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Graduate schools around the United States are working to improve access to science, technology, engineering, and mathematics (STEM) in a manner that reflects local and national demographics. The admissions process has been the focus of examination, as it is a potential bottleneck for entry into STEM. Standardized tests are widely used as part of the decision-making process; thus, we examined the Graduate Record Examination (GRE) in two models of applicant review: metrics-based applicant review and holistic applicant review to understand whether it affected applicant demographics at The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. We measured the relationship between GRE scores of doctoral applicants and admissions committee scores. Metrics-based review of applicants excluded twice the number of applicants who identified as a historically underrepresented minority compared with their peers. Efforts to implement holistic applicant review resulted in an unexpected result: the GRE could be used as a tool in a manner that did not reflect its reported bias. Applicant assessments in our holistic review process were independent of gender, racial, and citizenship status. Importantly, our recommendations provide a blueprint for institutions that want to implement a data-driven approach to assess applicants in a manner that uses the GRE as part of the review process.

BackgroundOutcomes for children with high-risk neuroblastoma are poor, and improved understanding of the mechanisms underlying neuroblastoma pathogenesis, recurrence, and treatment resistance will lead to improved outcomes. Aberrant growth factor receptor expression and receptor tyrosine kinase signaling are associated with the pathogenesis of many malignancies. A germline polymorphism in the FGFR4 gene is associated with increased receptor expression and activity and with decreased survival, treatment resistance, and aggressive disease for many malignancies. We therefore investigated the role of this FGFR4 polymorphism in neuroblastoma pathogenesis.Materials and methodsGermline DNA from neuroblastoma patients and matched controls was assessed for the FGFR4 Gly/Arg388 polymorphism by RT-PCR. Allele frequencies were assessed for association with neuroblastoma patient outcomes and prognostic features. Degradation rates of the FGFR4 Arg388 and Gly388 receptors and rates of receptor internalization into the late endosomal compartment were measured.ResultsFrequency of the FGFR4 AA genotype and the prevalence of the A allele were significantly higher in patients with neuroblastoma than in matched controls. The Arg388 receptor demonstrated slower degradation than the Gly388 receptor in neuroblastoma cells and reduced internalization into multivesicular bodies.ConclusionsThe FGFR4 Arg388 polymorphism is associated with an increased prevalence of neuroblastoma in children, and this association may be linked to differences in FGFR4 degradation rates. Our study provides the first evidence of a role for FGFR4 in neuroblastoma, suggesting that FGFR4 genotype and the pathways regulating FGFR4 trafficking and degradation may be relevant for neuroblastoma pathogenesis.

BackgroundUBE4B is an E3/E4 ubiquitin ligase whose gene is located in chromosome 1p36.22. We analyzed the associations of UBE4B gene and protein expression with neuroblastoma patient outcomes and with tumor prognostic features and histology.MethodsWe evaluated the association of UBE4B gene expression with neuroblastoma patient outcomes using the R2 Platform. We screened neuroblastoma tumor samples for UBE4B protein expression using immunohistochemistry. FISH for UBE4B and 1p36 deletion was performed on tumor samples. We then evaluated UBE4B expression for associations with prognostic factors and with levels of phosphorylated ERK in neuroblastoma tumors and cell lines.ResultsLow UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma and with worse outcomes in all patient subgroups. UBE4B protein expression was associated with neuroblastoma tumor differentiation, and decreased UBE4B protein levels were associated with high-risk features. UBE4B protein levels were also associated with levels of phosphorylated ERK.ConclusionsWe have demonstrated associations between UBE4B gene expression and neuroblastoma patient outcomes and prognostic features. Reduced UBE4B protein expression in neuroblastoma tumors was associated with high-risk features, a lack of differentiation, and with ERK activation. These results suggest UBE4B may contribute to the poor prognosis of neuroblastoma tumors with 1p36 deletions and that UBE4B expression may mediate neuroblastoma differentiation.

The faculty and student populations in academia are not representative of the diversity in the U.S. population. Thus, research institutions and funding agencies invest significant funds and effort into recruitment and retention programs that focus on increasing the flow of historically underrepresented minorities (URMs) into the science, technology, engineering, and mathematics (STEM) pipeline. Here, we outline challenges, interventions, and assessments by the University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS) that increased the diversity of the student body independently of grade point averages and Graduate Record Examination scores. Additionally, we show these efforts progressively decreased the attrition rates of URM students over time while eliminating attrition in the latest cohort. Further, the majority of URM students who graduate from the GSBS are likely to remain in the STEM pipeline beyond the postdoctoral training period. We also provide specific recommendations based on the data presented to identify and remove barriers that prevent entry, participation, and inclusion of the underrepresented and underserved in the STEM pipeline.

Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface-modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared spectroscopy. We examined whether these immunoliposomes were able to target cell lines expressing varying levels of surface GD2 and affect cellular proliferation. Anti-GD2 liposomes were generally targeted in a manner that correlated with GD2 expression and inhibited proliferation in cell lines to which they were efficiently targeted. The mechanism by which the immunoliposomes entered targeted cells appeared to be via clathrin-dependent uptake as demonstrated using flow cytometry and confocal microscopy. These studies suggest that anti-GD2-targeted, etoposide-loaded liposomes represent a potential strategy for more effective delivery of anti-cancer drugs that could be used for GD2 positive tumors.

The signaling of plasma membrane proteins is tuned by internalization and sorting in the endocytic pathway prior to recycling or degradation in lysosomes. Ubiquitin modification allows recognition and association of cargo with endosomally associated protein complexes, enabling sorting of proteins to be degraded from those to be recycled. The mechanism that provides coordination between the cellular machineries that mediate ubiquitination and endosomal sorting is unknown. We report that the ubiquitin ligase UBE4B is recruited to endosomes in response to epidermal growth factor receptor (EGFR) activation by binding to Hrs, a key component of endosomal sorting complex required for transport (ESCRT) 0. We identify the EGFR as a substrate for UBE4B, establish UBE4B as a regulator of EGFR degradation, and describe a mechanism by which UBE4B regulates endosomal sorting, affecting cellular levels of the EGFR and its downstream signaling. We propose a model in which the coordinated action of UBE4B, ESCRT-0, and the deubiquitinating enzyme USP8 enable the endosomal sorting and lysosomal degradation of the EGFR.

A new ATP-preferring nucleotidase that interacts with a component of the protein complexes believed to drive vesicle docking and fusion (SNAP-25) is identified. Binding of the recombinant protein, Hrs-2, to SNAP-25 is restrained by the presence of calcium in the concentration range that facilitates synaptic transmission. The findings suggest that Hrs-2 influences the regulation of secretory processes through calcium- and nucleotide-dependent moderation of vesicle-trafficking protein complexes.

Genetic counseling is a rapidly expanding field, and the supply of certified genetic counselors is currently unable to keep up with job demand. Research is fairly limited regarding the awareness and perceptions that prospective genetic counseling students have on the field and what factors most influence their interest. The current study includes data collected from 1389 undergraduate students in the sciences at 23 universities across the United States who were surveyed regarding information related to their awareness, perceptions, knowledge, and interest in genetic counseling. The majority of participants had heard of genetic counseling (78.0%), many from a high school course (37.3%), college course (28.1%), or online (11.5%). Familiarity was associated with factors such as female gender (p = 0.003) and length of time in school (p < 0.001). After taking the survey, participant interest was positively associated with several factors including female gender (p < 0.001) and Asian and Hispanic ethnicity (p = 0.012). Factors commonly reported as attractive about the field included direct patient care, the variety of roles available, cultural competency and psychosocial training, and helping others. Discussion elaborates upon specific factors related to student awareness and interest in genetic counseling and potential ways to tailor recruitment strategies for maximum benefit to the field. [ABSTRACT FROM AUTHOR]

The vasopressin-induced trafficking of aquaporin-2 (AQP2) water channels in kidney collecting duct is likely mediated by vesicle-targeting proteins (N-ethylmaleimide-sensitive factor attachment protein receptors). Hrs-2 is an ATPase believed to have a modulatory role in regulated exocytosis. To examine whether Hrs-2 is expressed in rat kidney, we carried out RT-PCR combined with DNA sequence analysis and Northern blotting using a digoxigenin-labeled Hrs-2 RNA probe. RT-PCR and Northern blotting revealed that Hrs-2 mRNA is localized in all zones of rat kidney. The presence of Hrs-2 protein in rat kidney was confirmed by immunoblotting, revealing a 115-kDa protein in kidney and brain membrane fractions corresponding to the expected molecular size of Hrs-2. Immunostaining and confocal laser scanning microscopy of LLC-[PK.sub.1] cells (a porcine proximal tubule cell line) transfected with Hrs-2 DNA confirmed the specificity of the antibody and revealed that Hrs-2 is mainly localized in intracellular compartments, including cathepsin D-containing lysosomal/endosomal compartments. The cellular and subcellular localization of Hrs-2 in rat kidney was examined by immunocytochemistry and confocal laser scanning microscopy. Hrs-2 immunoreactivity was observed in collecting duct principal cells, and weaker labeling was detected in other nephron segments. The labeling was predominantly present in intracellular vesicles, but labeling was also observed in the apical plasma membrane domains of some cells. Colabeling with AQP2 revealed colocalization in vesicles and apical plasma membrane domains, suggesting a role for Hrs-2 in regulated AQP2 trafficking. vesicle-targeting receptors; N-ethylmaleimide-sensitive factor attachment protein receptors; collecting duct; aquaporin-2