Search

The formally exact framework of equilibrium Density Functional Theory (DFT) is capable of simultaneously and consistently describing thermodynamic and structural properties of interacting many-body systems in arbitrary external potentials. In practice, however, DFT hinges on approximate (free-)energy functionals from which density profiles (and hence the thermodynamic potential) follow via an Euler–Lagrange equation. Here, we explore a relatively simple Machine-Learning (ML) approach to improve the standard mean-field approximation of the excess Helmholtz free-energy functional of a 3D Lennard-Jones system at a supercritical temperature. The learning set consists of density profiles from grand-canonical Monte Carlo simulations of this system at varying chemical potentials and external potentials in a planar geometry only. Using the DFT formalism, we nevertheless can extract not only very accurate 3D bulk equations of state but also radial distribution functions using the Percus test-particle method. Unfortunately, our ML approach did not provide very reliable Ornstein–Zernike direct correlation functions for small distances.

Objective Oesophageal cancer (OEC) is an aggressive disease with a poor survival rate. Prognostic markers are thus urgently needed. Due to the demonstrated prognostic value of histopathological growth pattern (HGP) in other cancers, we performed a retrospective assessment of HGP in patients suffering from invasive OEC.Design A first cohort composed of 89 treatment-naïve operated patients with OEC from The Cancer Genome Atlas (TCGA) public database was constituted, from which H&E images and RNA-sequencing data were retrieved. Next, a second cohort composed of 99 patients with OEC treated and operated in a Belgian hospital was established. H&E-stained sections and extracted tumorous RNA were obtained from the samples. HGP were assessed on H&E slides as infiltrative (IGP) or expansive (EGP). TCGA RNA-sequencing data were analysed through the gene set enrichment analysis and Cytoscape softwares. Real-time quantitative PCR (qPCR) experiments were performed to assess gene expression in the Belgian cohort.Results IGP patients displayed a grim prognosis compared with EGP patients, while IGP was found as associated with numerous lymphovascular emboli and perinervous infiltrations. Analyses of the TCGA expression data showed that angiogenesis, epithelial-to-mesenchymal transition (EMT) and inflammation were significantly upregulated in IGP compared with EGP samples. qPCR experiments of three genes appearing as highly upregulated in each pathway showed no difference in expression according to the HGP.Conclusion The current study demonstrates the poor prognostic value carried by IGP in OC and suggests angiogenesis, EMT and inflammation as key carcinogenetic pathways upregulated in this pattern.

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.

DNA mismatch repair (MMR) is a highly conserved pathway that corrects both base–base mispairs and insertion-deletion loops (IDLs) generated during DNA replication. Defects in MMR have been linked to carcinogenesis and drug resistance. However, the regulation of MMR is poorly understood. Interestingly, CNOT6 is one of four deadenylase subunits in the conserved CCR4-NOT complex and it targets poly(A) tails of mRNAs for degradation. CNOT6 is overexpressed in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and androgen-independent prostate cancer cells, which suggests that an altered expression of CNOT6 may play a role in tumorigenesis. Here, we report that a depletion of CNOT6 sensitizes human U2OS cells to N-methyl-N′nitro-N-nitrosoguanidine (MNNG) and leads to enhanced apoptosis. We also demonstrate that the depletion of CNOT6 upregulates MMR and decreases the mutation frequency in MMR-proficient cells. Furthermore, the depletion of CNOT6 increases the stability of mRNA transcripts from MMR genes, leading to the increased expression of MMR proteins. Our work provides insight into a novel CNOT6-dependent mechanism for regulating MMR.

Abstract Background Multiple job holding (MJH) is a common and growing phenomenon in many countries. Little is known about experiences with MJH among older workers. The objective of the present study is to gain insight in experiences with MJH among Dutch workers aged 45 years and older. Methods Multiple job holders were selected from the Study on Transitions in Employment, Ability, and Motivation (STREAM), a Dutch cohort study among persons aged 45 years and older. Purposive sampling was applied to assure heterogeneity regarding gender, educational level, health, financial situation, willingness to continue MJH, and type of MJH (only jobs as employee or also being self-employed). Interviews were conducted until data saturation occurred. Fifteen multiple job holders participated in this study (eight men, seven women). Interviews were digitally recorded, transcribed verbatim and analyzed, along with field notes, using thematic content analysis. The data were openly coded, after which codes were aggregated into themes, which formed a thematic map. In each phase of the analysis at least two researchers were involved to increase reliability. Results Experiences with MJH varied from positive to negative. They were influenced by characteristics of individual jobs, e.g. social support at work, as well as characteristics of the combination of jobs, e.g. positive spill-over effects, and conflicts between work schedules. The personal context of multiple job holders, e.g. their age, or reason for MJH, affected how work characteristics influenced experiences. Negative experiences with one job often coincided with negative experience in the other job(s), and problems in the personal context. Some multiple job holders were able to make changes to their situation when desired. For some, this was not possible, which augmented their negative experience. Conclusions This study adds to existing knowledge that experiences with MJH are not only influenced by work characteristics but also by the personal context of multiple job holders, and that some workers are able to change their situation when desired, while others are not. Future research should study how different combinations of work and personal characteristics influence sustainable employability of multiple job holders. Policies facilitating life-long learning could increase opportunities to change the MJH situation when desired.

Abstract Background An increasing number of retirees continue to work beyond retirement despite being eligible to retire. As the prevalence of chronic disease increases with age, working beyond retirement may go along with having a chronic disease. Working beyond retirement may be different for retirees with and without chronic disease. We aim to investigate whether demographic, socioeconomic and work characteristics, health and social factors predict working beyond retirement, in workers with and without a chronic disease. Methods Employees aged 56–64 years were selected from the Study on Transitions in Employment, Ability and Motivation (N = 1125). Questionnaire data on demographic and work characteristics, health, social factors, and working beyond retirement were linked to registry data from Statistics Netherlands on socioeconomic characteristics. Separate prediction models were built for retirees with and without chronic disease using multivariate logistic regression analyses. Results Workers without chronic disease were more likely to work beyond retirement compared to workers with chronic disease (27% vs 23%). In retirees with chronic disease, work and health factors predicted working beyond retirement, while in retirees without a chronic disease, work, health and social factors predicted working beyond retirement. In the final model for workers with chronic disease, healthcare work, better physical health, higher body height, lower physical load and no permanent contract were positively predictive of working beyond retirement. In the final model for workers without chronic disease, feeling full of life and being intensively physically active for > = 2 days per week were positively predictive of working beyond retirement; while manual labor, better recovery, and a partner who did not support working until the statutory retirement age, were negatively predictive of working beyond retirement. Conclusions Work and health factors independently predicted working beyond retirement in workers with and without chronic disease, whereas social factors only did so among workers without chronic disease. Demographic and socioeconomic characteristics did not independently contribute to prediction of working beyond retirement in any group. As prediction of working beyond retirement was more difficult among workers with a chronic disease, future research is needed in this group.

We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that [CD4.sup.+] Tfh TIL, [CD8.sup.+] TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Thl-oriented Tfh TIL ([PD-1.sup.hi][ICOS.sup.int] phenotype) provide help for immunoglobulin and IFN-[gamma] production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, [Ki-67.sup.+] TIL-B in active germinal centers) and cytotoxic ([GZMB.sup.+][CD8.sup.+] and [GZMB.sup.+][CD68.sup.+] TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a [CD25.sup.+][CXCR5.sup.+][GARP.sup.+][FOXP3.sup.+] phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-[beta]-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and [CD8.sup.+] TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade., Introduction Adaptive and innate antitumor immune responses and their exploitation in immunotherapy are recognized as key defenses in the fight against cancer. Across a diversity of tumor types, data support [...]

Attention to paid work in clinical health care—clinical work-integrating care (CWIC)—might be beneficial for patients of working age. However, the perceptions and expectations of patients about CWIC are unknown. The aim of this study was to develop an understanding of current practices, needs, and expectations among patients for discussing work with a medical specialist. A qualitative study was undertaken involving patients with diverse medical conditions (n = 33). Eight online synchronous focus groups were held. A thematic analysis was then performed. Three themes emerged from the data: (1) the process of becoming a patient while wanting to work again, (2) different needs for different patients, (3) patients' expectations of CWIC. We identified three different overarching categories of work-concerns: (a) the impact of work on disease, (b) the impact of disease or treatment on work ability, and (c) concerns when work ability remained decreased. For each category of concerns, patients expected medical specialists to perform differing roles. Patients indicated that they need support for work-related concerns from their medical specialists and/or other professionals. Currently, not all work concerns received the requested attention, leaving a portion of the patients with unmet needs regarding CWIC. Patients have a wide range of questions regarding work and health, which they want to discuss with their medical specialist In current clinical practice, not all work concerns get the requested attention, leaving some patients with unmet needs Cooperation with different health care professionals, including rehabilitation occupational health care, might aid in supporting patients with their work-related questions [ABSTRACT FROM AUTHOR]

Abstract Background The aims of the present study were to: 1) gain insight into reasons for working beyond the statutory retirement age from older workers’ perspectives, and 2) explore how the domains of the research framework Study on Transitions in Employment, Ability and Motivation (STREAM) can be applied to working beyond retirement age. Methods A qualitative research design included individual interviews (n = 15) and three focus groups (n = 18 participants) conducted with older workers aged 65 years and older continuing in a paid job or self-employment. Interview participants were recruited from an existing STREAM cohort study. Focus group participants were recruited from companies and employment agencies. The data were subjected to thematic analysis. Results The most important motives for working beyond retirement age were maintaining daily routines and financial benefit. Good health and flexible work arrangements were mentioned as important preconditions. The themes emerging from the categorization of the motives and preconditions corresponded to the domains of health, work characteristics, skills and knowledge, and social and financial factors from the STREAM research framework. However, our analysis revealed one additional theme—purpose in life. Conclusion This study offers important new insights into the various preconditions and motives that influence working beyond retirement age. In addition, the five domains of the STREAM research framework, including the additional domain of ‘purpose in life’, seem to be applicable to working beyond retirement age. This knowledge contributes to the development of work-related interventions that enhance older workers’ motivation to prolong their working lives.

OBJECTIVES: No study so far has combined register-based socioeconomic information with self-reported information on health, demographics, work characteristics, and the social environment. The aim of this study was to investigate whether socioeconomic, health, demographic, work characteristics and social environmental characteristics independently predict working beyond retirement. METHODS: Questionnaire data from the Study on Transitions in Employment, Ability and Motivation were linked to data from Statistics Netherlands. A prediction model was built consisting of the following blocks: socioeconomic, health, demographic, work characteristics and the social environment. First, univariate analyses were performed (P02 days/week, higher body height, and working in healthcare predicted working beyond retirement. If respondents had a permanent contract or worked in handcraft, or had a partner that did not like them to work until the official retirement age, they were less likely to work beyond retirement. CONCLUSION: Health, work characteristics and social environment predicted working beyond retirement, but register-based socioeconomic and demographic characteristics did not independently predict working beyond retirement. This study shows that working beyond retirement is multifactorial.

OBJECTIVES: Before actual retirement, employees may already distance themselves from work, which could be referred to as “mental retirement”. However, trajectories of work motivation, ie, work engagement, have not been studied yet. The present study aimed to (i) identify different trajectories of work engagement among older workers approaching the retirement age, and (ii) examine their associations with actual retirement. METHODS: In total 3171 employees aged 55–62 years, who participated in the Dutch Study on Transitions in Employment, Ability and Motivation were included in this study. Participants completed questionnaires in 2010, 2011, 2012, and 2013. Latent class growth mixture modeling was performed to identify groups of employees with similar three-year trajectories in work engagement. Logistic regression analyses were performed to study whether trajectory membership was associated with retirement. RESULTS: Of the 3171 employees, 16.2% made a transition from work to (early) retirement (N=513). Four trajectories of work engagement were identified: steady high (76.3%), steady low (12.7%), decreasing (6.2%), and increasing (4.8%). A steady low work engagement trajectory was associated with retirement [odds ratio (OR) 1.46], compared to a steady high work engagement trajectory. Although not statistically significant, an increasing work engagement trajectory seemed to be associated with retirement as well (OR 1.60). CONCLUSIONS: This study did not support the concept of mental retirement before actual retirement, ie, a decrease in work engagement among those facing retirement. However, as one in eight employees did experience steady low work engagement in the years before retirement, interventions promoting work motivation are recommended to support the employability of these employees.

Introduction: Tumor banks make a considerable contribution to translational research. Using emerging molecular tests on frozen material facilitates the development of new diagnostic and therapeutic strategies, especially in rare cases. However, standard quality control schemes are lacking in the current literature.Methods: In 2017, we have conducted a robust quality control test on 100 of 15,000 fresh frozen samples collected between 2000 and 2013 at the Jules Bordet Tumor Bank (Brussels). RNA and DNA extraction was done. The quality of RNA, DNA and proteins were evaluated, respectively by measuring RNA Integrity Number (RIN), by checking Electrophoretic Integrity (EI) and by performing Immunohistochemistry staining (IHC). A score, ranging from poor (1) to excellent (4), was attributed based on technical analysis.Results: RNA purity was scored 4 in 97% of the cases, 3 in 2%, and 2 in 1%. RIN scores were similarly 4 in 89%, 3 in 10%, and 2 in 1% of the cases. DNA purity was scored 4 in 94% and 3 in 6%, EI was scored 4 in 100% of the cases. Despite morphology loss after freezing, HER2, ER, and Ki67 IHC stainings yielded a score of 4 in the majority of samples. Furthermore, participating in the ISBER Proficiency Testing helped us validate our techniques and the technician's work. Seven processing schemes were carried out, the scores obtained were very satisfactory (20/27) or satisfactory (7/27).Conclusion: Tumor Banks can be precious for translational research. Nevertheless, firm quality controls should be applied to ensure high quality material delivery. Only then can biobanks contribute to diagnostics, biomarkers discovery and reliable molecular test development.