OncoCardioDB: a public and curated database of molecular information in onco-cardiology/cardio-oncology.

Numerous studies have been published which, separately, investigate the influence of molecular features on oncological and cardiac pathologies. Nevertheless, the relationship between both families of diseases at the molecular level is an emerging area within onco-cardiology/cardio-oncology. This paper presents a new open-source database that aims to organize the curated information concerning the molecular features validated in patients involved in both cancer and cardiovascular diseases. Entities like gene, variation, drug, study and others are modelled as objects of a database which is populated with curated information from 83 papers identified by systematic literature searched for up to 2021. Researchers will discover new connections among them to validate hypotheses or suggest new ones. Special care has been taken to use standard nomenclature for genes, pathologies and all the objects for which accepted conventions exist. The database can be consulted via the web with a system of simplified queries, but it also accepts any query. It will be updated and refined with the incorporation of new studies as they become available. Database URL http://biodb.uv.es/oncocardio/.

Plasma Exosomal Non-Coding RNA Profile Associated with Renal Damage Reveals Potential Therapeutic Targets in Lupus Nephritis.

Despite considerable progress in our understanding of systemic lupus erythematosus (SLE) pathophysiology, patient diagnosis is often deficient and late, and this has an impact on disease progression. The aim of this study was to analyze non-coding RNA (ncRNA) packaged into exosomes by next-generation sequencing to assess the molecular profile associated with renal damage, one of the most serious complications of SLE, to identify new potential targets to improve disease diagnosis and management using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The plasma exosomes had a specific ncRNA profile associated with lupus nephritis (LN). The three ncRNA types with the highest number of differentially expressed transcripts were microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and piwi-interacting RNAs (piRNAs). We identified an exosomal 29-ncRNA molecular signature, of which 15 were associated only with LN presence; piRNAs were the most representative, followed by lncRNAs and miRNAs. The transcriptional regulatory network showed a significant role for four lncRNAs (LINC01015, LINC01986, AC087257.1 and AC022596.1) and two miRNAs (miR-16-5p and miR-101-3p) in network organization, targeting critical pathways implicated in inflammation, fibrosis, epithelial-mesenchymal transition and actin cytoskeleton. From these, a handful of potential targets, such as transforming growth factor-ß (TGF-ß) superfamily binding proteins (activin-A, TGFB receptors, etc.), WNT/ß-catenin and fibroblast growth factors (FGFs) have been identified for use as therapeutic targets of renal damage in SLE.

Epigenetics of type 2 diabetes and diabetes-related outcomes in the Strong Heart Study.

BACKGROUND: The prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study. DNA methylation was measured using Illumina's MethylationEPIC beadchip. We also assessed the biological relevance of our findings using bioinformatics analyses. RESULTS: Among the 358 differentially methylated positions (DMPs) that were cross-sectionally associated either with fasting glucose or HOMA-IR, 49 were prospectively associated with incident type 2 diabetes, although no DMPs remained significant after multiple comparisons correction. Multiple of the top DMPs were annotated to genes with relevant functions for diabetes including SREBF1, associated with obesity, type 2 diabetes and insulin sensitivity; ABCG1, involved in cholesterol and phospholipids transport; and HDAC1, of the HDAC family. (HDAC inhibitors have been proposed as an emerging treatment for diabetes and its complications.) CONCLUSIONS: Our results suggest that differences in peripheral blood DNA methylation are related to cross-sectional markers of glucose metabolism and insulin activity. While some of these DMPs were modestly associated with prospective incident type 2 diabetes, they did not survive multiple testing. Common DMPs with diabetes epigenome-wide association studies from other populations suggest a partially common epigenomic signature of glucose and insulin activity.

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study.

BACKGROUND: Epigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45-74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989-1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993-1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings. RESULTS: Among 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein-protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases. CONCLUSION: We found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.

Biofluid Specificity of Long Non-Coding RNA Profile in Hypertension: Relevance of Exosomal Fraction.

Non-coding RNA (ncRNA)-mediated targeting of various genes regulates the molecular mechanisms of the pathogenesis of hypertension (HTN). However, very few circulating long ncRNAs (lncRNAs) have been reported to be altered in essential HTN. The aim of our study was to identify a lncRNA profile in plasma and plasma exosomes associated with urinary albumin excretion in HTN by next-generation sequencing and to assess biological functions enriched in response to albuminuria using GO and KEGG analysis. Plasma exosomes showed higher diversity and fold change of lncRNAs than plasma, and low transcript overlapping was found between the two biofluids. Enrichment analysis identified different biological pathways regulated in plasma or exosome fraction, which were implicated in fatty acid metabolism, extracellular matrix, and mechanisms of sorting ncRNAs into exosomes, while plasma pathways were implicated in genome reorganization, interference with RNA polymerase, and as scaffolds for assembling transcriptional regulators. Our study found a biofluid specific lncRNA profile associated with albuminuria, with higher diversity in exosomal fraction, which identifies several potential targets that may be utilized to study mechanisms of albuminuria and cardiovascular damage.

Novel molecular biomarkers of cancer therapy-induced cardiotoxicity in adult population: a scoping review.

AIM: Cancer treatments are associated with cardiotoxic events that predispose to cardiac pathology and compromise the survival of patients, making necessary the identification of new molecular biomarkers to detect cardiotoxicity. This scoping review aims to identify the available evidence on novel molecular biomarkers associated with cardiotoxicity in the adult population undergoing cancer therapy. METHODS AND RESULTS: The databases Medline, Web of Science, Scopus, and Embase were screened for the identification of published studies until 23 August 2020, searching for novel molecular biomarkers reported in cancer therapy-related cardiac dysfunction in adult patients. A total of 42 studies that met the eligibility criteria were included. Fourteen studies reported 44 new protein biomarkers, 18 studies reported 57 new single nucleotide polymorphism biomarkers, and 11 studies reported 171 new gene expression profiles associated with cardiotoxicity. Data were extracted for 272 novel molecular biomarkers reported and evaluated in 7084 cancer patients, of which only 13 were identified in more than one study (MPO, sST2, GDF-15, TGF-B1, rs1056892, rs1883112, rs4673, rs13058338, rs1695, miR-1, miR-25-3p, miR-34a-5p, and miR-423-5p), showing values for area under the curve > 0.73 (range 0.74-0.85), odds ratio 0.26-7.17, and hazard ratio 1.28-1.80. CONCLUSIONS: Multiple studies presented a significant number of novel molecular biomarkers as promising predictors for risk assessment of cardiac dysfunction related to cancer therapy, but the characteristics of the studies carried out and the determinations applied do not allow suggesting the clinical use of these molecular biomarkers in the assessment of cancer therapy-induced cardiotoxicity.

PROTEOMIC PROFILE OF ECHINOCOCCUS GRANULOSUS: A SYSTEMATIC REVIEW.

Cystic echinococcosis is a zoonotic disease caused by the larval stage of Echinococcus granulosus. This affliction is an endemic worldwide condition that represents a neglected parasitic disease with important socioeconomic repercussions. Proteomic characterization of larval and adult stages of E. granulosus, as well as the association between expression profiles and host interactions, is relevant for a better understanding of parasite biology, and eventually for drug design and vaccine development. This study aimed to develop a synthesis of the evidence available related to proteomics of E. granulosus. A systematic review was carried out to collect data concerning the proteomics of E. granulosus, without language or host restriction, published between 1980 and 2019. A systematic search was carried out in the Trip Database, BIREME-BVS, SciELO, Web of Science, PubMed, EMBASE, SCOPUS, EBSCO host, and LILACS, using MeSH terms, free words, and Boolean connectors, and adapting strategies to each source of information. Additionally, a manual cross-reference search was performed. Variables studied were the year of publication, geographic origin of the study, number of samples, hosts, parasitic organs, proteomic techniques, and parasite proteins verified. Nine-hundred and thirty-six related articles were identified: 17 fulfilled selection criteria, including slightly more than 188 samples. Most articles were published between 2014 and 2019 (64.7%) and were from Brazil and China (35.3% each). In reference to confirmed hosts in the primary articles, cattle (41.2%) and humans (23.5%) were the most frequently reported. Concerning proteomic techniques applied in the primary articles, LC-MS/MS was the most used (41.1%), and 890 proteins were reported by the primary articles. As the results of our search suggest, the information related to E. granulosus proteomics is scarce, heterogeneous, and scattered throughout several articles that include a diversity of tissues, samples, intermediate hosts, and proteomic techniques. Consequently, the level of evidence generated by our search is type 4.

Exosomal and Plasma Non-Coding RNA Signature Associated with Urinary Albumin Excretion in Hypertension.

Non-coding RNA (ncRNA), released into circulation or packaged into exosomes, plays important roles in many biological processes in the kidney. The purpose of the present study is to identify a common ncRNA signature associated with early renal damage and its related molecular pathways. Three individual libraries (plasma and urinary exosomes, and total plasma) were prepared from each hypertensive patient (with or without albuminuria) for ncRNA sequencing analysis. Next, an RNA-based transcriptional regulatory network was constructed. The three RNA biotypes with the greatest number of differentially expressed transcripts were long-ncRNA (lncRNA), microRNA (miRNA) and piwi-interacting RNA (piRNAs). We identified a common 24 ncRNA molecular signature related to hypertension-associated urinary albumin excretion, of which lncRNAs were the most representative. In addition, the transcriptional regulatory network showed five lncRNAs (LINC02614, BAALC-AS1, FAM230B, LOC100505824 and LINC01484) and the miR-301a-3p to play a significant role in network organization and targeting critical pathways regulating filtration barrier integrity and tubule reabsorption. Our study found an ncRNA profile associated with albuminuria, independent of biofluid origin (urine or plasma, circulating or in exosomes) that identifies a handful of potential targets, which may be utilized to study mechanisms of albuminuria and cardiovascular damage.

Echinococcus granulosus sensu lato Genotypes in Different Hosts Worldwide: A Systematic Review.

INTRODUCTION: The aim of this study was to develop a synthesis of the evidence available regarding verified E. granulosus sensu lato (s.l.) genotypes in different species worldwide. MATERIAL AND METHODS: A systematic review was performed including studies concerning genotypes of E. granulosus s.l. without language or genotyped method restriction, published between 1990 and 2020. A systematic search was carried out in Trip Database, BIREME, SciELO, LILACS, IBECS, PAHO-WHO, EMBASE, PubMed, Scopus, and WoS. Variables of interest were year of publication, country, number of samples, and hosts; genotypes, molecular marker, haplotypes and molecular biology techniques used. Descriptive statistics were applied. RESULTS: 2411 articles were analyzed, however 135 met the selection criteria, representing 8643 liver and lung samples. Of the samples selected 24% were human, the remaining samples pertained to non-human animal hosts; cattle and sheep prevailed with 28.6% and 26.6% of the studied samples, respectively. The reported evidence is mainly from Iran, Turkey, Argentina, China and Chile; with 50, 11, 6, 6 and 5 studies, respectively, published between 1992 and 2020 [most frequently during 2015-2020 (76/135 studies; 56.3%)]. The mitochondrial gene cox1 was generally sequenced and informative (91.8%). Genotypes most frequently identified were E. granulosus sensu stricto (s.s.) (83.2%). CONCLUSIONS: Based on this overall evidence, it can be concluded that publications related to genotypes of E. granulosus s.l. are heterogeneous. E. granulosus ss accounts for the vast majority of the global burden of E. granulosus s.l. worldwide. Further studies including larger number of cases and adequate internal validity are required to specify the distribution of genotypes in various host species. TRIAL REGISTRATION: PROSPERO CRD42018099827.

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions. Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model. Design, Setting, and Participants: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021. Exposure: Blood DNA methylation. Main Outcome and Measure: Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts. Results: The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts. Conclusions and Relevance: In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer.

The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.

DNA methylation and cancer incidence: lymphatic-hematopoietic versus solid cancers in the Strong Heart Study.

BACKGROUND: Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers. METHODS: Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms. RESULTS: Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers. CONCLUSIONS: This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.

Urinary- and Plasma-Derived Exosomes Reveal a Distinct MicroRNA Signature Associated With Albuminuria in Hypertension.

Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-ß1 (transforming growth factor ß1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-ß signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics (P<0.01). Similarly, decreased miR-26a levels were found in podocyte-derived exosomes after TGF-ß stress. Our results revealed an exosomes miRNA signature associated to albuminuria in hypertension. In particular, exosomes miR-26a seemed to play a key role in the regulation of TGF-ß, a relevant effector in podocyte damage. These findings support the use of exosomes miRNAs as biomarkers of cardiovascular risk progression and therapeutic tools in early kidney damage.

Genotipos de Echinococcus granulosus en hidatidosis humana alrededor del mundo: revisión sistemática / Echinococcus granulosus genotypes verified in human hydatid disease around the world: systematic review

Resumen Introducción: La evidencia sobre las características genotípicas de la infección por Echinococcus granulosus en humanos es escasa. Objetivo: Desarrollar un resumen de la evidencia disponible respecto a genotipos de E. granulosus verificados en hidatidosis humana en el mundo. Material y Métodos: Revisión sistemática. Se incluyeron artículos relacionados con genotipos de E. granulosus, en humanos, sin restricción de lenguaje ni método de secuenciación; publicados entre 1990-2019. Se realizó una búsqueda sistemática en WoS, EMBASE, MEDLINE, SCOPUS, Trip Database, BIREME, SciELO, LILACS, IBECS y OPS-OMS. Las variables en estudio fueron: año de publicación, país de origen, número de muestras, órganos parasitados, marcador molecular utilizado y genotipo identificado. Se aplicó estadística descriptiva. Resultados: Se identificaron 701 artículos relacionados; 62 cumplieron los criterios de selección, representando 1.511 muestras. La evidencia existente fue publicada entre 1994 y 2019 y proviene principalmente de Irán (45,2%). El método de secuenciación más utilizado fue amplificación por reacción de polimerasa en cadena más secuenciación tipo Sanger con genotipificación del gen cox1 (79,0%). Los genotipos identificados con mayor frecuencia fueron G1 (49,1%) y el complejo G1/G3 (32,2%). Conclusión: Las publicaciones relacionadas con genotipos de E. granulosus en humanos son escasas y heterogéneas. Eg G1 representa la mayor parte de la carga global mundial.

Abstract Background: The evidence regarding genotypic characteristics of Echinococcus granulosus infection in humans worldwide is scarce. Aim: To develop a synthesis of the available evidence regarding genotypes of E. granulosus verified in humans worldwide. Methods: Systematic review. Articles related with genotypes of E. granulosus, in humans, without language neither genotyped method restriction, published between 1990-2019 were included. A systematic in WoS, EMBASE, MEDLINE, SCOPUS, Trip Database, BIREME, SciELO, LILACS, IBECS, and PAHO-WHO was carried out. In study variables were year of publication, country, number of samples, host and parasite organs, genotype identified, molecular marker and genes. Descriptive statistics were applied. Results: 701 related articles were identified; 62 fulfilled selection criteria, representing 1,511 samples. The existing evidence was published between 1994 and 2019; and mainly comes from Iran (45.2%). The most commonly used sequencing method was PCR amplification and Sanger type sequencing with partial or total genotyping of the cox1 gene. Genotyped method most frequently used was cox1 (79,0%). Genotypes most frequently identified were G1 and G1/G3 complex (49.1% and 32.2%). Conclusions: Publications related to genotypes of Eg in humans are scarce, heterogeneous, and presenting differing results. Eg G1/G3 accounts for most of the global burden worldwide.

Clinical aspects of abdominal actinomycosis: a systematic review.

BACKGROUND: Abdominal actinomycosis (AA) is a rare infection. The aim of this study was to summarize the evidence available on AA. METHODS: A systematic review was conducted. Data sources included Trip Database, BIREME, SciELO, Cochrane Library, WoS, MEDLINE, EMBASE, SCOPUS, IBECS and LILACS. Eligibility criteria included: studies related to surgically treated AA, in adult population, without language and sex restriction, published between 1966 and 2019. The following variables were analysed: publication year, age, sex, geographical origin, location of lesions, clinical manifestations, risk factors, species isolated and treatments used. RESULTS: A total of 1505 studies were initially identified. After scrutinizing titles and abstracts, and checking duplications, 221 articles including 406 subjects with AA were included. All were case reports or series. Mean age of subjects was 49.2 years and 56.2% were female. The highest proportion of articles was published between 2015 and 2019 (18.7%). Publications were predominantly from the USA (12.2%). Structures usually involved were abdominal wall, colon and appendix. The most common presentation was abdominal mass (39.2%). In 42.1% of patients, an associated factor was found, highlighting intrauterine devices (14.3%). The microbiology studies highlighted Actinomyces israelli. Morbidity, recurrence and verified mortality were 18.2%, 1.0% and 2.2%, respectively. Penicillin was the most used antibiotic. CONCLUSION: Evidence about AA is scarce and dispersed within a reduced range of articles and cases.

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein-protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.

[Echinococcus granulosus genotypes verified in human hydatid disease around the world. Systematic review]. / Genotipos de Echinococcus granulosus en hidatidosis humana alrededor del mundo. Revisión sistemática.

BACKGROUND: The evidence regarding genotypic characteristics of Echinococcus granulosus infection in humans worldwide is scarce. AIM: To develop a synthesis of the available evidence regarding genotypes of E. granulosus verified in humans worldwide. METHODS: Systematic review. Articles related with genotypes of E. granulosus, in humans, without language neither genotyped method restriction, published between 1990-2019 were included. A systematic in WoS, EMBASE, MEDLINE, SCOPUS, Trip Database, BIREME, SciELO, LILACS, IBECS, and PAHO-WHO was carried out. In study variables were year of publication, country, number of samples, host and parasite organs, genotype identified, molecular marker and genes. Descriptive statistics were applied. RESULTS: 701 related articles were identified; 62 fulfilled selection criteria, representing 1,511 samples. The existing evidence was published between 1994 and 2019; and mainly comes from Iran (45.2%). The most commonly used sequencing method was PCR amplification and Sanger type sequencing with partial or total genotyping of the cox1 gene. Genotyped method most frequently used was cox1 (79,0%). Genotypes most frequently identified were G1 and G1/G3 complex (49.1% and 32.2%). CONCLUSIONS: Publications related to genotypes of Eg in humans are scarce, heterogeneous, and presenting differing results. Eg G1/G3 accounts for most of the global burden worldwide.

ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer.

Most of colorectal cancer CRC-related death is due to metastasis and the finding of markers for prognosis of invasiveness, constitutes an appealing challenge. Here, after analysing cDNA array containing 43 tumour and 5 normal mucosa samples, we report that the expression of the ZNF518B gene as a whole and that of its two major splicing isoforms are significantly increased in tumours. The canonical isoform was also up-regulated in a patients' cohort containing 70 tumour and 69 adjacent tissue samples. The effects of silencing ZNF518B on the phenotype of CRC cell lines were then studied. The gene does not affect cell proliferation, but plays a significant role in cell migration and invasiveness and induces changes in the epithelial-to-mesenchymal transition markers, suggesting that ZNF518B favours tumour cell dissemination. To study the regulation of the gene, transcription-related changes in nucleosomal organisation and epigenetic marks around the transcriptional start site were analysed. The positioning of a nucleosome over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with gene expression. Inhibition of histone deacetylases increases the transcription of ZNF518B, which may be a candidate for invasiveness prognosis in CRC and a target for epigenetic drugs.

OMICfpp: a fuzzy approach for paired RNA-Seq counts.

BACKGROUND: RNA sequencing is a widely used technology for differential expression analysis. However, the RNA-Seq do not provide accurate absolute measurements and the results can be different for each pipeline used. The major problem in statistical analysis of RNA-Seq and in the omics data in general, is the small sample size with respect to the large number of variables. In addition, experimental design must be taken into account and few tools consider it. RESULTS: We propose OMICfpp, a method for the statistical analysis of RNA-Seq paired design data. First, we obtain a p-value for each case-control pair using a binomial test. These p-values are aggregated using an ordered weighted average (OWA) with a given orness previously chosen. The aggregated p-value from the original data is compared with the aggregated p-value obtained using the same method applied to random pairs. These new pairs are generated using between-pairs and complete randomization distributions. This randomization p-value is used as a raw p-value to test the differential expression of each gene. The OMICfpp method is evaluated using public data sets of 68 sample pairs from patients with colorectal cancer. We validate our results through bibliographic search of the reported genes and using simulated data set. Furthermore, we compared our results with those obtained by the methods edgeR and DESeq2 for paired samples. Finally, we propose new target genes to validate these as gene expression signatures in colorectal cancer. OMICfpp is available at http://www.uv.es/ayala/software/OMICfpp_0.2.tar.gz . CONCLUSIONS: Our study shows that OMICfpp is an accurate method for differential expression analysis in RNA-Seq data with paired design. In addition, we propose the use of randomized p-values pattern graphic as a powerful and robust method to select the target genes for experimental validation.