Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Qishen Granules Modulate Metabolism Flexibility Against Myocardial Infarction via HIF-1 α-Dependent Mechanisms in Rats.

OBJECTIVE: To assess the cardioprotective effect and impact of Qishen Granules (QSG) on different ischemic areas of the myocardium in heart failure (HF) rats by evaluating its metabolic pattern, substrate utilization, and mechanistic modulation. METHODS: In vivo, echocardiography and histology were used to assess rat cardiac function; positron emission tomography was performed to assess the abundance of glucose metabolism in the ischemic border and remote areas of the heart; fatty acid metabolism and ATP production levels were assessed by hematologic and biochemical analyses. The above experiments evaluated the cardioprotective effect of QSG on left anterior descending ligation-induced HF in rats and the mode of energy metabolism modulation. In vitro, a hypoxia-induced H9C2 model was established, mitochondrial damage was evaluated by flow cytometry, and nuclear translocation of hypoxia-inducible factor-1 α (HIF-1 α) was observed by immunofluorescence to assess the mechanism of energy metabolism regulation by QSG in hypoxic and normoxia conditions. RESULTS: QSG regulated the pattern of glucose and fatty acid metabolism in the border and remote areas of the heart via the HIF-1 α pathway, and improved cardiac function in HF rats. Specifically, QSG promoted HIF-1 α expression and entry into the nucleus at high levels of hypoxia (P<0.05), thereby promoting increased compensatory glucose metabolism; while reducing nuclear accumulation of HIF-1 α at relatively low levels of hypoxia (P<0.05), promoting the increased lipid metabolism. CONCLUSIONS: QSG regulates the protein stability of HIF-1 α, thereby coordinating energy supply balance between the ischemic border and remote areas of the myocardium. This alleviates the energy metabolism disorder caused by ischemic injury.

Development of an intensive simulating training program in emergency medicine for medical students in China.

BACKGROUND: A national standardized emergency medicine (EM) curriculum for medical students, including specific competencies in procedural skills, are absent in many countries. The development of an intensive simulating training program in EM, based on a tight schedule, is anticipated to enhance the competency of medical students. METHODS: A 3-day intensive EM training program, consisting of four procedural skills and 8-hour case-based learning (CBL), was developed by experienced physicians from the EM department in Peking Union Medical College Hospital (PUMCH). Medical students from Peking Union Medical College (PUMC) and Tsinghua University (THU) participated in the training. Three written tests were cautiously designed to examine the short-term (immediately after the program) and long-term (6 months after the program) efficacy of the training. After completion of the training program, an online personal appraisal questionnaire was distributed to the students on WeChat (a mobile messaging App commonly used in China) to achieve anonymous self-evaluation. RESULTS: Ninety-seven out of 101 students completed the intensive training and took all required tests. There was a significant increase in the average score after the intensive simulating training program (pre-training 13.84 vs. 15.57 post-training, P<0.001). Compared with the pre-training test, 63 (64.9%) students made progress. There was no significant difference in scores between the tests taken immediately after the program and 6 months later (15.57±2.22 vs. 15.38±2.37, P=0.157). Students rated a higher score in all diseases and procedural skills, and felt that their learning was fruitful. CONCLUSIONS: The introduction of a standardized intensive training program in EM focusing on key competencies can improve clinical confidence, knowledge, and skills of medical students toward the specialty. In addition, having such a program can also enhance student's interest in EM as a career choice which may enhance recruitment into the specialty and workplace planning.

[Study on osteogenic ability of chitosan/beta-tricalcium phosphate scaffold combined with human bone morphogenetic protein].

OBJECTIVE: Using chitosan (CS)/beta-tricalcium phosphate (TCP)/recombinant human bone morphogenetic protein (rhBMP)-2 for the reconstruction of rabbits' mandible defect, to prove the feasibility of CS/beta-TCP as an injectable bone tissue engineering scaffold material. METHODS: Twenty-four New Zealand white rabbits were randomized into 4 groups on average: Experimental group 1 embedding CS/beta-TCP/rhBMP-2, experimental group 2 embedding CS/ beta-TCP, control group 1 embedding autograft bone group, control group 2 embedding nothing. At 2, 4 and 8 weeks after surgery, all rabbits were executed group by group. The new bone growth situations were observed with hematoxylin-eosin staining and immunofluorescence microscopy, the bone mineral density was detected by bone sonometers. RESULTS: After 2, 4, 8 weeks, there was significant difference among the areas of bone regeneration of all groups. The effect of experimental group 1 was better than experimental group 2. There was significant difference at different times, the areas of bone regeneration was gradually increased with time. The area of stained yellow in experimental group 1 was larger, the area of stained red was smaller. The quantities of bone density in experimental group 1 at every time after surgery were significantly higher than experimental group 1 and control group 2, but had no statistical significance with control group 1. CONCLUSION: CS/beta-TCP/rhBMP-2 has good biocompatibility, degradability and the capacity of guided and inducing osteogenesis. CS/beta-TCP as a good injection of carrier could become a promising carrier for rhBMP-2 and potential new degradable biological material for repairing bone defect in clinical application.

[Pulsed Nd:YAG laser-aided debonding for removing the metal brackets].

OBJECTIVE: To explore the possibility of pulsed Nd:YAG laser-aided debonding for removing orthodontic metal brackets and to compare the method with the conventional mechanical debonding method. METHODS: Fifty healthy premolars extracted for orthodontic purpose were randomly divided into five groups (10 teeth in each group). There were four experimental groups and one control group. Every tooth was bonded with bracket. Laser was used to irradiate the teeth in experimental groups with different electric currents (13.0, 13.5, 14.0, 14.5 A). During the irradiation, the brackets received 4.9 N of force until the brackets off. The time needed for debonding and the temperature change of the pulp cavity were recorded. The teeth in control group were debonded using mechanical method. The adhesive remnant index (ARI) was calculated using stereomicroscope and imagetool software. All samples were examined with a scanning electron microscope. RESULTS: The time taken between the four groups were (67.70 ± 7.18), (35.90 ± 4.28), (24.90 ± 3.76), (6.90 ± 2.33) s, highly statistical difference was found in the time needed for debonding (P < 0.01). The temperature in the pulp cavity among the four groups were (20.97 ± 3.10), (12.75 ± 3.14), (8.99 ± 2.47), (2.91 ± 1.88)°C, and statistical differences were found in temperature change of the pulp cavity (P < 0.05). ARI of three experimental groups and the control group were (8.55 ± 5.02)%, (15.42 ± 7.37)%, (5.55 ± 3.79)%, (13.72 ± 6.69)%, and (74.36 ± 29.44)%. The enamel surface of the control group was coarse with deep scratchs. The enamel surface was smooth and clean in the experimental groups. CONCLUSIONS: Pulsed Nd:YAG laser-aided debonding for removing metal brackets was feasible. Laser-aided debonding was better than conventional mechanical debonding method. The method reduced the damage to the enamel surface.