PPAR-γ regulates the polarization of M2 macrophages to improve the microenvironment for autologous fat grafting.

The unpredictable survival rate of autologous fat grafting (AFG) seriously affects its clinical application. Improving the survival rate of AFG has become an unresolved issue in plastic surgery. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates the adipogenic differentiation of adipocytes, but the functional mechanism in AFG remains unclear. In this study, we established an animal model of AFG and demonstrated the superior therapeutic effect of PPAR-γ regulation in the process of AFG. From day 3 after fat grafting, the PPAR-γ agonist rosiglitazone group consistently showed better adipose integrity, fewer oil cysts, and fibrosis. Massive macrophage infiltration was observed after 7 days. At the same time, M2 macrophages begin to appear. At day 14, M2 macrophages gradually became the dominant cell population, which suppressed inflammation and promoted revascularization and fat regeneration. In addition, transcriptome sequencing showed that the differentially expressed genes in the Rosiglitazone group were associated with the pathways of adipose regeneration, differentiation, and angiogenesis; these results provide new ideas for clinical treatment.

The Ideal Proportion of the Auricle Exposure via a Morphometric Analysis in Asian Women.

BACKGROUND: Ears are an important aesthetic feature that is vital to the overall attractiveness of the face. Although there have been many studies on the aesthetics of the auricle, there is currently a lack of consensus on the ideal proportion of auricle exposure for Asian women in frontal view. OBJECTIVES: This study aimed to investigate ideal proportion of auricle exposure in Asian women. METHODS: An observational study was carried out on the photographs of 84 women on the list of the 100 most beautiful faces in Asia (published by TCC Asia in 2020). The proportion of the distance between the outer canthus and the outermost point of auricle to the distance between the inner canthus and the outermost point of auricle was calculated as the auricle exposure proportion. Evaluators were asked to rank a set of photographs of the volunteer with varying auricle exposure proportions from most attractive to least attractive. RESULTS: Measurements of the photographs of the 84 women showed a mean ear exposure proportion of 0.600. With 487 questionnaire responses received, the proportion of auricle exposure that the evaluators considered most attractive was 0.600. People with aesthetic experience considered 0.625 the most attractive proportion, while the general group considered 0.600 the most attractive. CONCLUSIONS: The ideal proportion of the auricle exposure for Asian women is in the range of 0.60-0.625, which may help surgeons reconstruct aesthetically pleasing ears. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Research Trend of Soft Tissue Filler Injection from 2000 to 2022: A Bibliometric and Visualized Analysis.

Background: The demand for soft tissue filler injections has experienced a significant increase in recent years. Therefore, this study used bibliometric analysis to identify prominent research areas and emerging trends within the field. Methods: Publications concerning research on soft tissue filler injections were collected from the Web of Science Core Collection database. Subsequently, VOSviewer 1.6.18 and CiteSpace 6.2.R4 software were used to analyze the co-authorship, co-occurrence, and citations of countries, institutions, authors, hotspot keywords, and journals associated with these studies. Results: A total of 1370 records pertaining to filler injection research conducted between 2000 and 2022 were identified. The United States (524 publications) emerged as the country with the highest number of publications in this field, with Mayo Clinic (37 publications) making the most substantial contribution. Dermatologic Surgery emerged as the leading journal in this field, publishing the highest number of research articles (151 publications) and also being the most frequently co-cited. Cotofana proved to be the most prolific author with 51 publications, and Lemperle emerged as the most frequently co-cited author with 628 citations (including total link strength: 6587). The most popular keywords, in descending order of popularity, were "dermal filler," "injection," "soft-tissue augmentation," "complications," and "hyaluronic acid." Conclusions: The findings of this study offer a comprehensive overview of the main directions in filler injection research. Furthermore, they underscore the imperative of intensifying efforts to prevent complications linked to filler injections.

Monocular Vision Loss After Ear Filler Injection.

Ophthalmic artery occlusion caused by facial hyaluronic acid filler injection has always been a rare but devastating complication. With the pursuit of beauty, people have become more interested in ears and hyaluronic acid fillers. Herein, we report the case of a more serious rare complication of ophthalmic artery occlusion caused by ear filler injection. A 45-year-old woman developed vision loss on the left side immediately after receiving cosmetic hyaluronic acid injection in the ear, with only the visual field at the inferior temporal side remaining. She was diagnosed with central retinal artery occlusion in the left eye. After treatment with hyaluronidase injection, dexamethasone, hyperbaric oxygen, and oral alprostadil, blood flow was partially restored in the left ophthalmic artery, and her vision improved. Vascular complications after ear injections are rare. However, as the demand for ear filler injections increases, the probability of serious vascular complications is predicted to increase. The potential mechanism by which occlusion occurred involved the filler reaching the superficial temporal artery system through the superior auricular artery, thus occluding the ophthalmic artery. Having an understanding of anatomy is an important measure to avoid complications.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of contents or the online Instructions to Authors www.springer.com/00266 .

The Auricular Injection Technique: A New Treatment for Lying Ear.

SUMMARY: Lying-ear deformity refers to an auricle that bends backward excessively, is excessively folded against the head, and has a very prominent antihelix. It usually requires experienced surgeons to perform surgical treatment and a prolonged postoperative recovery process. This article proposes a simple and effective hyaluronic acid injection technique that significantly improves the shape of the outer ear and enhances perceived facial aesthetics. Twenty patients underwent treatment with multiple injections. Measure-related parameters were used to evaluate the postoperative effect, and the results were graded using a visual analog scale. Interrater reliability among graders was evaluated using intraclass correlation coefficients. After treatment, no serious complications, such as infection or embolism, occurred. Six months after the procedure, the average auriculocephalic angle increased from 25.11 ± 9.46 to 32.72 ± 8.29 degrees, the average conchoscaphal angle increased from 87.69 ± 9.06 to 95.94 ± 7.11 degrees, and patients' average visual analog scale score increased from 4.40 ± 1.14 to 8.57 ± 0.68. Interrater reliability was fair to good for visual analog scale before injection and 6 months after injection (intraclass correlation coefficients, 0.49 and 0.45, respectively; both P < 0.001). The patients were satisfied with the injection process and results. This injection protocol improved the shape of the outer ear, resulting in excellent postoperative outcomes.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

Improved process design for monoclonal antibody charge variants separation with multicolumn counter-current solvent gradient purification.

The multicolumn counter-current solvent gradient purification (MCSGP) method has proven effective in addressing the issue of elution profile overlap for difficult-to-separate proteins, leading to improved purity and recovery. However, during the MCSGP process, the flow rate and proportion of loaded proteins undergo changes, causing a significant discrepancy between the elution profiles of batch process design and the actual MCSGP process. This mismatch negatively impacts the purity and recovery of the target protein. To address this challenge, an improved process design (reDesign) was proposed with the first-run MCSGP to mimic the actual continuous process and obtain elution profiles that closely resemble the real ones. The reDesign was demonstrated with both a model protein mixture and a sample of monoclonal antibody (mAb) with charge variants. For model protein mixture, the reDesign-based MCSGP process (reMCSGP) showed a remarkable improvement in recovery, increasing from 83.6% to 97.8% while maintaining a purity of more than 95%. For mAb sample, the recovery of reMCSGP improved significantly to 93.9%, surpassing the performance of normal MCSGP processes at a given purity level of more than 84%. In general, the new process design strategy developed in this work could generate a more representative elution profile that closely mirrors actual conditions in continuous processes, which enhances the separation performance of MCSGP.

Exosomes Derived from Human Adipose-Derived Stem Cells Cannot Distinctively Promote Graft Survival in Cryopreservation Fat Grafting.

BACKGROUND: Cryopreserved fat has limited clinical applications due to its rapid absorption, high degree of fibrosis, and risk of complications after grafting. Many studies have verified that Adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) can improve fresh fat graft survival. This study assessed whether ADSC-Exos could improve the survival of cryopreserved fat grafts. METHODS: Exosomes were isolated from human ADSCs were subcutaneously engrafted with adipose tissues stored under different conditions (fresh; cryopreserved for 1 month) into the backs of BALB/c nude mice (n = 24), and exosomes or PBS were administered weekly. Grafts were harvested at 1, 2, 4, and 8 weeks, and fat retention rate, histologic, and immunohistochemical analyses were conducted. RESULTS: At 1, 2, and 4 weeks after the transfer, cryopreserved fat grafts in groups of exosome-treated showed better fat integrity, fewer oil cysts, and reduced fibrosis. Further investigations of macrophage infiltration and neovascularization revealed that those exosomes increased the number of M2 macrophages at 2 and 4 weeks (p<0.05), but had limited impact on vascularization (p>0.05). It's important to note that no significant differences (p>0.05) were observed between the two groups in both histological and immunohistochemical evaluations at 8 weeks post-transplantation. CONCLUSIONS: This study suggests that ADSC-Exos could improve the survival of cryopreserved fat grafts in the short term (within 4 weeks), but the overall improvement was poor (after 8 weeks). This suggests that the utility of using ADSC-Exos to treat cryopreserved adipose tissue grafts is limited. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A novel monospecific tetravalent IgG1-(scFv)2 version shown enhanced neutralizing and Fc-mediated effector functions against SARS-CoV-2.

Neutralizing monoclonal antibodies (nMABs) have been proved to be effective therapeutics in treating coronavirus disease (COVID-19). To enhance the potency of nMAB 553-15, we generated a novel monospecific tetravalent IgG1-(scFv)2 version. This was achieved by covalently fusing two forms of 553-15-derived single chain variable fragments (scFv) to the C-terminus of the hIgG1 (human Immunoglobulin G1) Fc fragment. We found that the Fc-fused VL-linker-VH format achieved similar binding affinity and neutralizing behavior as 553-15. The tetravalent versions were constructed by fusing the scFv domains to the C-terminus of nMAB 553-15. As a result, the tetravalent version 55,315-VLVH exhibited significantly higher binding activity to target spike protein variants and enhanced neutralization against VOCs (variants of concern) pseudovirus compared to 553-15. We also measured the Fc effector responses of candidates using wild-type Spike-expressing CHOK1 cells. The 55,315-VLVH enhanced the function of ADCP (antibody-dependent cellular phagocytosis) but had similar IL-6 release levels compared to the bivalent 553-15. It seemed that the novel tetravalent version avoids the pro-inflammatory effect induced by macrophage activation. However, the 55,315-VLVH displayed slightly increased potency in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), which might contribute to higher systemic inflammation. Further investigation is necessary to determine whether the tetravalent version is beneficial to balance efficiency and safety against COVID-19.

Efficacy analysis of axillary approach in the treatment of Ideberg type I and II scapular glenoid fractures: Case series.

RATIONALE: To investigate the clinical efficacy of the axillary approach in the surgical treatment of Ideberg type I and II scapular glenoid fractures. PATIENT CONCERNS AND DIAGNOSIS: Retrospective analysis of 13 cases of scapular glenoid fracture treated in the affiliated Hospital of Jining Medical College, Jiaxiang County People hospital, Zoucheng City people Hospital, Yanzhou District People Hospital, and Juancheng County people Hospital from December 2020 to January 2022. Eight males (including 1 bilateral) and 5 females, with an average age of 57.5 years (range from 33 to 75 years). According to Ideberg classification, there were 10 cases of type I a, 1 case of type I a combined with type I b, and 2 cases of type II. All patients were treated with axillary approach surgery and 7 patients with combined anterior shoulder dislocation were treated by first-stage manipulation and second-stage reoperation. Seven patients were fixed with a wire anchor, 3 patients with type I a were fixed with a "T" plate, and 5 patients were complicated with rotator cuff tear and were repaired with a wire anchor. At the last follow-up, the Constant-Murley shoulder function score, visual analog score, DASH score, and Hawkins grade were used to evaluate shoulder function, pain, and stability after treatment. INTERVENTION: The intervention was to treat patients with Ideberg type I and II scaphoid fractures using an axillary approach. OUTCOMES: All 13 patients in this group were followed up thoroughly, and the follow-up time was 12 to 25 months, with an average of 18.6 months. The operation time was 65 to 135 minutes, with an average of 85.6 minutes. Intraoperative blood loss ranged from 20 to 120 mL, averaging 55.6 mL. The duration of hospitalization ranged from 7 to 22 days, with an average of 9.6 days. The surgical incisions of all patients were grade-A healing. Bone healing of glenoid fractures was observed 3 months after the operation. LESSONS: The axillary approach for Ideberg type I and II scapular glenoid fractures is a feasible surgical approach with complete access through the muscle gap, minimal surgical trauma, mild postoperative pain, and satisfactory clinical results.

Deep Temporal Artery Anatomy: Implications for Improving the Safety of Deep Temporal Injections.

BACKGROUND: Knowledge of the anatomy of the deep temporal artery (DTA) is critical to ensure safe filling of the deep temporal region. However, current treatment guidelines still focus on how to avoid the superficial temporal artery and the middle temporal vein, and an understanding of the safety of avoiding DTA injury is lacking. OBJECTIVE: The purpose of this study was to determine the positioning and course of the DTA to help clinicians safely perform the injection and filling in the temporal region. METHODS: Computed tomography (CT) scans and dissections of the skulls of 34 fresh frozen cadavers perfused with lead oxide were performed. Reconstruction and trajectory analysis of all DTA branches were performed using Mimics and MATLAB software. RESULTS: In this study, the DTA was identified in all samples, which originated from the maxillary artery of the external carotid artery system. According to image reconstruction and anatomical observations, the distribution of the anterior and posterior branches of the DTA had two different distribution patterns. The anatomical level of the DTA is located between the temporal muscle and the periosteal layer. Compared with observations in previous studies, the anterior branch of the DTA is slightly different, and we found that its course is closer to the frontal area in Asian specimens. CONCLUSION: The anatomical information on the DTA described in this study may help improve awareness of the safety of temporal injection by aesthetic physicians. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266. .

Zygomatico-Orbital Artery: A Reevaluation of the Temporal Blood Vessels.

BACKGROUND: The current anatomical description of the zygomatico-orbital artery (ZOA) is mainly based on cadaver head studies and does not accurately reflect the complete anatomical information of the ZOA. The purpose of this study was to reveal the anatomical characteristics of the ZOA and to provide an anatomical basis for relevant operations in the temporal area. METHODS: Computed tomographic scans and autopsies were performed on 78 cadaver heads perfused with lead oxide. Mimics software was used to construct a three-dimensional image based on the bilateral intertragic notches and the right inferior orbital margin for a detailed analysis of the ZOA. RESULTS: The occurrence rate of ZOA in the 101 qualified hemisectioned cadaver heads was 86.14% (87 of 101). According to our observations, 46 of 87 (52.87%) originated from the superficial temporal artery above the zygomatic arch, 23 of 87 (26.44%) from the superficial temporal artery under the zygomatic arch, and 18 of 87 (20.69%) from the frontal branch of the superficial temporal artery. The ZOA communicates with the deep and superficial arches of the supraorbital artery, transverse facial artery, and ophthalmic artery. CONCLUSIONS: This study describes the anatomical characteristics of the ZOA. Moreover, these findings may guide skin flap transplantation and prevent associated injection complications.

Development of the Novel Bifunctional Fusion Protein BR102 That Simultaneously Targets PD-L1 and TGF-ß for Anticancer Immunotherapy.

Immune checkpoint inhibitors (ICIs) are remarkable breakthroughs in treating various types of cancer, but many patients still do not derive long-term clinical benefits. Increasing evidence shows that TGF-ß can promote cancer progression and confer resistance to ICI therapies. Consequently, dual blocking of TGF-ß and immune checkpoint may provide an effective approach to enhance the effectiveness of ICI therapies. Here, we reported the development and preclinical characterization of a novel bifunctional anti-PD-L1/TGF-ß fusion protein, BR102. BR102 comprises an anti-PD-L1 antibody fused to the extracellular domain (ECD) of human TGF-ßRII. BR102 is capable of simultaneously binding to TGF-ß and PD-L1. Incorporating TGF-ßRII into BR102 does not alter the PD-L1 blocking activity of BR102. In vitro characterization further demonstrated that BR102 could disrupt TGF-ß-induced signaling. Moreover, BR102 significantly inhibits tumor growth in vivo and exerts a superior antitumor effect compared to anti-PD-L1. Administration of BR102 to cynomolgus monkeys is well-tolerated, with only minimal to moderate and reversing red cell changes noted. The data demonstrated the efficacy and safety of the novel anti-PD-L1/TGF-ß fusion protein and supported the further clinical development of BR102 for anticancer therapy.

Effects of 1-stage revascularization and temporary external fixation combined with 2-stage Ilizarov technique in the treatment of bone defects in lower limb destruction injury: A case report.

RATIONALE: To evaluate the clinical effects of 1-stage revascularization, vacuum sealing drainage covering the wound, temporary external fixation and 2-stage Ilizarov bone transport for the treatment limb destruction injury. PATIENT CONCERNS AND DIAGNOSIS: Nine patients with limb destruction injury between September 2014 and June 2019 at our institute were evaluated retrospectively. The age of patient was 21 to 51 years with an average of 33 years. The injuries were caused by vehicle accidents in 4 patients, gunshot in 1 patient, and crushing injuries in 4 patients. All of them had vascular injury. The average length of bone defect was 9.5 (8.3-10) cm. Regular follow-up was performed on wound healing, bone transport time, bone healing time, external fixation index, and limb function. INTERVENTIONS: All patients underwent 1-stage revascularization and temporary external fixation during emergency surgery, and then gradual bone transport by Ilizarov fixator was performed until the broken fracture site was reunited. OUTCOMES: Nine patients were followed up for 12 to 48 months (average 30 months). Six patients were treated with autogenous cancellous bone graft for the second time, and 2 patients healed spontaneously. The mean wound healing time was 86 (73-90) days. The bone transport time was 97 (88.3-105.3) days, and the bone mineralization time was 164.5 (156.8-181.3) days, and the healing time of the docking sites was 6.8 (6.1-8.3) months. The external fixator time was 14.5 (12.5-17) months with the external fixation index was 1.5 (1.4-1.8) m/cm. At the last follow-up, according to the Association for the Study of the Method of Ilizarov functional scores, excellent functional outcomes were obtained in 5 patients, good in 1 patients, moderate in 2 patients. According to the Association for the Study of the Method of Ilizarov Radiological System, excellent functional outcomes were obtained in 6 cases and good in 2 cases. LESSONS: One-stage revascularization and temporary external fixation combined with 2-stage Ilizarov bone transport technique for the treatment of bone defects in limb destruction injury have satisfactory clinical effects and few complications, and can be applied under the condition of strict understanding of surgical indications.

Combination of Fusiform Capsulectomy of the Posterior Capsule and Percutaneous Flexion Tendon Release in the Treatment of Fused Knee with Severe Flexion Contracture During Total Knee Arthroplasty-A Report of Six Cases.

Purpose: This clinical research aims to assess the safety and efficacy of a combination of fusiform capsulectomy of the posterior capsule and percutaneous flexion tendon release in the treatment of a fused knee with severe flexion contracture during total knee arthroplasty (TKA). Methods: A retrospective analysis was performed in three patients (six knees) who had preoperative severe bony fused flexion contracture (>80°) prior to TKA and received a combination of fusiform capsulectomy of posterior capsule and percutaneous flexion tendon release during TKA between January 2016 and December 2019. The range of motion (ROM), knee functional score, postoperative complications, and radiographic results were evaluated. Result: Three patients (six knees) were enrolled in this study. The mean duration of follow-up was 42.83 ± 15.77 months. The postoperative knee ROM was 100.0 (76.0, 102.75) (p < 0.01). The knee society score (KSS) clinical score increased from a preoperative 30.0 (25.0, 36.0) to a postoperative 64.0 (65.0, 78.0) (p < 0.01), and the KSS function score increased from a preoperative 0.0 (0.0, 30.0) to a postoperative 55.0 (40.0, 55.0) (p < 0.01). No implant loosening, infection, neurovascular complications, or revision were recorded in the cohort until the last follow-up. Conclusion: The technique of a combination of fusiform capsulectomy of the posterior capsule and percutaneous flexion tendon release is an effective and safe method during primary TKA for a fused knee with severe flexion contracture.

Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia-reperfusion-induced acute lung injury by activating AMPK signaling.

BACKGROUND: Acute lung injury (ALI) caused by intestinal ischemia-reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves ALI under intestinal ischemia-reperfusion conditions. METHODS: To induce ALI, 72 male C57BL/6 mice were subjected to intestinal ischemia for 60 min and reperfusion for 3 h. Through intraperitoneal injection, C-176, a selective STING inhibitor, was injected 30 min before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK), was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary pyroptosis [Gasdermin-D (GSDMD), cleaved caspase-1], and apoptosis (TUNEL, cleaved caspase-3). RESULTS: C-176 administration significantly attenuated intestinal ischemia-reperfusion-mediated ALI; this effect was reflected by exacerbated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, and upregulated phospho-AMPK, cleaved caspase-1, cleaved caspase-3 and IFNß mRNA expression. Moreover, C-176 increased phospho-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects. CONCLUSION: C-176, a selective STING inhibitor, improves intestinal ischemia-reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation.

Erratum: HIF-1α or HOTTIP/CTCF Promotes Head and Neck Squamous Cell Carcinoma Progression and Drug Resistance by Targeting HOXA9.

[This corrects the article DOI: 10.1016/j.omtn.2019.12.045.].

Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint.

BACKGROUND: The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRPα, targeting SIRPα is an alternative approach to block the CD47-SIRPα pathway, which may result in differential efficacy and safety profiles. METHODS: SIRPα-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRPα-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated. RESULTS: BR105 shows broad binding activity across various SIRPα variants, and potently blocks the interaction of SIRPα and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRPγ, it does not inhibit T cell activation, unlike other non-selective SIRPα-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted. CONCLUSIONS: The novel and differentiated SIRPα-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints.

Cervical Myelopathy Due to Idiopathic Retro-odontoid Pseudotumor.

OBJECTIVE: A retro-odontoid pseudotumor (ROP) is commonly associated with atlantoaxial instability or rheumatoid arthritis. However, ROP in the absence of atlantoaxial instability or rheumatoid arthritis, which is termed idiopathic ROP (IROP), is a rare condition. The pathomechanisms and optimal treatment strategies for IROP remain controversial. The aim of the present study was to evaluate the radiographic and clinical characteristics of IROP patients and to assess the efficiency of atlantoaxial/occipitocervical fusion on IROP regression. METHODS: Data from 5 patients diagnosed with IROP were retrospectively reviewed. Posterior atlantoaxial or occipitocervical fixation and fusion were performed in 4 patients and C1 posterior arch resection alone in 1 patient. The patients' features, surgical procedures, and complications were recorded. The retro-odontoid soft tissue thickness was measured on preoperative and postoperative magnetic resonance imaging to evaluate IROP regression. RESULTS: The mean follow-up time was 37 months. ROP regression was achieved in patients who received atlantoaxial/occipitocervical fusion, but not for the patient with C1 posterior resection alone. There were no observed neurovascular complications associated with surgery. CONCLUSIONS: IROP was related to a restricted range of motion of the subaxial spine. Upper cervical fixation is an optional treatment that produces IROP regression over time. By contrast, direct removal of the IROP is unnecessary.