Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Effects and mechanism of low-intensity pulsed ultrasound on extracellular matrix in rabbit knee osteoarthritis / 中国骨伤

<p><b>OBJECTIVE</b>To observe the effects of low-intensity pulsed ultrasound (LIPUS) on repairing extracellular matrix in rabbit knee osteoarthritis and analyze its mechanism.</p><p><b>METHODS</b>Sixty adult female rabbits with an average weight of (2.0 ± 0.2) kg, were divided randomly into two groups (experimental group and control group, 30 rabbits in each group). All rabbits were replicated in right knees by Hulth method for knee osteoarthritis model. Two weeks after operation, the rabbits in experimental group were treated with LIPUS, and the ultrasonic frequency was (800 ± 5%)KHz and the maximum intensities of spatially averaged and time averaged (SATA) was (50 ± 10%) mw/cm2, for 1 time a day and every time 20 min, while the rabbits in control group were treated with sham LIPUS,the same operation with experimental group but without energy output. At the 2, 4, 8 weeks after treatment, 10 rabbits in each group were randomly killed for each time. The general changes of cartilage and its histopathological changes by HE staining were observed; the expression of collagen type II, proteoglycan, MMP-3, 7, 13 in cartilage were analyzed by immunohistochemical and RT-PCR technique; and the expression of NO in cartilage was analyzed by nitrate reduction method.</p><p><b>RESULTS</b>On the same observed time point, the damage degree of cartilage in experimental group was slighter than that of control group (P < 0.01), the expression of MMP-3, 7, 13 and NO in cartilage in experimental group was lower than that of control group (P < 0.01) while collagen type II and proteoglycan was higher than that of control group (P < 0.01).</p><p><b>CONCLUSION</b>Low-intensity pulsed ultrasound can repair the damaged cartilage by reducing the expression of MMP-3, 7, 13, inhibiting the secretion of NO and promoting the synthesis of collagen type II and proteoglycan in cartilage.</p>

Small needle-knife for the treatment of tennis elbow according to its classification / 中国骨伤

<p><b>OBJECTIVE</b>To observe clinical effect of different treatments for tennis elbow with small needle-knife according to its classification.</p><p><b>METHODS</b>From March 2011 to December 2012,100 patients with 123 tennis elbows were treated with small needle-knife, including 36 males and 64 females, ranging in age from 29 to 76 years old (averaged, 49 years old). The course of disease ranged from 3 months to 2 years (averaged, 7.2 months). According to the classification, 46 elbows were with extra-articular type, 34 elbows with intra-articular type, 20 elbows with mixed type. All the patients were treated with small needle-knife by using different methods according to its classification.</p><p><b>RESULTS</b>All patients were followed up for 6 to 12 months with an average of 8.2 months. After treatment, the symptoms and signs of the patients improved significantly (P < 0.01). According to the criteria of the Verhaar scoring system, 35 of 46 patients with extra-articular type got an excellent result, 9 good, 2 fair; 24 of 34 patients with intra-articular type got an excellent result, 9 good, 1 fair; 9 of 20 patients with mixed type got an excellent result, 8 good, 3 fair.</p><p><b>CONCLUSION</b>The causes of tennis elbow can not be explained by single pathogenesy, the patients with tennis elbow should be treated with different methods according to its classification, and the therapeutic effects can be improved.</p>

Effect of HSP70 on apoptotic of cartilage cells in knee osteoarthritis / 中国骨伤

<p><b>OBJECTIVE</b>To investigate the expression and relationship between HSP70 and caspase-3 in knee osteoarthritis.</p><p><b>METHODS</b>Forty adult SD rats were divided into experimental group and control group. Thirty rats in experimental group, anterior cruciate ligament transaction (ACLT) was cut off and partial meniscectomy of 1/3 inside incision were performed to reproduce knee osteoarthritis (KOA) model according to Hulth methos, and the other 10 rats was treated with nothing as control group. The rats were sent to the cage and free to move. At 1, 2 and 4 weeks later, the arthritis cartilage of femoral and tibial end were observed through immunohistochemistry staining and light microscope. Meanwhile, Mankin scale system was adopted for histomorphology evaluation.</p><p><b>RESULTS</b>Changes of KOA such as hyperplastic synovium,erosion on the surface of cartilage and so on were found in experiment group, the expression of HSP70 was augmentation all the time, but the expression of caspase-3 was reduction 1 week later; no similar changes were found in control group. Mankin scale system showed that there were significant differences in the first week as compared with the second week and 4th week (both P < 0.01).</p><p><b>CONCLUSION</b>Heat shock protein inhibit the apoptosis of cartilage cells and protect the cartilage cells in knee osteoarthritis, the conservative treatment for clinical provide objective scientific basis.</p>

Etiology and risk factors of infantile wheezing / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the etiology and risk factors of infantile wheezing.</p><p><b>METHODS</b>The clinical data of 180 infants with wheezing were retrospectively studied. The risk factors for wheezing attacks were investigated by logistic regression analysis.</p><p><b>RESULTS</b>Viral infection (33.3%) was the most common cause for wheezing attacks, followed by asthma (19.4%), parental smoking and special environments (15.6%), gastroesophageal reflux disease (12.8%), premature delivery (7.8%), Mycoplasma infection (6.7%), and bronchopulmonary dysplasia (4.4%). The multivariate logistic regression analysis showed 7 factors that significantly correlated with wheezing attacks: allergic history of parents, sensitization to alimentary or inspiratory allergens, viral or Mycoplasma infection, premature delivery and special environments.</p><p><b>CONCLUSIONS</b>The commonest cause of infantile wheezing is viral infection, followed by asthma. Genetic factors, individual atopic constitution and environmental factors play important roles in wheezing attacks.</p>