As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

ObjectiveTo study the differences in volatile oil content of bran-processed Atractylodes lancea and its standard decoction concentrate and freeze-dried powder， as well as the differences in the types and contents of chemical components in volatile oil， and to clarify the quality value transmitting. MethodTen batches of A. lancea rhizoma were collected and prepared into raw products and bran-processed products of A. lancea， standard decoction concentrate and freeze-dried powder of bran-processed A. lancea in order to extract the volatile oil， and the transfer rate of volatile oil in each sample was calculated. Quantitative analysis of the main chemical components（β-eudesmol， atractylon， atractylodin） in each volatile oil was performed by gas chromatography（GC） on the HP-5 quartz capillary column（0.32 mm×30 m， 0.25 μm） with a flame ionization detector（FID）， a split ratio of 10∶1 and a temperature program（initial temperature at 80 ℃， hold for 1 min， rise to 150 ℃ at 10 ℃·min^-1， hold for 10 min， rise to 155 ℃ at 0.5 ℃·min^-1， hold for 5 min， rise to 240 ℃ at 8.5 ℃·min^-1， hold for 8 min）. Cluster analysis and principal component analysis（PCA） were used to explore the overall differences in types and contents of chemical components between the standard decoction concentrate and freeze-dried powder. ResultThe transfer rates of volatile oil in the bran-processed products， standard decoction concentrate and freeze-dried powder were 70.51%， 1.57% and 40.90%， respectively. The average transfer rates of β-eudesmol， atractylon and atractylodin in the volatile oil of bran-processed A. lancea were 58.45%， 48.49% and 55.64%， respectively. In the standard decoction concentrate， only β-eudesmol and atractylodin were detected， and their average transfer rates were 0.22% and 0.10%， respectively. And only β-eudesmol was detected in the freeze-dried powder with the average transfer rate of 8.37%. The results of cluster analysis and PCA showed that there are obvious differences in the types and contents of chemical components between the standard decoction concentrate and freeze-dried powder. ConclusionThe quality value transmitting between bran-processed A. lancea and its standard decoction concentrate and freeze-dried powder is stable， and if the freeze-dried powder is selected as the reference material of dispensing granules， appropriate amount of volatile oil should be added back to make it consistent with the quality of the standard decoction concentrate.

Objective The present study aimed to establish a bone mineral density (BMD) reference database in China and to investigate the prevalence of osteoporosis in Chinese adults aged 50 years and older using dual energy X-ray absorptiometry (DXA). Method A total of 75321 examineers over 25 years old who underwent health checkups in 7 health check centers between 2008 and 2018 were included. All centers used a GE Lunar-DXA system to measure BMD of the lumbar spine (L1-L4), femoral neck, and total femur. The same European Spine Phantom (ESP) was used for scanning 10 times at every center, a regression equation was generated, and BMD data were cross-calibrated in each center. Peak BMD and standard deviation (SD) were identified according to 5-year age groups, and T scores were calculated based on the peak BMD and SD. Osteoporosis was defined according to the World Health Organization criteria. The prevalence of osteoporosis was standardized based on 2010 national census data for the Chinese population. Result The mean BMD values decreased with age, were highest in North China, followed by Northeast China, East China, and Southwest China, respectively, and increased with body mass index. Males aged 20-30 years and females aged 35-40 years had peak BMD values. Peak BMD values of the lumbar spine, femoral neck, and total femur were 1.09 g/cm2, 0.97 g/cm2, and 0.97 g/cm2 in males, and 1.11 g/cm2, 0.84 g/cm2, and 0.88 g/cm2 in females, respectively. Among all scanned sites, the prevalence of osteoporosis was highest in the femoral neck in males (4.58％) and in the lumbar spine in females (23.38％). The age-standardized prevalence of osteoporosis at any site was 6.46％ in males and 29.13％ in females aged 50 years and older. Based on the 2010 national census data, 10879115 males and 49286542 females currently have osteoporosis. Conclusion Mean BMD values varied according to geographic region, body mass index, age group, and sex in Chinese adults. The age-standardized prevalence of osteoporosis was 6.46％ in males and 29.13％ in females aged 50 years and older.

Objective: To explore the effects of temperature on the daily cases of varicella. Methods: The data of daily cases of varicella was collected during 2008 to 2016 in Lanzhou from National Notifiable Disease Report System, and the meteorological data at the same period was integrated from Gansu Meteorological Administration. Distributed lag nonlinear model was fitted to reveal the relationship between the daily mean temperature and the daily cases of varicella and susceptible population. The minimum morbidity temperature was defined as the reference for the estimation of RRs in different temperature level (-5.2 ℃, 1.7 ℃, 20.1 ℃ and 25.4 ℃). Results: The total of 21 254 cases were reported from 2008 to 2016, of which the ratio of male to female was 1.28 (11 951/9 303) and people aged 6-14 years accounted for 52.87%. The relationship between the daily mean temperature and the daily cases of varicella was M type. For all subjects, the accumulative effects of temperature had statistical significance from lag 0-14 d when temperatures was at -5.2 ℃, 1.7 ℃ and 20.1 ℃,while the RRs (95%CI) were 1.87 (1.64-2.12) , 1.33 (1.10-1.62) ,1.60 (1.38-1.86) ,while from lag 0-7 d when temperatures was at 25.4 ℃,and the RR (95%CI) was 2.51 (1.93-3.27) . The RR value of accumulative effects was 6.23(95%CI: 4.38-8.86) on lag 7 d when temperatures was at -5.2 ℃, which was the highest value at different temperature during lag days. The cumulative effects trends of different temperatures were similar for different gender population or different age subjects. However, the cumulative effects of was highest for children aged 6-14 years among all subjects, and the value of RR was 6.12 (95%CI:3.71-10.10) on lag 5d when temperatures was at -5.2 ℃. Conclusion We conclude that the increasing risk of varicella is associative with low and high temperature in Lanzhou. The effects of low temperature are stronger than those of high temperature. The children aged 6-14 years belong to the high-risk population of varicella.

Objective:To study the diuretic effect of micronized powder of Panax notoginseng (Burk.) F.H.Chen on rats.Methods:The metabolic cage method and weighing method were used in this experiment;The indictor of urine excretion in 6 h was used to study the diuretic effect of powder ofPanax notoginseng (Burk.) F.H.Chen in the water loaded rats;the output of Na +,K +,C1-in urine were measured to elucidate the related mechanization.Results:Powder of Panax notoginseng (Burk.) F.H.Chen under high dose after administration of 2h to 5h can significantly increase the urine volume of rat compared with the blank control group (P＜0.01,P＜0.05),but no diuretic effect after administration of 6h.powder of Panax notoginseng (Burk.) F.H.Chen under high dose could increase the urine Na+,Cl-(P ＜0.01) but reduce the K+ excretion,inhibitting the Na+ reabsorption and K+ excretion of renal tubule.It could significantly increase rat urine pH value (P＜0.01),the effect ofpH value by which is similar with the effect of hydrochlorothiazide and the effect of Jinqiancao granules.Conclusion:For the first time,this study investigated the diuretic effect of powder of Panax notoginseng (Burk.) F.H.Chen,The relevant mechanism is that powder of Panax notoginseng (Burk.) F.H.Chen have an impact on inhibitting the Na+ reabsorption and K+ excretion of renal tubule.

Objective To evaluate effects of the daily average temperature on the daily number of outpatient visits for eczema in Lanzhou city.Methods Clinical data were obtained from outpatients with eczema in the Department of Dermatology of 2 third-grade class-A hospitals in Lanzhou city from January 1st 2007 to December 31st 2015,and meteorological data during this period were also collected.Controlling for confounding factors like long-term trends and day of the week,a distributed lag non-linear model (DLNM) fitted with quasi-Poisson link function was used to assess the effects of daily average temperature on the daily number of outpatient visits for eczema,and the analysis was stratified by season,age and gender.Results The exposure-response relationship between the daily average temperature and daily number of outpatient visits for eczema could be roughly described by a W-shaped curve.Stratification analysis showed that the effect of the daily average temperature on outpatient visits for eczema was strongest in autumn and winter,followed by summer,and weakest in spring.Low temperature may have lagged,cumulative and persistent effects on the daily number of outpatient visits for eczema,with the maximum relative risk (RR) value (1.12 [95％ CI:1.03-1.22]) observed at-9 ℃ on lag day 14.With a 1 ℃decrease in the temperature,16％ (RR =1.16,95％ CI:1.00-1.03),14％ (RR =1.14,95％ CI:1.02-1.26) and 13％ (RR =1.13,95％ CI:1.02-1.25) increases in the daily number of outpatient visits for eczema were observed in men,teenagers and middle-aged adults respectively (P ＜ 0.05).However,low temperature had no significant effects on outpatient visits for eczema among women or the elderly (P ＞0.05).The effect of high temperature usually occurred following exposure without lag periods,and was gradually weakened over lag time (P ＞ 0.05).Conclusions In Lanzhou,the effect of daily average temperature on outpatient visits for eczema was strongest in autumn and winter.Changes of the daily temperature may be one of risk factors for eczema.Low temperature had lagged effects on the daily number of outpatient visits for eczema,and the effects were strongest on lag day 14.

Objective To evaluate effects of daily average temperature on the occurrence of urticaria in Lanzhou city,and to analyze differences in the effects between different populations.Methods Time-series data on daily outpatient visits for urticaria between January 1,2007 and December 31,2013 were collected from the First Hospital of Lanzhou University and Lanzhou University Second Hospital.Daily meteorological data during this peroid were obtained from the Gansu Meteorological Bureau.Distributed lag non-linear models were used to analyze the association between daily average temperature and occurrence of urticaria,and the analysis was stratified by age and gender.Results The association between daily average temperature and daily number of outpatient visits for urticaria was nonlinear.Low temperature had significant lag effects on the daily number of outpatient visits for urticaria,with the maximum relative risk (RR) value (1.014 [95％ CI 1.000-1.023]) observed at 6 ℃ on lag day 18.Stratification analysis demonstrated that the effects of high temperature on the number of outpatient visits for urticaria were apparent on the day of exposure in age groups of 0-18 and 19-64 years,but decreased on the day of exposure in the age group ≥ 65 years.The effects of low temperature,which showed similar trends along with the increment of lag days in all groups,were relatively delayed and occurred 2 to 4 days after exposure.Conclusions Air temperature affects the occurrence of urticaria in Lanzhou city.Low temperature has evident lag effects on the occurrence of urticaria,while high temperature does not have.

OBJECTIVETo observe the clinical effects of needle-pricking therapy, a newly medical and minimally invasive technique, for functional retrograde ejaculation and to explore its mechanism. Methods Thirty-six patients with functional retrograde ejaculation were randomly divided into an observation group(19 cases) and a control group(17 cases) In the observation group,needle-pricking therapy was used at Guanyuan(CV 4) and bilateral sacral plexus nerve,lumbar 1 nerve and greater occipital nerve stimulating points,once a week. In the control group, midodrine tablets were prescribed orally,three times a day. All the treatment was given for 9 weeks. The clinical effects of the two groups were observed, and the levels of luteinizing hormone(LH), testosterone(Tes) and estra4 diol(E2) were compared between the two groups.

RESULTSThe total effective rate of the observation group was, 89. 47%(17/19), which was better than 47.06% (8/17) of the control group(P<0. 05). The LH and Tes were obviously increased and E2 was decreased compared with those before treatment in the observation group(all P< 0. 01). Tes was raised(P<0. 05) and E2 was apparently declined in the control group(P<0. 01). After treatment, the differences of serum LH and Tes were statistically significant between the two groups(both P<0. 01).

CONCLUSIONNeedle-pricking therapy has advantages for functional retrograde ejaculation probably in that stimulating lumbosacral nerves can strengthen the function of pelvic floor muscles and urethral expansion muscle and regulate sexual gland axis.

Acupuncture Points ; Acupuncture Therapy ; Adult ; Ejaculation ; Humans ; Male ; Middle Aged ; Needles ; Sexual Dysfunction, Physiological ; physiopathology ; therapy ; Treatment Outcome

BACKGROUND:The tourniquet is usualy fuly used or bilateraly used in partial time during bilateral total knee arthroplasty. However, very few people try to use it on one side and on the other side in partial time.
OBJECTIVE:To investigate the effective strategy of using a tourniquet in simultaneous bilateral total knee arthroplasty.
METHODS:80 patients (160 knees) with severe osteoarthritis who underwent simultaneous bilateral total knee arthroplasty in the Department of Orthopedics, Chinese PLA Medical School from January to December 2013 were divided into two groups according to the different tourniquet strategies. In test group (n=40), left knees did not receive tourniquet, and right knees received tourniquet in partial time. In control group (n=40), al knees received tourniquet in the whole time. The perioperative and postoperative blood loss, 3-day postoperative thigh sweling rate and pain visual analog scale, 3-week and 1-year postoperative Knee Society Score were recorded in both groups.
RESULTS AND CONCLUSION:There were no statisticaly significant differences between two groups in perioperative total blood loss (P > 0.05). However, postoperative blood loss in test group was less than that in control group (P < 0.05). The visual analog scale scores were significantly lower in the test group than in the control group at 3 days after surgery (P < 0.05). Visual analog scale scores on the left side were lower than on the right side in the test group at 3 days post surgery (P < 0.05). Bilateral thigh sweling rate was significantly lower in the test group than in the control group at 3 days after surgery (P < 0.05). The thigh sweling rate was lower on the left side than on the right side in the test group at 3 days after surgery (P < 0.05). Knee Society Score was higher in the test group than in the control group in the early stage, and no significant difference in long-term Knee Society Score was detected (P > 0.05). These findings verify that taking the strategy that the first knee without tourniquet and the second knee with part time tourniquet technique in simultaneous bilateral total knee arthroplasty wil aleviate pain and sweling after operation and promote early functional rehabilitation without increasing the perioperative total blood loss.

Objective To investigate the criteria for assessing the clinical therapeutic effect of chronic urticaria in China.Methods The application of criteria for assessing the clinical therapeutic effect of chronic urticaria in China and their applicable scope were analyzed by frequency analysis and K-means clustering analysis, respectively.Results The criteria for assessing symptoms and therapeutic effect were different in the 857 papers included in this study. SSRI was used in 549 (64.17) out of the 857 papers included in this study.K-means clustering analysis showed that the applicable scope of SSRI with curative rate ( 100%≥SSRI>90%) , improvement rate ( 90%≥SSR<60%) , Significant effect rate (60%≥SSRI>20%) , and no response rate (20%≥SSR≥0%) as its criteria was wider than that of frequency analysis.Conclusion The criteria for the clinical assessment of chronic urticaria and its drug treatment effect should be unified and standardized.