In vivo study of the effect of anlotinib on the stemness of the lenvatinib-resistant hepatocellular carcinoma cells and the underlying mechanisms

Background:In vivo experiments were conducted to examine the effects of the targeted drug anlotinib on the stemness of hepatocellular carcinoma(HCC)cells and lenvatinib-resistant liver cancer cells and to explore the underlying molecular mechanisms.Methods:A subcutaneous xenograft model of Hep3B-derived HCC was established in nude mice,which were randomly divided into 2 groups(n=5 males per group):(1)intragastric administration of anlotinib(0.4 mg/kg)and(2)intragastric administration of normal saline.We constructed lenvatinib-resistant cell lines and randomly divided the mice into 3 groups(n=5 males per group):(1)intragastric administration of anlotinib,(2)intragastric administration of lenvatinib,and(3)intragastric administration of normal saline.After 2 weeks of treatment,tumor tissues were harvested,and mRNA and proteins were isolated from the tissues.Changes in the expression of cancer stemness markers(epithelial cell adhesion molecule[EpCAM],CD13,CD90,aldehyde dehydrogenase 1[ALDH1],CD44,and CD45),totipotency factors(sex-determining region Y-box 2[Sox2],Nanog,octamer-binding transcription factor 4[Oct4]),and genes related to the Notch signaling pathway were examined.Results:Compared with that in the control group,tumor size and weight were reduced in nude mice treated with anlotinib.These differences were statistically significant in both the types of nude mice.Anlotinib affected stemness markers and totipotency factors by downregulating the expression of CD133,CD90,and G-protein–coupled receptor 5(LGR5)and upregulating the expression of intercellular adhesion molecule 1(ICAM-1)and Sox2.In addition,lenvatinib-resistant cell lines increased Notch signaling pathway,whereas anlotinib inhibited Notch signaling pathway.Conclusions:The antitumor effect of anlotinib on HCC and lenvatinib-resistant HCC cellsmay occur through inhibition of the Notch signaling pathway.Anlotinib may be the drug of choice for sequential therapy in lenvatinib-resistant liver cancer.

Al−Mg−Mn−Er合金双面搅拌摩擦焊接头局部显微组织和强化机制

通过研究Al−Mg−Mn−Er合金双面搅拌摩擦焊接头的局部显微组织和强化机制揭示其软化机制。结果显示:焊核区形成细小等轴晶组织(5.61μm),而热机械影响区(45.32μm)和热影响区(100.73μm)仍为纤维状组织。从基体到焊核区,小角度晶界分数从75.6%降低到15.6%。退火效应导致位错密度从母材的1.8×10^(14)m^(−2)减小到焊核区的4.5×10^(12)m^(−2)。焊核区、热机械影响区和热影响区Al_(3)(Er,Zr)析出相的平均尺寸和体积分数与基体的(13.7 nm,0.13%)均接近。焊核区和热机械影响区的屈服强度最低,约为201 MPa;基体的屈服强度最高,约为295 MPa。位错强化和亚结构强化的损失是从基体到焊核区屈服强度降低的主要原因。

Venous thromboembolism in patients with liver cancer:a retrospective study

Background:Little is known about the association between venous thromboembolism(VTE)and tumors.In this study,we identified the clinical features of patients with liver cancer who presented with at least 1 VTE episode.Methods:This was a retrospective case-control study of a single-institution database with univariate and multivariate analyses usingχ^(2)and Fisher exact tests.Statistical significance was set at P<0.05.Results:The overall incidence of VTE in the patients with liver cancer was 1.2%.More than half(53.8%)of the 13 patients with liver cancer and venous thrombosis died within 2 months.The thrombus in 12 patients(92.3%)was located within the deep veins,whereas the other patient(7.7%)was diagnosed with a pulmonary embolism.Of the 11 patients,9(69.2%)had swelling and/or pain symptoms.All 6 patients with peripherally inserted central catheters(PICCs)had thrombosis,accounting for 46.2%of all patients with liver cancer and venous thrombosis.Compared with the controls,liver cancer patients with PICC tubes,thrombosis-related symptoms such as swelling and pain,traumatic stimulation such as fracture,acute respiratory distress syndrome,and interventional therapy or hemostasis drugs were prone to be diagnosed with VTE(P<0.05).Conclusions:Liver cancer and thrombosis are rare and have poor prognoses.Liver cancer with thrombosis may be associated with PICC catheterization,traumatic stimulation,or hemostatic drugs.Patients with liver cancer and thrombosis often present with swelling and pain.

p28^GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity

It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma （HCC）, plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum （ER） stress. During ER stress, p28GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell＇s ability to cope with the stress conditions. Furthermore, p28GANK upregulates glucose-regulated protein 78 （GRP78）, a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B （NF-κB） activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28GANK has potential implications for HCC progression under the ER stress conditions.

Short-term Outcomes of Laparoscopic vs.Open Hepatectomy for Primary Hepatocellular Carcinoma:A Prospective Comparative Study

Laparoscopic hepatectomy(LH)is a newly developed technique associated with advantages as open surgery,but the study on outcome of liver function recovery was scarce.This preliminary report was aimed to comparatively assess the short?term outcomes between LH and open hepatectomy(OH)for primary hepatocellular carcinoma(PHC).This study retrospectively analyzed the demographic data and short-term outcomes of 81 patients who underwent LH or OH for the primary treatment of PHC between Oct.2017 and May 2018 at Union Hospital,Tongji Medical College,Huazhong University of Science and Technology(China).A total of 81 PHC patients who received major liver resection were enrolled.There were 38(47%)patients in the LH group and 43(53%)patients in the OH group.The operative time was significantly longer(373.53±173.38 vs.225.43±55.08,P<0.01),and hospital stay(17.34±5.93 vs.21.70±6.89,P=0.003),exhaust time(2.32±0.62 vs.3.07±0.59,P<0.01)and defecation time(2.92±0.78 vs.3.63±0.58,P<0.01)were significantly shorter in LH group than in OH group.The recovery of liver function was significantly faster in LH group,including higher serum albumin(P=0.002),higher ratio of albumin/globulin(P=0.029)and lower direct bilirubin(P=0.001)than in OH group.It is suggested that LH can serve as a fast recovery and cheap surgical procedure in the treatment of PHC,which is safe and feasible.

COVID-19 infection with keratitis as the first clinical manifestation

·AIM:To report a case which keratitis is the first clinical manifestation of COVID-19 that occurred 3 d earlier than the common COVID-19 symptoms.·METHODS:Regular slit lamp examination,corneal scraping test,and chest computed tomography(CT)were performed for patients with COVID-19 infection.The ophthalmologic treatment included ganciclovir eye drop(50 mglmL,6 times/d).The treatment for diarrhea included Guifu Lizhong pills(TID).The antiviral therapy consisted of oseltamivir(75 mg capsule Q12 H);therapy preventing bacterial infection consisted of azithromycin(250 mg tablet QD)and moxifloxacin(0.4 g tablet Q12 H);and therapy for cough relief and fever prevention consisted of Chinese herbal decoction.·RESULTS:A 35-year-old male suddenly suffered pain,photophobia,and tears in his right eye for one day without systemic COVID-19 symptoms.Patient was diagnosed with keratitis,which was seemingly different from common keratitis.Ganciclovir eye drop was initiated.The corneal scraping test for COVID-19 was positive.The chest CT images were abnormal confirming the diagnosis of COVID-19 infection.The antiviral and antibacterial therapies were initiated.Chinese herbal therapy was used for cough relief and fever prevention.After roughly two weeks,patient recovered from COVID-19.·CONCLUSION:A new type of keratitis,atypical keratitis,is a clinical manifestation of COVID-19,and this clinical manifestation could appear 3 d earlier than fever and cough.The earlier a COVID-19 clinical manifestation is identified,the earlier can a patient be directed to stay at home,and significantly fewer people would be infected.

Analysis of floor failure depth by using electric profiling method in longwall gangue backfill mining

In underground mining, floor failure depth accompanying mining phases usually results from changes in the advance abutment pressure in the coal mass, and changes in stress redistribution in the areas that have already been mined. Although a variety of techniques have been applied to determine the failure depth, and a number of studies have provided the evidence for the decreasing of failure depth under backfilling, these methods and interactions have not been unequivocally identified. Based on the premise of one possible relation between the failure depth and filling body, which is that the filling materials （gangue） in the gob area can not only restrain the movement of the overlying strata effectively, but also can help to decrease failure depth of the floor in the coal mine. The failure depth in a specific longwall gangue backfilling mine was measured using the mine electricity profiling method. These electrode cables are arranged in a crossheading order to measure the depth and position of the destroyed floor using the DC method. After this, several different methods were used to interpret the recorded data from the field study for gaining failure depth, and the results were compared to the theoretical calculation values. And finally, the authors analyzed the reasons for failure depth form values recorded not indicating a large decrease trend when compared to the theoretical calculation. In this area, it is found that： ① The results using the mine electricity profiling method turns out to be robust and can be used in predicting floor failure depth, and the horizontal position of the maximum destroyed in working face of longwall backfilling. The maximum destroyed position and failure space of the floor can be identified by using this method. ②There is a time-delay processing between the advance of the working face and the failure of floor strata in the mining processing. ③Additionally, based on the data collected from field measurements, which includes three different test electrode spacing approaches （single, double and triple electrode spacing）, and the theoretical value from theoretical calculations. The premise mentioned above cannot be supported during the specific field test, and the role of the filling body in the mined area cannot decrease the floor failure depth effectively in comparison to the theory predictions. Basically, the failure depths in the two different methods have similar results and it is possible that there will not be a direct correlation between the filling body and failure depth. ④Although the failure depth cannot decrease effectiveness when using gangue backfilling in the field testing, due to gob gangue, filling materials being able to deliver the abutment pressure from the overburden in most cases, once they were compacted and rammed by the overburden pressure, it still can make the fracture of the gob area clog and be further consolidated. In this way, it is assumed that water-bursting accidents can be prevented effectively under backfill mining. For this reason, gangue backfilling may make a significant contribution to safety mining.

Effect of Xiaoaiping on the expression of circadian clock genes in human hepatoma HepG2 cells

Objective： Investigation of the effect of Xiaoaiping on the expression of circadian clock genes in human hepatoma HepG2 cells. Methods： Selecting the HepG2 cells in the logarithmic growth phase and assigning them to Xiaoaiping injection （XAP） group and control group. The two groups were treated with 75 mg/mL XAP or the same dose of normal saline. After 72 h of treatment, real-time PCR was used to detect the expression of circadian clock genes in HepG2 cells and Western Blot technology was used to detect the expression of related proteins. Results： The mRNA expression levels of PER1, NPAS2, NR1D1, and DEC1 in the XAP group was significantly higher than that in the control group （P〈 0.05）, while the mRNA expression levels of PER3, BMAL1, DEC2, and RORA were significantly lower in the XAP group than in the control group （P 〈 0.05）, and there was no significant difference between the mRNA expression levels of PER2, CRY1, CRY2, and TIM. Of course, the proteins＇ expression levels of the genes we had detected such as PERle3, CRYI-2, CLOCK, BMAL1 by Western Blot were consistent with the real-time PCR results above. Conclusion： XAP affects the expression of circadian clock genes in HepG2 cells.

Processing maps and microstructural evolution of Al-Cu-Li alloy during hot deformation

The hot deformation behavior of Al-Cu-Li alloy was investigated by hot compression tests in the temperature range of 340-500℃ with strain rate of 0.001-10.000 s^(-1).Based on the dynamic materials model(DMM),processing maps of the test alloy were developed for optimizing hot processing parameters.The optimum parameters of hot deformation for Al-Cu-Li alloy are at temperature of 400-430℃and strain rate of about 0.100 s^(-1),with efficiency of power dissipation of around 30%.The microstructural manifestation of the alloy deformed in instability domains is flow localization,and dynamic softening first occurs in flow localizations structure.In stable domains,dynamic recovery(DRV) and dynamic recrystallization(DRX) are the main microstructural evolution mechanism.DRX is gradually strengthened with the increase in deformation temperature and the decrease in strain rate.During hot deformation,the DRX mechanism of Al-Cu-Li alloy is dominated by continuous DRX(CDRX).A DRX model of Al-Cu-Li alloy is proposed based on the microstructural evolution process of the test alloy.