Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Objective:To observe the clinical and pathological features of choroidal malignant melanoma (CM).Methods:A retrospective case study. From 2011 to 2021, paraffin specimens from 15 eyes of 15 CM patients diagnosed by pathological examination in the Department of Pathology, the Second Affiliated Hospital of Soochow University were included in the study. The age, gender, clinical manifestations, treatment plan and pathological examination results of patients were collected retrospectively through the hospital information system. The clinical characteristics, immunohistochemical staining and molecular pathological characteristics were analyzed.Results:Among the 15 cases, 8 males and 7 females. The average age was 61. All patients were monocular paroxysm. There were 8 cases of decreased vision, blurred vision and dark shadow in front of the eyes; 1 case had red eye, lacrimation and purulent secretion; 2 cases had visual loss and no light perception; 4 cases had retinal detachment. The average diameter of the tumors was 1.4 cm. The general appearance of the tumor was hemispherical, "mushroom-shaped" or flat diffuse. Most of the tumor cells were arranged in solid, flaky and cross clusters, and some of them were arranged in false "chrysanthemum form" around the blood vessels with necrosis. In 15 eyes, spindle-cell type, epithelioid type and mixed cell type were 6, 2 and 7 eyes, respectively. The cytoplasm was partly double stained or eosinophilic, partly clear, and partly rich in pigment. The cells had poor adhesion, marked atypia, rough chromatin, frequent mitotic figures, and prominent nucleoli. Immunohistochemical staining was positive for HMB45, SOX10, S100 and Melan-A in 15 patients, but negative for epithelial markers AE1/3, lymphatic markers LCA, neuroendocrine markers CgA and Syn. Genetic testing results showed that none of the patients found C-KIT, BRAF, NRAS gene mutations. Fifteen patients were followed up for 8-96 months, of which 12 survived and 3 died after recurrence and/or metastasis.Conclusion:CM has no specific clinical clinical manifestations, and he diagnosis depends on histological morphology and immunohistochemical staining.

Objective:To explore the clinical significance of the MYCN gene, PHOX2B gene and plasma cell-free DNA (cfDNA) in risk stratification and predicting the prognosis of high-risk neuroblastoma (NB). Methods:This was a prospective study involving 94 high-risk NB children admitted to Beijing Children′s Hospital, Capital Medical University from August 2017 to December 2018.Relative levels of MYCN and PHOX2B and cfDNA at diagnosis, and 4 and 6 cycles of chemotherapy were detected, and their differences were compared by the Chi- square test.Kaplan-Meier survival analysis was performed to explore their prognostic potential in high-risk NB. Results:Among the 94 high-risk NB children, 14 cases (14.9%) had MYCN amplification, 76 cases (80.8%) had positive expression of PHOX2B and 56 cases (59.6%) had cfDNA level higher than 100 μg/L.The proportion of high lactate dehydrogenase (LDH, ≥1 500 U/L) level in the MYCN gene amplification group (6/14 cases) was higher than that in the normal group (9/80 cases) ( P=0.009). The proportion of multi-site metastasis (54/76 cases) and high neuron specific enolase (NSE) level (NSE≥370 μg/L, 37/76 cases) in PHOX2B positive group were significantly higher than those in the negative group (5/14 cases, 2/14 cases) ( P=0.015, 0.020). The proportion of high LDH and high NSE in high cfDNA concentration (≥229.6 μg/L)group (13/37 cases, 28/37 cases) were significantly higher than those in low cfDNA concentration group (2/48 cases, 10/48 cases) (all P<0.001). With the decreased tumor burden during the treatment, the copy number of PHOX2B gene and cfDNA level were significantly lower than those at the initial diagnosis [0 (0-719.6) copies vs.1 723.5 (0-186 000.0) copies; 19.0 (1.1-225.5) μg/L vs.200.6 (8.0-5 247.4) μg/L, all P<0.001]. The 2-year event-free survival (EFS) rate of the MYCN gene amplification group was significantly lower than that of the normal group[(33.3±13.1)% vs.(58.5±7.1)%, P=0.020]. The 2-year EFS rate of PHOX2B positive group was significantly lower than that of the negative group[(47.9±7.1)% vs.(79.1±11.1)%, P=0.043]. EFS rate in high cfDNA concentration group was significantly lower than that in cfDNA low concentration group[(38.6±9.8)% vs.( 71.7±8.2)%, P=0.001]. After 6 cycles of chemotherapy, EFS rate in the PHOX2B positive group was significantly lower than that in the negative group [(16.7±14.4)% vs.( 60.6±6.6)%, P=0.014]; which was significantly lower in the Metaiodobenzylguanidine (MIBG) positive group than that of the negative group[(35.2±11.7)% vs.(65.8±7.1)%, P=0.037]. The MYCN gene and cfDNA concentration were not correlated with the prognosis of high-risk NB.Survival analysis of the combination of PHOX2B and MYCN gene ( PHOX2B+ /MIBG + , PHOX2B+ or MIBG + , PHOX2B-/MIBG -) showed a significant difference in the survival among three groups[0 vs.(53.6±1.2)% vs.(65.5±7.4)%, P=0.003]. Conclusions:The MYCN and PHOX2B gene and cfDNA concentration are of significance in risk stratification and predicting the prognosis of high-risk NB.Compared with the MYCN gene and cfDNA concentration, the PHOX2B gene is more suitable for monitoring the curative effect of chemotherapy on high-risk NB.A combined analysis of PHOX2B gene and MIBG before treatment can be more accurate in evaluating the treatment effect and residual lesions.

Objective: To evaluate the clinical application of single-arm external stent combined with free flap in the treatment of forearm fractures of Gustilo type Ⅲ. Methods: A retrospective study was conducted of the 16 patients who had been treated at Repair and Reconstruction Center, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University from September 2015 to January 2018 for open forearm fractures combined with soft tissue defects with single-arm external stent combined with free flap. They were 11 men and 5 women, aged from 18 to 64 years (average, 41.6 years). By the Gustilo classification, 9 cases were type ⅢB and 7 type ⅢC. The area of soft tissue defects at the upper arm and hand ranged from 7.5 cm×5.5 cm to 16.5 cm × 11.0 cm. Emergency debridement was performed at the primary stage. After repair of major blood vessels, nerves and tendons, the reduced fractures were fixated with a single-arm external stent. The soft tissue defects were repaired with free flaps at the secondary stage. Nine cases were repaired with a free anterolateral perforating branch flap and 7 with a free ilioinguinal flap. The single-arm external stent became the ultimate fixation mode in 5 cases but was changed into plate fixation after survival of the flaps in the other 11 cases. Complications were recorded postoperatively. At the last follow-up, the upper limb function was evaluated according to the tentative criteria for evaluation of the upper limb function proposed by the Hand Surgery Society of Chinese Medical Association. Results: Of all the free flaps, 14 survived smoothly but 2 anterolateral ones survived only after the venous crisis appearing at 24 h after operation was relieved by exploration. The 16 patients were followed up for 9 to 18 months (average, 13.5 months). The fractures united well with fine alignment of the fracture ends and recovered force line. According to the Anderson criteria for forearm fractures, 10 cases were excellent, 4 good and 2 fair after operation. According to the tentative criteria for evaluation of the upper limb function proposed by the Hand Surgery Society of Chinese Medical Association, 11 cases were excellent and 5 good. No nail infection or nonunion occurred. Conclusion In the treatment of forearm fractures of Gustilo type Ⅲ, single-arm external stent plus free flap can effectively restore the force line of upper extremity, promote bone healing, allow reasonable timing for wound repair, reduce postoperative complications like infection and osteomyelitis and facilitate functional recovery of the affected extremity.

Objective: To investigate the translucency parameters (TP) and the color parameters of computer-aided design and computer-aided manufacturing (CAD/CAM) materials for veneer restorations in order to guide clinical practice. Methods: Eleven groups of CAD/CAM materials (A2 shade) were included in this study: IPS e.max CAD HT/LT, IPS Empress CAD HT/LT, Lava^TM Ultimate HT/LT, VITA SUPRINITY HT/T, VITA ENAMIC HT/T, VITABLOCS Mark Ⅱ, and were named as Group A, B, C, D, E, F, G, H, I, J, K. Each material was designed and milled to disk-shaped specimens (10.0 mm×8.0 mm×0.7 mm) (n=6). The specimens were polished with silicon carbide paper and the thickness of specimens were adjusted into (0.60±0.03) mm. The color parameters of specimens were individually measured with the colorimeter against black and white ceramic tiles background to obtain the TP values. The color parameters of the specimens against the composite resin background were also measured and the color differences (ΔE values) between specimens and the A2 shade tab were calculated. Results: One-way ANOVA showed that the translucency parameters of the 11 groups of materials were statistically significant (F=253.69, P<0.05). The ΔE values of CAD/CAM material groups ranged from 1.78 to 4.12 (ΔE values<5.5). Conclusions The microstructure of CAD/CAM materials and the types of material translucency influence the optical properties. The CAD/CAM materials in this experiment have achieved color matching with the A2 shade tab.

Objective To summarize the clinical features of neuroblastoma (NB)with N - myc gene amplifi-cation in order to analyze tumor shrinkage and bone marrow remission in the early stage of chemotherapy,and to eva-luate the children's initial sensitivity to chemotherapy. Methods The medical records of 38 patients with N - myc am-plification of NB were reviewed (bone marrow or tumor tissues were positive during fluorescence in situ hybridization probe),who were treated between February 2012 to December 2016 at the Hematology Oncology Center,Beijing Chil-dren's Hospital,Capital Medical University. The regimens included chemotherapy,surgery,stem cell transplantation, radiotherapy,and maintenance treatment. The data were reviewed for the medical history. The variations of biomarker, bone marrow cells and the primary site were analyzed before and after 2 courses of CAV (Cyclophosphamide + Adriamy-cin + Vincristine)regimen chemotherapy,in order to observe the short - term effect of chemotherapy and the results were described with statistics. Results Total 38 cases were studied,22 boys(58. 9％)and 16 girls(42. 1％). The median age was 30 months. The primary sites of 37 cases of tumor were located in the retroperitoneal and adrenal area,1 case located in the posterior mediastinum. Bone marrow cytology was negative in 12 cases of them,but bone marrow biopsy suggested bone marrow metastasis,while bone marrow cytomorpholigic examinations were positive in the other 26 cases. Of all the 37 cases the lactate dehydrogenase (LDH)levels were reported higher than the normal value. LDH level was under 500 U/ L in one case,9 cases above 4000 U/ L. The neuron specific enolase (NSE)level of all the cases was higher than the normal and NSE level in 36 cases was higher than 100 μg/ L. In one patient the diameter of tumor was less than 5 cm,lager than 10 cm in 32 cases. The lesion of 33 tumor cases before chemotherapy by enhanced CT was ≤100 cm3 in 12 cases,> 100 - 500 cm3 in 11 cases,among which 6 cases ranged from 500 - 1000 cm3 ,4 cases larger than 1000 cm3 . All the 38 cases received 2 courses of chemotherapy. LDH levels of 4 cases became normal,and LDH levels fell under 500 U/ L in 18 cases,while LDH levels of the other 3 cases were above 1000 U/ L. Among 38 cases, the NSE level in 6 cases was reduced to normal,and 16 cases reduced to 25 - 100 μg/ L. The bone marrow examination of 36 cases reversed to negative. According to the image examination,the overall response rate after 2 courses of chemo-therapy was 84. 8％ . One case achieved very good partial remission,21 cases achieved partial response,7 cases a-chieved metastatic remission,2 cases had no remission,while 2 cases showed progression. After 2 courses of chemother-apy,the tumor diameter in 7 cases was less than 5 cm,while that of 22 cases was above 10 cm. Conclusions The ma-jority primary site of NB with N - myc gene amplification is located in retroperitoneal and adrenal area. Patients with the huge tumor have a heavy burden and the biomarker is always high at the early stage. NB with N - myc gene amplifica-tion is sensitive to chemotherapy. After 2 courses of chemotherapy,there is a sharp decrease in the level of biomarker and the tumor burden. Chemotherapy can diminish the burden of tumor in early stage. But because of the huge burden and the huge size of tumor,it's not the best time for surgery and stem cell collection. The patients should go on receiving chemotherapy for remission of disease.

Objective To investigate the short-term acute rejection incidence of the recipients under the steroid-free immunosuppressive therapy after liver transplantation. Methods This retrospective study included 186 patients who were divided into two groups by random number table.The patients in no steroid group (the study group, n =94) received tacrolimus (Tac) with mycophemolate mofetil (MMF) or cyclosporine with MMF,and those in the steroid group (the control group,n =92) received the aforementioned immunosuppressive therapy combined with steroids.The acute rejection incidence was analyzed during six months post-transplantation.Results There was no significant difference in the gender,age,indication for transplantation,Child-Pugh score,MELD score,operating time,bleeding and transfusion volume during the operation,warm ischemia time and cold ischemia time between the two groups (P＞0.05).Liver biopsy was done on 9 cases of each group.The acute rejection incidence had no significant difference between the study group and the control group (5/94 vs 4/92,5.3％ vs 4.4％,P＞0.05).Conclusion The steroid-free immunosuppressive therapy after liver transplantation did not increase the short term acute rejection incidence.

Objective To characterize the clinical course of biliary complications after right lobe living donor liver transplantation (RL-LDLT) and to identify the independent risk factors for biliary strictures.Methods 105 consecutive RL-LDLT recipients operated from April 2007 to April 2010 were followed up. The clinical and operative data were reviewed. The biliary complications and independent risk factors of biliary stricture were studied.Results The median follow-up duration was 49.5 months ranging from 562 to 1675 days.A total of 40 patients (38.1 ％) experienced 11 bile leak episodes (10.4％ ) and 37 (35.2％) biliary stricture episodes after transplantation.Bile leaks occurred at a median time of 9 days ranging from 4 to 54 days after transplantation.For biliary strictures,the occurring time was delayed and scattered wide with a median of 7.6 months ranging from 12 to 790 days after transplantation. Moreover, the biliary stricture incidence in the first year after transplantation was significantly higher than later.The independent risk factors for biliary strictures were CMV infection,bile leaks and bile duct size (≤3 mm).Conclusion The independent risk factors for biliary strictures after RL-LDLT were CMV infection,bile leaks and bile duct size (≤3mm).In order to avoid biliary complications,careful preoperative evaluations are necessary. The dissection of bile ducts should be meticulous to protect its blood supply.CMV infection should be prevented after transplantation.Close surveillance of biliary complications should be given to RL-LDLT recipients during the first year after transplantation.

ObjectiveTo surnmarize the experience of tacrolimus or cyclosporine A-based immunosuppression after pediatric living-donor liver transplamation.Methods The clinical data of 30 children undergoing living-donor liver trarsplantation from October 2006 to January 2010 were analyzed retrospectively.In 30 patients,7 were given Tac-based immunosuppression (group A),10 given CsA-based immunosuppression (group B),and 13 switched from CsA to Tac for complications or adverse effects of drugs.Dosages and blood concentrations of immunosuppressants were recorded.Changes of liver and kidney functions were monitored.Incidence of rejection,infection and adverse effects of drugs were observed.ResultsIn the premise of the stable concentration and liver and kidney functions,the weight of children was increased by about 50％ and the per- kilogram dosage of CNIs was decreased significantly 1year postoperatively.There was no case of rejection in group A and 4 cases of rejection in group B(40％,4/10),and the original symptoms were gradually alleviated after the increased dosage in immunosuppressants.During the first 3 months,there was 1case of abdominal infection in group A (1/7) and 3 cases of lung infection in group B (3/10),and the original symptoms were gradually alleviated after anti-infective therapy.There was 1CMV lgM-positive case in group A (1/7) and 2 CMV IgM-positive cases in group B (2/10),and the original symptoms were gradually alleviated after using ganciclovir.The original symptoms of the 13 children switched from CsA to Tac were gradually alleviated.ConclusionThe two CNIs can be safely used in children undergoing pediatric livlng-donor liver transplantation.Both of them show the same effect in promoting the restoration of liver and kidney functions,but tacrolimus has more satisfactory effect in inhibiting the rejection and it has leas adverse effects.