Search

Incomplete Freund's adjuvant (IFA) has been used for many years to induce autoimmune diseases in animal models, including experimental autoimmune encephalitis and collagen-induced arthritis. However, it remains unclear why it is necessary to emulsify autoantigen and heat-killed Mycobacterium tuberculosis (HKMtb) with IFA to induce experimental autoimmune diseases. Here, we found that immunization with self-antigen and HKMtb was insufficient to induce autoimmune diseases in mice. Furthermore, IFA or one of its components, mineral oil, but not mannide monooleate, was required for the development of experimental autoimmune disease. Immunization with autoantigen and HKMtb emulsified in mineral oil facilitated innate immune activation and promoted the differentiation of pathogenic CD4 + T cells, followed by their accumulation in neuronal tissues. Several water-soluble hydrocarbon compounds were identified in mineral oil. Of these, immunization with HKMtb and autoantigen emulsified with the same amount of hexadecane or tridecylcyclohexane as mineral oil induced the development of experimental autoimmune encephalitis. In contrast, immunization with HKMtb and autoantigen emulsified with tridecylcyclohexane, but not hexadecane, at doses equivalent to those found in mineral oil, resulted in neuronal dysfunction. These data indicate that tridecylcyclohexane in mineral oil is a critical component in the induction of experimental autoimmune disease., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bisphenol A (BPA) is widely used in manufacturing plastic products, and it has been reported that exposure through the airway or orally aggravates allergic airway inflammation. Because BPA is detected in the atmosphere and indoor environments, the eyes can also be exposed to BPA. After ocular exposure to BPA and antigen via eye drops, we observed enhanced antigen uptake of antigen-presenting cells (APCs) in tear duct-associated lymphoid tissue (TALT). Additionally, we observed the formation of germinal center (GC) B cells in TALT and induction of allergic airway inflammation in mice sensitized with BPA and antigen via eye drops, followed by airway antigen exposure. We also found that DNAX-activating protein of 12 kDa (DAP12)-deficient mice displayed impaired activation of APCs enhanced by ocular exposure to BPA. These results indicate that ocular sensitization to BPA and allergen triggers allergic inflammation via TALT activation, and that DAP12 might be a key molecule for modulating the ocular immune system., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Design: Retrospective multicenter study., Objectives: To evaluate how preoperative neck pain influences clinical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL)., Setting: Fourteen medical institutions in Japan., Methods: We enrolled 90 patients with cervical OPLL who underwent posterior decompression and were followed for a minimum of two years. We collected demographic data, medical history, and imaging findings. Patients were divided into two groups based on preoperative neck pain presence (Pre-op. neck pain (-) and (+) groups), and their outcomes were compared., Results: There were no significant differences in patient demographics between the Pre-op. neck pain (-) and (+) groups. Both groups showed similar distributions of ossification types and K-line positivity. Perioperative complications were comparable between the two groups. Radiographic analysis revealed no significant differences in C2-7 angles or cervical range of motion, pre- and postoperatively. Both groups demonstrated significant improvement in postoperative Japanese orthopedic association (JOA) scores, but there were no significant differences in scores or recovery rates. In the Pre-op. neck pain (-) group, factors associated with appearance of postoperative neck pain included pre- and postoperative lower JOA scores and larger C2-7 angles in neutral and extension positions., Conclusions: It emerges that lower pre- and postoperative JOA scores or larger C2-7 angles in neutral and extension positions predispose to postoperative neck pain even in those patients without preoperative neck pain. Therefore, this is worth discussing at the time of consenting patients for surgical decompression and fixation., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography to that of controls after Plasmodium yoelii non-lethal infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC, precursors resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, insulin-like growth factor-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Pancreatic cancer is one of the most refractory malignancies. In situ vaccines (ISV), in which intratumorally injected immunostimulatory adjuvants activate innate immunity at the tumor site, utilize tumor-derived patient-specific antigens, thereby allowing for the development of vaccines in patients themselves. Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy that selectively kills cancer cells exclusively in the NIR-irradiated region. Extending our previous research showing that ISV using the unique nanoparticulate Toll-like receptor 9 (TLR9) ligand K3-SPG induced effective antitumor immunity, here we incorporated NIR-PIT into K3-SPG-ISV so that local tumor destruction by NIR-PIT augments the antitumor effect of ISV. In the mouse model of pancreatic cancer, the combination of K3-SPG-ISV and CD44-targeting NIR-PIT showed synergistic systemic antitumor effects and enhanced anti-programmed cell death-1 (PD-1) blockade. Mechanistically, strong intratumoral upregulation of interferon-related genes and dependency on CD8 + T cells were observed, suggesting the possible role of interferon and cytotoxic T cell responses in the induction of antitumor immunity. Importantly, this combination induced immunological memory in therapeutic and neoadjuvant settings. This study represents the first attempt to integrate NIR-PIT with ISV, offering a promising new direction for cancer immunotherapy, particularly for pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection. The reduction of CXCL12 and interleukin-7 signals in the bone marrow impairs the lymphopoietic niche, leading to the depletion of common lymphoid progenitors, B cell progenitors, and mature B cells, including plasma cells in the bone marrow. We found that interferon-γ (IFNγ) is responsible for the upregulation of Sca1 on CAR cells, yet the decline in CAR cell and B cell populations in the bone marrow is IFNγ-independent. In contrast to the decline in B cell populations, HSCs and multipotent progenitors increased with the expansion of myelopoiesis and erythropoiesis, indicating a bias in the differentiation of multipotent progenitors during malaria infection. These findings suggest that malaria may affect host immunity by modulating the bone marrow niche., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Study Design: Retrospective multicenter study., Objectives: To investigate surgical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL) when performed by board-certified spine (BCS) or non-BCS (NBCS) surgeons., Methods: We included 203 patients with cervical OPLL who were followed for a minimum of 1 year after surgery. Demographic information, medical history, and imaging findings were collected. Clinical outcomes were assessed preoperatively and at the final follow-up using the Japanese Orthopedic Association (JOA) score and the visual analog scale (VAS) for the neck. We compared outcomes between BCS surgeons, who must meet several requirements, including experience in more than 300 spinal surgeries, and NBCS surgeons., Results: BCS surgeons performed 124 out of 203 cases, while NBCS surgeons were primary in 79 cases, with 73.4% were directly supervised by a BCS surgeon. There was no statistically significant difference in surgical duration, estimated blood loss, and perioperative complication rates between the BCS and NBCS groups. Moreover, no statistically significant group differences were observed in each position of the C2-7 angle and cervical range of motion at preoperation and the final follow-up. Preoperative and final follow-up JOA scores, VAS for the neck, and JOA score recovery rate were comparable between the two groups., Conclusions: Surgical outcomes, including functional recovery, complication rates, and cervical dynamics, were comparable between the BCS and NBCS groups. Consequently, posterior decompression for cervical OPLL is considered safe and effective when conducted by junior surgeons who have undergone training and supervision by experienced spine surgeons., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α is required for CT- or CTB-induced IL-1β production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The call for second generation malaria vaccines needs not only the identification of novel candidate antigens or adjuvants but also a better understanding of immune responses and the underlying protective processes. Plasmodium parasites have evolved a range of strategies to manipulate the host immune system to guarantee survival and establish parasitism. These immune evasion strategies hamper efforts to develop effective malaria vaccines. In the case of a malaria vaccine targeting the N-terminal domain of P. falciparum serine repeat antigen 5 (SE36), now in clinical trials, we observed reduced responsiveness (lowered immunogenicity) which may be attributed to immune tolerance/immune suppression. Here, immunogenicity data and insights into the immune responses to SE36 antigen from epidemiological studies and clinical trials are summarized. Documenting these observations is important to help identify gaps for SE36 continued development and engender hope that highly effective blood-stage/multi-stage vaccines can be achieved., Competing Interests: Declaration of Competing Interest TH is the inventor of BK-SE36; TH, KJI, and TT are inventors of BK-SE36/CpG. NP and TH are both supported by a research fund from Nobelpharma Co., Ltd. (NPC), the clinical trial sponsor of Burkina Faso trials. These involvements did not influence the writing of this review and the decision to submit the article for publication., (Copyright © 2023 Elsevier B.V. All rights reserved.)

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9 H -xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Temizoz, Shibahara, Hioki, Hayashi, Kobiyama, Lee, Surucu, Sag, Kumanogoh, Yamamoto, Gursel, Ozen, Kuroda, Coban and Ishii.)

Langerhans cells (LCs) are mainly present in the epidermis and mucosa, and have important roles during skin infection. Migration of LCs to lymph nodes is essential for antigen presentation. However, due to the difficulties in isolating and culturing human LCs, it is not fully understood how LCs move and interact with the extracellular matrix (ECM) through their adhesion molecules such as integrin, during the immune responses. In this study, we aimed to investigate LC motility, cell shape and the role of integrin under inflammatory conditions using monocyte-derived Langerhans cells (moLCs) as a model. As a result, lipopolysaccharide (LPS) stimulation increased adhesion on fibronectin coated substrate and integrin α5 expression in moLCs. Time-lapse imaging of moLCs revealed that stimulation with LPS elongated cell shape, whilst decreasing their motility. Additionally, this decrease in motility was not observed when pre-treated with a neutralising antibody targeting integrin α5. Together, our data suggested that activation of LCs decreases their motility by promoting integrin α5 expression to enhance their affinity to the fibronectin, which may contribute to their migration during inflammation., (© 2024 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy., (© 2023. Springer Nature Limited.)

Introduction: Segmental spinal deformity results from vertebral compression fracture (VCF) and progressive collapse of the fractured vertebral body (VB). The VB stenting (VBS) system Ⓡ comprises a balloon-assisted, expandable, intrasomatic, metal stent that helps maintain the restored VB during balloon removal and cement injection, which minimizes cement leakage. We performed a prospective, multicenter, clinical trial of the VBS system in Japanese patients with acute VCF owing to primary osteoporosis., Methods: Herein, 88 patients, 25 men and 63 women aged 77.4±8.3 years, with low back pain, numerical rating scale (NRS) score of ≥4, and mean VB compression percentage (VBCP) of <60% were enrolled. The primary endpoints were the VBCP restoration rate and reduction in low back pain 1 month and 7 days after VBS surgery, respectively. Secondary endpoints included changes in VBCP, NRS pain score, Beck index, kyphosis angle, and quality of life according to the short form 36 (v2) score. Safety was assessed as adverse events, device malfunctions, and new vertebral fractures., Results: Overall, 70 patients completed the study. VBS surgery increased the restoration rates of anterior and midline VBCP by 31.7%±26.5% (lower 95% confidence intervals (CI): 26.8) and 31.8%±24.6% (lower 95% CI: 27.2), respectively, and the reduction in NRS pain score was -4.5±2.4 (upper 95% CI: -4.0). As these changes were greater than the predetermined primary endpoint values (20% for VBCP and -2 for NRS score), they were judged clinically significant; these changes were maintained throughout the 12-month follow-up (p<0.001). Likewise, significant improvement was observed in the Beck index, kyphosis angle, and quality of life score, which were maintained throughout the follow-up. There were three serious adverse events. New fractures occurred in 12 patients-all in the adjacent VB., Conclusions: VBS surgery effectively restored the collapsed VB, relieved low back pain, and was tolerable in patients with acute osteoporotic VB fracture., Competing Interests: Conflicts of Interest: Ryuichi Takemasa participated in the multicenter clinical trial as a medical expert and received an honorarium from Depyu Synthes Japan. The other authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: Reoperation is usually associated with poor results and increased morbidity and hospital costs. However, the rates, causes, and risk factors for reoperation in patients undergoing lumbar spinal fusion surgery remain controversial. This study aimed to identify the risk factors for early reoperation after posterior lumbar interbody fusion surgery and to compare the clinical outcomes between patients who underwent reoperation and those who did not., Methods: We investigated a multicenter medical record database of 1263 patients who underwent posterior lumbar interbody fusion surgery between 2012 and 2015. A total of 72 (5.7%) reoperations within two years after surgery were identified and were propensity-matched for age, sex, number of fusion segments, and surgeon's experience., Results: We analyzed a total of 114 patients (57 who underwent reoperation (R group) and 57 who did not (C group)). The mean age was 62.6 ± 13.4 years, with 78 men and 36 women. The mean number of fused segments was 1.2 ± 0.5. Surgical site infection was the most common cause of reoperation. There were significant differences in the incidence of diabetes mellitus (p = 0.024), preoperative ambulation status (p = 0.046), and ASA grade (p < 0.001) between the C and R groups. The recovery rate of the Japanese Orthopaedic Association score was significantly lower in the R group compared to the C group (R: 50.5 ± 28.8%, C: 63.9 ± 33.7%, p = 0.024). There were significant differences in the bone fusion rate (R: 63.2%, C: 96.5%, p < 0.001) and incidence of screw loosening (R: 31.6%; C: 10.5%; p = 0.006)., Conclusion: Diabetes mellitus, preoperative ambulation status, and ASA grade were significant risk factors for early reoperation following posterior lumbar interbody fusion surgery. The patients who underwent early reoperation had worse clinical outcomes than those who did not., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Although the surgical release of the sternocleidomastoid muscle (SCM) is required for residual congenital muscular torticollis (CMT), the surgical outcomes between bipolar and unipolar SCM release remained unclear. The purpose of the present study was to assess surgical outcomes after bipolar and unipolar release of SCM in adolescent/adult patients with neglected CMT., Methods: Twenty-one consecutive adolescent/adult patients with neglected CMT who underwent surgical treatment were enrolled. Clinical and radiographic outcomes were evaluated at preoperative and final follow-up., Results: The bipolar release of SCM was performed in 3 patients (B group; males, n = 1, females, n = 2) and the unipolar release of SCM in 18 patients (U group; males, n = 6, females, n = 12). The mean age at surgery was 40.0 ± 17.0 years in Group B, and that was 32.3 ± 13.1 years in Group U ( p = 0.47). The mean follow-up period was 16.0 ± 5.7 months in Group B and 10.4 ± 7.6 months in Group U ( p = 0.22). Cervicomandibular angle correction rates were comparable at 75.4 ± 2.4% for the B group and 73.1 ± 11.7% for the U group ( p = 0.62). There was no significant difference in clinical outcome according to the modified Cheng and Tang score between the two groups ( p = 0.89). No major complications arose, although one patient exhibited a transient neurological deficit of the greater auricular nerve, and one patient developed a hematoma in the B group., Conclusions: The unipolar SCM release appeared to be a non-inferiority and less invasive procedure, minimizing surgical scars and avoiding potential auricular nerve damage in adolescent/adult patients with neglected CMT.

The new coronavirus infection causes severe respiratory failure following respiratory tract infection with severe acute respiratory syndrome-related coronavirus (SARS-CoV-2). All currently approved vaccines are administered intramuscularly; however, intranasal administration enhances mucosal immunity, facilitating the production of a less invasive vaccine with fewer adverse events. Herein, a recombinant vaccine combining the SARS-CoV-2 spike protein receptor-binding domain (RBD), or S1 protein, with CpG-deoxyoligonucleotide (ODN) or aluminum hydroxide (alum) adjuvants was administered intranasally or subcutaneously to mice. Serum-specific IgG titers, IgA titers in the alveolar lavage fluid, and neutralizing antibody titers were analyzed. The nasal administration of RBD protein did not increase serum IgG or IgA titers in the alveolar lavage fluid. However, a significant increase in serum IgG was observed in the intranasal group administered with S1 protein with CpG-ODN and the subcutaneous group administered with S1 protein with alum. The IgA and IgG levels increased significantly in the alveolar lavage fluid only after the intranasal administration of the S1 protein with CpG-ODN. The neutralizing antibody titers in serum and bronchoalveolar lavage were significantly higher in the intranasal S1-CpG group than in every other group. Hence, the nasal administration of the S1 protein vaccine with CpG adjuvant might represent an effective vaccine candidate.

Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the spleen, a process termed extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria regulate not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbes on hematopoietic pathology remains unclear. Here, we find that systemic single injections of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium, rapidly activate BM myelopoiesis and slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we term delayed EMH. Mechanistically, delayed EMH triggered by A. m. is mediated entirely by the MYD88/TRIF innate immune signaling pathway, which persistently stimulates splenic myeloid cells to secrete interleukin (IL)-1α, and in turn, activates IL-1 receptor (IL-1R)-expressing splenic HSPCs. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) or IL-1α partially diminishes A. m.-induced delayed EMH, while inhibition of both pathways alleviates splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders., (© 2023 The Authors.)

This study aimed to determine whether a trunk orthosis with joints providing resistive force (TORF) modifies sagittal malalignment during level walking in patients with lumbar spinal stenosis (LSS). Fifteen patients, 6 months after undergoing surgery for LSS, performed level walking at a self-selected speed while wearing a TORF. Dynamic sagittal alignment, including sagittal vertical axis, lumbar lordosis, and pelvic tilt, and spatiotemporal data as well as lower limb kinematic and kinetic data were recorded using a three-dimensional motion analysis system and six force plates. Statistical analysis was performed to compare these data with and without the TORF, respectively. Compared to the condition without the TORF, the use of the TORF significantly decreased positive sagittal vertical axis (p < 0.05) and increased the lumbar lordosis and pelvic tilt (p < 0.05). Peak hip flexion angle and extension moment during loading response (LR) significantly increased (p < 0.05), and peak hip extension angle and flexion moment during PS statistically decreased (p < 0.05). There was no difference in spatiotemporal data between the two conditions. Our findings suggest that TORF may modify the dynamic sagittal global alignment and lower limb kinematic and kinetics in postoperative LSS patients during level walking., (© 2023. The Author(s).)

Background: Although vaccination is recommended for protection against invasive pneumococcal disease, the frequency of pneumococcal pneumonia is still high worldwide. In fact, no vaccines are effective for all pneumococcal serotypes. Fusion pneumococcal surface protein A (PspA) has been shown to induce a broad range of cross-reactivity with clinical isolates and afford cross-protection against pneumococcal challenge in mice. Furthermore, we developed prime-boost-type mucosal vaccines that induce both antigen-specific IgG in serum and antigen-specific IgA in targeted mucosal organs in previous studies. We investigated whether our prime-boost-type immunization with a fusion PspA was effective against pneumococcal infection in mice and cynomolgus macaques., Methods: C57BL/6 mice were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan. Six weeks later, PspA was administered intranasally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some mice were given intranasal Streptococcus pneumoniae and the severity of infection was analyzed. Macaques were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan at week 0 and week 4. Then, 13 or 41 weeks later, PspA was administered intratracheally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some macaques were intranasally administered S. pneumoniae and analyzed for the severity of pneumonia., Results: Serum samples from mice and macaques injected with antigens in combination with CpG oligodeoxynucleotides and/or curdlan contained antigen-specific IgG. Bronchial samples contained antigen-specific IgA after the fusion PspA boosting. This immunization regimen effectively prevented S. pneumoniae infection., Conclusions: Prime-boost-type immunization with a fusion PspA prevented S. pneumoniae infection in mice and macaques., (© 2023. The Author(s).)

Competing Interests: All authors, except CB, are members of the Science and Technology Expert Group for the 100 Days Mission. CB is the Deputy Head of the International Pandemic Preparedness Secretariat, which is hosted by Wellcome, and is a former employee of WHO. VD is the President of the US National Academy of Medicine. SS is the former Chief Scientist at WHO. RAB is the former Director of the US Biomedical Advanced Research and Development Authority (BARDA), is on the Scientific Advisory Board for Qiagen, is on the Board of Directors for Foundation for Innovative New Diagnostics, and holds stock in Cue Health. JC is the Chief Technology Officer of Univercells and the Chief Executive Officer of Quantoom Biosciences. TCC is the Chief Health Scientist at the Singapore Ministry of Health and is the Executive Director of the Office for Healthcare Transformation of the Singapore Ministry of Health. RD-A is the Global Head at Johnson & Johnson Global Public Health Research and Development, which receives grants and contracts from BARDA, the US National Institutes of Health (NIH), the EU (including the Innovative Health Initiative), the Bill & Melinda Gates Foundation, Flanders Agency Innovation and Entrepreneurship, the European and Developing Countries Clinical Trials Partnership, and the Singapore Agency for Science, Technology and Research; is Co-Chair of the Therapeutics Clinical Working Group of Accelerating COVID-19 Therapeutic Interventions and Vaccines at NIH; is a board member of the INTREPID Alliance; is a member of the American Society of Gene Therapy; and holds stock and stock options with Merck Sharp & Dohme and Johnson & Johnson. RE-P is the acting Chief of Staff for the Coalition of Epidemic Preparedness Innovations (CEPI) Manufacturing and Supply Chain division. GFG is the Dean of the Savaid Medical School (University of Chinese Academy of Sciences, Beijing, China). KI is the Director of the International Vaccine Design Center (Institute of Medical Science, University of Tokyo, Tokyo, Japan) and is a member of Scientific Advisory Committees for CEPI and the Global Health Innovative Technology Fund. YKT is the Head of the Division of Laboratory Systems and Networks at Africa Centres for Disease Control and Prevention (Africa CDC). TL received support through a grant from the University of Oxford (Oxford, UK) to support the running of the Vaccine Taskforce via the UK National Institute for Health and Care Research trial and the AstraZeneca partnership for development of COVID-19 vaccines, was a consultant to Vaccitech, and is an inventor on a patent application for a vaccine against SARS CoV-2. SM is Chief Science Officer for Africa CDC. J-AR is the Ambassador for Global Health at the Norwegian Ministry of Foreign Affairs; is a Gavi, the Vaccine Alliance board member representing the Nordic+ constituency; and is the former technical-level Co-Chair of the Access to COVID-19 Tools Accelerator Facilitation Council. US is the Executive Director of the Serum Institute of India. MS is the former WHO Assistant Director-General for Drug Access, Vaccines and Pharmaceuticals. RS is the former Secretary of the Department of Biotechnology at the Indian Ministry of Science and Technology. J-FT is the Head of Research and Development at Sanofi Vaccines; owns shares from Sanofi; and received shares from GlaxoSmithKline until January, 2021, as a former employee. NSW is the Founder and Chief Executive Officer of Vaccines for All and is a consultant to Africa CDC for the Partnership for Africa Vaccine Manufacturing initiative at CEPI India.

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparum serine repeat antigen5 (SE36), adsorbed to aluminium hydroxide gel and reconstituted, prior to administration, with synthetic oligodeoxynucleotides bearing CpG motifs. In healthy Japanese adult males, BK-SE36/CpG was well tolerated. This study assessed its safety and immunogenicity in healthy malaria-exposed African adults and children., Methods: A double-blind, randomised, controlled, age de-escalating clinical trial was conducted in an urban area of Ouagadougou, Burkina Faso. Healthy participants (n=135) aged 21-45 years (Cohort 1), 5-10 years (Cohort 2) and 12-24 months (Cohort 3) were randomised to receive three vaccine doses (Day 0, 28 and 112) of BK-SE36/CpG or rabies vaccine by intramuscular injection., Results: One hundred thirty-four of 135 (99.2%) subjects received all three scheduled vaccine doses. Vaccinations were well tolerated with no related Grade 3 (severe) adverse events (AEs). Pain/limitation of limb movement, headache in adults and fever in younger children (all mild to moderate in intensity) were the most frequently observed local and systemic AEs. Eighty-three of BK-SE36/CpG (91%) recipients and 37 of control subjects (84%) had Grade 1/2 events within 28 days post vaccination. Events considered by the investigator to be vaccine related were experienced by 38% and 14% of subjects in BK-SE36/CpG and control arms, respectively. Throughout the trial, six Grade 3 events (in 4 subjects), not related to vaccination, were recorded in the BK-SE36/CpG arm: 5 events (in 3 subjects) within 28 days of vaccination. All serious adverse events (SAEs) (n=5) were due to severe malaria (52-226 days post vaccination) and not related to vaccination. In all cohorts, BK-SE36/CpG arm had higher antibody titres after Dose 3 than after Dose 2. Younger cohorts had stronger immune responses (12-24-month-old > 5-10 years-old > 21-45 years-old). Sera predominantly reacted to peptides that lie in intrinsically unstructured regions of SE36. In the control arm, there were no marked fold changes in antibody titres and participants' sera reacted poorly to all peptides spanning SE36., Conclusion: BK-SE36/CpG was well-tolerated and immunogenic. These results pave the way for further proof-of-concept studies to demonstrate vaccine efficacy., Clinical Trial Registration: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1921, PACTR201701001921166., Competing Interests: TH is the inventor of BK-SE36; TH and KI are inventors of BK-SE36/CpG. NP and TH are supported by a research fund from Nobelpharma Co., Ltd NPC, the clinical trial sponsor. TS is an employee and SE is medical adviser of NPC. These involvements did not influence the design of the study, the collection, analyses, access to and interpretation of data, and the writing of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Ouédraogo, Bougouma, Palacpac, Houard, Nebie, Sawadogo, Berges, Soulama, Diarra, Hien, Ouedraogo, Konaté, Kouanda, Myoui, Ezoe, Ishii, Sato, D’Alessio, Leroy, Tiono, Cousens, Horii and Sirima.)

Background Postoperative surgical site infections (SSIs) are a significant complication of surgical procedures, leading to increased morbidity, prolonged hospital stays, and substantial healthcare costs; however, the use of drain tip cultures to diagnose SSIs in patients is controversial. The objective of this study was to evaluate the efficacy of drain tip cultures for the prediction of postoperative SSIs in patients recovering from hip arthroplasty. Methodology The data were collected from 1204 patients who underwent hip arthroplasty procedures over 15 years, and statistical analysis was performed to evaluate the diagnostic value of drain tip culture in determining surgical site infection. We also used these data to evaluate whether preexisting conditions such as hypertension or diabetes affected the probability of a patient getting an SSI. Results Drain tip cultures were positive in 12 of 1,112 cases of primary hip arthroplasty, but only one of these 12 patients was ultimately diagnosed with an SSI (sensitivity, 12.5%; specificity, 99.0%; p = 0.0834). Results from postoperative drain tip cultures performed in patients undergoing revision arthroplasty included two false positives and three false negatives; interestingly, no true positives were detected in any of the revision arthroplasty cases we evaluated (sensitivity, 0％; specificity, 97.8％; p = 0.9355). Conclusion Our results indicate that drain tip cultures have no statistically significant predictive value for the diagnosis of postoperative SSIs and thus should not be used as a primary diagnostic or predictive tool for SSIs. We recommend exploring other diagnostic tools for the postoperative diagnosis of SSIs. Standardized guidelines should therefore be established to improve the predictive value of the different methods., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Toga et al.)

Protein or peptide cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine adjuvant. Here, we present cholicamideβ ( 6 ), a self-assembling small-molecule vaccine adjuvant with an improved toxicity profile and proven efficacy in vivo . We demonstrate that cholicamideβ ( 6 ), which is less cytotoxic than its parent compound, forms virus-like particles to potently activate dendritic cells with the concomitant secretion of cytokines. When combined with a peptide antigen, cholicamideβ ( 6 ) potentiated the antigen presentation on dendritic cells to induce antigen-specific T cells. As a therapeutic cancer vaccine adjuvant in mice, a mixture of cholicamideβ ( 6 ) and a peptide antigen protected mice from the challenges of malignant cancer cells without overt toxicity. Cholicamideβ ( 6 ) may offer a translational opportunity as an unprecedented class of small-molecule cancer vaccine adjuvants.

In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international mobility continue to rise, highly infectious respiratory diseases will likely emerge more frequently and their impact is expected to be substantial. How quickly a safe and efficacious vaccine can be deployed against rising infectious respiratory diseases may be the most important challenge that humanity will face in the near future. While some organizations are engaged in addressing the World Health Organization's "blueprint for priority diseases", the lack of worldwide preparedness, and the uncertainty around universal vaccine availability, remain major concerns. We therefore propose the establishment of an international candidate vaccine pool repository for potential respiratory diseases, supported by multiple stakeholders and countries that contribute facilities, technologies, and other medical and financial resources. The types and categories of candidate vaccines can be determined based on information from previous pandemics and epidemics. Each participant country or region can focus on developing one or a few vaccine types or categories, together covering most if not all possible potential infectious diseases. The safety of these vaccines can be tested using animal models. Information for effective candidates that can be potentially applied to humans will then be shared across all participants. When a new pandemic arises, these pre-selected and tested vaccines can be quickly tested in RCTs for human populations., Competing Interests: Peter Hotez is a co-inventor of a COVID-19 recombinant protein vaccine technology owned by Baylor College of Medicine (BCM) that was recently licensed by BCM non-exclusively and with no patent restrictions to several companies committed to advance vaccines for low- and middle-income countries. The co-inventors have no involvement in license negotiations conducted by BCM. Similar to other research universities, a long-standing BCM policy provides its faculty and staff, who make discoveries that result in a commercial license, a share of any royalty income, according to BCM policy. Jerome H. Kim services as the consultant for SK bioscience and Moderna. Other authors declare no competing financial interests.

Background: The radiographic outcomes of nonoperative treatment of dropped head syndrome are still unknown. The purpose of the present study was to assess the change in sagittal spinopelvic radiographic parameters after the short and intensive rehabilitation (SHAiR) program in patients with dropped head syndrome., Methods: This study included 48 consecutive patients with dropped head syndrome who presented with an inability to maintain horizontal gaze and who underwent the SHAiR program during the period of 2018 to 2019. Patients were divided into 2 groups according to their ability to maintain horizontal gaze at the time of final follow-up: those who had regained horizontal gaze (the "effective" group) and those who had not regained horizontal gaze (the "noneffective" group). Sagittal radiographic parameters including the sagittal vertical axis (SVA), the C2-7 angle, the C2-7 SVA, T1 slope, thoracic kyphosis of T1-5 and T5-12, lumbar lordosis, pelvic tilt, pelvic incidence, sacral slope, and curve flexibility, and demographic data and clinical outcomes were compared between the 2 groups using an unpaired t test, chi-square test, and Fisher exact test, as appropriate., Results: Thirty-five patients in the effective group and 13 patients in the noneffective group were analyzed. The rate of response in regaining horizontal gaze with the SHAiR program was 73%. The C2-7 angle, the C2-7 SVA, T1 slope, and thoracic kyphosis (T1-5) demonstrated significant correction in the effective group (p < 0.05). There were no significant changes in other parameters below the mid-thoracic spine-i.e., the thoracolumbar and lumbar spine and pelvis-following the SHAiR program. Scores of the Neck Disability Index and visual analog scale for pain improved significantly in both groups., Conclusions: The SHAiR program improved horizontal gaze among a large percentage of our patients and reduced cervical pain among patients overall. The correction of thoracic kyphosis (T1-5) might be an important treatment target to restore the appropriate T1 tilt in patients with dropped head syndrome., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A558)., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Background and Aims: This study evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on pancreatic adenocarcinoma (PA) practice in our region and discussed the effects of our institution's regional collaborative system, the "Early Stage Pancreatic Cancer Diagnosis Project," which was originally unrelated to this study's purpose., Methods: We retrospectively investigated 150 patients with PA at Yokohama Rosai Hospital by defining three time periods: before (C0), during the first year (C1), and during the second year (C2) of the COVID-19 pandemic., Results: Among the three periods (C0, C1, and C2), there were significantly less patients with stage I PA (14.0%, 0%, and 7.4%, p = 0.032) in C1, and significantly more patients with stage III PA (10.0%, 28.3%, and 9.3%, p = 0.014) in C1. The pandemic significantly prolonged the median durations from disease onset to patients' first visits (28, 49, and 14 days, p = 0.012). In contrast, there was no significant difference in the median durations from referral to first visit to our institution (4, 4, and 6 days, p = 0.391)., Conclusions: The pandemic advanced the stage of PA in our region. Although the pancreatic referral network remained functional during the pandemic, there were delays from disease onset to patients' first visit to healthcare providers, including clinics. While the pandemic caused temporary damage to PA practice, the routine regional collaboration provided by our institution's project allowed for early resilience. A notable limitation is that the impact of the pandemic on PA prognosis was not evaluated., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest associated with this study and received no funding or financial support for its conduct., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA delivery in both in vitro and in vivo melanoma cancer. We found that the transfection efficacy of the mRNA-EGFP-loaded Ppoly system was significantly higher than that of lipofectamine and free mRNA in both 2D and 3D melanoma cancer cells; also, this delivery system did not show cytotoxicity. In addition, the biodistribution results revealed time-dependent and significantly higher mEGFP expression in complexes with Ppoly compared to free mRNA. We then checked the anti-tumour effect of intratumourally injected free mRNA-OVA, a foreign antigen, and loaded Ppoly; the results showed a considerable decrease in both tumour size and weight in the group treated with OVA-mRNA in loaded Ppoly compared to other formulations with an efficient adaptive immune response by dramatically increasing most leukocyte subtypes and OVA-specific CD8+ T cells in both the spleen and tumour tissues. Collectively, our findings suggest that the local delivery of cationic cyclodextrin-based polymer complexes containing foreign mRNA antigens might be a good and reliable concept for cancer immunotherapy.

Background and Objectives : Thoracic ossification of the ligamentum flavum (OLF) often causes myelopathy and/or radiculopathy. The disease is frequently observed in East Asian populations. Although thoracic OLF in young athletes who have underwent decompression surgery has been reported, the removal of posterior spinal bony elements and ligamentous complex may often cause postoperative thoracolumbar instability. We established a novel surgical technique that preserves the posterior spinal elements, including the spinous processes, facet joints, and supraspinous and interspinous ligaments for thoracic OLF. This is the first case report to describe a navigation-assisted micro-window excision of thoracic OLF. Case: A 32-year-old male right-handed professional baseball pitcher with significant weakness and numbness in the left leg was referred to our hospital. The patient was diagnosed with thoracic OLF at T10-11 based on radiographic and magnetic resonance images in August 2022. After exposure of the left T10-11 laminae via a small unilateral incision, the location of T10-11 OLF was detected over the lamina by O-arm navigation. Then, the micro-window was made directly above the OLF using a navigated air drill, and the OLF was removed on the ipsilateral side. The contralateral side of OLF was also resected through the same micro-window, achieving complete spinal cord decompression. Results : The next day of the surgery, his leg weakness and numbness were significantly improved. Six weeks after the surgery, he started pitching. Three months after surgery, his symptoms had gone completely, and he pitched from the mound. Approximately 6 months after surgery, he successfully pitched in a professional baseball game. Conclusions: A navigation-assisted micro-window excision of thoracic OLF effectively preserved the spinal posterior bony elements and ligamentous complex. However, long-term clinical outcomes should be evaluated in future studies.

Background/aim: Monoclonal antibodies (mAbs) that target tumor antigens have recently been developed. Their antitumor activity is mainly achieved through antibody-dependent cellular cytotoxicity (ADCC) via effector cells such as tumor-infiltrated macrophages and natural killer (NK) cells. CpG oligodeoxynucleotides (ODNs) have potent antitumor activity and are considered to increase the tumor infiltration of macrophages and NK cells; however, a completely solubilized novel CpG-schizophyllan (SPG) complex, K3-SPG, displays more potent antitumor activity. We recently reported the significant antitumor activity of anti-glypican-1 (GPC1) mAb against GPC1-positive esophageal squamous cell carcinoma (ESCC) via ADCC. The aim of this study was to evaluate the potential synergistic antitumor activity of anti-GPC1 mAb and K3-SPG and elucidate the underlying mechanisms using a xenograft model of GPC1-positive human ESCC cells., Materials and Methods: The established human esophageal cancer cell line TE14 was subcutaneously injected into SCID mice. Xenograft mice were treated with anti-GPC1 mAb, K3-SPG, or their combination. Antitumor activity was evaluated by measuring the tumor volume. For FACS analysis, agents were administrated, and tumors were resected 1 day after the final treatment., Results: Anti-GPC1 mAb or K3-SPG monotherapy showed dose-dependent antitumor activity, and combination therapy with anti-GPC1 mAb and K3-SPG showed antitumor activity (p=0.0859). Flow cytometry revealed significantly increased numbers of macrophages (p=0.0133) and of the ratio of activated NK cells/total NK cells (p=0.0058) following K3-SPG or combination therapy., Conclusion: Combination therapy with K3-SPG and anti-GPC1 mAb or another antitumor mAb may represent a new cancer treatment option acting via ADCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Lateral patellar facet impingement (LPFI) can cause anterior knee pain (AKP) after patellar resurfaced total knee arthroplasty (TKA). Recently, lateral patellar facetectomy (LPF), which has been used for LPFI, has been performed during primary TKA, providing good clinical outcomes. However, the effect of LPF on AKP in primary patellar resurfaced TKA has not been sufficiently studied. The purpose of this study was to examine the effect of LPF on the development of AKP in patellar resurfaced TKAs with minimum follow-up of 3 years. This retrospective cohort study included 84 knees of 66 consecutive patients who underwent patellar resurfaced TKA between April 2007 and November 2014 in our hospital. The subjects were divided into two groups: TKA with LPF (LPF group; 47 knees) and TKA without LPF (no-LPF group; 37 knees). Postoperative AKP, the primary outcome, the Japanese Orthopaedic Association (JOA) score, and range of motion were investigated at the final visit and compared between the two groups. Six knees (16.2%) had AKP in the no-LPF group, whereas none of the knees had AKP in the LPF group at the final visit. The incidence of AKP was significantly lower in the LPF group ( p  = 0.004). The postoperative JOA score and flexion angle were significantly higher in the LPF group than in the no-LPF group. LPF correlated with less incidence of postoperative AKP and improved the JOA score and knee flexion angle. In patellar resurfaced TKA, LPF may be considered an additional maneuver to avoid postoperative AKP., Competing Interests: None declared., (Thieme. All rights reserved.)

Patients with cervical spondylotic myelopathy or ossification of the posterior longitudinal ligament have been considered to be prone to falls due to lower extremity dysfunction and gait instability. Anticipatory postural adjustments (APAs) are unconscious muscular activities to counterbalance perturbation. To date, there are no reports on APAs in cervical myelopathy patients, and quantification of postural control remains difficult. Thirty participants were enrolled, of which 15 were cervical myelopathy patients and 15 were normal age- and sex-matched controls. A three-dimensional motion capture system with force plates was used, and the APA phase was defined as the time between start of movement at the center of pressure and heel-off of the step leg. The APA phase (0.47 vs. 0.39 s, p < 0.05) and turning time (2.27 vs. 1.83 s, p < 0.01) were significantly longer, whereas step length tended to be shorter (305.18 vs. 361.04 mm, p = 0.06) in cervical myelopathy patients. There was a significant correlation between Japanese Orthopaedic Association lower extremity motor dysfunction scores and step length ( p < 0.01). Cervical myelopathy patients are prone to falls due to longer APA phases with shorter step lengths. Analysis of the APA phase aids the visualization and quantification of postural control during initial gait in cervical myelopathy patients.

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca 2+ influx by store-operated Ca 2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Atopic dermatitis (AD) is a common allergic eczema that affects up to 10% of adults in developed countries. Immune cells in the epidermis, namely, Langerhans cells (LCs), contribute to the pathogenesis of AD, although their exact role(s) in disease remain unclear. Methods: We performed immunostaining on human skin and peripheral blood mononuclear cells (PBMCs) and visualized primary cilium. Result and discussion: We show that human dendritic cells (DCs) and LCs have a previously unknown primary cilium-like structure. The primary cilium was assembled during DC proliferation in response to the Th2 cytokine GM-CSF, and its formation was halted by DC maturation agents. This suggests that the role of primary cilium is to transduce proliferation signaling. The platelet-derived growth factor receptor alpha (PDGFRα) pathway, which is known for transducing proliferation signals in the primary cilium, promoted DC proliferation in a manner dependent on the intraflagellar transport (IFT) system. We also examined the epidermal samples from AD patients, and observed aberrantly ciliated LCs and keratinocytes in immature and proliferating states. Our results identify a potential relationship between the primary cilium and allergic skin barrier disorders, and suggest that targeting the primary cilium may contribute to treating AD., Competing Interests: FF and FO were employed by Mandom Corporation The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Toriyama, Rizaldy, Nakamura, Atsumi, Toriyama, Fujita, Okada, Morita, Itoh and Ishii.)

Background and Aim: This study aimed to compare the efficacy and safety of endoscopic ultrasound-guided gallbladder drainage and percutaneous transhepatic gallbladder drainage as a bridge to surgery in patients with acute cholecystitis unfit for urgent cholecystectomy., Methods: This retrospective study included 46 patients who underwent cholecystectomy following endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) or percutaneous transhepatic gallbladder drainage (PTGBD) for acute cholecystitis in NTT Tokyo Medical Center. We surveyed 35 patients as the EUS-GBD group and 11 patients as the PTGBD group, and compared the rate of technical success of the cholecystectomy and periprocedural adverse events. A 7-F, 10-cm double pigtail plastic stent was used for ultrasound-guided gallbladder drainage., Results: The rate of technical success of cholecystectomy was 100% in both groups. Regarding postsurgical adverse events, no significant difference was noted between the two groups (EUS-GBD group, 11.4%, vs. PTGBD group, 9.0%; p = 0.472)., Conclusions: EUS-GBD as a BTS seems to be an alternative for patients with AC because it can ensure lower adverse events. On the other hand, there are two major limitations in this study--the sample size is small and there is a risk of selection bias.

Alcaligenes faecalis was previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we compared A. faecalis lipid A (ALA) with monophosphoryl lipid A, a licensed lipid A-based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA-TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Various vaccine adjuvants have been developed to eliminate HBV from patients with chronic HBV infection. In addition, spermidine (SPD), a type of polyamine, has been reported to enhance the activity of immune cells. In the present study, we investigated whether the combination of SPD and vaccine adjuvant enhances the HBV antigen-specific immune response to HBV vaccination. Methods: Wild-type and HBV-transgenic (HBV-Tg) mice were vaccinated 2 or 3 times. SPD was orally administered in drinking water. Cyclic guanosine monophosphate-AMP (cGAMP) and nanoparticulate CpG-ODN (K3-SPG) were used as the HBV vaccine adjuvants. The HBV antigen-specific immune response was evaluated by measuring the HBsAb titer in blood collected over time and the number of interferon-γ producing cells by enzyme-linked immunospot assay. Results: The administration of HBsAg + cGAMP + SPD or HBsAg + K3-SPG + SPD significantly enhanced HBsAg-specific interferon-γ production by CD8 T cells from wild-type and HBV-Tg mice. The administration of HBsAg, cGAMP, and SPD increased serum HBsAb levels in wild-type and HBV-Tg mice. In HBV-Tg mice, the administration of SPD + cGAMP or SPD + K3-SPG with HBV vaccination significantly reduced HBsAg levels in the liver and serum., Conclusions: These results indicate that the combination of HBV vaccine adjuvant and SPD induces a stronger humoral and cellular immune response through T-cell activation. These treatments may support the development of a strategy to completely eliminate HBV., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Objectives : The global trend toward increased protection of medical personnel from occupational radiation exposure requires efforts to promote protection from radiation on a societal scale. To develop effective educational programs to promote radiation protection, we clarify the actual status and stage of behavioral changes of spine surgeons regarding radiation protection. Materials and Methods : We used a web-based questionnaire to collect information on the actual status of radiation protection and stages of behavioral change according to the transtheoretical model. The survey was administered to all members of the Society for Minimally Invasive Spinal Treatment from 5 October to 5 November 2020. Results : Of 324 members of the Society for Minimally Invasive Spinal Treatment, 229 (70.7%) responded. A total of 217 participants were analyzed, excluding 12 respondents who were not exposed to radiation in daily practice. A trunk lead protector was used by 215 (99%) participants, while 113 (53%) preferred an apron-type protector. Dosimeters, thyroid protector, lead glasses, and lead gloves were used by 108 (50%), 116 (53%), 82 (38%), and 64 (29%) participants, respectively. While 202 (93%) participants avoided continuous irradiation, only 120 (55%) were aware of the source of the radiation when determining their position in the room. Regarding the behavioral change stage of radiation protection, 134 (62%) participants were in the action stage, while 37 (17%) had not even reached the contemplation stage. Conclusions : We found that even among the members of the Society for Minimally Invasive Spinal Treatment, protection of all vulnerable body parts was not fully implemented. Thus, development of educational programs that cover the familiar risks of occupational radiation exposure, basic protection methods in the operating room, and the effects of such protection methods on reducing radiation exposure in actual clinical practice is warranted.

Background and Objectives : The phase angle, calculated by bioelectrical impedance analysis, can help elucidate the pathology of patients with idiopathic dropped head syndrome (IDHS) and explain the motor dysfunction associated with the horizontal gaze disorder. The aim of this study was to clarify the characteristics of phase angle in IDHS patients and the relationship between the phase angle and the severity of horizontal gaze disorder. Materials and Methods : This cross-sectional study included 43 female patients with IDHS and 69 healthy female volunteers. A multi-frequency segmental body composition analyzer was used to calculate body composition parameters, including whole-body and lower extremity phase angles. Propensity score (PS) matching analysis was performed to compare the body composition parameters between the IDHS and healthy groups. Variables that determine the PS were identified by correlation analysis, using the whole-body phase angle as the dependent variable. In addition, correlation analysis was performed between the severity of horizontal gaze disorder as assessed by McGregor's slope (McGS), phase angle, and other body composition parameters. Results : Unadjusted group comparisons showed no significant difference in whole-body and lower extremity phase angles between the IDHS and healthy groups. PS matching created a total of 38 matched pairs for age, height, and fat-free mass index. Although the comparison between groups of matched samples showed no significant difference in the whole-body phase angle, the lower extremity phase angle in the IDHS group was significantly lower than that in the healthy group ( p = 0.033). Correlation analysis showed significant negative correlations only between McGS and whole-body ( r = -0.31, p = 0.043) and lower extremity phase angle ( r = -0.39, p = 0.009) in the IDHS group. Conclusions : Abnormal body composition of the lower extremities were observed in IDHS patients. Furthermore, it was suggested that horizontal gaze disorder in IDHS patients is associated with whole-body and lower extremity phase angles.

Background: Simultaneous bilateral quadriceps tendon rupture is rare, particularly in young individuals with no prior medical history. We present the case of a young man who presented with bilateral quadriceps tendon rupture., Case Presentation: A 27-year-old Japanese man missed a step while descending a flight of stairs, stumbled, and became aware of severe pain in both knees. He had no past medical history, but was severely obese, with a body mass index of 43.7 kg/m 2 (height 177 cm, weight 137 kg). Five days after injury, he was referred to our hospital for examination and treatment. Bilateral quadriceps tendon rupture was diagnosed based on magnetic resonance imaging, and quadriceps tendon repair with suture anchor was performed on both knees 14 days after injury. The postoperative rehabilitation protocol was to immobilize both knees in extension for 2 weeks, then to gradually proceed with weight-bearing and gait training using hinged knee braces. Both knees obtained a range of motion from 0° to 130° without any extension lag by 3 months postoperatively. One year postoperatively, tenderness was evident at the suture anchor in the right knee. That suture anchor was therefore removed in a second operation, and histological evaluation of the tendon of the right knee revealed no pathological changes. As of 19 months after the primary surgery, the patient showed a range of motion from 0° to 140° in both knees, did not complain of any disability, and had fully returned to normal daily activities., Conclusions: We experienced simultaneous bilateral quadriceps tendon rupture in a 27-year-old man with no past medical history other than obesity. Suture anchor repair was performed for both quadriceps tendon ruptures and achieved a favorable postoperative outcome., (© 2023. The Author(s).)

The presence of main pancreatic duct (MPD) dilatation is important for diagnosing pancreatic ductal adenocarcinomas (PDACs). However, we occasionally encounter PDAC cases without MPD dilatation. The objectives of this study were to compare the clinical findings and prognosis of pathologically diagnosed PDAC cases with and without MPD dilatation and to extract factors related to the prognosis of PDAC. The 281 patients pathologically diagnosed with PDAC were divided into two groups: the dilatation group ( n = 215), consisting of patients with MPD dilatation of 3 mm or more, and the non-dilatation group ( n = 66), consisting of patients with MPD dilatation less than 3 mm. We found that the non-dilatation group had more cancers in the pancreatic tail, more advanced disease stage, lower resectability, and worse prognoses than the dilatation group. Clinical stage and history of surgery or chemotherapy were identified as significant prognostic factors for PDAC, while tumor location was not. Endoscopic ultrasonography (EUS), diffusion-weighted magnetic resonance imaging (DW-MRI), and contrast-enhanced computed tomography had a high tumor detection rate for PDAC even in the non-dilatation group. Construction of a diagnostic system centered on EUS and DW-MRI is necessary for the early diagnosis of PDAC without MPD dilatation, which can improve its prognosis.