Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women.

Previous studies showed positive associations between milk intake and Parkinson's disease (PD) in men but not in women, but few studies were available in women. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD; cohort studies with a long follow-up are needed. We investigated associations between intake of milk and other dairy products with PD incidence in women from the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a dietary questionnaire. Hazard ratios (HR) were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We examined the impact of adjustment for premotor symptoms (constipation/depression). During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. Main analyses showed a J-shaped association between total milk intake and PD (P-non linearity = 0.045), with a significant linear positive association among drinkers (HR/1-SD = 1.09, 95% CI = 1.01-1.18, P = 0.024), that was explained in secondary analyses by a different pattern of association for plain milk (alone or with cereals) and milk added to drinks (tea/coffee/chicory). PD incidence increased significantly with plain milk consumption (HR/1-SD = 1.08 [1.02-1.14], P = 0.014). A U-shaped relation was observed for milk added to drinks (P-non linearity = 0.038), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.030) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.21], P = 0.848). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. A J-shaped association between total milk intake and PD was explained by a different pattern of association for plain milk intake and milk added to drinks. Reverse causation is unlikely to explain a positive association of plain milk with PD incidence in women. The U-shaped relation for milk added to drinks could be explained by an interaction between milk and coffee/tea/chicory. Further studies are warranted to elucidate the underlying mechanisms.

Trajectories of long-term exposure to PCB153 and Benzo[a]pyrene (BaP) air pollution and risk of breast cancer.

BACKGROUND: While genetic, hormonal, and lifestyle factors partially elucidate the incidence of breast cancer, emerging research has underscored the potential contribution of air pollution. Polychlorinated biphenyls (PCBs) and benzo[a]pyrene (BaP) are of particular concern due to endocrine-disrupting properties and their carcinogenetic effect. OBJECTIVE: To identify distinct long term trajectories of exposure to PCB153 and BaP, and estimate their associations with breast cancer risk. METHODS: We used data from the XENAIR case-control study, nested within the ongoing prospective French E3N cohort which enrolled 98,995 women aged 40-65 years in 1990-1991. Cases were incident cases of primary invasive breast cancer diagnosed from cohort entry to 2011. Controls were randomly selected by incidence density sampling, and individually matched to cases on delay since cohort entry, and date, age, department of residence, and menopausal status at cohort entry. Annual mean outdoor PCB153 and BaP concentrations at residential addresses from 1990 to 2011 were estimated using the CHIMERE chemistry-transport model. Latent class mixed models were used to identify profiles of exposure trajectories from cohort entry to the index date, and conditional logistic regression to estimate their association with the odds of breast cancer. RESULTS: 5058 cases and 5059 controls contributed to the analysis. Five profiles of trajectories of PCB153 exposure were identified. The class with the highest PCB153 concentrations had a 69% increased odds of breast cancer compared to the class with the lowest concentrations (95% CI 1.08, 2.64), after adjustment for education and matching factors. The association between identified BaP trajectories and breast cancer was weaker and suffered from large CI. CONCLUSIONS: Our results support an association between long term exposure to PCB153 and the risk of breast cancer, and encourage further studies to account for lifetime exposure to persistent organic pollutants.

Long-term exposure to air pollution at residential and workplace addresses and breast cancer risk: A case-control study nested in the French E3N-Générations cohort from 1990 to 2011.

BACKGROUND: An increasing evidence links air pollution to breast cancer (BC) risk. Yet, pollutant exposure estimates at the workplace location in pollution exposure assessment have not been considered. OBJECTIVES: This study investigates the association between particulate matters (PM2·5, PM10) and nitrogen dioxide (NO2) atmospheric concentrations (1990-2011), at the women's residential and workplace locations, and BC risk. METHODS: This case-control study of 2419 BC cases and 2984 controls, was nested in the French prospective E3N cohort. The annual mean PM2·5, PM10 and NO2 concentrations were estimated using a Land Use Regression model (50 m x 50 m resolution) and assigned to the women's geocoded residential and workplace locations, from cohort recruitment to their index date (date of case diagnosis). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using multivariate logistic regression models. RESULTS: An increased BC risk was observed for a 10 µg/m3 increase of the 1990-2011 average PM2·5 concentration estimates (OR=1·28; CI 1·00, 1·63). An increased risk was suggested for a 10 µg/m3 increase for PM10 (OR=1·09; CI 0·92, 1·30) and NO2 (OR=1·05; CI 0·97, 1·13). No effect modification by menopausal status, nor difference by hormone receptor status were observed. DISCUSSION: This study is the first to estimate BC risk and long-term air pollutant exposure from both, residential and workplace location histories. Results suggest that residential PM2·5, PM10 and NO2 concentrations are strongly correlated with workplace ones, indicating that residential data may serve as proxy for overall exposure. Future studies should consider exposure during commuting.

Multi-pollutant exposure profiles associated with breast cancer risk: A Bayesian profile regression analysis in the French E3N cohort.

BACKGROUND: Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effects of exposure to multiple air pollutants on breast cancer (BC) risk. OBJECTIVES: We aimed to assess the association between combined exposures to multiple air pollutants and breast cancer risk. METHODS: The study was based on a case-control study nested within the French E3N cohort (5222 incident BC cases/5222 matched controls). For each woman, the average of the mean annual exposure to eight pollutants (benzo(a)oyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO2), ozone, particulate matter and fine particles (PMs)) was estimated from cohort inclusion in 1990 to the index date. We used the Bayesian Profile Regression (BPR) model, which groups individuals according to their exposure and risk levels, and assigns a risk to each cluster identified. The model was adjusted on a combination of matching variables and confounders to better consider the design of the nested case-control study. Odds ratios (OR) and their 95 % credible intervals (CrI) were estimated. RESULTS: Among the 21 clusters identified, the cluster characterised by low exposures to all pollutants, except ozone, was taken as reference. A consistent increase in BC risk compared to the reference cluster was observed for 3 clusters: cluster 9 (OR=1.61; CrI=1.13,2.26), cluster 16 (OR=1.59; CrI=1.10,2.30) and cluster 15 (OR=1.38; CrI=1.00,1.88) characterised by high levels of NO2, PMs and PCB153. The other clusters showed no consistent association with BC. DISCUSSION: This is the first study assessing the effect of exposure to a mixture of eight air pollutants on BC risk, using the BPR approach. Overall, results showed evidence of a positive joint effect of exposure to high levels to most pollutants, particularly high for NO2, PMs and PCB153, on the risk of BC.

Safety and immunogenicity of a 4-component GMMA-based Shigella vaccine in healthy European adults: Stage 1 of a randomized, controlled phase I/II clinical trial.

BACKGROUND: We report data from Stage 1 of an ongoing two-staged, phase I/II randomized clinical trial (NCT05073003) with a 4-component Generalized Modules for Membrane Antigens-based vaccine against Shigella sonnei and S. flexneri 1b, 2a and 3a (altSonflex1-2-3, GSK). METHODS: 18-50-year-old Europeans (N=102) were randomized (2:1) to receive two injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at pre-specified timepoints. RESULTS: The most common solicited administration-site event (until 7 days post-each injection) and unsolicited adverse event (until 28 days post-each injection) were pain (altSonflex1-2-3: 97.1%; Placebo: 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days post-injection 1 and remained substantially higher than pre-vaccination at 3 or 6 months post-vaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (ELISA: post-injection 1: 91.0%; post-injection 2 [Day {D}113; D197]: 100%; 97.0%; serum bactericidal activity (SBA): post-injection 1: 94.4%; post-injection 2: 85.7%; 88.9%) followed by S. sonnei (ELISA: post-injection 1: 77.6%; post-injection 2: 84.6%; 78.8%; SBA: post-injection 1: 83.3%; post-injection 2: 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a. CONCLUSIONS: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population.

What is the context? Shigella bacteria cause severe and often bloody diarrhea, called shigellosis, that affects mostly young children and can be life-threatening. Shigellosis is particularly common in low- and middle-income countries due to inadequate sanitation and limited access to healthcare. Since the immune response to Shigella is serotype-specific, an ideal vaccine should include multiple Shigella serotypes to ensure broad protection. What is new? We developed a novel vaccine against Shigella that includes Shigella sonnei and three prevalent Shigella flexneri serotypes. In Stage 1 (phase I) of the study, healthy European adults received two vaccine injections given 3 or 6 months apart. We found that: The vaccine was well tolerated, and no safety signals or concerns were identified.Regardless of the interval between injections, specific antibodies were elicited against all four Shigella serotypes, with highest levels against Shigella flexneri 2a and Shigella sonnei.Functional antibody levels peaked after the first injection, remaining higher than the baseline up to 6 months. A second injection did not boost responses but restored functional antibody levels to those after the first injection. What is the impact? The vaccine can now be tested in Stage 2 (phase II) of the study in Africa, a region highly affected by shigellosis.

Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

Macronutrient composition of plant-based diets and breast cancer risk: the E3N prospective cohort study.

PURPOSE: Recent evidence suggests that plant-based diets may reduce the risk of breast cancer (BC). However, the macronutrient composition of plant-based diets and its potential impact on BC risk has not been well explored. This analysis investigated the association of macronutrient composition with BC risk across a spectrum of plant-based diet indexes using a multidimensional approach. DESIGN: This study followed 64,655 participants from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort from 1993 to 2014. Diets were evaluated using validated 208-item diet history questionnaires at baseline (1993) and follow-up (2005), to calculate adherence to the overall plant-based diet (PDI), healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI). The association of macronutrient composition with BC risk was assessed via generalized additive time-dependent Cox models across different levels of these indexes. Response surfaces were generated to visualize compositional associations at the 25th, 50th, and 75th percentile of each index (low, moderate, and high). RESULTS: A total of 3,932 incident BC cases were identified during the 21-year follow-up. There was a significant association between macronutrient composition and BC risk for hPDI, uPDI, and PDI (all P < 0.001). Akaike information criterion favored the hPDI model for characterizing the association between macronutrients and BC. BC risk was highest for individuals with a lower hPDI score who also consumed a diet containing lower protein (10%), lower carbohydrate (35%), and higher fat (55%). The lowest risk of BC was observed in those with higher hPDI scores with the lowest intake of protein (10%). At higher PDI and uPDI, diets containing higher protein (30%) and fat (45%) had the highest BC risk. CONCLUSION: These results demonstrate a complex relationship between macronutrient composition, plant-based diet quality, and BC risk. Further research is needed to examine specific foods that may be driving these associations. REGISTRY: The protocol is registered at clinicaltrials.gov as NCT03285230.

Multiple xenoestrogen air pollutants and breast cancer risk: Statistical approaches to investigate combined exposures effect.

Studies suggested that exposure to air pollutants, with endocrine disrupting (ED) properties, have a key role in breast cancer (BC) development. Although the population is exposed simultaneously to a mixture of multiple pollutants and ED pollutants may act via common biological mechanisms leading to synergic effects, epidemiological studies generally evaluate the effect of each pollutant separately. We aimed to assess the complex effect of exposure to a mixture of four xenoestrogen air pollutants (benzo-[a]-pyrene (BaP), cadmium, dioxin (2,3,7,8-Tétrachlorodibenzo-p-dioxin TCDD)), and polychlorinated biphenyl 153 (PCB153)) on the risk of BC, using three recent statistical methods, namely weighted quantile sum (WQS), quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR). The study was conducted on 5222 cases and 5222 matched controls nested within the French prospective E3N cohort initiated in 1990. Annual average exposure estimates to the pollutants were assessed using a chemistry transport model, at the participants' residence address between 1990 and 2011. We found a positive association between the WQS index of the joint effect and the risk of overall BC (adjusted odds ratio (OR) = 1.10, 95% confidence intervals (CI): 1.03-1.19). Similar results were found for QGC (OR = 1.11, 95%CI: 1.03-1.19). Despite the association did not reach statistical significance in the BKMR model, we observed an increasing trend between the joint effect of the four pollutants and the risk of BC, when fixing other chemicals at their median concentrations. BaP, cadmium and PCB153 also showed positive trends in the multi-pollutant mixture, while dioxin showed a modest inverse trend. Despite we found a clear evidence of a positive association between the joint exposure to pollutants and BC risk only from WQS and QGC regression, we observed a similar suggestive trend using BKMR. This study makes a major contribution to the understanding of the joint effects of air pollution.

Testing S. sonnei GMMA with and without Aluminium Salt-Based Adjuvants in Animal Models.

Shigellosis is one of the leading causes of diarrheal disease in low- and middle-income countries, particularly in young children, and is more often associated with antimicrobial resistance. Therefore, a preventive vaccine against shigellosis is an urgent medical need. We have proposed Generalised Modules for Membrane Antigens (GMMA) as an innovative delivery system for Shigella sonnei O-antigen, and an Alhydrogel formulation (1790GAHB) has been extensively tested in preclinical and clinical studies. Alhydrogel has been used as an adsorbent agent with the main purpose of reducing potential GMMA systemic reactogenicity. However, the immunogenicity and systemic reactogenicity of this GMMA-based vaccine formulated with or without Alhydrogel have never been compared. In this work, we investigated the potential adjuvant effect of aluminium salt-based adjuvants (Alhydrogel and AS37) on S. sonnei GMMA immunogenicity in mice and rabbits, and we found that S. sonnei GMMA alone resulted to be strongly immunogenic. The addition of neither Alhydrogel nor AS37 improved the magnitude or the functionality of vaccine-elicited antibodies. Interestingly, rabbits injected with either S. sonnei GMMA adsorbed on Alhydrogel or S. sonnei GMMA alone showed a limited and transient body temperature increase, returning to baseline values within 24 h after each vaccination. Overall, immunisation with unadsorbed GMMA did not raise any concern for animal health. We believe that these data support the clinical testing of GMMA formulated without Alhydrogel, which would allow for further simplification of GMMA-based vaccine manufacturing.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4ß7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.

Rehabilitation activities with tablet (REACT) in Parkinson's disease.

INTRODUCTION: There is evidence to demonstrate that plasticity is "use-dependent" and that intensive practice may be necessary to modify neural organization. PURPOSE: The main aim of this work is to investigate the REACT usability, an innovative app, to assist People with Parkinson Disease (PwPD) at home. METHODS: A pilot study has been conducted enrolling 20 consecutive PwPD. Before home rehabilitation activities started, each patient received training on the REACT app and how to use the device and the services in daily practice. Motor and cognitive evaluations were administered to assign personalized exercises, tailored to patients' needs and potential. PwPD carried out REACT home program for 1 month, four times a week. The app included motor exercise and tutorial of activities of daily living (ADL) and functional cognitive stimulation. REACT-app usability was evaluated with the System Usability Scale (SUS). RESULTS: The results from SUS questionnaire were, on average, above the threshold of "good usability" (SUS score > 68), as reported in the literature. The 47% of PwPD that used the app rated the usability of the solution as "excellent." Almost all SUS items reached the reference benchmark (except items 4, 5, and 7). No adverse events occurred. CONCLUSIONS: REACT can be considered a useful and safe tool to support the continuity of care and treatment at home, in PwPD. Larger-scale trials are needed to validate the good acceptance and efficacy of home rehabilitation through technology applications.

A Novel Automatic Algorithm to Support Lung Ultrasound Non-Expert Physicians in Interstitial Pneumonia Evaluation: A Single-Center Study.

INTRODUCTION: Lung ultrasound (LUS) is widely used in clinical practice for identifying interstitial lung diseases (ILDs) and assessing their progression. Although high-resolution computed tomography (HRCT) remains the gold standard for evaluating the severity of ILDs, LUS can be performed as a screening method or as a follow-up tool post-HRCT. Minimum training is needed to better identify typical lesions, and the integration of innovative artificial intelligence (AI) automatic algorithms may enhance diagnostic efficiency. AIM: This study aims to assess the effectiveness of a novel AI algorithm in automatic ILD recognition and scoring in comparison to an expert LUS sonographer. The "SensUS Lung" device, equipped with an automatic algorithm, was employed for the automatic recognition of the typical ILD patterns and to calculate an index grading of the interstitial involvement. METHODS: We selected 33 Caucasian patients in follow-up for ILDs exhibiting typical HRCT patterns (honeycombing, ground glass, fibrosis). An expert physician evaluated all patients with LUS on twelve segments (six per side). Next, blinded to the previous evaluation, an untrained operator, a non-expert in LUS, performed the exam with the SensUS device equipped with the automatic algorithm ("SensUS Lung") using the same protocol. Pulmonary functional tests (PFT) and DLCO were conducted for all patients, categorizing them as having reduced or preserved DLCO. The SensUS device indicated different grades of interstitial involvement named Lung Staging that were scored from 0 (absent) to 4 (peak), which was compared to the Lung Ultrasound Score (LUS score) by dividing it by the number of segments evaluated. Statistical analyses were done with Wilcoxon tests for paired values or Mann-Whitney for unpaired samples, and correlations were performed using Spearman analysis; p < 0.05 was considered significant. RESULTS: Lung Staging was non-inferior to LUS score in identifying the risk of ILDs (median SensUS 1 [0-2] vs. LUS 0.67 [0.25-1.54]; p = 0.84). Furthermore, the grade of interstitial pulmonary involvement detected with the SensUS device is directly related to the LUS score (r = 0.607, p = 0.002). Lung Staging values were inversely correlated with forced expiratory volume at first second (FEV1%, r = -0.40, p = 0.027), forced vital capacity (FVC%, r = -0.39, p = 0.03) and forced expiratory flow (FEF) at 25th percentile (FEF25%, r = -0.39, p = 0.02) while results directly correlated with FEF25-75% (r = 0.45, p = 0.04) and FEF75% (r = 0.43, p = 0.01). Finally, in patients with reduced DLCO, the Lung Staging was significantly higher, overlapping the LUS (reduced median 1 [1-2] vs. preserved 0 [0-1], p = 0.001), and overlapping the LUS (reduced median 18 [4-20] vs. preserved 5.5 [2-9], p = 0.035). CONCLUSIONS: Our data suggest that the considered AI automatic algorithm may assist non-expert physicians in LUS, resulting in non-inferior-to-expert LUS despite a tendency to overestimate ILD lesions. Therefore, the AI algorithm has the potential to support physicians, particularly non-expert LUS sonographers, in daily clinical practice to monitor patients with ILDs. The adopted device is user-friendly, offering a fully automatic real-time analysis. However, it needs proper training in basic skills.

Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis.

PURPOSE: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome. RESULTS: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis. CONCLUSIONS: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).

Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and mortality: EPIC cohort study in 9 European countries.

Dioxins and polychlorinated biphenyls (PCBs) are toxic, endocrine disruptors and persistent chemicals for which the main exposure source is diet due to their bioaccumulation and biomagnification in food chains. Cohort studies in the general populations have reported inconsistent associations between these chemicals in serum/plasma and mortality. Our objective was to study the association between dietary intake of 17 dioxins and 35 PCBs and all-cause, cancer-specific and cardiovascular-specific mortalities were assessed in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with European food contamination data provided by the European Food Safety Authority. We applied multivariable Cox regressions. The analysis included 451,390 adults (mean ± SD age:51.1 ± 9.7 years) with 46,627 deaths and a median follow-up of 17.4 years (IQR = 15.2-19.1). A U-shaped non-linear association with all-cause mortality for dietary intake of dioxins (Pnon-linearity<0.0001), DL-PCB (Pnon-linearity = 0.0001), and NDL-PCBs (Pnon-linearity<0.01) was observed. For example, the hazard ratios (95%Confidance interval) for all-cause mortality obtained with the spline model was equal to 1.03 (1.02-1.05) for low levels of intake to dioxins (7 pg TEQ/day), 0.93 (0.90-0.96) for moderate levels of intake (25 pg TEQ/day), while for high levels of intake (55 pg TEQ/day) it was 1.03 (0.97-1.09). Intake of dioxins, DL-PCBs and NDL-PCBs was not associated with cardiovascular mortality. There was no association between intakes of dioxins and cancer mortality, but a U-shaped association was observed for intake of DL-PCBs and intakes of NDL-PCBs and cancer mortality. The PCBs and dioxins are known to have endocrine disrupting properties which can lead to non-monotonic dose responses. These results need to be interpreted with caution and further studies are needed to better clarify the association between dietary intake of dioxins and PCB and mortality in the general population.

Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals.

Shigellosis is leading bacterial cause of diarrhea with high prevalence in children younger than 5 years in low- and middle-income countries, and increasing number of reports of Shigella cases associated to anti-microbial resistance. No vaccines against Shigella are still licensed, but different candidates based on the O-antigen portion of lipopolysaccharides are in clinic. Generalized Modules for Membrane Antigens (GMMA) have been proposed as an alternative delivery system for the O-antigen, and a 4-component vaccine candidate (altSonflex1-2-3), containing GMMA from S. sonnei and S. flexneri 1b, 2a and 3a is being tested in a phase 1/2 clinical trial, with the aim to elicit broad protection against the most prevalent Shigella serotypes. Here, the 4-component GMMA vaccine candidate has been compared to a more traditional glycoconjugate formulation for the ability to induce functional antibodies in mice and rabbits. In mice, in the absence of Alhydrogel, GMMA induce higher IgG antibodies than glycoconjugates and stronger bactericidal titers against all Shigella serotypes. In the presence of Alhydrogel, GMMA induce O-antigen specific IgG levels similar to traditional glycoconjugates, but with a broader range of IgG subclasses, resulting in stronger bactericidal activity. In rabbits, GMMA elicit higher functional antibodies than glycoconjugates against S. sonnei, and similar responses to S. flexneri 1b, 2a and 3a, independently from the presence of Alhydrogel. Different O-antigen based vaccines against Shigella are now in clinical stage and it will be of particular interest to understand how the preclinical findings in the different animal models translate in humans.

SPTBN1 Mediates the Cytoplasmic Constraint of PTTG1, Impairing Its Oncogenic Activity in Human Seminoma.

Seminoma is the most common testicular cancer. Pituitary tumor-transforming gene 1 (PTTG1) is a securin showing oncogenic activity in several tumors. We previously demonstrated that nuclear PTTG1 promotes seminoma tumor invasion through its transcriptional activity on matrix metalloproteinase 2 (MMP-2) and E-cadherin (CDH1). We wondered if specific interactors could affect its subcellular distribution. To this aim, we investigated the PTTG1 interactome in seminoma cell lines showing different PTTG1 nuclear levels correlated with invasive properties. A proteomic approach upon PTTG1 immunoprecipitation uncovered new specific securin interactors. Western blot, confocal microscopy, cytoplasmic/nuclear fractionation, sphere-forming assay, and Atlas database interrogation were performed to validate the proteomic results and to investigate the interplay between PTTG1 and newly uncovered partners. We observed that spectrin beta-chain (SPTBN1) and PTTG1 were cofactors, with SPTBN1 anchoring the securin in the cytoplasm. SPTBN1 downregulation determined PTTG1 nuclear translocation, promoting its invasive capability. Moreover, a PTTG1 deletion mutant lacking SPTBN1 binding was strongly localized in the nucleus. The Atlas database revealed that seminomas that contained higher nuclear PTTG1 levels showed significantly lower SPTBN1 levels in comparison to non-seminomas. In human seminoma specimens, we found a strong PTTG1/SPTBN1 colocalization that decreases in areas with nuclear PTTG1 distribution. Overall, these results suggest that SPTBN1, along with PTTG1, is a potential prognostic factor useful in the clinical management of seminoma.

Block of the Angiotensin Pathways Affects Flow-Volume Spirometry in Patients with SARS-CoV-2 Infection.

BACKGROUND: Angiotensin Converting Enzyme 2 (ACE2) is an endothelial cell receptor used by SARS-CoV- 2 virus to enter cells. Pulmonary function tests (PFTs), mainly spirometry, are the main diagnostic tools for most respiratory diseases. PFTs are mandatory for assessing the response to therapy. AIM: We evaluated patients after the SARS-CoV-2 infection through flow-volume spirometry that evaluates the role of drugs inhibiting the ACE2 pathway. MATERIAL AND METHODS: We evaluated 112 Caucasian patients 3-6 months after COVID-19 disease, i.e. after the date of negative molecular or antigenic nasopharyngeal swab. The series of patients showed a great variability due to a wide spectrum of age, the severity of disease manifestations, hospitalization, invasive/non-invasive ventilation, comorbidities, the presence/absence of a previous pneumological diagnosis and the variants of the virus. Patients were divided into those who were being treated with angiotensin receptor blocker (ARB) or ACE2 inhibitors (ACEi) (ARB/ACEi, group 1, 23 females and 12 males, aged 63.63 ± 10.40), and those who were not treated with these drugs (group 2, 38 females and 37 males, aged 55.12 ± 16.51). Distal airflow obstruction (DAO) was evaluate as forced expiratory flow (FEF) at 25%, 50% and 75% of total flow. RESULTS: Group 1 presented lower peripheral oxygen saturation percentage vs group 2 (96.54 ± 3.06 vs 97.30 ± 1.19%, p < 0.05). Spirometry data were worst in group1: Forced expiratory volume at first minute (FEV1) (91.20 ± 17.09 vs 97.56 ± 16.40%, p < 0.05), Forced vital capacity (94.06 ± 17.48 vs 99.13 ± 17.71%, p < 0.05), and Tiffenau Index (0.78 ± 0.12 vs 0.84 ± 0.10, p < 0.05). There was a DAO in group1. In group 1, we found also a reduction in FEF 25 (73.97 ± 27.28 vs 86.89 ± 22.44%, p < 0.05), FEF 50 (74.69 ± 33.01 vs 85.67 ± 23.74%, p < 0.05), and FEF 25-75 (74.14 ± 35.03 vs 83.92 ± 25.38%, p < 0.05) but not in FEF 75 (73.06 ± 39.37 vs 82.27 ± 43.33%, p < 0.05). DISCUSSION: In patients treated with ARB/ACEi the indexes of respiratory function were shifted towards the lower limits (albeit within normal limits). These parameters were significantly reduced compared to patients not treated with these drugs. This indicates that the COVID-19 disease is not only a pulmonary disease, but also a vascular one.