Hexabromocyclododecane decreases tumor-cell-binding capacity and cell-surface protein expression of human natural killer cells

Hexabromocyclododecane (HBCD) is a flame retardant that decreases the lytic function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. Thus, HBCD has the potential to increase cancer incidence and viral infections. NK cells must bind to their targets for lysis to occur. Thus, concentrations of HBCD that decrease lytic function were examined for their ability to alter NK binding to tumor targets. Levels of HBCD that caused a loss of binding function were examined for effects on expression of cell surface proteins needed for binding. NK cells exposed to HBCD for 24 h, 48 h or 6 days or to HBCD for 1 h followed by 24 h, 48 h or 6 days in HBCD-free media were examined for binding function and cell surface protein expression. The results indicated that exposure of NK cells to 10 μM HBCD for 24 h (which caused a greater than 90% loss of lytic function) caused a very significant decrease in NK cell binding function (70.9%), and in CD16 and CD56 cell-surface protein expression (57.8 and 24.6% respectively). NK cells exposed to 10 μM HBCD for 1 h followed by 24 h in HBCD-free media (which caused a 89.3% loss of lytic function) showed decreased binding function (79.2%), and CD 16 expression (48.1%). Results indicate that HBCD exposures decreased binding function as well as cell-surface marker expression in NK cells and that these changes may explain the losses of lytic function induced by certain HBCD exposures

Hexabromocyclododecane decreases the lytic function and ATP levels of human natural killer cells

This study investigates the effect of hexabromocyclododecane (HBCD) on the lytic function of human natural killer (NK) cells and on ATP levels in NK cells. NK cells are capable of lysing tumor cells, virally infected cells, and antibody-coated cells. HBCD is a brominated cyclic alkane used primarily as an additive flame retardant. If HBCD interferes with NK cell function, this could increase risk of tumor development and/or viral infection. NK cells were exposed to various concentrations of HBCD for 24 and 48 h and 6 days before determining lytic function and ATP levels. ATP levels and lytic function were also determined in NK cells that were exposed to HBCD for 1 h followed by 24 and 48 h, and 6 days in HBCD-free media. The results indicated that exposure of NK cells to 10 µm HBCD for 24 h causes a very significant decrease in both NK cell lytic function and ATP levels (93.5 and 90.5%, respectively). Exposure of NK cells to 10 µm HBCD for 1 h followed by 24 h in HBCD-free media showed a progressive and persistent loss of lytic function (89.3%) as well as a decrease in ATP levels (46.1%). The results indicate that HBCD exposures decreased lytic function as well as ATP levels. However, a decrease in lytic function was not necessarily accompanied by a similar decrease in ATP. Importantly, these results also indicate that a brief (1 h) exposure to HBCD causes a progressive loss of lytic function over a 6 day period

Three Shots

This article examines the background circumstances to the death in custody of Kumanjayi Walker, including policing, incarceration and dispossession of Aboriginal people under the Northern Territory Intervention - a Federal Government discriminatory policy since 2007

A Comprehensive Infrastructure for Big Data in Cancer Research: Accelerating Cancer Research and Precision Medicine

Advancements in next-generation sequencing and other -omics technologies are accelerating the detailed molecular characterization of individual patient tumors, and driving the evolution of precision medicine. Cancer is no longer considered a single disease, but rather, a diverse array of diseases wherein each patient has a unique collection of germline variants and somatic mutations. Molecular profiling of patient-derived samples has led to a data explosion that could help us understand the contributions of environment and germline to risk, therapeutic response, and outcome. To maximize the value of these data, an interdisciplinary approach is paramount. The National Cancer Institute (NCI) has initiated multiple projects to characterize tumor samples using multi-omic approaches. These projects harness the expertise of clinicians, biologists, computer scientists, and software engineers to investigate cancer biology and therapeutic response in multidisciplinary teams. Petabytes of cancer genomic, transcriptomic, epigenomic, proteomic, and imaging data have been generated by these projects. To address the data analysis challenges associated with these large datasets, the NCI has sponsored the development of the Genomic Data Commons (GDC) and three Cloud Resources. The GDC ensures data and metadata quality, ingests and harmonizes genomic data, and securely redistributes the data. During its pilot phase, the Cloud Resources tested multiple cloud-based approaches for enhancing data access, collaboration, computational scalability, resource democratization, and reproducibility. These NCI-led efforts are continuously being refined to better support open data practices and precision oncology, and to serve as building blocks of the NCI Cancer Research Data Commons

2021 Interim Guidance to Health Care Providers for Basic and Advanced Cardiac Life Support in Adults, Children, and Neonates With Suspected or Confirmed COVID-19

In April 2020, the American Heart Association (AHA) Emergency Cardiovascular Care (ECC) Committee and Get With The Guidelines-Resuscitation Adult and Pediatric Task Forces published their Interim Guidance for Basic and Advanced Cardiac Life Support in Adults, Children, and Neonates With Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) at the start of the SARS-CoV-2 pandemic. In October 2020, the AHA published new cardiopulmonary resuscitation (CPR) guidelines with the latest evidence-based algorithms and recommendations for Basic Life Support, Advanced Cardiac Life Support, Pediatric Advanced Life Support, Neonatal Advanced Life Support, and Maternal Cardiac Arrest Resuscitation

Engineered Single-Domain Antibodies with High Protease Resistance and Thermal Stability

The extreme pH and protease-rich environment of the upper gastrointestinal tract is a major obstacle facing orally-administered protein therapeutics, including antibodies. Through protein engineering, several Clostridium difficile toxin A-specific heavy chain antibody variable domains (VHHs) were expressed with an additional disulfide bond by introducing Ala/Gly54Cys and Ile78Cys mutations. Mutant antibodies were compared to their wild-type counterparts with respect to expression yield, non-aggregation status, affinity for toxin A, circular dichroism (CD) structural signatures, thermal stability, protease resistance, and toxin A-neutralizing capacity. The mutant VHHs were found to be well expressed, although with lower yields compared to wild-type counterparts, were non-aggregating monomers, retained low nM affinity for toxin A, albeit the majority showed somewhat reduced affinity compared to wild-type counterparts, and were capable of in vitro toxin A neutralization in cell-based assays. Far-UV and near-UV CD spectroscopy consistently showed shifts in peak intensity and selective peak minima for wild-type and mutant VHH pairs; however, the overall CD profile remained very similar. A significant increase in the thermal unfolding midpoint temperature was observed for all mutants at both neutral and acidic pH. Digestion of the VHHs with the major gastrointestinal proteases, at biologically relevant concentrations, revealed a significant increase in pepsin resistance for all mutants and an increase in chymotrypsin resistance for the majority of mutants. Mutant VHH trypsin resistance was similar to that of wild-type VHHs, although the trypsin resistance of one VHH mutant was significantly reduced. Therefore, the introduction of a second disulfide bond in the hydrophobic core not only increases VHH thermal stability at neutral pH, as previously shown, but also represents a generic strategy to increase VHH stability at low pH and impart protease resistance, with only minor perturbations in target binding affinities. These are all desirable characteristics for the design of protein-based oral therapeutics

More important than guns or grog: The role of television for the health and wellbeing of Australian Aboriginal prisoners

Published online: 30 Nov 2018This article examines the provision of television in the South Australian prison system and its importance to the identity, health, wellbeing and ontological security of Aboriginal prisoners. Existing research has explored the use of broadcast and print media by prisoners in the United Kingdom, United States and Europe and has established that television has an impact on incarcerated audiences far beyond its role as an ‘electronic babysitter’ or a means of filling time. It is also recognised that television plays a significant role in the lives of Aboriginal people (Michaels 1986). However, little is known about television in relation to incarcerated Aboriginal and Torres Strait Islander Australians. This article draws on data concerning in-cell television (‘TV’) among Aboriginal men in prison,1 which found that, when asked to identify the most important factors in the prison environment, 87 per cent of participants identified access to in-cell television as the single most important factor contributing to their congruency with prison accommodation. The article further indicates that access to in-cell television has the potential to reduce incidents of suicide and self-harm and should be adopted as a ‘best-practice’ principle for Aboriginal prisoners in Australian correctional environments.Elizabeth Grant and Yvonne Jewkeshttp://heinonline.org/HOL/Index?index=journals/cicj&collection=journal