Zoledronic acid induces ferroptosis by upregulating POR in osteosarcoma.

Osteosarcoma, usually originating in the stroma, is the most common primary bone cancer in adolescents, and its prognosis is poor. Surgery, adjuvant and neoadjuvant chemotherapy and radiation therapy are not satisfactory at the present time. Therefore, it is critical to develop novel therapeutic strategies to improve the quality of life and long-term survival rate of osteosarcoma patients. In this study, we discovered that zoledronic acid (ZOL) dramatically increased cell death in osteosarcoma cells, and this cytotoxicity was greatly reversed by liproxstatin-1 (a ferroptosis inhibitor). ZOL also had an obvious effect on lipid peroxidation and reactive oxygen species (ROS), which suggested that ZOL most certainly induces ferroptosis in osteosarcoma cells. In addition, we further found that ZOL increases cytochrome P450 oxidoreductase (POR) expression dose dependently in osteosarcoma cell lines. Knockdown of POR attenuated ZOL-induced cytotoxicity and attenuated the effect of ferroptosis in osteosarcoma cells, which indicated that POR plays an important role in ferroptosis. Moreover, we also found that ZOL inhibits osteosarcoma growth in vivo. Our findings suggest that ZOL induces ferroptosis by upregulating POR expression to increase ROS levels and upregulate lipid peroxidation levels in osteosarcoma cells. POR may be used as a therapeutic target to inhibit osteosarcoma.

Interleukin-23 mediates the reduction of GADD45a expression to attenuate oxidative stress-induced cellular senescence in human fibroblasts.

The interleukin-23 (IL-23) plays a key role in various inflammatory diseases, such as spondyloarthritis, by acting on target cells through the IL-23/IL-17 pathway. Recent studies have suggested that IL-23 can also directly affect fibroblasts. Senescent fibroblasts are implicated in many physiological and pathological processes, including those related to inflammatory diseases. However, it remains unclear whether IL-23 can influence fibroblast senescence and contribute to pathogenesis. In our study, we investigated the effects of IL-23 on oxidative stress-induced senescence in human fibroblasts, using the H2O2-induced senescence model, and found that IL-23 pre-treatment significantly attenuated senescence in these cells. RNA-seq and in vitro experiments indicate that IL-23 may act by regulating GADD45a expression and the p38/MAPK pathway. Furthermore, we confirmed that IL-23 inhibits oxidative stress-induced up-regulation of GADD45a expression and subsequent activation of the p38/MAPK pathway through GADD45a knockdown and overexpression experiments. Our study is the first to demonstrate that IL-23 can effectively suppress the senescence of fibroblasts induced by oxidative stress, by inhibiting the H2O2-triggered induction of GADD45a and subsequent activation of the p38/MAPK pathway. These findings have significant implications for understanding the role of IL-23 in immune-inflammatory diseases and may provide a new avenue for the diagnosis and treatment of these conditions.

Comparison of clinical efficacy between postoperative simultaneous and sequential integrated boost intensity-modulated radiotherapy for high-grade glioma / 中华放射肿瘤学杂志

Objective:To compare the efficacy and side effects between simultaneous and sequential integrated boost intensity-modulated radiotherapy after operation for high-grade glioma.Methods:We retrospectively analyzed 142 patients with high-grade glioma who underwent postoperative radiotherapy from January 2010 to December 2017. All patients were divided into the simultaneous and sequential integrated boost intensity-modulated radiotherapy groups. Concurrent temozolomide chemotherapy was delivered during radiotherapy in two groups. The follow-up outcomes were statistically compared between two groups.Results:For the whole group, the median overall survival (OS) was 24 months, the median progression-free survival (PFS) was 17 months, and the median disease-free survival (DFS) was 25 months. In the simultaneous and sequential integrated boost intensity-modulated radiotherapy groups, the median OS were 27.2 and 21.0 months ( P=0.950), the median PFS were 21.2 and 15.0 months ( P=0.21), and the median DFS were 28.0 and 18.0 months ( P=0.171), and the disease control rates were 92.86% and 85.17%( P=0.541), respectively. There was no statistical difference in OS, PFS, DFS, short-term efficacy and side effects between two groups. However, the conformity index in the simultaneous integrated boost intensity-modulated radiotherapy group was better than that in the sequential integrated boost intensity-modulated radiotherapy group ( P=0.032). Conclusions:Postoperative simultaneous and sequential integrated boost intensity-modulated radiotherapy yield no statistical differences in the survival, short-term efficacy and side effects in the treatment of high-grade glioma. However, the conformity index in the simultaneous integrated boost intensity-modulated radiotherapy group is significantly better, which can be recommended for postoperative radiotherapy of high-grade glioma.

Application of the preclinical education integrated with clinical medicine in the teaching of clinical anatomy / 中华医学教育探索杂志

This project starts with the teaching of clinical anatomy for eight-year medical students, selects specialists to enter the courses according to the content of clinical anatomy, and explores the deep integration of basic and clinical education. This study used the self-made questionnaire to evaluate the effect of the integrated teaching model, and Likert scale was used to score. Meanwhile, the correlation between the scores of each question and total points was analyzed with the item analysis. Moreover, we assessed the principal components through the exploratory factor analysis. The results showed that more than 95% questioned students thought the preclinical education integrated with clinical medicine teaching model is necessary and practical, which can assist medical students in the anatomical structure learning combined with clinical disease, and meanwhile cultivate students' clinical thinking. Only fewer than 10% thought it can connect the basic knowledge and clinical cases effectively, and over 35% thought there are difficulties. Additionally, more than half students (54%) hold the negative attitude which clinicians can't completely replace basic teachers in teaching. Our finding suggests that the integrated teaching model is attractive and feasible. Nonetheless, clinicians can’t replace preclinical teachers completely in the clinical anatomy education yet.

Silico analysis of interaction between full-length SARS-CoV2 S protein with human Ace2 receptor: Modelling, docking, MD simulation.

Many key residues, which mediate the interaction between SARS-CoV2 spike glycoprotein (S protein) and human ACE2 receptor, have been reviewed using the SARS-CoV2 S spike protein with human ACE2 complex. The initial SARS-CoV2 S protein and ACE2 protein complex structure is formed by RBD structure of SARS-CoV2 S protein and ACE2 protein. However, the cryo-EM structure study targeting SARS-Cov S protein with human ACE2 complex has shown that there exist different binding conformations during the binding process facing ACE2 protein. It suggests the interaction between SARS-CoV2 S spike protein complex might have different binding conformations, which request full-length of SARS-CoV2 S protein complex in the structure-functional analysis. In this study, we built a full-length SARS-CoV2 S protein with human ACE2 complex by computational methods. Residues K31, H34, E35 in ACE2 protein were showed both in our full-length model and RBD structure model, which recognized as critical residues in previous studies. Surprisingly, ACE2 residues E564, R559, N556 were only found participating in the interaction of our full-length model, which suggested the full-length model has bigger binding interface. This finding was further supported by the interaction network of full-length model and RBD model. Meanwhile, the method bias was taken into consideration. Eventually, the MM-PBSA results showed the full-length model had a stronger binding free energy (almost 5-fold) than the RBD structure model of SARS-CoV2 S spike protein complex. In computational level, we present a stronger binding model containing a full-length structure of SARS-CoV2 S protein with ACE2 complex.

Research trends and hot spots in campus bullying using CiteSpace software / 中国学校卫生

Objective@#To explore the hot issues and developing trend of the research of campus bulling,and to provide a reference for the research on campus bullying.@*Methods@#The power of research, high-impact authors, highly cited journals, high-frequency keywords, and burst terms related to school bullying from the Web of Science database were analyzed using CiteSpace software. The data collection time was May 9, 2018.@*Results@#A total of 3 561 literature data were obtained. The results showed that the country with the highest number of publications was the United States; England had the highest centrality and was in a critical position in the research. The University of Turku in Finland was the core research institution. Salmivalli C was the author of the highest publication, Olweus D was the most frequent cited author. The high-impact journal was Aggressive Behavior. In terms of high-frequency keywords, the core vocabulary such as bully, adolescence, and victim were listed. Middle school students were the most frequently studied; in the form of bullying, the frequency of violence, aggression, and cyberbully was more common; depression, mental health and health appeared more frequently in terms of bullying outcomes. Mutant words including school children, bullying, victimization, relational aggression were more common.@*Conclusion@#The research hotspots on campus bullying during the past decade include violence, gender, social support, and mental health. Bullying among college students will be a hot research topic in the future. Continued efforts should be carried out in the field of campus bullying in China.

Effects of short term low dose melatonin and ketamine on depressive behavior and BDNF expression in rats with chronic stress depression / 中华行为医学与脑科学杂志

Objective To evaluate the antidepressant action of melatonin in stress model of depres-sion and the effects of the melatonin on depressive-like behavior.Methods Forty male Wistar rats were ran-domly divided into four groups(n=10):controls group(CON),chronic unpredictable mild stress group (CUS),chronic unpredictable mild stress group + melatonin group(CUS+MT)and chronic unpredictable mild stress group +ketamine group(CUS+KET).The rats in CUS group,CUS+MT group and CUS+KET group were given different stress stimulation for 42 days to establish the chronic mild unpredictable stress ani-mal model.Sucrose preference experiments was used to detect the depression model and the level of depres-sion was tested by forced swim test.The influence of Short-term low doses of melatonin on the level of BDNF and GluR1 in the prefrontal cortex,was detected by immunohistochemistry(IHC)on 58 day after the start of the experiment.Results (1)The CUS showed depressant-like behavior,and the percent sucrose uptake scores and the cumulative immobility time of the CUS group were decreased significantly(P<0.05).(2)After injection melatonin 14 d,the cumulative immobility time of CUS+MT group((60.70±18.56)s)and CUS+KET group((56.43±20.46)s)were decreased significantly in comparison to the CUS group(146.34±34.10) s).It was observed a highly significant(P<0.05)decrease of and up-regulation of the BDNF cells in CUS+MT group((1 328.99±282.46)/mm2)and CUS+KET group((1 224.76±116.53)/mm2)in comparison to the CUS group,the number of BDNF cells in CUS+MT group was increased significantly in comparison to the CUS+KET group;(3)After administration drug 14 days,the number of GluR1 cells of CUS+KET((807.82± 153.25)/mm2)but not CUS+MT((632 ± 156.34)mm2)significantly increased compared with CUS ((807.82±193.25)/mm2).Conclusion The results indicate that the melatonin induce an antidepressant-like action like ketamine.The antidepressant effects of melatonin may be related with the level of BNDF.