Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

Geochronology and geochemistry of the five magmatic rocks in the Ningzhen region,China

The Ningzhen region of China is located in the easternmost part of the middle-lower Yangtze River Cu–Fe polymetallic metallogenic belt. From west to east, it comprises five main intermediate–acidic intrusive complexes: the Qilinmen, Anjishan, Xiashu–Gaozi, Shima, and Jianbi complexes. Geochemical investigations show that these five intrusive complexes exhibit high contents of SiO_2, at 64.74–73.40 wt%, Al_2O_3, at 14.15–17.37 wt%, and K_2O + Na_2O, at 6.49–8.68 wt%. The majority of the samples belong to the high-K calc-alkaline series, with a few samples plotting in the calc-alkaline and tholeiitic series. Trace element analysis shows that the samples are enriched in large ion lithophile elements(LILE) and are depleted in high field strength elements(HFSE).The chondrite-normalized rare earth element(REE) patterns are characterized by right-inclined curves, showing light rare earth element(LREE) enrichment. In addition,the(La/Yb)Nratios are high at 15.02–37.28, with an average of 29.13, and slightly negative or none Eu anomalies are present. In the(La/Yb)N–d Eu diagram, the samples plot within the crust-mantle type field. Laser ablation–inductively coupled plasma–mass spectrometry(LA–ICP–MS) zircon U–Pb dating yielded ages of122.0 ± 1.0 Ma, 106.1 ± 0.8 Ma, 108.7 ± 1.4 Ma,103.5 ± 1.9 Ma, and 96.8 ± 1.7 Ma for the Qilinmen,Anjishan, Xiashu–Gaozi, Shima, and Jianbi complexes,respectively. On the basis of this research and knowledge of several known metal deposits related to these complexes, we suggest that the Mesozoic large-scale diagenesis and metallogenesis in the Ningzhen region may have ceased at 100 Ma or about 95 Ma.

新型高性能柔性紫外图像传感器

柔性电子技术与紫外（UV）传感技术相结合的柔性紫外图像传感器具有体积小、可弯曲甚至折叠等特点，在犯罪调查、漏油检测、火灾监测和电力线检测等领域有着广阔的应用前景。然而，在实际应用中紫外线辐射的信号强度低，因此高性能柔性紫外光电探测器的研制至关重要。

Generating HDR radiance maps from single LDR image

We present a method of generating high dynamic range(HDR)radiance maps from a single low dynamic range(LDR)image and its camera response function(CRF).The method first models and estimates the inverse CRF and then multiplies the inverse CRF by a weighting function to make it smooth near the maximum and minimum pixel values,and finally conducts the smooth inverse CRF on the input LDR image to generate HDR image.In the method,the inverse CRF is estimated using one single LDR image and an empirical model of CRF,based on measured RGB distributions at color edges.Unlike most existing methods,the proposed method expands image from both high and low luminance regions.Thus,the algorithm can avoid the artifacts and detail loss in dark area which results from extending image only from bright region.Extensive experimental results show that the approach induces less contrast distortion and produces high visual quality HDR image.

Bilirubin inhibits lung carcinogenesis by up-regulating cystatin A expression in tumor-infiltrating macrophages

As one of the leading causes of cancer deaths worldwide,the pathogenesis of lung cancer is still not completely understood.Bilirubin,a product of heme metabolism,has long been considered a waste product of the body.Increasing evidence suggests that bilirubin has additional antioxidant,anti-inflammatory,and proteasome inhibitory activities.However,the specific role of bilirubin in the formation and development of lung cancer has not been elucidated.

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification

Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

Change of Disease Spectrum Characteristics of Psychiatric Inpatients Before and After Lockdown Lifted During the COVID-19 Pandemic—Wuhan City,Hubei Province,China,2021

Summary What is already known about this topic?The coronavirus disease 2019(COVID-19)pandemic poses a significant threat to mental health globally and may change the proportion of hospitalized patients.What is added by this report?This report analyzed and compared the disease characteristics of psychiatric inpatients one year before and after Wuhan lifted lockdown during COVID-19.About 50%of the inpatients were diagnosed with bipolar disorder;females and adolescents had a higher prevalence of mental disorders.What are the implications for public health practice?More attention should be paid to the mental health of children,adolescents,and females.

基于RNA-Seq技术分析鼠源宿主防御肽对铜绿假单胞菌成熟生物被膜的清除作用

【目的】利用RNA-Seq技术探究修饰后的鼠源宿主防御肽CRAMP对铜绿假单胞菌PAO1成熟生物被膜的影响。【方法】采用结晶紫法检测生物被膜量,激光共聚焦扫描显微镜(CLSM)观察生物被膜形态学变化;利用Illumina二代高通量测序平台,采用PE150测序策略分析了CRAMP修饰肽干预PAO1生物被膜与对照组在转录水平的基因表达差异;利用1,3-萘二酚方法测定了PAO1生物被膜中藻酸盐含量。【结果】CRAMP修饰肽能显著减少PAO1成熟生物被膜量,并且在0.98-62.50μg/mL范围内呈一定浓度依赖性,CLSM显示CRAMP修饰肽能够显著减少细菌总荧光强度。转录组测序获得了12636700段干净读对,共鉴定出1582个差异基因,发现800个基因表达上调,782个基因表达下调。GO功能富集分析显示,1226个基因比对到GO功能分析数据库,在这些差异表达基因中,与分子功能、生物过程和细胞组成有关。KEGG通路富集分析显示,有603个表达差异显著基因比对到KEGG中的96条代谢途径,其中主要是各类氨基酸代谢途径、脂肪酸代谢途径、三羧酸循环、生物被膜调控系统等。分析发现CRAMP修饰肽可能作用于PAO1 c-di-GMP系统,增强细菌运动性和生物被膜分散,并且与其密度感应(quorum sensing,QS)系统和藻酸盐合成相关。最后经验证,CRAMP修饰肽显著减少了PAO1成熟生物被膜中藻酸盐的含量。【结论】CRAMP修饰肽对PAO1成熟生物被膜具有明显的清除作用,且能导致成熟生物被膜藻酸盐含量下降。通过转录组数据分析,可能是由于CRAMP修饰肽使PAO1 c-di-GMP水平下调导致的,具体机制还有待进一步探究。

Tuning electrospinning hierarchically porous nanowires anode for enhanced bioelectrocatalysis in microbial fuel cells

Pore structure plays critical roles in electrode kinetics but very challenging to tailor porous nanowires with rationally distributed pore sizes in a bioelectrochemical system.Herein a hierarchically porous nanowires-material is delicately tuned for an optimal pore structure by adjusting the weight percentage of SiO_(2)-hard template in an electrospinning precursor solution.The asprepared optimal electrospinning nanowires further used as an anode of microbial fuel cells(MFCs),delivering a maximum output power density of 1,407.42 mW·m^(−2)with 4.24 and 10 times higher than that of the non-porous fiber and carbon cloth anode,respectively.The great enhancement is attributed to the rational pore structure which offers the largest surface area while the rich-mesopores well match with the size of electron mediators for a high density of catalytic centers.This work provides thoughtful insights to design of hierarchical porous electrode for high-performance MFCs and other bioelectrochemical system devices.

Basic reason for the accumulation of charge on the surface of polymer dielectrics

Due to their outstanding electrical insulation performance,low energy loss and high reliability,polymer dielectrics are widely used in flexible electronics,capacitors and large-scale power transmission equipment[1–5].However,polymer dielectrics accumulate large amounts of charge on their surface during use,which causes local electric field distortion and induces flashover,explosion,and equipment damage[6–9].Although researchers have attempted to develop methods to reduce the accumulation of surface charge through material modification,such as plasma treatment[10],direct fluorination[11],and coating[7,9,12],each of these methods has drawbacks;thus,the bottleneck has yet to be overcome.