Theory-driven game-based assessment of general cognitive ability: Design theory, measurement, prediction of performance, and test fairness.

Games, which can be defined as an externally structured, goal-directed type of play, are increasingly being used in high-stakes testing contexts to measure targeted constructs for use in the selection and promotion of employees. Despite this increasing popularity, little is known about how theory-driven game-based assessments (GBA), those designed to reflect a targeted construct, should be designed, or their potential for achieving their simultaneous goals of positive reactions and high-quality psychometric measurement. In the present research, we develop a theory of GBA design by integrating game design and development theory from human-computer interaction with psychometric theory. Next, we test measurement characteristics, prediction of performance, fairness, and reactions of a GBA designed according to this theory to measure latent general intelligence (g). Using an academic sample with GPA data (N = 633), we demonstrate convergence between latent GBA performance and g (ß = .97). Adding an organizational sample with supervisory ratings of job performance (N = 49), we show GBA prediction of both GPA (r = .16) and supervisory ratings (r = .29). We also show incremental prediction of GPA using unit-weighted composites of the g test battery beyond that of the g-GBA battery but not the reverse. We also show the presence of similar adverse impact for both the traditional test battery and GBA but the absence of differential prediction of criteria. Reactions were more positive across all measures for the g-GBA compared to the traditional test battery. Overall, results support GBA design theory as a promising foundation from which to build high-quality theory-driven GBAs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mxi1 and mxi1-0 antagonize N-myc function and independently mediate apoptosis in neuroblastoma.

Neuroblastoma (NB) is the third most common malignancy of childhood, and outcomes for children with advanced disease remain poor; amplification of the MYCN gene portends a particularly poor prognosis. Mxi1 antagonizes N-Myc by competing for binding to Max and E-boxes. Unlike N-Myc, Mxi1 mediates transcriptional repression and suppresses cell proliferation. Mxi1 and Mxi1-0 (an alternatively transcribed Mxi1 isoform) share identical Max and DNA binding domains but differ in amino-terminal sequences. Because of the conservation of these critical binding domains, we hypothesized that Mxi1-0 antagonizes N-Myc activity similar to Mxi1. SHEP NB cells and SHEP cells stably transfected with MYCN (SHEP/MYCN) were transiently transfected with vectors containing full-length Mxi1, full-length Mxi1-0, or the common Mxi domain encoded by exons 2 to 6 (ex2-6). After incubation in low serum, parental SHEP/MYCN cell numbers were reduced compared with SHEP cells. Activated caspase-3 staining and DNA fragmentation ELISA confirmed that SHEP/MYCN cells undergo apoptosis in low serum, while SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 do not. However, SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 and grown in normal serum showed proliferation rates similar to SHEP cells. Mxi ex2-6 did not affect cell number in low or normal serum, suggesting that amino terminal domains of Mxi1 and Mxi1-0 are critical for antagonism. In the absence of N-Myc, Mxi1 and Mxi1-0 induce apoptosis independently through the caspase-8-dependent extrinsic pathway, while N-Myc activates the caspase-9-dependent intrinsic pathway. Together, these data indicate that Mxi1 and Mxi1-0 antagonize N-Myc but also independently impact NB cell survival.

Type III TGF-ß receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-ß receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, TßRIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. TßRIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. TßRIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. TßRIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for TßRIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus.

Neuroblastoma is the most common solid tumor of infancy, and mutations in several genes have been implicated as playing a role in tumor development. Here, we describe a pediatric patient with a constitutional microduplication of 2p24.3 who developed Stage 4 neuroblastoma at age 11 months. He represents the sixth patient described in the literature with partial trisomy 2p and neuroblastoma. All previous cases had duplication events spanning two genes implicated in neuroblastoma, MYCN and ALK. Our patient is unique because his duplicated region includes the MYCN gene only; the ALK gene is unaffected. These data, combined with the relatively high incidence of neuroblastoma reported in partial trisomy 2p patients, support the notion that MYCN duplication should be added to the growing list of genetic factors associated with an increased risk of neuroblastoma. The mechanism of increased risk is unclear, but the fact that our patient had dramatic amplification of MYCN in his tumor suggests that a germline duplication might predispose to further amplification. Additionally, our patient has several morphologic features common to patients with partial trisomy 2p including high forehead, hypertelorism, postaxial polydactyly, and developmental delay despite having a microduplication spanning approximately 1 Mb and including just three intact genes. This case may therefore help further delineate the genotype-phenotype correlations associated with partial trisomy 2p.

Hereditary intrinsic factor deficiency in chaldeans.

Juvenile vitamin B(12) or cobalamin (Cbl) deficiency is notoriously difficult to explain due to numerous acquired and inherited causes. The consequences of insufficient Cbl are megaloblastic anemia, nutrient malabsorption, and neurological problems. The treatment is straightforward with parenteral Cbl supplementation that resolves most health issues without an urgent need to clarify their cause. Aside from being clinically unsatisfying, failing to elucidate the basis of Cbl deficiency means important information regarding recurrence risk is not available to the individual if the cause is contagious or inherited. Acquired causes have largely disappeared in the Modern World because they were mostly due to parasites or malnutrition. Today, perhaps the most common causes of juvenile Cbl deficiency are Imerslund-Gräsbeck syndrome and inherited intrinsic factor deficiency (IFD). Three genes are involved and genetic testing is complicated and not widely available. We used self-identified ancestry to accelerate and confirm the genetic diagnosis of IFD in three families of Chaldean origin. A founder mutation limited to Chaldeans from Iraq in the intrinsic factor gene GIF was identified as the cause. World events reshape the genetic structure of populations and inherited diseases in many ways. In this case, all the patients were diagnosed in the USA among recent immigrants from a single region. While IFD itself is not restricted to one kind of people, certain mutations are limited in their range but migrations relocate them along with their host population. As a result, self-identified ancestry as a stratifying characteristic should perhaps be considered in diagnostic strategies for rare genetic disorders.

N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma.

Amplification of the MYCN proto-oncogene is associated with a poor prognosis in patients with metastatic neuroblastoma (NB). MYCN encodes the N-Myc protein, a transcriptional regulator that dimerizes with the Max transcription factor, binds to E-box DNA sequences, and regulates genes involved in cell growth and apoptosis. Overexpression of N-Myc leads to transcriptional activation and an increase in NB cell proliferation. Mxi1, a member of the Myc family of transcriptional regulators, also binds to Max. However, Mxi1 is a transcriptional repressor and inhibits proliferation of NB cells, suggesting that Mxi1 functions as an N-Myc antagonist. Our laboratory previously identified Mxi1-0, an alternatively transcribed Mxi1 isoform. Mxi1-0 has properties distinct from those of Mxi1; in contrast to Mxi1, Mxi1-0 is unable to suppress c-Myc-dependent transcription. We now show that Mxi1-0 expression increases in response to MYCN overexpression in NB cells, with a positive correlation between MYCN and MXI1-0 RNA levels. We also show that N-Myc expression differentially regulates the MXI1 and MXI1-0 promoters: Increased MYCN expression suppresses MXI1 promoter activity while enhancing transcription through the MXI1-0 promoter. Finally, induction of Mxi1-0 leads to increased proliferation, whereas expression of Mxi1 inhibits cell growth, indicating differential roles for these two proteins. These data suggest that N-Myc differentially regulates the expression of MXI1 and MXI1-0 and can alter the balance between the two transcription factors. Furthermore, MXI1-0 appears to be a downstream target of MYCN-dependent signaling pathways and may contribute to N-Myc-dependent cell growth and proliferation.

The PICALM protein plays a key role in iron homeostasis and cell proliferation.

The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM's function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.

Cardiac arrest and possible seizure activity after vincristine injection.

PURPOSE: A case of cardiac arrest and possible seizure activity after vincristine injection in a child is reported. SUMMARY: A two-year-old African-American girl with stage IV hepatoblastoma arrived at a clinic to receive her fourth dose of vincristine as part of standard induction therapy. The patient had tolerated her first three doses of vincristine sulfate 0.7 mg (1.5 mg/m(2)) i.v. without any adverse events. Laboratory tests, including a comprehensive metabolic panel, conducted before chemotherapy administration were unremarkable. Shortly after the administration of vincristine, the patient experienced tonic extension of all four extremities and upward sustained deviation of the eyes. The patient then became limp and exhibited perioral cyanosis. Further evaluation revealed a lack of central pulses and a heartbeat. Cardiopulmonary resuscitation was begun with chest compressions and positive-pressure ventilation via a bag-mask device. After approximately 45 seconds, her pulses returned, and perioral cyanosis resolved. She was admitted to the pediatric intensive care unit for further evaluation. Her serum electrolyte, glucose, and ammonia concentrations were within normal limits. No yeast or bacteria were isolated from the patient's blood. No contributing cardiac or neurologic factors were identified. The patient recovered without sequelae and was discharged after 72 hours. Subsequent doses of vincristine were administered with no adverse events, and the patient successfully completed her treatment regimen. CONCLUSION: A two-year-old girl with hepatoblastoma had seizurelike activity and cardiac arrest shortly after receiving i.v. vincristine. She received multiple doses of the drug before and after this event without a similar reaction. No contributing factors for the one-time event were identified.

Bortezomib as a therapeutic candidate for neuroblastoma.

Outcomes remain poor in neuroblastoma despite intensive treatment. Agents with potential efficacy can be drawn from anti-neoplastic drugs introduced for other malignancies. Bortezomib, a proteasome inhibitor, modulates cell-signaling molecules leading to apoptosis. Bortezomib, alone and in combination with other agents, was tested across an in vitro panel of neuroblastic, stromal, and chemo-resistant neuroblastoma cell types to determine its effect on cell viability and to assess for interactions between bortezomib and other chemotherapeutic agents that either limit or increase overall response. Each subtype of neuroblastoma was sensitive to bortezomib and killing occurred with EC50 values of approximately 50 nM. When bortezomib was combined with other agents (doxorubicin, etoposide, SN-38, carboplatin, or cisplatin), no antagonism was observed. The bortezomib-doxorubicin combination was especially effective, demonstrating synergy on isobolographic analysis and resulting in a decrease in EC50 from 50 ng/mL with doxorubicin alone to 5 ng/mL with 25 nM bortezomib. Interestingly, the different cell types exhibited varying response patterns to treatment with bortezomib alone and in combination with other drugs suggesting different mechanisms may be engaged. A decision analysis, incorporating these results showing efficacy in all cell types, the synergy obtained in combination, and the available toxicity data, supports a phase II clinical trial of bortezomib in neuroblastoma.

Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-kappaB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Signaling from p53 to NF-kappa B determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-KB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Delayed, recurrent opsoclonus-myoclonus syndrome responding to plasmapheresis.

Opsoclonus-myoclonus syndrome is a distinct neurologic disorder characterized by opsoclonic eye movements, multifocal myoclonus, and ataxia, traditionally described as "dancing eyes, dancing feet." A presenting sign in 2% of children with neuroblastoma, it usually heralds a favorable prognosis for the tumor. Although opsoclonus-myoclonus syndrome usually presents at initial diagnosis or relapse, there are reports of delayed presentation, usually a few months after diagnosis. This report describes a patient with ganglioneuroblastoma who developed recurrent symptoms of opsoclonus-myoclonus syndrome 9 years after completing treatment, without evidence of recurrent tumor. Believed to be autoimmune in origin, opsoclonus-myoclonus syndrome frequently responds to immunomodulatory therapies, such as steroids or intravenous immunoglobulin. This patient did not respond adequately to either agent, so plasmapheresis, a less commonly used modality in opsoclonus-myoclonus syndrome, was attempted. His symptoms resolved after he received therapy with a combination of plasmapheresis and steroids over a 1-year period. After being slowly weaned off all therapy, he has been symptom-free now for over 3 years. Armstrong MB, Robertson PL, Castle VP. Delayed, recurrent opsoclonus-myoclonus syndrome responding to plasmapheresis.

Testicular chloroma in a nonleukemic infant.

Extramedullary myeloid cell tumors (EMCT) are localized collections of immature myeloid cells that occur outside of the bone marrow. Usually observed concurrently with bone marrow disease, EMCT also may occur in the absence of overt marrow leukemia. In this report, we describe an infant with a testicular mass that was identified as an EMCT after orchiectomy. Unlike the only previously reported case of infantile testicular chloroma, this patient did not exhibit bone marrow disease at diagnosis. Because systemic chemotherapy is considered to be superior to local control (surgery, radiation therapy), the patient was treated with intensively timed induction chemotherapy followed by 3 cycles of maintenance treatment (according to CCG protocol #2891) but no radiation therapy. The patient remains disease-free 18 months after diagnosis.