Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Objective:To explore the predictive value of different critical values of slow gait speed on adverse outcomes in elderly maintenance hemodialysis (MHD) patients.Methods:The study was a prospective cohort study. The clinical data of elderly patients (≥ 60 years old) who received MHD treatment in the Third Affiliated Hospital of Guangzhou Medical University from March 1 to June 30, 2021 were collected, including demographic characteristics, diseases-related data and laboratory examination results. The follow-up period was one year. The six-meter walking test was used to measure the gait speed (m/s), and 0.6 m/s, 0.8 m/s and 1.0 m/s were used as the different critical values of the gait speed for grouping. The differences of clinical data between different groups were compared. Logistic regression analysis method was used to assess the association of slow gait speed with adverse outcomes (falls and hospitalization) in elderly MHD patients. The receiver operating characteristic (ROC) curve was performed to evaluate the best critical value of slow gait speed to predict the risk of falls and hospitalization.Results:A total of 108 elderly patients with MHD were included, with 57 males and 51 females. There were 43 patients (39.8%) of falls and 34 patients (31.5%) of hospitalization. There were statistically significant differences in age, Charlson's comorbidity index, and the proportions of hypertension, family support needed in daily life, walking aids needed, falls and hospitalization events among the four groups of the patients grouped according to gait speed (all P < 0.05). Multivariate logistic regression analysis results showed that the risk of falls predicted by gait speed of 0.6- < 0.8 m/s was higher than that by gait speed of > 1.0 m/s ( OR=3.973, 95% CI 1.116-14.136, P=0.033). The risk of hospitalization predicted by gait speed < 0.6 m/s was higher than that by gait speed > 1.0 m/s ( OR=9.147, 95% CI 1.658-50.453, P=0.011). The logistic regression analysis was performed with the critical values of 0.6 m/s, 0.8 m/s and 1.0 m/s as the classification variables, and the results showed that the gait speed of < 0.8 m/s was an influencing factor of the falls risk in elderly MHD patients (≥ 0.8 m/s as reference, OR=3.200, 95% CI 1.099-9.318, P=0.033). The gait speed < 0.8 m/s and < 0.6 m/s were influencing factors of hospitalization (≥ 0.8 m/s as reference, OR=3.899, 95% CI 1.355-11.216, P=0.012; ≥ 0.6 m/s as reference, OR=4.226, 95% CI 1.107-16.140, P=0.035). The area under the ROC curve for gait speed of < 0.6 m/s, < 0.8 m/s and < 1.0 m/s to predict the risk of falls were 0.605(95% CI 0.493-0.717, P=0.065), 0.668(95% CI 0.562-0.774, P=0.003), and 0.634 (95% CI 0.529-0.739, P=0.019), respectively. The best critical value of slow gait speed to predict the risk of fall was 0.73 m/s, and the area under the ROC curve was 0.720(95% CI 0.623-0.817, P < 0.001), with the sensitivity and specificity of 0.846 and 0.512, respectively. The area under the ROC curve for gait speed of < 0.6 m/s, < 0.8 m/s and < 1.0 m/s to predict the risk of hospitalization were 0.629(95% CI 0.509-0.749, P=0.032),0.683(95% CI 0.573-0.793, P=0.002), and 0.608(95% CI 0.497- 0.719, P=0.073). The best critical value of slow gait speed to predict the risk of hospitalization was 0.81 m/s, and the area under the ROC curve was 0.688(95% CI 0.576-0.800, P=0.002), with the sensitivity and specificity of 0.689 and 0.676, respectively. Conclusion:The critical value of gait speed 0.8 m/s can be used to predict the risk of falls and hospitalization in elderly MHD patients.

This article reported a case of kaposiform lymphangiomatosis (KLA) identified in the fetal stage and diagnosed at the neonatal stage. A routine ultrasound examination at 19 weeks of gestation showed multiple masses in the whole body of the fetus (involving neck, chest wall and armpit) complicated by pleural and peritoneal effusion. Shunting was performed to drain pleural effusion from the right chest in another hospital at 26 +5 weeks of gestation. The patient was born at 34 +3 weeks of gestation by cesarean section due to "intrauterine distress" and required invasive ventilator assisted ventilation support after birth because of respiratory distress. A large amount of hemorrhagic effusion was drained out during the shunting. Coagulation dysfunction and thrombocytopenia occurred on the 3rd day after birth and KLA was suspected. Empirical treatment with sirolimus turned out to be ineffective. Biopsy was taken on postnatal day 7. However, the patient died on the 12th day after birth due to respiratory and circulatory failure. Pathological findings obtained the day after death were consistent with the features of KLA. The diagnosis of KLA was confirmed based on the clinical manifestations and pathological results.

Objective To study the effect of multi-disciplinary team (MDT) management on the outcome in neonates with omphalocele.Method A retrospective non-randomized controlled clinical study was conducted.Neonates who were diagnosed as omphalocele and admitted to the surgical neonatal intensive care unit of the Guangzhou Women and Children Medical Center from December 2010 to December 2017 were collected.Because MDT was established in December 2014,infants were assigned into non-MDT group and MDT group according to their dates of admission.The characteristics and outcomes between non-MDT group and MDT group were compared using x2,t-test or rank-sum test.Multivariate analysis was performed by Logistic regression.Result A total of 91 neonates were included in the study,50 were in non-MDT group and 41 were in MDT group.The mortality in MDT group (2.4％,1/41) was lower than that in non-MDT group (18.0％,9/50),the difference was statistically significant (P ＜ 0.05).The median time of mechanical ventilation of giant omphalocele in non-MDT group (18.3 hours) was longer than that in MDT group (41.7 hours),the difference was also statistically significant (P ＜ 0.05).After adjusting for the associated confounding risk factors,the risk of death in non-MDT group was 54 times higher than that in MDTgroup (OR=54.19,95％CI2.64 ～1 113.49,P＜0.05).Conclusion There was significant association between the MDT management and the decreased risk of death of omphalocele.

Objective To summarize the experience of perioperative management for repair of congenital diaphragmatic hernia (CDH) supported by extracorporeal membrane oxygenation (ECMO). Method Retrospective review was conducted for the clinical data of CDH patients who received surgical repair on ECMO from December 2016 to June 2018 in Guangzhou Women and Children's Medical Center. Result Four fetus with prenatal diagnosis of left-side CDH were transferred to our Center and received standardized perinatal management. Moderate-severe pulmonary hypoplasia was recognized after evaluation by fetal imaging. Four cases were initiated with veno-arterial ECMO at 3, 35, 41, 11 h of life, respectively. Repair of the diaphragmatic defect was performed within two weeks after cannulation of ECMO. Furthermore, activated clotting time goals were adjusted to 180～220 s, activated partial thromboplastin time were stabilized between 50～80 s, platelets count were maintained>100×109/L and hematocrit was kept>30％before the surgery. The surgeries of four patients were completed on the 0.9th, 0.5th, 3.6th, 5.1th day of life on ECMO, respectively. The defect was repaired by parachute patch. The operative time was 85～210 min. According to CDH Staging System defect size (A to D), there were two with defects at grade C and other two at grade D. Postoperative total volume of drainage was 215～1301 ml and ECMO duration was 3.0～39.3 d. Three of them survived during neonatal period, while one died. Conclusion Repair of CDH on ECMO is feasible and help to improve neonatal survival, especially for those with moderate-severe pulmonary hypoplasia.

Objective To evaluate the diagnostic value of MRI-measured fetal percent predicted lung volume (PPLV) for the prognosis of left congenital diaphragmatic hernia (CDH) in fetus. Methods Clinical data of 32 children who were admitted to Women and Children's Medical Center of Guangzhou from September 2012 to December 2017 for prenatally diagnosed left CDH were retrospectively analyzed. These children were divided into two groups, the survival group (n=24) and the death group (n=8), according to the postoperative outcomes at 30 days after CDH repair. Moreover, they were also divided into non-pulmonary hypertension (non-PH) group (n=20) and PH group (n=12), based on whether they suffered from PH or not. Clinical data such as gestational age, birth weight, Apgar score and PPLV values in different groups were compared with t- or Fisher's exact test. The receiver operating characteristic (ROC) curve of the MRI-measured fetal PPLV values of the 32 children was plotted. Results (1) Comparing with the death group, fetal PPLV was significantly higher [(39.5±2.5)% vs (20.4±2.1)%, t=4.27], the gestations on initial diagnosis of CDH was later [(31.6±4.2) vs (25.4±4.6) gestational weeks, t=3.40], Apgar score of the neonates at 5 min was higher (8.7±1.5 vs 5.7±3.8, t=3.26), and fewer cases of PH were reported in the survival group [16.7% (4/24) and 8/8], all P<0.01. The area under the ROC curve of PPLV values for mortality prediction was 0.930 (95%CI: 0.843-1.016, P<0.01). When the PPLV value was 28.55%, its sensitivity and specificity for death prediction in children with left CDH were 100% and 79%, respectively. (2) Comparing with the PH group, fetal PPLV was significantly higher [(41.7±2.6)% vs (23.0±2.0)%, t=4.98], the gestations on initial diagnosis of CDH was later [(32.3±3.4) vs (26.3±5.2) gestational weeks, t=3.81], neonatal Apgar score at 5 min was higher (8.6±1.4 vs 6.8±2.5, t=2.62) and death rate was lower [0(0/20) vs 8/12] in the non-PH group (all P<0.01). The area under the ROC curve of the PPLV values for predicting PH was 0.902 1 (95%CI : 0.800-1.004, P＜0.01). When the PPLV value was 33.67%, its sensitivity and specificity for PH prediction was 100% and 75%, respectively. Conclusions Prenatal MRI measurement of PPLV can be used to predict death or as a warning sign of PH in children with left CDH, which may provide evidence for prenatal evaluation and rational clinical decision-making.

Objective:To obtain a high specificity and high affinity anti-human PD-L1 monoclonal antibody which can be used for clinical diagnosis and block PD-L1 and PD-1 binding.Methods:BALB/c mice were immunized with recombinant PD-L1 protein.The positive cell clones stably secreting anti-human PD-L1 monoclonal antibody were obtained by classical hybridoma cell fusion technique.The specificity,affinity,subtype and other characteristics of the antibody were identified by ELISA.Immunofluorescence and indirect immunofluorescence were used to detect the tumor cells.Antibody blocking activity was confirmed by tumor killing test.Results:Two cell strains stably secreting monoclonal antibodies against human PD-LI were screened out.Abl and Ab2 had high titer and affinity.The antibody titers were 1:2.56×106 and 1:3×105,and the affinity was 1.5×109 L/mol and 2.5×10s L/mol respectively.There was no cross reaction between these two antibodies and PD-L2.Immunoblotting,indirect immunofluorescence confirmed that the antibody can be used to the diagnosis.Experiment showed that PD-L1 antibodies can increases tumor-killing activity of CIK cells.Conclusion:Two hybridoma cell lines capable of stably secreting highly specific and high affinity anti-human PD-L1 monoclonal antibody are obtained.They can specifically bind to PD-L1 molecules on tumor cells and can be used to the diagnosis of tumor phenotype and prognosis.Antibody blocking function can be applied to combined CIK cell immunotherapy.

Objective To observe the clinical efficacy and safety of etoposide capsule (VP16) in the treatment of recurrent small cell lung cancer. Methods Retrospective analysis 39 patients,aged≥65, with relapsed small cell lung cancer, who were at least three months after the end of the first-line treatment since January 2012 to January 2014 in Tianjin fifth central hospital.Etoposide was administered by daily oral at 100 mg/day for seven consecutive days and withdraw for 14 days,21 days as a therapeutic cycle,repeat treatment until disease progression or intolerable side effects occur, analyze the progression-free survival and overall survival.Observe the clinical benefit rate,the overall response rate and safety.Results The clinical benefit rate (DCR) and overall response rate (ORR) after the treatment were 61.5% and 30.77%.The progression-free survival (PFS) was 2.8 months, and the overall survival (OS) was 7.3 months.Neutropenia is the most common toxicities, and grade Ⅲ or Ⅳ occurred in 7.7% of the patients.No grade Ⅲ or Ⅳ thrombocytopenia, or grade Ⅲ or Ⅳ non-hematologic toxicity was occured.Conclusion Etoposide oral capsules monotherapy may be considered as one of the safe and effective choice of the second-line treatment of elderly patients with relapsed small cell lung cancer.

Objective:To identify enolase,47 kD allergen,from Litopenaeus vannamei by Mass spectrometry. Methods: The proteins were extracted from Litopenaeus vannamei tissue with acetone precipitation method. The protein components were analyzed by SDS-PAGE and Western blot. By using Matrix-Assisted Laser Desorption/Ionization time of flight mass spectrometry ( MALDI-TOF/TOF-MS) ,the 47 kD allergen from Litopenaeus vannamei was identified as enolase. Results:By SDS-PAGE,we proved that the native protein components from Litopenaeus vannamei were completely. According to the Western blot result more than 14 components could react with the positive serum. MALDI-TOF/TOF analysis results showed that the suspected proteins were enolase. A sensitization frequency was 55%. Conclusion:Enolase was identified as a new allergen of Litopenaeus vannamei.

Objective To evaluate the clinical efficacy and safety of different full spectrum light times in treating patients with Alzheimer's disease (AD).Methods A total of 127 AD patients with sleep disorder were randomly divided into a blank group (n=34),a 30 min group (n=31),a 60 min group (n=33) and a 120 min group (n=29).After one month treatment by 10 000 lux full spectrum fluorescent light,the improvements of sleep quality,excessive daytime sleepiness,cognitive ability,mental state,dementia degree were graded by Pittsburgh sleep quality index (PQSI),Epworth sleepiness scale (ESS),Neuropsychiatric inventory (NPI),mini-mental state examination (MMSE),global deterioration scale (GDS).The scores were compared among the groups before the treatment and after the treatment respectively.Results (1) Compared with before treatment,the scores of PQSI,ESS,NPI of the 30 min group,60min group and 120min group were statistically significant (in 30 min group 14.4 ±5.2vs 11.7±4.9,14.4±4.1 vs 11.8±3.7,14.2±1.3 vs 10.9±1.7,t=2.071,2.609,8.446.P=0.043,0.011,0.000; in 60 min group13.4±4.0 vs 8.1±3.7,14.5±3.0 vs 9.4±2.0,13.7±5.8 vs 8.7±4.3,t=5.650,8.209,3.902,all P＜0.01 ;in 120 min group 14.0±3.2 vs 7.0±2.3,14.7-±2.3 vs 7.0± 1.9,14.9±3.6 vs 8.1±3.7,t=9.474,13.926,7.062,all P＜0.01),but the scores of MMSE,GDS were not statistical significances(all P＞0.05).(2)Compared with the blank group,the scores of PQSI,ESS,NPI of 30 min group,60 min group and 120 min group were statistically significant (30 min group t=1.936,4.524,2.482,P=0.031,0.000,0.016.60 min group t=5.945,5.153,7.319,all P=0.000.120 min group t=7.896,6.767,10.776,all P=0.000), but the scores of MMSE,GDS were not statistical significances(all P＞0.05).(3)Compared with the 30 min group,the scores of PQSI,ESS,NPI of 60 min group and 120 min group were statistically significances (60 min group t =3.288,2.694,3.354,P=0.002,0.009,0.001.120 min group t=4.615,3.930,6.303,all P =0.000),the scores of MMSE,GDS were not statistical significances (all P＞0.05).Compared with the 60 min group,the scores of ESS of 120 min group was statistically significant(t=4.854,P=0.000),but the scores of PQSI,NPI,MMSE,GDS were not statistical significances (all P ＞ 0.05).Conclusion It is demonstrated good curative effects that light therapy treat patients on AD patients in the matter of sleep quality,excessive daytime sleepiness,mental state,but have not apparent effect for their cognitive ability and dementia degree.And the effect of light therapy with 60 or 120 minutes is better than that of 30 minute,illumination time of 120 minutes is superior to that of 60 minutes in improving excessive daytime sleepiness.Light therapy has no obvious impacts in the cognitive ability and the degree of dementia in the patients with AD and has not appear obvious adverse reaction in the process of treatment.