Sepsis-associated encephalopathy (SAE) is a life-threatening deterioration of mental status in relation to long-term and disabling cognitive dysfunction that is common in intensive care units worldwide. Cortistatin-14 is a neuropeptide structurally resembling somastostatin, which has been proven to play a crucial role in sepsis. The present study aimed to explore the neuroprotective role of cortistatin-14 in sepsis-associated encephalopathy and its underlying mechanisms in a mouse model. A septic mice model was established using the cecal ligation and puncture (CLP) method. The novel object recognition test (NORT), open field test (OFT), elevated plus maze test (EPMT), and tail suspension test (TST) were used to explore the behavioral performance of the mice. Transmission electron microscopy was used to observe the microstructure of the blood-brain barrier (BBB). Evans Blue staining was used to examine the integrity of the BBB. Immunofluorescence was used to examine the morphology and infiltration of microglia. A multiplex cytokine bead array assay was used to determine cytokine and chemokine levels in mouse serum and brain tissues. NORT revealed that cortistatin treatment improved cognitive impairment in septic mice. OFT, EPMT, and TST indicated that cortistatin-14 relieved the anxiety-related behaviors of CLP mice. In addition, cortistatin-14 treatment decreased the levels of various inflammatory cytokines, including interleukin-1β, interleukin-6, interferon-γ, and tumor necrosis factor-α in both the serum and brain of septic mice. Cortistatin reduced sepsis-induced blood-brain barrier disruption and inhibited microglial activation after the onset of sepsis. Cortistatin exerts neuroprotective effects against SAE and cognitive dysfunction in a CLP-induced mouse model of sepsis.

Background: Pancreatic adenocarcinoma (PAC) is a malignant tumor with less than 5% of 5-year overall survival. Although immunotherapy has shown excellent and lasting efficacy in many solid tumors, immunomonotherapy is ineffective in PAC. The combinations of immune checkpoint inhibitors (ICIs) with radiotherapy/chemotherapy has shown encouraging results. Identifying predictive biomarkers is of great sense for PAC patients to benefit from immunotherapy. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples of 83 Chinese PAC patients were collected from Shandong Provincial Hospital Affiliated to Shandong First Medical University. Next-generation sequencing (NGS) of targeted-450 cancer genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations, tumor mutational burden (TMB), and microsatellite instability (MSI) were assayed. PD-L1 expression was determined using Combined Positive Score (CPS). Results: A total of 83 PAC patients were enrolled in this cohort, including 50 (60.2%) males and 33 (39.8%) females. Among them, 79.5% (66/83) and 20.5% (17/83) were primary and metastatic lesions, respectively. The most common mutant genes were KRAS (84.3%, 70/83), TP53 (75.9%, 63/83), CDKN2A (27.7%, 23/83), SMAD4 (26.5%, 22/83) and ARID1A (12.0%, 10/83). In addition, some gene alterations associated with immune hyperprogression (HP) were detected in 9.6% (8/83) patients, including 11q13 amp (2.4%, 2/83), and CDKN2A/B gene loss (7.2%, 6/83). There are 32 (38.6%) PD-L1 positive patients, including 25 patients with CPS 1-10 and 7 patients with CPS≥20. We found that SPTA1 mutations were specifically detected in PD-L1 positive group, while OBSCN and ATM mutations were specifically detected in PD-L1 negative group. The median TMB value was 3.3 muts/Mb and only 4 (4.8%) patients had TMB-values higher than 10 muts/Mb (TMB-H). There are 3 patients (3.6%) showed MSI-H. Interestingly, all 3 MSI-H patients were TMB-H, and 2 of them also showed PD-L1 positive without any HP related mutations. Both patients received immunotherapy and were benefited for more than 11 months, including one of whom had received immunomonotherapy. Conclusions: We described the characteristics of TMB, MSI and PD-L1 expression in Chinese patients with PAC. In the absence of HP related mutations, comprehensive consideration of TMB, MSI and PD-L1 status may guide PAC immunotherapy and benefit PAC patients. Citation Format: Yu Wang, Yantian Xu, Alei Feng, Qiang Wen, Xiaoliang Shi, Shanshan Zhang, Fei Pang. Comprehensive analysis and potential clinical applications of immunotherapy-related biomarkers in Chinese patients with pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5753.