Engineering Iron Oxide Nanoparticles for Clinical Settings

Iron oxide nanoparticles (IONPs) occupy a privileged position among magnetic nanomaterials with potential applications in medicine and biology. They have been widely used in preclinical experiments for imaging contrast enhancement, magnetic resonance, immunoassays, cell tracking, tissue repair, magnetic hyperthermia and drug delivery. Despite these promising results, their successful translation into a clinical setting is strongly dependent upon their physicochemical properties, toxicity and functionalization possibilities. Currently, IONPs-based medical applications are limited to the use of non-functionalized IONPs smaller than 100 nm, with overall narrow particle size distribution, so that the particles have uniform physical and chemical properties. However, the main entry of IONPs into the scene of medical application will surely arise from their functionalization possibilities that will provide them with the capacity to target specific cells within the body, and hence to play a role in the development of specific therapies. In this review, we offer an overview of their basic physicochemical design parameters, giving an account of the progress made in their functionalization and current clinical applications. We place special emphasis on past and present clinical trials

Use of Bovine Serum Albumin as inductor of capacitation in deer red sperm

Trabajo presentado al 18th International Congress of Animal Reproduction (ICAR), celebrado en Tours (Francia) del 26 al 30 de junio de 2016.The in vitro fertílization may be an important technology in farms of hispanicus red deer by the great availability of ovaries from hunted females. However, the knowledge about this assisted reproductive technique in this species is limited. The main problem is the need to use a non-defined substances as estrous sheep serum (ESS) to carry out the sperm capacitation. lt seems that EES induces cholesterol efflux, possibly for the action of albumin (BSA). The aim of this work was to study the effect of BSA on capacitation of red deerspermatozoa. Sperm samples from three males were collected by electroejaculation and subsequent frozen. Several BSA concentrations (0, 0.003, 0.1, 0.3, 1, 3, 10, 30 mg/mL) and a positive control with 20% EES (CEES) were added to synthetic oviductal fluid (SOF) and used as capacitation media. After thawing and incubation for 15 min in 5% C02 (four replicates), different sperm physiological parameters and protein tyrosine phosphorylation, as capacitation biomarker, were assessed. The effect of BSA concentration was studied by GLM-ANOVA analysis. The highest concentration of BSA (3, 10, 30 mg/ml) displayed (p<0.05) lower values of sperm motility (25.9; 19.4; 21.3 %), viability (32.6; 33.8; 32,5 %), mitochondrial activity (30.7; 30.7; 30.3) and acrosome integrity (32.4; 32.2; 30.3 %) in relation to CEES (35:5, 42.2; 36.5; 40.0 %, respectively). In addition, the presence of reactive oxygen species (ROS) was significantly higher with the lowest concentrations (0 and 0.003 mg/mL) of BSA (1543.5; 1858.6) in relation to 0.1, 0.3, 1, 3, 10,30 mg/ml of BSA (297.4; 179.5; 101.4; 78.7; 116.7; 42.5) and CEES (49.1). The effect of BSA and CEES on tyrosíne phosphorylation protein showed that one protein around 70 kDa was differently expressed between treatments displaying the lowest intensity (P<0.05) relativized tubuline, for 3, 10, 30 mg/ml of BSA and CEES (681, 0, 91, and 752 respectively) in relation to 0 and 0.003 mg/ml of BSA (1543 and 1858, respectively). In conclusion, the addition of BSA to capacitation media acts as potent antioxidant in a similar way to CEES. Moreover the expression of tyrosine phosphorylation protein was similar between the highest concentrations of BSA and CEES. Nevertheless, more studies are needed in relation to knowledge of the sperm fertilizatíon ability when BSA is present in the capacitation media since, many sperm parameters were negatively affected after addition of this protein.Peer Reviewe

Changes in chromatin state derived of sperm capacitation in red deer spermatozoa

Trabajo presentado a la 20th Annual Conference of the European Society for Domestic Animal Reproduction (ESDAR) and the 13th Conference of the Spanish Association for Animal Reproduction (AERA), celebradas en Lisboa (Portugal) del 27 al 29 de octubre de 2016.In this study it was evaluated the state of chromatin after a capacitation time in red deer spermatozoa. Thawed semen from three red deer was used after selection in 45% Percoll. Spermatozoa were capacitated with a synthetic oviductal fluid (SOF) with 20% estrus sheep serum (ESS), and the high DNA stability (HDS) was evaluated at different incubation times (1, 5, 15, 30, 45, 60, 120 min and 24 h) in the capacitation medium. In addition, samples of non-capacitated spermatozoa (incubated with SOF without ESS) were evaluated at 0, 120 min and 24 h. A heterologous vitro fertilization trial, oocyte from sheep and spermatozoa from deer, was performed with capacitated sperm samples for 5, 15, 30 and 60 m in and non-capacitated sperm samples at0 m in. Results showed that HDS increased with the incubation time with the highest values at 15 (6.48), 30 (6.14) and 45 (6.06) min. of incubation in relation to non-capacitated sperm samples initially evaluated. However, the highest percentage of cleaved embryos was register for capacitated spermatozoa for 5 (19.5%), 15 (19.88%) and 30 (18.19%) min., with lower values for non-capacitated samples (5.6%) or 60 m in capacited (8.36%). More studies are needed to know the relation of the changes in chromatin state and the fertilization ability after capacitation time.Peer Reviewe

The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma

Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.status: publishe

International Prospective Registry of Acute Coronary Syndromes in Patients With COVID-19

Background Published data suggest worse outcomes in acute coronary syndrome (ACS) patients and concurrent coronavirus disease 2019 (COVID-19) infection. Mechanisms remain unclear. Objectives The purpose of this study was to report the demographics, angiographic findings, and in-hospital outcomes of COVID-19 ACS patients and compare these with pre–COVID-19 cohorts. Methods From March 1, 2020 to July 31, 2020, data from 55 international centers were entered into a prospective, COVID-ACS Registry. Patients were COVID-19 positive (or had a high index of clinical suspicion) and underwent invasive coronary angiography for suspected ACS. Outcomes were in-hospital major cardiovascular events (all-cause mortality, re–myocardial infarction, heart failure, stroke, unplanned revascularization, or stent thrombosis). Results were compared with national pre–COVID-19 databases (MINAP [Myocardial Ischaemia National Audit Project] 2019 and BCIS [British Cardiovascular Intervention Society] 2018 to 2019). Results In 144 ST-segment elevation myocardial infarction (STEMI) and 121 non–ST-segment elevation acute coronary syndrome (NSTE-ACS) patients, symptom-to-admission times were significantly prolonged (COVID-STEMI vs. BCIS: median 339.0 min vs. 173.0 min; p < 0.001; COVID NSTE-ACS vs. MINAP: 417.0 min vs. 295.0 min; p = 0.012). Mortality in COVID-ACS patients was significantly higher than BCIS/MINAP control subjects in both subgroups (COVID-STEMI: 22.9% vs. 5.7%; p < 0.001; COVID NSTE-ACS: 6.6% vs. 1.2%; p < 0.001), which remained following multivariate propensity analysis adjusting for comorbidities (STEMI subgroup odds ratio: 3.33 [95% confidence interval: 2.04 to 5.42]). Cardiogenic shock occurred in 20.1% of COVID-STEMI patients versus 8.7% of BCIS patients (p < 0.001). Conclusions In this multicenter international registry, COVID-19–positive ACS patients presented later and had increased in-hospital mortality compared with a pre–COVID-19 ACS population. Excessive rates of and mortality from cardiogenic shock were major contributors to the worse outcomes in COVID-19 positive STEMI patients

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.This work was supported by a European Research Council (ERC) Advanced Grant under the European Community’s Seventh Framework Program (FP7/2007-2013)/ERC Grant Agreement No. 268626—EPINORC project (to M. Esteller), the Ministerio de Economía y Competitividad (MINECO) under Grant No. SAF2014-55000-R (to M. Esteller) and the Instituto de Salud Carlos III (ISCIII), under the FIS PI16/01278 Project (to J. Seoane), the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE) (to M. Esteller), CIBER 2016 CB16/12/00312 (CIBERONC) (to M. Esteller), co-financed by the European Development Regional Fund, ‘A way to achieve Europe’ ERDF, the AGAUR—Catalan Government (Project No. 2009SGR1315 and 2014SGR633) (to M. Esteller), the Cellex Foundation (to M. Esteller), Obra Social “La Caixa” (to M. Esteller), the CERCA Program and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya) (to M. Esteller) and a grant from the National Health and Medical Research Council of Australia (APP1061551, to TP). M.W. Boudreau is a member of the NIH Chemistry-Biology Interface Training Program (T32-GM070421)

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure