Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme’s activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.

Problem definition: Transshipment/inventory sharing has been used in practice because of its risk-pooling potential. However, human decision makers play a critical role in making inventory decisions in an inventory sharing system, which may affect its benefits. We investigate whether the opportunity to transship inventory influences decision makers’ inventory decisions and whether, as a result, the intended risk-pooling benefits materialize. Academic/practical relevance: Previous research in transshipment, which is focused on finding optimal stocking and sharing decisions, assumes rational decision making without any systematic bias. As one of the first to study inventory sharing from a behavioral perspective, we demonstrate a persistent stocking-decision bias relevant for inventory sharing systems. Methodology: We develop a behavioral model of a multilocation inventory system with transshipments. Using four behavioral studies, we identify, test, estimate, and mitigate a demand-side underweighting bias: although inventory sharing brings both a supply-side benefit and a demand-side benefit, players underestimate the latter. We show analytically that such bias leads to underordering. We also explore whether reframing the inventory sharing decision reduces this bias. Results: Our results show that subjects persistently reduce their order quantities when transshipments are allowed. This underordering, which persists even when a decision-support system suggests optimal quantities, causes insufficient inventory in the system, in turn reducing the risk-pooling benefits of inventory sharing. Underordering is evidently caused by an underweighting bias; although players correctly estimate the supply-side potential from transshipment, they only estimate 20% of the demand-side potential. Managerial implications: Although inventory sharing can profitably reduce inventory, too much underordering undermines its intended risk-pooling benefits. The demand-side benefits of transshipment need to be emphasized when implementing inventory sharing systems.

Abstract-E-commerce has become a thriving business model. With easy access to various tools and third-party cashiers, it is straightforward to create and launch e-commerce web applications. However, it remains difficult to create secure ones. While third-party cashiers help bridge the gap of trustiness between merchants and customers, the involvement of cashiers as a new party complicates logic flows of checkout processes. Even a small loophole in a checkout process may lead to financial loss of merchants, thus logic vulnerabilities pose serious threats to the security of e-commerce applications. Performing manual code reviews is challenging because of the diversity of logic flows and the sophistication of checkout processes. Consequently, it is important to develop automated detection techniques. This paper proposes the first static detection of logic vulnerabilities in e-commerce web applications. The main difficulty of automated detection is the lack of a general and precise notion of correct payment logic. Our key insight is that secure checkout processes share a common invariant: A checkout process is secure when it guarantees the integrity and authenticity of critical payment status (order ID, order total, merchant ID and currency). Our approach combines symbolic execution and taint analysis to detect violations of the invariant by tracking tainted payment status and analyzing critical logic flows among merchants, cashiers and users. We have implemented a symbolic execution framework for PHP. In our evaluation of 22 unique payment modules, our tool detected 12 logic vulnerabilities, 11 of which are new. We have also performed successful proof-ofconcept experiments on live websites to confirm our findings.

Problem definition: The continuously soaring prices of new drugs and their uncertain effectiveness in clinical practice have put substantial risks on insurers/payers. To induce insurer coverage of their new drugs, manufacturers start to propose an innovative outcome-based reimbursement (OBR) scheme under which manufacturers refund insurers (and possibly patients) if the drugs fail to achieve a prespecified treatment target. We investigate the impact of OBR on insurers, manufacturers, and patients. Academic/practical relevance: Although OBR sounds intuitively appealing, its true impact is under much debate and depends particularly on the design of OBR. Our study sheds light on the optimal design of OBR and the debate around OBR, considering key trade-offs and key elements not covered in prior literature. Methodology: We develop a Stackelberg game under which the manufacturer designs a rebate scheme for its drug, either non-OBR or OBR, considering the trade-off between a favorable formulary position and the rebate provided. The insurer subsequently determines its formulary for the drug as well as other alternative drugs within the same disease category considering the trade-off between its spending and patient health benefits. Using data on 14 drugs treating a common disease, hyperlipidemia, we estimate through a multinomial logit model the demand of the 14 drugs and conduct counterfactual analyses on the impact of OBR. Results: Under the optimal OBR, the manufacturer lowers the insurer’s risk but inflates the wholesale price (hence, may not reduce insurer spending). OBR also induces a better formulary position for the manufacturer, which, hence, improves patient access to new drugs. Further, rebates to the insurer and patients affect demand through different mechanisms. Including patient rebates in OBR lowers patient expenses and increases drug demand but further increases insurer spending. Managerial implications: We demonstrate the structure of an optimal formulary and its application in practice. We caution insurers/payers who are seeking OBR to reduce their spending.

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The collaboration on hotel room booking service between hotels and third-party websites provides hotels much benefit on increasing capacity utilization. But the commonly used "first-come first-serve" (FCFS) form put hotels in a disadvantageous position especially when the websites have much more market attractiveness than the hotels. This paper proposes a new form named "setting Online-Exclusive-Rooms (OERs)" for a hotel to collaborate with a third-party website on room booking service. The form is presented by solving a two-stage decision problem: in the first stage, the hotel determines the quantity of OERs which can only be booked online through the third-party website; in the second stage, the hotel sets an acceptance policy to treat the additional request from the website. Analytical results indicate that "setting OERs" can improve the expected revenue of hotels compared with the current widely used "FCFS" form.

The modern information network environment largely changed consumer habits. Hotel Reservation way becomes increasingly diversified. By building the traditional and Internet booking ways' demand functions which were linear in self-and cross-price effects and the hotel revenue function, we determine the optimal pricing strategy of the hotel's Internet booking way. The effect of the optimal strategy is also discussed, and numerical simulation verifies that the optimal strategy can greatly improve the hotel revenue. All of the research propositions help hotel managers make deeper understanding of fixed room quantity's influence on pricing strategies, and provide managers the basis of pricing strategy.

Evidence suggests that histone modification disorders are involved in leukemia pathogenesis. We previously reported that LukS-PV, a component of Panton–Valentine leukocidin (PVL), has antileukemia activities that can induce differentiation, increase apoptosis, and inhibit proliferation of acute myeloid leukemia (AML) cells. Furthermore, LukS-PV inhibited hepatoma progression by regulating histone deacetylation, speculating that LukS-PV may exert antileukemia activity by targeting histone modification regulators. In this study, the results showed that LukS-PV induced apoptosis by downregulating the methyltransferase SET8 and its target histone H4 monomethylated at Lys 20 (H4K20me1). Furthermore, chromatin immunoprecipitation sequencing and polymerase chain reaction identified the kinase PIK3CB as a downstream target gene for apoptosis mediated by SET8/H4K20me1. Finally, our results indicated that LukS-PV induced apoptosis via the PIK3CB-AKT-FOXO1 signaling pathway by targeting SET8. This study indicates that SET8 downregulation is one of the mechanisms by which LukS-PV induces apoptosis in AML cells, suggesting that SET8 may be a potential therapeutic target for AML. Furthermore, LukS-PV may be a drug candidate for the treatment of AML that targets epigenetic modifications.