CircTHSD4 promotes the malignancy and docetaxel (DTX) resistance in prostate cancer by regulating miR-203/HMGA2 axis

Objective:Circular ribose nudeic acids(circRNAs)are implicated in tumor progression and drug resistance of prostate cancer(PCa).The current work explored the function of circ_0005203(aircTHSD4)in the malignancy and docetaxel(DTX)resistance of PCa.Methods:circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real time reverse transcription quantitative polymerase chain reaction(RT-qPCR).In addition,a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells.In addition,we performed a Western blot(WB)assay to detect high mobility.group A2 protein(HMGA2)levels.Besides,functional associations of two molecules were investigated through dual luciferase reporter assay.Cell Counting Kit(CCK)-8,colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells,whereas flow cytometry was performed to determine cell apoptosis.Furthermore,a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells.Results:According to RT-qPCR results,circTHSD4 was up-regulated within PCa tissues and cells,which predicted the dismal prognostic outcome of PCa cases.circTHSD4 silencing within PCa cells markedly suppressed cell growth,migration,and colony fomation.circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model.Further,circTHSD4 silencing enhanced docetaxel(DTX)sensitivity in PCa cells.Furthermore,we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR 203.Conclusion:Together,our findings suggest that cirCTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR 203/HMGA2 axis.

Abemaciclib抑制c-Myc高表达小细胞肺癌增殖、侵袭和迁移的生物学功能的研究

背景与目的 c-Myc高表达小细胞肺癌(small cell lung cancer, SCLC)因易复发转移导致患者生存率极低,细胞周期依赖性激酶4和6(cyclin-dependent kinases 4 and 6, CDK4/6)抑制剂Abemaciclib在多种肿瘤的治疗中均起到关键作用,但其对SCLC的作用及机制仍不明晰。本研究旨在分析Abemaciclib抑制c-Myc高表达的SCLC增殖、侵袭和迁移的作用和分子机制,以期为减少患者的复发和转移拓展新的方向。方法 通过STRING数据库分析了CDK4/6和c-Myc蛋白相互作用网络,免疫组化实验分析了31例SCLC癌组织和配对的相邻正常组织中CDK4/6及c-Myc的表达,CCK-8实验和平板克隆实验检测Abemaciclib对SCLC增殖的影响,Transwell及划痕实验检测Abemaciclib对SCLC的侵袭和迁移能力的影响,Western blot检测Abemaciclib对CDK4/6及相关转录因子的影响,流式细胞术分析了Abemaciclib对SCLC的细胞周期和免疫检查点的调节作用。结果 通过STRING蛋白相互作用网络分析发现CDK4/6的表达均与c-Myc相关,c-Myc可以直接调节ASCL1(achaete-scute complex homolog 1)、NEUROD1(neuronal differentiation 1)和Yes相关蛋白1(Yes-associated protein 1, YAP1)的表达,CDK4和c-Myc均调控程序性死亡配体1(programmed cell death ligand 1, PD-L1)的表达。通过免疫组化实验发现,CDK4/6及c-Myc在SCLC癌组织中的表达高于癌旁组织(P<0.0001)。CCK-8实验、平板克隆实验、Transwell实验及划痕实验验证了Abemaciclib可以有效地抑制SBC-2和H446OE的增殖、侵袭和迁移(P<0.0001)。Western blot进一步分析了Abemaciclib在抑制SBC-2和H446OE细胞内CDK4(P<0.05)和CDK6(P<0.05)的同时,也影响了c-Myc(P<0.05)、ASCL1(P<0.05)、NEUROD1(P<0.05)和YAP1(P<0.05)等与SCLC浸润和转移相关的蛋白。流式细胞术发现Abemaciclib不仅抑制SCLC的细胞周期进程(P<0.0001),还可以提高SBC-2(P<0.01)和H446OE(P<0.001)细胞表面PD-L1的表达。结论 Abemaciclib明显抑制SCLC的增殖、侵袭、迁移和细胞周期进程,其通过抑制CDK4/6下调c-Myc、ASCL1、YAP1和NEUROD1蛋白表达的同时,也提高了PD-L1的表达。

利用单转录本表达Cas9和sgRNA条件性编辑果蝇基因组

CRISPR/Cas9(clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9)系统具有高效、简单、易编辑等特性,在基因工程方面具有巨大潜能。在果蝇(Drosophila melanogaster)基因功能研究中,CRISPR/Cas9系统也得到了广泛应用。然而利用传统的CRISPR/Cas9系统编辑果蝇基因时,Cas9与sgRNA表达元件往往分别存在于不同果蝇中,需要通过复杂的遗传杂交过程将Cas9与sgRNA整合到一个个体中,操作周期长且较为复杂。本研究在CRISPR/Cas9系统基础上引入tRNA-sgRNA系统和triplex元件,利用triplex元件连接Cas9和tRNA-sgRNA基因,稳定单转录本切割后Cas9 mRNA的末端,实现一个转录本可以同时表达Cas9蛋白和sgRNA,通过一次杂交即可得到相应表型的后代,简化了遗传操作过程。本研究利用这一新的条件性基因编辑系统,分别对果蝇眼部white(w)基因和翅成虫盘broad(br)基因进行条件性敲除,观察到与预期相符的对应表型。因此,该条件性基因编辑系统在高效性、可扩展性和易操作性等方面是对现有CRISPR/Cas9系统进行的重大改进。

Cutting the root:the next generation of T cells engagers against cancer stem cells to overcome drug resistance in triple-negative breast cancer

Triple-negative breast cancer(TNBC)is the most difficult type of breast cancer to treat.TNBC is defined by the lack of expression of three receptors:estrogen receptor(ER);progesterone receptor(PR);and human epidermal growth factor receptor 2(HER2).Chemotherapy is currently first-line treatment for TNBC;however,due to the high heterogeneity of TNBC,most patients eventually develop chemotherapy resistance,which is associated with a poor prognosisl-2.Emerging immune checkpoint blockade(ICB)therapies have been shown to have promising therapeutic efficacy in treating solid tumors.A phase III clinical trial reported that the combination of ICB and chemotherapy lengthened progression-free survival in patients with metastatic PD-L1+TNBC3;however,most patients had primary resistance or acquired resistance to ICB.Thus,the intrinsic mechanisms underlying ICB resistance are still under investigation4.

Influence of sample preparation on nanoindentation results of twinninginduced plasticity steel

Nanoindentation is an attractive characterization technique,as it not only measures the local properties of a material but also facilitates understanding of deformation mechanisms at submicron scales.However,because of the complex stress-strain field and the small scale of the deformation under the nanoindenter,the results can be easily influenced by artifacts induced during sample preparation.In this work,a systematic study was conducted to better understand the influence of sample preparation methods on the nanoindentation results of ductile metals.All experiments were conducted on a steel(Fe-22Mn-0.65C,wt%)with twinning-induced plasticity(TWIP),which was selected for its large grain size and sensitivity to different surface preparation methods.By grouping the results obtained from each nanoindent,chemical polishing was found to be the best sample preparation method with respect to the resulting mechanical properties of the material.In contrast,the presence of a deformation layer left by mechanical polishing and surface damage induced by focused ion beam(FIB)scanning were confirmed by the dislocation-nucleation-induced pop-in events of nanoindentation.

Using electrogeochemical approach to explore buried gold deposits in an alpine meadow-covered area

Exploration for buried gold ores and other deeply buried ores, especially in high altitude localities, is one of the tough challenges facing the geological world today.Fast and efficient ore prospecting methods are badly needed to deal with the situation. This paper documents a test that, for the first time, uses an electrogeochemical approach to prospect ores in the alpine meadow-covered Bangzhuoma area and its periphery in Qinghai–Tibet Plateau.The results were compared with conventional soil measurements from a 2 D prospection, and an ideal model of electrogeochemical anomaly formation in the area was established based on the comparison in order to provide theoretical guidance to buried ore prospecting in areas with similar conditions. The research shows that:(1) For exploration of deeply-buried mineral deposits, an electrogeochemical approach is better than soil measurements in terms of correspondence between element content values and anomaly forms and spatial distribution of known deposits in sections. Anomalies of high to low temperature element associations(Bi–Mo; Au–Ag–As–Bi and Au–Ag)and clear zonation were also observed along vertical vein runs in the sections. Based on integration of the observation with geological characteristics of the sections, we propose to use Au, Ag and As as the electrogeochemical indicators and Bi and Mo as the electrogeochemical tracing elementsto guide further analysis.(2) Judging from element statistics and the scale, intensity, and range of anomalies in plan maps, we found that an electrogeochemical approach is less affected by topography and secondary actions. The plan maps also show that elemental differentiation coefficients of the study area are in an ascending order of Ag(0.67) \ Mo(0.85) \ Bi(0.97) \ Au(1.51) \ As(2.35),better representing the element distribution in the area and yielding more striking and concentrated anomalies for known deposits than that of the soil measurements. Apart from that, electrogeochemical anomalies were observed in the south of lines 002 and 003 and the central of lines 008 and 009. We suggest the existence of deeply-buried mineral deposits based on analyses of element combinations and gold grade variations in samples taken from exploratory trenches in the area.(3) A three-stage(referring to the ore body dissolution, the mineralogenetic particle migration, and the mineralogenetic particle unloading) electrogeochemical ideal model was established for the study area, which takes into account moderate rainfall, high altitude, low air pressure, well-developed vegetation and roots, and an Upper Triassic Nieru Formation carbonaceous sandy slate as overburden.

A geochronological and geochemical study on the granodiorite porphyry and its implication for the mineralization in the Dayaoshan metallogenic belt,Southeastern China

A systematic study combining U-Pb zircon dating,lithogeochemical and Sr-Nd isotopic analyses was carried out upon the Xinping granodiorite porphyry in the Dayaoshan metallogenic belt to understand its petrogenesis and tectonic significance.LA-ICP-MS U-Pb zircon dating yielded a 442.7±5.8 Ma age,indicating that the granodiorite porphyry was emplaced during the Llandovery Silurian of the Early Paleozoic.The granodiorite porphyry shares the same geochemical characteristics such as Eu negative anomaly as other syn-tectonic granite plutons in the region,including the granodiorite porphyry in Dawangding and granite porphyries in the Dali Cu-Mo deposit and Longtoushang old deposit,indicating a similar magma evolution process.The Xinping granodiorite porphyry has high contents of SiO2(67.871.8%)and K2O(1.78-3.42%)and is metaluminous-peraluminous with A/CNK ratios ranging from 0.97 to 1.06,indicative of high-potassium calc-alkaline to calc-alkaline affinity.It is a I-type granite enriched in large ion lithophile elements Rb,Sr,while depleted in Ba and high field-strength element Nb.Tectonically,a collision between the Yunkai Block from the south and the Guangxi Yunnan-North Vietnam Block from the north during the Early Paleozoic was followed by uplifting of the Dayaoshan terrane.The Xinping granodiorite porphyry was likely emplaced during the collision.Sr-Nd isotopic analyses show that the granodiorite porphyry has initial 87Sr/86Sr ratios(Isr)of 0.7080-0.7104,εNd(t)range from-0.08 to-4.09,and t2DM between 1.19 and 1.51 Ga,well within the north-east low-value zone of the Cathaysia block,indicating a Paleoproterozoic Cathaysia basement source and an involvement of under plating mantle magma.Field observations,geochronological data,and 3D spatial distribution all lead to the conclusion that the Early Paleozoic Xinping granodiorite porphyry does not have any metallogenic and temporal relationships with the Xinping gold deposit(which has a Jurassic-Early Cretaceous age based on previous studies)but a close metallogenic relation to W-Mo mineralization.

Electrokinetic energy conversion of electro-magneto-hydro-dynamic nanofluids through a microannulus under the time-periodic excitation

In this work,the effects of externally applied axial pressure gradients and transverse magnetic fields on the electrokinetic energy conversion(EKEC)efficiency and the streaming potential of nanofluids through a microannulus are studied.The analytical solution for electro-magneto-hydro-dynamic(EMHD)flow is obtained under the condition of the Debye-Huuckel linearization.Especially,Green’s function method is used to obtain the analytical solutions of the velocity field.The result shows that the velocity distribution is characterized by the dimensionless frequency?,the Hartmann number Ha,the volume fraction of the nanoparticlesφ,the geometric radius ratio a,and the wallζpotential ratio b.Moreover,the effects of three kinds of periodic excitations are compared and discussed.The results also show that the periodic excitation of the square waveform is more effective in increasing the streaming potential and the EKEC efficiency.It is worth noting that adjusting the wallζpotential ratio and the geometric radius ratio can affect the streaming potential and the EKEC efficiency.

Molecular phenotypes reveal heterogeneous engraftments of patient-derived hepatocellular carcinoma xenografts

Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.

Comprehensive Evaluation of Service Level of Transmission Equipment Maintenance Plan

With the interconnection of power grid, the increase of coupling, the rapid development of new energy, the inter-provincial cross-regional power market transactions, it is an important way that the integrated presentation of grid outage maintenance plan to ensure the safety of power grid, ensure the normal operation of the market, improve the efficiency of maintenance and reduce the cost of maintenance. Maintenance plan is in the annual, monthly, daily and other dimensions of time rolling management process. Maintenance planning level assessment can improve the service level of maintenance plan compilers and the efficiency of maintenance, it also achieves fine management of the power grid. This paper presents an evaluation model of maintenance business level, which is a comprehensive evaluation model of multi-index. The indexes in the model are based on the maintenance service level measurement, the efficiency of the maintenance plan, the emergencies of the maintenance plan and others Impact factors and other aspects of multi-angle assessment. The validity and correctness of the evaluation system and the comprehensive evaluation method are verified by the analysis of practical examples.

Simulation Research on Ran-Assisted WLAN Offloading Scheme

Wireless Local Area Network (WLAN) offloading is an important approach to address the data traffic challenge faced by Long Term Evolution (LTE) network. Legacy offloading solutions based on the core network suffer from the limitations of load unbalance and user experience degradation. To solve this problem, 3GPP has recently proposed a radio access network (RAN) assisted WLAN offloading scheme. In this article, we thoroughly analyze the performance of this new scheme, with emphasis on the RAN auxiliary parameters and control rules defined in it. Furthermore, two kinds of offloading algorithms based on this scheme are proposed and compared with the traditional solutions by simulation. Results show that the RAN-assisted offloading scheme can increase average user throughput and leverage resources available in both LTE and WLAN systems.

Mitochondria-targeted nanoparticles overcome chemoresistance via downregulating BACH1/CD47 axis in ovarian carcinoma

The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.

Effects of calcination temperature on physicochemical property and activity of CuSO4/TiO2 ammonia-selective catalytic reduction catalysts

CuSO4/TiO2 catalysts with high catalytic activity and excellent resistant to SO2 and H2 O,were thought to be promising catalysts used in Selective catalytic reduction of nitrogen oxides by NH3.The performance of catalysts is largely affected by calcination temperature.Here,effects of calcination temperature on physicochemical property and catalytic activity of CuSO4/TiO2 catalysts were investigated in depth.Catalyst samples calcined at different temperatures were prepared first and then physicochemical properties of the catalyst were characterized by N2 adsorption-desorption,X-ray diffraction,thermogravimetric analysis,Raman spectra,Fourier-transform infrared spectroscopy,X-ray photoelectron spectroscopy,temperature-pro grammed desorption of NH3,temperature-programmed reduction of H2 and in situ diffuse reflectance infrared Fourier transform spectroscopy.Results revealed that high calcination temperature had three main effects on the catalyst.First,sintering and anatase transform into rutile with increase of calcination temperature,causing a decrement of specific surface area.Second,decomposition of CuSO4 under higher calcination temperature,resulting in disappears of Br(?)nsted acid sites(S-OH),which had an adverse effect on surface acidity.Third,CuO from the decomposition of CuSO4 changed surface reducibility of the catalyst and favored the process of NH3 oxidation to nitrogen oxides(NOx).Thus,catalytic activity of the catalyst calcined under high temperatures(≥600℃)decreased largely.

Revisiting chemoresistance in ovarian cancer:Mechanism,biomarkers,and precision medicine

Among the gynecological cancers,ovarian cancer is the most lethal.Its therapeutic options include a combination of chemotherapy with platinum-based compounds and cytoreductive surgery.Most ovarian cancer patients exhibit an initial response to platinum-based therapy,however,platinum resistance has led to up to 80%of this responsive cohort becoming refractory.Ovarian cancer recurrence and drug resistance to current chemotherapeutic options is a global challenge.Chemo-resistance is a complex phenomenon that involves multiple genes and signal transduction pathways.Therefore,it is important to elucidate on the underlying molecular mechanisms involved in chemo-resistance.This inform decisions regarding therapeutic management and help in the identification of novel and effective drug targets.Studies have documented the individual bidmarkers of platinum-resistance in ovarian cancer that are potential therapeutic targets.This review summarizes the molecular mechanisms of platinum resistance in ovarian cancer,novel drug targets,and clinical outcomes.

Correlation between KCNQ1 gene polymorphism and type 2 diabetes mellitus in Huaihai region of China

Objective:This article aims to discuss the distribution of KCNQ1 gene polymorphism in the Chinese Han population in the Huaihai region of China and the correlation between KCNQ1 gene polymorphism and incidence of type 2 diabetes(T2DM).Methods:From December 2010 to July 2011,200 T2DM inpatients and outpatients in the Endocrinology Department of the Affiliated Hospital of Xuzhou Medical College were selected as the case group and,200 healthy people identified by the health examination center in the same re-gion were selected as the control group.The polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)test was used to examine the gene polymorphism of the two groups.Results:(1)Analysis on the control group showed that at the KCNQ1 rC237892 locus,the genotype frequencies of CC,CT and TT were 36.0%(72/200),51.0%(102/200)and 13.0%(26/200)respectively,and the allelic frequencies of C and T were 61.5%(246/400)and 38.5%(154/400)respectively.Analysis on the case group showed the genotype frequencies of CC,CT and TT were 47.5%(95/200),44.0%(88/200)and 8.5%(17/200)respectively,and the allelic frequencies of C and T were 69.5%(278/400)and 30.5%(122/400)respectively.Comparison between the genotype distributions and allelic frequencies of the two tested groups at KCNQ1 rC237892 locus showed differences with statistical significance(P<0.05).(2)Comparison be-tween the genotype distributions and allelic C and A frequencies of the control group and the case group showed differences with no statistical significance(P>0.05).Conclusion:Polymorphism at KCNQ1 rs2237892 locus may be correlated to the incidence of T2DM in the Chinese Han population in Huaihai region of China;polymorphism at rsl51290 locus may be irrelevant to the incidence of T2DM in the Chinese Han population in Huaihai region of China.