Mechanisms of checkpoint inhibition-induced adverse events.

Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non-small-cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self-tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune-related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field.

Factors affecting strontium absorption in drownings.

This study examines the effects of age, gender, a cold water medium versus warm water medium, and salinity on strontium levels determined in left ventricular blood in drownings. Significant differences in the amount of strontium absorbed into the bloodstream (p<0.001) were detected between individuals who drowned in fresh water versus those drowning in seawater, and between those drowning in cold water versus warm water (p=0.030). However, no significant differences were noted in the strontium concentrations of left ventricular blood according to gender or age.

Comparison between lung weight and blood strontium in bodies found in seawater.

This paper examines the use of lung weight increase as an indicator of seawater drowning compared to the amount of Sr absorbed by the blood. The study population was limited to male victims older than 20 years. Significant differences between cases of drowning and "non-drowning" were detected in terms of the lung-heart weight ratio (L/H) (p<0.001) or lung-body weight ratio (L/B) (p=0.005). However, using lung weight (L), L/H or L/B to distinguish between seawater drownings and saltwater non-drownings some overlap was produced. The factor rendering least overlap was L/B, which also appeared to be non-dependent on the victim's age. Our findings suggest that a value of L/B higher than 19.5 g/kg could be a useful indicator of death by drowning, but that when a lower value is found, additional drowning diagnoses would be needed to establish the manner of death.

A new method for the simultaneous analysis of growth and death of immunophenotypically defined cells in culture.

BACKGROUND: Internal standards have been used in flow cytometry methods to enumerate lymphoid subsets and hemopoietic progenitor cells ex vivo. However, the currently available methods cannot be readily applied to the analysis of cultured cells because of the frequent occurrence of cell death during in vitro assays. METHODS: This paper reports a new method for the enumeration of both viable and nonviable cells in culture. Cells were counted with the aid of an internal reference standard of microbeads, and live versus dead cell discrimination was performed using 7-amino-actinomycin D which allows the double staining of surface antigens. RESULTS: The method is more precise, accurate and sensitive than either conventional light microscopy-based or automated cell counting. Additionally, it may be used to accurately measure the number of apoptotic cells in a culture. RESULTS: Through the enumeration of surviving cells it is demonstrated that, when applied to the study of mitogen-activated T lymphocytes, current flow cytometry techniques (which do not use internal standards) for the study of the viability and apoptosis overestimate the fraction of viable cells and underestimate both the fraction of dead and apoptotic cells. CONCLUSIONS: The new method overcomes these limitations and is of use in the in vitro study of cell growth and apoptosis.