Study of breast cancer incidence in patients of lymphangioleiomyomatosis

The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized user

Aging and Brain Deterioration

Carlos Dotti and Vicente Rodríguez (coordinators).Advanced age significantly increases the risk of developing chronic diseases such as cancer, diabetes, cardiovascular, immune and mental disease. Regarding the latter, advanced age is a necessary factor for the development of non-hereditary forms of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Despite years of intense research, we still do not know how these diseases occur, this being one of the main reasons for the lack of adequate interventions to prevent or cure these pathologies. To overcome the current limitations in the field, we plan to: 1) generate basic knowledge on the mechanisms responsible for cognitive, behavioral, motor, metabolic and sociability disorders that occur with age, 2) define the mechanisms that determine individual susceptibility to neurodegeneration, 3) design and develop strategies to improve brain aging, and 4) explore social and environmental conditions of the older population to know their influence in brain degeneration. Individual, social and policy interventions must be considered for future research.Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Study of breast cancer incidence in patients of lymphangioleiomyomatosis

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000–2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32–5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29–9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized users

PM20D1-Derived treatment decreases amyloid pathology and improves cognitive performance in C. elegans and mouse models of Alzheimer's disease

Resumen del trabajo presentado a la 16th International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AP/PD), celebrada en Barcelona (España) del 15 al 20 de marzo de 2022.[Aims]: Alzheimer’s disease (AD) is a complex disorder caused by a combination of genetic and non-genetic factors, which are investigated by genome- (GWAS) and epigenome- (EWAS) wide association studies, respectively. Combining the strengths of both type of studies, we have recently identified a new genetic-epigenetic interaction on Peptidase M20 Domain Containing 1 (PM20D1) associated with AD. We showed that PM20D1 expression depends on a haplotype-dependent chromatin loop between PM20D1 enhancer and promoter regions, that PM20D1 expression is increased by AD-like stressors, and that its overexpression improves cognitive performance and reduces AD pathologies. However, the precise mechanism by which PM20D1 exerts its protective role in AD remains largely unknown. PM20D1 facilitates the condensation of fatty acids and amino acids generating a series of compounds named N-acyl amino acids (NAAs). NAAs are present in all tissues, including brain, yet little is known about their function and regulation.[Methods]: To investigate their role in AD, we NAA-treated AD primary cultures, worms and mouse models, and measured AD-related pathologies and cognitive performance. Furthermore, to unveil the underlying mechanisms, we applied snRNA-seq approaches and cell-type specific manipulations.[Results]: Following this approach, we demonstrate that NAAs modify the cellular phase of AD and improves cell survival, amyloid burden and cognitive performance.[Conclusions]: Our results therefore support the use of NAAs as a therapeutic approach for AD.Peer reviewe

Phylogenetic and in silico structural analysis of the Parkinson disease‐related kinase PINK1

10 páginas, 5 figuras, 1 tablaParkinson disease (PD) is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Mutations in PINK1 were shown to cause recessive familial PD, and today are proposed to be associated with the disease via mitochondrial dysfunction and oxidative damage. The PINK1 gene comprises eight exons, which encode a ubiquitously expressed 581 amino acid protein that contains an N-terminal mitochondrial targeting domain and a serine/threonine protein kinase. To better understand the relationship between PINK1 and PD we have first analyzed the evolutionary history of the gene showing its late emergence in evolution. In addition, we have modeled the three-dimensional structure of PINK1 and found some evidences that help to explain the effect of some PD-related mutations in this protein's function.Contract grant sponsor: The Ministerio de Ciencia e Innovacio´n, Spain; Contract grant number: SAF2009-10434; Contract grant sponsor: Generalitat Valenciana; Contract grant number: ACOMP/2010/096.Peer reviewe

Phylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1

10 páginas, 5 figuras, 1 tablaParkinson disease (PD) is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Mutations in PINK1 were shown to cause recessive familial PD, and today are proposed to be associated with the disease via mitochondrial dysfunction and oxidative damage. The PINK1 gene comprises eight exons, which encode a ubiquitously expressed 581 amino acid protein that contains an N-terminal mitochondrial targeting domain and a serine/threonine protein kinase. To better understand the relationship between PINK1 and PD we have first analyzed the evolutionary history of the gene showing its late emergence in evolution. In addition, we have modeled the three-dimensional structure of PINK1 and found some evidences that help to explain the effect of some PD-related mutations in this protein's function.Contract grant sponsor: The Ministerio de Ciencia e Innovacio´n, Spain; Contract grant number: SAF2009-10434; Contract grant sponsor: Generalitat Valenciana; Contract grant number: ACOMP/2010/096.Peer reviewe

MRI reveals reduced microstructural brain integrity in the APP/SEN1 mouse model of Alzheimer's disease

Póster presentado al FENS Forum, celebrado en Paris del 9 al 13 de julio de 2022 y al 19th Christmas Meeting, celebrado en el Instituto de Neurociencias (IN-CSIC-UMH) los días 20 y 21 de diciembre de 2022.Grant PGC2018-101055-B-I00.Peer reviewe

A DNA methylation fingerprint of 1628 human samples

Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human disease

A DNA methylation fingerprint of 1628 human samples

Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human disease