Search

Background In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs. Methods A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms. Results A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons. Conclusions The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration., BACKGROUND: In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs.METHODS: A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms.RESULTS: A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons.CONCLUSIONS: The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration.

Background: In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs. Methods: A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms. Results: A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons. Conclusions: The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration.

Background In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs. Methods A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms. Results A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons. Conclusions The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration., BACKGROUND: In the last decade, interest in working life expectancy (WLE) and socioeconomic differences in WLE has grown considerably. However, a comprehensive overview of the socioeconomic differences in WLE is lacking. The aim of this review is to systematically map the research literature to improve the insight on differences in WLE and healthy WLE (HWLE) by education, occupational class and income while using different ways of measuring and estimating WLE and to define future research needs.METHODS: A systematic search was carried out in Web of Science, PubMed and EMBASE and complemented by relevant publications derived through screening of reference lists of the identified publications and expert knowledge. Reports on differences in WLE or HWLE by education, occupational class or income, published until November 2022, were included. Information on socioeconomic differences in WLE and HWLE was synthesized in absolute and relative terms.RESULTS: A total of 26 reports from 21 studies on educational and occupational class differences in WLE or HWLE were included. No reports on income differences were found. On average, WLE in persons with low education is 30% (men) and 27% (women) shorter than in those with high education. The corresponding numbers for occupational class difference were 21% (men) and 27% (women). Low-educated persons were expected to lose more working years due to unemployment and disability retirement than high-educated persons.CONCLUSIONS: The identified socioeconomic inequalities are highly relevant for policy makers and pose serious challenges for equitable pension policies. Many policy interventions aimed at increasing the length of working life follow a one-size-fits-all approach which does not take these inequalities into account. More research is needed on socioeconomic differences in HWLE and potential influences of income on working life duration.

Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD + supplementation. Autophagy decreases in Rev1−/− mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD+ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1−/− MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Peptide receptor radionuclide therapy with 177Lu-DOTATATE improves the outcome of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Nevertheless, stable disease has been the main response pattern observed, with some rare complete responses. Lu-177 exerts about two-thirds of its biological effects via the indirect effects of ionizing radiation that generate reactive oxygen species, eventually leading to oxidative damage and cell death. This provides a rationale for targeting the antioxidant defence system in combination with 177Lu-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during 177Lu-DOTATATE therapy were assessed in vitro and in vivo using a xenograft mouse model. In vitro, the combination resulted in a synergistic effect in cell lines exhibiting a BSO-mediated GSH decrease. In vivo, BSO neither influenced 177Lu-DOTATATE biodistribution nor induced liver, kidney or bone marrow toxicity. In terms of efficacy, the combination resulted in reduced tumour growth and metabolic activity. Our results showed that disturbing the cell redox balance using a GSH synthesis inhibitor increased 177Lu-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with 177Lu-DOTATATE., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Low back pain (LBP) is the leading cause of disability worldwide and has an excessive societal burden. Accumulating evidence has shown that some medical approaches such as imaging in absence of clear indications, medication and some invasive treatments may contribute to the problem rather than alleviating it. Objectives: To determine the extent of de-implementation of non-evidence-based hospital treatments for LBP care in the Netherlands in the last three decades. Methods: Using a register-based population-level observational study with Dutch hospital data, providing a nearly complete coverage of hospital admissions in the Netherlands in 1991–2018, we assessed five frequently applied non-evidence-based hospital treatments for LBP. Time trends in treatment use (absolute and per 100,000 inhabitants) were plotted and analysed using Poisson regression. Results: The use of bed rest for non-specific LBP and hernia nuclei pulposi, and discectomy for spinal stenosis decreased 91%, 81% and 86% since the availability of evidence/guidelines, respectively. De-implementation, beyond 84%, was reached after 18 and 17 years for bed rest for non-specific LBP and discectomy respectively, while it was not reached after 28 years for bed rest for hernia nuclei pulposi. For spinal fusion and invasive pain treatment, there was an initial increase followed by a reduction. Overall, these treatments reduced by 85% and 75%, respectively. Conclusions: In the Netherlands, de-implementation of five non-recommended hospital LBP treatments, if at all, took several decades. Although de-implementation was substantial, slow de-implementation has likely resulted in considerable waste of resources and avoidable harm to many patients in Dutch hospitals. Significance: Medically intensive approaches to low-back pain care contribute to the high societal burden of this disease. There have been calls to avoid such care. Using Dutch hospital data, we showed that de-implementation of five non-re

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e. non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk., SCOPUS: ar.j, info:eu-repo/semantics/published

Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD + supplementation. Autophagy decreases in Rev1−/− mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD+ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1−/− MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.

The Paris Agreement set goals to minimize global warming by reducing CO2 emissions. In the Netherlands, the Paris Agreement is translated into policies that aim for circularity and sustainability at different governmental levels. These policies are directed at the sustainability transitions within different fields, such as the built environment. The construction sector is responsible for high levels of CO2 emissions, however, there is a big housing shortage in the Netherlands and the aim is to construct 900.000 new houses by the end of 2030. This challenge requires a transition to a more sustainable way of constructing, to stay below the critical threshold of 1.5 °C global warming. The transition from traditional housing constructions to timber constructions can arguably be a solution to this challenge. To accelerate this transition, the Metropole Region of Amsterdam (MRA) has written a covenant that aims to construct 20% of the total housing production in the MRA by timber, by 2025. This is a high ambition, as currently only some pilot projects are constructed out of timber. While the covenant might give body to this transition in the MRA, there are still a lot of questions about how different policy instruments can foster the timber transition in the MRA. Many studies have been conducted on transitions and innovation policies, and affluent policy instruments for the transition of innovations are presented in literature. However, literature lacks in presenting how a combination of different policy instruments can foster a sustainability transition. This research, which is case study based, therefore researches the different policy instruments that are or can be implemented to foster the transition of timber constructions in the MRA. The literature study presents the theories that make up the theoretical framework and give a deeper understanding of the concepts that are used. The empirical research consists of a document analysis, a stakeholder analysis, interviews, Architecture, Urbanism and Building Sciences | Management in the Built Environment

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.

The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch syndrome, represent variants of uncertain significance (VUS). The inability to classify most VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based quantitative tool to improve the classification of VUS in MMR proteins. To derive a formula that translates CIMRA assay results into the odds of pathogenicity (OddsPath) for VUS in PMS2 we used a set of clinically classified PMS2 variants supplemented by inactivating variants that were generated by an in cellulo genetic screen, as proxies for cancer-predisposing variants. Validation of this OddsPath revealed high predictive values for benign and predisposing PMS2 VUS. We conclude that the OddsPath provides an integral metric that, following the other, higher penetrance, MMR proteins MSH2, MSH6 and MLH1 can be incorporated as strong evidence type into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).

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.

The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch syndrome, represent variants of uncertain significance (VUS). The inability to classify most VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based quantitative tool to improve the classification of VUS in MMR proteins. To derive a formula that translates CIMRA assay results into the odds of pathogenicity (OddsPath) for VUS in PMS2 we used a set of clinically classified PMS2 variants supplemented by inactivating variants that were generated by an in cellulo genetic screen, as proxies for cancer-predisposing variants. Validation of this OddsPath revealed high predictive values for benign and predisposing PMS2 VUS. We conclude that the OddsPath provides an integral metric that, following the other, higher penetrance, MMR proteins MSH2, MSH6 and MLH1 can be incorporated as strong evidence type into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).

The Paris Agreement set goals to minimize global warming by reducing CO2 emissions. In the Netherlands, the Paris Agreement is translated into policies that aim for circularity and sustainability at different governmental levels. These policies are directed at the sustainability transitions within different fields, such as the built environment. The construction sector is responsible for high levels of CO2 emissions, however, there is a big housing shortage in the Netherlands and the aim is to construct 900.000 new houses by the end of 2030. This challenge requires a transition to a more sustainable way of constructing, to stay below the critical threshold of 1.5 °C global warming. The transition from traditional housing constructions to timber constructions can arguably be a solution to this challenge. To accelerate this transition, the Metropole Region of Amsterdam (MRA) has written a covenant that aims to construct 20% of the total housing production in the MRA by timber, by 2025. This is a high ambition, as currently only some pilot projects are constructed out of timber. While the covenant might give body to this transition in the MRA, there are still a lot of questions about how different policy instruments can foster the timber transition in the MRA. Many studies have been conducted on transitions and innovation policies, and affluent policy instruments for the transition of innovations are presented in literature. However, literature lacks in presenting how a combination of different policy instruments can foster a sustainability transition. This research, which is case study based, therefore researches the different policy instruments that are or can be implemented to foster the transition of timber constructions in the MRA. The literature study presents the theories that make up the theoretical framework and give a deeper understanding of the concepts that are used. The empirical research consists of a document analysis, a stakeholder analysis, interviews, Architecture, Urbanism and Building Sciences | Management in the Built Environment

SCOPUS: ar.j, info:eu-repo/semantics/published

Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial., SCOPUS: ar.j, info:eu-repo/semantics/published

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.

We report a case of colorectal involvement by a mantle cell lymphoma (MCL) that had been considered before as inflammatory bowel disease. Diagnosis of low-grade MCL can be difficult, and here we highlight the importance of thorough histopathological examination in case of supposed inflammatory bowel disease that does not react to therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

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.

Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT., SCOPUS: ar.j, SCOPUS: ar.j, info:eu-repo/semantics/published

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. Keywords: Lynch syndrome; mRNA splicing; mismatch repair genes; splicing aberrations; variant interpretation and classification; variant type.

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.

Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes’ rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes’ rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC). Methods: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC. Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes. Interpretation: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. Fund: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux., SCOPUS: ar.j, info:eu-repo/semantics/published

info:eu-repo/semantics/published

SCOPUS: le.j, info:eu-repo/semantics/published

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., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data. Methods: Two sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories. Results: Concordance between the training runs met our prespecified validation criterion. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible. Conclusion: The CIMRA assay accurately predicts pathogenic and benign MMR gene variants. Quantitative combination of assay results with in silico analysis correctly classified the majority of variants. Using this calibration, CIMRA assay results can be integrated into the diagnostic algorithm for MMR gene variants.

SCOPUS: no.j, info:eu-repo/semantics/published

Tumor-infiltrating B cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their roles in tumor immunity are not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2+ and triple-negative BC patients from the BIG 02-98 clinical trial (10-year median follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared with normal breast tissues, which is associated with global, CD4+, and CD8+ tumor infiltrating lymphocytes (TIL); higher tumor grades; higher proliferation; and hormone receptor negativity. All B cell differentiation stages are detectable, but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with T follicular helper (TFH) TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal that TIL-B are responsive to B cell receptor (BCR) stimulation ex vivo, express activation markers, and produce cytokines and Igs despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to promote effective antitumor immunity at the tumor site., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising

Primary hepatic lymphomas (PHLs) are rare liver tumors, frequently misdiagnosed preoperatively. As these tumors could be successfully treated with chemotherapy, their early recognition is essential, potentially, to avoid useless surgery. We report on the case of a cirrhotic patient with hemochromatosis who presented a PHL, initially diagnosed as a hepatocellular carcinoma (HCC), and we analyze recent data from the literature on this subject., info:eu-repo/semantics/published

An important role for tumor infiltrating B lymphocytes (TIL-B) in the immune response to cancer is emerging; however, very little is known about the antigen specificity of antibodies produced in situ. The presence of IgA antibodies in the tumor microenvironment has been noted although their biological functions and clinical significance are unknown. This study used a 91-antigen microarray to examine the IgG and IgA autoantibody repertoires in breast cancer (BC). Tumor and adjacent breast tissue supernatants and plasma from BC patients together with normal breast tissue supernatants and plasma from healthy controls (patients undergoing mammary reduction and healthy blood donors) were analyzed to investigate relationships between autoantibodies and the clinical, histological and immunological features of tumors. Our data show that >84% of the BC samples tested contain autoantibodies to one or more antigens on the array, with ANKRD30BL, COPS4, and CTAG1B being most frequently reactive. Ex vivo TIL-B responses were uncoupled from systemic humoral responses in the majority of cases. A comparison of autoantibody frequencies in supernatants and plasma from patients and controls identified eight antigens that elicit BC-associated autoantibody responses. The overall prevalence of IgG and IgA autoantibodies was similar and while IgG and IgA responses were not linked they did correlate with distinct clinical, pathological and immunological features. Higher levels of ex vivo IgG responses to BC-associated antigens were associated with shorter recurrence-free survival (RFS), HER2 overexpression and lower tumor-infiltrating CD8+ T cell counts. Higher IgA levels were associated with estrogen and progesterone receptor-negative cancers but were not significantly associated with RFS. Furthermore, ex vivo IgA but not IgG autoantibodies reactive to BC-associated antigens were linked with germinal center and early memory B cell maturation and the presence of tertiary lymphoid structures, SCOPUS: ar.j, info:eu-repo/semantics/published

© 2017 Elsevier Ltd Exit from work leads to different effects on health, partially depending on the socioeconomic status (SES) of people in the work exit. Several studies on the effects of exit from work on health across socioeconomic groups have been performed, but results are conflicting. The aim of this review is to systematically review the available evidence regarding the effects of exit from work on health in high and low socioeconomic groups. A systematic literature search was conducted using Pubmed, Embase, Web of Science, CINAHL and PsycINFO. Search terms related to exit from work, health, SES and design (prospective or retrospective). Articles were included if they focused on: exit from work (early/statutory retirement, unemployment or disability pension); health (general, physical or mental health and/or health behaviour); SES (educational, occupational and/or income level); and inclusion of stratified or interaction analyses to determine differences across socioeconomic groups. This search strategy resulted in 22 studies. For general, physical or mental health and health behaviour, 13 studies found more positive effects of exit from work on health among employees with a higher SES compared to employees with a lower SES. These effects were mainly found after early/statutory retirement. In conclusion, the effects of exit from work, or more specific the effects of early/statutory retirement on health are different across socioeconomic groups. However, the findings of this review should be interpreted with caution as the studies used heterogeneous health outcomes and on each health outcome a limited number of studies was included. Yet, the positive effects of exit from work on health are mainly present in higher socioeconomic groups. Therefore, public health policies should focus on improving health of employees with a lower SES, in particular after exit from work to decrease health inequalities.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma (<5% of Hodgkin’s lymphomas) predominantly affecting the middle-aged man, with an indolent behavior. Given the rare occurrence of this lymphoma, there are currently no clear guidelines for initial treatment or relapse. In this report, we present the follow-up of 2 patients treated by radioimmunotherapy for first relapse of their NLPHL. Both patients were initially treated with rituximab and relapsed 1 year after the end of their treatment., SCOPUS: ar.j, info:eu-repo/semantics/published

T follicular helper cells (TFH cells) are important regulators of antigen-specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown. This study presents data from human breast cancer, advocating a role for tumor-infiltrating CXCL13-producing (CXCR5-) TFH cells, here named TFHX13 cells, in promoting local memory B cell differentiation. TFHX13 cells potentially trigger tertiary lymphoid structure formation and thereby generate germinal center B cell responses at the tumor site. Follicular DCs are not potent CXCL13 producers in breast tumor tissues. We used the TFH cell markers PD-1 and ICOS to identify distinct effector and regulatory CD4+ T cell subpopulations in breast tumors. TFHX13 cells are an important component of the PD-1hiICOSint effector subpopulation and coexpanded with PD-1hiICOSintFOXP3hi Tregs. IL2 deprivation induces CXCL13 expression in vitro with a synergistic effect from TGFβ1, providing insight into TFHX13 cell differentiation in response to Treg accumulation, similar to conventional TFH cell responses. Our data suggest that human TFHX13 cell differentiation may be a key factor in converting Treg-mediated immune suppression to de novo activation of adaptive antitumor humoral responses in the chronic inflammatory breast cancer microenvironment., SCOPUS: ar.j, info:eu-repo/semantics/published

Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis.

Objectives: The aims of this article are to (1) determine whether and to what extent general perceived health and quality of supervision predict voluntary early retirement pension (VERP) and (2) assess whether quality of supervision modifies the association between general perceived health and VERP. Methods: Employees aged 49-64 years who participated in the Danish Work Environment Cohort Study in 2000 were selected. Their questionnaire data about health and work were linked to register data on social transfer payments, among others VERP, from 2001 to 2012 in the Danish Register for Evaluation of Marginalization (N=1167). Cox proportional hazards analyses were performed to identify the prospective association of general perceived health and quality of supervision on VERP. Relative excess risks due to interaction (RERIs) were calculated to assess whether quality of supervision modified the association between health and VERP. Results: Employees with poor health at baseline had an increased risk of VERP during follow-up (hazard ratio [HR]=1.23; 95% confidence interval [CI] 1.02-1.49). Quality of supervision at baseline was not associated to VERP during follow-up (HR=1.04; 95% CI 0.90-1.21). There was no statistically significant interaction of poor health and poor quality of supervision with regard to risk of VERP (RERI=-0.33; 95% CI -1.79 to 1.14). Conclusions: This study did not support the notion that quality of supervision buffers the association between poor health and VERP. Future research is needed to determine whether other aspects of supervision, for example supervisors' opportunities to effectuate workplace adjustments, may modify the association of poor health and VERP.