Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer

Background:Bladder cancer,characterized by a high potential of tumor recurrence,has high lifelong monitoring and treatment costs.To date,tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types.Nonetheless,the existence of soft tumor cells in bladder tumors remains elusive.Thus,our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods:The stiffness of bladder cancer cells was determined by atomic force microscopy(AFM).The modified microfluidic chip was utilized to separate soft cells,and the 3D Matrigel culture system was to maintain the softness of tumor cells.Expression patterns of integrinβ8(ITGB8),protein kinase B(AKT),and mammalian target of rapamycin(mTOR)were determined by Western blotting.Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59(TRIM59).The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.Results:Using our newly designed microfluidic approach,we identified a small fraction of soft tumor cells in bladder cancer cells.More importantly,the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens,in which the number of soft tumor cells was associated with tumor relapse.Furthermore,we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells.Simultaneously,we detected a remarkable up-regulation in ITGB8,TRIM59,and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions:The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness.Meanwhile,the soft tumor cells become more sensitive to chemotherapy after stiffening,that offers new insights for hampering tumor progression and recurrence.

Industrial layout reconstruction, the role of local government and variation of pollution distribution in China

In recent years, high-polluting industries have been gradually shifted from the eastern developed regions to the central and western underdeveloped regions in China. Certain environmental regulations have been in place accordingly in various regions, but the pollution in the central and western regions has risen sharply. Based on the data of interprovincial panel in China from 2006 to 2015, this paper calculates high-pollution industry dynamic agglomeration index, environmental pollution agglomeration index and relative environmental regulation intensity index, and uses Generalized Method of Moments to carry out the regression analyses of the whole samples,regional heterogeneity and temporal heterogeneity. The results show that there is an inverted Ushaped relationship between relative environmental regulation and environmental pollution concentration in China. The concentration degrees of industrial wastewater pollution and industrial waste gas pollution are deepened, which are mainly caused by the transfer of highly polluting industries. However, the concentration of industrial solid waste pollution caused by the transfer is not obvious. Furthermore, the deepening of industrialization intensifies the concentration of regional environmental pollution. Environmental Kuznets Curve does exist in China,but it is not significant. The increase of labor cost and quality will reduce the concentration of environmental pollution.

抗氧化和长期抗菌活性迷迭香酸明胶生物降解膜的研制

开发新的方法将天然活性物质加入到凝胶基的食用薄膜中,以获得有效的抗氧化和长期的抗菌活性,具有重要的意义.在这里,天然活性化合物迷迭香酸（RosA）首先通过EDC/NHS化学结合在明胶骨架上.然后用甘油偶联物进行塑化,并与二醛黄原胶交联,制备活性RosA-明胶食用薄膜.结果表明,该食品膜具有良好的耐水性能、较强的力学性能和较好的紫外光阻隔性能.RosA的共轭使以明胶为基础的可食用薄膜具有预期的有效抗氧化和抗菌活性.有趣的是,经过3个月的贮藏后,RosA-明胶食用膜仍具有较好的抗菌活性,显示出较长期的抗菌活性.总之,所制备的RosA-明胶食用薄膜在食品和医药包装领域具有广阔的应用前景.

Eigenvalues of a Differential Operator and Zeros of the Riemann ■-Function

The eigenvalues of a differential operator on a Hilbert-Polya space are determined.It is shown that these eigenvalues are exactly the nontrivial zeros of the Riemann ■-function.Moreover,their corresponding multiplicities are the same.

Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells

Background:Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer.However,the critical elements in control of chemotherapy resistance remain obscure.Methods:We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin(DOX)and mitomycin C(MMC)of bladder cancer cells in a 3D culture system.We then detected the expression of multidrug resistant gene ABCB1,dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1(COUPTF1),cell proliferation marker Ki-67,and cellular senescence marker senescence-associatedβ-galactosidase(SA-β-Gal)in these cells.We further tested the effects of integrin blockade or protein kinase B(AKT)inhibitor on the senescent state of bladder cancer.Also,we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrinα2β1 ligand peptide TFA(TFA).Results:Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC.In mechanism,collagen activated the integrinβ1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p21/p53 pathway,thus attenuating chemotherapy-induced apoptosis.In addition,TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice.Meanwhile,TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo.Conclusions:Based on our finding that integrinβ1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel,we suggest that integrinβ1 might be a feasible target for bladder cancer eradication.

Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling

The extracellular matrix(ECM)serves as signals that regulate specific cell states in tumor tissues.Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression.In this study,we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status.Experiments were conducted using 3D collagen,fibrinogen.

Foreword

This special issue on Analytic Number Theory is dedicated to Jing-run Chen's Theorem(1+2)on the Goldbach Conjecture,the proof of which was first published in SCIENCE CHINA Mathematics exactly 50 years ago.Jing-run Chen was born on May 22,1933 in Fujian province,China.In 1953,he graduated from Xiamen University with a B.Sc.degree in Mathematics.

黎曼ζ-函数之二:算子及其指标 献给杨乐先生80华诞

作为Ω={s:Re(s)≥1/2}上的有界函数,s-1/s^2ζ(s)在哈代空间H^2(Ω)上乘积作用诱导的有界线性算子的指标为零的充分必要条件是黎曼假设成立;通过KS-(逆)变换,这一结果对应到希尔伯特空间L^2([1,∞])上的某乘法卷积算子的一个等价命题,该命题的一种离散表述是:算子Aζ=(1/mn{m/n+1})m,n≥1作用在l^2(N)上的指标为零当且仅当黎曼假设成立。对Dirichlet L-函数也有类似结果。应用KS-变换等手段,文章中将给出这些结果的证明细节。

非交换半群上的ζ-函数

自然数是由素数生成的乘法半群,从推广素数乘积的非交换性得到一类具有算术性质的非交换半群,自然数上的M¨obius函数和Riemannζ-函数等得到了自然推广.经典的Thompson群的生成半群等例子都是我们研究的特殊情形,它们上面的ζ-函数和经典的ζ-函数有类似的性质,但也有本质差别.本文证明类似的素数定理对许多非交换算术半群成立.而Thompson半群的ζ-函数至少有两个极点,这种现象反映了非交换半群中因子分解的复杂性.