CBP501 induces immunogenic tumor cell death and CD8 T cell infiltration into tumors in combination with platinum, and increases the efficacy of immune checkpoint inhibitors against tumors in mice

CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate and functions as an enhancer of platinum uptake into cancer cells. Here we show that CBP501 promotes immunogenic cell death (ICD) in combination with platinum agents. CBP501 enhanced a clinically relevant low dose of cisplatin (CDDP) in vitro as evidenced by upregulation of ICD markers, including cell surface calreticulin exposure and release of high-mobility group protein box-1. Synergistic induction of ICD by CDDP plus CBP501 as compared to CDDP alone was confirmed in the well-established vaccination assay. Furthermore, cotreatment of CDDP plus CBP501 significantly reduced the tumor growth and upregulated the percentage of tumor infiltrating CD8+ T cell in vivo. Importantly, the antitumor effect of CDDP plus CBP501 was significantly reduced by anti-CD8 antibody treatment. Based on this novel effect of CBP501, we analyzed the combination treatment with immune checkpoint inhibitors in vivo. Mice treated with CBP501 in combination with CDDP and anti-PD-1 or anti-PD-L1 showed an additive antitumor effect. These results support the conclusion that CBP501 enhances CDDP-induced ICD in vitro and in vivo. The findings also support the further clinical development of the CBP501 for enhancing the antitumor activity of immune checkpoint inhibitors in combination with CDDP

Switchable quaternary ammonium transformation leading to salinity-tolerance-conferring plant biostimulants

Since their discovery by Menshutkin in 1890, quaternary ammonium salts have been synthesized by alkylating tertiary amines, with the development of new synthetic methods having received limited attention. Here we describe a photoredox-catalyzed method for synthesizing quaternary ammonium salts that involves reacting α-haloalkylammonium salts with olefins. This chemistry enables selective and switchable alkylations and alkenylations that afford a variety of structurally new quaternary ammonium salts. The key to success is attributable to the photocatalytic generation of distonic α-ammonium radicals under both oxidative and reductive quenching conditions. Furthermore, during the course of our reaction-development-based chemical-screening campaign, we serendipitously discovered that the synthesized quaternary ammonium salts confer plants with salinity tolerance. The discovery of a novel class of salinity-tolerance-conferring molecule is expected to impact agrochemical development as salinity damage increasingly becomes a global problem

A Case of a Giant Sublingual Epidermoid Cyst Removed by Content Reducing Surgery

The frequency of epidermoid cysts in the maxillofacial region is relatively low. Reported: a case of a giant sublingual epidermoid cyst on the floor of the mouth. Case: 38-year-old woman. Chief complaint: oral swelling and respiratory distress. History of present illness: no special notes. Current medical history: she was aware of swelling of the floor of the mouth six months before visiting our department and was referred to our department because of increasing size. Present symptoms: at the time of examination, forced respiration and dysarthria were observed and a spherical soft elastic and well-defined mass was observed on the floor of the mouth. Due to the lesion, the tongue was displaced to the pharyngeal side and the tip of the tongue could not be confirmed. Imaging tests revealed a 65 mm × 76 mm × 54 mm well-defined mass on the mylohyoid muscle, and a dermoid or epidermoid cyst was suspected. Based on the clinical diagnosis of the cyst, the bulk of the cyst contents was reduced under general anesthesia, and the cyst was removed by intraoral surgery. The pathological diagnosis was an epidermoid cyst. For sublingual giant epidermoid cysts, removal by content reducing surgery was considered to be effective

CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection

Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T-cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4+, CD8+, and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4+ and CD8+ TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8+ TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8+ TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8+ T cells was correlated with an improved clinical outcome, raising the possibility that CD8+ T cells might play a pivotal role in the anti-tumor immune response against MPMs. Thus, the stimulation of CD8+ lymphocytes might be an efficacious immunotherapy for MPM patients