Genotoxicity of Superparamagnetic Iron Oxide Nanoparticles in Granulosa Cells

Nanoparticles that are aimed at targeting cancer cells, but sparing healthy tissue provide an attractive platform of implementation for hyperthermia or as carriers of chemotherapeutics. According to the literature, diverse effects of nanoparticles relating to mammalian reproductive tissue are described. To address the impact of nanoparticles on cyto- and genotoxicity concerning the reproductive system, we examined the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on granulosa cells, which are very important for ovarian function and female fertility. Human granulosa cells (HLG-5) were treated with SPIONs, either coated with lauric acid (SEONLA) only, or additionally with a protein corona of bovine serum albumin (BSA;SEONLA-BSA),or with dextran (SEONDEX). Both micronuclei testing and the detection of H2A.X revealed no genotoxic effects of SEONLA-BSA, SEONDEX or SEONLA. Thus, it was demonstrated that different coatings of SPIONs improve biocompatibility, especially in terms of genotoxicity towards cells of the reproductive system

Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm

Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. Methods: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), betablockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. Results: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. Conclusion: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies

NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination

Recurrent melanocytic nevi and melanomas in dermoscopy: results of a multicenter study of the International Dermoscopy Society

IMPORTANCE Differentiating recurrent nevi from recurrent melanoma is challenging. OBJECTIVE To determine dermoscopic features to differentiate recurrent nevi from melanomas. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of 15 pigmented lesion clinics from 12 countries; 98 recurrent nevi (61.3%) and 62 recurrent melanomas (38.8%) were collected from January to December 2011. MAIN OUTCOMES AND MEASURES Scoring the dermoscopic features, patterns, and colors in correlation with the histopathologic findings. RESULTS In univariate analysis, radial lines, symmetry, and centrifugal growth pattern were significantly more common dermoscopically in recurrent nevi; in contrast, circles, especially if on the head and neck area, eccentric hyperpigmentation at the periphery, a chaotic and noncontinuous growth pattern, and pigmentation beyond the scar's edge were significantly more common in recurrent melanomas. Patients with recurrent melanomas were significantly older than patients with recurrent nevi (mean [SD] age, 63.1 [17.5] years vs 30.2 [12.4] years) (P<.001), and there was a significantly longer time interval between the first procedure and the second treatment (median time interval, 25 vs 8 months) (P<.001). In a multivariate analysis, pigmentation beyond the scar's edge (P=.002), age (P<.001), and anatomic site (P=.002) were significantly and independently associated with the diagnosis of recurrent melanoma in dermoscopy. CONCLUSIONS AND RELEVANCE Dermoscopically, pigmentation beyond the scar's edge is the strongest clue for melanoma. Dermoscopy is helpful in evaluating recurrent lesions, but final interpretation requires taking into account the patient age, anatomic site, time to recurrence, growth pattern, and, if available, the histopathologic findings of the first excision

Allele-Level KIR Genotyping of More Than a Million Samples: Workflow, Algorithm, and Observations

The killer-cell immunoglobulin-like receptor (KIR) genes regulate natural killer cell activity, influencing predisposition to immune mediated disease, and affecting hematopoietic stem cell transplantation (HSCT) outcome. Owing to the complexity of the KIR locus, with extensive gene copy number variation (CNV) and allelic diversity, high-resolution characterization of KIR has so far been applied only to relatively small cohorts. Here, we present a comprehensive high-throughput KIR genotyping approach based on next generation sequencing. Through PCR amplification of specific exons, our approach delivers both copy numbers of the individual genes and allelic information for every KIR gene. Ten-fold replicate analysis of a set of 190 samples revealed a precision of 99.9%. Genotyping of an independent set of 360 samples resulted in an accuracy of more than 99% taking into account consistent copy number prediction. We applied the workflow to genotype 1.8 million stem cell donor registry samples. We report on the observed KIR allele diversity and relative abundance of alleles based on a subset of more than 300,000 samples. Furthermore, we identified more than 2,000 previously unreported KIR variants repeatedly in independent samples, underscoring the large diversity of the KIR region that awaits discovery. This cost-efficient high-resolution KIR genotyping approach is now applied to samples of volunteers registering as potential donors for HSCT. This will facilitate the utilization of KIR as additional selection criterion to improve unrelated donor stem cell transplantation outcome. In addition, the approach may serve studies requiring high-resolution KIR genotyping, like population genetics and disease association studies

Long-Term Effects of Self-Control on Alcohol Use and Sexual Behavior among Urban Minority Young Women

High risk alcohol use and sexual behaviors peak in young adulthood and often occur in the same individuals. Alcohol use has been found to impair decision-making and contribute to high risk sexual activity. However, the association between alcohol use and risky sexual behavior may also reflect enduring individual differences in risk taking, sociability, self-control, and related variables. Both behaviors can serve similar functions related to recreation, interpersonal connection, and the pursuit of excitement or pleasure. The present study examined the extent to which high risk drinking and sexual behavior clustered together in a sample of urban minority young adult women, a demographic group at elevated risk for negative outcomes related to sexual health. We tested whether psychosocial functioning measured at the beginning of high school predicted classes of risk behaviors when girls were tracked longitudinally into young adulthood. Latent class analysis indicated three distinct profiles based on high risk drinking and sexual behavior (i.e., multiple sex partners) in young adulthood. The largest class (73% of the sample) reported low levels of risky drinking and sexual behavior. The next largest class (19%) reported high risk drinking and low risk sexual behavior, and the smallest class (8%) reported high levels of both behaviors. Compared to women from other racial/ethnic groups, black women were more likely to be categorized in the high risk drinking/low risk sex class. Multinomial logistic regression indicated that self-control in adolescence had a broad and enduring protective effect on risk behaviors eight years later and was associated with a greater probability of being in the low risk drinking/low risk sex class. Findings are discussed in terms of understanding the phenotypic expressions of risk behavior as they relate to early psychosocial development and the long-term protective function of self-control in reducing high risk drinking and sexual behaviors

Reduced RBM3 expression is associated with aggressive tumor features in esophageal cancer but not significantly linked to patient outcome

Abstract Background RBM3 expression has been suggested as prognostic marker in several cancer types. The purpose of this study was to assess the prevalence and clinical significance of altered RBM3 expression in esophageal cancer. Methods RBM3 protein expression was measured by immunohistochemistry using tissue microarrays containing samples from 359 esophageal adenocarcinoma (EAC) and 254 esophageal squamous cell cancer (ESCC) patients with oncological follow-up data. Results While nuclear RBM3 expression was always high in benign esophageal epithelium, high RBM3 expression was only detectable in 66.4% of interpretable EACs and 59.3% of ESCCs. Decreased RBM3 expression was linked to a subset of EACs with advanced UICC stage and presence of distant metastasis (P = 0.0031 and P = 0.0024). In ESCC, decreased RBM3 expression was associated with advanced UICC stage, high tumor stage, and positive lymph node status (P = 0.0213, P = 0.0061, and P = 0.0192). However, RBM3 expression was largely unrelated to survival of patients with esophageal cancer (EAC: P = 0.212 and ESCC: P = 0.5992). Conclusions In summary, the present study shows that decreased RBM3 expression is associated with unfavourable esophageal cancer phenotype, but not significantly linked to patient prognosis

Characterisation of barley resistance to rhynchosporium on chromosome 6HS

Key Message: Major resistance gene to rhynchosporium, Rrs18, maps close to the telomere on the short arm of chromosome 6H in barley. Rhynchosporium or barley scald caused by a fungal pathogen Rhynchosporium commune is one of the most destructive and economically important diseases of barley in the world. Testing of Steptoe × Morex and CIho 3515 × Alexis doubled haploid populations has revealed a large effect QTL for resistance to R. commune close to the telomere on the short arm of chromosome 6H, present in both populations. Mapping markers flanking the QTL from both populations onto the 2017 Morex genome assembly revealed a rhynchosporium resistance locus independent of Rrs13 that we named Rrs18. The causal gene was fine mapped to an interval of 660 Kb using Steptoe × Morex backcross 1 S₂ and S₃ lines with molecular markers developed from Steptoe exome capture variant calling. Sequencing RNA from CIho 3515 and Alexis revealed that only 4 genes within the Rrs18 interval were transcribed in leaf tissue with a serine/threonine protein kinase being the most likely candidate for Rrs18.Max Coulter, Bianca Büttner, Kerstin Hofmann, Micha Bayer, Luke Ramsay, Günther Schweizer, Robbie Waugh, Mark E. Looseley, Anna Avrov

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated A beta compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by gamma-secretase and the generation of toxic beta-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials