Resistance to EGFR-Targeted Therapy: A Family Affair

The EGFR-directed antibody cetuximab has proven, albeit modest, clinical benefit as monotherapy in head and neck and colorectal cancers. In a recent study, Yonesaka et al. uncovered a new mechanism of cetuximab resistance mediated by increased ERBB2 signaling via amplification of ERBB2 or increased levels of the ERBB3/ERBB4 ligand heregulin

Cortical Correlates of the Auditory Frequency-Following and Onset Responses: EEG and fMRI Evidence

The frequency-following response (FFR) is a measure of the brain\u27s periodic sound encoding. It is of increasing importance for studying the human auditory nervous system due to numerous associations with auditory cognition and dysfunction. Although the FFR is widely interpreted as originating from brainstem nuclei, a recent study using MEG suggested that there is also a right-lateralized contribution from the auditory cortex at the fundamental frequency (Coffey et al., 2016b). Our objectives in the present work were to validate and better localize this result using a completely different neuroimaging modality and to document the relationships between the FFR, the onset response, and cortical activity. Using a combination of EEG, fMRI, and diffusion-weighted imaging, we show that activity in the right auditory cortex is related to individual differences in FFR–fundamental frequency (f0) strength, a finding that was replicated with two independent stimulus sets, with and without acoustic energy at the fundamental frequency. We demonstrate a dissociation between this FFR–f0-sensitive response in the right and an area in left auditory cortex that is sensitive to individual differences in the timing of initial response to sound onset. Relationships to timing and their lateralization are supported by parallels in the microstructure of the underlying white matter, implicating a mechanism involving neural conduction efficiency. These data confirm that the FFR has a cortical contribution and suggest ways in which auditory neuroscience may be advanced by connecting early sound representation to measures of higher-level sound processing and cognitive function

Student Teaching Abroad Inter-Group Outcomes: A Comparative, Country-Specific Analysis

As student diversity becomes the norm in U.S. schools, future teachers must be comprehensively prepared to work with the increasingly diverse student population through application of informed instruction that enhances general and individual student learning and outcomes. Teacher Education programs increasingly promote student teaching in international settings as a substantive step to develop teachers who embody these new competencies and instructional practices. The proposed paper presentation offers a framework and analysis highlighting similarities and differences between two groups of student teachers in Belize (2005 and 2008). Findings are comparative and relate to the type and degree of (1) cultural-, professional-, and character-development influences on student teachers, and (2) emergent common intergroup patterns

The Music-In-Noise Task (MINT): A Tool for Dissecting Complex Auditory Perception

The ability to segregate target sounds in noisy backgrounds is relevant both to neuroscience and to clinical applications. Recent research suggests that hearing-in-noise (HIN) problems are solved using combinations of sub-skills that are applied according to task demand and information availability. While evidence is accumulating for a musician advantage in HIN, the exact nature of the reported training effect is not fully understood. Existing HIN tests focus on tasks requiring understanding of speech in the presence of competing sound. Because visual, spatial and predictive cues are not systematically considered in these tasks, few tools exist to investigate the most relevant components of cognitive processes involved in stream segregation. We present the Music-In-Noise Task (MINT) as a flexible tool to expand HIN measures beyond speech perception, and for addressing research questions pertaining to the relative contributions of HIN sub-skills, inter-individual differences in their use, and their neural correlates. The MINT uses a match-mismatch trial design: in four conditions (Baseline, Rhythm, Spatial, and Visual) subjects first hear a short instrumental musical excerpt embedded in an informational masker of “multi-music” noise, followed by either a matching or scrambled repetition of the target musical excerpt presented in silence; the four conditions differ according to the presence or absence of additional cues. In a fifth condition (Prediction), subjects hear the excerpt in silence as a target first, which helps to anticipate incoming information when the target is embedded in masking sound. Data from samples of young adults show that the MINT has good reliability and internal consistency, and demonstrate selective benefits of musicianship in the Prediction, Rhythm, and Visual subtasks. We also report a performance benefit of multilingualism that is separable from that of musicianship. Average MINT scores were correlated with scores on a sentence-in-noise perception task, but only accounted for a relatively small percentage of the variance, indicating that the MINT is sensitive to additional factors and can provide a complement and extension of speech-based tests for studying stream segregation. A customizable version of the MINT is made available for use and extension by the scientific community

Novel association of APC with intermediate filaments identified using a new versatile APC antibody

<p>Abstract</p> <p>Background</p> <p>As a key player in suppression of colon tumorigenesis, Adenomatous Polyposis Coli (APC) has been widely studied to determine its cellular functions. However, inconsistencies of commercially available APC antibodies have limited the exploration of APC function. APC is implicated in spindle formation by direct interactions with tubulin and microtubule-binding protein EB1. APC also interacts with the actin cytoskeleton to regulate cell polarity. Until now, interaction of APC with the third cytoskeletal element, intermediate filaments, has remained unexamined.</p> <p>Results</p> <p>We generated an APC antibody (APC-M2 pAb) raised against the 15 amino acid repeat region, and verified its reliability in applications including immunoprecipitation, immunoblotting, and immunofluorescence in cultured cells and tissue. Utilizing this APC-M2 pAb, we immunoprecipitated endogenous APC and its binding proteins from colon epithelial cells expressing wild-type APC. Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), we identified 42 proteins in complex with APC, including β-catenin and intermediate filament (IF) proteins lamin B1 and keratin 81. Association of lamin B1 with APC in cultured cells and human colonic tissue was verified by co-immunoprecipitation and colocalization. APC also colocalized with keratins and remained associated with IF proteins throughout a sequential extraction procedure.</p> <p>Conclusion</p> <p>We introduce a versatile APC antibody that is useful for cell/tissue immunostaining, immunoblotting and immunoprecipitation. We also present evidence for interactions between APC and IFs, independent of actin filaments and microtubules. Our results suggest that APC associates with all three major components of the cytoskeleton, thus expanding potential roles for APC in the regulation of cytoskeletal integrity.</p

ERBBs in the gastrointestinal tract: Recent progress and new perspectives

The gastrointestinal epithelium does much more than provide a physical barrier between the intestinal lumen and our internal milieu. It is actively engaged in absorption and secretion of salt and water via ion transporters, exchangers and selective ion channels. It is also a continuously self-renewing epithelium that undergoes ordered growth and differentiation along its vertical axis. From this dual perspective, we will consider the actions of the ERBB family of ligands and receptors in the maintenance of gastrointestinal homeostasis and discuss instances when the actions of this family go awry such as in cancer and Ménétrier's disease

Investigating biological activity spectrum for novel styrylquinazoline analogues

In this study, series of ring-substituted 2-styrylquinazolin-4(3H)-one and 4-chloro-2-styrylquinazoline derivatives were prepared. The syntheses of the discussed compounds are presented. The compounds were analyzed by RP-HPLC to determine lipophilicity. They were tested for their inhibitory activity on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial strains and against eight fungal strains. Several compounds showed biological activity comparable with or higher than that of the standard isoniazid. It was found that the electronic properties of the R substituent, and not the total lipophilicity of the compound, were decisive for the photosynthesis-inhibiting activity of tested compounds

Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype

OBJECTIVE: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis. BACKGROUND: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown. DESIGN/METHODS: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored. RESULTS: Analysis showed that there was a three-way interaction between the time, treatment effect, and disease phenotype (P \u3c 0.06). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (P \u3c 0.01), and not by patients with SPMS (P = 0.97). This difference may have been due to faster brain atrophy progression seen in the PPMS placebo group compared to SPMS placebo (P \u3c 0.02). Although backward selection (P \u3c 0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates in the linear-mixed model, the adjusted overall treatment effect was still driven by PPMS (P \u3c 0.01). INTERPRETATION: The previously reported overall treatment effect of ibudilast on worsening of brain atrophy in progressive MS appears to be driven by patients with PPMS that may be, in part, because of the faster atrophy progression rates seen in the placebo-treated group