Identification of miR-660-5p targets involved in breast cancer progression

Background: Breast cancer (BC) is the most diagnosed cancer in women globally. MicroRNAs (miRNAs) participate in different processes of BC; their deregulation can make them act as oncogenes or tumor suppressors, participating in cancer progression. Using the TCGA (The Cancer Genome Atlas) database, we found miR-660-5p significantly overexpressed and associated with poor survival in patients with this pathology. It is reported that miR-660-5p induces proliferation, migration, and invasion in BC. However, the specific targets of this miRNA that induce each of these processes are unknown. In this project we propose to identify the targets of miR-660-5p involved in proliferation, migration, invasion, and angiogenesis in BC cells. Methods: The basal levels of miR-660-5p were determined by RT-qPCR. The effect of miR-660-5p was evaluated on proliferation, invasion, and migration processes in MDA-MB-231 and MCF-7 cells, and angiogenesis in HUVEC cells transfected with the miR-660-5p inhibitor. We identified targets of miR-660-5p using different databases, and we evaluated their expression by RT-qPCR in plate. Results: In this study, we found that miR-660-5p is significantly upregulated in BC cells MDA-MB-231 and MCF-7, compared to normal breast cells MCF-10A. In addition, we observed a significantly decrease in the processes of proliferation, migration, and invasion in BC cells, compared to untreated cells and negative control group. Similarly, we observed a significantly decrease in the angiogenesis process in HUVEC cells, compared to untreated cells and negative control group. Likewise, by analyzing the different databases and the literature, we found a total of 28 miR-660-5p targets involved in oncological processes. Conclusions: miR-660-5p is overexpressed in BC cells compared to healthy breast cells. Furthermore, miR-660-5p induces the processes of proliferation, migration and invasion in BC cells, and angiogenesis in HUVEC cells

Synbiotic therapy decreases microbial translocation and inflammation and improves immunological status in HIV-infected patients: a double-blind randomized controlled pilot trial

BACKGROUND: HIV-infection results in damage and dysfunction of the gastrointestinal system. HIV enteropathy includes pronounced CD4+ T-cell loss, increased intestinal permeability, and microbial translocation that promotes systemic immune activation, which is implicated in disease progression. A synbiotic is the combination of probiotics and prebiotics that could improve gut barrier function. Our study goal was to determine whether the use of a synbiotic, probiotics or a prebiotic can recover immunological parameters in HIV-infected subjects through of a reduction of microbial translocation and pro-inflammatory cytokine production. METHODS: A randomized, double-blind controlled study was performed; twenty Antiretroviral treatment-naïve HIV-infected subjects were subgrouped and assigned to receive a synbiotic, probiotics, a prebiotic, or a placebo throughout 16 weeks. RESULTS: We had no reports of serious adverse-events. From baseline to week 16, the synbiotic group showed a reduction in bacterial DNA concentrations in plasma (p = 0.048). Moreover, the probiotic and synbiotic groups demonstrated a decrease in total bacterial load in feces (p = 0.05). The probiotic group exhibited a significant increment of beneficial bacteria load (such as Bifidobacterium; p = 0.05) and a decrease in harmful bacteria load (such as Clostridium; p = 0.063). In the synbiotic group, the CD4+ T-cells count increased (median: +102 cells/μL; p = 0.05) and the level of Interleukin 6 cytokine decreased significantly (p = 0.016). CONCLUSIONS: Our study showed a significant increase in CD4+ T lymphocyte levels in the synbiotic group, which could delay the initiation of antiretroviral therapy and decrease costs in countries with limited resources

Checklist of the vascular plants of the Cantabrian Mountains

We present the first standardized list of the vascular flora of the Cantabrian Mountains, a transitional zone between the Eurosiberian and Mediterranean biogeographic regions in northwestern Spain. The study area comprises 15000 km2 divided in UTM grid cells of 10 km x 10 km, for which we revised occurrence data reported in the Spanish Plant Information System (Anthos) and the online database of Iberian and Macaronesian Vegetation (SIVIM). We used a semi-automatic procedure to standardize taxonomic concepts into a single list of names, which was further updated by expert-based revision with the support of national and regional literature. In the current version, the checklist of the Cantabrian Mountains contains 2338 native species and subspecies, from which 56 are endemic to the study area. The nomenclature of the checklist follows Euro+Med in 97% of taxa, including annotations when other criteria has been used and for taxa with uncertain status. We also provide a list of 492 non-native taxa that were erroneously reported in the study area, a list of local apomictic taxa, a phylogenetic tree linked to The Plant List, a standardized calculation of Ellenberg Ecological Indicator Values for 80% of the flora, and information about life forms, IUCN threat categories and legal protection status. Our review demonstrates how the Cantabrian mountains represent a key floristic region in southern Europe and a relevant phytogeographical hub in south-western Europe. The checklist and all related information are freely accessible in a digital repository for further uses in basic and applied researchThis research was supported by the Jardín Botánico Atlántico de Gijón (SV-20-GIJON-JBA) and SEEDALP project (Spanish Reearch Agency; PID2019-108636GA/AEI/10.13039/501100011033)Peer reviewe

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues