Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers

Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors

Commandeering a biological pathway using aptamer-derived molecular adaptors

Induction of molecular proximity can mediate a discrete functional response in biological systems. Therefore, creating new and specific connectivity between non-interacting proteins is a means of imposing rational control over biological processes. According to this principle, here we use composite RNA aptamers to generate molecular adaptors that link various ‘target’ molecules to a common ‘utility’ molecule, with the utility molecule being an entry point to a pathway conscripted to process the target molecule. In particular, we created a bi-functional aptamer that simultaneously binds to the green fluorescent protein (serving as a surrogate extracellular target) and the opsonin C3b/iC3b (serving as the utility molecule). This bi-functional aptamer enabled us to commandeer the C3-based opsonization-phagocytosis pathway to selectively transport an extracellular target into the lysosome for degradation. This novel strategy has the potential for powerful therapeutic applications with extracellular proteins involved in tumor development or surface markers on cancer cells as the target molecules

Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers

Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors

Can Lemborexant for Insomnia Prevent Delirium in High-Risk Patients with Pancreato-Biliary Disease after Endoscopic Procedures under Deep Sedation?

Background and aim: Pancreato-biliary patients who undergo endoscopic procedures have high potential risk of delirium. Although benzodiazepine has traditionally been used to treat insomnia, this drug might increase delirium. Lemborexant may be useful for patients with insomnia, without worsening delirium, although there is no evidence for high-risk patients with pancreato-biliary disease. The aim of this pilot study was to evaluate the safety and efficacy of lemborexant for insomnia and the frequency of delirium after endoscopic procedures under deep sedation in patients with pancreato-biliary disease. Method: This retrospective study included consecutive patients who were administered lemborexant after endoscopic procedures for pancreato-biliary disease between September 2020 and June 2022. The primary outcome of this study was evaluation of the safety and efficacy of lemborexant for insomnia. Frequency of delirium was the secondary outcome. Result: In total, 64 patients who had the complication of insomnia after an endoscopic procedure were included in the study. Risk factors for delirium were advanced age (n = 36, 56.3%), dementia (n = 10, 15.6%), and regular alcohol use (n = 13, 20.3%), as well as the sedatives midazolam and pentazocine that were administered to all patients at the time of the endoscopic procedure. Successful asleep was achieved by 61/64 patients (95.3%). No fall event was observed during the night following the procedure in any patient. However, mild consciousness transformation was observed in one patient. Conclusions: In conclusion, lemborexant use may be effective and safe for use after endoscopic procedures in pancreato-biliary patients, without increasing the risk of delirium

Comparison of Endoscopic Hemostasis for Endoscopic Sphincterotomy Bleeding between a Novel Self-Assembling Peptide and Conventional Technique

Introduction: Recently, a novel self-assembling peptide hemostatic gel has become available in Japan. However, the safety and efficacy of this novel self-assembling peptide hemostatic gel remain unclear for bleeding after EST. The aim of this study was to evaluate the safety and efficacy of a novel self-assembling peptide hemostatic gel for bleeding after EST, and to perform a comparison to a conventional endoscopic hemostasis technique. Method: This retrospective study was carried out between January 2019 and October 2022. Patients who developed bleeding associated with EST were enrolled. The patients were divided into two groups based on the hemostasis technique used: a conventional hemostasis technique (Group A) or a novel self-assembling peptide hemostatic gel hemostasis technique (Group B). Result: A total of 62 patients (Group A, n = 36; Group B, n = 26) were included. Endoscopic hemostasis was initially obtained in 72.2% (26/32) of patients in Group A and in 88.4% (23/26) of patients in Group B, which was not significantly different (p = 0.1320). However, the procedure time was significantly shorter in Group B (mean, 9.38 min) compared with Group A (mean, 15.4 min) (p = 0.0103). There were no significant differences in the severity of bleeding between the two groups (p = 0.4530). Post-EST bleeding was observed in six patients (Group A, n = 4; Group B, n = 2). Adverse events were more frequently observed in Group A (n = 12) than in Group B (n = 1) (p = 0.0457). Conclusions: PuraStat application for EST bleeding might be safe and effective, and is comparable to the conventional endoscopic hemostasis technique, although further prospective randomized trials are needed