Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Statins and Gliomas: A Systematic Review of the Preclinical Studies and Meta-Analysis of the Clinical Literature

Background Gliomas represent most common primary brain tumors. Glioblastoma (GBM) is the most common subtype and carries a poor prognosis. There is growing interest in the anti-glioma properties of statins. The aim of this study was to conduct a systematic review of the preclinical literature and to meta-analyze existing clinical studies to determine what benefit, if any, statins may confer in the context of glioma. Methods The PubMed, Embase, Cochrane, and Web of Science libraries were queried in May 2021. Preclinical studies were included if they investigated the anti-cancer effects of statins in glioma in vitro and in vivo. Clinical studies were included if they reported incidence rates of glioma by statin use, or mortality outcomes among GBM patients by statin use. Pooled point estimates were calculated using a random-effects model. Results In total, 64 publications, 51 preclinical and 13 clinical, were included. Preclinical studies indicated that statins inhibited glioma cell proliferation, migration, and invasion. These effects were time- and concentration-dependent. Synergistic anti-glioma effects were observed when statins were combined with other anti-cancer therapies. Clinical observational studies showed an inverse, albeit non-statistically significant, association between statin use and incidence rate of glioma (HR = 0.84, 95% CI 0.62-1.13, I-2 = 72%, p-heterogeneity = 0.003, 6 studies). Statin use was not associated with better overall survival following GBM surgery (HR = 1.05, 95% CI 0.85-1.30, I-2 = 30%, p-heterogeneity = 0.23, 4 studies). Conclusion Statins were potent anti-cancer drugs that suppressed glioma growth through various mechanisms in vitro; these effects have translated into the clinical realm, clinically but not statistically, in terms of glioma incidence but not GBM survival.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA-mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1(N17)) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization

Charcot-marie-tooth: Present situation and prospects [Enfermedad de charcot-marie-tooth: Actualidad perspectivas]

The Charcot-Marie-Tooth disease is defined as a sensory-motor polineurophatic abnormality, of demyelinating or axonal type, and genetic and clinical heterogeneity. Objective: This review is intended to update the clinical spectrum of this disease, as well as to know the molecular and therapeutic advances that contribute to understand and manage better this heterogeneous entity. Development: The Charcot-Marie-Tooth disease is a genetically complex syndrome with more than 30 associated genes; it is one of the more common hereditary neuropathies, whose reports indicate an estimated prevalence of 17-25 cases / 100,000 inhabitants. The clinical spectrum is broad, without an established genotype-phenotype correlation; however, there are a number of clinical features that allow their inclusion in several clinical subtypes. Typically, the patients present with distal muscle weakness and atrophy often associated with foot sensory loss and mild to moderate depression of tendon reflexes. Conclusions: The Charcot-Marie-Tooth classification is complex and constantly subject to a review of new genes and mutations. The observed clinical variability coincides with the involvement of different genes and proteins that help maintain function and integrity of the peripheral nerve, so that they become an important research target for developing new and better therapies. © INNN 2012

Characterization of the 5? and 3? breakpoints of the Spanish (??)0-thalassemia deletion in Mexican patients

The Charcot-Marie-Tooth disease is defined as a sensory-motor polineurophatic abnormality, of demyelinating or axonal type, and genetic and clinical heterogeneity. Objective: This review is intended to update the clinical spectrum of this disease, as well as to know the molecular and therapeutic advances that contribute to understand and manage better this heterogeneous entity. Development: The Charcot-Marie-Tooth disease is a genetically complex syndrome with more than 30 associated genes; it is one of the more common hereditary neuropathies, whose reports indicate an estimated prevalence of 17-25 cases / 100,000 inhabitants. The clinical spectrum is broad, without an established genotype-phenotype correlation; however, there are a number of clinical features that allow their inclusion in several clinical subtypes. Typically, the patients present with distal muscle weakness and atrophy often associated with foot sensory loss and mild to moderate depression of tendon reflexes. Conclusions: The Charcot-Marie-Tooth classification is complex and constantly subject to a review of new genes and mutations. The observed clinical variability coincides with the involvement of different genes and proteins that help maintain function and integrity of the peripheral nerve, so that they become an important research target for developing new and better therapies. " INNN 2012.",,,,,,,,,"http://hdl.handle.net/20.500.12104/40008","http://www.scopus.com/inward/record.url?eid=2-s2.0-84887435229&partnerID=40&md5=4c40cb9231b6f09fa1e175e8b36db5b6",,,,,,"2",,"Archivos de Neurociencias",,"11