Bioaccumulation factors for PCBs revisited

Bioaccumulation factors (BAFs)for individual polychlorinated biphenyl (PCB) congeners in Barents Sea and White Sea marine calanoid copepods were 1-3 orders of magnitude higher than BAFs in the same species in Canadian and Alaskan Arctic Ocean areas, and in freshwater plankton (Lake Ontario) reported from the mid- to early 1980s. The present study reviews variability in PCB BAFs from the North American Great Lakes and the Arctic Ocean, and discusses possible explanations for the large variation among different studies. BAFs are higher in recent arctic marine and Great Lakes studies than previously reported, and they are at least 10 times higher than those predicted from the octanol-water partition coefficient (KOW). If the recent high BAFs are realistic, it means that earlier reported BAFs are too low. This is likely due to earlier erroneously high quantification of water PCB concentrations, and it implies that bioaccumulation in zooplankton is more efficient than previously assumed. Evidence is presented supporting that also trophic transfer and biomagnification of PCBs in zooplankton leads to BAFs well above those predicted by simple equilibrium partitioning. Overall, miss-measurement of water PCB concentrations and biomagnification contribute significantly to variability in BAFs for PCBs within and among studies. This large variability of BAFs for PCBs in zooplankton illustrated in the present study is of importance for future assessments of potential new bioaccumulative chemicals that rely on measured BAFs, such as the European Union Registration, Evaluation and Authorization of Chemicals program (REACH). © 2005 American Chemical Society

Mexico-UK Sub-millimeter Camera for AsTronomy

MUSCAT is a large format mm-wave camera scheduled for installation on the Large Millimeter Telescope Alfonso Serrano (LMT) in 2018. The MUSCAT focal plane is based on an array of horn coupled lumped-element kinetic inductance detectors optimised for coupling to the 1.1mm atmospheric window. The detectors are fed with fully baffled reflective optics to minimize stray-light contamination. This combination will enable background-limited performance at 1.1 mm across the full 4 arcminute field-of-view of the LMT. The easily accessible focal plane will be cooled to 100 mK with a new closed cycle miniature dilution refrigerator that permits fully continuous operation. The MUSCAT instrument will demonstrate the science capabilities of the LMT through two relatively short science programmes to provide high resolution follow-up surveys of Galactic and extra-galactic sources previously observed with the Herschel space observatory, after the initial observing campaigns. In this paper, we will provide an overview of the overall instrument design as well as an update on progress and scheduled installation on the LMT.Comment: Accepted for publication in the Journal of Low Temperature Detector

Cell fate following irradiation of MDA-MB-231 and MCF-7 breast cancer cells pre-exposed to the setrahydroisoquinoline sulfamate microtubule disruptor STX3451

The compound STX3451 is not commercially available.SUPPLEMENTARY MATERIAL : TABLE S1: Data analysis comparing flow cytometric quantification of individual cell cycle phases across 24-h and 48-h timelines. TABLE S2: Data analysis of flow cytometric quantification of the cell cycle distribution in MCF-7 cells exposed to STX3451 and radiation. TABLE S3: Statistical analysis of cell cycle distribution in MCF-7 cells exposed to STX3451 and radiation. TABLE S4: Data analysis comparing flow cytometric quantification of individual cell cycle phases across 24-h and 48-h timelines in MDA-MB-231 cells. TABLE S5: Statistical analysis of cell cycle progression in MDA-MB-231 cells exposed to STX3451 and radiation. TABLE S6: Statistical analysis of cell cycle distribution in MDA-MB-231 cells exposed to STX3451 and radiation. TABLE S7: Annexin-V analysis of MCF-7 cells 48-h. TABLE S8: Annexin-V statistical analysis of MDA-MB-231 48-h. TABLE S9: Colony formation in MCF-7 cells. TABLE S10: Colony formation in MDA-MB-231 cells. TABLE S11: The total number of Mn in MCF-7 cells that were terminated 2- and 24-h after radiation. TABLE S12: The total number of Mn in MDA-MB-231 cells terminated 2- and 24-h after radiation. TABLE S13: Number of Mn per cell in MCF-7 cells terminated 2-h after radiation. TABLE S14: Number of Mn per cell in MCF-7 cells terminated 24-h after radiation. TABLE S15: Number of Mn per cell in MDA-MB-231 cells terminated 2-h after radiation. TABLE S16: The number of Mn per cell in MDA-MB-231 cells that were terminated 24-h after radiation. TABLE S17: Superoxide detection in MCF-7 cells treated with the various modalities. TABLE S18: Superoxide detection in pre-sensitized MDA-MB-231 cells. TABLE S19: Statistical analysis of ATM expression in combination treated MCF-7 and MDA-MB-231 cells 2- and 24-h post-radiation. TABLE S20: Nontumored animal toxicity assay; VIDEO S1: not applicable.Atetrahydroisoquinoline (THIQ) core is able tomimic theAand B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by sulfamoylation. The non-steroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radiation biology. We investigated whether 24 h pre-treatment with STX3451 could pre-sensitize MCF-7 and MDA-MB-231 breast cancer cells to radiation. This regimen showed a clear increase in cytotoxicity compared to the individual modalities, results that were contiguous in spectrophotometric analysis, flow cytometric quantification of apoptosis induction, clonogenic studies and microscopy techniques. Drug pre-treatment increased radiation-induced DNA damage, with statistically more double-strand (ds) DNA breaks demonstrated. The latter could be due to the induction of a radiation-sensitive metaphase block or the increased levels of reactive oxygen species, both evident after compound exposure. STX3451 pre-exposure may also delay DNA repair mechanisms, as the DNA damage response element ataxia telangiectasia mutated (ATM) was depressed. These in vitro findings may translate into in vivo models, with the ultimate aim of reducing both radiation and drug doses for maximal clinical effect with minimal adverse effects.The Research Committee of the University of Pretoria, the Struwig-Germeshuysen Trust, the Cancer Association of South Africa (CANSA), the National Research Foundation (NRF) and the Research Development Programme of the University of Pretoria (RDP-UP).https://www.mdpi.com/journal/moleculesam2023Physiolog

MUSCAT: The Mexico-UK Sub-Millimetre Camera for AsTronomy

The Mexico-UK Sub-millimetre Camera for AsTronomy (MUSCAT) is a large-format, millimetre-wave camera consisting of 1,500 background-limited lumped-element kinetic inductance detectors (LEKIDs) scheduled for deployment on the Large Millimeter Telescope (Volc\'an Sierra Negra, Mexico) in 2018. MUSCAT is designed for observing at 1.1 mm and will utilise the full 40' field of view of the LMTs upgraded 50-m primary mirror. In its primary role, MUSCAT is designed for high-resolution follow-up surveys of both galactic and extra-galactic sub-mm sources identified by Herschel. MUSCAT is also designed to be a technology demonstrator that will provide the first on-sky demonstrations of novel design concepts such as horn-coupled LEKID arrays and closed continuous cycle miniature dilution refrigeration. Here we describe some of the key design elements of the MUSCAT instrument such as the novel use of continuous sorption refrigerators and a miniature dilutor for continuous 100-mK cooling of the focal plane, broadband optical coupling to Aluminium LEKID arrays using waveguide chokes and anti-reflection coating materials as well as with the general mechanical and optical design of MUSCAT. We explain how MUSCAT is designed to be simple to upgrade and the possibilities for changing the focal plane unit that allows MUSCAT to act as a demonstrator for other novel technologies such as multi-chroic polarisation sensitive pixels and on-chip spectrometry in the future. Finally, we will report on the current status of MUSCAT's commissioning.Comment: Presented at SPIE Astronomical Telescopes + Instrumentation, 2018, Austin, Texas, United State

Characterisation of paediatric brain tumours by their MRS metabolite profiles

1H‐magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single‐voxel MRS (point‐resolved single‐voxel spectroscopy sequence, 1.5 T: echo time [TE] 23–37 ms/135–144 ms, repetition time [TR] 1500 ms; 3 T: TE 37–41 ms/135–144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann–Whitney U‐tests and Kruskal–Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours

A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: safety, efficacy, visual morbidity, and outcomes

BACKGROUND: Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes. METHODS: Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis. RESULTS: Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. CONCLUSIONS: BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG

Molecular insights into an ancient form of Paget’s disease of bone

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals over 55 years of age. PDB like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting up to 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 years. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few non69 collagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence with western blotting indicating p62 abnormalities including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin associated (UBA) domain. Ancient microRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB associated bone tumours. Our work displays the use of proteomics to inform diagnosis of ancient disease such as atypical PDB, which has unusual features presumably potentiated by as yet unidentified environmental or genetic factors