The Effect of Heat Shock Protein 90 Inhibitor on Pain in Cancer Patients: A Systematic Review and Meta-Analysis.

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an essential role in tumor growth. Numerous Hsp90 inhibitors have been discovered and tested in preclinical and clinical trials. Recently, several preclinical studies have demonstrated that Hsp90 inhibitors could modulate pain sensitization. However, no studies have evaluated the impact of Hsp90 inhibitors on pain in the patients. This study aims to summarize the pain events reported in clinical trials assessing Hsp90 inhibitors and to determine the effect of Hsp90 inhibitors on pain in patients. We searched PubMed, EBSCOhost, and clinicaltrials.gov for Hsp90 inhibitor clinical trials. The pain-related adverse events were summarized. Meta-analysis was performed using the data reported in randomized controlled trials. We identified 90 clinical trials that reported pain as an adverse effect, including 5 randomized controlled trials. The most common types of pain reported in all trials included headache, abdominal pain, and back pain. The meta-analysis showed that Hsp90 inhibitors increased the risk of abdominal pain significantly and appeared to increase the risk for back pain. In conclusion, Hsp90 inhibitor treatment could potentially increase the risk of pain. However, the meta-analysis demonstrated only moderate evidence for the connection between Hsp90 inhibitor and pain.

Anti-inflammatory activities of novel heat shock protein 90 isoform selective inhibitors in BV-2 microglial cells.

Heat shock protein 90 (Hsp90) is a family of chaperone proteins that consists of four isoforms: Hsp90α, Hsp90ß, glucose-regulated protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1). They are involved in modulating the folding, maturation, and activation of their client proteins to regulate numerous intracellular signaling pathways. Previous studies demonstrated that pan-Hsp90 inhibitors reduce inflammatory signaling pathways resulting in a reduction of inflammation and pain but show toxicities in cancer-related clinical trials. Further, the role of Hsp90 isoforms in inflammation remains poorly understood. This study aimed to determine anti-inflammatory activities of Hsp90 isoforms selective inhibitors on the lipopolysaccharide (LPS)-induced inflammation in BV-2 cells, a murine microglial cell line. The production of inflammatory mediators such as nitric oxide (NO), interleukin 1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) was measured. We also investigated the impact of Hsp90 isoform inhibitors on the activation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinases (MAPKs). We found that selective inhibitors of Hsp90ß reduced the LPS-induced production of NO, IL-1ß, and TNF-α via diminishing the activation of NF-κB and Extracellular signal-regulated kinases (ERK) MAPK. The Hsp90α, Grp94, TRAP1 inhibitors had limited effect on the production of inflammatory mediators. These findings suggest that Hsp90ß is the key player in LPS-induced neuroinflammation. Thereby providing a more selective drug target for development of medications involved in pain management that can potentially contribute to the reduction of adverse side effects associated with Hsp90 pan inhibitors.

Linked OXTR Variants Are Associated with Social Behavior Differences in Bonobos (Pan paniscus).

Single-nucleotide polymorphisms (SNPs) in forkhead box protein P2 (FOXP2) and oxytocin receptor (OXTR) genes have been associated with linguistic and social development in humans, as well as to symptom severity in autism spectrum disorder (ASD). Studying biobehavioral mechanisms in the species most closely related to humans can provide insights into the origins of human communication, and the impact of genetic variation on complex behavioral phenotypes. Here, we aimed to determine if bonobos (Pan paniscus) exhibit individual variation in FOXP2 and OXTR loci that have been associated with human social development and behavior. Although the ASD-related variants were reported in 13-41% of the human population, we did not find variation at these loci in our sample of 13 bonobos. However, we did identify a novel variant in bonobo FOXP2, as well as four novel variants in bonobo OXTR that were 17-184 base pairs from the human ASD variants. We also found the same linked, homozygous allelic combination across the 4 novel OXTR SNPs (homozygous TGTC) in 6 of the 13 bonobos, indicating that this combination may be under positive selection. When comparing the combined OXTR genotypes, we found significant group differences in social behavior; bonobos with zero copies of the TGTC combination were less social than bonobos with one copy of the TGTC combination. Taken together, our findings suggest that these OXTR variants may influence individual-level social behavior in bonobos and support the notion that linked genetic variants are promising risk factors for social communication deficits in humans.

Exploring action dynamics as an index of paired-associate learning.

Much evidence exists supporting a richer interaction between cognition and action than commonly assumed. Such findings demonstrate that short-timescale processes, such as motor execution, may relate in systematic ways to longer-timescale cognitive processes, such as learning. We further substantiate one direction of this interaction: the flow of cognition into action systems. Two experiments explored match-to-sample paired-associate learning, in which participants learned randomized pairs of unfamiliar symbols. During the experiments, their hand movements were continuously tracked using the Nintendo Wiimote. Across learning, participant arm movements are initiated and completed more quickly, exhibit lower fluctuation, and exert more perturbation on the Wiimote during the button press. A second experiment demonstrated that action dynamics index novel learning scenarios, and not simply acclimatization to the Wiimote interface. Results support a graded and systematic covariation between cognition and action, and recommend ways in which this theoretical perspective may contribute to applied learning contexts.