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 investigate the expression level of flap endonuclease 1 (FEN1) in bone marrow mononuclear cells of patients with acute myeloid leukemia (AML) and its relationship with clinicopathologic features and therapeutic effect, so as to provide a new direction for disease monitoring and targeted therapy in AML patients.Methods:The data of 57 newly treated AML patients and 26 healthy individuals (the healthy control) from the First Clinical College of Guangdong Medical University and Fujian Medical University Union Hospital from November 2018 to December 2020 were retrospectively analyzed. Bone marrow samples of all subjects were collected. Quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) was used to detect FEN1 mRNA expression in bone marrow mononuclear cells of all subjects. Bone marrow samples from 9 newly-diagnosed AML patients and 4 healthy controls were collected, and FEN1 protein expression level was detected by using Western blotting. Differences in FEN1 mRNA expression in AML patients achieving different therapeutic effects were compared among AML patients whose data with evaluable efficacy. AML patients were divided into high FEN1 expression group (≥ critical value) and low FEN1 expression group (< critical value), taking the median relative expression level of FEN1 mRNA as the critical value. The correlation of FEN1 expression level with clinicopathologic features, laboratory indicators, cellular and molecular genetic changes in AML patients at initial diagnosis was analyzed.Results:The median relative expression of FEN1 mRNA in newly treated AML patients was higher than that in healthy controls [0.696 (0.025-3.661) vs. 0.246 (0.013-1.237), Z = 1.75, P = 0.041]. Western blotting showed that the expression level of FEN1 protein in AML patients was higher than that in healthy controls. The relative expression of FEN1 mRNA in 15 recurrent AML patients was higher than that in 19 patients patients achieving complete remission (CR) [1.153 (0.047-4.172) vs. 0.259 (0.023-1.148), Z = 2.71, P = 0.009]. The proportion of patients with French-American-British(FAB) type M 5, fever at initial diagnosis and lymph node enlargement in FEN1 high expression group (32 cases) was higher than that in FEN1 low expression group (25 cases) (all P < 0.05). There were no significant differences in the proportion of gender, age, fatigue, pale skin mucosa and large liver and spleen of patients between the two groups (all P > 0.05). At initial diagnosis, the white blood cell count, lactate dehydrogenase, C-reactive protein and bone marrow primitive cell proportion in FEN1 high expression group were higher than those in FEN1 low expression group (all P < 0.05), and the hemoglobin and platelet count in FEN1 high expression group were lower than those in FEN1 low expression group (all P < 0.05). There were no significant differences in procalcitonin level, the proportion of chromosome karyotype, cytogenetic prognosis grade and patients with or without gene mutation between the two groups (all P > 0.05). Conclusions:FEN1 expression is up-regulated in AML patients and further increased in relapsed patients. FEN1 expression in AML patients is associated with adverse clinicopathological features and poor detection results of laboratory indicators, which may become indicators for disease monitoring in AML patients.

OBJECTIVE To establish a method for the simultaneous determination of 10 rhubarb anthraquinones in Compound gentian sodium bicarbonate tablets and the content of rhaponticin，which are the characteristic components of artifacts，and to use the method to evaluate the quality of compound preparation containing Rheum officinale. METHODS The ultra-performance liquid chromatography （UPLC） method was adopted to determine the contents of 10 rhubarb anthraquinones （aloe-emodin-8-O-glucoside， rheinic acid-8-O-β-D-glucoside，emodin-8-O-glucoside，chrysophanol-8-O-β-D-glucoside，emodin monomethyl ether-8-O-β-D-glucoside， aloe-emodin，rheinic acid，emodin，chrysophanol，emodin monomethyl ether） and rhaponticin in 40 batches of Compound gentian sodium bicarbonate tablets from 8 manufacturers. The determination was performed on the Agilent Eclipse Plus C18 column with a mobile phase consisted of acetonitrile-0.1% phosphoric acid solution （gradient elution） at a flow rate of 0.3 mL/min； the column temperature was set at 30 ℃ ，and the injection volume was 5 μL. Combining principal component analysis and cluster analysis to synthesize the results of content determination，the quality of samples from different manufacturers was evaluated. RESULTS All of above 11 components showed favorable linear relationships with peak areas in their respective mass concentration ranges （r≥0.999 3），with RSDs of precision，repeatability and stability 296261547@qq.com less than 3% （n＝6）； average sample recoveries ranged 96.82%-98.92% （RSD≤1.74%，n＝6）； their contents were 0971-8247794。E-mail：304436784@qq.com 0.011 7-0.252 0，0-0.323 3，0.131 3-1.236 6，0.081 1-1.056 2，0.015 2-0.189 8，0.001 8-0.152 3，0-0.255 2，0.001 9-0.223 4，0.054 3-0.303 0，0.022 7-0.172 2，0-2.835 9 mg/g，respectively. The cumulative variance contribution of the first three principal components was 95.533%； the 40 batches of samples can be clustered into 4 categories：samples from enterprises a and d were in a category of their own，samples from enterprises f，b，g and e were in a category，and samples from enterprises c and h were in a category. There were large differences in the content of rhubarb anthraquinone in the samples from 8 manufacturers，and rhaponticin was only detected in the sample from one enterprise. CONCLUSIONS Established UPLC method is stable and reliable； it can be used for the content determination of 10 rhubarb anthraquinones and rhaponticin in Compound gentian sodium bicarbonate tablets.

Objective:To investigate the expression level of small nucleolar RNA SNORD15A in bone marrow of patients with acute leukemia (AL) and its relationship with clinical characteristics and prognosis of patients.Methods:Bone marrow blood samples of 53 newly treated AL patients and 29 healthy subjects without clinical diagnosis of hematologic diseases or other malignant diseases (control group) at the Affiliated Hospital of Guangdong Medical University from March 2018 to December 2021 were collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of SNORD15A in bone marrow blood mononuclear cells of the two groups. The median relative expression of SNORD15A (0.148) was used as the boundary, and AL patients were divided into low expression group (<0.148) and high expression group (≥0.148). The relationship between the expression level of SNORD15A and the clinical characteristics, clinical indicators and overall survival (OS) of AL patients was analyzed. Kaplan-Meier method was used for survival analysis and log-rank test was performed; Cox proportional hazards model was used for univariate and multivariate analyses of OS of patients.Results:The relative expression of SNORD15A was 0.148 (0.012-1.376) in newly treated AL patients and 0.921 (0.513-2.288) in the control group, and the difference was statistically significant ( Z = -6.85, P < 0.01). The differences in SNORD15A relative expression between patients with different prognostic stratification, efficacy and with or without fever and bleeding were statistically significant (all P < 0.05). The differences in platelet count, plateletcrit and albumin levels between SNORD15A low expression group and high expression group were statistically significant (all P < 0.05), and the differences in molecular biology and cytogenetic characteristics were not statistically significant (all P > 0.05). The patients in SNORD15A high expression group had better OS than the low expression group ( P < 0.05). The results of univariate Cox regression analysis showed that SNORD15A was an influencing factor for patients' OS ( HR = 0.063, 95% CI 0.005-0.766, P < 0.05); the results of multivariate Cox regression analysis showed that fatigue ( HR = 4.754, 95% CI 1.014-22.290), fever ( HR = 0.147, 95% CI 0.029-0.746) and hemoglobin ( HR = 0.970, 95% CI 0.944 -0.998) were independent influencing factors for OS (all P < 0.05). Conclusions:SNORD15A is lowly expressed in AL and may be an indicator for disease monitoring and prognostic assessment in AL patients.

Brain/diagnostic imaging* ; Head

BACKGROUND: Family clustering of esophageal cancer (EC) has been found in high-risk areas of China. However, the relationships between cancer family history and esophageal cancer and precancerous lesions (ECPL) have not been comprehensively reported in recent years. This study aimed to provide evidence for identification of high-risk populations. METHODS: This study was conducted in five high-risk areas in China from 2017 to 2019, based on the National Cohort of Esophageal Cancer. The permanent residents aged 40 to 69 years were examined by endoscopy, and pathological examination was performed for suspicious lesions. Information on demographic characteristics, environmental factors, and cancer family history was collected. Unconditional logistic regression was applied to evaluate odds ratios between family history related factors and ECPL. RESULTS: Among 33,008 participants, 6143 (18.61%) reported positive family history of EC. The proportion of positive family history varied significantly among high-risk areas. After adjusting for risk factors, participants with a family history of positive cancer, gastric and esophageal cancer or EC had 1.49-fold (95% confidence interval [CI]: 1.36-1.62), 1.52-fold (95% CI: 1.38-1.67), or 1.66-fold (95% CI: 1.50-1.84) higher risks of ECPL, respectively. Participants with single or multiple first-degree relatives (FDR) of positive EC history had 1.65-fold (95% CI: 1.47-1.84) or 1.93-fold (95% CI: 1.46-2.54) higher risks of ECPL. Participants with FDRs who developed EC before 35, 45, and 50 years of age had 4.05-fold (95% CI: 1.30-12.65), 2.11-fold (95% CI: 1.37-3.25), and 1.91-fold (95% CI: 1.44-2.54) higher risks of ECPL, respectively. CONCLUSIONS: Participants with positive family history of EC had significantly higher risk of ECPL. This risk increased with the number of EC positive FDRs and EC family history of early onset. Distinctive genetic risk factors of the population in high-risk areas of China require further investigation. TRIAL REGISTRATION ChiCTR-EOC-17010553.
Case-Control Studies ; China/epidemiology* ; Esophageal Neoplasms/pathology* ; Humans ; Precancerous Conditions/pathology* ; Risk Factors ; Stomach Neoplasms

Objective:To investigate the effect of intravenous prophylactic administration of dezocine before anesthesia induction on choking during induction period in patients undergoing general anesthesia.Methods:A total of 92 patients with tracheal intubation surgery under general anesthesia from November 2020 to May 2021 in the Zhejiang Taizhou Hospital were selected and randomly divided into the observation groupand the control group by random number table, with 46 cases in each group. The observation group was intravenously injected with 0.1 mg/kg dezocine while the control group was intravenously injected with 0.9% sodium chloride 5 ml before anesthesia induction. Anesthesia induction was performed at 10 min after injection in the two groups. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and catecholamine, interleukin-6 (IL-6) levels were recorded at before anesthesia induction (T 0), 1 min before endotracheal intubation (T 1), 1 min after intubation (T 2), and 5 min after endotracheal intubation (T 3). The incidence and degree of choking, the agitation score, visual analog scale (VAS) score, Ramsay sedation score and the incidence of adverse reactions in the two groups were compared. Results:The levels of HR, SBP and DBP at T 0, T 1, T 2 and T 3 in the two groups had no significant differences ( P>0.05). The levels of catecholamine and IL-6 in the control group were higher than those in the observation group: (120.49 ± 15.13) ng/L vs.(113.53 ± 17.14) ng/L, (16.80 ± 2.61) ng/L vs. (13.46 ± 1.55) ng/L, there were statistical differences ( P<0.05). The recovery time to spontaneous breathing in the observation group was shorter than that in the control group: (8.76 ± 2.14) min vs. (9.87 ± 2.09) min, there was statistical difference ( P<0.05). The incidence of choking in the observation group was lower than that in the control group: 2.17%(1/46) vs. 21.74%(10/46), there was statistical difference ( P<0.05). The scores of agitation score and VAS in the observation group were lower than that in the control group, and the scores of Ramsay sedation score was higher than that in the control group: (1.43 ± 0.26) scores vs. (2.11 ± 0.14) scores, (3.55 ± 1.03) scores vs. (4.86 ± 1.15) scores, (3.13 ± 0.76) scores vs. (1.54 ± 0.32) scores, there were statistical differences ( P<0.05). The incidence of adverse reactions in the observation group was lower than that in the control group: 6.52%(3/46) vs. 23.91% (11/46), there was statistical differences ( χ2 = 5.39, P<0.05). Conclusions:For patients with tracheal intubation under general anesthesia, preventive injection of dezocine before anesthesia induction can effectively inhibit the stress response of patients, with little impact on the patients′ circulatory system and respiratory system, and can also effectively reduce the incidence of choking in the induction period.

Objective:To observe the effect of emotional resilience training on compassion fatigue and psychological resilience of intensive care unit nurses.Methods:A total of 70 intensive care unit nurses were randomly divided into experiment group and control group, each of 35 cases. Control group nurses were given routine psychological guidance intervention, in addition, the experiment group was carried out 8 weeks of emotional resilience training. The effect of intervention was assessed by Chinese version of the compassion fatigue scale and Connor-Davidson resilience scale before and after intervention.Results:After intervention, the average scores of compassion satisfaction, secondary traumatic stress and total compassion fatigue scores were (26.46±4.99)pionts, (17.80±4.05)pionts and (69.14±5.70)pionts, significantly lower than in the control group (28.86±4.14)pionts, (20.11±4.38)pionts and (75.51±10.32)pionts, the difference was statistically significant ( t value was 2.190, 2.296, 3.197, P<0.05). After intervention, the average scores of tenacity, power, optimism and total resilience scores were (34.23±6.06)pionts, (25.77±5.01)pionts, (14.31±3.22)pionts and (74.31±9.55)pionts, significantly higher than in the control group (30.86±6.23)pionts, (23.31±3.29)pionts, (12.11±2.04)pionts and (66.29±7.28)pionts, the difference was statistically significant ( t value was 2.295-3.956, P<0.05). Conclusion:Emotional resilience training can effectively reduce the compassion fatigue and improve psychological resilience of intensive care unit nurses.

The composition of human oral microorganism is numerous and complex and is easily affected by many factors. With the development of metagenomic technology, the important role of oral microbiome in the development of tumor has attracted extensive attention. A literature retrieval was conducted through PubMed, Embase, CNKI and WanFang database for an analysis on the characteristics of oral bacteria and its association with oral cancer, esophageal cancer and gastric cancer. The results indicated that oral microbiome can be influenced by age, gender, race, and lifestyle. Specific oral bacteria were associated with high risk of upper gastrointestinal cancer, indicating a potential role of oral microbiota to be the biomarker for upper gastrointestinal cancer. This paper summarizes the progress in the research of the association between oral microbiome and upper gastrointestinal cancer, showing a new direction for the exploration of microbiological etiology of upper gastrointestinal cancer and providing scientific evidence for the optimization of early detection and treatment of upper gastrointestinal cancer.

With the development of multi-omics and high throughput sequencing technology, studies have shown that the disorder of microbiota is related to various cancers. Nevertheless, the research on the relationship between upper digestive tract cancer or precancerous lesions and gastrointestinal microecology is still less. Fusobacterium nucleatum, one of the oral symbiotic bacteria, is also an opportunistic pathogen, which can promote the formation of tumor microenvironment and can be used as a new biomarker for the early detection and early diagnosis of cancer. In this study, by searching CNKI, Wanfang data, PubMed and Embase databases, it was found that the abundance of F. nucleatum in cancer tissues is higher than that in paracancerous tissues and associated with poor prognosis. The research of relationship between F. nucleatum and precancerous lesions needs to be carried out urgently. In addition, the types of specimens, sequencing technology, strain subtypes, carcinogenic mechanism and other directions still need to be explored.