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The development of biocompatible and efficient polymeric micelles for drug delivery has been drawing great attention. Herein, amphiphilic molecule (PMPC) was synthesized with zwitterionic linear polyethyleneimine (PEI) as the hydrophilic...

In this paper we study the competitive order timing decisions of two manufacturers with demand forecasting updating and uncertain raw material price. Manufacturers can order the raw materials early when the market is highly uncertain with a fixed wholesale price (Contract procurement) or late when the market is less uncertain with an uncertain raw material price (Spot trading). Different from most existing literature, we assume the spot price and the market demand is correlated. We find that in the monopoly setting the manufacturer prefers the contract procurement to the spot trading when the unit wholesale price for the contract procurement is not greater than the expected unit spot price of the raw material. In the duopoly setting, we characterize the equilibria of a strategic order timing game in which manufacturers choose when to buy the raw materials. We find that when the demand during the contract procurement stage and the spot price uncertainty is small both manufacturers prefer the contract procurement strategy and when the demand during the contract procurement stage and the spot price uncertainty is large both manufacturers prefer the spot trading. When the demand during the contract procurement stage and the spot price uncertainty is high and purchase costs do not decline too severely over time, the unique equilibrium of this game is that one manufacturer chooses contract procurement to order early and the other chooses spot trading to order late. Further, we find that the correlation of spot purchasing price and the market demand signal during the contract procurement stage will weaken the advantages of spot trading strategy. When the spot purchasing price and the market demand signal during the contract procurement stage are not correlated, manufacturers prefer spot trading under the highly volatile spot trading price, fluctuating demand, and high information precision.

Chemotherapeutic nanodrugs have to penetrate through many biological barriers before reaching the tumor cells. Thus, high stability of the nanocarrier before reaching tumor cells and fast release of the carried drugs in targeted tumor cells are required. In this work, inspired by the intrinsic zwitterionic surface property, mainly formed by glutamic acid and lysine residues, of the plasma protein surface, the zwitterionic poly(glutamyl lysine-co-aspartic acid-co-cysteine) peptide (P(EK-D-C)) was synthesized for conjugating n-mercaptoalkanoic acid (MA) with different chain lengths on cysteine residues through a disulfide linkage to load hydrophobic doxorubicin (DOX). The results showed that the slightly negative-biased zwitterionic nanodrugs were very stable in both resistance to nonspecific plasma protein adsorption and prevention of premature DOX release at physiological pH 7.4 due to the zwitterionic polypeptide shell and the sharp contrast in polarity between the shell and DOX-loaded core, while they can quickly release the loaded DOX through responding to both low pH values in the endosome/lysosome and high glutathione concentrations in the tumor cell cytoplasm. Furthermore, the enhanced internalization of these nanodrugs led to about 60% higher in vitro cytotoxicity against MCF-7 cells at pH 6.7 than at pH 7.4, whereas the in vitro cytotoxicity of DOX·HCl at pH 6.7 was only 75% of the value at pH 7.4. In vivo results revealed that the stable nanodrugs conjugated with the long hydrophobic 12-mercaptododecanoic acid had higher tumor inhibition rate and lower systematic toxicity on MCF-7 tumor-bearing mice than the less stable nanodrugs conjugated with the short 8-mercaptooctaoic acid and were significantly superior to DOX·HCl. These results indicate that the combination of high stability in circulation and fast release in tumor cells of nanodrugs can enhance high efficacy targeted chemotherapy. This pH/redox-sensitive zwitterionic polypeptide nanocarrier might provide an excellent vehicle for solid tumor treatment.

To simplify the preparation process and increase the drug-loading capacity of antitumor nanodrugs, doxorubicin-loaded micelles based on zwitterionic oligopeptides were fabricated through two step reactions in mild conditions. Zwitterionic oligopeptides Glu–Lys–Cys–Glu–Lys (EKCEK) were reacted with methacrylohydrazide (MAH) by click reaction, the product was further conjugated with doxorubicin (Dox) to form amphipathic molecules, and finally the amphipathic molecules self-assembled into doxorubicin-loaded micelles (EKCEK–Dox) in deionized water. TEM and DLS results showed that the EKCEK–Dox micelles were of the regular sphere, with the mean diameter approximately 70 nm. The drug-loading capacity of the prepared micelles was up to 44.6%, and the micelles were very stable in PBS solution. In vitro antitumor experiment showed that the EKCEK–Dox micelles had significant inhibition efficacy on MCF-7 cells, which was much better than the clinical antitumor drug (Doxil®). The IC50 of the EKCEK–Dox micelles (5.6 μg Dox equiv. per mL) was significantly lower than Doxil (8.9 μg Dox equiv. per mL). Therefore, the drug delivery system based on zwitterionic oligopeptides will be a promising strategy for cancer chemotherapy.

Zwitterionic materials have been employed to achieve excellent biocompatibility and the well-suppressed nonspecific protein adsorption of nanoparticles. However, a thick and compact zwitterionic la...

Pathological TDP‐43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD‐TDP); however, how TDP‐43 aggregation and function are regulated remain poorly understood. Here, we show that O‐GlcNAc transferase OGT‐mediated O‐GlcNAcylation of TDP‐43 suppresses ALS‐associated proteinopathies and promotes TDP‐43's splicing function. Biochemical and cell‐based assays indicate that OGT's catalytic activity suppresses TDP‐43 aggregation and hyperphosphorylation, whereas abolishment of TDP‐43 O‐GlcNAcylation impairs its RNA splicing activity. We further show that TDP‐43 mutations in the O‐GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP‐43 overexpression in Drosophila motor neurons. We finally demonstrate that O‐GlcNAcylation of TDP‐43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O‐GlcNAcylation might be a target for the treatment of TDP‐43‐linked pathogenesis.

Private cost information and entrepreneurial moral hazard are serious problems that result from the significant information asymmetry associated with creators and their backers in reward-based crowdfunding. We establish a dynamic game-theoretic model to investigate the effect of moral hazard on the quality and price decisions of a creator (male) when his cost efficiency is unobservable. Backers (female) in the crowdfunding stage directly observe neither the cost efficiency nor the product quality of the creator. They then make pledge decisions based on expectations about the quality after observing the campaign parameter signals (i.e., the reward price and funding goal) and whether the regulation mechanism is implemented with a strong hand (tighter regulations mean that the creators have less moral hazard). We find that compared with the information symmetry case, when the efficiency of creators is not known to backers, an efficient creator always provides a higher level of product quality when moral hazard is present but not always when moral hazard is absent. In addition, we investigate the effect of moral hazard on the creator and consumer surplus when the creator's cost efficiency is unobservable. Interestingly, we show that moral hazard may benefit both the creator and consumers. This explains the puzzling measures of some reward crowdfunding platforms such as Kickstarter and Indiegogo, which take no active role in managing or monitoring the entrepreneurial projects. Finally, we find that reasonably the efficient creator can better signal his efficiency by using two signaling devices, i.e., the reward price and funding goal; in this case, interestingly, the existence of moral hazard may still benefit both the creators and consumers. This confirms the robustness of our main results.

In this paper, we study how funds regulation influences a venture’s token issuing strategy, cash diversion behavior and signaling effectiveness, when he has private knowledge on product quality (i.e., high or low). We first analyze this problem under complete information, which extends Gan et al. (2021) to the case when funds are regulated. We find that a higher funds regulation level incentives the venture’s cash diversion behavior and induces a higher profit. Then, under information asymmetry, we characterize the high-quality venture's token issuing strategies under strict funds regulation and no funds regulation, respectively. We find that the relative sizes of informed and uniformed investors are important in token sizes' signaling effectiveness, which in turn influences the venture's token issuing strategies. Moreover, our theoretical results are (partially) consistent with some empirical observations in quality signaling and open new avenues for future empirical study. At last, we show that funds regulation may improve signaling effectiveness but it does not always benefit the high-quality venture under information asymmetry. Specifically, we show that a strict funds regulation may hurt the high-quality venture in a small ICO market; and even when the ICO market is large, the high-quality venture may prefer a moderate funds regulation level. Our results are robust when the number of investors in the ICO market is random.

In recent years, there emerge some new financing techniques as additional financing options for the entrepreneurs, especially for those, such as start-ups, that ordinarily faced difficulties in accessing the traditional financing techniques. Among these new techniques, reward-based crowdfunding (crowdfunding) and the initial coin offerings (ICOs) are the two most popular strategies. In this paper, we build a stylized model to investigate how the product characteristics affect the entrepreneur's financing choice between crowdfunding and ICO. We show that ICO (resp. crowdfunding) is more suitable for intangible (resp. tangible) products that typically have high (resp. low) fixed costs and low (resp. high) production costs. This result is built off of their different fundraising mechanisms. Under crowdfunding (resp. ICOs), the fundraising is through sacrificing the profit in the funding stage (resp. both funding and market stages). Moreover, speculators can be a double-edged sword to ICOs. On the one hand, the participation of speculators can increase the financing success rate of ICOs. On the other hand, the competition from speculators in the token transaction market will hurt the entrepreneur. We also show that ICOs become more preferable than crowdfunding in the presence of the R\&D failure risk. Finally, we examine the setting with endogenous product quality and show that ICOs lead to higher product quality than crowdfunding when the startup cost is low, or when either of the platform traffic and the production cost is high.

In this paper, we consider a supplier serving two competing manufacturers who produce and sell their products in the same market faced with the uncertain demand. The manufacturers can either participate in the supplier development programme by reserving their capacities from the supplier before the demand is realized, which is referred to as the advance reservation, or do not by reserving their capacities after the demand is realized, which is referred to as the regular reservation. Given the unit capacity wholesale prices for both the advance reservation and the regular reservation, we study the manufacturers' capacity reservation and selling, and the supplier's capacity building decisions in equilibrium when the advance reservation strategy is adopted by neither, one, or both of manufacturers. We further investigate the equilibrium reservation strategies of manufacturers. We discover that completely symmetric manufacturers may choose different capacity reservation strategies, in which case, a unique mixed strategy equilibrium also arises. We also identify the conditions under which the capacity reservation preferences of all supply chain members can be aligned, thus achieving the efficiency of the supply chain. Our findings underscore the importance of operational characteristics in determining the capacity reservation strategies.

To augment the antitumor efficacy and minimize the significant side effects of chemotherapeutic drugs on health organs, a novel albumin-mimicking nanodrug, which is based on zwitterionic poly(glutamatyl lysine

Albumin mimics could be an attractive platform for nanodrug carriers through systematic administration because of high safety and plentiful properties to be adjusted for a high drug efficacy, such as pH-triggered targeting cellular uptake and drug release. In this work, negative-biased zwitterionic nanodrug carriers based on zwitterionic polypeptide chains that mimic albumin were prepared, which have an outermost layer of zwitterionic glutamic acid (E) and lysine (K) pairs with a small amount of aspartic acid (D) to adjust the overall ζ potential. On the other hand, doxorubicin (Dox) was encapsulated in a hydrophobic core by 11-maleimidoundecanoic acid covalently linked with additional cysteine (C) residues on the polypeptide. The results show that the negative-biased zwitterionic nanodrug carriers can sensitively enhance the cellular uptake in responding to a pH change from 7.4 to 6.7 without reversing the ζ potential to a positive charge, leading to accelerating the Dox release rate in a slightly acidic environment through the polypeptide secondary structure change. Moreover, the anionic nanodrug carrier can also be easily enzymatically digested by trypsin for quick drug release. In short, this negative-biased zwitterionic nanodrug delivery vector could be an ideal candidate for a safer tumor inhibition with a high efficacy than conventional synthetic polymer-based ones.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma (NHL) that is clinically aggressive and has a poor prognosis. Platelet-derived growth factor receptors (PDGFRs) and their ligands (PDGFs) play important roles in angiogenesis, cancer cell proliferation, survival, migration and poor prognosis in various tumours. However, the significance of PDGFRs in NKTCL remains unknown. Herein, the present study aimed to investigate the important role of PDGFRα in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFRα expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFRα expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFRα blockade in two NKTCL cell lines was conducted through proliferation assay, cell-cycle evaluation and apoptosis detection by flow cytometry analyses. Furthermore, we detected in vivo activity of imatinib in mouse model of NKTCL. We found that the expression of PDGFRα was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFRα expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFRα expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFRα expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFRα expression (P = 0.003) were independent prognostic factors in NKTCL patients. Biological assessment assays in two NKTCL cell lines revealed that a specific PDGFR antagonist, imatinib, inhibited cell viability, blocked cell cycle progression at G0/G1 stage and induced apoptosis. Similarly, the in vivo assay showed that imatinib delayed mouse model tumour growth. In conclusion, NKTCL tumour cells have prominent PDGFRα expression, which can serve as a candidate prognostic marker. PDGFR antagonists have significant biological effect on NKTCL and may be useful therapeutic agents for treatment of NKTCL.

Up-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine-induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain-deleted GAPDH (GAPDHΔCD) affected metabolism, up-regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down-regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDHΔCD similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining. Conclusion: GAPDH increases histone methylation levels by up-regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631–645).

Inventory displayed on the retail sales floor not only performs the classical supply function but also plays a role in affecting consumers’ buying behavior and hence the total demand. Empirical evidence from the retail industry shows that for some types of products, higher levels of on-shelf inventory have a demand-increasing effect (“billboard effect”) while for some other types of products, higher levels of on-shelf inventory have a demand-decreasing effect (“scarcity effect”). This suggests that retailers may use the amount of shelf stock on display as a tool to influence demand and operate a store backroom to hold the inventory of items not displayed on the shelves, introducing the need for efficient management of the backroom and on-shelf inventories. The purpose of this study is to address such an issue by considering a periodic-review inventory system in which demand in each period is stochastic and depends on the amount of inventory displayed on the shelf. We first analyze the problem in a finite-horizon setting and show under a general demand model that the system inventory is optimally replenished by a base-stock policy and the shelf stock is controlled by two critical points representing the target levels to raise up/drop down the on-shelf inventory level. In the infinite-horizon setting, we find that the optimal policies simplify to stationary base-stock type policies. Under the billboard effect, we further show that the optimal policy is monotone in the system states. Numerical experiments illustrate the value of smart backroom management strategy and show that significant profit gains can be obtained by jointly managing the backroom and on-shelf inventories.

Long-term resistance of biomaterials to the bacterial biofilm formation without antibiotic or biocide is highly demanded for biomedical applications. In this work, a novel biodegradable biomaterial with excellent capability to prevent long-term bacterial biofilm formation is prepared by the following two steps. Ethylcarboxybetaine ester analogue methacrylate (ECBEMA), poly(ethylene glycol) monomethacrylate (PEGMA), and 3-methacryloxypropyletris(trimethylsiloxy)silane (TRIS) were copolymerized to obtain p(ECBEMA-PEGMA-TRIS) (PEPT). Then, PEPT was cross-linked by isocyanate-terminated polylactic acid (IPDI-PLA-IPDI) to obtain the final PEPTx-PLAy (x and y are the number-average molecular weights (Mn) of PEPT and PLA, respectively) with optimal mechanical strength and adjustable surface regeneration rate. Static contact angle measurement, protein adsorption measurement, and attenuated total reflectance infrared (ATR-IR) results show that the PEPT19800-PLA800 film surface can generate a zwitterionic layer to resist nonspecific protein adsorption after surface hydrolysis. Quartz crystal microbalance with dissipation (QCM-D) results indicates that the PEPT19800-PLA800 film can undergo gradual degradation of the surface layer at the lowest swelling rate. Particularly, this material can efficiently resist the bacterial biofilm formation of both Gram-positive bacteria and Gram-negative bacteria over 14 and 6 days, respectively. Moreover, the material also shows an ideal self-healing feature to adapt to harsh conditions. Thus, this nonfouling material shows great potential in biomedical applications and marine antifouling coatings without antibiotic or biocide.

This paper investigates the effects of multiple purchases that arise in the retailing of consumer goods, in which the product choice and consumer surplus depend not only on what to purchase but also on how many units to purchase. We incorporate the multiple purchases into consumer choice behavior and study a series of associated operational problems. Most of the discrete choice models in the current literature often assume that a customer chooses exactly one unit of a product. The assumption of “one purchase” is too restrictive in some practical scenarios (e.g., consumer goods) because customers often purchase multiple units of a product. We take the widely-used multinomial logit (MNL) model as a showcase and incorporate the effects of multiple purchases into the classic discrete choice model. In the new choice framework, consumers first form a consideration set, then select one product from consideration set and determine the purchase quantity of the selected product. In the absence of fixed cost, we characterize the structure of the optimal policy for the assortment optimization problem; whereas in the presence of product-differentiated fixed costs, the assortment problem becomes NP-complete, so we propose an efficient heuristic. We further develop a polynomial time algorithm for the assortment problem with identical fixed cost for each product. For the joint assortment and pricing problem, we show it can be decoupled into multiple multi-product pricing problems with different assortment sizes, each of which can be transformed into a single-variable problem. For the price competition problem, we characterize the existence and uniqueness of the Nash equilibrium. We combine the alternating optimization algorithm with the expectation maximization algorithm to overcome the non-concavity and missing data issues in estimation. An empirical study on JD.com data shows that incorporating the effects of multiple purchases into discrete choice models can improve model fitting and prediction accuracy, while ignoring the effects of multiple purchases may lead substantial losses.

We provide a dynamic, game-theoretic model in which a creator (she) determines whether to signal her private product quality information by reward price in crowdfunding, when facing a potential imitator (he). The imitator will imitate the product with a quality decision after observing the creator's reward price and engages in a price competition with her in the regular market. The imitator's product has a market acceptance level, which reflects that fact that it can not perfectly bring out the same utility to consumers as the innovative product. We find that the introduction of an imitator may help the creator signal her quality. Moreover, when the acceptance level is low, the imitator may choose the same quality as the creator and the low-quality creator may be the one to resolve quality information uncertainty; and when the acceptance level is high, he may choose a different quality level and the high-quality creator may set a even lower price than the low-quality creator to achieve separation. We also show that, after incorporating the imitator's strategic behavior, the high-quality creator could benefit from concealing her product quality information by misleading the imitator to choose a less competitive product; while the low-quality creator may prefer disclosing her product quality information to reduce the competitive intensity. Our main results remain robust under alternative model settings, e.g., endogenous target goal, various introduction timing of the imitator's product, allowing non-pledging backers buying in regular market.

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies., Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive disease. Here, the authors identify recurrent somatic mutations of GNAQ in NKTCL, and model how this mutation contributes to NKTCL pathogenesis.

Purpose NK/T-cell neoplasms are rare, highly aggressive, and insensitive to chemotherapy. These lymphomas have a poor prognosis, with patients being vulnerable to relapse. Hence, there is a need for alternative treatments. The purpose of this study is to investigate whether anti-PD1 takes effect on NK/T cell lymphoma. Methods The expression of PD-L1 in NK/T cell lines was investigated by flow cytometry and by Western blot. In vivo, overall survival and median survival time of mice bearing an NK/T cell line tumor was assessed. Tumor-infiltrating T cells and monocyte-derived suppressor cells were evaluated by flow cytometry. Levels of PD-L1 and components of the JAK-STAT pathway were assessed in tumor tissues by immunohistochemistry. Results NK/T cell lines had greater expression of PD-L1 than normal peripheral blood human NK cells. In vivo, anti-PD1 treatment improved overall survival and median survival time of mice bearing an NK/T cell line. Furthermore, anti-PD1 treatment increased levels of PD-L1. Cultured tumor-infiltrating lymphocytes from mice treated with anti-PD1 had greater levels of IFN-γ than cultured lymphocytes from untreated animals. Further, levels of JAK2 and STAT1 were greater in mice treated with anti-PD1. Conclusion In vivo, anti-PD1 inhibited the progression of an NK/T-cell lymphoma and up-regulated PD-L1 expression. This up-regulation may be through the IFN-γ-associated JAK-STAT pathway.