Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials

Lanthanides are a series of critical elements widely used in multiple industries, such as optoelectronics and healthcare. Although initially considered to be of low toxicity, concerns have emerged during the last few decades over their impact on human health. The toxicological profile of these metals, however, has been incompletely characterized, with most studies to date solely focusing on one or two elements within the group. In the current study, we assessed potential toxicity mechanisms in the lanthanide series using a functional toxicogenomics approach in baker’s yeast, which shares many cellular pathways and functions with humans. We screened the homozygous deletion pool of 4,291 Saccharomyces cerevisiae strains with the lanthanides and identified both common and unique functional effects of these metals. Three very different trends were observed within the lanthanide series, where deletions of certain proteins on membranes and organelles had no effect on the cellular response to early lanthanides while inducing yeast sensitivity and resistance to middle and late lanthanides, respectively. Vesicle-mediated transport (primarily endocytosis) was highlighted by both gene ontology and pathway enrichment analyses as one of the main functions disturbed by the majority of the metals. Protein–protein network analysis indicated that yeast response to lanthanides relied on proteins that participate in regulatory paths used for calcium (and other biologically relevant cations), and lanthanide toxicity included disruption of biosynthetic pathways by enzyme inhibition. Last, multiple genes and proteins identified in the network analysis have human orthologs, suggesting that those may also be targeted by lanthanides in humans.

Since their discovery, lanthanides have presented both difficulty and opportunity for researchers. As a series, these elements behave rather similarly: most of them form +3 ions in aqueous solution (1), prefer highly electronegative anionic ligands (2), and form insoluble hydroxide precipitates at neutral pH if not otherwise complexed (3). Although the chemical similarities between these elements made their initial isolation and characterization a significant challenge, they now have unique applications in industry and medicine. Several lanthanides have become critical materials for many clean and sustainable energy technologies that will drive the future of our societies and are used, for example, in the production of batteries, magnets, motors, and other electronic components (4); low-concentration mixtures of lanthanides are used in Chinese agriculture to increase body weight gain among livestock (5, 6); lanthanum carbonate (sold under the commercial name of Fosrenol) is a noncalcium phosphate binder used to control hyperphosphataemia (7); and gadolinium is employed in diagnostic medicine, as an essential component of MRI contrast agents (8, 9).The growing use of lanthanides has increased the potential for human exposure to large concentrations of these metals, requiring more detailed investigations into their toxicological properties. For instance, administration of gadolinium-based contrast agents has been associated with the development of nephrogenic systemic fibrosis in patients with compromised renal function (10–12). Moreover, accumulation of gadolinium in the brains of patients who received repeated doses of gadolinium-based contrast agents has also been reported (13). Despite the current ubiquity of lanthanides, their toxicological profile has been incompletely characterized because until recently they were considered to be of low toxicological concern (14, 15). Previous toxicity studies primarily focused on lanthanum or cerium (and, to a lesser extent, neodymium and gadolinium), with the notion that these metals were representative of the series (14, 16–18). However, to our knowledge, no comprehensive mechanistic assay has been conducted to evaluate metal toxicity across the series, and little is known about what toxicological mechanisms may be shared by the different lanthanides.Saccharomyces cerevisiae is one of the best-characterized model organisms (19, 20), and there are many tools available for analyzing its genomic data (21–23). For example, yeast functional toxicogenomic screening is a powerful tool for investigating cellular mechanisms of cytotoxicity (24, 25). This method makes use of the yeast deletion libraries generated by the Yeast Deletion Project (26), a consortium of researchers across the United States and Canada, to establish relationships between genes and chemical exposures. Researchers used heterozygous and homozygous deletion pools of barcoded yeast strains to derive mechanistic toxicological information about a wide array of chemicals, pharmaceuticals, metals, and biological compounds (27, 28). As eukaryotes, yeast and humans share many cellular pathways and functions, and many components of cell biology identified in S. cerevisiae have homologs in human biology (29–31). Consequently, functional toxicogenomic screening offers unique opportunities to evaluate the mechanisms of cytotoxicity and general biological activity across the lanthanide series in yeast and explore potentially conserved mechanisms in humans.Here, we identify fundamental cellular functions disrupted by lanthanides using functional toxicogenomics in S. cerevisiae. The metals studied had distinct behaviors: early lanthanides showed limited unique functional effects, while middle and late lanthanides had prominent and distinct ones. Although the functional effects of each lanthanide were different and suggested some very efficient element discrimination by endogenous molecules, we observed a few common trends. In particular, vesicle-mediated transport (primarily endocytosis) was perturbed by the majority of the lanthanides tested. Moreover, protein–protein network analysis suggested that lanthanides mimic calcium ions, interacting with calcium-binding proteins and disrupting processes regulated by this cation. Finally, several of the highly interconnected proteins targeted by multiple lanthanides in the network analysis are conserved in humans, suggesting their roles in the origin of the human health issues associated with lanthanide exposure and opening many directions for the determination of mechanisms associated with toxicity.     

Adaptive radiation therapy of breast cancer by repeated imaging during irradiation

Breast cancer is the most frequent cancer among females and also a leading cause of cancer related mortality worldwide. A multimodality treatment approach may be utilized for optimal management of patients with combinations of surgery, radiation therapy (RT) and systemic treatment. RT composes an integral part of breast conserving treatment, and is typically used after breast conserving surgery to improve local control. Recent years have witnessed significant improvements in the discipline of radiation oncology which allow for more focused and precise treatment delivery. Adaptive radiation therapy (ART) is among the most important RT techniques which may be utilized for redesigning of treatment plans to account for dynamic changes in tumor size and anatomy during the course of irradiation. In the context of breast cancer, ART may serve as an excellent tool for patients receiving breast irradiation followed by a sequential boost to the tumor bed. Primary benefits of ART include more precise boost localization and potential for improved normal tissue sparing with adapted boost target volumes particularly in the setting of seroma reduction during the course of irradiation. Herein, we provide a concise review of ART for breast cancer in light of the literature.     

Association of simple hematological parameters with disease manifestations,activity, and severity in patients with systemic sclerosis

Clinical Rheumatology - Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), mean platelet volume (MPV), and red cell distribution width (RDW) may potentially reflect...     

Inter-Organizational Collaboration in the Implementation of Evidence-based Practices Among Public Agencies Serving Abused and Neglected Youth

This study examined the role of inter-organizational collaboration in implementing new evidence-based practices for addressing problem behaviors in at-risk youth. Semi-structured interviews were conducted with 38 systems leaders of probation, mental health, and child welfare departments of 12 California counties participating in a large randomized controlled trial to scale-up the use of Multidimensional Treatment Foster Care. Three sets of collaboration characteristics were identified: (1) characteristics of collaboration process, (2) characteristics of the external environment, and (3) characteristics of participating organizations and individuals. Inter-organizational collaboration enables an exchange of information and advice and a pooling of resources individual agencies may require for successful implementation.     

Is it possible that direct rigid laryngoscope-related ischemia–reperfusion injury occurs in the tongue during suspension laryngoscopy as detected by ultrasonography: a prospective controlled study

Abstract

Background: Tongue-related complications can be seen in suspension laryngoscopy (SL) procedures.

Aims/objectives: This study aimed to detect tongue edema associated with the pressure exerted by a rigid direct laryngoscope by measuring the tongue area using ultrasonography (USG) in patients undergoing SL procedures.

Material and methods: The study group included 31 patients and the control group consisted of 33 patients. Submental USG examinations of the tongue in the coronal plane were performed. In the study and control groups, the first examination (TA¹) was done immediately after intubation and the second examination (TA²) was done after the surgery procedure but before extubation. The USG results regarding tongue area for both the groups were compared.

Results: The study and control groups significantly differed in terms of the postoperative tongue area measurements (TA²), as well as tongue edema (based on the TA²???TA¹) values.

Conclusions and significance: Direct rigid laryngoscopes may cause tongue edema in SL procedures which was demonstrated by the USG. This tongue edema can be a result of ischemia–reperfusion injury in the tongue due to the pressure exerted by a direct rigid laryngoscope. This study is the first to demonstrate the possible role of USG examination in determining the side effects of SL procedures on the tongue.

Trial Registration ClinicalTrials.gov Identifier: NCT04205253     

Effects of age of onset on disease characteristics in non‐segmental vitiligo

In patients with vitiligo, the clinical and laboratory features of the disease may vary according to time of onset. This is addressed in the literature by only a few studies with conflicting results. The aim of this study was to determine the demographic and clinical features of patients with non‐segmental vitiligo and to establish the association between vitiligo and autoimmune diseases with a focus on time of disease onset. A total of 224 vitiligo patients for whom complete medical records were available were evaluated retrospectively. Demographic data, scores on the Vitiligo Area Score Index (VASI), clinical features, vitiligo disease activity, repigmentation status, presence of any accompanying autoimmune disease, antinuclear antibody (ANA) titers, serum levels of glucose, thyroid‐stimulating hormone (TSH), thyroxine (T4) hormone, anti‐thyroid peroxidase (anti‐TPO), and anti‐thyroglobulin (anti‐TG) were recorded. The prevalence of halo nevi was significantly higher (P < 0.001) among children than in other patient groups. The prevalence of leukotrichia was higher in adults with adult‐onset disease than in either pediatric patients or adults with childhood‐onset disease (P = 0.002). Both anti‐TG and anti‐TPO levels were significantly higher in adults with adult‐onset disease than in pediatric patients and adult patients with childhood‐onset disease. The prevalence of autoimmune disease was 22.2%. Anti‐TG levels were significantly higher in patients with treatment‐related repigmentation than in those without repigmentation. This study shows that clinical features and associations with autoimmune disease may vary according to the age of onset of vitiligo.