Inefficient Entry Research Articles

Manganese-coordinated nanoparticle with high drug-loading capacity and synergistic photo-/immuno-therapy for cancer treatments

Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with “cold” and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.

Botulinum neurotoxin X lacks potency in mice and in human neurons.

The family of botulinum neurotoxins comprises the most potent toxins known to humankind. New members of this family of protein toxins as well as more distantly related homologs are being identified. The discovery of BoNT/X via bioinformatic screen in 2017 as a putative new BoNT serotype raised concern about its potential as a pathogenic agent with no available countermeasures. This study for the first time assessed both recombinantly produced and native purified BoNT/X for its vertebrate neurotoxicity.

Subsidizing startups under imperfect information

How is firm creation affected by imperfect information? Our model of rational inattention generates inefficient entry and labor misallocation, because startups make error-prone decisions. Learning decisions of prospective entrepreneurs alter the effects of lump-sum transfers to startups: the total employment gain is amplified due to an unintended increase in inefficient entry, most entrants hire fewer workers, and misallocation goes up. The transfer changes the learning incentives and makes even productive startups lean towards more conservative hiring. We show that this novel information channel works against well-known mechanisms, and thus can help reconcile recent empirical evidence on startup policies.

Implementation and Evaluation of Integrating an Electronic Health Record With the ACGME Case Log System.

It is essential to log resident-performed procedures to assess training programs and fulfill specialty requirements, but resident case numbers are often underreported. Current systems require inefficient data entry steps, and residents and fellows report that user interfaces and administrative burden contribute to logging inaccuracy. To determine the accuracy, feasibility, and acceptability of a single logging approach for resident case logging. In 2018, we implemented a case logging system integrated with the institutional electronic health record (EHR) and the Accreditation Council for Graduate Medical Education (ACGME) case log system to record procedures performed by ophthalmology residents. We compared the proportion of resident-performed cataract extractions in the EHR that were reported to ACGME for 3 periods: before the deployment of the new system (6 months), during the transition (6 months), and after the change (2 years). Resident satisfaction with the new system was evaluated using surveys. An analysis of resident cataract surgeries showed that the percentage of resident cases logged increased from 85% prior to implementation to 91% after implementation. The integrated system became the preferred case logging method, with 100% of all logged cases being entered using the new platform. Surveys showed that the percentage of trainees who were moderately or very satisfied with the case log process increased from 55% before implementation to 100% after implementation. A resident case log system integrated with an EHR more accurately reflects resident operative volume and increases trainee satisfaction with the logging process.

Improving Access and Decreasing Healthcare Utilization for Patients With Acute Spine Pain: Five-Year Results of a Direct Access Clinic.

Spine pain is one of the largest and costliest burdens to our healthcare systems. While evidence-based guidelines for spine pain have been established, and continue to evolve, the actual management of this condition continues to burden the healthcare system. This has led to increased costs due to inefficient entry to healthcare, utilization of treatments unsupported by clinical guidelines, and patient navigation through our healthcare systems. The purpose of this study was to assess the healthcare utilization and related outcomes for Active Duty Service Members (ADSM) receiving healthcare services in a novel acute spine pain clinic (ASPC) during the first 5 years of operation at a large Military Treatment Facility. In 2014 the Physical Medicine and Rehabilitation and Physical Therapy (PT) services designed a novel acute spine clinic intended to directly receive ADSM with acute spine symptoms for an initial evaluation by a Physical Therapist. The inclusion criteria into the ASPC were: ADSM, pain less than or equal to 7 days, no more than three prior episodes of acute spine pain in the past 3 years, and not currently receiving care from Chiropractic, Pain Management, or PT services. The exclusion criteria were: significant and/or progressive neurological deficits, bowel or bladder dysfunction, unstable vital signs or fever, hematuria or extensive trauma. A total of 1,215 patients presented to the ASPC for evaluation between 2014 and 2019. The most common chief complaint was acute pain in the lumbar spine (73%), followed by cervical spine pain (15%), and thoracic spine pain (12%) represented the fewest. The average number of PT visits per patient was 3.5 (range 1-13) with 61.1% utilizing three or fewer visits. Over 95% of cases returned to work the same day as their initial evaluation. Sixty-six percent returned to work without restriction the same day as their initial evaluation. Light duty recommendations were provided to 412 (33.9%) patients ranging from one to 30 days, with greater than 85% of the light duty being less than 14 days. Recommendations to not return to work (sick-in-quarters) were issued to 56 (4.6%) patients. The sick-in-quarters recommendations were for a 24-hour period in 48 cases, 48 hours for seven cases, and 72 hours for one case. All encounters in which the patient first sought care at the ASPC for low back pain met the Healthcare Effectiveness Data Set standard for low back pain care of having no imaging within 28 days of the first encounter for nonspecific low back pain. A medical record review of 100 randomly selected patients within 12 months of the initial evaluation demonstrated decreased utilization of medication, imaging, and referral to surgical services. This innovative approach demonstrates the potential benefits of rapid access to treatment and education for patients with acute spine pain by a Physical Therapist. Modeling this approach at Military Treatment Facilities may lead to decreased utilization of medications, radiology services, specialty care referrals, and reduced cost of care provided to individuals with acute spine pain.

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

ABSTRACT Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.

Word‐of‐mouth communication and search

AbstractWe develop a word‐of‐mouth search model where information flows from the old to the new generation for an experience good with unknown quality. We study the features of the social network that determine product quality and welfare and characterize the demand‐side (under provision of search effort) and supply‐side (inefficient entry by firms) factors that result in inefficiencies. One striking result is to show that the more connected but also the less‐unequal a friendship network is (in the sense of second order stochastic dominance of the degree distribution), the less can disreputable (low‐quality) firms thrive in equilibrium.

Antigenic Characterization of New Lineage II Insect-Specific Flaviviruses in Australian Mosquitoes and Identification of Host Restriction Factors.

We describe two new insect-specific flaviviruses (ISFs) isolated from mosquitoes in Australia, Binjari virus (BinJV) and Hidden Valley virus (HVV), that grow efficiently in mosquito cells but fail to replicate in a range of vertebrate cell lines. Phylogenetic analysis revealed that BinJV and HVV were closely related (90% amino acid sequence identity) and clustered with lineage II (dual-host affiliated) ISFs, including the Lammi and Nounané viruses. Using a panel of monoclonal antibodies prepared to BinJV viral proteins, we confirmed a close relationship between HVV and BinJV and revealed that they were antigenically quite divergent from other lineage II ISFs. We also constructed chimeric viruses between BinJV and the vertebrate-infecting West Nile virus (WNV) by swapping the structural genes (prM and E) to produce BinJ/WNVKUN-prME and WNVKUN/BinJV-prME. This allowed us to assess the role of different regions of the BinJV genome in vertebrate host restriction and revealed that while BinJV structural proteins facilitated entry to vertebrate cells, the process was inefficient. In contrast, the BinJV replicative components in wild-type BinJV and BinJ/WNVKUN-prME failed to initiate replication in a wide range of vertebrate cell lines at 37°C, including cells lacking components of the innate immune response. However, trace levels of replication of BinJ/WNVKUN-prME could be detected in some cultures of mouse embryo fibroblasts (MEFs) deficient in antiviral responses (IFNAR-/- MEFs or RNase L-/- MEFs) incubated at 34°C after inoculation. This suggests that BinJV replication in vertebrate cells is temperature sensitive and restricted at multiple stages of cellular infection, including inefficient cell entry and susceptibility to antiviral responses.IMPORTANCE The globally important flavivirus pathogens West Nile virus, Zika virus, dengue viruses, and yellow fever virus can infect mosquito vectors and be transmitted to humans and other vertebrate species in which they cause significant levels of disease and mortality. However, the subgroup of closely related flaviviruses, known as lineage II insect-specific flaviviruses (Lin II ISFs), only infect mosquitoes and cannot replicate in cells of vertebrate origin. Our data are the first to uncover the mechanisms that restrict the growth of Lin II ISFs in vertebrate cells and provides new insights into the evolution of these viruses and the mechanisms associated with host switching that may allow new mosquito-borne viral diseases to emerge. The new reagents generated in this study, including the first Lin II ISF-reactive monoclonal antibodies and Lin II ISF mutants and chimeric viruses, also provide new tools and approaches to enable further research advances in this field.

Resistance mechanisms adopted by a Salmonella Typhimurium mutant against bacteriophage

Bacteriophages have key roles in regulating bacterial populations in most habitats. A Salmonella Typhimurium mutant (N18) with impaired sensitivity to phage fmb-p1 was obtained and examined, the adsorption efficiency of fmb-p1 to N18 was reduced to 6%, compared to more than 97% for wild type S. Typhimurium CMCC50115. Reduced adsorption was accompanied by a reduction of 90% in the LPS content compared to wild type. Electron microscopy showed phage scattered around N18 with minimal engagement, while the phage were efficiently adsorbed to the wild type with tails oriented towards the bacterial surface. Evidence suggests fmb-p1 can slightly infect N18 and this does not give rise to an increase of phage titer. RT-qPCR data show that several Salmonella genes involved in lipopolysaccharide synthesis and five virulence related genes were down-regulated upon exposure of N18 to phage fmb-p1. In contrast, phage resistance related genes such as the SOS response, restriction-modification (RM), and Cas1 gene were up-regulated in N18. These data suggest that although inefficient adsorption and entry is the primary mechanism of resistance, transcriptional responses to phage exposure indicate that alternative resistance mechanisms against phage infection are also brought to bear, including digestion of phage nucleic acids and activation of the SOS. These findings may help develop strategies for biocontrol of Salmonella where multi-resistant bacteria are encountered or emerge in applications for food production, bioremediation or wastewater treatment.

Asymmetric regulation for competition in European railways?

There is an increasing number of voices calling for asymmetric regulation to reinforce competition in European railways as they are liberalized in December 2020. The regulatory framework defined in the Directives of the European Union (EU) might be insufficient to ensure effective and widespread competition. But the EU Directive declares tracks a natural monopoly, and structural measures in the form of vertical separation with transport activities have been imposed. Behavioral obligations have also been imposed on infrastructure managers in the form of access obligations. There is no room for asymmetry between competing networks, as tracks are a natural monopoly. Furthermore, as access conditions are ruled by the principle of nondiscrimination, it does not seem possible to introduce asymmetries in favor of newcomers, for instance in the form of access charges below the price charged to incumbent railway undertakings. For the rest of railway assets, which only exceptionally can be considered essential facilities, the EU Directives either impose no access obligations (rolling stock, drivers, ticketing systems) or when they impose access obligations (maintenance facilities), there is no formal asymmetry, as all undertakings are subject to the same access obligations. National regulatory authorities considering the introduction of asymmetric access obligations should take into account economic literature describing how asymmetries attract inefficient market entry, and they should consider that obligations introduced at a national level might fragment the Single European Railway Area.

The Antitrust Prohibition of Excessive Pricing

Excessive pricing by a dominant firm is unlawful in many countries. To assess whether it is excessive, the dominant firm’s price is often compared with price benchmarks. We examine the competitive implications of two such benchmarks: a retrospective benchmark where the price that prevails after a rival enters the market is used to assess whether the dominant firm’s pre-entry price was excessive, and a contemporaneous benchmark, where the dominant firm’s price is compared with the price that the firm charges contemporaneously in another market. We show that the two benchmarks restrain the dominant firm’s behavior when it acts as a monopoly, but soften competition when the dominant firm competes with a rival. Moreover, a retrospective benchmark promotes entry, but may lead to inefficient entry.

A T7 autogene-based hybrid mRNA/DNA system for long-term shRNA expression in cytoplasm without inefficient nuclear entry

The transient silencing effects currently demonstrated by nonviral siRNA delivery systems limit the therapeutic utility of RNAi, but it remains a technical challenge to prolong duration of gene silencing. We have developed a T7 autogene-based hybrid mRNA/DNA system to enable long-term expression of shRNA in cytoplasm in vitro and in vivo. This hybrid mRNA/DNA system consists of T7 polymerase (T7pol) mRNA, pT7/shRNA-encoding DNA fragment and T7 autogene plasmid, and it can generate higher levels of T7pol proteins, compared to pCMV-triggering T7 autogene system, especially without the need of nuclear entry of any gene. A large amount of T7pol proteins produced are used to induce pT7-driven expression of shRNA in cytoplasm, and through cellular processing of RNA hairpins, mature siRNAs are generated for more than 13 days. We here demonstrate that a single liposomal delivery of this hybrid system leads to the long-term silencing effects in vitro and in vivo, in contrast to the conventional siRNA methods relying on the repeated administrations every 2 or 3 days. These sustainable shRNA expression properties in cytoplasm can provide an efficient strategy to address the limitations caused by shRNA-encoding plasmid DNA systems such as low nuclear entry efficiency and short-term silencing effect. The development of long-term shRNA expression system in vivo could scale down administration frequency of RNAi therapeutics in the treatment of chronic diseases, thereby increasing its clinical utility.

An Adaptive Read-Write Partitioning Flash Translation Layer Algorithm

The classic demand-based flash translation layer (DFTL) algorithm is well-known since it can solve the contradiction between mapping flexibility and the size of mapping cache by dynamically loading mapping entries. However, DFTL failed to utilize the spatial locality and hot-cold characteristics of the request and had an inefficient mapping entry eviction scheme. This paper proposes an adaptive read-write partitioning flash translation layer algorithm (ARWFTL). First, the cache mapping table (CMT) is divided into the read CMT and the write CMT. The size of the two can be adaptively adjusted by sensing the characteristics of the upper workload and the read-write latency of the underlying flash page. Second, a priority eviction window is set at the tail of the write CMT to evict the clean mapping entry firstly. When there is no clean mapping entry in the priority eviction window, the tail mapping entry and other mapping entries that belong to the same translation page are clustered to write back into the translation page. Then, other written back mapping entries are set to be clean and the tail mapping entry is evicted. Third, a hot data window is set at the head of the write CMT to recognize the hot and cold data of write requests. Then, the hot and cold data are stored in different data blocks of flash to avoid hot and cold data entanglement and reduce valid page migrations in garbage collection. Experimental results show that, compared with DFTL, ARWFTL can reduce the translation page write counts, the valid page migration counts, the block erase counts, and the average response time by 92.8%, 47.7%, 31.7%, and 31.4%, respectively. In addition, ARWFTL is also superior to the other recent DFTL-based improved algorithms, and even exceeds the pure page-level FTL in some indicators.

Blocking in a Timing Game with Asymmetric Players

We examine innovation as a market-entry timing game with complete information and observable actions. We allow for heterogenous payoffs between players, and for a leader's payoff functions to be multi-peaked and non-monotonic. Assuming that the follower's payoff is non-increasing with the time of the leader's entry, we characterize all pure-strategy subgame perfect equilibria for the two-player asymmetric model, showing that there are at most two equilibria. Firm heterogeneity allows for equilibria with different characteristics than previously examined in the literature. For example, a firm may wish to enter earlier blocking its rival's entry, so as to avoid an anticipated lower future payoff if it waited. A notable feature of this blocking equilibrium is that rents need not be equalized between the leader and follower. We also show that if the followers' payoffs are non-monotonic, the iterative incentives to block each other's product launch may lead to starkly inefficient early entry in a continuous version of the centipede game.

Abstract 1952: Design and characterization of an NQO1-activated spiroisoindolinone derivative for glioma treatment

Abstract Primary brain tumors and cancers metastasizing to CNS are the most challenging and lethal malignancies to treat. Chemotherapy with radiation has been a mainstay in their treatment, however, the adverse effects such as the bone marrow suppression, inefficient drug entry through the BBB, intratumoral heterogeneity, and the overexpression of MGMT repair protein are all impediments for successful treatment. Therefore, there is a great need for innovative exploitation of targets selectively expressed in CNS cancers for effective therapy. Such an approach is also likely to spare the normal tissues from the therapeutic insult and prevent the adverse effects. A potential cancer-specific target is the antioxidant enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). NQO1 is a 2-electron reductase responsible for the detoxification of quinones. Its expression is typically quite low in normal tissues but is highly overexpressed in many solid tumor types, including brain cancers. Based on these observations, we have designed a BBB permeable small molecule NQO1-directed drug, spiroisoindolinone GNQ-9 for glioma therapy. GNQ-9 was prepared through rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimine generated in situ from 3-hydroxyisoindolinone with benzoquinone. GNQ-9 exhibited potent antiproliferative activities against a variety of cancer cell lines, particularly, the NQO1 overexpressing tumor cells and showed minimal cytotoxicity towards a panel of normal cell counterparts (astrocytes, HIVECs, and fibroblasts from lung, pancreatic, breast, and colon). Cytotoxicity studies revealed a strong correlation between NQO1 bioreduction and anticancer activity of GNQ-9. Further, cotreatment with dicoumarol (DIC) significantly reversed the cytotoxic effect of GNQ against U87MG cells demonstrating the NQO1 dependent-cytotoxicity. The ability of GNQ-9 to participate in a redox cycle with NQO1 allows for outstanding potency, as one molecule of GNQ-9 processed by NQO1 generates several ROS molecules and induce oxidative stress and DNA damage. This was confirmed by GNQ-9 generated ROS production using the DCF-DA and DHE. GNQ-9 was also an intercalator and a topo II inhibitor. Other studies revealed that GNQ-9 induces autophagy and apoptosis through ROS with an increased expression of LC3-II and beclin-1 proteins. A marked loss of mitochondrial membrane potential was also noted. Further, the efficacy of GNQ-9 was tested in intracranial xenograft model developed by injecting the luciferase-expressing and NQO1-proficient U87 glioblastoma cells; a significant reduction in the tumor growth was noted with GNQ-9 as a single agent. Serum ALT and AST levels in the tumor-bearing nude mice were not altered, suggesting a lack of toxicity. We conclude that GNQ-9, as an NQO1-targeted drug heightens the tumor redox and induces selective apoptosis in gliomas (supported by CPRIT grants RP130266 and RP170207 to KSS). Citation Format: Surendra R. Punganuru, Hanumantha Rao Madala, Viswanath Arutla, Kalkunte S. Srivenugopal. Design and characterization of an NQO1-activated spiroisoindolinone derivative for glioma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1952.

An inhibitor screen identifies histone-modifying enzymes as mediators of polymer-mediated transgene expression from plasmid DNA

Effective transgene expression in mammalian cells relies on successful delivery, cytoplasmic trafficking, and nuclear translocation of the delivered vector, but delivery is impeded by several formidable physicochemical barriers on the surface of and within the target cell. Although methods to overcome cellular exclusion and endosomal entrapment have been studied extensively, strategies to overcome inefficient nuclear entry and subsequent intranuclear barriers to effective transient gene expression have only been sparsely explored. In particular, the role of nuclear packaging of DNA with histone proteins, which governs endogenous gene expression, has not been extensively elucidated in the case of exogenously delivered plasmids. In this work, a parallel screen of small molecule inhibitors of chromatin-modifying enzymes resulted in the identification of class I/II HDACs, sirtuins, LSD1, HATs, and the methyltransferases EZH2 and MLL as targets whose inhibition led to the enhancement of transgene expression following polymer-mediated delivery of plasmid DNA. Quantitative PCR studies revealed that HDAC inhibition enhances the amount of plasmid DNA delivered to the nucleus in UMUC3 human bladder cancer cells. Native chromatin immunoprecipitation (N-ChIP)-qPCR experiments in CHO-K1 cells indicated that plasmids indeed interact with intracellular core Histone H3, and inhibitors of HDAC and LSD1 proteins are able to modulate this interaction. Pair-wise treatments of effective inhibitors led to synergistic enhancement of transgene expression to varying extents in both cell types. Our results demonstrate that the ability to modulate enzymes that play a role in epigenetic processes can enhance the efficacy of non-viral gene delivery, resulting in significant implications for gene therapy and industrial biotechnology.

The antitrust prohibition of excessive pricing

Excessive pricing by a dominant firm is unlawful in many countries. To assess whether it is excessive, the dominant firm’s price is often compared with price benchmarks. We examine the competitive implications of two such benchmarks: a retrospective benchmark where the price that prevails after a rival enters the market is used to assess whether the dominant firm’s pre-entry price was excessive, and a contemporaneous benchmark, where the dominant firm’s price is compared with the price that the firm charges contemporaneously in another market. We show that the two benchmarks restrain the dominant firm’s behavior when it acts as a monopoly, but soften competition when the dominant firm competes with a rival. Moreover, a retrospective benchmark promotes entry, but may lead to inefficient entry.

Design and Characterization of an NQO1‐Activated Spiroisoindolinone Derivative for Glioma Treatment

Primary brain tumors and cancers metastasizing to CNS are most challenging and lethal malignancies to treat. Chemotherapy with radiation has been a mainstay in their treatment, however, the adverse effects such as the bone marrow suppression, inefficient drug entry through the BBB, intratumoral heterogeneity, overexpression of MGMT repair protein are all impediments for successful treatment. Therefore, there is a great need for innovative exploitation of targets selectively expressed in CNS cancers for effective therapy. Such an approach is also likely to spare the normal tissues from the therapeutic insult and prevent the adverse effects. A potential cancer‐specific target is the antioxidant enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). NQO1 is a 2‐electron reductase responsible for the detoxification of quinones. Its expression is typically quite low in normal tissues but is highly overexpressed in many solid tumor types, including brain cancers. Based on these observations, we have designed a BBB permeable small molecule NQO1–directed drug, spiroisoindolinone GNQ‐9 for glioma therapy. GNQ‐9 was prepared through rhodium(III)‐catalyzed redox‐neutral coupling reaction of N‐acyl ketimine generated in situ from 3‐hydroxyisoindolinone with benzoquinone. GNQ‐9 exhibited potent antiproliferative activities against a variety of cancer cell lines, particularly, the NQO1 overexpressing tumor cells and showed minimal cytotoxicity towards a panel of normal cell counterparts (astrocytes, HIVECs, and fibroblasts from lung, pancreatic, breast, and colon). Cytotoxicity studies revealed a strong correlation between NQO1 bioreduction and anticancer activity of GNQ‐9. Further, cotreatment with dicoumarol (DIC) significantly reversed the cytotoxic effect of GNQ against U87MG cells demonstrating the NQO1 dependent‐cytotoxicity. The ability of GNQ‐9 to participate in a redox cycle with NQO1 allows for outstanding potency, as one molecule of GNQ‐9 processed by NQO1 generates several ROS molecules and induce oxidative stress and DNA damage. This was confirmed by GNQ‐9 generated ROS production using the DCF‐DA and DHE. GNQ‐9 was also an intercalator and a topo II inhibitor. Other studies revealed that GNQ‐9 induces autophagy and apoptosis through ROS with an increased expression of LC3‐II and beclin‐1 proteins. A marked loss of mitochondrial membrane potential was also noted. Further, the efficacy of GNQ‐9 was tested in intracranial xenograft model developed by injecting the luciferase‐expressing and NQO1‐proficient U87 glioblastoma cells; a significant reduction in the tumor growth was noted with GNQ‐9 as a single agent. Serum ALT and AST levels in the tumor‐bearing nude mice were not altered, suggesting a lack of toxicity. We conclude that GNQ‐9, as an NQO1‐targeted drug heightens the tumor redox and induces selective apoptosis in gliomas.Support or Funding Informationsupported by CPRIT grants RP130266 and RP170207This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Theory of Inefficient College Entry and Excessive Student Debt

Abstract When workers are myopic and the amount of financing provided by the government is sufficiently large, some workers acquire education even if they are better off without it. We show that government-provided loans generate a propagation mechanism that exacerbates inefficient college entry. Further, the extent of this inefficiency depends on the speed at which loans are provided, and not just on their amount. The extent of inefficient college entry also depends on the distribution of myopic workers in the population, and inefficiencies can arise even if not all workers are myopic. We extend the model to study the impact of the dropout rate and heterogeneous expectations as well the dynamic implications of inefficient college entry.

So close but yet so far? Labour Migration Governance in Italy and Spain

AbstractSouthern European countries have traditionally been perceived as weak immigration countries with inefficient legal entry avenues for foreign workers, high irregular migration rates and poor integration policies. In recent years, however, the adoption of more efficient control policies, new recruitment strategies and embryonic integration plans throughout the region has led to a change of paradigm in the governance of migration. And yet policy reforms do not seem to have produced the same results everywhere. The aim of this article is to enquire into possible explanations for the divergent paths of labour migration governance in Southern Europe, using Italy and Spain as comparative cases. As it will emerge, policy efficacy in the field of labour migration relates not only to the quality and consistency of policy design and implementation but also to factors that escape direct political control.