MicroRNAs in colorectal cancer

Colorectal cancer (CRC) is the third most common type of cancer worldwide, currently representing the most common gastrointestinal cancer with 13% of all malignant tumors. MicroRNAs (miRNAs) are small non-coding RNAs that repress the translation of target genes. Since their discovery, they have been shown to play an important role in the development of cancer, since they can act as tumor suppressors or oncogenes. A literature review was performed in different databases such as Medline, PubMed, Cochrane, nature, Wolters Kluwer, ScienceDirect, Scopus, SpringerLink, Wiley Online Library. Studies were included from 2003 to 2018. Colorectal cancer presents genetic heterogeneity, because it can develop in different ways, the pathway through which cancer occurs depends on the gene initially altered. The aberrant expression of microRNAs is implicated in the development of colorectal cancer and its progression. Three existing steps in the maturation of the microRNAs have been identified: 1) transcription of the pri-miRNA, 2) cleavage in the nucleus to form the pre-miRNA and 3) a final excision in the cytoplasm to form the mature microRNA. It has been discovered that miRNAs have an impact on cell proliferation, apoptosis, stress response, maintenance of stem cell potency and metabolism, all important factors in the etiology of cancer. The data analyzed in this article highlights the importance of the study of microRNAs in colorectal cancer, however, for the carcinogenic process, progression, therapeutic management and prognosis, more multicenter randomized clinical trials are needed with a detailed analysis

Bioinformatics analysis of mutations in SARSCoV- 2 and clinical phenotypes

1 p.-1 fig.-8 tab.Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially reported in Wuhan (China) hasspread worldwide. Like other viruses, SARS-CoV-2 accumulates mutations with each cycle of replication by continuously evolving a viral strain with one or more single nucleotide variants (SNVs). However, SNVs that cause severe COVID-19 or lead to immune escape or vaccine failure are not well understood. We aim to identify SNVs associated with severe clinical phenotypes.Methods: In this study, 27429 whole-genome aligned consensus sequences of SARS-CoV-2 were collected from genomic epidemiology of SARS-CoV-2 project in Spain (SeqCOVID) [1]. These samples were obtained from patients who required hospitalization and/or intensive care unit admission (ICU), excluding those registered in the first pandemic wave.Besides, 248 SARS-CoV-2 genomes were isolated from COVID-19 hospitalized patients from Gregorio Marañon General University Hospital (GMH) of which 142 were fully vaccinated. Bioinformatics tools using R and Python programming languages were developed and implemented comparing those to SARS-CoV-2 Wuhan-Hu-1 (reference genome).Results: Using a selection threshold mutational frequency 10%, 27 SNVs were expected to have association with hospitalization and ICU risk. The reference haplotype differing at the SNV coding for lysine at the residue 203 (N:R203K) was found to have negative association with COVID-19 hospitalization risk (p = 5.37 x 10-04). Similarly, a negative association was observed when the residue at 501 is replaced by tyrosine (S:N501Y) (p = 1.33 x 10-02). The application of a Chi-square test suggested that SNV-haplotypes coding for mutants residues such as (S:A222V, N:A220V, ORF10:V30L) and (ORF1a:T1001I, ORF1a:I2230T, S:N501Y, S:T716S, S:S982A, ORF8:Q27*, N:R203K, N:S235F) have negative associations with COVID-19 hospitalization risk (p = 6.58 x 10-07 and p = 2.27 x 10-16, respectively) and COVID-19 ICU risk (p = 1.15 x 10-02 and p = 2.51 x 10-02, respectively). Focusing on the SNV-haplotype coding the mutations (S:A222V, N:A220V, N:D377Y, ORF10:V30L) were observed to increase the risk of COVID-19 hospitalization (p = 2.71 x 10-04). Results from SARS-CoV-2 genomes analysis from GMH showed 63 coding SNVs which met the established threshold value. Applying a Chi-square test, the SNV-haplotype carrying coding variants for mutant residues in 5 ORF proteins and surface and membrane glycoprotein and nucleocapsid phosphoprotein was significantly associated with vaccine failure in hospitalized COVID-19 patients (p = 7.91 x 10-04).Conclusions: SNV-haplotypes carrying variants lead to non-synonymous mutations located along SARS-CoV-2 wholeproteome may influence COVID-19 severity and vaccine failure suggesting a functional role in the clinical outcome for COVID-19 patients.This research work was funded by the European Commission-NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global)Peer reviewe

Serological reactivity against T. cruzi-derived antigens: Evaluation of their suitability for the assessment of response to treatment in chronic Chagas disease.

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects more than 6 million people worldwide. Following a mostly asymptomatic acute phase, the disease progresses to a long-lasting chronic phase throughout which life-threatening disorders to the heart and/or gastrointestinal tract will manifest in about 30% of those chronically infected. During the chronic phase, the parasitemia is low and intermittent, while a high level of anti-T. cruzi antibodies persist for years. These two features hamper post-chemotherapeutic follow-up of patients with the tools available. The lack of biomarkers for timely assessment of therapeutic response discourages a greater use of the two available anti-parasitic drugs, and complicates the evaluation of new drugs in clinical trials. Herein, we investigated in a blinded case-control study the serological reactivity over time of a group of parasite-derived antigens to potentially address follow up of T. cruzi chronically infected subjects after treatment. We tested PFR2, KMP11, HSP70, 3973, F29 and the InfYnity multiplexed antigenic array, by means of serological assays on a multi-national retrospective collection of samples. Some of the antigens exhibited promising results, underscoring the need for further studies to determine their potential role as treatment response biomarkers.We thank Dr. A. Egui, Dr A. Fernández-Villegas and A. López-Barajas from IPBLNsingle bondCSIC (Granada, Spain), Carme Subirá from ISGlobal (Barcelona, Spain), and Suelene B. N. Tavares from Hospital das Clínicas (Goiás, Brazil) for their technical assistance. We also want to thank Dr. B. Carrilero from Hospital Virgen de la Arrixaca (Murcia, Spain), Dr. Dayse E.C. de Oliveira from Hospital das Clínicas (Goiás, Brazil), and Dr. Raúl Chadi from Hospital General de Agudos “Dr. I. Pirovano” for their clinical follow up of patients. ISGlobal authors thanks the support by the Departament d'Universitats i Recerca de la Generalitat de Catalunya, Spain (AGAUR; 2017SGR00924), funding by the Instituto de Salud Carlos III project PI18/01054 and RICET Network for Cooperative Research in Tropical Diseases (RD12/0018/0010) and FEDER, and the support to ISGlobal from the Spanish Ministry of Science Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023″ Program (CEX2018–000806-S), and from the Generalitat de Catalunya through the CERCA Program. IPBLN work was financially supported by grants SAF2016–81003-R and SAF2016–80998-R from the Programa Estatal I + D + i (MINECO) and ISCIII RICET (RD16/0027/0005) and FEDER. MJP research is supported by the Ministry of Health, Government of Catalunya (PERIS 2016–2010 SLT008/18/00132). TAJ thanks the support of Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq/ 313011/2018–4) and Fundação Oswaldo Cruz/MS (25380.001603/2017–89). Authors also thank Drugs for Neglected Diseases initiative and Fundacion Mundo Sano for financial support. For this project, DNDi received financial support from the following donors: UK Aid, UK; Directorate-General for International Cooperation (DGIS), The Netherlands; Swiss Agency for Development and Cooperation (SDC), Switzerland; Médecins Sans Frontières (MSF), International. The donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Genomic surveillance and impact of SARS-CoV-2 mutations

Resumen del póster presentado a las II Jornadas Científicas PTI + Salud Global, celebradas los días 5 y 6 de octubre de 2022 en el Auditorio Santiago Grisolía de Valencia (España).Peer reviewe

Trends and outcome of neoadjuvant treatment for rectal cancer: A retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project

Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons. Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006–2009; II)2010–2013; III)2014–2017. Survival analyses were run for 3-year survival in timeframes I-II. Results: Out of 14, 391 patients, 8871 (61.6%) received neoadjuvant treatment. Long-course chemo/radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemotherapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%, p = 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p = 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p = 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59–0.87, Cochrane-Mantel-Haenszel P = 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, preoperative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers. Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN + benefited the most

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

The DnaB.DnaC complex: a structure based on asymmetric interactions among dimers assembled around an occluded channel

Replicative helicases are motor proteins that unwind DNA at replication forks. Escherichia coli DnaB is the best characterized member of this family of enzymes. We present the 26 Angstrom resolution three-dimensional structure of the DnaB hexamer in complex with its loading partner, DnaC, obtained from cryo-electron microscopy. Analysis of the volume brings insight into the elaborate way the two proteins interact, and provides a structural basis for control of the symmetry state and inactivation of the helicase by DnaC, The complex is arranged on the basis of interactions among DnaC and DnaB dimers, DnaC monomers are observed for the first time to arrange as three dumb-bell-shaped dimers that interlock into one of the faces of the helicase, This could be responsible for the freezing of DnaB in a C-3 architecture by its loading partner. The central channel of the helicase is almost occluded near the end opposite to DnaC, such that even single-stranded DNA could not pass through. We propose that the DnaB N-terminal domain is located at this face

The DnaB·DnaC complex: a structure based on dimers assembled around an occluded channel

Replicative helicases are motor proteins that unwind DNA at replication forks. Escherichia coli DnaB is the best characterized member of this family of enzymes. We present the 26 Å resolution three-dimensional structure of the DnaB hexamer in complex with its loading partner, DnaC, obtained from cryo-electron microscopy. Analysis of the volume brings insight into the elaborate way the two proteins interact, and provides a structural basis for control of the symmetry state and inactivation of the helicase by DnaC. The complex is arranged on the basis of interactions among DnaC and DnaB dimers. DnaC monomers are observed for the first time to arrange as three dumb-bell-shaped dimers that interlock into one of the faces of the helicase. This could be responsible for the freezing of DnaB in a C(3) architecture by its loading partner. The central channel of the helicase is almost occluded near the end opposite to DnaC, such that even single-stranded DNA could not pass through. We propose that the DnaB N-terminal domain is located at this face