USP45 and Spindly are part of the same complex implicated in cell migration

Abstract Ubiquitylation is a protein modification implicated in several cellular processes. This process is reversible by the action of deubiquinating enzymes (DUBs). USP45 is a ubiquitin specific protease about which little is known, aside from roles in DNA damage repair and differentiation of the vertebrate retina. Here, by using mass spectrometry we have identified Spindly as a new target of USP45. Our data show that Spindly and USP45 are part of the same complex and that their interaction specifically depends on the catalytic activity of USP45. In addition, we describe the type of ubiquitin chains associated with the complex that can be cleaved by USP45, with a preferential activity on K48 ubiquitin chain type and potentially K6. Here, we also show that Spindly is mono-ubiquitylated and this can be specifically removed by USP45 in its active form but not by the catalytic inactive form. Lastly, we identified a new role for USP45 in cell migration, similar to that which was recently described for Spindly

The influence of tumor invasion in anastomotic line on survival of patient with gastric stump cancer

RACIONAL: O câncer do coto gástrico desenvolve- se no remanescente gástrico de gastrectomia realizada há pelo menos 5 anos por doença benigna e os sítios mais comuns de acometimento são próximo à anastomose e na pequena curvatura. Considera-se que o coto gástrico é estado pré-canceroso. OBJETIVOS: Identificar o padrão de disseminação de linfonodos acometidos, quantificar a invasão tumoral da linha de anastomose e correlacionar: a invasão da linha de anastomose com o comprometimento linfonodal e mesenterial, o acometimento linfonodal com sobrevivência e o acometimento da linha de anastomose com sobrevivência. MÉTODOS: Estudo retrospectivo com revisão de prontuários, peças cirúrgicas e exames anátomo-patológicos de 113 pacientes com diagnóstico de câncer de coto gástrico definido como adenocarcinoma desenvolvido no remanescente gástrico de gastrectomia realizada há pelo menos cinco anos por doença benigna. RESULTADOS: A disseminação linfonodal não se mostrou específica; 75% dos pacientes apresentaram invasão tumoral da linha de anastomose; em 66,7% dos casos ocorreu invasão da linha anastomótica e linfonodal concomitantes; menos de 10% dos casos exibiam invasão mesenterial; houve óbito em 86,5% dos casos com invasão linfonodal e 64,7% com invasão da linha de anastomose e em 100% com invasão mesenterial. CONCLUSÕES: 1) O câncer de coto gástrico não tem padrão de disseminação linfonodal específico; 2) a linha de anastomose sofre freqüente invasão tumoral; 3) apesar de freqüente a invasão da linha anastomótica, não apresenta correlação estatística significante com o comprometimento linfonodal regional ou mesenterial; 4) a presença de invasão linfonodal implica em sobrevida menor, em especial a de linfonodos do mesentério; 5) a presença de acometimento neoplásico da linha anastomótica não se correlaciona com pior resultado de sobrevivência.AIM: To identify the lymph node metastatic pattern for gastric stump cancer; to quantify the anastomotic site invasion by tumor growth; to correlate the invasion of anastomotic site with metastasis in lymph node in general and mesenterial lymph node involvement and the survival. METHODS: One hundred and thirteen patients with gastric stump cancer were retrospectively analyzed along with their medical records, surgical specimens and histopathologic exams. RESULTS: seventy five percent of patients had tumoral invasion in the anastomotic site. In 66.7% there was invasion of the anastomotic site with metastatic lymph nodes. Nine percent had mesenterial lymph node invasion. Fatal cases occurred in 86,5% with metastatic lymph node, 64,7% with invasion of the anastomotic site and 100% with mesenterial lymph node invasion. CONCLUSIONS: Metastatic lymph node dissemination is not specific to gastric stump cancer and does not present a pattern in the lymph node dissemination. Although frequent the tumor invasion in anastomotic line, there is no significant statistical correlation with the invasion of regional or mesenterial lymph nodes. Lymph node invasion reduces survival, mainly when mesenterial lymph node dissemination is present. Tumor invasion in anastomotic line does not reduce survival

UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival

International audienc

Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis.

OBJECTIVE Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown. RESEARCH DESIGN AND METHODS 821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9-53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1-3 according to target-to-background ratio tertiles. RESULTS One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake. CONCLUSIONS Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.The PESA study is funded by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Santander Bank. B.I. is supported by the European Commission (grant numbers 819775 and 945118), by the Spanish Ministry of Science and Innovation (PID2019- 110369RB-I00), and by the Red Madrilena de ~ Nanomedicina en Imagen Molecular-Comunidad de Madrid (S2017/BMD-3867 RENIM-CM). A.D. is an Alfonso Martin Escudero fellow and is scientifically supported by La Caixa Foundation. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacion (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/ 10.13039/501100011033).S

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.

BACKGROUND Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, “la Caixa” Foundation. We thank the PESA participants and the imaging, administrative, and medical PESA teams. The PESA study is equally co-funded by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Santander Bank (Madrid, Spain) and also receives funding from the Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI15/02019), the European Regional Development Fund (ERDF—A Way to Build Europe), and the European Social Fund (ESF—Investing in Your Future). CNIC is a Severo Ochoa Center of Excellence (CEX2020- 001041-S) and is supported by the ISCIII, the Spanish Ministry for Science and Innovation, and the Pro-CNIC Foundation. CT-P was supported by a “la Caixa” Foundation fellowship (ID 100010434, LCF/BQ/DI19/11730052). MC-C was supported by a Miguel Servet type II research contract (ISCIII, CPII21/00007) and the Fondo de Investigación Sanitaria (ISCIII, PI20/00819). We acknowledge the Sephardic Foundation on Aging and other donors of the Alzheimer’s Disease Research (grant number A2022034S), a programme of the BrightFocus Foundation, for support of this research. This work was also partially produced with the support of a 2021 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation awarded to MC-C (the Foundation takes no responsibility for the opinions, statements, and contents of this project, which are entirely the responsibility of its authors). BI was supported by the European Research Council (ERC-2018-CoG 819775-MATRIX). MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW2014.0363), the Swedish Research Council (2017-02869, 2021-02678, 2021-06545), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF-agreement (ALFGBG-813971, ALFGBG-965326), the Swedish Brain Foundation (FO2021-0311), and the Swedish Alzheimer Foundation (AF-740191). MS-C receives funding from the European Research Council (grant agreement number 948677), project “PI19/00155”, funded by ISCIII and co-funded by the EU, and a fellowship from “la Caixa” Foundation (ID 100010434) and from the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 847648 (LCF/BQ/PR21/11840004). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018), the EU’s Horizon Europe research and innovation programme under grant agreement number 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation, USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 860197 (MIRIADE), the EU Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915, #2022-00732), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALFagreement (#ALFGBG-715986, #ALFGBG-965240), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270), Hjärnfonden, Sweden (#FO2017-0243, #ALZ2022-0006), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022–2025 grant (SG-23-1038904 QC).S

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation

Rare Variants Associated with Arrhythmogenic Cardiomyopathy: Reclassification Five Years Later.

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis

Cell type-specific genetic regulation of gene expression across human tissues

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue

The impact of sex on gene expression across human tissues

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation