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The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of POLE and POLD1, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers. In 2015, we reported the likely pathogenic (class 4) germline POLE c.1373A > T p.(Tyr458Phe) variant and we have now characterized this variant to verify that it is a class 5 pathogenic variant. For this purpose, we investigated (1) mutator phenotype in tumors from two carriers, (2) mutation frequency in cell-based mutagenesis assays, and (3) structural consequences based on protein modeling. Whole-exome sequencing of two tumors identified an ultra-mutator phenotype with a predominance of base substitutions, the majority of which are C > T. A SupF mutagenesis assay revealed increased mutation frequency in cells overexpressing the variant of interest as well as in isogenic cells encoding the variant. Moreover, exonuclease repair yeast-based assay supported defect in proofreading activity. Lastly, we present a homology model of human POLE to demonstrate structural consequences leading to pathogenic impact of the p.(Tyr458Phe) mutation. The three lines of evidence, taken together with updated co-segregation and previously published data, allow the germline variant POLE c.1373A > T p.(Tyr458Phe) to be reclassified as a class 5 variant. That means the variant is associated with PPAP.

Este artigo tem como objetivo oferecer contribuições à compreensão do trabalho em plataformas digitais a partir da sua forma de remuneração. O salário por peça é identificado, na teoria do valor de Marx, como uma forma de remuneração que permite o aumento da produtividade e da intensidade do trabalho, assim como o prolongamento da jornada de trabalho, com particular incidência sobre a subjetividade dos trabalhadores. Foi realizada uma revisão bibliográfica da literatura mais recente sobre o trabalho em plataformas digitais e da literatura acerca do conceito de salário por peça, tendo como principal referência o volume I do livro “O Capital”, de Marx. Em seguida, foram construídas categorias a partir das características do salário por peça identificadas na revisão de literatura, que nortearam a elaboração de um questionário. O questionário foi aplicado entre maio e julho de 2021 com 87 entregadores em plataformas digitais, em 19 estados do país. A hipótese que norteou esse estudo é a de que o trabalho em plataformas digitais promove um retorno do salário por peça. Os resultados da aplicação do questionário confirmaram a hipótese e colocaram em destaque a importância que possui a forma de remuneração para compreender a disposição desses trabalhadores em perfazer longas jornadas e suportar péssimas condições de trabalho. Sugere-se a realização de mais estudos para um melhor entendimento da relação entre salário por peça e trabalho em plataformas digitais.

BackgroundPatients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts.MethodsAfter a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. TheWNK2gene was disrupted in HT-29 cells by gene editing, andWNK2variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion.ResultsWe identified 2 rare germline variants in theWNK2gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2.ConclusionAfter whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in theWNK2gene. Functional studies suggested germlineWNK2variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

List of primers used in Sanger sequencing and SNPs utilized to genotype the 84 normal adjacent and tumor samples.

List of recurrent mutated genes ranked by MutSig tool.

supplementary material legends (tables and figures)

Baseline characteristics of CRC patients (discovery dataset, Sanger validation dataset and TCGA datasets).

Supplementary Figures (1 to 15)

Mutations validated in Biomark platform (Fluidigm) and by Sanger Sequencing.

List of all SNVs found

List of recurrent mutations

List of statistically significant functions in which mutated genes are implicated.

Mutations found in AMER1 gene across different datasets

Supplementary Figure 1 from Tgfbr1 Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development

SomaticPOLEmutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as ‘POLEExoD driver’, ‘POLEExoD driver plusPOLEVariant’, and ‘POLEVariant TMB-H’. Intriguingly, TMB was highest in tumors bearing ‘POLEExoD driver plusPOLEVariant’ (pPOLEvariants categorize a unique subset ofPOLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes.SignificanceSomaticPOLEExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations inPOLEExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.

Germline variants that affect the proofreading activity of polymerases epsilon (POLE) and delta (POLD1) predispose to colorectal adenomas and carcinomas, among other cancers. All cancer-associated pathogenic variants reported to date consist of non-disruptive genetic changes affecting the sequence that codifies the exonuclease domain (ED). Generally, disruptive (frameshift, stop-gain) POLE and POLD1 variants and missense variants outside the ED do not predispose to cancer. However, this statement may not be true for some, very specific variants that would indirectly affect the proofreading activity of the corresponding polymerase. We evaluated, by using multiple approaches, the possibility that POLD1 c.883G>A; p.(Val295Met), -a variant located 9 amino acids upstream the ED and present in ~0.25% of hereditary cancer patients-, affects POLD1 proofreading activity. Our findings show cumulative evidence that support no alteration of the proofreading activity and lack of association with cancer. The variant is classified as likely benign according to the ACMG/AMP guidelines.

Mutational processes in germline and in somatic cells are vastly different, and it remains unclear how the same genetic background affects somatic and transmissible mutations. Here, we estimate the impact of an inherited pathogenic variant in the exonuclease domain of polymerase delta (Polδ) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, thePOLD1L474P variant increases the mutation burden only slightly, contributing ∼11.8% and ∼14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of inherited pathogenic variants inPOLD1harbor a DNA rearrangement that results in a homozygous state of the pathogenic variant, leading to an extremely high mutation rate. Thus, mutations in both alleles ofPOLD1gene are required for strong increase in mutation rate suggesting recessiveness of Poldδ proofreading. These results show a similar role of Polδ in germline and somatic replication, and, together with previous findings, illustrate the important differences between Polδ and Polε in the disruption of their replication fidelity.

While constitutional pathogenic variants in theAPCgene cause familial adenomatous polyposis,APCc.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on theAPCI1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of theAPCI1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.

OBJECTIVE. To describe the results of tracheostomy in a series of cases in patients with COVID-19 admitted to the intensive care unit in two hospitals in the Northwest Mexico. MATERIAL AND METHODS. A prospective, descriptive, longitudinal study was carried out on a series of cases from April 2020 to August 2020. Data such as age, sex, hospital of origin, risk factors for the development of severe COVID-19, ventilatory and gasometric parameters before and 72 hours after, the days of oro-tracheal intubation were taken into account. Descriptive statistics with frequencies and percentages were used for the qualitative variables, for the numerical measures of central tendency as the mean and the median, the distribution of the results. RESULTS. From April to August 2020, in the two Intensive Care Units (ICUs) of these hospitals, 134 COVID-19 cases were admitted. In 14 patients (10.4%) tracheotomies were performed, 13 (92.8%) were male, mean age 49.21 years, 85% tested positive. The mean duration of oro-tracheal intubation was 22.7. Obesity combined with diabetes and arterial hypertension represented a risk factor in 57.1% of the cases. In 10 patients, the procedure was performed in the ICU bed. There were changes in some ventilatory parameters before and 72 hours after the procedure. The average number of days after weaning from the ventilator was 5.5 days. There were 3 deaths in our series. CONCLUSION. The adequate and prudent selection of COVID-19 patients for tracheostomy makes it easier to choose with greater justification the patients with the best prognosis, avoiding unnecessary procedures in a patient and a greater risk of contagion in the personnel.

[Purpose]: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. [Methods]: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. [Results]: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies, This work was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds (SAF2016-80888-R, SAF2015-68016-R, Severo Ochoa SVP-2014-068895 contract [L.M.-P.]); Instituto de Salud Carlos III (PI16/00563, PI16/00588, PI14/00613, PI19/00553, CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract [P.M.]); Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology).

Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts.After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. TheWe identified 2 rare germline variants in theAfter whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the

ObjectiveGermline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC.DesignWe analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications.ResultsP or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (pTP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants).ConclusionTP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.

Cerebellofaciodental syndrome (MIM #616202) is an autosomal recessive condition characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features, and short stature. To date, eight patients carrying biallelic BRF1 variants have been reported. Here, we describe two siblings with congenital microcephaly and corpus callosum hypoplasia, pre and postnatal growth retardation, congenital heart defect and severe global developmental delay. We also detected additional findings not previously reported in this syndrome, including bilateral sensorineural hearing impairment and inner ear malformation. Whole exome sequencing identified a novel homozygous missense variant (c.654G>C, p.[Trp218Cys]) in BRF1, predicted to affect the protein structure. Expression assessment showed extremely low BRF1 protein expression caused by the identified variant, supporting its causal involvement. The description of new patients with cerebellofaciodental syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions.

The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA.

The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes

Background: Patients and families with suspected, but genetically unexplained (unsolved) genetic tumour risk syndromes lack appropriate treatment and prevention, leading to preventable morbidity and mortality. To tackle this problem, patients from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) are analysed in the European Commission's research project "Solving the unsolved rare diseases" (Solve-RD). The aim is to uncover known and novel cancer predisposing genes by reanalysing available whole-exome sequencing (WES) data of large cohorts in a combined manner, and applying a multidimensional omics approach. Approach: Around 500 genetically unsolved cases with suspected hereditary gastrointestinal tumour syndromes (polyposis, early-onset/familial colorectal cancer and gastric cancer) from multiple European centres are aimed to be included. Currently, clinical and germline WES data from 294 cases have been analysed. In addition, an extensive molecular profiling of gastrointestinal tumours from these patients is planned and deep learning techniques will be applied. The ambitious, multidisciplinary project is accompanied by a number of methodical, technical, and logistic challenges, which require the development and implementation of new analysis tools, the standardisation of bioinformatics pipelines, and strategies to exchange data and knowledge. Results: and Outlook. The first re-analysis of 229 known and proposed cancer predisposition genes allowed solving 2-3% of previously unsolved GENTURIS cases. The integration of expert knowledge and new technologies will help to identify the genetic basis of additional unsolved cases within the ongoing project. The ERN GENTURIS approach might serve as a model for other genomic initiatives. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257 (Solve-RD). This study makes use of data shared/provided through RD-Connect, which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 305444.

224 Background: Driver mutations in the exonuclease domain (ExoD) of DNA polymerase epsilon ( POLE) have been associated with high tumor mutation burden (TMB). High TMB is an important marker for immunotherapy, and thus understanding the mechanisms that lead to high TMB is an area of active investigation. Many tumors with POLE ExoD driver mutations have additional POLE variants of uncertain significance (VUS). Some of these VUS lie within the ExoD, while most lie outside the ExoD. This study investigates the role of such POLE VUS on TMB and POLE functionality of ExoD-mutated tumors. Methods: Retrospective colorectal cancer (CRC) genomic profiles from Caris Life Sciences (n=1,870) were separated into groups based on the presence of POLE ExoD mutations and the TMB status. Groups were defined as: ‘TMB-high (TMB-H) POLE ExoD driver without additional POLE VUS’, ‘TMB-H POLE ExoD driver plus POLE VUS’, and ‘TMB-low (TMB-L) POLE variant(s) without ExoD driver’. An additional group with ‘TMB-H POLE variant(s) without ExoD driver’ was identified as potentially novel drivers for future study. The microsatellite instability status (MSI or MSS) was also considered. The level of TMB, the presence of polymerase proofreading-associated mutational signatures and POLE stability/functionality analyzed using AlphaFold2 models and Rosetta Molecular Modeling Suite, were evaluated. Results: POLE variants were identified in 4.9% of the CRCs studied (92/1870). In all, 52.2% (48/92) of those tumors were TMB-H, and 38.0% (35/92) of them contained POLE ExoD drivers. The highest median TMB (mTMB) was found in the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, and this was significantly different from the ‘TMB-H POLE ExoD driver without additional POLE VUS’ and the ‘TMB-L POLE variant without ExoD driver’ group, even when MSI tumors were excluded (p

Dissertação (mestrado) — Universidade de Brasília, Instituto de Ciências Sociais, Departamento de Sociologia, 2021. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Esta dissertação, com o título “Intermitência e trabalho em plataformas digitais: o retorno do salário por hora e por peça”, de autoria de Laura Valle Gontijo, sob orientação do professor doutor Sadi Dal Rosso, realizada no Departamento de Sociologia da Universidade de Brasília e defendida no dia 30 de novembro de 2021, tem como tema as formas mais recentes de trabalho precário, como o trabalho em plataformas digitais e o trabalho intermitente. Os objetivos desse trabalho são: contribuir com a investigação acerca do trabalho em plataforma digital e do trabalho intermitente, a partir do materialismo dialético, que permite compreender os fenômenos sociais na sua totalidade e no seu desenvolvimento histórico, e proporcionar elementos teóricos que contribuam para a formulação das reivindicações dos trabalhadores por melhores condições de vida e trabalho. É feito um resgate da discussão sobre salário por peça e por hora no volume I de “O Capital”, em Marx, e comparadas as suas características com o trabalho em plataformas digitais, a partir do resultado de um questionário aplicado com 87 entregadores, e com o trabalho intermitente, a partir de uma análise de dados da Relação Anual de Informações Sociais (Rais) e do Novo Cadastro Geral de Empregados e Desempregados (Novo Caged). Em um segundo momento, é feita uma discussão sobre as mudanças nas formas de remuneração ao longo do século XX e início do XXI, identificando elementos que corroboram com a hipótese da reintrodução do salário por peça e por hora, como forma de pagamento. Como conclusão, sugere-se que as reformas trabalhistas sinalizam um momento de transição de uma forma de remuneração para outra. Conclui-se que houve, de forma inequívoca, uma diminuição do nível de proteção ao emprego, na última década, e piora das condições de trabalho dos empregados formais. Observa-se um crescimento dos vínculos de trabalho precários, em detrimento dos vínculos estáveis. Há uma prevalência das longas jornadas, no caso dos trabalhadores em plataformas digitais, e de jornadas parciais, no caso dos trabalhadores intermitentes. Foi possível constatar ainda um alto nível de consciência política entre os trabalhadores em plataformas digitais, reconhecendo esse trabalho como uma escravidão ou semiescravidão e, prevalece uma divisão de opiniões entre os entregadores em relação à adoção da Carteira de Trabalho. This thesis “Intermittency and work on digital labour: a return of hourly and piece-based remuneration” by Laura Valle Gontijo, supervised by Professor Sadi Dal Rosso, PhD, defended at Departamento de Sociologia, Universidade de Brasília, on November, 30, 2021, appoaches the most recentlly forms of precarius labour, such as digital labour and intermittent labour. It ́s goals are to contribute for an investigation about digital labour and intermittent labour from the perspective of dialectical materialism, which allows a comprehensive understanding about social phenomena in a historical view and provide theoretical elements that contribute for proposing worker ́s demands for improving their living and working conditions. A reflexion about piece-based and hourly based remuneration was carried out on “The Capital – Vol 1”, by Karl Marx, comparing its characteristics with digital labour and intermittent labour, based on a survey regarding 87 deliverymen and with an intermittent labour according to government labour statistics (Relação Anual de Informações Sociais - Rais and Novo Cadastro Geral de Empregados e Desempregados - Novo Caged). In a second step the analysis follows a discussion regarding the changes in remuneration types that took place during the 20th and early ́s decades of 21st centuries, corroborating the hypothesis that piece and hourly remuneration are replacing standard 8-hours work day. It is argued that labour reforms have been introducing a new form of remuneration representing a transition phase. Evidence from official labour market statistics data, Rais and Novo Caged, point out a declining level of labour protection on the last decade, and a worsening working conditions of formal sector ́s employees. Data analysis revealed that precarious employment ́s relations have been increasing instead of formal jobs contracts. It also showed long working hours for digital workers and few working hours for intermittent ones. The survey with deliverymen on digital labour revealed that there is a high level of political awareness, with some of them referring to this work as slavery or semi-slavery and a dissent towards adopting or not formal working agreement.

Simple Summary A relevant proportion of colorectal cancer patients diagnosed at young age and/or with family history of that type of cancer do not carry germline mutations in know hereditary cancer genes. Moreover, studies aimed to identify additional high-risk colorectal cancer genes were either unsuccessful or identified genes that explain extremely few cases. We aimed to evaluate the role of the accumulation of colorectal cancer low-risk variants in familial and early-onset colorectal cancer patients. We observed that the accumulation of low-risk variants may explain a relevant number of these cases, particularly in the presence of family history of colorectal cancer and of the personal history of multiple colorectal cancers. If validated in other series of patients, the identification of familial/early-onset colorectal cancer patients with accumulation of low-risk variants will translate into personalized clinical management and to the identification of additional at-risk family members. Abstract A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

El dioxido de carbono es el principal Gas de Efecto Invernadero (GEI) debido a su abundancia en la atmosfera. Las tecnologias de captura y almacenamiento de CO2 (CAC) contribuyen a mitigar los efectos del cambio climatico al reducir sus emisiones. Para ello se requieren ambientes geologicos adecuados como los acuiferos salinos profundos con gran potencial a escala industrial en Espana. Estos deben tener unas caracteristicas apropiadas para asegurar la estanqueidad del CO2 y la viabilidad tecnica del proceso de inyeccion, estando la capacidad del almacen condicionada por los mecanismos trampa que tienen lugar en profundidad. En este trabajo se ha desarrollado la configuracion estatica del dispositivo de ensayos ATAP (Alta Temperatura-Alta Presion) para reproducir el mecanismo trampa de mineralizacion o secuestro mineral aplicandolo a un acuifero de arenisca para almacenamiento de CO2 en estado supercritico (SCCO2). El equipo permite observar los cambios producidos en una muestra de roca tras haber sido saturada con los fluidos existentes en el almacen (salmuera y SCCO2), en las condiciones de presion y temperatura caracteristicas del almacenamiento (hasta 120oC y 500 bar). Para verificar dichos cambios se ha empleado la tecnica de tomografia axial computada y picnometria de He. Las variaciones de porosidad producidas en la roca almacen son comparadas con las obtenidas en estudios de saturacion de SCCO2 mediante inyeccion y en reactor realizadas por otros autores. Palabras clave: Secuestro mineral, acuifero salino profundo, almacenamiento en areniscas, CO2 supercritico, equipo alta presion y temperatura

The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition. © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). DOI: 10.1016/j.mam.2019.03.001