Sources of inter-individual variability leading to significant changes in anti-PD-1 and anti-PD-L1 efficacy identified in mouse tumor models using a QSP framework.

While anti-PD-1 and anti-PD-L1 [anti-PD-(L)1] monotherapies are effective treatments for many types of cancer, high variability in patient responses is observed in clinical trials. Understanding the sources of response variability can help prospectively identify potential responsive patient populations. Preclinical data may offer insights to this point and, in combination with modeling, may be predictive of sources of variability and their impact on efficacy.

A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls.

Maintaining normal potassium (K+) concentrations in the extra- and intracellular fluid is critical for cell function. K+ homeostasis is achieved by ensuring proper distribution between extra- and intracellular fluid compartments and by matching K+ excretion with intake. The Na+-K+-ATPase pump facilitates K+ uptake into the skeletal muscle, where most K+ is stored.

Testing for the "Blues": Using the Modified Emotional Stroop Task to Assess the Emotional Response of Gorillas.

We adapted the emotional Stroop task developed for primates to test whether gorillas would show response slowing for images of 'negative' compared to images of 'positive' items placed within previously reinforced borders. Three zoo-housed male gorillas participated in six phases of an emotional Stroop paradigm. In Phase One, they learned to select blue borders over yellow borders in a forced choice task presented on the touchscreen.

Determining risk factors for triple whammy acute kidney injury.

Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as "triple whammy". Diuretics and RAS inhibitors, such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter.

Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling.

Sex differences in blood pressure and the prevalence of hypertension are found in humans and animal models. Moreover, there has been a recent explosion of data concerning sex differences in nitric oxide, the renin-angiotensin-aldosterone system, inflammation, and kidney function. These data have the potential to reveal the mechanisms underlying male-female differences in blood pressure control.

Modeling Sex Differences in the Renin Angiotensin System and the Efficacy of Antihypertensive Therapies.

The renin angiotensin system is a major regulator of blood pressure and a target for many anti-hypertensive therapies; yet the efficacy of these treatments varies between the sexes. We use published data for systemic RAS hormones to build separate models for four groups of rats: male normotensive, male hypertensive, female normotensive, and female hypertensive rats. We found that plasma renin activity, angiotensinogen production rate, angiotensin converting enzyme activity, and neutral endopeptidase activity differ significantly among the four groups of rats.

Sex-specific long-term blood pressure regulation: Modeling and analysis.

Hypertension is a global health challenge: it affects one billion people worldwide and is estimated to account for >60% of all cases or types of cardiovascular disease. In part because sex differences in blood pressure regulation mechanisms are not sufficiently well understood, fewer hypertensive women achieve blood pressure control compared to men, even though compliance and treatment rates are generally higher in women. Thus, the objective of this study is to identify which factors contribute to the sexual dimorphism in response to anti-hypertensive therapies targeting the renin angiotensin system (RAS).