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Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146–5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3′UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target. Significance: The tumor–stromal cross-talk mediated by cancer-associated fibroblast–derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.

Holograms hidden inside transparent materials are important for information encryption storage because of their advantages of secrecy, and could completely avoid information loss caused by surface wear. Inside the transparent material, the modified filaments array was need for hologram fabrication to change the optical phase or amplitude of incident laser, which is sensitive to the change of refractive index. Then the uniformity of modified filaments inside transparent materials is highly required. In this study, by tuning the interval time of the double-pulse processing, holograms with improved imaging quality were fabricated by double-pulse femtosecond laser and the effect and mechanism of self-trapped excitons (STEs) on the ablation have been systematically studied. The imaging quality of the hologram fabricated with double-pulse laser was superior to that of the one fabricated with the single-pulse laser and 350 fs was verified to be the best time interval for double-pulse processing. The evolution of the electrons dynamics was investigated by using the pump-probe technology. With the double-pulse time interval increasing, the residual electrons, excitons, STEs, and defects caused by the first sub-pulse would become dominated sequentially. The results demonstrated the controllability of STEs and quality improvement of final structures by double-pulse femtosecond laser processing.

Supplementary Data

Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146–5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3′UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target.Significance:The tumor–stromal cross-talk mediated by cancer-associated fibroblast–derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.

Supplementary Materials and Methods, Figures and Tables

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non–steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency–induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding–disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL–induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC.Significance:This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.

Supplementary Experimental Procedures and Figure Legends. Supplementary Table 1-Comparison of secreted proteins in the culture medium of EBC-1 and EBC-1/SR cells using L-series 507 antibody array. Supplementary Table 2-Names and significant targets of 42 compounds tested against EBC-1/SR and MKN-45/SR cells as single agents or in combination with SGX-523. Supplementary Table 3-Established patient derived xenograft models (more than 10) for in vivo efficacy studies.

Supplementary Figure 3-c-Myc determines clinical response and resistance for c-Met targeted therapy.

Supplementary Figure 2-c-Myc downregulation is essential for c-Met inhibition caused growth arrest in MET-addicted cells.

Use of kinase inhibitors in cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met–addicted cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c-Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc–blocking agents as a tactic to thwart resistance to kinase inhibitors. Cancer Res; 75(21); 4548–59. ©2015 AACR.

Supplementary Figure 1-Multiple kinases are co-activated in c-Met-resistant cells.

A one-step method was proposed to prepare a high-performance surface-enhanced Raman scattering (SERS) substrate based on bulk MoS2 via femtosecond laser pulse modification. The Raman spectra of Rho...

Nonlinear optical properties have been extensively studied due to their promising nonlinear effects and various applications. With ultrashort duration and ultrahigh intensity, a femtosecond laser can fabricate various superior-quality micro-/nanostructures to improve the nonlinearity of materials, which are promising for stable and high-performance nonlinear devices. In this contribution, yttria-stabilized zirconia (YSZ) with fs laser-induced micro-/nanostructures is demonstrated to exhibit unique anisotropic light-material interaction and nonlinear optical response on [100], [110], and [111] planes. Time-resolved reflectivity of YSZ after fs laser excitation is investigated by a pump-probe experiment, which is consistent with simulations through the plasma model combined with a two-temperature model. These results indicate two early ablation mechanisms: Coulomb explosion and melting. Anisotropic crack structures are formed due to thermal stress, which is always ignored in fs laser fabrication and is verified by Raman mapping and analysis of slip systems on different crystal planes. Through the

Grid-to-rod fretting (GTRF) caused by flow induced vibration is one of the most important mechanisms of fuel rod failure in PWRs, which has a strong impact on the economy and safety of nuclear power plant. To avoid rod failure due to GTRF, several verification tests which are high costs and long term are always carried out for new design fuel assemblies. So as to deal with the disadvantages of tests and speed up progress in fuel design, a progressive analysis method to predict GTRF performance of fuel rod is developed, and systemic tests are carried out to verify the analysis method. The method consists of three main parts, including flow field analysis, structure vibration analysis and wear analysis. In the first part, the flow field excitation force is obtained by the large eddy simulation method, and this CFD method is verified by a particle image velocimetry (PIV) test with a 5 × 5 fuel bundle. In the second part, to get the vibration response of fuel rod, a nonlinear vibration model which can consider end-of-life gaps is established. Full scale fuel rod vibration in air and water conditions are tested to validate the predicted fuel rod response from analysis. In the third part, the fuel rod wear is estimated by tribological theory with fuel rod vibration response, the wear coefficient and the typical feature of wear scar. The GTRF method is finally verified by a long-term wear test of full-scale fuel assembly. It turns out that this method can effectively predict the wear characteristics of fuel rod cladding at the early stage of design. It provides a feasible solution for rapid design iteration of fuel assembly, and could reduce the development costs and risks.

By the analysis of the three-dimensional flow field of the fuel assembly grid, the high-frequency flow-induced vibration test of small-scale test assembly, the preliminary research on the overall and local flow-induced vibration mechanism and influencing factors of the fuel assembly grid is carried out. A system of evaluation index based on the three-dimensional flow field analysis of the grid and the flow-induced vibration test of 5 × 5 small test assembly is preliminarily established, which can more accurately evaluate the flow-induced vibration characteristics of the PWR fuel assembly grid.

As the core component and the first safety barrier of a nuclear power plant, the structural integrity of fuel assemblies (FAs) is an important factor in ensuring the safety of nuclear power. Safety analysis and evaluation of fuel assemblies under seismic conditions is a requirement of nuclear power plant design codes and safety reviews. The mechanical properties of a single FA determine the operational and seismic performance of the core fuel assembly. Due to the complexity of the FAs in terms of structure and boundary conditions, test is the most common method to obtain the mechanical properties. In order to predict the mechanical properties of the fuel assembly, a nonlinear finite element detailed model was developed. The contact and frictional behavior between the fuel rod cladding and the spring/dimple convexity were considered in the modeling to simulate the nonlinear behavior of the fuel rod better. To verify the validity of the model, virtual tests of lateral stiffness test, forced vibration test and impact test were conducted on the model. The comparison with the experimental results shows that the model can reflect the mechanical properties of the fuel assembly well. The modeling method and calculation conclusions in this paper are of guidance for fuel assembly design.

The third-generation semiconductors are the cornerstone of the power semiconductor leap forward and have attracted much attention because of their excellent properties and wide applications. Meanwhile, femtosecond laser processing as a convenient method further improves the performance of the related devices and expands the application prospect. In this work, an approximate 3 times improvement of the internal quantum efficiency (IQE) and a 5.5 times enhancement of the photoluminescence (PL) intensity were achieved in the GaN film prepared using a one-step femtosecond laser fabrication method. Three types of final micro/nanostructures were found with different femtosecond laser fluences, which could be attributed to the decomposition, melting, bubble nucleation, and phase explosion of GaN. The mechanisms of the microbump structure formation and enhancement of IQE were studied experimentally by the time-resolved reflection pump-probe technique, X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Simulations for the laser-GaN interaction have also been performed to ascertain the micro/nanostructure formation principle. These results promote the potential applications of femtosecond lasers on GaN and other wide band gap semiconductors, such as UV-light-emitting diodes (LEDs), photodetectors, and random lasers for use in sensing and full-field imaging.

A novel Gram-negative, aerobic, motile and short rod-shaped bacterium with exopolysaccharides production, designated as LZ-4T, was isolated from cultivable phycosphere microbiota of harmful algal blooms-causing marine dinoflagellate Alexandrium catenella LZT09 which produces paralytic shellfish poisoning toxins. Strain LZ-4T was able to use thiosulfate (optimum concentration 10 mM) as energy source for bacterial growth. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain LZ-4T belonged to the genus Limnobacter, showing high 16S rRNA gene sequences similarities with L. thiooxidans DSM 13612T (99.4%), L. humi NBRC 11650T (98.2%) and L. litoralis NBRC 105857T (97.2%), respectively. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between LZ-4T and L. thiooxidans DSM 13612T were 78.9 and 21.9%, respectively. Both values were far lower than the thresholds (95–96% for ANI and 70% for dDDH) generally accepted for new species delineation. The respiratory quinone of strain LZ-4T was Q-8. The dominant cellular fatty acids were determined as summed feature 3 (C16:1 ω6c/ω7c), summed feature 8 (C18:1 ω6c/ω7c) and C16:0. Polar lipids profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids and three unidentified polar lipids. The genomic DNA G+C content of strain LZ-4T was 52.5 mol%. Based on polyphasic characterization, strain LZ-4T represents a novel species of the genus Limnobacter, for which the name Limnobacter alexandrii sp. nov. is proposed. The type strain is LZ-4T (=CCTCC AB 2019004T =KCTC 72281T).

In marine environment, alkaline phosphatase (ALP) is a nonspecific phosphatase with metal ions as its active site. Metal ions have different effects on ALP activity. Therefore, a probe that specifically detects ALP needs to be developed. In this paper, to eliminate the interference of acid phosphatase, we designed and synthesized a highly selective fluorescent probe CyP based on pH to detect ALP activity. The response mechanism of detecting ALP was explained. The photophysical properties, enzyme kinetics, stability, selectivity, and potential quantitative ability of the probe under different pH values were investigated. The effects of metal ions on the ALP activity of marine Chlorella vulgaris and Escherichia coli were also analyzed. Excessive metal ions such as Zn2+, Cu2+, Hg2+, Pb2+, and Cd2+ inhibit while Mn2+, Co2+, and alkaline-earth metal ions promote the ALP activity of Chlorella and E. coli.

Numerous valuable studies on electron dynamics have focussed on the extraordinary properties of molybdenum disulfide (MoS2); however, most of them were confined to the level below the damage threshold. Here the electron dynamics of MoS2 under intense ultrafast laser irradiation was investigated by experiments and simulations. Two kinds of ablation mechanisms were revealed, which led to two distinct types of electron dynamics and final ablation morphology. At a higher fluence, the emergence of superheated liquid induced a dramatic change in the transient reflectivity and micro-honeycomb structures. At a lower fluence, the material was just removed by sublimation, and the ablation structure was relatively flat. X-ray photoelectron spectroscopic (XPS) measurements demonstrated that thermal decomposition only occurred at the higher fluence. Furthermore, a theoretical model was developed to deeply reveal the ultrafast dynamics of MoS2 ablation. The simulation results were in good agreement with the temporal and spatial reflectivity distribution obtained from the experiment. The electron and lattice temperature evolution was also obtained to prove the ablation mechanism. Our results revealed ultrafast dynamics of MoS2 above the damage threshold and are helpful for understanding the interaction mechanism between MoS2 and intense ultrafast lasers, as well as for MoS2 processing applications., Optoelectronics: Digging into molybdenum disulfide Ultrafast damage-causing laser pulses affect bulk molybdenum disulfide differently depending on their energy per area, revealing further insight into the ultrafast electron dynamics. The research group of Lan Jiang from Beijing Institute of Technology, in cooperation with Tianhong Cui of University of Minnesota, has predicted and examined what happened to molybdenum disulfide on electron and lattice level when intense femtosecond laser pulses irradiate. Lower damage-causing energies per area, known as fluences, removed material through inducing a solid-to-gas transition. Higher fluences caused superheating, liquidation, and the formation of nanocracks and nanoridges. Tests on electron dynamics obtained by the materials’ reflectivity with different fluences were followed by theoretical simulations, which further helped to reveal the electron and lattice temperature evolution. The findings further understandings for laser processing of molybdenum disulfide and for its use in optoelectronics.

Femtosecond laser fabrication has grown to be a major method of extreme manufacturing because of the extreme energy density and spatial and temporal scales of femtosecond lasers. The physical effects and the mechanism of interaction between femtosecond lasers and materials are distinct from those in traditional processes. The nonlinear and nonequilibrium effects of the interaction have given rise to new concepts, principles, and methods, such as femtosecond pulse durations are shorter than many physical/chemical characteristic times, which permits manipulating, adjusting, or interfering with electron dynamics. These new concepts and methods have broad application prospects in micro/nanofabrication, chemical synthesis, material processing, quantum control, and other related fields. This review discusses the cutting-edge theories, methods, measurements, and applications of femtosecond lasers to micro/nano-manufacturing. The key to future development of femtosecond laser manufacturing lies in revealing its fabrication mechanism from the electronic level and precisely regulating the electronic dynamics.

Selective catalytic hydrogenation of p-chloronitrobenzene on Pt-based catalysts is a green and high-efficient way for p-chloroaniline production. However, supported monometallic Pt catalysts often exhibit undesirable p-chloroaniline selectivity. We herein reported supported Pt catalysts with N-doped carbon (NC) as an overcoating (Pt/Al2O3@NC) to overcome the disadvantage. Three Pt/Al2O3@NC catalysts with different NC coating amounts were prepared by in situ carbonization of an ionic liquid. For comparison, Al2O3 coated by NC and Pt/Al2O3 coated by SiO2 were also prepared. A combination characterization confirmed that the NC overcoating was successfully formed on Pt/Al2O3 surface and Pt particles were completely coated by NC layers when ion liquid amount increased to 25 μl per g catalyst. Due to the intimate contact of NC layers and Pt particles Pt-NC heterojunctions were effectively formed on the catalyst surface. For the catalytic hydrogenation of p-chloronitrobenzene, Pt/Al2O3@NC with 25 μl ionic liquid as the NC precursor exhibited 100% selectivity to p-chloroaniline at 100% conversion of p-chloronitrobenzene. A lower ionic liquid amount led to decreased selectivity to p-chloroaniline. Furthermore, no deactivation was observed on Pt/Al2O3@NC during 5 catalytic cycles. The findings in the study demonstrate that coating noble metal catalysts by N-doped carbon is a promising method to enhance the selectivity and stability for catalytic hydrogenation of p-chloronitrobenzene.

Transparent conductive oxides (TCO) are widely used in optoelectronic devices due to their high visible light transmittance and high electrical conductivity. Fabricating micro-nano structures on TCO films with femtosecond lasers can further enhance their optoelectronic properties. However, most of the existing researches on femtosecond laser processing of TCO films focus on materials such as indium tin oxide (ITO) and ZnO, and the research on fluorine-doped tin oxide (FTO) is still insufficient. In this paper, the ablation rules of FTO film irradiated by femtosecond laser is studied in detail. When the fluence is reduced to 1/e2 of the peak value as the radius of the laser spot, the ablation threshold measured by epitaxy method is 1.27 J/cm2. The experiment explores the ablation morphology of FTO film irradiated by single femtosecond laser pulse. When the laser fluence is 2.8-8.3 J/cm2, a bowl-shaped micro-crater is ablated, and when the laser fluence is 9.6-23.4 J/cm2, a secondary crater with a vertical inner wall and a flat bottom generates in the center of the ablated bowl-shaped crater. The pump-probe technique was used to study the ultrafast dynamics of the femtosecond laser interaction with FTO film, and we found that the phase explosion was responsible for the bowl-shaped crater formation.

The hepatotoxicity of Microcystin-LR (MC-LR) is mainly caused by its Adda moiety. In this study, we used TiO

Near-threshold femtosecond laser produces nanostructures on the gold film, which has received much attention in applications. However, the theoretical researches on the early stage of gold film excitation induced by the femtosecond laser are scarce, because of the ultrafast and non-equilibrium characteristics. In this study, stress and temperature distributions in different thicknesses of gold film induced by the near-threshold fluences were calculated. At the fluence below the melting threshold, we found that only the 30 nm gold films might be damaged by the non-thermal deformation. At the fluence of the melting threshold, the dominant damage mechanism shifted from non-thermal deformation to thermal melting as the gold film thickness increased. Our study provided a way to distinguish the dominant damage mechanism of gold film and it was valuable for the theoretical study of near-threshold processing.

As a very promising method for improving the performance of organic photovoltaic (OPV) devices, femtosecond laser processing is advantaged at high processing precision, small heat-affected zone and can achieve selective morphology control of the active layer. However, almost current studies focused on single pulse processing. In this work, the single and double pulse processing laws of poly(3-hexyl-thiophene) (P3HT): phenyl-C61-butyricacid methyl ester (PCBM) blend films were explored by using temporally-shaped femtosecond laser processing system. When single pulse processing is used, it indicated a structural transformation process from bump to ablation crater. The temporally-shaped double pulse femtosecond laser processing results showed the effect of ablation enhancement compared with the single pulse, and the ablation depth and the ablation area increased. (For bumps, it facilitated further fragmentation). When the double pulse delay is 0.5ps, the effect of ablation enhancement (bump fragmentation) was the strongest. This letter proposed an ablation enhancement approach based on temporally-shaped femtosecond laser processing, which can further control the morphology of the active layer for promoted performance of OPV devices.