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*

Micronutrients (MNs), including vitamins and trace elements, play an indispensable role in human metabolism, immune function and other aspects. Due to the chronic microinflammation and long-term chemoradiotherapy, patients with malignant tumors often suffer from malnutrition, resulting in different degrees of MNs deficiency. In severe cases, MNs deficiency is closely related to the adverse clinical outcomes. Therefore, reasonable MNs supplementation is of great significance in improving the prognosis and quality of life of patients with tumors. Recently, multiple guidelines have made recommendations on the application of MN supplementation in various clinical settings, providing evidence for the standardized MN supplementation in patients with malignant tumors.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Objective:To explore the clinical effects of combined medial and lateral approaches in treating of calcaneal fractures combined with sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus joint.Methods:Four adult cadaver specimens (8 feet) were selected, of which two (4 feet) were dissected on the medial side of the calcaneus to observe the adjacency and exposure range of sustentaculum tali. The other two specimens were simulated as medial and lateral approaches to reduce and fix calcaneal fractures. Retrospective analysis of 9 cases (9 feet) of Sanders II-IV type calcaneal fractures with combined medial and lateral approaches in the treatment of fractures and/or dislocations of sustentaculum tali-talus joint was performed. The average age was 49.9±11.3 (25-58) years. During the operation, the medial incision was made first, and the sustentaculum tali fracture was temporarily reduced and fixed to the talus. Then the lateral incision was made to expose the lateral side of the calcaneus, and the fracture fragments were reduced and fixed; the sustentaculum tali was fixed laterally with screws, and 2 cases were additionally fixed medially with absorbable rods. At the same time, six cases (8 feet) of calcaneal fractures with sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus were treated with lateral approach as a control group. The lateral sides of both groups were fixed with calcaneal locking plate and implanted with demineralized bone matrix into the cavity after articular surface reduction. The B?hler and Gissane angles of the two groups of patients were measured at 1 year after operation. The American Orthopaedic Foot and Ankle Society (AOFAS) scoring system was used to evaluate the clinical efficacy.Results:The sustentaculum tali-talus joint had a shape of an inverted "V" with two divided parts. The tip of the sustentaculum tali was exposed through the front window of the posterior tibial tendon. The sustentaculum tali and the medial side of the calcaneal body was completely exposed and fixed through the window between the posterior tibial tendon and the flexor digitorum longus tendon. The postoperative incision blood loss in the combined medial and lateral approach group was 73.6±4.3 ml, which was greater than that in the lateral approach group (70.6±7.1 ml) ( t=2.18, P=0.045). The lateral incision healed in both groups. The medial incision healed delayed in 1 patient in the combined medial and lateral approach group. The fractures in the combined medial-lateral approach group and the lateral approach group were both healed. The healing duration was 12.2±2.1 weeks and 12.8±2.8 weeks, respectively, without significant difference ( t=0.50, P=0.622). The B?hler angles of the combined medial-lateral approach group and the lateral approach group were 37.0°±5.7° and 27.9°±4.0° at 1 year after operation, respectively. These values were greater than the preoperative values of 4.7°±3.4° and 3.9°±2.9° ( P<0.05), with significant difference between groups ( t=3.76, P=0.002). The Gissane angles were 133.2°±9.8° and 139.1°±9.4° respectively, which were lower than those of 172°±7.3° and 175.6°±5.6° before operation ( P<0.05). There was no significant difference between the groups ( t=1.26, P=0.226). The AOFAS score of the combined medial and lateral approach group was 93.6±4.0 points, which was higher than that of the lateral approach group (84.3±8.2 points) ( t=3.03, P=0.008). Conclusion:Intra-articular calcaneal fractures combined with a high probability of sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus joint. Compared with the simple lateral approach, the use of the combined medial-lateral approach and the medial-lateral surgical sequence is beneficial to restore the calcaneal alignment and anatomic shape, especially the alignment relationship of the medial calcaneus and talus, so as to obstain better early clinical outcomes.

BACKGROUND: After general thoracic surgery, a chest tube is usually placed for closed drainage to expel gas accumulation in the thoracic cavity and fluid accumulation to promote lung re-expansion. It can also be observed whether there is active bleeding after the operation and whether there is a pulmonary leak. The conventional drainage of the chest cavity is connected with a water-sealed drainage bottle, and the patient condition is judged by observing the drainage situation and the fluctuation of the water column, which is a very classic method. However, the water-sealed bottle has the disadvantages of being easy to overturn and inconvenient to carry, which is not conducive to the early activities of patients. Under the concept of accelerated rehabilitation, our center applied a new type of anhydrous thorax negative pressure drainage device and achieved good results. The purpose of this study was to observe the effect of a new type of anhydrous thoracic negative pressure drainage device in patients after thoracic surgery. METHODS: Retrospective analysis of patients who underwent lung surgery in the First Affiliated Hospital of Zhejiang University Medical College from January 2018 to December 2019, patients were divided into two groups. One group of patients used a traditional closed-chest drainage water-sealed bottle as a control group, and the other group used a new type of anhydrous negative-pressure drainage bottle as an experimental group. Patients' gender, age, hypertension, diabetes, smoking history, surgical incisions and surgical methods, and the length of hospital stay and postoperative hospital stay were calculated. RESULTS: There were no statistical differences in age, gender, comorbidities (hypertension, diabetes, smoking history), scope of surgery, and duration of surgery between the two groups of patients, but there were statistical differences in surgical incisions between the two groups of patients (P=0.01). We found that patients using the new waterless negative pressure drainage device were shorter than patients with water negative pressure drainage device in terms of postoperative hospital stay and total hospitalization time, and the difference was statistically significant (P=0.02, P=0.04). CONCLUSIONS The new type of anhydrous thoracic negative pressure drainage device has a good effect on the rapid recovery and advancement after thoracic surgery.

Purpose: Cervical cancer is one of the most fatal diseases among women in under-developed countries. To improve cervical cancertreatment, discovery of new targets is needed. In this study, we investigated the expression of NUP210, miR-22, and Fas in cervicalcancer tissues and their functions in cell cycle regulation. Materials and Methods: We detected and compared the expression levels of NUP210, miR-22, and Fas in cervical cancer tissueswith paired normal tissues using immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction.NUP210 was knocked down in HeLa cells via lentivirus, followed by cell cycle and proliferation analysis. Using a luciferase reporterassay, we explored the link between miR-22 and NUP210. We overexpressed miR-22 in HeLa cells and analyzed cell cycle and proliferationfunction. We then overexpressed miR-22 in NUP210 knockdown cells to explore the connection between Fas and miR-22-NUP210 signaling. Results: We found that NUP210 was overexpressed in cervical cancer patients. Knocking down NUP210 restored cell apoptosisand proliferation. We confirmed miR-22 as a regulator of NUP210 and verified that miR-22 was inhibited in cervical cancer development.We also found that restoring miR-22 expression could induce cell apoptosis. Finally, we found that miR-22-regulated expressionof NUP210 could alter Fas expression and, in turn, elicit cell cycle arrest and proliferation. Conclusion miR-22 in cervical cancer is downregulated, resulting in NUP210 overexpression and inhibition of Fas-induced cellapoptosis.

OBJECTIVE: To analyze the characteristics of BK polymavirus (BKV) infection and the optimal time window for intervention in kidney transplant recipients (KTRs). METHODS: We retrospectively analyzed the clinical data and treatment regimens in 226 KTRs in our center between January, 2013 and January, 2018. Among the recipients, 157 had a urine BKV load ≥1.0×10 copy/mL after transplantation, and 69 had a urine BKV load below 1.0×10 copy/mL (control group). RESULTS: Among the 157 KTRs, 60 (38.2%) recipients were positive for urine BKV, 66 (42.0%) had BKV viruria, and 31(19.7%) had BKV viremia. The incidence of positive urine occult blood was significantly higher in BKV-positive recipients than in the control group ( < 0.05). The change of urine BKV load was linearly related to that of Tacrolimus trough blood level (=0.351, < 0.05). In urine BKV positive group, the average estimated glomerular filtration rate (eGFR) was below the baseline level (60 mL·min·1.73 m) upon diagnosis of BKV infection reactivation, and recovered the normal level after intervention. In patients with BKV viruria and viremia, the average eGFR failed to return to the baseline level in spite of improvement of the renal function after intervention. CONCLUSIONS Positive urine occult blood after transplantation may be associated with BKV infection reactivation in some of the KTRs. BKV infection is sensitive to changes of plasma concentration of immunosuppressive agents. Early intervention of BKV replication in KTRs with appropriate dose reduction for immunosuppression can help to control virus replication and stabilize the allograft function.
BK Virus ; physiology ; Humans ; Kidney Transplantation ; Polyomavirus Infections ; virology ; Retrospective Studies ; Transplant Recipients ; Tumor Virus Infections ; virology ; Viral Load ; Virus Replication

Objective To evaluate the clinical value of maternal serum 25(OH)D level and bilateral uterine artery S/D mean in early prediction of pre-eclampsia(PE). Methods Sixty normal pregnancy women(normal group),40 mild preeclampsia women(MPE group)and 60 severe preeclampsia women(SPE group)who were examined in Changzhou First People′s Hospital and Changzhou Maternal and Child Health Care Hospital between January 2016 and June 2018 were included. The mean value of S/D of bilateral uterine artery was measured from 15th to 20th weeks in all the 3 groups,and serum 25(OH)D level of the mother was measured at 24th week. Meanwhile, the ROC curves of S/D mean value,serum 25(OH)D level and combined detection were drawn to compare the area under each curve(AUC),and the diagnostic efficiency of S/D mean value,serum 25(OH)D level and combined detection PE were also calculated. Results The incidence of adverse pregnancy outcome in SPE group was significantly higher than that in MPE group,and that in MPE group was significantly higher than that in normal group(P < 0.05). The mean value of S/D of bilateral uterine artery in SPE group was(4.09 ± 0.62),which was higher than that in MPE group(3.26 + 0.55)and in normal group(2.62 ± 0.51),while the mean value of S/D in MPE group was significantly higher than that in normal group and the difference was statistically significant(P < 0.05). The level of serum 25(OH)D in SPE group was(32.44 ± 5.84),which was significantly lower than that in MPE group(37.15 ± 5.90)and in normal group(42.57 ± 7.44),while the serum 25(OH)D level in MPE group was significantly lower than that in normal group,and the difference was statistically significant(P < 0.05). The mean value of S/D of bilateral uterine artery in the pre-eclampsia group was negatively correlated with 25(OH)D level(r = -0.66,P < 0.01). The area under the ROC curve separately detected by S/D mean value and 25(OH)D level was 0.787 and 0.719 respectively,both of which were lower than that by jointly detection(0.908)and the difference was statistically significant(P < 0.001). Conclusion Both the mean S/D value of bilateral uterine arteries and serum 25(OH)D level can be used for the diagnosis and monitoring of pre-eclampsia,and the diagnostic efficacy of the combined detection is superior to that of single detection.

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 single amino acid mutation of the full human scFvs against TSLP to enhance its affinity.Methods: The specific scFvs against TSLP was screened in our previous study and here the three-dimensional structures of TSLP and anti-TSLP scFvs were simulated by Discovery Studio system,then the molecular docking was made.The amino acids of binding epitope were randomly mutated and the mutated amino acids were selected which could remarkably improve the affinity of scFvs.The primers were designed based on the sequence of mutation amino acids and the scFv sequences were mutated by the overlapping extension PCR.The DNA of mutated scFvs was ligated with the expression vector pLZ16 and transformed into E.coli DH5αF′.Then the scFvs were expressed and the scFvs with improved affinity were selected by ELISA and BIAcore.Results: The five scFvs with single amino acid mutation were screened out by DS system,which could elevate the affinity of scFvs.The mutated anti-TSLP-scFvs were amplified by PCR,which size was about 1 000 bp.The mutated scFvs with correct sequence were expressed,and the mutated scFvs with improved affinity were detected by ELISA and BIAcore.The affinity of selected mutated scFv (M4) has been about 10 times higher than the scFv nonmutation.Conclusion: The affinity of anti-TSLP-scFv has been improved successfully.