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Background: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM., Methods: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells., Results: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts., Conclusion: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future., (© 2024. The Author(s).)

Rationale: Extracorporeal membrane oxygenation (ECMO) is the last trump card for severe respiratory failure. The main complications of ECMO are bleeding and thrombosis, both of which can be life-threatening. Large blood clots can cause central airway obstruction (CAO) during ECMO, and CAO should be removed as soon as possible because of asphyxiation. However, there is no comprehensive reports on its frequency and management. The purpose of this study is to share therapeutic experiences for rare and serious conditions and provide valuable insights., Patient Concerns: We report 3 patients placed on ECMO for severe respiratory failure., Diagnosis: CAO due to large blood clots occurred during ECMO in all 3 patients., Interventions: Large blood clots were removed using flexible bronchoscopy, grasping forceps, and net retrieval devices in all 3 patients., Outcomes: In all 3 patients, large blood clots were removed multiple times during ECMO. The patients' respiratory conditions improved and they were eventually weaned off the ECMO., Lessons: CAO due to large blood clots during ECMO is rare. The frequency of CAO requiring bronchoscopic removal was estimated to be approximately 1,5%. When this occurs, clots should be removed as soon as possible. Net retrieval devices are useful tools for the collection of large blood clots., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Background: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes., Objective: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs)., Methods: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps., Results: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo., Conclusion: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.

Background: Biofilm-related infections are serious problems in the Orthopedics field, and Staphylococcus aureus are the most popular causative agents of bacterial infections associated with arthroplasty. Several studies demonstrated a synergistic effect of the electric intervention (EI) and the antibiotic administration in killing bacteria in biofilm; however, a constant, long-time EI was needed. In the present study, the effective removal of biofilm formed with S. aureus on a titanium ring by multiple times of one minute-EI was observed and described., Methods: A methicillin-sensitive S. aureus clinical isolate was used to form biofilm on a titanium ring. After applying a series of EI with various combinations of the frequencies and timings, the amount and principal components of biofilms were assessed with crystal violet staining, live bacterial cell count, and fluorescence staining with confocal laser scanning microscopy., Results: More than 60% biofilm removal was observed in the 2-time EI applied at 24 (1) and 72 (3) h (days) post bacterial exposure (PBE) and in the 3-time EI at 0 (0), 24 (1), and 72 (3) h (days) PBE, or at 24 (1), 48 (2), and 72 (3) h (days) PBE. The live bacterial cell numbers, the proportion of live and dead cells, and the amount of extracellular polysaccharide substances (EPS) of biofilm were similar with or without EI. It was assumed that an excess amount of the biofilm removal shown in the several EI was not attributed to the effect of the electrolysis., Conclusions: The effective removal of biofilm was observed when multiple times 1 min EI was applied without any changes in the proportion of live and dead bacteria or the amount of EPS. The mechanisms to explain extra biofilm removal remain to be elucidated., Competing Interests: Declaration of competing interest Authors do not have any relevant conflict of interest., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)