OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

ObjectiveTo explore the intervention effect and mechanism of Buzhong Yiqiwan （BZYQ） on colitis mice. MethodSixty-four C57BL/6 mice were randomly divided into 2 weeks blank group， 2 weeks model group， 2 weeks high-dose BZYQ （12 g·kg^-1） group， 2 weeks low-dose BZYQ （6 g·kg^-1） group， 4 weeks blank group， 4 weeks model group， 4 weeks high-dose BZYQ （12 g·kg^-1） group， and 4 weeks low-dose BZYQ （6 g·kg^-1） group. The colitis model was induced in mice by feeding 3% dextran sodium sulfate （DSS） for 7 days. The mice received BZYQ （12 and 6 g·kg^-1） by gavage on the 8^th day after modeling， once per day， and sacrificed on the 2^nd and 4^th weeks， correspondingly. The colon length and weight of mice in each group were measured. Hematoxylin-eosin （HE） staining was used for pathological observation and colonic mucosal inflammation was scored. The mRNA and protein expression of NOD-like receptor thermoprotein domain 3 （NLRP3）， apoptosis-associated speck-like protein containing a CARD （ASC）， and cysteinyl aspartate-specific protease-1 （Caspase-1） was detected by real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. Enzyme-linked immunosorbent assay （ELISA） was used to detect the content of inflammatory cytokines， such as interleukin （IL）-1β， IL-18， and IL-33 in colonic tissues. ResultCompared with the 2 weeks blank group， the 2 weeks model group showed shortened colon length， increased colon weight （P<0.05）， loss of epithelial cells， destruction of gland structure， infiltration of a large number of inflammatory cells in mucosa and submucosa， local crypt abscess， and increase in mucosal inflammation score （P<0.01） as revealed by light microscopy， elevated levels of IL-1β， IL-18， and IL-33 in colonic tissues （P<0.05）， and increased mRNA and protein expression of NLRP3， ASC， and Caspase-1 （P<0.05）. The intervention of BZYQ （12 g·kg^-1） restored colon length， alleviated mucosal injury （P<0.05）， down-regulated the content of IL-18 （P<0.05）， reduced the mRNA expression of NLRP3 and ASC as well as the protein expression of ASC and Caspase-1 compared with the conditions in the 2 weeks model group. Compared with the 4 weeks blank group， the 4 weeks model group showed decreased colon length， increased colon weight （P<0.05）， decreased glands in the mucosal layer， expansion of glandular cavity， atrophy of crypt， local connective tissue hyperplasia and lymphocyte infiltration， increased inflammation score （P<0.01） as revealed by the light microscopy， increased expression of IL-1β， IL-18， and IL-33 （P<0.05）， and elevated mRNA and expression of NLRP3 inflammasome complex （P<0.05）. Compared with the conditions in the 4 weeks model group， the intervention of BZYQ （12 and 6 g·kg^-1） could improve colon length and weight （P<0.05）， and the intervention of BZYQ （12 g·kg^-1） could also improve the inflammation score of the colon （P<0.05）. Different from the acute stage， the intervention of BZYQ （12 and 6 g·kg^-1） increased the content of IL-33 in the intestinal mucosa and up-regulated the mRNA and protein expression of NLRP3 inflammasome complexes ASC and Caspase-1 （P<0.05）. ConclusionBZYQ can relieve the injury of colitis induced by DSS in mice. The mechanism is related to the regulation of intestinal immune response mediated by NLRP3 inflammasome， and it has different regulatory effects in acute and chronic inflammation stages.

The anterior cruciate ligament (ACL) injury is a common sports injury that has a significant impact on knee function and patients′ mobility. With the popularity of national fitness campaign in China, the incidence of ACL injury is increasing year by year. Currently, there still lacks clinical standards or guidelines on how to choose appropriate treatment methods, surgical plans and rehabilitation protocols for ACL injury. In order to timely reflect the new treatment concept of ACL injury, standardize its diagnosis and treatment and improve the curative effect, the Sports Medicine Society of Chinese Research Hospital Association and the Editorial Board of Chinese Journal of Trauma organized domestic orthopedic and sports medicine experts to formulate the "clinical evidence-based guideline for the diagnosis and treatment of anterior cruciate ligament injury (2022 version)" based on the level of evidence-based medicine and in compliance with the principle of scientificity, practicability and advancement. The present guideline includes 12 recommendations for the diagnosis, treatment and rehabilitation of ACL injury in order to provide guidance and assistance for the clinical diagnosis and treatment of ACL injury in China.

Ureteral artery fistula (UAF) is a rare complication after long-term indwelling of ureteral stent. In this study, two cases were presented. Both of them underwent pelvic tumor surgery and radiotherapy, and had a history of cutaneous terminal ureterostomy and long-term indwelling of ureteral stents. The first case, a 52-year-old female, was admitted to hospital because of intermittent bleeding from ureteral dermostomy for 1 week on April 2, 2020. CT examination revealed hematocele in the left upper urinary tract, and left nephrectomy was performed.However, bleeding still presented and the distal ureteral resection was performed at the same time, and partial ureteral was ligated. Postoperative diagnostic was ureteral artery fistula. After 8 months of follow-up, no recurrent bleeding presented. Another case, a 82-year-old male, was admitted to hospital because of bleeding at the ureteral dermostomy for an hour on June 15, 2020. Contrast enhanced CT examination revealed intersecting of the left ureter and common iliac artery, and interventional surgery was performed, by which UAF was diagnosed. Embolization of left internal iliac artery and stent implantation of common iliac artery and external iliac artery were performed intraoperatively. The bleeding stopped immediately after the operation, and there was no further bleeding during follow-up of 6 months.

Objective:To analyze the clinical presentation, potential pathogenesis, diagnosis, management and prognosis of dural arteriovenous fistula (DAVF) manifesting as bithalamic lesions.Methods:The clinical data of three patients with DAVF manifesting as bithalamic lesions from the First Affiliated Hospital of Xi'an Jiaotong University between August 2019 and August 2020 were analyzed retrospectively, and related literatures were reviewed.Results:Patient 1, a 56-year-old female, presented with a one-month aggressive clinical course of weakness, somnolence, nausea, vomiting, urine incontinence and sitting instability. Patient 2, a 53-year-old male, presented with a one-month aggressive clinical course of disturbance of consciousness, walking with difficulty and decreased higher cortex function. Patient 3, a 68-year-old male, presented with an eight-day aggressive clinical course of memory loss, disturbance of consciousness and mental symptoms. In these three patients, cranial computed tomography (CT) scans showed bilateral hypodensity shadow in thalamus while magnetic resonance imaging (MRI) demonstrated bithalamic edema. Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) presented venous or venous sinus closely related with arteries. Digital substraction angiography (DSA) of the patient 1 demonstrated bilateral occipital artery-straight sinus DAVF treated with surgical excision. Four months later, the patient was consciousness with modified Rankin scale (mRS) score of 5. DSA of the patient 2 demonstrated DAVF supplied by the right external carotid artery and the symptoms were relieved after endovascular embolization. One year after operation, there was no recurrence and mRS score was 2. DSA of the patient 3 demonstrated occipital sinusional area DAVF treated with surgical excision. More than one year after surgery, the patient was conscious with mRS score of 5.Conclusions:DAVF-induced bithalamic lesions is a rare disorder in which clinical presentations are not specific.When cranial CT or MRI demonstrating bithalamic lesions, MRA or CTA showing venous or venous sinus closely related with arteries or presenting with disturbance of consciousness or cognitive decline, DAVF should be considered. DSA is the gold standard for diagnosis of DAVF. Endovascular embolization and surgical excision are the main treatments of DAVF.

Objective To study the relationship between serum UA level and early outcome in acute ischemic stroke (AIS) patients. Methods Four hundred and twenty-one AIS patients admitted to the First Affiliated Hospital of Xi'an Jiaotong University from March 2015 to March 2016 were divided into good outcome group (n = 232) and poor outcome group (n = 189) according to their modified Rankin scale (mRS) score. Their demographic data, risk factors for vascular disease, laboratory testing parameters, imaging and clinical data and NIHSS score were recorded and compared. The relationship between serum UA level and early poor outcome in AIS patients was analyzed by unconditioned logistic regression analysis. Results The incidence of AF and cerebral infarction in the territory of anterior cerebral artey and middle cerebral artery, SBP, serum TC,LDL and urea levels,NIHSS and mRS score, and mortality were significantly higher and the hospital stay time was significantly longer while the serum UA level and GCS score were significantly lower in poor outcome group than in good outcome group (P＜0.05,P＜0.01). Unconditioned logistic regression analysis showed that SBP,NIHSS score and serum UA level were the major risk factors for the early poor outcome in AIS patients (OR = l.017,95％CI:1.003-1.031,P = 0.018;OR = 1.274,95％CI:1.178-1.378,P=0.000;OR=0.993,95％CI:0.989-0.996, P = 0.000). Conclusion The low serum UA level is related with the early poor outcome in AIS patients.

Objective: To investigate the levels of the Twist and Vimentin proteins in oral squamous cell carcinoma (OSCC) and analyze the clinical significance of Twist and Vimentin. Methods: Eighty-five samples of OSCC and fifteen samples of normal oral mucosa were collected. Immunohistochemistry (SP method) was used to detect the expression of proteins, including Twist and vimentin. The relationship among these proteins and clinical pathological parameters was analyzed using SPSS statistical software. Results : In the normal group, 13.3% (2/15) of samples were positive for the Twist protein; this value was significantly lower than that in OSCC group (80.0%, 66/85) (χ2=26.98, P < 0.001). The expression of Twist was associated with clinical stage (χ2=5.40, P=0.02) and lymph node metastasis (χ2=8.35, P=0.006), while no correlations were found between the expression of Twist and sex (χ2=0.23, P=0.63), age (χ2= 0.31, P=0.58), location (χ2=1.46, P=0.235) or degree of differentiation (χ2=1.52, P=0.47). Additionally, 6.7% of samples (1/15) were positive for vimentin; this value was significantly lower than that in OSCC group (74.1%, 63/85) (χ2=20.71, P < 0.001). The expression of vimentin was associated with clinical stage (χ2=4.51, P=0.034) and lymph node metastasis (χ2=6.75, P=0.009), while no correlations were found between the expression of vimentin and sex (χ2=0.40, P=0.53), age (χ2=0.17, P=0.68), location (χ2=0.74,P=0.39) or degree of differentiation (χ2=4.58, P=0.10). Spearman correlation analyses showed that Twist protein expression was positively correlated with vimentin (r=0.578, P＜0.05). Conclusion Our data demonstrate that in OSCC, Twist and vimentin levels were upregulated, and Twist protein expression was positively correlated with vimentin, which indicates that both Twist and vimentin may be involved in the occurrence of OSCC.

Objective To investigate the safety and short-term effectiveness of the hybrid operation for the treatment of intracranial complex ruptured aneurysms.Methods From December 2014 to March 2017,14 consecutive patients with complex ruptured aneurysm treated with hybrid operation at the Department of Neurosurgery,Nanfang Hospital,Southern Medical University were enrolled retrospectively,including 13 with acute spontaneous aneurismal subarachnoid hemorrhage and 1 with hemorrhage in the recurrent aneurysm embolization.Twelve aneurysms were treated with shape clipping.Digital subtraction angiography (DSA) was used to evaluate the clipping effect of aneurysms.Two patients with aneurysm were treated with extracranial-intracranial (EC-IC) bypass and aneurysm trapping.Endovascular balloon occlusion for trapping aneurysms was performed after DSA evaluation of the patency of bridge vessel.Results Of the 14 patients,11 were treated with emergency hybrid operation after angiography,2 were treated with elective surgery,and 1 with emergency surgery for rescue because of bleeding during embolization.DSA revealed that the aneurysm clips in 3 of 12 patients needed to be adjusted,including 2 parent artery stenosis and 1 with incomplete clipping.After adjustment,the clipping was satisfactory.In intracranial and extracranial bypass surgery,angiography revealed that the blood vessels were patent.Trapping of the aneurysms was performed in the one-stage operation.One patient discharged voluntarily after procedure because of serious vasospasm.Onepatient had perfusion pressure breakthrough after surgery and received hematoma evacuation and decompression.The Glasgow outcome scale (GOS) score was 3 at discharge.Other patients had no new neurological dysfunction after operation.Thirteen patients were followed up for 3-24 months after operation.There were no new neurological dysfunction,including GOS 5 in 8 cases and 4 in 5 cases.Six patients underwent DSA examination,in 4 of them the aneurysm clipping did not show aneurysm recurrence,and the parent arteries were patent.Two patients treated with vascular bypass.There were no recurrence of aneurysms,and the parent arteries and anastomotic vessels were patent.Conclusion After preliminary observation,using hybrid operation for the treatment of complicated intracranial ruptured aneurysms was safe and effective.

Objective To study the effects of different preservation methods on the isolated liver injury and regeneration.Methods Twelve Sprague-Dawley rats were randomly assigned to two groups:static cold storage (SCS) and hypothermic machine perfusion (HMP) (n =6 each).Histidinetryptophan-ketoglutarate solution (HTK) was used as preservation solution.The graft was preserved in HTK (4 C) for 6 h in SCS group,and that was perfused using HTK in HMP group.Liver tissue was obtained and fixed in 10％ neutral formalin for immunohistochemistry.The fresh liver tissue was collected and stored in-80℃ for RT-PCR and Western blotting analyses.Results Compared to SCS,HMP improved liver regeneration ability in terms of PCNA and ki67 detection and promoted cell proliferation in PCR levels (Cdc25A,cdk1,cdk6) and Western blotting levels (Cyelin D1,Cyclin E1).Conclusion HMP is superior to SCS in liver regeneration,and expected to be the ideal method for preservation of donor liver.

Objective:To analyze the clinico-pathological characteristics, pathological diagnosis, and treatment of rhabdoid tu-mor. Methods:The medical records of four rhabdoid tumor patients that were admitted to the Tianjin Medical University Cancer Insti-tute and Hospital since 2000 were analyzed based on existing literature. Results:In one of the four cases, the tumor originated from the kidney, whereas in the other three, the tumor occurred from extra-renal soft tissues. Histologic analysis revealed that the tumor cells were loosely arranged with diffuse growth, vesicular nuclei, dyed cytoplasm, visible eosinophilic inclusions, and more nuclear fission. The results of immunohistochemical staining showed that the vimentin and epithelial membrane antigen were positive, whereas CK, CD99, CD34, and S-100 were positive at different degrees. MyoD1, Desmin, and INI-1 were negative. Conclusion:Rhabdoid tumor is rare and highly aggressive. It occurs mainly in the kidney and can also be found in other systems. The unique pathological form and im-munohistochemical staining observed on the tumor can be used as reference for diagnosis.