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Mutations in human CILK1 (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent to the human CILK1 A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the intrinsically disordered C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEFs) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia, and upregulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild-type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. The CILK1 A615T mutant protein was not increased to the same level as the wild-type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single-residue variant of CILK1 is compromised, and this impairs the maintenance of primary cilia and Hedgehog signaling.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1–silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition–associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor–resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

Key Clinical Message Our report details a rare case of gastrointestinal bleeding in an adult male from Meckel's diverticulum. Diagnostic tests were negative except for technetium‐99m pertechnetate scintigraphy with SPECT/CT, highlighting importance of diverse modalities.

This paper investigates the interfacial, tensile, and fatigue properties of a novel smart fiber‐metal laminate (FML) based on a nickel‐titanium (Ni‐Ti) shape memory alloy and a woven glass fiber reinforced epoxy. Initial tests, using the single cantilever beam (SCB) geometry, have shown that this unique system offers high values of metal‐composite interfacial fracture toughness. Tensile tests have shown that the mechanical properties of these FMLs lie between those offered by its constituent materials and that their tensile modulus and strength can be easily predicted using a rule of mixtures approach. Tension‐tension fatigue tests have shown that the fatigue performance of notched smart FMLs is superior to that offered by the plain Ni‐Ti alloy. A subsequent optical examination of unnotched laminates tested to failure under tension‐tension fatigue loading has shown that the fracture mechanisms occurring within the Ni‐Ti FMLs are strongly dependent on the applied cyclic stress. POLYM. COMPOS., 28:534–544, 2007. © 2007 Society of Plastics Engineers

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0–122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3–4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

In Chapter 1, Dr Igor Kopylov and I extend random expected utility (REU) from Gul and Pesendorfer (2006) in two directions. First, we rewrite it in terms of types that combine the expected utility maximization with endogenous tie-breaking. Thus a salient expected utility function, such as the risk neutral one, can be maximized with a positive probability. We characterize discrete random expected utility (DREU) where random choices are represented uniquely by a probability distribution μ over finitely many types. Second, we extend DREU to partial random expected utility (PREU) where μ can be affected by the feasible menu, but still determined uniquely by random choice data. PREU captures various kinds of context dependence with both behavioral and normative motivations. We use PREU to identify self-selection where a type can become more likely, but only if its feasible options are improved. Such self-selection implies the standard monotonicity for random choices. It can even agree with the random utility model of Block and Marschak (1960), which becomes misspecified in this case. Finally, we discuss applications of DREU and PREU to random risk aversion. In Chapter 2, I extend the discussion on random risk attitudes in PREU from the previous chapter via an experiment to test whether the distribution of risk attitudes changes depending on the construction of the menu. Specifically, when an unattractive certain option is added to a menu, does the average decision maker exhibit higher levels of risk aversion? I find that there is a systematic decrease in the choice of the riskier lottery when the certain option is added. What's more, when the certain option is a decoy, there is a significant increase in the choice of the safer lottery. This violates core axioms that characterize random utility in standard literature, evidencing the need for menu-dependence to model heterogeneity. I also discuss the persistence of decoy effects, and observe that when the certain decoy is removed, the enhanced level of risk aversion persists. Finally, I identify that cognitive levels do not have an effect on susceptibility to decoy effects, supporting the belief that it is a universal phenomenon. In Chapter 3, I discuss the difficulty to identify in stochastic choice models. Instead, I use a multi-utility (MU) model by Aizerman and Malishevski (1981) due to its simpler choice primitives. I consider three cases where individual types are respectively modeled by (i) an arbitrary utility, (ii) expected utility, and (iii) quasilinear utility. I discover that while the expected utility case is still computationally difficult to identify, there is promise with the other two models. I dedicate the majority of this chapter to the algorithmic identification of heterogeneity in a quasilinear framework. My algorithm allows for incompleteness as well as noise. I propose candidate indices to measure type dispersion and noisiness. What's more, I extend the discussion to constant threshold representations (CTR) (Jamison and Lau, 1973), a special case of MU where agents are unable to distinguish small differences in utility. I implement a novel algorithmic approach that attempts to fit CTR into general datasets. While I do not provide any theoretical complexity guarantees for the CTR case, my initial findings suggest that my algorithm works reasonably fast in practical settings.

Mutations in human (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent of the human A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEF) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia and up-regulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. CILK1 A615T mutant protein was not increased to the same level as the wild type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single residue variant of CILK1 is compromised and this impairs the maintenance of primary cilia and Hedgehog signaling.

Purpose - Current online testing often lacks credibility, integrity, and reliability, though many online tests are implemented. Online testing with face recognition is a relatively new form of web-based testing model in comparison to current testing. The purpose of this paper is to discuss implementation of face recognition technology to increase quiz efficacy and build credible online quiz systems.Design methodology approach - While existing models of web-based quiz systems are being improved, most current quiz models do not consider the function of fraud detection during a web-based quiz. Online testing credibility includes the perceptions of the student and teacher on how the site would meet their expectations and how believable the testing scores are.Findings - In a survey of faculty (25) and students (257) on online testing credibility, 80 percent of the teachers and 98 percent of the students doubt the score credibility of the current online testing system. After explaining and implementing face recognition system to the subjects, 74 percent of the teachers and 69 percent of the students positively believe the online testing result. According to hypothetical examination, face recognition, practicality, and interaction greatly shape users' opinions regarding online testing credibility.Originality value - The most prominent finding in this paper is that face recognition technology positively improves the online testing credibility.

Purpose Current online testing often lacks credibility, integrity, and reliability, though many online tests are implemented. Online testing with face recognition is a relatively new form of webbased testing model in comparison to current testing. The purpose of this paper is to discuss implementation of face recognition technology to increase quiz efficacy and build credible online quiz systems. Designmethodologyapproach While existing models of webbased quiz systems are being improved, most current quiz models do not consider the function of fraud detection during a webbased quiz. Online testing credibility includes the perceptions of the student and teacher on how the site would meet their expectations and how believable the testing scores are. Findings In a survey of faculty 25 and students 257 on online testing credibility, 80 percent of the teachers and 98 percent of the students doubt the score credibility of the current online testing system. After explaining and implementing face recognition system to the subjects, 74 percent of the teachers and 69 percent of the students positively believe the online testing result. According to hypothetical examination, face recognition, practicality, and interaction greatly shape users' opinions regarding online testing credibility. Originalityvalue The most prominent finding in this paper is that face recognition technology positively improves the online testing credibility.