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Grass leaves develop from a ring of primordial initial cells within the periphery of the shoot apical meristem, a pool of organogenic stem cells that generates all of the organs of the plant shoot. At maturity, the grass leaf is a flattened, strap-like organ comprising a proximal supportive sheath surrounding the stem and a distal photosynthetic blade. The sheath and blade are partitioned by a hinge-like auricle and the ligule, a fringe of epidermally derived tissue that grows from the adaxial (top) leaf surface. Together, the ligule and auricle comprise morphological novelties that are specific to grass leaves. Understanding how the planar outgrowth of grass leaves and their adjoining ligules is genetically controlled can yield insight into their evolutionary origins. Here we use single-cell RNA-sequencing analyses to identify a ‘rim’ cell type present at the margins of maize leaf primordia. Cells in the leaf rim have a distinctive identity and share transcriptional signatures with proliferating ligule cells, suggesting that a shared developmental genetic programme patterns both leaves and ligules. Moreover, we show that rim function is regulated by genetically redundant Wuschel-like homeobox3 (WOX3) transcription factors. Higher-order mutations in maize Wox3 genes greatly reduce leaf width and disrupt ligule outgrowth and patterning. Together, these findings illustrate the generalizable use of a rim domain during planar growth of maize leaves and ligules, and suggest a parsimonious model for the homology of the grass ligule as a distal extension of the leaf sheath margin.

These are figures associated with a second manuscript that has been submitted for consideration for co-publication. It describes the platform and hopefully will facilitate the reviewers' assessment of this manuscript on XMT-1536. we are also happy to make this available as supplementary data for this publication if desired.

These are figures associated with a second manuscript that has been submitted for consideration for co-publication. It describes the platform and hopefully will facilitate the reviewers' assessment of this manuscript on XMT-1536. we are happy to make this available as supplementary data for publication in any format if desired.

Supplementary methods, data and Figures

Supplementary Figures

After significant effort over the last 30 years, antibody–drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs have been approved by the FDA to date, with additional ADCs in late stages of development. Here, we introduce dolaflexin, a novel ADC technology that overcomes key limitations of the most common ADC platforms with two key features: a higher drug-to-antibody ratio and a novel auristatin with a controlled bystander effect. The novel, cell permeable payload, auristatin F-hydroxypropylamide, undergoes metabolic conversion to the highly potent, but less cell permeable auristatin F to balance the bystander effect through drug trapping within target cells. We conducted studies in mice, rats, and cynomolgus monkeys to complement in vitro characterization and contrasted the performance of dolaflexin with regard to antitumor activity, pharmacokinetic properties, and safety in comparison with the ADC platform utilized in the approved ADC ado-trastuzumab emtansine (T-DM1). A HER2-targeted dolaflexin ADC was shown to have a much lower threshold of antigen expression for potent cell killing in vitro, was effective in vivo in tumors with low HER2 expression, and induced tumor regressions in a xenograft model that is resistant to T-DM1.

Psychiatric conditions are common in autism; however, a multitude of barriers exist in accessing community-based mental health care for autistic youth. Perhaps the first and most formidable barrier is identifying a provider that offers mental health treatment to autistic youth within the many service systems involved in supporting the autism community. These systems typically function independently of one another, contributing to the complexity of accessing services. To identify gaps caused by New York’s multisystem care model for autistic youth, and as part of a larger quality improvement initiative to advance suicide risk management in several New York City emergency departments, we conducted a telephone survey to identify outpatient mental health service availability for autistic youth with depressive symptoms or suicidal thoughts or behaviors in New York City across the state’s mental health and developmental disability systems. Results demonstrated that while a greater proportion of clinics in the mental health system compared with agencies in the developmental disability system offered outpatient mental health services to autistic youth (47.1% vs 25.0%), there is remarkably limited service availability overall. Efforts to reduce these care inequities through policy reform and improving workforce capacity are urgently needed. Lay abstract Autistic children and adolescents experience high rates of co-occurring mental health conditions, including depression and suicidality, which are frequently identified by stakeholders as treatment priorities. Unfortunately, accessing community-based mental health care is often difficult for autistic youth and their families. The first obstacle families confront is finding a provider that offers mental health treatment to autistic youth within the many service systems involved in supporting the autism community. The mental health and developmental disability systems are two of the most commonly accessed, and previous work has shown there is often confusion over which of these systems is responsible for providing mental health care to autistic individuals. In this study, we conducted a telephone survey to determine the availability of outpatient mental health services for autistic youth with depressive symptoms or suicidal thoughts or behaviors in New York City across the state’s mental health and developmental disability systems. Results showed that while a greater percentage of clinics in the mental health system compared with in the developmental disability system offered outpatient mental health services to autistic youth (47.1% vs 25.0%), many more did not offer care to autistic youth and there were very few options overall. Therefore, it is important that changes to policy are made to increase the availability of services and that mental health care providers’ knowledge and confidence in working with autistic youth are improved.

Shared systems in leaf development The long, narrow leaves of grasses look rather different from the often shorter, flatter leaves of eudicot plants. Richardson et al . combined developmental genetics and computational modeling to reveal that these two types of leaves, which are widely separated by evolution, have more in common than expected. Expression of similar patterning genes in the primordial zone is confined to a wedge for the eudicot leaf but expanded to concentric domains in the grass leaf, driving development of the cylindrical, encircling sheath characteristic of grass leaves. Addition or removal of gene expression in a marginal zone contributes to the development of the broader leaf characteristic of eudicots. Thus, grass and eudicot leaves are diversified elaborations of shared toolkits. —PJH

The soil microbiome consists of a vast variety of microorganisms which contribute to essential ecosystem services including nutrient recycling, protecting soil structure, and pathogen suppression. Recalcitrant organic compounds present in soils contaminated with fuel oil can lead to a decrease in functional redundancy within soil microbiomes. Ecopiling is a passive bioremediation technique involving biostimulation of indigenous hydrocarbon degraders, bioaugmentation through inoculation with known petroleum-degrading consortia, and phytoremediation. The current study investigates the assemblage of soil microbial communities and pollutant-degrading potential in soil undergoing the Ecopiling process, through the amplicon marker gene and metagenomics analysis of the contaminated soil. The analysis of key community members including bacteria, fungi, and nematodes revealed a surprisingly diverse microbial community composition within the contaminated soil. The soil bacterial community was found to be dominated by Alphaproteobacteria (60–70%) with the most abundant genera such as Lysobacter, Dietzia, Pseudomonas, and Extensimonas. The fungal community consisted mainly of Ascomycota (50–70% relative abundance). Soil sequencing data allowed the identification of key enzymes involved in the biodegradation of hydrocarbons, providing a novel window into the function of individual bacterial groups in the Ecopile. Although the genus Lysobacter was identified as the most abundant bacterial genus (11–46%) in all of the contaminated soil samples, the metagenomic data were unable to confirm a role for this group in petrochemical degradation. Conversely, genera with relatively low abundance such as Dietzia (0.4–9.0%), Pusillimonas (0.7–2.3%), and Bradyrhizobium (0.8–1.8%) did possess genes involved in aliphatic or aromatic compound degradation.

Target selection for antibody–drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10–15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.

After significant effort over the last 30 years, antibody–drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs have been approved by the FDA to date, with additional ADCs in late stages of development. Here, we introduce dolaflexin, a novel ADC technology that overcomes key limitations of the most common ADC platforms with two key features: a higher drug-to-antibody ratio and a novel auristatin with a controlled bystander effect. The novel, cell permeable payload, auristatin F-hydroxypropylamide, undergoes metabolic conversion to the highly potent, but less cell permeable auristatin F to balance the bystander effect through drug trapping within target cells. We conducted studies in mice, rats, and cynomolgus monkeys to complement in vitro characterization and contrasted the performance of dolaflexin with regard to antitumor activity, pharmacokinetic properties, and safety in comparison with the ADC platform utilized in the approved ADC ado-trastuzumab emtansine (T-DM1). A HER2-targeted dolaflexin ADC was shown to have a much lower threshold of antigen expression for potent cell killing in vitro, was effective in vivo in tumors with low HER2 expression, and induced tumor regressions in a xenograft model that is resistant to T-DM1.

Esteban and Ray (2001) develop a model with an increasing marginal cost of contribution and overturn the Olson hypothesis that large groups are unable to provide themselves with a rival public good. Pecorino and Temimi (2008) consider fixed, but avoidable, participation costs in this framework. They conclude that public good provision must fall to zero in a large group if the degree of rivalry is sufficiently high, because the individual payoff goes to zero at the interior equilibrium. Thus, individuals prefer a corner solution of zero contributions to incurring the fixed participation cost. However, when the degree of rivalry is sufficiently low, they conclude that provision of the public good will rise without bound. We show that this latter conclusion is incorrect, and that any degree of rivalry will lead to a total breakdown in public good provision in a sufficiently large group. Not including the fixed participation cost, the difference in the payoff to an individual when she contributes to the public good and when she does not contribute goes to zero in a large group. Thus, in a sufficiently large group, she will not be willing to incur the participation costs. The same result also applies to the Morgan (2000) lottery mechanism.

We show that there exist models with rational agents, three periods, and five states of the world, which have a strong bubble in one of these states. However, no finite-horizon rational strong bubble model, with standard Walrasian markets, can have fewer than five states.

Cytochrome P450 enzymes are hemeproteins that catalyze the monooxygenation of a wide-range of structurally diverse substrates of endogenous and exogenous origin. These heme monooxygenases receive electrons from NADH/NADPH via electron transfer proteins. The cytochrome P450 enzymes, which constitute a diverse superfamily of more than 8,700 proteins, share a common tertiary fold but 55% and Bhattacharyya coefficient > 80%), despite the low sequence identity (< 25%) and sequence similarity (< 50%) across the cytochrome P450 superfamily. Noticeable differences in Cα atom fluctuations of structural elements responsible for substrate binding were noticed. These differences in residue fluctuations might be crucial for substrate selectivity in these enzymes.

Antibody-drug conjugates (ADCs) consist of a tumor-targeted antibody, a drug (payload) with specified mechanism of action, and the chemical framework for attaching them to each other. By selective delivery of the payload to the tumor and not to normal tissues, ADCs can provide greater efficacy and tolerability than systemic chemotherapies, which can translate to longer duration of treatment and response, as well as more options for combination therapies without the concern of overlapping toxicity. To preempt potential resistance to therapy, we have engineered a dual-payload ADC (DP-ADC) that delivers two mechanistically distinct payloads to a single target cell. To build a precision dual payload-ADC (DP-ADC), we leveraged our Synthemer platform, which enables us to chemically attach the payloads to a synthetic scaffold in a defined manner, and then to chemically attach the loaded scaffold to the antibody. This approach allows for unambiguous control of architecture and ratio of the payloads: the payloads are incorporated in a fixed ratio into the scaffold and subsequently into the ADC. Moreover, the synthetic design also allows for selection of solubilizing groups and charge compensation for each payload, allowing for optimal properties of the ADC. Our prototype DP-ADC combines the microtubule inhibitor auristatin F hydroxypropyl amide (AF-HPA) with the DNA monoalkylator I-BiP (related to pyrrolobenzodiazepine), at a payload ratio of 3:1. The drug-to-antibody ratio (DAR) was 12 AF-HPA and 4 I-BiP (16 total), achieved by conjugating 4 of the loaded dual-payload scaffolds to the antibody. The DP-ADC exhibited comparable antigen binding to the unconjugated antibody, and cytotoxic potency comparable to both single-payload ADCs alone. Using cell-based assays that specifically probe the mechanism of action of each payload, we demonstrated that the DP-ADC exerted both expected mechanisms of action on the tumor cell in a target-dependent manner. Considerations for the selection of payload combinations will also be presented. While synergistic action is typically assumed to be preferred if not required, a recent study demonstrated that the observed clinical benefit of most combinations can be explained by the drugs’ independent modes of action, not synergy. Indeed, AF-HPA and I-BiP did not exhibit synergy in cytotoxicity studies in cancer cell lines, yet their combination in a DP-ADC is still expected to confer potential clinical benefit over either single-payload ADC across a patient population. Citation Format: Jeremy R. Duvall, Marc Damelin, Mariya V. Kozytska, Barrett J. Nehilla, Marina Protopopova, Patrick R. Conlon, LiuLiang Qin, Mark Nazzaro, Josh D. Thomas, Qingxiu Zhang, Dorin Toader, Timothy B. Lowinger. An antibody-drug conjugate carrying a microtubule inhibitor and a DNA alkylator exerts both mechanisms of action on tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 232.

Dolasynthen is a novel, fully synthetic, structurally homogeneous platform that enables the construction of ADCs with tunable drug-to-antibody ratios (DAR), from a low of 2 to a high of 24. The resulting ADCs exhibit excellent physicochemical properties and fully homogeneous conjugates can be created through a variety of bioconjugation chemistries. Analogous to our first platform, Dolaflexin®, Dolasynthen is loaded with the proprietary payload Auristatin F hydroxypropylamide (AF-HPA) with precisely defined numbers of the cytotoxin per Dolasynthen scaffold.Studies that evaluate the tolerability and efficacy of Dolasynthen in preclinical models are described herein. ADCs containing a range of DAR values were generated following conjugation of Dolasynthen to two different monoclonal antibodies. The DAR of the ADCs was achieved by controlled reduction of native disulfide bonds in IgG1 antibodies, chromatographic fractionation, or through use of site-specific conjugation technologies. ADCs with both DAR6 and DAR12 were evaluated in vitro and also in vivo in the mouse, rat and monkey, for efficacy, tolerability and PK. Dolasynthen conjugates had excellent physicochemical properties and displayed the expected cell binding and in vitro cytotoxicities. In vivo pharmacology of Dolasynthen ADCs in in vivo xenograft models showed dose-dependent tumor growth inhibition at low mg/kg mAb doses. Tolerability in the rat at multiple doses was determined, including histopathological evaluation. Dolasynthen ADCs showed excellent PK characteristics in mouse, rat and NHP. Overall, the Dolasynthen platform appears to offer significant potential for clinical application. Citation Format: Dorin Toader, Marc Damelin, Anouk Dirksen, Shawn P. Fesler, Scott D. Collins, Barrett J. Nehilla, Jian Xu, Ling Xu, Kalli C. Cattcott, Alex Uttard, Winnie Lee, Susan Clardy, Cheri A. Stevenson, LiuLiang Qin, Patrick R. Conlon, Mariya V. Kozytska, Chen-Ni Chin, David H. Lee, Timothy B. Lowinger. Dolasynthen–a novel, homogeneous Auristatin F hydroxypropyl amide antibody-drug conjugate platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2687.

This paper reports my experience as a teacher of clinical ultrasound (US) in an African hospital. While US in tropical countries has received some attention and a few papers - though possibly fewer than deserved by this issue-are available in the medical literature on this subject, very little has been done in terms of assessment of teaching.Given the increasing number of groups, NGOs and volunteers that go to Africa and other resource limited settings to do this, I thought that sharing my experience with those who have walked or are thinking of walking the same path could be mutually beneficial.The first section of the article presents the situation where I've been working in the past 13 years, the second section details our teaching programme.This report describes the rationale for the implementation of ultrasound training programmes in rural areas of Africa and lessons learnt with 13 years experience from the UK with recommendations for the way forward.Questo articolo presenta la mia esperienza di insegnamento dell'ecografia clinica in un ospedale africano. L'uso dell'ecografia nei paesi tropicali è menzionato da alcuni articoli – meno di quanto l'argomento meriterebbe – nella letteratura medica, ma poco o nulla è stato detto sulla valutazione dell'addestramento ecografico in questo contesto.Dato il sempre maggior numero di gruppi, organizzazioni non governative, volontari e altro che si recano in Africa a insegnare l'ecografia, ho pensato di presentare la mia esperienza a coloro che hanno fatto o intendono fare la stessa cosa, in modo da aprire una discussione.La prima parte dell'articolo presenta la situazione in cui ho lavorato negli ultimi 10 anni, la seconda parte presenta il programma in modo dettagliato.Viene anche descritta la giustificazione logica dell'istituzione di programmi di addestramento ecografico in zone rurali Africane e lezioni apprese in 10 anni di esperienza nel Regno Unito con le indicazioni su come procedere in futuro.

This paper presents simple new multisignal generalizations of the two classic methods used to justify the first-order approach to moral hazard principal-agent problems, and compares these two approaches with each other. The paper first discusses limitations of previous generalizations. Then a state-space formulation is used to obtain a new multisignal generalization of the Jewitt (1988) conditions. Next, using the Mirrlees formulation, new multisignal generalizations of the convexity of the distribution function condition (CDFC) approach of Rogerson (1985) and Sinclair-Desgagne (1994) are obtained. Vector calculus methods are used to derive easy-to-check local conditions for our generalization of the CDFC. Finally, we argue that the Jewitt conditions may generalize more flexibly than the CDFC to the multisignal case. This is because, with many signals, the principal can become very well informed about the agent's action and, even in the one-signal case, the CDFC must fail when the signal becomes very accurate.

This chapter describes the interview approach, structure, and format utilized in the research reported in this book. This research was unique in that it was based on the intimate partner’s perspective of the child molesters’ familial interaction, attitudes, and deviant activities. Adding to the project’s uniqueness was the fact that these intimate adult partners were also the mothers of the molested children. The research looked at many aspects of the child molester’s history, and the roadmap for this journey was a detailed and penetrating set of lifestyle questions. Each facet of a child molester’s normal, and criminal, lifestyle was on the table for examination. It was the purpose of the interviews to explore the disturbing and destructive phenomena generally called “child molesting” from an insider’s perspective.

Cases involving child molestation are offensive and difficult for all concerned in their investigation. This is true whether the investigation is conducted by law enforcement, child protective services, or medical personnel. While there have been an untold number of studies focusing on the molester and the child victim, there is a dearth of information on the mothers of the child victims. This chapter informs the reader on the data gathered from the in-depth interviews of 20 women who were the spouses or exclusive partners of men who molested 34 of their biological children. It provides the reader with insight into the women’s history, their experience with childhood abuse, and their relationship with the molester.

The interviews conducted with the 20 wives and girlfriends revealed that a total of 34 children had been targets of some form of sexual abuse or victimization. The current chapter introduces some of the specifics of the cases, focusing on demographics of victims, reactions of mothers, and common behaviors exhibited by molesters in their interactions with the children, both sexual and otherwise. In 65 % of the cases, the abuser was the child’s biological father, and 40 % of the time, more than one child was targeted. While the mothers uniformly said they had responded to the initial discovery of the abuse with shock and disbelief, we found that the women reported observing many of the same, suspicious, behaviors by the molesters. For example, many of the women reported that the molesters would bath or shower with the children, invade the child’s privacy, ask the woman to shave her pubic region, and use pornography (e.g., showing it to the child or viewing it in locations where the child may see it).

This paper discusses appropriate application areas for natural language interfaces (NLIs) to databases. This requires comparing NLIs with competing approaches, including other user-friendly interfaces, and training of users with less user-friendly interfaces. Also, since NLI technology is still limited, users may need to learn how to use NLIs themselves. This suggests that NLI popularity may snowball at some point, as users become familiar with NLIs. We use a simple prototype NLI to illustrate when NLIs can achieve flexibility unattainable by simpler interfaces. Currently existing commercial NLIs and application-specific customization are also discussed.

We investigate policy reform in a modelwith both lobbying, which involves afree-rider problem, and ordinary rentseeking, which does not. These activitiesinvolve similar skills, so a reform whichreduces rents shifts labor into lobbying.Also, because of the free-rider problem,the marginal return to the industry fromlobbying may greatly exceed an individualfirm's return to lobbying. Thus, the shiftinto lobbying caused by rent reduction maylead to large increases in transfers to thelobbying industry. Under somecircumstances, a reform which reducesavailable rents increases total rents plustransfers to the industry.

An asymmetric information model of a finite horizon “nth order” rational asset price bubble is presented, where (all agents know that)n the asset is worthless. Also, the model has only two agents, so the first order version of the bubble is simpler than other first order bubbles in the literature.

This paper considers learning rates in finitely repeated prisoners’ dilemmas. If players think their opponents might be relatively cooperative (e.g., tit-for-tat or grim types), they will cooperate in finitely repeated prisoners’ dilemmas (see Kreps et al., J. Econom. Theory 27 (1982) 245). However, if there are actually no cooperative types, players will eventually learn this and cooperation will break down. This paper shows that this learning is extremely slow, so it will take an extremely long time for cooperation to break down. Thus, suppose the world is either “good” or “bad.” The probability of a grim type is δ>0 if the world is good, and zero if the world is bad. Successive generations pair up to play finitely repeated prisoners’ dilemmas. Players observe play in previous generations and use Bayes’ rule to update their prior, π, that the world is good. We show that, if the world is really bad, then π falls O(δ 2 log (1/δ)) per generation on average. Thus, if δ is small, there is less cooperation if the world is good, but cooperation may become more stable. For a representative 19 period repeated prisoners’ dilemma, beliefs fall one percentage point on average after a thousand generations. To derive these learning rates, we must refine existing results on the sensitivity of repeated games to Kreps et al. (1982) type perturbations. Specifically, we show cooperation is possible in perturbed prisoners’ dilemmas repeated O(log(1/δ)) times. This improves significantly on the O(1/δ) results in previous work. The paper thus provides two new reasons why cooperation tends to be stable, even in short horizon repeated games.

The ADC XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR of 12 AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. The non-clinical DMPK properties of XMT-1522 have been characterized in vitro in plasma and microsomal stability studies, and in vivo in plasma and tissue disposition and excretion studies. Sample analysis for total AF-HPA drug payload and released (free) AF-HPA and its metabolites was performed by ESI+ LC/MS/MS; total antibody was determined by ELISA. The half-life for AF-HPA release in plasma was found to be greater than 120 hours in all species tested. Microsomal stability studies showed that AF-HPA was further converted to other metabolites including the carboxylic acid auristatin F (AF), as well as monomethyl auristatin F-HPA (MMAF-HPA) and MMAF. The pharmacokinetic profiles of XMT-1522 were evaluated in mouse, rat and cynomolgus monkey. The antibody of XMT-1522 is cross-reactive with monkey, but not rodent, HER2. In mouse and rat, XMT-1522 exposure was dose-proportional; exposure was slightly greater than dose-proportional in monkey consistent with saturation of target-mediated clearance. All species showed extended exposure to total AF-HPA drug payload, with measured clearance and volume of distribution similar for total AF-HPA and the antibody component of XMT-1522. Exposure to free AF-HPA and AF was less than 1/1000th the exposure of total AF-HPA. These data indicate the vast majority of AF-HPA in plasma is antibody-conjugated, indicating high stability of the ADC in systemic circulation. XMT-1522 tissue disposition was studied in NCI-N87 HER2-positive gastric cancer xenograft tumor bearing mice. After a single 3 mg/kg dose of XMT-1522, free AF-HPA and its metabolite AF were measurable in tumor tissue until the last time point measured (2 weeks). Total AF-HPA and free AF-HPA achieved peak tumor concentrations 48 hours after dosing. In contrast, AF achieved peak tumor concentration 7 days after dosing and showed only a slight decline in tumor concentration at 14 days, consistent with intracellular trapping of this poorly cell-permeable metabolite. Exposure to free AF-HPA or AF in other tissues was at least an order of magnitude lower than in tumor; in tissues with measurable free drug, AF was the predominant species. XMT-1522 excretion studies, conducted in rat, indicated that the AF-HPA payload was mainly excreted by the gastrointestinal route. In the first 96 hours after administration 33% of the AF-HPA dose was excreted in feces, compared to 3% excreted in urine. The major contributing metabolites both in feces and urine were conjugated AF-HPA, AF, and free AF-HPA. In conclusion, the plasma kinetics, tissue distribution and excretion profile of XMT-1522 are acceptable for clinical evaluation in cancer patients. Citation Format: Alex Yurkovetskiy, Dmitry Gumerov, Elena Ter-Ovanesyan, Patrick Conlon, Michael Devit, Charlie Bu, Natalya Bodyak, Timothy Lowinger, Donald Bergstrom. Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 48. doi:10.1158/1538-7445.AM2017-48

I. INTRODUCTION The export-led growth performance of the East Asian newly industrialized countries has increased interest in liberalization among developing countries in general. Such reforms are felt to benefit the economy, not only because they reduce the usual economic distortions, but also because they tend to drive agents out of rent seeking and into productive activities. However, the presence of lobbyists working for vested interests, such as import competing industries, makes these distortions difficult to remove.(1) Developed countries, of course, face similar problems. In analyzing the political and economic consequences of a reform, it is essential to consider the full range of rent-related activities in which individuals may engage. Our model focuses on two activities, rent seeking and lobbying, and examines the feedback effects resulting from reforms which target one or the other of these activities.(2) In particular, when people are driven out of rent seeking by a reform, their most natural alternative may be some other rent-related activity such as lobbying. We refer to reforms which target lobbying as primary reforms, while reforms which target rent-seeking activities are called secondary reforms. Primary reforms target the decision making process. An example is an institutional reform which lowers (all else equal), the marginal product of lobbying. Secondary reform focuses on the side effects resulting from the policy which has been put in place by lobbying. An example is the replacement of quotas by their tariff equivalent (tariffication) in an attempt to reduce rent seeking associated with the trade regime. In our model, import competing firms may lobby for protection which takes the form of a combination of tariffs and quotas. Raising the domestic price of the imported good increases the returns to sector specific capital located in the protected industry. To the extent that binding quotas are utilized, rents will accrue to those who acquire the import licenses. Rent seeking consists of resources (time) spent attempting to acquire the import licenses.(3) An important feature of the model is that, for the individuals involved, rent seeking and lobbying are highly substitutable activities. The presumption is that the skills required for these activities are more closely related to one another than they are to productive activities. This type of substitution between rent related activities is suggested by Rodrik [1994, p. 86, footnote 6]: "To the extent that rent-seeking behavior dissipates some of the rents of trade protection, the efficiency gains of reform may be larger than those measured here. However, the rent-seeking literature generally exaggerates these gains. If individuals can waste resources competing for the rents generated by, say, quotas, they can also waste resources lobbying the government for the reimposition of quotas that have been taken away."(4) Our assumption about the nature of rent seeking and lobbying activities has important implications for understanding the response to reform. In particular, this response depends on the extent to which reform is directed at rent seeking (secondary reform) or lobbying (primary reform). Feedback effects arise both because of labor market linkages, and because rents are created as a side effect of lobbying for trade protection. As we show below, the feedback effects from primary reforms often tend to reinforce the original reform, while the feedback effects associated with secondary reforms tend to retard the reform process. Near autarky, however, a primary reform can actually raise rents by increasing the volume of trade. Thus, in this situation, any primary reform should presumably be accompanied by secondary reform. Though the model presented here is extremely simple, and is a rather specific example of reform of the trade regime, the insights gained may apply to rent seeking and lobbying more generally. …

This article considers a simple model of an information retrieval (IR) technology, and uses this model to examine performance measures for IR systems. In particular, we show that, if a user is employing an IR system optimally, then reasonable performance measures will tend to be relatively robust, or insensitive, to small variations in assumptions about the user's behavior. A simple empirical illustration of this approach is reported, though more work will be needed to determine exactly how robust performance measures will be in practical applications.

This paper considers the “weak announcement proofness” criterion of Matthews et al. ( J. Econ. Theory (1991)) and shows that this criterion is not always weaker than announcement proofness. It is also shown that, in the class of simple sender–receiver games considered by Matthews et al. , if one equilibrium Pareto dominates all of the others, then weak announcement proofness usually selects that equilibrium. Journal of Economic Literature Classification Numbers: C72, D82.

This paper models the information processing problems of a firm by using the computation and optimization of mathematical functions as an analogy to the firm's information processing and decision making activities. This representation allows us to model the division of labor through the concept of functional nestedness, while the decentralization of information and decision making can be modeled through functional separability. The approach is illustrated through a series of simple applications, which examine, for example, how decision problem structures affect the demand for information technology, and how developments in information technology influence the demand for managerial skill.

It is shown that, in finitely repeated smooth games, e -equilibria are capable of supporting full cooperation up to very near the end of the horizon, with very small amounts of irrationality, e . Furthermore, behavior, even near the end of the horizon, is highly insensitive to the amount of irrationality assumed. Journal of Economic Literature Classification Numbers: C73, L13.

This article examines a simple model of an information retrieval (IR) technology, and uses this model to examine the optimal use of such a technology. In particular, we show that, if we understand optimal behavior, then we can (a) use observed behavior to shed light on the user's objective function, and (b) analyze how a user's behavior changes as her environment changes, for various specifications of the user's objective function. We also show how user satisfaction varies with the underlying stochastic behavior of the retrieval process.

This paper suggests a new approach to modeling credible reputation in the finite time horizon context, using continuous time and interactions which arrive via a Poisson process. Behavior in the present model does not depend on small ad hoc irrationalities as the end of the horizon nears, and the model preserves the intuitive result that as the end of the horizon nears, the level of reputation declines towards zero. While the current paper considers the predatory pricing case, the approach should also apply whenever reputation and/or cooperation are important.

The type II sodium-dependent potassium transporter NaPi2b (SLC34A2) is highly expressed in non-squamous NSCLC and non-mucinous ovarian cancer (OC) with restricted normal tissue expression, suggesting it may be a suitable ADC target for these indications. XMT-1536 is a novel, highly potent anti-NaPi2b ADC comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform. The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin derivative that is capable of bystander effect killing. In cell binding assays, XMT-1535 antibody binds to OC cells with low nanomolar affinity, which is unaffected by conjugation of the Dolaflexin drug conjugate. In vitro cytotoxicity assays show picomolar potency of XMT-1536 in OVCAR3 (OC; 32,000 NaPi2b molecules/cell; IC50 2 pM), TOV21G (OC; 10,000 NaPi2b molecules/cell; IC50 40 pM), and HCC-4006 (NSCLC; 52,000 NaPi2b molecules/cell; IC50 130 pM). In each cell line, XMT-1536 is 1-2 logs more potent than a non-binding Dolaflexin ADC control, consistent with target-dependent cytotoxic effect. XMT-1536 was tested in mouse xenograft models of OC and NSCLC. In the OVCAR3 OC model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg (0.21 mg/kg payload equivalent dose), and complete tumor regressions after a single dose of 5 mg/kg (0.36 mg/kg payload dose) or 3 weekly doses of 3 mg/kg. In contrast, a non-binding Dolaflexin ADC with comparable drug loading was inactive after 3 weekly administrations of 3 mg/kg, consistent with the anti-tumor activity of XMT-1536 being mediated through binding to the NaPi2b target. XMT-1536 was also tested in a patient-derived model of KRAS mutant NSCLC, where 3 weekly doses of 3 mg/kg led to significant tumor growth delay and regressions in some animals. Evaluation of XMT-1536 in additional patient derived xenograft models is on-going and will be updated at the meeting. XMT-1535 is cross-reactive with cynomolgous monkey NaPi2b, allowing an informative evaluation of whether XMT-1536 retains good tolerability in non-human primate. XMT-1536 was administered to cynomolgous monkeys in an exploratory single dose study up to 5 mg/kg ADC (4294 μg/m2 auristatin payload equivalents), with no observed target-mediated toxicity and limited adverse findings. Of note, there was no evidence of bone marrow toxicity, which has been observed generally for cleavable auristatin ADCs, and specifically for a recently published auristatin-based NaPi2b ADC (Lin et al., Clinical Cancer Research, 2015). Based on these data XMT-1536 is advancing to early clinical development for the treatment of NaPi2b-expressing tumors. Citation Format: Natalya Bodyak, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Reddy Bollu, Patrick Conlon, Venu R. Gurijala, Dennis McGillicuddy, Cheri Stevenson, Elena Ter-Ovanesyan, Peter U. Park, Laura Poling, Winnie Lee, Michael DeVit, Dongmei Xiao, LiuLiang Qin, Timothy B. Lowinger, Donald A. Bergstrom. Discovery and preclinical development of a highly potent NaPi2b-targeted antibody-drug conjugate (ADC) with significant activity in patient-derived non-small cell lung cancer (NSCLC) xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1194.

A shorter and more intuitive proof is given of Dekel′s implicit expected utility representation of a preference ordering satisfying the betweenness property. Journal of Economic Literature Classification Number D81.

This paper shows the effects of wage indexation schemes in the presence of relative price variations. In particular, it is shown that indexation schemes which seem reasonable can nevertheless leave the level of employment vulnerable to terms of trade shocks. The indexation scheme which isokates the employment level from the effects of price variations is derived, and the effects of commercial policies in the presence of indexation are examined.

The CRESH functional form has many desirable properties. It is globally regular for a wide range of parameter values, it includes the CES as a special case, and it has stable patterns of relative substitutability. However, while the CRESH form is defined to be implicitly additively separable, theordinary separability structure of the CRESH form has never been investigated. In this article, that deficiency is corrected by describing the separability structure of CRESH functions. In particular, it is shown that the CRESH form is separability flexible in the important three input case. This and its other properties may make the CRESH function the form of choice among existing three input production functions.