Carcinogenicity of hexavalent chromium

Hexavalent chromium (Cr(VI)), a commonly used industrial metal, is a well known human lung carcinogen. Epidemiology and animal studies suggest that the particulate Cr(VI) compounds, specifically the water insoluble compounds, are the more potent carcinogens, however, the carcinogenic mechanism remains unknown. Here we summarize recent Cr(VI)-induced human tumour, in vivo, cell culture and in vitro studies and put the data into context with three major paradigms of carcinogenesis: multistage carcinogenesis, genomic instability, and epigenetic modifications. Based on these studies, we propose a mechanism for chromate carcinogenesis that is primarily driven by the genomic instability paradigm

The role of the teacher in computer-supported collaborative inquiry learning

The article presents an analysis of practices in teaching with computer-supported collaborative inquiry learning environments. We describe the role of the teacher in computer-supported collaborative inquiry learning by five principles which span the whole instructional process, from the preparation of the lesson up to the assessment of learning achievement. For successful implementation of computer-supported projects the teacher has to (1) envision the lesson, (2) enable collaboration, (3) encourage students, (4) ensure learning, and (5) evaluate achievement. We analyse classroom scenarios provided by eight teachers or mentors who implemented one of four different approaches developed by multimedia researchers: WISE, Modeling Across the Curriculum, Co-Lab, or ReCoIL. Teachers or mentors responded to a semistructured questionnaire about their experiences in implementing the inquiry lesson. A comparison of different classroom scenarios according to the mentioned five principles informed our analysis of teacher activities that contribute to the success of student inquiry while using such technology-enhanced approaches. We conclude with a discussion of the often neglected role of the teacher in computer-supported learning

Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model

BACKGROUND: Efforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic development process. One of the major factors believed to be limiting effective screening of these treatments is the absence of an animal model more predictive of human responses to treatments. The pig may potentially fill this gap with a gyrencephalic brain that is larger in size with a more similar gray-white matter composition to humans than traditional stroke animal models. In this study we develop and characterize a novel pig middle cerebral artery occlusion (MCAO) ischemic stroke model. METHODS: Eleven male pigs underwent MCAO surgery with the first 4 landrace pigs utilized to optimize stroke procedure and 7 additional Yucatan stroked pigs studied over a 90 day period. MRI analysis was done at 24 hrs and 90 days and included T2w, T2w FLAIR, T1w FLAIR and DWI sequences and associated ADC maps. Pigs were sacrificed at 90 days and underwent gross and microscopic histological evaluation. Significance in quantitative changes was determined by two-way analysis of variance and post-hoc Tukey’s Pair-Wise comparisons. RESULTS: MRI analysis of animals that underwent MCAO surgery at 24 hrs had hyperintense regions in T2w and DWI images with corresponding ADC maps having hypointense regions indicating cytotoxic edema consistent with an ischemic stroke. At 90 days, region of interest analysis of T1 FLAIR and ADC maps had an average lesion size of 59.17 cc, a loss of 8% brain matter. Histological examination of pig brains showed atrophy and loss of tissue, consistent with MRI, as well as glial scar formation and macrophage infiltration. CONCLUSIONS: The MCAO procedure led to significant and consistent strokes with high survivability. These results suggest that the pig model is potentially a robust system for the study of stroke pathophysiology and potential diagnostics and therapeutics

Loss of mouse Stmn2 function causes motor neuropathy

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS

A Questionnaire on Materialisms

Recent philosophical tendencies of “Actor-Network Theory,” “Object-Oriented Ontology,” and “Speculative Realism” have profoundly challenged the centrality of subjectivity in the humanities, and many artists and curators, particularly in the UK, Germany, and the United States, appear deeply influenced by this shift from epistemology to ontology. October editors asked artists, historians, and philosophers invested in these projects—from Graham Harman and Alexander R. Galloway to Armen Avanessian and Patricia Falguières to Ed Atkins and Amie Siegel—to explore what the rewards and risks of assigning agency to objects may be, and how, or if, such new materialisms can be productive for making and thinking about art today

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Elucidating a Mechanism of Particulate Hexavalent Chromium-Induced Carcinogenesis

Hexavalent chromium (Cr(VI)) compounds are well established human lung carcinogens. Solubility plays a key role in the carcinogenicity of Cr(VI), with the most potent carcinogens being the particulate Cr(VI) compounds; however, their carcinogenic mechanism remains poorly understood. The best mechanistic model for particulate Cr(VI) appears to be one that involves genomic instability, but little is known about the ability of particulate Cr(VI) to induce numerical chromosome instability. We found that chronic exposure to particulate Cr(VI) induced concentration- and time-dependent increases in aneuploidy in the form of hypodiploidy, hyperdiploidy and tetraploidy, and these aneuploid cells were able to survive and emerge with a transformed phenotype. Centrosome amplification and spindle assembly checkpoint defects are two mechanisms for chromosome instability. Consistent with these mechanisms, chronic exposure to particulate Cr(VI) induced concentration- and time-dependent increases in spindle assembly checkpoint bypass and centrosome amplification that correlated with aneuploidy. Centrosome amplification persisted in cells transformed with particulate Cr(VI) and in Cr-induced tumors suggesting centrosome amplification is an early and persistent event in particulate Cr(VI)-induced carcinogenesis. The mechanisms of particulate Cr(VI)-induced chromosome instability include a physico-chemical and a biological component. For the physico-chemical mechanism, we found that chromate anions are responsible for the particulate Cr(VI)-induced aneuploidy, centrosome amplification, spindle assembly checkpoint bypass and DNA damage and the particle and lead cation appear to have no effect. In addition, zinc chromate is more potent than lead chromate, suggesting that unlike lead, zinc may be involved in zinc chromate-induced chromosome instability. We focused on the biological mechanism of particulate Cr(VI)-induced centrosome amplification and found that multiple mechanisms were involved. Particulate Cr(VI) induced numerous centriolar defects indicating that centriole splitting, acentriolar centrosome formation and centrosome overduplication were involved in Cr(VI)-induced centrosome amplification. We delved further into the mechanism of centrosome overduplication and found that a DNA-damage induced prolonged G2 arrest involving dysregulation of Nek2 was most likely involved. Altogether, these data indicate that Cr(VI) induces cancer by disrupting genomic stability. We propose chronic DNA damage induces a prolonged G2 arrest facilitating centrosome amplification and spindle assembly checkpoint bypass, which induce numerical chromosome instability, ultimately leading to neoplastic transformation and cancer

Neoplastic Transformation of Human Bronchial Cells by Lead Chromate Particles

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen with widespread exposure among people in occupational settings and the general public. However, no studies have examined the chromate-induced malignant transformation of human lung epithelial cells, its predominant target. Human papillomavirus–immortalized human bronchial epithelial (BEP2D) cells were used to better understand the mechanisms involved in human bronchial carcinogenesis induced by particulate chromate. We found that aneuploid cells increased in a concentration-dependent manner after chronic exposure to lead chromate. Moreover, chronic exposure to lead chromate induced BEP2D cell transformation. Transformed BEP2D cells developed through a series of sequential steps, including altered cell morphology, loss of cell contact inhibition and anchorage-independent growth. Specifically, a 5-day exposure to lead chromate induced foci formation with 0, 1, 5, and 10 μg/cm2 lead chromate inducing 0, 7, 3, and 15 foci in 10 dishes. Anchorage independence was observed in cell lines derived from these foci. These foci-derived cells also showed centrosome amplification and increases in aneuploid metaphases. Our study demonstrates that particulate Cr(VI) is able to transform human bronchial epithelial cells, and that chromosome instability may play an important role in particulate Cr(VI)-induced neoplastic transformation