Inhibition of the transcription factor ZNF281 by SUFU to suppress tumor cell migration.

Although the Hedgehog (Hh) pathway plays an evolutionarily conserved role from Drosophila to mammals, some divergences also exist. Loss of Sufu, an important component of the Hh pathway, does not lead to an obvious developmental defect in Drosophila. However, in mammals, loss of SUFU results in serious disorder, even various cancers. This divergence suggests that SUFU plays additional roles in mammalian cells, besides regulating the Hh pathway. Here, we identify that the transcription factor ZNF281 is a novel binding partner of SUFU. Intriguingly, the Drosophila genome does not encode any homologs of ZNF281. SUFU is able to suppress ZNF281-induced tumor cell migration and DNA damage repair by inhibiting ZNF281 activity. Mechanistically, SUFU binds ZNF281 to mask the nuclear localization signal of ZNF281, culminating in ZNF281 cytoplasmic retention. In addition, SUFU also hampers the interactions between ZNF281 and promoters of target genes. Finally, we show that SUFU is able to inhibit ZNF281-induced tumor cell migration using an in vivo model. Taken together, these results uncover a Hh-independent mechanism of SUFU exerting the anti-tumor role, in which SUFU suppresses tumor cell migration through antagonizing ZNF281. Therefore, this study provides a possible explanation for the functional divergence of SUFU in mammals and Drosophila.

Study on the protective effect of OM-MSCs on Golgi apparatus after intracerebral hemorrhage in Sprague-Dawley rats.

INTRODUCTION: The present study aimed to assess alterations in apoptosis rate, Golgi morphology and GOLPH3 expression following intracerebral hemorrhage (ICH) both before and after intervention with OM-MSCs. The objective was to investigate the impact of ICH on Golgi apparatus (GA) stress and to explore the potential protective effects of OM-MSCs on GA following ICH. MATERIAL AND METHODS: A total of 54 Sprague-Dawley rats were allocated into three experimental groups: sham operation group, ICH group and OM-MSCs group. ICH models were established by collagenase method while OM-MSCs were cultured in vitro. In OM-MSCs intervention group, one million OM-MSCs were stereotactically injected into unilateral striatum of rats 48 hours after ICH modeling while other two groups received an equivalent volume of PBS. Brain tissues were collected at 1 day, 3 day and 7 day post intervention and subsequently assessed for cellular apoptosis, morphological change of GA and expression of GOLPH3. The obtained data were subjected to statistical analysis by SPSS 21.0. RESULTS: 1. Apoptosis rate in the 1 d and 3 d ICH groups was significantly higher compared to sham operation group (P < 0.05), but significantly lower compared to OM-MSCs intervention group (P < 0.05). 2. While no noticeable morphological changes were observed in sham operation group, GA in ICH group exhibited a significant increase fragmentation. After OM-MSCs intervention, the fragmentation of GA decreased significantly. 3. On 3 d, expression of GOLPH3 in ICH group was significantly higher than that in sham operation group (P < 0.05) but significantly lower than that of OM-MSCs intervention group (P < 0.05). CONCLUSIONS: The rate of apoptosis, fragmentation of GA, and expression of GOLPH3 exhibited significant increases following ICH in SD rats. Conversely, all of these factors demonstrated significant decreases subsequent to early intervention with OM-MSCs, thereby exerting neuroprotective effects.

Usp8 promotes tumor cell migration through activating the JNK pathway.

Tumor metastasis is the most cause of high mortality for cancer patients. Identification of novel factors that modulate tumor cell migration is of great significance for therapeutic strategies. Here, we find that the ubiquitin-specific protease 8 (Usp8) promotes tumor cell migration through activating the c-Jun N-terminal kinase (JNK) pathway. Genetic epistasis analyses uncover Usp8 acts upstream of Tak1 to control the JNK pathway. Consistently, biochemical results reveal that Usp8 binds Tak1 to remove ubiquitin modification from Tak1, leading to its stabilization. In addition, human USP8 also triggers tumor cell migration and activates the JNK pathway. Finally, we show that knockdown of USP8 in human breast cancer cells suppresses cell migration. Taken together, our findings demonstrate that a conserved Usp8-Tak1-JNK axis promotes tumor cell migration, and providing USP8 as a potential therapeutic target for cancer treatment.

Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China.

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

Anxiety Status and Influencing Factors of Rural Residents in Hunan During the Coronavirus Disease 2019 Epidemic: A Web-Based Cross-Sectional Survey.

Objective: To explore the status quo of anxiety and its influencing factors among rural residents in Hunan Province during the coronavirus disease 2019 epidemic, and to provide an effective basis for prevention of and intervention for anxiety symptoms among rural residents. Methods: Convenience sampling was used. An online questionnaire was distributed to Hunan rural residents through the questionnaire star platform from February 26-29, 2020. The general data and anxiety of Hunan rural residents were investigated, and the data were analyzed using SPSS 18.0. Results: The mean Self-Rating Anxiety Scale score of 179 rural residents in Hunan was 40.93 ± 9.36. Based on the cutoff criteria, 32 residents had anxiety, including 26 with mild anxiety, five with moderate anxiety, and one with severe anxiety. The detection rate of anxiety was 17.88%. Self-rated health status, level of concern about the epidemic, and self-rated impact of the epidemic on one's life were the factors influencing the anxiety score of rural residents in Hunan (P < 0.05). Conclusion: During the coronavirus disease 2019 epidemic, the detection rate of anxiety in rural residents in Hunan was higher than that of the general population in China. The relevant departments should pay attention to the mental health of rural residents and implement targeted mental health prevention and intervention measures during the epidemic situation.

From Best Evidence to Best Practice: Enteral Nutrition from Continuous Nasal Feeding in Stroke Patients.

BACKGROUND: Best evidence regarding enteral nutrition from continuous nasal feeding in stroke patients is limited. The aim of this study was to explore the best evidence of continuous nasal feeding in stroke patients and translate the evidence into clinical practice. METHODS: This study utilized the standard procedures of the Joanna Briggs Institute (JBI) evidence-based nursing centers' clinical evidence-practice application system. The baseline assessment of stroke patients in the neurology ward was conducted. A pre- and post-implementation audit approach was used in this study and adopted the Getting Research into Practice program. We analyzed the compliance of nurses with best practice and its impact on patients' gastrointestinal function and complications, aspiration, aspiration pneumonia, nurses' daily workload of nasal feeding, and the length of hospitalization before and after implementing the evidence-based strategies. RESULTS: After application of the evidence-based strategies, nurses' compliance with best practice was improved. The incidence of patients' gastrointestinal complications including vomit (χ2 = 5.195, P=0.023), palirrhea (χ2 = 4.216, P=0.039), diarrhea (χ2 = 4.514, P=0.042), constipation (χ2 = 5.535, P=0.035) and gastric retention (χ2 = 4.541, P=0.042) decreased significantly after the application of the best evidence. The working time of nurses undergoing nasal feeding decreased from 23.71 ±3.22 min to 7.73 ±1.14 min (P =0.000) and the length of patient's hospitalization decreased from 35.63 ±4.45 days to 35.00 ±3.70 days (P=0.534). The rate of aspiration, aspiration pneumonia did not show a significant difference after implementation of the evidence-based strategies. CONCLUSION: The results revealed that the evidence-based practice of continuous nasal feeding in stroke patients is an effective method to improve nursing quality and reduce gastrointestinal complications, which was worthy of clinical application.