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The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations., (© 2024. The Author(s).)

Purpose: Although global heart dose has been associated with late cardiac toxic effects in patients who received radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructure dosimetry are limited. We investigated whether dose to the left anterior descending artery (LAD) correlates with adverse cardiac events., Methods and Materials: We identified 375 consecutively treated female patients from 2012 to 2018 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses (LAD D mean , LAD D max , heart D mean , and heart D max ) were calculated and converted to 2-Gy equivalent doses (EQD 2 ). Univariate and multivariable Cox regression analyses were performed to determine association with cardiac toxic effects. Potential dose thresholds for each of the 4 dose parameters were identified by receiver operating characteristic (ROC) curve analysis, after which Kaplan-Meier analysis was performed to compare cardiac event-free survival based on these constraints., Results: Median follow-up time was 48 months. Thirty-six patients experienced a cardiac event, and 23 patients experienced a major cardiac event. On univariate and multivariable analyses, increased LAD D mean , LAD D max , and heart D mean were associated with increased risk of any cardiac event and a major cardiac event. ROC curve analysis identified a threshold LAD D mean EQD 2 of 2.8 Gy (area under the ROC curve, 0.69), above which the risk for any cardiac event was higher (P = .001). Similar results were seen when stratifying by LAD D max EQD 2 of 6.7 Gy (P = .005) and heart D mean EQD 2 of 0.8 Gy (P = .01)., Conclusions: Dose to the LAD correlated with adverse cardiac events in this cohort. Contouring and minimizing dose to the LAD should be considered for patients receiving radiation therapy for left-sided breast cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has widely affected existing academia-sponsored community service initiatives. Little is known about the strategies to sustain these initiatives during a public health crisis and the potential effects on community well-being and education. In this case study, we describe the impact of the pandemic on service partnerships between our medical school and the Latinx community, discuss the challenges and opportunities of transitioning to a virtual community service model, and offer solutions and considerations., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Engineered microbial communities show promise in a wide range of applications, including environmental remediation, microbiome engineering, and synthesis of fine chemicals. Here we present methods by which bacterial aggregates can be directed into several distinct architectures by inducible surface expression of heteroassociative protein domains (SpyTag/SpyCatcher and SynZip17/18). Programmed aggregation can be used to activate a quorum-sensing circuit, and aggregate size can be tuned via control of the amount of the associative protein displayed on the cell surface. We further demonstrate reversibility of SynZip-mediated assembly by addition of soluble competitor peptide. Genetically programmable bacterial assembly provides a starting point for the development of new applications of engineered microbial communities in environmental technology, agriculture, human health, and bioreactor design.

Networks assembled by reversible association of telechelic polymers constitute a common class of soft materials. Various mechanisms of chain migration in associative networks have been proposed; yet there remains little quantitative experimental data to discriminate among them. Proposed mechanisms for chain migration include multichain aggregate diffusion as well as single-chain mechanisms such as "walking" and "hopping", wherein diffusion is achieved by either partial ("walking") or complete ("hopping") disengagement of the associated chain segments. Here, we provide evidence that hopping can dominate the effective diffusion of chains in associative networks due to a strong entropic penalty for bridge formation imposed by local network structure; chains become conformationally restricted upon association with two or more spatially separated binding sites. This restriction decreases the effective binding strength of chains with multiple associative domains, thereby increasing the probability that a chain will hop. For telechelic chains this manifests as binding asymmetry, wherein the first association is effectively stronger than the second. We derive a simple thermodynamic model that predicts the fraction of chains that are free to hop as a function of tunable molecular and network properties. A large set of self-diffusivity measurements on a series of model associative polymers finds good agreement with this model.

Programmable colloidal assembly enables the creation of mesoscale materials in a bottom-up manner. Although DNA oligonucleotides have been used extensively as the programmable units in this paradigm, proteins, which exhibit more diverse modes of association and function, have not been widely used to direct colloidal assembly. Here we use protein-protein interactions to drive controlled aggregation of polystyrene microparticles, either through reversible coiled-coil interactions or through intermolecular isopeptide linkages. The sizes of the resulting aggregates are tunable and can be controlled by the concentration of immobilized surface proteins. Moreover, particles coated with different protein pairs undergo orthogonal assembly. We demonstrate that aggregates formed by association of coiled-coil proteins, in contrast to those linked by isopeptide bonds, are dispersed by treatment with chemical denaturants or soluble competing proteins. Finally, we show that protein-protein interactions can be used to assemble complex core-shell aggregates. This work illustrates a versatile strategy for engineering colloidal systems for use in materials science and biotechnology.

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer., Competing Interests: The authors declare no conflict of interest.

We present a protein immobilization system, based on the Src Homology 3 (SH3) affinity domain, allowing for a transient interaction between a fibronectin ligand and a biomaterial surface. This strategy leads to enhanced retention of the fibronectin fragment over adsorbed fibronectin, and increased cellular proliferation and motility over either covalently immobilized or adsorbed fibronectin. The results indicate that intermediate affinity protein immobilization could provide benefits for tissue engineering beyond the traditional immobilization techniques, adsorption or covalent attachment., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)