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*

Objective:To explore the effect of the enriched environment(EE)on pyroptosis in rats with cerebral ischemia-reperfusion injury(CIRI).Methods:45 male Sprague-Dawley rats were randomly divided into three groups: a sham surgery(Sham)group, a cerebral ischemia-reperfusion(CIR)group and an enriched environment(EE)group, with 15 rats in each group.Except for the Sham group, the right middle cerebral artery occlusion model was established in the other two groups.After surgery, the EE group was fed in EE, and the other two groups were fed in standard environment.All the rats were assessed using the modified neurological severity score(mNSS)before modeling and on the 1st day, 7th day and 14th day following surgery.On the 14th day after surgery, 2, 3, 5-triphenyltetrazolium chloride(TTC)staining was used to evaluate the infarct volume, hematoxylin and eosin(HE)staining was used to examine pathomorphological changes of the hippocampal CA1 region on the ischemic side of the rats in each group, immunohistochemical assay was used to detect the expression of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)and cysteinyl aspartate specific proteinase-1(caspase-1)proteins in the CA1 region, and ultrastructural changes in neurons in the CA1 region were observed under transmission electron microscopy.Results:Compared with the Sham group, the mNSS scores of the CIR group and the EE group were significantly higher on the 1st day and 7th day after surgery( P<0.05), but there was no significant difference between the CIR and EE groups( P>0.05). On the 14th day after surgery, compared with the CIR group, the EE group showed a decrease in the mNSS score and the cerebral infarct volume( P<0.05), alleviated pathomorphological changes, decreased expression of NLRP3 and caspase-1 proteins( P<0.05), and alleviated pathological changes of pyroptosis in the ultrastructure of neurons. Conclusions:EE can reduce the damage of neurological function, reduce the cerebral infarct volume, and play a protective role for the brain in CIRI rats.The mechanism may be related to the down-regulation of the expression of NLRP3 and caspase-1 proteins related to the classical pyroptosis pathway, leading to the inhibition of pyroptosis.

Objective To investigate and validate the effect of relevant parameters of pancreatic anatomic structure under standard pancreatic neck transection in predicting postoperative pancreatic fistula (POPF). Methods A total of 140 patients who underwent pancreaticoduodenectomy (PD) in The General Hospital of Western Theater Command from June 2016 to December 2019 were enrolled as prediction group, and 82 patients who underwent PD in the same hospital from January 2020 to March 2021 were enrolled as validation group. Baseline levels were compared between the two groups. A univariate analysis was performed for the prediction group to screen out the risk factors for POPF, and in the validation group, the interclass correlation coefficient (ICC) was used to compare the consistency between preoperative imaging measurements and actual intraoperative measurements. The risk factors for POPF were validated in each group. The t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of continuous data with skewed distribution between groups; the chi-square test was used for comparison of categorical data between groups. The multivariate logistic regression analysis was used to investigate the risk factors for POPF. Youden index was calculated, GraphPad Prism was used to plot the receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) was calculated. ICC was used for the reliability analysis of preoperative imaging measurements and actual intraoperative measurements. Results Pancreatic duct diameter at the pancreatic neck (odds ratio [ OR ]=0.347, 95% confidence interval [ CI ]: 0.192-0.626, P < 0.001), the major axis of the pancreatic neck parenchyma ( OR =1.127, 95% CI : 1.031-1.231, P =0.008), and the minor axis of the pancreatic neck parenchyma ( OR =1.350, 95% CI : 1.137-1.602, P =0.001) were risk factors for POPF. Pancreatic duct diameter at the pancreatic neck had an AUC of 0.785 (95% CI : 0.128-0.302, P < 0.001) and a cut-off value of 2.7 mm; the major axis of the pancreatic neck parenchyma had an AUC of 0.669 (95% CI : 0.564-0.774, P =0.006) and a cut-off value of 19.3 mm, and the minor axis of the pancreatic neck parenchyma had an AUC of 0.720 (95% CI : 0.627-0.813, P < 0.001) and a cut-off value of 9.9 mm. Preoperative imaging measurements were highly consistent with actual intraoperative measurements for 30 patients in the validation group, with an ICC of > 0.75 ( P < 0.001). Grouping validation of cut-off values showed that there was a significant different in the incidence rate of POPF between the high-risk group and the low-risk group based on pancreatic duct diameter at the pancreatic neck ( χ 2 =0.645, P =0.011), as well as between the high-risk group and the low-risk group based on the minor axis of the pancreatic neck parenchyma ( χ 2 =5.901, P =0.015). Conclusion Structural features of the pancreatic neck under standard pancreatic neck transection are risk factors for POPF, which can be differentiated by preoperative CT, and the method is easy and convenient in clinical practice.

Objective:To observe the expression patterns of miR-195 and DLL4 in colorectal cancer, and to explore the relationship between miR-195 and DLL4 and clinicopathological parameters and prognosis of patients with colorectal cancer.Methods:The relative expression of miR-195 in 56 colorectal cancer tissues was detected by real-time fluorescent quantitative PCR the expression of DLL4 protein and tumor microvessel density (MVD) were detected by bloting and immunohistochemistry. Colon cancer cell line SW480 was treated with miR-195. The expression of DLL4, Jagged1, (the intracellular domain of notch, NICD), CyclinD1, Hes1, Bcl-2 and NF-kB were detected by bloting.Results:The expression level of DLL4 protein in colorectal cancer tissues was significantly higher than that in normal intestinal mucosa (30/56 vs.16/56, t=5.323, P=0.018). The expression level of miR-195 was significantly lower than that in normal intestinal mucosa (36/56 vs.20/56, t=2.371, P=0.008). The expression of DLL4 was negatively correlated with the expression of miR-195 ( r=- 0.881, P=0.015) , which was closely related to the differentiation degree, lymph node metastasis and TNM stage . The prognosis of patients with high expression of DLL4 was significantly worse than that with low expression of DLL4 ( P=0.013). The prognosis of patients with low expression of miR-195 was worse than that with high expression of miR-195 ( P=0.009) . Conclusion:The antagonistic expression of miR-195 and Notch might be closely related to the occurrence and development of colorectal cancer, which can be used as a new reference index for prognosis of colorectal cancer.

Objective:To summarize the clinical features and pathological changes of peripheral tissues from patients with neuronal intranuclear inclusion disease (NIID) diagnosed by genetic tests.Methods:Repeat-primed polymerase chain reaction was used to confirm the GGC repeated expansion in the 5′ untranslated region of the NOTCH2NLC gene in patients with suspected NIID who had visited the Department of Neurology of Peking University First Hospital from January 2018 to February 2020. The clinical data and pathological changes of peripheral tissues from patients with genetically diagnosed NIID were collected retrospectively and analysed. Immunostaining with anti-p62 and anti-ubiquitin antibody was performed on peripheral biopsy specimens.Results:Totally nine patients with NIID who had GGC repeated expansion in the NOTCH2NLC gene were found. Five patients were familial (from three faimilies), and four patients were sporadic. The age of onset was 36-61(51.33±7.12) years. The most common symptoms in this NIID group were episodic emotion and personality change (8/9), paroxysmal disturbance of consciousness (6/9) and intermitant head discomfort (6/9). Other symptoms included cognitive dysfunction, limb weakness, limb sensory disturbance, bladder dysfunction, ataxia, seizures and psychiatric symptoms. Brain magnetic resonance imaging showed high signals along the corticomedullary junction on diffusion-weighted image in eight out of nine patients. Skin biopsied samples from nine patients demonstrated the presence of eosinophilic intranuclear inclusions (IIs), appearing in the nucleus of fibroblasts, fat cells and ductal epithelial cells of sweat glands on hematoxylin-eosin staining. IIs were positive on anti-p62 and anti-ubiquitin immunostaining. Electron microscopy indicated the IIs were composed of a pile of filament materials without membrane. Muscle biopsies from two patients showed no obvious neurogenic or myogenic pathologic changes, except in one patient several rimmed vacuoles fibers were found. In one patient sural nerve biopsy showed severe demyelinating pathological changes. No IIs were found in the muscles and peripheral nerve tissue either by histological examination or by immunohistochemical staining with anti-p62 or anti-ubiquitin, while IIs were found by immunofluorescence staining with both anti-p62 and anti-ubiquitin in three patient′s tissue. Conclusions:The phenotype of this NIID patient group is adult-onset NIID, with episodic encephalopathy as the main clinical manifestation. Skin biopsy has high pathological diagnostic value for NIID. The immunofluorescence staining with anti-p62 and anti-ubiquitin is easier to detect the presence of IIs than histological staining and immumohistochemical staining.

In this paper, the history and current situation of environmental health standardization in China are reviewed, and the experience and shortcomings in the process of environmental health standardization in China are analyzed, suggestions for the next step of environmental health standards are also put forward.

In this paper, the history and current situation of environmental health standardization in China are reviewed, and the experience and shortcomings in the process of environmental health standardization in China are analyzed, suggestions for the next step of environmental health standards are also put forward.

OBJECTIVE：To compare the content changes of active/toxic ingredient genkwanin in ethanol extract from Wikstroemia indica before and after processing with “sweat soaking method ”and the effects of processing method on its anti-oxidation ability. METHODS ：HPLC method was adopted to determine the content of genkwanin in W. indica before and after processing with “sweat soaking method ”. The separation was performed on Diamonsil C 18 column with 0.2％ phosphoric acid solution-methanol as mobile phase （gradient elution ）at the flow rate of 1 mL/min. The column temperature was 30 ℃ and detection wavelength was set at 346 nm. The sample size was 20 µL. SD rats were randomly divided into blank group ，W. indica raw product ethanol extract group （317.52 mg/kg，called“raw-product group ”as short ）and W. indica processed product ethanol extract group （317.52 mg/kg，called“processed-product group ”as short ），with 6 rats in each group. Blank group was given constant volume of 1.0％CMC-Na solution intragastrically ，and administration groups were given relevant medicine suspension intragastrically；all of them were given 20 mL/kg，once a day ，for consecutive 14 days. The contents of serum oxidant stress indexes（MDA，CAT，SOD）in rats were determined by ELISA. RESULTS ：The linear range of genkwanin were 0.147-27.360 μg （r＝0.999 9）；RSDs of precision ，reproducibility and stability tests were all lower than 3％ ；average recoveries were 98.64％-98.92％（RSD＜1％，n＝3）. Before and after processing with “sweat soaking method ”，average contents of genkwanin in W. indica were 0.377 6 and 0.234 0 mg/g. Compared with blank group ，the serum content of SOD in raw-product group was increased significantly ，while CAT content was decreased significantly （P＜0.05 or P＜0.01）；the serum content of MDA was decreased significantly in processed-product group ，while SOD content was increased significantly （P＜0.05 or P＜0.01）. MDA content of processed-product group was significantly lower than that of raw-product group ，while SOD content was significantly higher than raw-product group （P＜0.05）. CONCLUSIONS ：After proce ssing with “sweat soaking method ”，the content of genkwanin in W. indica is decreased ，and antioxidant activity is increased .“Sweat soaking method ”processes certain function of “reducing toxicity and increasing efficiency ”.

OBJECTIVE：To investigate the “dose-effect-toxicity”correlation of Miao medicine Wikstroemia indica before and after processed on anti-immnue inflammation of mice . METHODS ：Mice were divided into blank group ，model group ，ethanol extract of W. indica raw product groups 1-6，ethanol extract of W. indica processed product by “sweat soaking method ”groups 1-6 （hereinafter called “raw groups 1-6”“processed groups 1-6”for short ，drug dosage were 0.13，0.20，0.26，0.52，1.04，2.6 g/kg）， positive group （cyclophosphamide，36.4 mg/kg），with 10 mice in each group. Except for blank group ，other groups were given 1％ 2，4-dinitrofluorobenzene-acetone-sesame oil mixed solution to induce delayed type hypersensitivity model. After modeling， blank group and model group were given constant volume of 1.0％ CMC-Na solution intragastrically ，and administration groups were given relevant medicine 20 mL/kg intrag astrically，oncea day ，for consecutive 5 d. A fter last medication ，ear swelling degree of mice were recorded ；the inhibition rate of swelling degree， half effective dose （ED50） and 95％ confidence 158-02-32）； interval（CI）of raw and processed products were calculated ； the weight of heart ，liver，spleen，lung and kidney were measured and the indexes of organs were calculated ；ELISA 1161472062@qq.com and modified chemical oxidation method were used to determine the serum levels of inflammatory factors （TNF-α， IL-10） and liver and renal function indexes （ALT，AST， TBIL，BUN，CREA）. RESULTS：Compared with blank group ，the degree of ear swelling in the model group was significantly increased（P＜0.05）. Compared with model group ，ear swelling degree of mice were decreased significantly in different doses groups of ethanol extract of raw and processed products of W. indica （P＜0.05）. The inhibition rate of swelling increased with the increase of dose ，ED50 and 95％CI of delayed hypersensitivity ear swelling were 0.239 6（0.129 0，0.445 2）g/kg and 0.147 3（0.076 8，0.282 7）g/kg，respectively. Compared with blank group ，liver index and serum TNF-α level of mice were increased significantly in model group ，while lung index and serum IL- 10 level were decreased significantly （P＜0.05）. Compared with model group ，the levels of liver indexes （positive group ，raw group 3，processed groups 1-6）and serum TNF-α levels（positive group ，raw groups 1-3，processed groups 1-4） were decreased significantly in different administration groups ；while the levels of lung indexes （positive group ，raw groups 3-6 and processed groups 3-6），serum IL- 10 levels（raw groups 1，2，4 and 5，processed groups 2-6），ALT，AST，BUN and CREA levels （raw groups 4-6），TBIL levels （raw groups 3-6 ）were increased significantly （P＜ 0.05）. CONCLUSIONS ：The ethanol extract of raw product of W. indica has certain anti-inflammatory activity ，and has certain hepatorenal toxicity to mice ，with certain “dose-effect-toxity”correlation. The ethanol ectract of processed product of W. indica has certain anti-inflammatory activity too ，but its hepatorenal toxicity was lower than raw product. The “sweat soaking method ” possesses the function of “retaining efficiency and reducing toxicity ”for processing W. indica .

This paper introduces the conducting systematic reviews and Meta-analyses of observational studies of etiology (COSMOS-E) and illustrates the critical issues of COSMOS-E with a published systematic review. This document provides researchers with guidance on all steps in systematic reviews of observational studies of etiology, from shaping the research question, defining exposure and outcomes, to assessing the risk of bias and statistical analysis.