Publications

Supplementary Figures S1, S2 and S3 from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

<p>Supplementary Figure S1. Cell viability and colony formation assays of the indicated cell lines. Supplementary Figure S2. Multidimensional scaling plots Supplementary Figure S3. Cell viability assays and western blots</p>

CSL–MAML-dependent Notch1 signaling controls T lineage–specific IL-7Rα gene expression in early human thymopoiesis and leukemia

Supplementary Table 3 from KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer

<p>Supplementary Table 3. The twenty-eight HDAC inhibitors used in the study and their specificity</p>

Supplementary Table 3 from Epigenetic <i>EGFR</i> Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas

<p>Supplementary Table 3</p>

[P1–410]: HIGHER PREVALENCE OF CEREBRAL WHITE MATTER HYPERINTENSITIES IN HOMOZYGOUS APOE‐ε4 ALLELE CARRIERS AGED 45 TO 75: RESULTS FROM THE ALFA STUDY

Cerebral white matter hyperintensities (WMH) are believed to be the consequence of small vessel disease and are associated with risk and progression of Alzheimer's disease (AD). The ε4 allele of the Apolipoprotein E (APOE) gene is the major factor accountable for AD heritability. However, the relationship between WMH and APOE genotype in healthy subjects remains controversial. We aimed at investigating the association between APOE-ε4 and vascular risk factors with WMH, and explore their interactions, in the Alzheimer and Families (ALFA) cohort of cognitively healthy adults (45–75 years). WMH were assessed with the Fazekas Scale from magnetic resonance images (575 participants: 74 APOE-ε4 homozygotes, 220 APOE-ε4 heterozygotes and 281 noncarriers) and individuals classified into normal (Fazekas<2) and pathological (≥2). In addition to APOE, cardiovascular risk factors were recorded and cardiovascular and dementia risk scores computed. Stepwise logistic regression analysis was used to study the association between pathological Fazekas and APOE genotype after correcting for cardiovascular and sociodemographic factors. APOE-ε4 homozygotes, but not heterozygotes, bear a significantly higher risk (OR 3.432; 95% CI [1.297–9.082]; p=0.013) of displaying pathological WMH, which is independent of cardiovascular risk factors effect. As expected, age, hypertension and cardiovascular and dementia risk scales were also positively associated to pathological WMH. Cognitively healthy late-middle aged APOE-ε4 homozygotes show a higher risk of presenting pathological WMH. The control of modifiable risk factors in individuals at higher risk of developing WMH might represent a preventive strategy to reduce or delay dementia's onset.

Empirical evidence on tax cooperation between sub-central administrations

The literature on horizontal tax interdependence pays limited attention to interactions in administrative policies, although they can play a large role in determining the amount of tax revenues collected. We investigate the incentives for sub-central tax authority cooperation in a decentralized context, with the aim of identifying the determinants of that cooperation. Our results are congruent with standard theory; in particular, the existence of reciprocity is essential for sharing tax information, but there is sluggishness in this process, which is partly the result of the short-sighted behaviour of tax authorities influenced by budget constraints. Hence, this is good news for the functioning of a decentralized tax administration, as in the medium-long run the gains to be made from sharing tax information are achieved.

Figure S11 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

&lt;p&gt;Protein levels of ERBB4 was measured by FACS (A) and immunoblotting (B) in JEKO1 cells engineered to increase the expression of ERBB. Drug sensitivity for idelalisib (C) and ibrutinib (D) was evaluated in the different clones of engineered JEKO1. (A) Representative plot of two independent experiments. Boxplot and density plot shows the median MFI values of the two replicates: negative control (black), JEKO1-CNT (control, grey) and JEKO1-ERBB4 (sgRNA-erbb4, red). Results are presented from Welch Two Sample test performed on MFI values of the two experiments. (B) Immunoblotting for ERBB4 in JEKO1-CNT (control, grey) and JEKO1-ERBB4 (sgRNA-erbb4, red). Representative image of two independent experiments. Data on the barplot represents the mean of two experiments, errors bars represent standard deviation of the mean. * for p&lt;0.05 from a t-test. (C-D) Cell viability was evaluated by MTT assay (72h). JEKO1-CNT (control, blue) and JEKO1-ERBB4 (ERBB4-sgRNA3 in red) cells were stimulated with PBS (left panel) or HBEGF (30ng/mL, right panel) for 4 hours and the exposed to increasing concentrations of idelalisib (C) or ibrutinib (D). Error bars correspond to standard deviation of the mean. Data derived from two independent experiments. Statistically significant differences were evaluated by moderated t-test comparing each treatment to control. * for p&lt;0.05.&lt;/p&gt;

Epigenomic Analysis of Acute Myeloid Leukemia Identifies Specific Patterns and Markes with Clinical and Biological Relevance.

Supplementary Figure 3 from Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells

Supplementary Figure 3 from Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells

An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Abstract Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2 -Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2 -Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.

Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease

Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the “chronic inflammation-dysplasia-cancer” carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations.

Supplementary Figure 1 from A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer

&lt;p&gt;Flow chart indicating study design and biological and bioinformatic filters&lt;/p&gt;

Supplemental Figure S2 from The NCI-60 Methylome and Its Integration into CellMiner

&lt;p&gt;Relationship between methylation and lack of SLFN11 and MGMT expression in the NCI-60.&lt;/p&gt;

Targeting lymphoid-derived IL-17 signaling to delay skin aging

Abstract Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, γδ T cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-κB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments.

Promoter hypermethylation of the phosphatase DUSP22 mediates PKA‐dependent TAU phosphorylation and CREB activation in Alzheimer's disease

ABSTRACT Genetic screening in Alzheimer's disease (AD) has identified only a handful of genes that are mutated in the disorder. Thus, for a very large proportion of patients, the biology of their disease is poorly understood. Epigenetic alterations may provide an explanation in these cases. Using DNA methylation profiles of human hippocampus from controls and patients, we have identified the presence of promoter hypermethylation of the dual‐specificity phosphatase 22 (DUSP22) gene in AD. DUSP22 is a likely candidate gene for involvement in the pathogenesis of the disorder since, as we demonstrate here, it inhibits PKA activity and thereby determines TAU phosphorylation status and CREB signaling. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study

Abstract Background and purpose The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery ( n = 643) and Replication ( n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery ( p value &lt; 10 –06 ) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. Results The meta-analysis revealed an epigenome-wide significant association in EXOC4 ( p value = 8.4 × 10 –08 ) and in MERTK ( p value = 1.56 × 10 –07 ). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts ( p value = 1.14 × 10 –06 and p value = 1.3 × 10 –02 , respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = − 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = − 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. Conclusions DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation.

Genetic proxies for predicting plasma protein levels reveal TIMP2 role in human cognitive performance

Abstract Background Murine studies have identified blood proteins that influence brain aging, but translating these findings to humans remains challenging. We used an innovative approach to investigate whether genetically predicted blood levels of proteins linked to brain aging in animal models are associated with cognitive performance in individuals at risk of Alzheimer’s disease (AD) [ Figure 1 ]. Method Through systematic review, we identified 13 circulating proteins with an aging/rejuvenating effect on the mouse brain. We retrieved summary statistics of protein quantitative trait loci (pQTLs) associated with these proteins in human plasma from the Fenland study (Pietzner et al., 2021). We validated their predictive capacity by computing protein‐based genetic scores (protPRS) in 1,380 cognitively unimpaired (CU) individuals from the Knight‐ADRC cohort and analyzing their association with plasma protein levels (measured by Somalogic). We also computed the protPRS for 410 CU individuals at risk for AD from the ALFA+ study (60% women, 55% APOE‐ε4 carriers; Table 1 ) and assessed their associations with cognitive performance through linear models adjusted by age, sex, and years of education. Stratified models by sex, APOE‐ε4 carriership, and Aβ status were also assessed. pQTLs included in the significant scores were annotated to explore their biological significance. Result Most computed protPRS (10/13) significantly predicted plasma protein levels in the Knight‐ADRC cohort. In ALFA+, we found a significant association between genetic predisposition to elevated plasma TIMP2 (TIMP2‐protPRS) and better cognitive performance (PACC and episodic memory composites). Associations of TIMP2‐protPRS with PACC remained significant in stratified models [ Figure 2 ]. TIMP2‐protPRS was associated with the actual plasma TIMP2 levels in ALFA+. The annotated pQTLs included in the TIMP2‐protPRS were associated with traits related with cognition and neuropsychiatric disorders. We also found an age‐dependent expression of genes regulating blood TIMP2 levels in the human brain. Conclusion Protein‐based PRS computation may overcome translational challenges encountered in animal studies. Through this method, we showed that genetically predicted levels of plasma TIMP2, known for its rejuvenating effect on mice’s brain, are linked to cognitive performance in CU at risk of AD. This highlights TIMP2 as a potential therapeutic target for age‐related brain diseases.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study

Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.