF-MF long term measurements were obtained for 61.1% of controls and 81.6% of leukaemia cases; 8.8% of controls were exposed at over 0.1 microTesla (p,T), 3.5% and 2.1% at respectively over 0.2 and 0.3 p,T. 25% of controls? fathers had smoked over 10 cigarettes/day during the year of conception, varying according to education and region. Maternal smoking was less common (71.4% did not smoke in pregnancy). Maternal passive smoking during pregnancy was reported by 31.2% of controls; the child?s passive smoking for 28.6%. Occupational exposure to solvents was estimated in 18.3% of controls? fathers and 7.7% of mothers. Contact with public was more frequent among mothers (36.1%) than fathers (23.4%). Conclusions: SETIL represents a data source on exposure of Italian children to a broad array of potential carcinogenic factors. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated effects of air pollution on the incidence of cerebrovascular events. Objectives: We assessed the association between long-term exposure to multiple air pollutants and the incidence of stroke in European cohorts. Methods: Data from 11 cohorts were collected, and occurrence of a first stroke was evaluated. Individual air pollution exposures were predicted from land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE). The exposures were: PM2.5 [particulate matter (PM) ≤ 2.5 μm in diameter], coarse PM (PM between 2.5 and 10 μm), PM10 (PM ≤ 10 μm), PM2.5 absorbance, nitrogen oxides, and two traffic indicators. Cohort-specific analyses were conducted using Cox proportional hazards models. Random-effects meta-analysis was used for pooled effect estimation. Results: A total of 99,446 study participants were included, 3,086 of whom developed stroke. A 5-μg/m3 increase in annual PM2.5 exposure was associated with 19% increased risk of incident stroke [hazard ratio (HR) = 1.19, 95% CI: 0.88, 1.62]. Similar findings were obtained for PM10. The results were robust to adjustment for an extensive list of cardiovascular risk factors and noise coexposure. The association with PM2.5 was apparent among those ≥ 60 years of age (HR = 1.40, 95% CI: 1.05, 1.87), among never-smokers (HR = 1.74, 95% CI: 1.06, 2.88), and among participants with PM2.5 exposure < 25 μg/m3 (HR = 1.33, 95% CI: 1.01, 1.77). [ABSTRACT FROM AUTHOR]

Background: Land use regression (LUR) models have been developed mostly to explain intraurban variations in air pollution based on often small local monitoring campaigns. Transferability of LUR models from city to city has been investigated, but little is known about the performance of models based on large numbers of monitoring sites covering a large area. Objectives: We aimed to develop European and regional LUR models and to examine their transferability to areas not used for model development. Methods: We evaluated LUR models for nitrogen dioxide (NO2) and particulate matter (PM; PM2.5, PM2.5 absorbance) by combining standardized measurement data from 17 (PM) and 23 (NO2) ESCAPE (European Study of Cohorts for Air Pollution Effects) study areas across 14 European countries for PM and NO2. Models were evaluated with cross-validation (CV) and hold-out validation (HV). We investigated the transferability of the models by successively excluding each study area from model building. Results: The European model explained 56% of the concentration variability across all sites for NO2, 86% for PM2.5, and 70% for PM2.5 absorbance. The HV R2s were only slightly lower than the model R2 (NO2, 54%; PM2.5, 80%; PM2.5 absorbance, 70%). The European NO2, PM2.5, and PM2.5 absorbance models explained a median of 59%, 48%, and 70% of within-area variability in individual areas. The transferred models predicted a modest-to-large fraction of variability in areas that were excluded from model building (median R2: NO2, 59%; PM2.5, 42%; PM2.5 absorbance, 67%). Conclusions: Using a large data set from 23 European study areas, we were able to develop LUR models for NO2 and PM metrics that predicted measurements made at independent sites and areas reasonably well. This finding is useful for assessing exposure in health studies conducted in areas where no measurements were conducted. [ABSTRACT FROM AUTHOR]

This observational study evaluated SARS-CoV-2 IgG seroprevalence and related clinical, demographic, and occupational factors among workers at the largest tertiary care University-Hospital of Northwestern Italy and the University of Turin after the first pandemic wave of March–April 2020. Overall, about 10,000 individuals were tested; seropositive subjects were retested after 5 months to evaluate antibodies waning. Among 8769 hospital workers, seroprevalence was 7.6%, without significant differences related to job profile; among 1185 University workers, 3.3%. Self-reporting of COVID-19 suspected symptoms was significantly associated with positivity (Odds Ratio (OR) 2.07, 95%CI: 1.76–2.44), although 27% of seropositive subjects reported no previous symptom. At multivariable analysis, contacts at work resulted in an increased risk of 69%, or 24% for working in a COVID ward; contacts in the household evidenced the highest risk, up to more than five-fold (OR 5.31, 95%CI: 4.12–6.85). Compared to never smokers, being active smokers was inversely associated with seroprevalence (OR 0.60, 95%CI: 0.48–0.76). After 5 months, 85% of previously positive subjects still tested positive. The frequency of SARS-COV-2 infection among Health Care Workers was comparable with that observed in surveys performed in Northern Italy and Europe after the first pandemic wave. This study confirms that infection frequently occurred as asymptomatic and underlines the importance of household exposure, seroprevalence (OR 0.60, 95%CI: 0.48–0.76). [ABSTRACT FROM AUTHOR]

Simple Summary: The ATR-CHK1 axis of the DNA damage response is crucial for the survival of most colorectal cancer stem cells (CRC-SCs), but a significant fraction of primary CRC-SCs either is resistant to ATR or CHK1 inhibitors or survives the abrogation of the ATR-CHK1 cascade despite an initial response. Here, we demonstrate that the targeting of RAD51 or MRE11 improves the sensitivity of primary CRC-SCs to the CHK1/2 inhibitor prexasertib by sequentially inducing replication stress, the abrogation of cell cycle checkpoints, and the emergence of mitotic defects. This results in the induction of mitotic catastrophe and CRC-SC killing via a caspase-dependent apoptosis. Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients. [ABSTRACT FROM AUTHOR]