Potentilla anserine L. polysaccharide protects against cadmium-induced neurotoxicity

Cadmium is a toxic metal that can damage the brain and other organs. This study aimed to explore the protective effects of Potentilla anserine L. polysaccharide (PAP) against CdCl₂-induced neurotoxicity in N2a and SH-SY5Y cells and in the cerebral cortex of BALB/c mice. In addition, we aimed to identify the potential mechanisms underlying these protective effects. Relative to CdCl₂ treatment alone, pretreatment with PAP prevented the reduction in cell viability evoked by CdCl₂, decreased rates of apoptosis, promoted calcium homeostasis, decreased ROS accumulation, increased mitochondrial membrane potential, inhibited cytochrome C and AIF release, and prevented the cleavage of caspase-3 and PARP. In addition, PAP significantly decreased the CdCl₂-induced phosphorylation of CaMKII, Akt, and mTOR. In conclusion, PAP represents a potential therapeutic agent for the treatment of Cd-induced neurotoxicity, functioning in part via attenuating the activation of the mitochondrial apoptosis pathway and the Ca²⁺-CaMKII-dependent Akt/mTOR pathway.     

Communicating regulatory high-throughput sequencing data using BioCompute Objects

This project demonstrates the use of the IEEE 2791–2020 Standard (BioCompute Objects [BCO]) to enable the complete and concise communication of results from next generation sequencing (NGS) analysis. One arm of a clinical trial was replicated using synthetically generated data made to resemble real biological data and then two independent analyses were performed. The first simulated a pharmaceutical regulatory submission to the US Food and Drug Administration (FDA) including analysis of results and a BCO. The second simulated an FDA review that included an independent analysis of the submitted data. Of the 118 simulated patient samples generated, 117 (99.15%) were in agreement in the two analyses. This process exemplifies how a template BCO (tBCO), including a verification kit, facilitates transparency and reproducibility, thereby reinforcing confidence in the regulatory submission process.     

Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Pulmonary metastases in urogenital cancers: Surgical treatment and outcomes

IntroductionMetastasis is remaining one of the major problems in cancer treatment. Like many other malignancies, urogenital tumors originating from kidney, prostate, testes, and bladder tend to metastasize to the lungs.The aim of this retrospective study is to evaluate the operative results and prognosis of pulmonary metastasectomy in patients with primary urogenital tumors.MethodsThis study was approved by the local ethical committee. We retrospectively analyzed the surgical and oncological results of patients who underwent lung resections for urogenital cancer metastases in our department between 2002 and 2018. Demographic data and clinicopathological features were extracted from the medical records. Survival outcomes according to cancer subtypes and early postoperative results of VATS and thoracotomy were analyzed.Results22 out of 126 patients referred for pulmonary metastasectomy to our department had metastases from urogenital tumors. These patients consisted of 17 males and five females. Their metastasis originated from renal cell carcinoma (RCC; n = 9), bladder tumor (n = 7), testis tumors (n = 4), and prostate cancer (n = 2). There was no intraoperative complication. Postoperative complications were seen in 2 patients.ConclusionsAlthough pulmonary metastasectomy in various types of tumors is well known and documented, the data is limited for metastases of urogenital cancers in the literature. Despite the limitations of this study, we aim to document our promising results of pulmonary metastasectomy in patients with primary urogenital tumors and wanted to emphasize the role of minimally invasive approaches.     

The updated pre-test probability model of the 2019 ESC guidelines improves prediction of obstructive coronary artery disease

Introduction and ObjectivesThe 2019 ESC guidelines on chronic coronary syndromes updated the method for estimating the pre-test probability (PTP) of obstructive coronary artery disease (CAD). We aimed to compare the performance of the new PTP method against the 2013 prediction model in patients with stable chest pain undergoing coronary computed tomography angiography (CCTA) for suspected CAD.MethodsWe conducted a single-center cross-sectional study enrolling 320 consecutive patients undergoing CCTA for suspected CAD. Obstructive CAD was defined as any ≥50% luminal stenosis on CCTA. Whenever invasive coronary angiography was subsequently performed, patients were reclassified accordingly. The two PTP prediction models were assessed for calibration, discrimination and the ability to change the downstream diagnostic pathway.ResultsThe observed prevalence of obstructive CAD was 16.3% (n=52). The 2013 prediction model significantly overestimated the likelihood of obstructive CAD (relative overestimation of 130%, p=0.005), while the updated 2019 method showed good calibration (relative underestimation of 6.5%, p=0.712). The two approaches showed similar discriminative power, with C-statistics of 0.73 (95% CI: 0.66-0.80) and 0.74 (95% CI: 0.66-0.81) for the 2013 and 2019 methods, respectively (p=0.933). Reclassification of PTP using the new method resulted in a net reclassification improvement of 0.10 (p=0.001).ConclusionsThe updated 2019 prediction model provides a more accurate estimation of pre-test probabilities of obstructive CAD than the previous model. Adoption of this new score may improve disease prediction and influence the selection of non-invasive testing.     

Immunogenicity and protective efficacy of adenoviral and subunit RSV vaccines based on stabilized prefusion F protein in pre-clinical models

Respiratory Syncytial Virus (RSV) remains a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously described the derivation of an RSV Fusion protein (F) stabilized in its prefusion conformation (preF) as vaccine immunogen and demonstrated superior immunogenicity in naive mice of preF versus wild type RSV F protein, both as protein and when expressed from an Ad26 vaccine vector. Here we address the question if there are qualitative differences between the two vaccine platforms for induction of protective immunity. In naïve mice, both Ad26.RSV.preF and preF protein induced humoral responses, whereas cellular responses were only elicited by Ad26.RSV.preF. In RSV pre-exposed mice, a single dose of either vaccine induced cellular responses and strong humoral responses. Ad26-induced RSV-specific cellular immune responses were detected systemically and locally in the lungs. Both vaccines showed protective efficacy in the cotton rat model, but Ad26.RSV.preF conferred protection at lower virus neutralizing titers in comparison to RSV preF protein. Factors that may contribute to the protective capacity of Ad26.RSV.preF elicited immunity are the induced IgG2a antibodies that are able to engage Fcγ receptors mediating Antibody Dependent Cellular Cytotoxicity (ADCC), and the induction of systemic and lung resident RSV specific CD8 + T cells. These data demonstrate qualitative improvement of immune responses elicited by an adenoviral vector based vaccine encoding the RSV preF antigen compared to the subunit vaccine in small animal models which may inform RSV vaccine development.     

Miocardio no compactado: ¿una enfermedad o un rasgo fenotípico?

Left ventricular noncompaction is a poorly defined and controversial entity, with wide phenotypic expression: from a simple anatomical trait to a disease with overt cardiac affection. Current diagnostic criteria rely exclusively on morphologic features of hypertrabeculation, which have low specificity for identifying true cardiomyopathy cases. The management of left ventricular noncompaction is also heterogeneous, and there are no dedicated clinical practice guidelines. The most common cardiovascular complications are heart failure, ventricular arrhythmias, and systemic embolisms. In this review, we discuss the diagnostic limitations of the available criteria, and propose a comprehensive alternative approach (including functional imaging variables, tissue characterization, genetics, and family screening) that may help in the differential diagnosis of hypertrabeculation cases. We also describe the genetic background of the disease and discuss the overlap with other cardiomyopathies. Finally, we focus on controversial issues in clinical management and suggest the use of the previously-mentioned variables for risk stratification and for individualization of patient follow-up.     

Registro español de marcapasos. XIX informe oficial de la Asociación del Ritmo Cardiaco de la Sociedad Española de Cardiología (2021)

Introduction and objectivesThis document includes cardiac pacing activity performed in Spain in 2021: figures for implanted devices, demographic and clinical factors, characteristics of the implanted material, and remote monitoring data.MethodsThe European Pacemaker Patient Card, the CardioDispositivos.es online platform, the centers’ own databases and the data provided by the supplier companies are used as sources of information.Results17.360 procedures were registered from 95 hospitals, which represents 43% of the activity. The implantation rates of conventional and resynchronization pacemakers were 822 and 31 units per million population, respectively. 652 leadless pacemakers were implanted. The mean age of implantation is high (78.8 years), and atrioventricular block is the most frequent electrocardiographic abnormality. Dual-chamber pacing mode predominated, nonetheless single-chamber pacing was performed in 19% of patients in sinus rhythm, mainly in the elderly. 28.5% of implanted conventional pacemakers and 56,2% of low-energy resynchronization pacemakers were included in the remote monitoring program.ConclusionsIn 2021 the number of conventional pacemakers increased by 8.3% and resynchronizers by 18.9%, despite the decrease in low-energy resynchronization, probably attributable to the development of physiological pacing. Leadless pacemakers increased by 25%. The expansion of remote monitoring continued, consolidating as a fundamental follow-up method.