👤 Jenna B Emerson

The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. ClinicalTrials.gov Identifier: NCT03802396. Show less

Dual specificity phosphatase 6 (DUSP6) is a protein phosphatase that deactivates extracellular-signal-regulated kinase (ERK). Since the ovarian cancer biomarker human epididymis protein 4 (HE4) interacts with the ERK pathway, we sought to determine the relationship between DUSP6 and HE4 and elucidate DUSP6's role in epithelial ovarian cancer (EOC). Viability assays revealed a significant decrease in cell viability with pharmacological inhibition of DUSP6 using (E/Z)-BCI hydrochloride in ovarian cancer cells treated with carboplatin or paclitaxel, compared to treatment with either agent alone. Quantitative PCR was used to evaluate levels of ERK pathway response genes to BCI in combination with recombinant HE4 (rHE4), carboplatin, and paclitaxel. Expression of EGR1, a promoter of apoptosis, was higher in cells co-treated with BCI and paclitaxel or carboplatin than in cells treated with chemotherapeutic agents alone, while expression of the proto-oncogene c-JUN was decreased with co-treatment. The effect of BCI on the expression of these two genes opposed that of rHE4. Pathway focused quantitative PCR also revealed suppression of Show less