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 (
) and E-cadherin (
). 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.
Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another.
The aim of ...this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea.
In the European Prospective Investigation into Cancer and Nutrition (EPIC)–InterAct case–cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992–2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D.
Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was −12.0 (95% CI: −20.0, −5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or −11.0 (95% CI: −20.0, −2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly.
These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations.
Generalized modules for membrane antigens (GMMA) represent a technology particularly attractive for designing affordable vaccines against Gram-negative bacteria. We explored such technology for the ...development of O-antigen-based vaccines against Shigella and nontyphoidal Salmonella. Adsorption of GMMA on Alhydrogel was required for abrogation of pyrogenicity in rabbits, and Shigella sonnei GMMA on Alhydrogel was well tolerated and immunogenic in humans. Quantification of key antigens in formulated vaccines was fundamental for release and to check stability overtime. Traditionally, the direct quantification of antigens adsorbed on aluminum salts has been challenging, and the quantification of each active ingredient in multicomponent formulated vaccines has been even more complicated. To directly quantify each active ingredient and unbound drug substances in formulated vaccines, we developed the Formulated Alhydrogel competitive ELISA (FAcE) and the competitive ELISA method, respectively. The methods were both fully characterized, assessing specificity, repeatability, intermediate precision, and accuracy, for S. sonnei OAg quantification, both in a single component or multicomponent GMMA formulation also containing S. flexneri GMMA. The developed immunological methods allowed us to fully characterize Shigella GMMA drug products, supporting their preclinical and clinical development. The same methods, already extended to GMMA from nontyphoidal Salmonella and Neisseria meningitidis, could be potentially extended to any antigen formulated on Alhydrogel.
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
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
GMMA immunogenicity in mice and rabbits, and we found that
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
GMMA adsorbed on Alhydrogel or
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.
Landscapes have been drastically transformed by human activities, generally resulting in the loss of semi-natural habitat. In the United Kingdom, wildlife habitat mainly consists of small patches of ...semi-natural habitat that are poorly connected to each other. In May 2019 the United Kingdom Government published an outcome indicator framework for measuring progress against the goals and outcomes of the 25 Year Environment Plan (YEP) for England. The indicator of the Quantity, Quality and Connectivity of Habitats (D1) is one of seven indicators within the Wildlife theme and it follows the principle of making areas of semi-natural habitat “more, bigger, better and joined up.” In this study, we describe the process of co-designing the connectivity metric for indicator D1. In consultation with experts and stakeholders we selected three candidate landscape connectivity metrics to produce the indicator. The first metric comes from a suite of rules of thumb for practitioners and it is the proportion of habitat patches in the landscape that have a nearest neighbor ≤ 1 km away. The second metric is a habitat fragmentation index from the Natural England National Biodiversity Climate Change Vulnerability Assessment Tool (NBCCVAT). The third and final metric is from the software Condatis and it represents the ability of a species to move through a landscape. We tested each metric on a set of simulated landscapes representing different levels of habitat addition strategies and different spatial configurations. We asked if the metrics are able to detect changes in the connectivity of each of these landscapes after habitat addition. Two of the three metrics (NBCCVAT and Condatis) performed well and were sensitive to change. They both increased as the total extent of habitat increased and each showed particular sensitivity to one spatial arrangement over the other. Given these results, one or both of these metrics could be used to produce the indicator. We discuss the implications of using one or both of the metrics and highlight the fundamental choices that need to be made to produce the indicator.
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices ...to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI < 18.5 kg/m
) or obese (BMI ≥ 30 kg/m
) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
•It is essential to identify the chemical mixtures to which the population is exposed through the diet.•The sparse non-negative matrix under-approximation (SNMU) was applied to dietary exposure data ...from 74522 women in France.•Overall, 8 dietary chemical mixtures, which explained 83% of the total variance, were identified.•This study is the largest ever conducted to identify dietary exposure to chemical mixtures.
Due to the large number of chemical food contaminants, consumers are exposed simultaneously to a wide range of chemicals which can interact and have a negative impact on health. Nevertheless, due to the multitude of possible chemical combinations it is unrealistic to test all combined toxicological effects. It is therefore essential to identify the most relevant mixtures to which the population is exposed through the diet and investigate their impact on heath.
The present study aims to identify and describe the main chemical mixtures to which women enrolled in the E3N study, a large French prospective cohort, are chronically exposed through the diet.
74522 women who had answered a validated semi-quantitative food frequency questionnaire in 1993, were included in the present study. Dietary exposure to chemical contaminates was estimated based on the food contamination measured in 186 core food in France collected between 2007 and 2009 by the French agency for food, environment and occupational health, and safety (ANSES) in the framework of the second French total diet study (2TDS). The sparse non-negative matrix under-approximation (SNMU) was used to identify mixtures of chemical substances. A k-means clustering classification of the whole study population was then performed to define clusters with similar co-exposure profiles.
Overall, 8 mixtures which explained 83% of the total variance, were retained. The first mixture, entitled “Minerals, inorganic contaminants, and furans”, explained the highest proportion of the total variance (38%), and was correlated in particular with the consumption of “Offal” (rho = 0.22), “Vegetables except roots” (rho = 0.20), and “Eggs” (rho = 0.19). The other seven mixtures explained between 17% and 1% of the variance. Finally, 5 clusters were identified based on the adherence to the 8 mixtures.
This study, being the largest ever conducted to identify dietary exposure to chemical mixtures, represents a concrete attempt to prioritize mixtures for which it is essential to investigate combined health effects based on exposure.
Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer.
...Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis.
A positive association was found between ovarian cancer and intake of industrial
elaidic acid HR comparing fifth with first quintile
= 1.29; 95% confidence interval (CI) = 1.03-1.62;
= 0.02, q-value = 0.06. Dietary intakes of
-6 linoleic acid (HR
= 1.10; 95% CI = 1.01-1.21;
= 0.03) and
-3 α-linolenic acid (HR
= 1.18; 95% CI = 1.05-1.34;
= 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertile
= 1.39; 95% CI = 0.99-1.94;
= 0.06) and α-linolenic acids (OR
= 1.30; 95% CI = 0.98-1.72;
= 0.06).
Our results suggest that higher intakes and circulating levels of industrial
elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer.
If causal, eliminating industrial
-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.
Applications for fluoropolymers and PFOA include surface coatings for stain, oil, and water resistance on household products, carpets, textiles, and food packaging; personal care products; seals; ...coatings for cables and wires; and construction materials. Since the previous classification of PFOA (as “possibly carcinogenic to humans”, Group 2B) by the IARC Monographs in 2014,2 many new studies have investigated the association between exposure to PFOA and cancer in experimental animals and humans, as well as mechanistic endpoints relevant to the key characteristics of carcinogens. ...PFOA induces oxidative stress, modulates receptor-mediated effects (via PPARα, CAR/PXR, and PPARγ), and alters cell proliferation, cell death, and nutrient and energy supply in human primary cells and experimental systems. For testicular cancer, additional evidence was a positive association in an ecological analysis conducted by the Working Group of available data on orchiectomies from the Veneto region of Italy, and a US study finding no associations.9 For all other cancers, the evidence was “inadequate”, as there were only sporadic positive findings.
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