ABSTRACT
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.
ABSTRACT
Pulmonary embolism is the cardiovascular disease caused by endogenous or exogenous emboli blocking the pulmonary artery system. Pulmonary embolism is clinically very common and has a high recurrence rate. Its etiology is complicated. Pulmonary embolism recurrence can be caused by many factors, which affect its prognosis. Complicated diseases, residual thrombosis, anticoagulation therapy and respiratory disorders are the main factors that lead to pulmonary embolism recurrence. Some blood test indicators can also reflect the recurrence of pulmonary embolism. This paper reviews the risk factors and prevention strategies of pulmonary embolism recurrence, with the purpose of reducing recurrence rate, improving prognosis and thereby providing objective evidence for clinical practice.
ABSTRACT
Abdominal pain is a prominent syndrome in patients with irritable bowel syndrome (IBS), which greatly affects the quality of life of patients. Due to the complexity of etiology and great individual variation, abdominal pain treatment in IBS patients is still a clinical difficulty. The treatment of IBS pain includes non ‑ drug therapy (lifestyle intervention such as diet and exercise, gut microbiota modulation), drug therapy (antispasmodics, peppermint oil, antidepressants, non ‑ absorbed antibiotic) and psychological behavior intervention. This article reviewed the status and progress of pain treatment in IBS, so as to provide evidences for clinicians.
ABSTRACT
Objective:To analyze the results of external quality assessment (EQA) of different levels laboratories of iodine deficiency disorders (IDD) in Inner Mongolia in 2018, and to understand the detection ability of these laboratories.Methods:In 2018, the Inner Mongolia region level laboratories and all 12 league and municipal level laboratories were assessed for salt iodine, urinary iodine and water iodine (74 banner, county and district level laboratories participated in the urinary iodine assessment, and 100 banner, county and district level laboratories participated in the salt iodine assessment). As 3+-Ce 4+ catalytic spectrophotometry (WS/T 107.1-2006) was used to measure the iodine in urine, direct titrimetric method (GB/T 13025.7.1-2012) was used to measure the salt iodine, and water iodine was determined based on "Determination of Iodine in Drinking Water by As 3+-Ce 4+ Catalytic Spectrophotometry" in the range of 0 - 100 μg/L. The examination results of EQA of different levels of IDD laboratories in Inner Mongolia were statistically analyzed. Results:Regional level leboratory passed all the 3 assessments, qualified rates of salt iodine, urinary iodine and water iodine were 83.3% (10/12), 91.7% (11/12), and 100.0% (12/12), respectively, at league and municipal level; qualified rates of salt iodine and urinary iodine were 95.0% (95/100), and 90.5% (67/74), respectively, at banner, county and district level in 2018.Conclusions:The detection ability of IDD laboratories at all levels in the whole region has been stabilized, but there are still fluctuations in some laboratories. It is suggested that the technical and responsibility training, instrument verification, experimental environment control and quality control of laboratories at all levels should be continued.
ABSTRACT
<p><b>OBJECTIVE</b>To explore the formation of pre-metastatic niche in the mouse lung and to study the underlying molecular mechanisms whereby primary breast carcinoma-derived factors mediate recruitment of bone marrow-derived cells (BMDCs) and affect the formation of pre-metastatic lung environment before the arrival of tumor cells.</p><p><b>METHODS</b>Mammary carcinoma 4T1 cells were inoculated into the mammary gland to construct mouse model of breast cancer. Confocal microscopy was used to detect the recruitment of BMDCs in the pre-metastatic lungs. The expression of factors in the mouse sera and 4T1 cell culture media was assayed using RayBio Custom mouse cytokine antibody array kit. The mice were injected daily with recombinant VEGF for 7 consecutive days to observe the effect of VEGF on BMDCs recruitment in the mouse lung.</p><p><b>RESULTS</b>No BMDCs were observed in the lungs of control and 4T1-tumor-bearing mice on day 0. On day 7 and 14, clusters of BMDCs observed in the lungs of 4T1-tumor-bearing mice were 8.7±2.2/objective field and 48.8±3.2/objective field, respectively, significantly higher than those in the control mice (1.1±0.8/objective field and 3.1±1.7/objective field) (P<0.05 for both). Confocal microscopic observation found that metastatic breast cancer cells preferentially facilitate BMDCs recruitment sites in the pre-metastatic mouse lungs. The levels of VEGF, GM-CSF, and IL-6 in the serum of 4T1-tumor-bearing mice were significantly increased compared with those in the control group (P<0.05 for all). However, VEGF was detected only in the culture media of 4T1 cells. The amount of BMDCs in the mouse lung tissue was (22.8±3.6)/objective field in the VEGF group and (3.1±0.4)/objective field in the control group (P<0.05). There were 36.8±5.4 metastatic foci in the lung tissue of VEGF group and 12.6±2.2 in the control group (P<0.05).</p><p><b>CONCLUSIONS</b>The results of this study demonstrate that primary breast cancer cells can alter the lung microenvironment during the pre-metastatic phase and induce the formation of pre-metastatic niche. Primary tumor cell-derived VEGF may be a crucial factor responsible for the formation of pre-metastatic niche.</p>