Pressure-induced structural transition and low-temperature recovery of sodium pentazolate

Pentazolate compounds have attracted extensive attention as high energy density materials.The synthesis and recovery of pentazolate compounds is of great importance for their potential applications.Here,we report the synthesis of Pmn2_(1)-NaN_(5)and Pm-Na_(2)N_(5)through compressing and laser heating pure NaN_(3)at~60 GPa.Upon decompression,the pressureinduced structural transition from Pmn2_(1)-NaN_(5)into Cm-NaN_(5)is observed in the pressure range of 14-23 GPa for the first time.The cyclo-N_(5)^(-)can be traced down to 4.7 GPa at room temperature and recovered to ambient pressure under low temperature condition(up to 160 K).The Pm-Na_(2)N_(5)is suggested to decompose into the P4/mmm-NaN_(2)at 23 GPa,and be stable at ambient conditions.This work provides insight into the high-pressure behaviors of pentazolate compounds and an alternative way to stabilize energetic polynitrogen compounds.

奥希替尼在非小细胞肺癌靶向治疗中的获得性耐药机制

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFRTKI)在治疗癌症的同时仍面临不可避免的耐药。通过研究EGFR-TKI发生耐药的机制从而发现一些新的分子标志物和药物靶点,促进了第三代TKIs的发展并针对耐药提出合理化建议。经临床验证,T790M是一个可用于判断预后的生物学标志物,可导致第一代和第二代TKIs的难治性。对于T790M阴性的患者,尽管靶向治疗和检查点阻断治疗结合可能提供有希望的替代方案,细胞毒性药物序贯EGFR-TKI治疗仍是疾病进展后可接受的标准治疗方式。在T790M阳性患者中,第三代EGFR-TKI药物奥希替尼在随机临床试验中优于铂类二联化疗和第一代EGFR-TKI。文章综述了近年来有关奥希替尼在非小细胞肺癌患者获得性耐药机制及治疗的主要文献,并展望了未来可能的研究方向。

Deregulated expression and subcellular localization of CPSF6,a circRNA-binding protein,promote malignant development of esophageal squamous cell carcinoma

Objective:Cleavage and polyadenylation specific factor 6(CPSF6)has been documented as an oncoprotein in different types of cancer.However,functions of CPSF6 have not been investigated yet in esophageal squamous cell carcinoma(ESCC).Here,we aimed to investigate the potential clinical values and biological functions of CPSF6 in ESCC.Methods:For determining the expression level of CPSF6 in ESCC patients,we analyzed published data,performed quantitative real-time polymerase chain reaction(RT-qPCR)and immunohistochemistry assays.Kaplan-Meier curves and log-rank tests were used for survival analyses.GO and KEGG analyses were done for CPSF6-related genes.Cell proliferation,colony formation and xenograft assays were conducted to verify the effects of CPSF6 on ESCC.In addition,cell cycle and apoptosis assays were also performed to manifest the functions of CPSF6 and circCPSF6.RNA pulldown and radioimmunoprecipitation(RIP)assays were used for confirming the interaction between circCPSF6(hsa_circ_0000417)and CPSF6 protein.The regulatory relationship between CPSF6 protein and circCPSF6 was determined by RT-qPCR.Results:We found that CPSF6 was upregulated in ESCC tissues and overexpression of cytoplasmic CPSF6 was associated with poor prognosis.GO and KEGG analyses suggested that CPSF6 could mainly affect cell division in ESCC.Further experiments manifested that CPSF6 promoted cell proliferation and colony formation in vitro.Xenograft assay showed that knockdown of CPSF6 significantly decreased tumor growth rate in vivo.Subsequently,we verified that depletion of CPSF6 led to cell cycle arrest and apoptosis.Finally,we validated that CPSF6,as a circRNA-binding protein,interacted with and regulated its circular isoform circCPSF6(hsa_circ_0000417),of which depletion also resulted in cell cycle arrest and cell apoptosis in ESCC.Conclusions:These findings gave us insight that overexpression of cytoplasmic CPSF6 protein is associated with poor prognosis in ESCC and CPSF6 may function as an oncoprotein,at least in part,through regulating circCPSF6 expression.

Optimization of plasma-processed air(PPA)inactivation of Escherichia coli in button mushrooms for extending the shelf life by response surface methodology

The effect of plasma-processed air(PPA)treatment with different conditions(time,power andflow rate)on the inactivation of Escherichia coli(E.coli)in button mushroom was evaluated.Response surface methodology(RSM)was applied to optimize PPA treatments on the E.coli of button mushrooms.According to the response surface analysis,the optimal treatment parameters were a treatment time of 12 min,treatment power of 90 W and flow rate of 1.2 l min-1.As with verifying tests from the optimization exercise,the number of E.coli reduced by 5.27 log CFU/g at the determined optimum conditions.The scanning electronic microscopy(SEM)micrography showed that the surface of the E.coli was significantly changed under the optimized PPA treatment.Quality parameters of button mushrooms treated at the determined optimum conditions were compared with untreated samples during the storage for 12 d at 4°C?±?1°C.The PPA treatment was found to be effective in inhibiting microbes and preserving postharvest quality in button mushrooms,and these results suggested PPA treatment may provide an alternative for the sterilization of foodborne and maintaining postharvest of fruits and vegetables.

诱导性多能干细胞的低基因组稳定性使非同源末端连接增加

背景与目的诱导性多能干细胞(induced pluripotent stem cells,iPSCs)和胚胎干细胞(embryonic stem cells,ESCs)具有许多共同特征,包括相似的形态、基因表达和体外分化谱。然而,iPSCs的基因组稳定性远低于ESCs。在本研究中,我们研究了iPSCs中DNA损伤修复的改变是否为其具有更大诱变倾向的原因。方法将小鼠iPSCs、ESCs和胚胎成纤维细胞暴露于电离辐射(4 Gy),导致双链DNA断裂。照射4 h后使用全基因组重测序评估DNA损伤修复的保真度。我们还分析了分别源自iPSCs或ESCs的小鼠的基因组稳定性。结果照射后,与胚胎干细胞和胚胎成纤维细胞相比,iPSCs具有较低的DNA损伤修复能力,有更多的体细胞突变和短片段插入缺失。iPSCs有更多的非同源末端连接DNA修复和更少的同源重组DNA修复。源自iPSCs的小鼠比ESCs小鼠以及C57对照小鼠的DNA损伤修复能力更低。结论本研究结果部分表明,iPSCs的低基因组稳定性及其在体内的高致瘤性是由DNA损伤修复的低保真度所致。

An overview of multiomics:a powerful tool applied in cancer molecular subtyping for cancer therapy

During the process of carcinogenesis and tumor progression,various molecular alternations occur in different omics levels.In recent years,multiomics approaches including genomics,epigenetics,transcriptomics,proteomics,metabolomics,single-cell omics,and spatial omics have been applied in mapping diverse omics profiles of cancers.The development of high-throughput technologies such as sequencing and mass spectrometry has revealed different omics levels of tumor cells or tissues separately.While focusing on a single omics level results in a lack of accuracy,joining multiple omics approaches together undoubtedly benefits accurate molecular subtyping and precision medicine for cancer patients.With the deepening of tumor research in recent years,taking pathological classification as the only criterion of diagnosis and predicting prognosis and treatment response is found to be not accurate enough.Therefore,identifying precise molecular subtypes by exploring the molecular alternations during tumor occurrence and development is of vital importance.The review provides an overview of the advanced technologies and recent progress in multiomics applied in cancer molecular subtyping and detailedly explains the application of multiomics in identifying cancer driver genes and metastasis-related genes,exploring tumor microenvironment,and selecting liquid biopsy biomarkers and potential therapeutic targets.

具有全sp^(2)杂化聚合氮层超氮化合物的高压合成研究

类石墨烯全sp^(2)杂化二维结构具有承载非平庸的拓扑电子结构的能力.本文利用激光加热对顶砧技术,在高温高压条件下首次获得全sp^(2)杂化类石墨烯二维聚合氮结构.全sp^(2)杂化的聚合氮层由环状N18单元组成,与钾原子层构成了类三明治结构的K_(2)N_(16)超氮材料.K_(2)N_(16)能带结构呈现拓扑半金属特性,是新型的高阶色散狄拉克费米子材料.全sp^(2)杂化的聚合氮的合成研究为探索新型拓扑材料提供了新的高压策略.

MiR-3653 blocks autophagy to inhibit epithelial-mesenchymal transition in breast cancer cells by targeting the autophagy-regulatory genes ATG12 and AMBRA1

Background:Metastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer.Autophagy accelerates tumor metastasis.In our work,we aimed to investigate the possibility of microRNAs(miRNAs)which participate in the regulation of autophagy to inhibit tumor metastasis.Methods:MiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis.The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction.In vivo and in vitro assays were conducted to determine the function of miR-3653.The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot.The relationship between miR-3653 and epithelial-mesenchymal transition(EMT)was assessed by Western blot.Student’s t-test was used to analyze the difference between any two groups,and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test.Results:miR-3653 was downregulated in breast cancer cells with high metastatic ability,and high expression of miR-3653 blocked autophagic flux in breast cancer cells.Clinically,low expression of miR-3653 in breast cancer tissues(0.054±0.013 vs.0.131±0.028,t=2.475,P=0.014)was positively correlated with lymph node metastasis(0.015±0.004 vs.0.078±0.020,t=2.319,P=0.023)and poor prognosis(P<0.001).miR-3653 ameliorated the malignant phenotypes of breast cancer cells,including proliferation,migration(MDA-MB-231:0.353±0.013 vs.1.000±0.038,t=16.290,P<0.001;MDA-MB-468:0.200±0.014 vs.1.000±0.043,t=17.530,P<0.001),invasion(MDA-MB-231:0.723±0.056 vs.1.000±0.035,t=4.223,P=0.013;MDA-MB-468:0.222±0.016 vs.1.000±0.019,t=31.050,P<0.001),and colony formation(MDA-MB-231:0.472±0.022 vs.1.000±0.022,t=16.620,P<0.001;MDA-MB-468:0.650±0.040 vs.1.000±0.098,t=3.297,P=0.030).The autophagy-associated genes autophagy-related gene 12(ATG12)and activating molecule in beclin 1-regulated autophagy protein 1(AMBRA1)are target genes of miR-3653.Further studies showed that miR-3653 inhibited EMT by targeting ATG12 and AMBRA1.Conclusions:Our findings suggested that miR-3653 inhibits the autophagy process by targeting ATG12 and AMBRA1,thereby inhibiting EMT,and provided a new idea and target for the metastasis of breast cancer.

Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells

Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.

In silico design of anti-tumor mini-protein targeting MDM2

We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L-and Damino acids,which was exceptionally stable in serum.Therefore,we further used it as a scaffold to design mini-proteins targeting p53 positive tumor cells.Based on bifunctional grafting,key residues from the transactivation domain of p53 and a designed unnatural amino acid were grafted into the helix constituted by L-amino acids to confer the mini-protein with MDM2 inhibitory activity.Meanwhile,ten Arg residues were introduced to improve its membrane penetrating capacity.Among the mini-proteins,UPROL-10e showed nano-molar binding affinity on MDM2 and cellular toxicity on p53 expressing HCT116cells.

On-tissue chemical derivatization enables spatiotemporal heterogeneity visualization of oxylipins in esophageal cancer xenograft via ambient mass spectrometry imaging

On-tissue chemical derivatization(OTCD)effectively enhances ionization efficiency of low abundant and poorly ionized functional molecules to improve detection sensitivity and coverage of mass spectrometry imaging(MSI).Combination OTCD and MSI provides a novel strategy for visualizing previously undisclosed metabolic heterogeneity in tumor.Herein,we present a method to visualize heterogeneous metabolism of oxylipins within tumor by coupling OTCD with airflow-assisted desorption electrospray ionization(AFADESI)-MSI.Taking Girard’s P as a derivatization reagent,easily ionized hydrazide and quaternary amine groups were introduced into the structure of carbonyl metabolites via condensation reaction.Oxylipins,including 127 fatty aldehydes(FALs)and 71 oxo fatty acids(FAs),were detected and imaged in esophageal cancer xenograft with AFADESI-MSI after OTCD.Then t-distributed stochastic neighbor embedding and random forest were exploited to precisely locate the distribution of oxylipins in heterogeneous tumor tissue.With this method,we surprisingly found almost all FALs and oxo FAs significantly accumulated in the core region of tumor,and exhibited a gradual increase trend in tumor over time.These results reveal spatiotemporal heterogeneity of oxylipins in tumor progression,highlighting the value of OTCD combined with MSI to gain deeper insights into understanding tumor metabolism.

Tumor-derived miR-20b-5p promotes lymphatic metastasis of esophageal squamous cell carcinoma by remodeling the tumor microenvironment

DEAREDITOR,Esophageal squamous cell carcinoma(ESCC)is one of the most common fatal malignancies worldwide and is especially common in East Asian regions,including China.Screening lymph node metastasis(LNM)-related biomarkers and elucidating the mechanism could provide promising therapeutic targets and help ESCC patients to select reasonable individual therapies.

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

Automatic detection method of bladder tumor cells based on color and shape features

Bladder urothelial carcinoma is the most common malignant tumor disease in urinary system,and its incidence rate ranks ninth in the world.In recent years,the continuous development of hyperspectral imaging technology has provided a new tool for the auxiliary diagnosis of bladder cancer.In this study,based on microscopic hyperspectral data,an automatic detection algorithm of bladder tumor cells combining color features and shape features is proposed.Support vector machine(SVM)is used to build classification models and compare the classification performance of spectral feature,spectral and shape fusion feature,and the fusion feature proposed in this paper on the same classifier.The results show that the sensitivity,specificity,and accuracy of our classification algorithm based on shape and color fusion features are 0.952,0.897,and 0.920,respectively,which are better than the classification algorithm only using spectral features.Therefore,this study can effectively extract the cell features of bladder urothelial carcinoma smear,thus achieving automatic,real-time,and noninvasive detection of bladder tumor cells,and then helping doctors improve the e±ciency of pathological diagnosis of bladder urothelial cancer,and providing a reliable basis for doctors to choose treatment plans and judge the prognosis of the disease.

催化水解反应的肽基模拟酶的活性来源、催化机理及应用

肽基材料由于其与蛋白质高度相似和结构可控等优势,是构建人工模拟酶的一种理想材料;此外,小肽中氨基酸排列的多样性、序列的自组装特性、纳米结构稳定性、结构简单易于设计、良好生物相容性等优势,使得构建具有高效催化活性的肽基模拟酶具有非常好的应用前景。利用肽基材料通过理性设计活性位点来构建模拟酶具有多方面优势:(1)氨基酸序列可以直接从天然酶中的活性位点获得,保留酶的功能,但降低了酶固有的复杂性;(2)肽序列中可以嵌入各种具有特定结构及功能的活性位点,便于对模拟酶进行人工理性设计;(3)肽具有良好的生物相容性,可以在温和条件下催化反应进行。根据催化降解化学键的不同,可将肽基水解模拟酶分为以下几种:催化酯键降解的肽基模拟酶、催化肽键降解肽基模拟酶、催化糖苷键水解的肽基模拟酶。本文主要分析了具有水解酶活性的肽基模拟酶的活性来源、构建方法及微观结构、催化反应类型、催化影响因素、活性改善方法、作用机理及未来潜在应用等;以期为构建具有高效水解催化活性的模拟酶提供借鉴,推进肽基水解模拟酶的研究发展及实际应用。

Enhanced Expression of miR-425 Promotes Esophageal Squamous Cell Carcinoma Tumorigenesis by Targeting SMAD2

Esophageal squamous cell carcinoma （ESCC） is one of the most common and deadly cancers in the world, Currently, clinical therapy of ESCC remains limited and the five-year survival rate is poor. The function of miR-425 has been reported in multiple human cancers. However. the tumorigenic role and clinical significance of miR-425 in ESCC remains unclear. We found that enhanced expression of miR- 425 in ESCC cell lines not only promoted cell proliferation and colony formation, but also increased cellular metastasis. Furthermore, we revealed the mechanism that miR-425 inhibited the expression of SMAD2 by targeting the second binding site in the 3＇-untranslated region （3＇-UTR） in ESCC. This mode of action influenced not only SMAD2 rnRNA expression but also protein expression. In addition, we detected the expression of miR-425 in ESCC tissues and plasma. Moreover, we analyzed the relationship between miR-425 expression and SMAD2 mRNA expression. We found that miR-425 was overexpressed in ESCC tissues and the plasma relative to adjacent normal tissues and plasma of healthy individuals. Furthermore, there was a negative correlation between miR-425 expression and SMAD2, Taken together, our results show that miR-425 functions as an oncogene by targeting the 3＇-UTR of SMAD2 and indicate the potential utility of plasma miR-425 as a novel biomarker for ESCC diagnosis.

TRAP1 Shows Clinical Significance and Promotes Cellular Migration and Invasion through STAT3/MMP2 Pathway in Human Esophageal Squamous Cell Cancer

Tumor necrosis factor receptor-associated protein 1 （TRAP1）, an important member of mitochondrial heat shock protein 90 family, is involved in multiple biological processes in several types of tumors. However, its pathological role in esophageal squamous cell cancer （ESCC） remains unknown. Herein, we demonstrated the clinical value of TRAP1, and its role in apoptosis and motility in ESCC. The clinical potential of TRAP1 was investigated through immunohistochemical analysis in 328 ESCC samples, which revealed that strong TRAP1 expression was associated with increased risk of lymph node metastasis, while high TRAP1 expression correlated with poor prognosis. Expression of TRAP1 was found to be an independent prognostic factor for patients with ESCC. Additionally, the upregulation of TRAP1 antagonized cisplatin-induced apoptosis while its downregulation sensitized cells to cisplatin-induced apoptosis. As revealed by the transwell assay, TRAP1 overexpression promoted cellular migration and invasion as compared to the control groups. In contrast, silencing of endogenous TRAP1 expression attenuated the ability of migration and invasion. Finally, the molecular mechanism investigated in the present study demonstrated that TRAP1-mediated migration and invasion occurred through STAT3/MMP2 signaling pathway. In conclusion, TRAP1 may be considered as a molecular predictive marker for prognosis and a novel molecular candidate for therapeutic target in ESCC.

Downregulation of miR-503 Promotes ESCC Cell Proliferation,Migration,and Invasion by Targeting Cyclin D1

Esophageal squamous cell carcinoma （ESCC） is one of the most aggressive cancers in China, but the underlying molecular mechanism of ESCC is still unclear. Involvement of micro- RNAs has been demonstrated in cancer initiation and progression. Despite the reported function of miR-503 in several human cancers, its detailed anti-oncogenic role and clinical significance in ESCC remain undefined. In this study, we examined miR-503 expression by qPCR and found the downregulation of miR-503 expression in ESCC tissue relative to adjacent normal tissues. Fur- ther investigation in the effect of miR-503 on ESCC cell proliferation, migration, and invasion showed that enhanced expression of miR-503 inhibited ESCC aggressive phenotype and overexpres- sion of CCND1 reversed the effect of miR-503-mediated ESCC cell aggressive phenotype. Our study further identified CCND1 as the target gene of miR-503. Thus, miR-503 functions as a tumor suppressor and has an important role in ESCC by targeting CCND1.

RASSF6-TRIM16 axis promotes cell proliferation,migration and invasion in esophageal squamous cell carcinoma

Ras-association(RA) domain family number 6(RASSF6) is a member of the Ras-association domain protein family.It is epigenetically inactive and negatively regulates the malignant progression of some tumors.However,its precise role in esophageal squamous cell carcinoma(ESCC) has not been reported.In this study,we performed immunohistochemistry(IHC) assay.The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients.Consistent with the clinical obse rvations,the upregulation of RASSF6 greatly promotes ESCC cell proliferation,migration and invasion as well as the cell cycle transition to Gl/S phase in vitro.According to models in vivo,the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis.Mechanistically,RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16(TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelialmesenchymal transition(EMT).Together,these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.

miR-503-3p promotes epithelialemesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin

Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of mi R-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined.Here, we found that mi R-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified mi R-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of mi R-503-3p in breast cancer cells inhibited expression of epithelialemesenchymal transition（EMT）-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their m RNA30 untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for mi R-503-3p in induction of breast cancer EMT and suggest that plasma mi R-503-3p may be a useful diagnostic biomarker for breast cancer.