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BACKGROUND/PURPOSE: Emerging evidence has shown that various failures in cancer therapy, such as drug resistance, metastasis, and cancer relapse are attributed to cancer stem cells (CSCs). Also, growing attention has been paid to the regulation of non-coding RNAs in cancer stemness. Here, we aimed to investigate the contribution of LINC01296 in the modulation of oral CSCs. MATERIALS AND METHODS: The phenotypic assays including migration, invasion, and colony-forming abilities were carried out in CSCs of two types of oral cancer cells (SAS and GNM) following the knockdown of LINC01296. In addition, the percentage of cells expressing stemness marker, ALDH1, and drug resistance marker, ABCG2, was examined as well as the self-renewal capacity after silencing of LINC01296. Moreover, a luciferase reporter was used to validate the direct interaction between LINC01296 and miR-143. RESULTS: Our results showed that LINC01296 was significantly overexpressed in oral cancer tissues and positively correlated with stemness markers. The phenotypic and flow cytometry assays demonstrated that suppression of LINC01296 reduced the aggressiveness, cancer stemness features, and colony-forming and self-renewal abilities in oral CSCs. Furthermore, we demonstrated that LINC01296 may enhance cancer stemness features through suppression of the effect of miR-143. CONCLUSION: Silencing of LINC01296 may be a promising direction for oral cancer therapy by reducing cancer stemness via regulation of miR-143.

We examine price negotiation in the payment card industry by exploiting a unique merchant-, industry-, and city-level data set. Motivated by the substantial variation in acquirer fees and heterogeneous merchant card transactions, we use Nash bargaining to model the negotiation over the acquirer fee between an acquirer and a merchant. We find that the merchants secure a larger incremental surplus than the acquirer on average. Moreover, merchants might face upward pressure on acquirer fees as the card penetration rate rises over time, and policies that weaken the acquirer's bargaining power could relieve the upward fee pressure.

N-Heterocyclic carbene ligated transition-metal catalysts often show interesting properties and reactivity as compared to conventional ligand systems. In (NHC)Ni and (NHC)Pd hydrides, a dramatic reactivity changed from cross-hydroalkenylation to transfer-dehydroaromatization was observed under optimized conditions. This account summarizes our recent efforts and stories behind this serendipitous discovery. The mechanistic studies revealed that the keys to divert the desired reactivity are the differences in the olefin insertion selectivity and the hydrometallated species reactivity.

Background/purpose The habit of areca nut chewing has been regarded as an etiological factor of precancerous oral submucous fibrosis (OSF). In the present study, we aimed to evaluate the anti-fibrosis effect of honokiol, a polyphenolic component derived from Magnolia officinalis. Methods The cytotoxicity of honokiol was tested using normal and fibrotic buccal mucosal fibroblasts (fBMFs) derived from OSF tissues. Collagen gel contraction, Transwell migration, invasion, and wound healing capacities were examined. Besides, the expression of TGF-β/Smad2 signaling as well as α–SMA and type I collagen were measured as well. Results Honokiol exerted higher cytotoxicity of fBMFs compared to normal cells. The arecoline-induced myofibroblast activities, including collagen gel contractility, cell motility and wound healing capacities were all suppressed by honokiol treatment. In addition, the expression of the TGF-β/Smad2 pathway was downregulated along with a lower expression of α–SMA and type I collagen in honokiol-receiving cells. Conclusion Our data suggest that honokiol may be a promising compound to alleviate the progression of oral fibrogenesis and prevent the transformation of OSF oral epithelium into cancer.

Cross-dimerization of a methylenecyclopropane (1) and an unactivated alkene (2) with typical hydroalkenylation reactivity was observed for the first time by using a [NHC-Ni(allyl)]BArF catalyst (NHC=N-heterocyclic carbene). Results show that the C-C cleavage of 1 did not involve a Ni0 oxidative addition, which was crucial in former systems. Thus the method reported here emerges as a complementary method for attaining highly chemo- and regioselective synthesis of methylenecyclopentanes (3) with broad scope. An efficient NHC/NiII -catalyzed rearrangement of 1 leads to the convergent synthesis of 3 in the presence of 2.

Background/Purpose Various microRNAs (miRs) have been found to be associated with the development of the precancerous condition of the oral cavity, oral submucous fibrosis (OSF). The expression of miR-29c is dysregulated in oral cancer, but its role in OSF has not been investigated. The purpose of the study is to investigate the functional role of miR-29c and its target in OSF. Methods The expression levels of miR-29c in OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs) were assessed using next-generation sequencing and real-time Polymerase Chain Reaction (PCR) analysis. MiR-29c mimic and inhibitors were employed to examine its functional role of myofibroblast transdifferentiation. In addition, several myofibroblast phenotypes, such as collagen gel contraction and migration were tested, and a luciferase reporter assay was conducted to confirm the relationship between miR-29c and its predicted target, tropomyosin-1 (TPM1). Results We observed that miR-29c expression was downregulated in fBMFs. fBMFs transfected with miR-29c mimics exhibited reduced migration ability and collagen gel contractility, whereas inhibition of miR-29c in normal BMFs induced the myofibroblast phenotypes. Results from the luciferase reporter assay showed that TPM1 was a direct target of miR-29c and the expression of TPM1 was suppressed in the fBMFs transfected with miR-29c mimics. Besides, we confirmed that the expression of miR-29c was indeed downregulated in OSF specimens. Conclusion MiR-29c seems to exert an inhibitory effect on myofibroblast activation, such as collagen gel contractility and migration ability, via suppressing TPM1. These results suggested that approaches to upregulate miR-29c may be able to ameliorate the progression of OSF.

Background/purpose Betel nut chewing is the major risk factor of oral submucous fibrosis (OSF). Various studies have sought to discover alternative strategies to alleviate oral fibrogenesis. In the present study, we aimed to evaluate the anti-fibrosis effect of paeonol, a phenolic component derived from Paeonia Suffruticosa. Methods The cytotoxicity of paeonol was tested using normal and fibrotic buccal mucosal fibroblasts (fBMFs) derived from OSF tissues. Collagen gel contraction, Transwell migration, invasion, and wound healing capacities were examined. Besides, the activation of TGF-β/Smad2 signaling and expression levels of type I collagen, α-SMA, and long non-coding RNA HOTAIR were measured as well. Results Paeonol exerted a higher cytotoxic effect on fBMFs compared to normal BMFs. The arecoline-induced myofibroblast activities, including collagen gel contractility, cell motility, and wound healing ability were all suppressed by paeonol treatment. In addition, the activation of the TGF-β/Smad2 pathway was inhibited along with a lower expression of α-SMA and type I collagen in paeonol-treated cells. Also, the administration of paeonol decreased the mRNA expression of HOTAIR in fBMFs. Conclusion Our results indicate that paeonol may be a promising compound to attenuate the progression of oral fibrogenesis in OSF patients.

This paper examines the effects of Internet channel on the commercialization of firm innovation, which is measured by new product sales (NPS). We estimate our empirical model with the GMM-threshold...

Though the properties of N-heterocyclic carbenes (NHCs) are generally dominated by the very strong σ donating character, electronic activation has emerged as an effective method to cooperate with typical carbon-framework steric optimization for highly enantioselective chiral NHC–transition-metal catalysis in recent years. NHC electronic changes associated with structural variations are now better understood by quantitative analysis using various methods. Here we highlighted and correlated some interesting chiral induction improvement methods, which were brought by electronic and steric cooperation on chiral NHC–transition-metal catalysis.1 Introduction2 Hemilabile Sidechains on NHC Ligands3 Electronic and Bond Angle Changes Brought by NHC Core Size Variations4 Electronic Activators on the NHC Core5 Conjugated Systems and Fused Ring Structures6 Remote Electronic Activators on the N-Aryl Ring7 Summary and Outlook

A cross-hydroalkenylation/rearrangement cascade (HARC), using a cyclopropene and alkyne as substrate pairs, was achieved for the first time by using new [(NHC)Ni(allyl)]BArF catalysts (NHC=N-heterocyclic carbenes). By controlling the (NHC)NiII H relative insertion reactivity with cyclopropene and alkyne, a broad scope of cyclopentadienes was obtained with highly selectively. The structural features of the new (NHC)NiII catalyst were important for the success of the reaction. The mild reaction conditions employed may serve as an entry for exploring (NHC)NiII -assisted vinylcyclopropane rearrangement reactivity.

We consider a two-stage tournament in which two alliances compete in stage one. Members of the winning alliance then compete against each other in stage two. Members’ investment in stage one could increase their alliance's winning probability, but could also be appropriated and used against them by their partners-turned-rivals in stage two. This hold-up problem creates a negative incentive for within-alliance cooperation. We test this theoretical benchmark in an experiment. In a second experiment, we investigate whether ex-ante informal agreements deter appropriation. We find that such agreements are honored, and thus encourage investments, only under the fixed matching condition.

The photo- and structural properties of a series of Au(iii) indolizine complexes were determined. Controlled release of halogenated indolizine derivatives from the corresponding Au(iii) complexes was achieved by photoinduced C-X bond formation, which provided turn-on luminescence with an increase in emission intensity of up to 67 times.

Enantioenriched 1,4-dienes are versatile building blocks in asymmetric synthesis, therefore their efficient synthesis directly from chemical feedstock is highly sought after. Here, we show an enantioselective cross-hydroalkenylation of cyclic 1,3-diene and hetero-substituted terminal olefin by using a chiral [NHC-Ni(allyl)]BArF catalyst. Using a structurally flexible chiral C2 NHC-Ni design is key to access a broad scope of chiral 1,4-diene 3 or 3′ with high enantioselectivity. This study also offers insights on how to regulate chiral C2 NHC-Ni(II) 1,3-allylic shift on cyclic diene 1 and to build sterically more hindered endocyclic chiral allylic structures on demand., Chiral 1,4-dienes are versatile building blocks in asymmetric synthesis, therefore their production is highly sought after. Here, the authors report an efficient enantioselective cross-hydroalkenylation of cyclic 1,3-dienes and terminal olefins affording chiral 1,4-dienes by using a chiral NHC-Ni(allyl)]BArF catalyst.

Diastereodivergent heterocycle synthesis has been recognized as an important tool for drug discovery in recent years, yet strategies based on nickelacycle formation have not been established. Here, we report a NHC-Ni catalyzed highly 1,3- and 1,4-diastereodivergent heterocycle synthesis from enyne, which is achieved by manipulating the enyne N-substituent (allowing switching of selectivity from up to 2:98 to 98:2). The key to success is the efficient diastereodivergent formation of a nickelacyclopentene, with broad enyne scope at mild conditions, which subsequently provides reductive hydroalkenylation, acylation and silylation products on demand. Diastereoisomers which are sterically hard to distinguish or difficult to access by conventional routes are now accessible easily, including those with very similar 4°, contiguous and skipped stereocenters. Diastereoselective cyclisation of heteroatom-substituted enynes offers a valuable route to bioactive heterocycles. Here, a diastereodivergent nickel-catalysed cyclisation of heteroenynes offers access to diastereomers of 1,3- and 1,4-hydroalkenylation products, controlled by the choice of substituents.

This study investigates the effects of financial deepening on innovation for various democratic levels of political institutions using panel data from 74 countries spanning 1970–2010. Our results show that banking market deepening is associated with increased innovation only when political institutions are sufficiently democratic. In contrast, the enhancing effect of stock market deepening on innovation requires a lower level of political democracy. Further, we find that increasing the state's openness and competitiveness in the executive recruitment of leaders is the main channel through which political democratization promotes the role of banking and stock markets for financing innovation. Our results are robust to the use of the instrumental variable approach; alternative measures for financial deepening, democracy and innovation input; long-differenced variables; and alternative specifications.

5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) has been used in the treatment of various precancerous and malignant lesions. Our previous work has demonstrated that ALA-PDT possesses the potential to serve as an adjuvant therapy against head and neck cancer via eliminating the cancer stem cells (CSCs) property. This study aimed to further investigate the possible molecular mechanism underlying the effect of ALA-PDT. Our results revealed that ALA-PDT upregulated the expression of microRNA-145 (miR-145) in two oral cancer cell lines. Overexpression of miR-145 in oral CSCs further enhanced the treatment effect of ALA-PDT with lower self-renewal, invasion capacities and reduced CD44 expression, while inhibition of miR-145 exhibited the opposite phenomena. These findings suggest that the anti-CSCs effect of ALA-PDT is due to an elevation of miR-145. Keywords: 5-Aminolevulinic acid-mediated photodynamic therapy, Oral cancer stem cells, microRNA-145

Cross-hydroalkenylation of a vinyl ether (1) with an α-olefin (2) was first achieved by a set of [NHC-Ni(allyl)]BArF (NHC=N-heterocyclic carbene) catalysts. Both 1,2- and 1,3-disubstituted allyl ethers were obtained, highly selectively, by using NHCs of different sizes. In contrast, the chemoselectivity (i.e., 1 as acceptor and 2 as donor) was controlled mostly by electronic effects through the catalyst-substrate interaction. Sterically bulkier alkenes (2) were used as preferred donors compared to smaller alkenes. This electronic effect also served as a basis for the first tail-to-head cross-hydroalkenylations of 1 with either a vinyl silane or boronic ester.

This paper empirically examines international knowledge spillover through bilateral trade. We extend the knowledge production function using a spatial autoregressive term and time-varying weights matrices, and we estimate this model using a sample of 30 countries over the period 1975–2010. We find that there is a positive spillover effect of innovation from one country to its trade partners through bilateral import flows. The spillover effect accounts for approximately 1.3%–3.6% of the total effect of R&D input on innovation output over time.

Simple Summary The conventional methods that seek to predict clinical treatment response are based on the number of circulating tumor cells (CTCs) present in liquid biopsies or genetic profiling of extracted CTCs. This paper presents a novel process by which CTCs can be extracted from blood samples taken from head and neck cancer patients and then expanded ex vivo to form organoids that can be tested with a panel of anti-cancer treatments. The resulting drug sensitivity profiles derived from cisplatin treatment of organoids were subsequently found to correlate with clinical treatment response to cisplatin in patients. CTCs extracted from liquid biopsies for ex vivo expansion negates the need for complicated and potentially risky biopsies of tumor material, thereby supporting the application of this procedure for checkups and treatment monitoring. Abstract The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments.

We construct a structural model that allows us to jointly estimate the demand for smartphones and paid apps using a Bayesian approach. Our data comes from more than 500 college students in Hong Kong and Shanghai. We find that the utility cost rather than the upfront monetary cost of jailbreaking smartphones determines its prevalence. Users mainly jailbreak smartphones to use paid apps for free, a reason more important among Android users than iPhone users. Paid apps contribute the lion’s share of the profits (between 66% and 59%) for both the Android and iPhone. Strictly prohibiting jailbreaking would decrease the aggregate market share of smartphones in the cell phone market. Apple, however, would sell even more iPhones at the expense of Android smartphones.

Purpose It is clinically important to accurately predict facial soft tissue changes prior to orthognathic surgery. However, the current simulation methods are problematic, especially in anatomic regions of clinical significance, e.g., the nose, lips and chin. We developed a new 3-stage finite element method (FEM) approach that incorporates realistic tissue sliding to improve such prediction. Methods In Stage One, soft-tissue-change was simulated using FEM with patient-specific mesh models generated from our previously developed eFace template. Postoperative bone movement was applied on the patient mesh model with standard FEM boundary conditions. In Stage Two, the simulation was improved by implementing sliding effects between gum tissue and teeth using a nodal force constraint scheme. In Stage Three, the result of the tissue sliding effect was further enhanced by reassigning the soft tissue-bone mapping and boundary conditions using nodal spatial constraint. Finally, our methods have been quantitatively and qualitatively validated using 40 retrospectively evaluated patient cases by comparing it to the traditional FEM method and the FEM with sliding effect using a nodal force constraint method. Results The results showed that our method was better than the other two methods. Using our method, the quantitative distance errors between predicted and actual patient surfaces for the entire face and any sub-regions thereof were below 1.5 mm. The overall soft tissue change prediction was accurate to within 1.1 ± 0.3 mm, with the accuracy around the upper and lower lip regions of 1.2 ± 0.7 mm and 1.5 ± 0.7 mm, respectively. The results of qualitative evaluation completed by clinical experts showed an improvement of 46% in acceptance rate compared to the traditional FEM simulation. More than 80% of the result of our approach was considered acceptable in comparison with 55% and 50% following the other two methods. Conclusion The FEM simulation method with improved sliding effect showed significant accuracy improvement in the whole face and the clinically significant regions (i.e., nose and lips) in comparison with the other published FEM methods, with or without sliding effect using a nodal force constraint. The qualitative validation also proved the clinical feasibility of the developed approach. This article is protected by copyright. All rights reserved.

This paper analyses how trade liberalisation affects the markups of Chinese firms based on firm-level production data, highly disaggregated transaction-level product trade data and tariff data at the eight-digit Harmonised System (HS) level. Our results show that there is a pro-competition effect of output tariff reduction, that is decreasing output tariffs relate to a lower markup, and that there is a cost-reduction effect of input tariff reduction, that is decreasing input tariffs relate to a higher markup. Interestingly, there are heterogeneous effects of trade liberalisation on firm-level markups. The cost-reduction effect of input tariff reduction is partially offset by the competition effect of new firm entry in more-concentrated industries. Furthermore, there is a weaker effect of trade liberalisation on processing trade firms and state-owned enterprises. Finally, our results are robust to the use of an instrumental variable approach to control for the endogeneity of tariffs and sample selection.

Highly selective cross-hydroalkenylation of endocyclic-1,3-dienes at the least substituted site with a-olefins was achieved by set of neutral NHC-Ni(II)H(OTf), and by cationic Ni(II) catalysts with novel NHC structure. Under the heteroatom assistance, skipped dienes were obtained in good yield by using as low as equal molar amount of substrate pairs and 2-5 mol% catalyst. A rare 4,3- product selectivity (i.e., H at C4 and alkenyl group at C3 of diene) was observed, which is different from known dimerizations of a-olefins with both acyclic Co and Fe systems. The substituent effects of NHC, 1,3-diene and a-olefins on chemo-, regio- and diastereo-selectivity were studied. High level of chirality transfer was observed by using chiral cyclohexadiene derivatives.