Publications by authors named "Aaron Meyer"

42 Publications

Early-Onset Alzheimer's Disease Masquerading as Catatonia.

Case Rep Neurol Med 2020 12;2020:1493481. Epub 2020 Sep 12.

University of California, San Diego, CA, USA.

A 35-year-old woman with a history of sexual trauma was brought in by her family for further evaluation of depressive symptoms and progressive decline in activities of daily living. She was admitted to the inpatient psychiatric unit for the treatment of suspected catatonia. After failure to respond to standard medical treatment, she received an extensive workup, which ultimately revealed a PSEN1 mutation consistent with early-onset Alzheimer's disease. Diagnosis was challenging because of her young age, lack of reliable family history, and reports of recent sexual abuse by her biological father. This case is a cautionary reminder for clinicians that end stages of dementia can present similar to catatonia with mutism, lack of spontaneous movement, and refusal to eat. The clues to the diagnosis were profound cortical atrophy and lack of improvement with optimal medical management.
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http://dx.doi.org/10.1155/2020/1493481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509543PMC
September 2020

Systems biology approaches to measure and model phenotypic heterogeneity in cancer.

Curr Opin Syst Biol 2019 Oct 11;17:35-40. Epub 2019 Sep 11.

Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine, OHSU, Portland, OR, USA.

The recent wide-spread adoption of single cell profiling technologies has revealed that individual cancers are not homogenous collections of deregulated cells, but instead are comprised of multiple genetically and phenotypically distinct cell subpopulations that exhibit a wide range of responses to extracellular signals and therapeutic insult. Such observations point to the urgent need to understand cancer as a complex, adaptive system. Cancer systems biology studies seek to develop the experimental and theoretical methods required to understand how biological components work together to determine how cancer cells function. Ultimately, such approaches will lead to improvements in how cancer is managed and treated. In this review, we discuss recent advances in cancer systems biology approaches to quantify, model, and elucidate mechanisms of heterogeneity.
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http://dx.doi.org/10.1016/j.coisb.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449235PMC
October 2019

Correction: Measurement and models accounting for cell death capture hidden variation in compound response.

Cell Death Dis 2020 Aug 24;11(8):699. Epub 2020 Aug 24.

Department of Bioengineering, University of California, Los Angeles, CA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41419-020-2576-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445293PMC
August 2020

Measurement and models accounting for cell death capture hidden variation in compound response.

Cell Death Dis 2020 04 20;11(4):255. Epub 2020 Apr 20.

Department of Bioengineering, University of California, Los Angeles, CA, USA.

Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug-response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, additive compound pairs with distinct growth/death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.
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http://dx.doi.org/10.1038/s41419-020-2462-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171175PMC
April 2020

Molecular chains under tension: Thermal and mechanical activation of statistically interacting extension and contraction particles.

Phys Rev E 2020 Feb;101(2-1):022504

Department of Physics, University of Rhode Island, Kingston, Rhode Island 02881, USA.

This work introduces a methodology for the statistical mechanical analysis of polymeric chains under tension controlled by optical or magnetic tweezers at thermal equilibrium with an embedding fluid medium. The response of single bonds between monomers or of entire groups of monomers to tension is governed by the activation of statistically interacting particles representing quanta of extension or contraction. This method of analysis is capable of describing thermal unbending of the freely jointed or wormlike chain kind, linear or nonlinear contour elasticity, and structural transformations including effects of cooperativity. The versatility of this approach is demonstrated in an application to double-stranded DNA undergoing torsionally unconstrained stretching across three regimes of mechanical response including an overstretching transition. The three-regime force-extension characteristic, derived from a single free-energy expression, accurately matches empirical evidence.
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http://dx.doi.org/10.1103/PhysRevE.101.022504DOI Listing
February 2020

Baseline MRI associates with later naming status in primary progressive aphasia.

Brain Lang 2020 02 24;201:104723. Epub 2019 Dec 24.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Physical Medicine & Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Cognitive Science, Johns Hopkins University, Baltimore, MD, USA.

Advanced imaging studies in neurodegenerative disease have yielded new insights into subtypes of disease, progression of disease in various brain regions, and changes in structural and functional connectivity between brain regions related to symptom progression. However, few studies have revealed imaging markers at baseline that correlate with rate or degree of decline in function. Here we tested the hypothesis that imaging features at baseline correlate with outcome of naming in primary progressive aphasia. We obtained longitudinal multimodal imaging in 15 individuals with primary progressive aphasia at the same time points as assessment of naming. We found that functional connectivity between particular brain regions (measured with resting state functional connectivity magnetic resonance imaging) is strongly associated with accuracy of naming 21 months later, independently of baseline severity of naming impairment. These data indicate that functional connectivity may carry information about later performance in naming, and is potentially useful for refining prognosis.
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http://dx.doi.org/10.1016/j.bandl.2019.104723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282486PMC
February 2020

Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

Nat Commun 2019 Nov 26;10(1):5461. Epub 2019 Nov 26.

Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13458-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877538PMC
November 2019

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

Nat Commun 2019 11 6;10(1):5031. Epub 2019 Nov 6.

Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.
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http://dx.doi.org/10.1038/s41467-019-13108-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834678PMC
November 2019

Patterns of Decline in Naming and Semantic Knowledge in Primary Progressive Aphasia.

Aphasiology 2018 28;32(9):1010-1030. Epub 2018 Jun 28.

Department of Neurology, Johns Hopkins University School of Medicine, Phipps 446, 600 N. Wolfe Street, Baltimore, Maryland 21287 USA; Telephone (410) 614-2381;

Background: Individuals with primary progressive aphasia (PPA) and their caregivers want to know what to expect so that they can plan support appropriately. The ability to predict decline in naming and semantic knowledge, and advise individuals with PPA and their caregivers regarding future planning, would be invaluable clinically.

Aims: The aims of this study were to investigate patterns of decline in naming and semantic knowledge in each of the clinical variants of PPA (logopenic variant PPA, lvPPA; nonfluent agrammatic PPA, nfaPPA; and semantic variant PPA, svPPA) and to examine the effects of other variables on rate of decline. We hypothesized that speech-language rehabilitation, higher education, and higher baseline test scores would be associated with slower decline, and older age with faster decline.

Methods And Procedures: A total of ninety-four participants with PPA underwent language testing, including thirty six participants with lvPPA, thirty-one participants with nfaPPA, and twenty-seven participants with svPPA. All participant groups were similar in age and education. We focused on decline on three tests: the short form of the Boston Naming Test (BNT), the Hopkins Assessment of Naming Actions (HANA), and the short form of the Pyramids and Palm Trees Test (PPTT).

Outcome And Results: Across language tests, the most precipitous rates of decline (loss of points per month) occurred in nfaPPA, followed by svPPA, then lvPPA. Female sex, longer symptom duration, higher baseline test score, and speech-language rehabilitation were associated with slower decline.

Conclusions: PPA variants were distinguishable by rapidity of decline, with nfaPPA having the most precipitous decline. As hypothesized, higher baseline test scores and speech-language rehabilitation were associated with slower decline. Surprisingly, age and education were not important prognostically for individuals in this study. Further study of prognostically-relevant variables in PPA is indicated in this population.
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http://dx.doi.org/10.1080/02687038.2018.1490388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317736PMC
June 2018

Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition.

Cell Mol Bioeng 2018 26;11(6):451-469. Epub 2018 Jul 26.

Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.

Introduction: Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed.

Methods: To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model.

Results: We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming.

Conclusions: Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development.
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http://dx.doi.org/10.1007/s12195-018-0542-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244947PMC
July 2018

Versatile targeting system for lentiviral vectors involving biotinylated targeting molecules.

Virology 2018 12 2;525:170-181. Epub 2018 Oct 2.

Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address:

Conjugating certain types of lentiviral vectors with targeting ligands can redirect the vectors to specifically transduce desired cell types. However, extensive genetic and/or biochemical manipulations are required for conjugation, which hinders applications for targeting lentiviral vectors for broader research fields. We developed envelope proteins fused with biotin-binding molecules to conjugate the pseudotyped vectors with biotinylated targeting molecules by simply mixing them. The envelope proteins fused with the monomeric, but not tetrameric, biotin-binding molecules can pseudotype lentiviral vectors and be conjugated with biotinylated targeting ligands. The conjugation is stable enough to redirect lentiviral transduction in the presence of serum, indicating their potential in in vivo . When a signaling molecule is conjugated with the vector, the conjugation facilitates transduction and signaling in a receptor-specific manner. This simple method of ligand conjugation and ease of obtaining various types of biotinylated ligands will make targeted lentiviral transduction easily applicable to broad fields of research.
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http://dx.doi.org/10.1016/j.virol.2018.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269213PMC
December 2018

Dissecting FcγR Regulation through a Multivalent Binding Model.

Cell Syst 2018 07 27;7(1):41-48.e5. Epub 2018 Jun 27.

Department of Bioengineering, Jonsson Comprehensive Cancer Center, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Many immune receptors transduce activation across the plasma membrane through their clustering. With Fcγ receptors (FcγRs), this clustering is driven by binding to antibodies of differing affinities that are in turn bound to multivalent antigen. As a consequence of this activation mechanism, accounting for and rationally manipulating immunoglobulin (Ig)G effector function is complicated by, among other factors, differing affinities between FcγR species and changes in the valency of antigen binding. In this study, we show that a model of multivalent receptor-ligand binding can effectively account for the contribution of IgG-FcγR affinity and immune complex valency. This model in turn enables us to make specific predictions about the effect of immune complexes of defined composition. In total, these results enable both rational immune complex design for a desired IgG effector function and the deconvolution of effector function by immune complexes.
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http://dx.doi.org/10.1016/j.cels.2018.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062446PMC
July 2018

Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections.

Proc Natl Acad Sci U S A 2018 07 18;115(27):7117-7122. Epub 2018 Jun 18.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

Maternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood-brain barrier, thus allowing infection of the brain later in life.
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http://dx.doi.org/10.1073/pnas.1719266115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142255PMC
July 2018

Long-Term maintenance of anomia treatment effects in primary progressive aphasia.

Neuropsychol Rehabil 2019 Oct 30;29(9):1439-1463. Epub 2018 Jan 30.

Center for Aphasia Research and Rehabilitation, Georgetown University Medical Center , Washington , DC , USA.

This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). Naming accuracy was measured at baseline, and it was measured at 1 month, 8 months, and 15 months post-treatment. The change in naming accuracy from baseline to each post-treatment evaluation was calculated within each treatment condition, and within a matched untrained condition. The change in naming accuracy was then compared between the three conditions. The results of these analyses indicate that phonological and orthographic treatments are both effective in the Prophylaxis and Remediation of anomia in all three variants of PPA. For Prophylaxis items, some of the effects of each treatment can persist for as long as 15 months post-treatment. These long-term treatment effects were more robust in the orthographic treatment condition and for participants with the semantic variant of PPA.
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http://dx.doi.org/10.1080/09602011.2018.1425146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066454PMC
October 2019

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance.

Integr Biol (Camb) 2017 Dec;9(12):912-924

Department of Chemical Engineering, University of Massachusetts Amherst, 686 N Pleasant St. 159 Goessmann Laboratory, Amherst, MA 01003, USA.

Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.
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http://dx.doi.org/10.1039/c7ib00128bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725273PMC
December 2017

Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells.

Mol Cancer Res 2017 12 18;15(12):1656-1666. Epub 2017 Sep 18.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). Phosphatidylserine is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here, it is reported that exposure of cancer cells to phosphatidylserine-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS-Gas6-AXL signaling axis. These findings suggest that anticancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy. This study demonstrates that motility behavior of AXL-expressing tumor cells can be elicited by Gas6-bearing apoptotic bodies generated from tumor treatment with therapeutics that produce killing of a portion of the tumor cells present but not all, hence generating potentially problematic invasive and metastatic behavior of the surviving tumor cells. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957761PMC
December 2017

Antibiotic discovery throughout the Small World Initiative: A molecular strategy to identify biosynthetic gene clusters involved in antagonistic activity.

Microbiologyopen 2017 06 22;6(3). Epub 2017 Jan 22.

Department of Biological Sciences, Bowling Green State University, Bowling Green, OH, USA.

The emergence of bacterial pathogens resistant to all known antibiotics is a global health crisis. Adding to this problem is that major pharmaceutical companies have shifted away from antibiotic discovery due to low profitability. As a result, the pipeline of new antibiotics is essentially dry and many bacteria now resist the effects of most commonly used drugs. To address this global health concern, citizen science through the Small World Initiative (SWI) was formed in 2012. As part of SWI, students isolate bacteria from their local environments, characterize the strains, and assay for antibiotic production. During the 2015 fall semester at Bowling Green State University, students isolated 77 soil-derived bacteria and genetically characterized strains using the 16S rRNA gene, identified strains exhibiting antagonistic activity, and performed an expanded SWI workflow using transposon mutagenesis to identify a biosynthetic gene cluster involved in toxigenic compound production. We identified one mutant with loss of antagonistic activity and through subsequent whole-genome sequencing and linker-mediated PCR identified a 24.9 kb biosynthetic gene locus likely involved in inhibitory activity in that mutant. Further assessment against human pathogens demonstrated the inhibition of Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus in the presence of this compound, thus supporting our molecular strategy as an effective research pipeline for SWI antibiotic discovery and genetic characterization.
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http://dx.doi.org/10.1002/mbo3.435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458470PMC
June 2017

The Relationship Between Baseline Volume in Temporal Areas and Post-Treatment Naming Accuracy in Primary Progressive Aphasia.

Aphasiology 2017 2;31(9):1059-1077. Epub 2017 Mar 2.

Center for Aphasia Research and Rehabilitation, Georgetown University Medical Center, Washington, DC.

Background: Structural imaging has not been used previously to predict the effect of treatment in primary progressive aphasia (PPA).

Aims: This study examined relationships between baseline brain volume and the effects of phonological and orthographic treatments for anomia in PPA. It was predicted that lower baseline volume would be associated with lower post-treatment naming accuracy for treated items and smaller generalization effects.

Methods & Procedures: Twenty-one individuals with PPA participated. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). All 21 participants had Prophylaxis items, while 10 participants had Remediation items. Naming accuracy for untrained and trained items (Exemplar set 1) was measured. In addition, stimulus generalization was examined by having participants name an alternative exemplar of each untrained and trained item (Exemplar set 2). Correlational analyses focused on the relationships between naming accuracy and volume of regions previously identified as having a role in naming and semantic processing.

Outcomes & Results: Unexpectedly, there were no significant correlations between baseline volume and post-treatment accuracy for treated items. However, baseline volume within the left temporal pole was positively correlated with post-treatment accuracy for Untrained Exemplar set 2 Prophylaxis items, while baseline volume in the left inferior temporal gyrus was positively correlated with post-treatment accuracy for Untrained Exemplar set 1 Remediation items.

Conclusions: These findings suggest that lower volume in the left temporal pole is associated with decline for Untrained items, while lower volume in the left inferior temporal gyrus is associated with a lack of improvement for Untrained items. Possible explanations for the different patterns observed across Exemplar sets are discussed.
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http://dx.doi.org/10.1080/02687038.2017.1296557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889050PMC
March 2017

Systems Approaches to Cancer Biology.

Cancer Res 2016 12 18;76(23):6774-6777. Epub 2016 Nov 18.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.

Cancer systems biology aims to understand cancer as an integrated system of genes, proteins, networks, and interactions rather than an entity of isolated molecular and cellular components. The inaugural Systems Approaches to Cancer Biology Conference, cosponsored by the Association of Early Career Cancer Systems Biologists and the National Cancer Institute of the NIH, focused on the interdisciplinary field of cancer systems biology and the challenging cancer questions that are best addressed through the combination of experimental and computational analyses. Attendees found that elucidating the many molecular features of cancer inevitably reveals new forms of complexity and concluded that ensuring the reproducibility and impact of cancer systems biology studies will require widespread method and data sharing and, ultimately, the translation of important findings to the clinic. Cancer Res; 76(23); 6774-7. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135591PMC
December 2016

JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.

Cancer Res 2016 09 22;76(18):5219-28. Epub 2016 Jul 22.

Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts

Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling-based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients. Cancer Res; 76(18); 5219-28. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026573PMC
September 2016

A requirement for filopodia extension toward Slit during Robo-mediated axon repulsion.

J Cell Biol 2016 04 18;213(2):261-74. Epub 2016 Apr 18.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239

Axons navigate long distances through complex 3D environments to interconnect the nervous system during development. Although the precise spatiotemporal effects of most axon guidance cues remain poorly characterized, a prevailing model posits that attractive guidance cues stimulate actin polymerization in neuronal growth cones whereas repulsive cues induce actin disassembly. Contrary to this model, we find that the repulsive guidance cue Slit stimulates the formation and elongation of actin-based filopodia from mouse dorsal root ganglion growth cones. Surprisingly, filopodia form and elongate toward sources of Slit, a response that we find is required for subsequent axonal repulsion away from Slit. Mechanistically, Slit evokes changes in filopodium dynamics by increasing direct binding of its receptor, Robo, to members of the actin-regulatory Ena/VASP family. Perturbing filopodium dynamics pharmacologically or genetically disrupts Slit-mediated repulsion and produces severe axon guidance defects in vivo. Thus, Slit locally stimulates directional filopodial extension, a process that is required for subsequent axonal repulsion downstream of the Robo receptor.
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http://dx.doi.org/10.1083/jcb.201509062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084274PMC
April 2016

Telerehabilitation of Anomia in Primary Progressive Aphasia.

Aphasiology 2016 Apr 4;30(4):483-507. Epub 2015 Sep 4.

Center for Aphasia Research and Rehabilitation, Georgetown University Medical Center.

Background: The efficacy of telerehabilitation-based treatment for anomia has been demonstrated in post-stroke aphasia, but the efficacy of this method of anomia treatment delivery has not been established within the context of degenerative illness.

Aims: The current study evaluated the feasibility and efficacy of a telerehabilitation-based approach to anomia treatment within the three subtypes of primary progressive aphasia (PPA).

Methods & Procedures: Each of the three telerehabilitation participants represented a distinct subtype of PPA. Following a baseline evaluation of language and cognition, a phonological treatment and an orthographic treatment were administered to all participants over the course of six months. One month after the end of treatment, a post-treatment evaluation began. All treatment sessions and the majority of the evaluation sessions were administered via telerehabilitation. Treatment effects were examined within each subject, and treatment effects were also compared between each telerehabilitation participant and a group of in-person participants who had the same subtype of PPA.

Outcomes & Results: All three telerehabilitation participants exhibited positive treatment effects. CGR (nonfluent/agrammatic variant PPA) and WCH (logopenic variant PPA) showed maintenance of naming for prophylaxis items in both treatment conditions, while ACR (semantic variant PPA) demonstrated increased naming of remediation items in the phonological treatment condition. Compared to in-person participants with the same subtype of PPA, each of the telerehabilitation participants typically showed effects that were either within the expected range or larger than expected.

Conclusions: Telerehabilitation-based anomia treatment is feasible and effective in all three subtypes of PPA.
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http://dx.doi.org/10.1080/02687038.2015.1081142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831866PMC
April 2016

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Cancer Discov 2016 Apr 16;6(4):382-99. Epub 2016 Mar 16.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Unlabelled: Kinase inhibitor resistance often involves upregulation of poorly understood "bypass" signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

Significance: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087317PMC
http://dx.doi.org/10.1158/2159-8290.CD-15-0933DOI Listing
April 2016

Prophylaxis and remediation of anomia in the semantic and logopenic variants of primary progressive aphasia.

Neuropsychol Rehabil 2018 Apr 18;28(3):352-368. Epub 2016 Feb 18.

a Center for Aphasia Research and Rehabilitation , Georgetown University Medical Center , Washington , DC , USA.

This study evaluated the efficacy of phonological and orthographic treatments for anomia in the semantic and logopenic variants of primary progressive aphasia (svPPA and lvPPA, respectively). Both treatments were administered for 6 months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (remediation items). Oral naming accuracy was measured for trained and untrained picture exemplars, as well as matched items from an untrained condition (UC). Written naming and scene description tasks were also conducted. For all tasks, the change in naming accuracy from baseline to 1 month post-treatment was compared between the UC and each treatment condition. These comparisons indicated that both treatments were effective in the remediation and prophylaxis of anomia in both variants. Furthermore, generalisation to untrained exemplars occurred in both subtypes, whereas item generalisation occurred in lvPPA, and task generalisation was present in svPPA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081283PMC
http://dx.doi.org/10.1080/09602011.2016.1148619DOI Listing
April 2018

Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain.

Sci Rep 2015 Oct 19;5:15150. Epub 2015 Oct 19.

Massachusetts Institute of Technology, Department of Biological Engineering, 77 Massachusetts Ave., Cambridge, MA 02139.

Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.
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http://dx.doi.org/10.1038/srep15150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609913PMC
October 2015

Prophylactic Treatments for Anomia in the Logopenic Variant of Primary Progressive Aphasia: Cross-Language Transfer.

Aphasiology 2015;29(9):1062-1081

Center for Aphasia Research and Rehabilitation, Georgetown University Medical Center.

Background: Treatment studies for anomia in PPA have rarely compared multiple treatments in the same individual, and few anomia treatment studies have included participants with the logopenic variant of PPA (lvPPA).

Aims: The goals of this study were to evaluate two types of treatment for anomia in a bilingual participant (ND) with lvPPA, and to examine possible cross-language transfer of treatment effects.

Methods & Procedures: ND is a Norwegian-English bilingual woman with lvPPA who began this study at the age of 69. In the phonological treatment, ND listened to a word while viewing a corresponding picture, and she repeated the word. In the orthographic treatment, ND read a word out loud while viewing the corresponding picture, and she then copied the word. Both treatments were conducted in English, and accuracy for three tasks (oral naming, written naming, and naming to definition) was assessed in English and Norwegian. The treatment occurred over a one-year period, with eight sessions at the laboratory during the first month, followed by monthly laboratory sessions and thrice-weekly home practice sessions during the subsequent 11 months. Post-treatment assessments were conducted at 1 week, 8 months, 1 year, 20 months, and 3 years.

Outcomes & Results: Compared to untrained items, the orthographic treatment resulted in greater English written naming accuracy. This treatment also resulted in cross-language transfer: greater Norwegian oral naming and naming to definition accuracy. The phonological treatment resulted in marginally greater English oral naming accuracy, but it did not have a significant effect on naming accuracy in Norwegian.

Conclusions: These findings suggest that the orthographic treatment was effective in strengthening the orthographic representations of the treated items, which facilitated ND's written naming performance. The pattern of cross-language transfer suggests that the orthographic treatment also strengthened the language-independent semantic representations of the treated items, thereby facilitating access to their Norwegian phonological representations.
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http://dx.doi.org/10.1080/02687038.2015.1028327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524746PMC
January 2015

The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity.

Cell Syst 2015 Jul;1(1):25-36

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139 ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA 02139.

The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6-AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged. Integrating quantitative experiments with mathematical modeling, we show here that AXL operates to sense local spatial heterogeneity in ligand concentration, a feature consistent with its physiological role in inflammatory cell responses. This effect arises as a result of an intricate reaction-diffusion interaction. Our results demonstrate that AXL functions distinctly from other RTK families, a vital insight for envisioned design of AXL-targeted therapeutic intervention.
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http://dx.doi.org/10.1016/j.cels.2015.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520549PMC
July 2015

Phonological short-term memory in logopenic variant primary progressive aphasia and mild Alzheimer's disease.

Cortex 2015 Oct 16;71:183-9. Epub 2015 Jul 16.

Center for Aphasia Research and Rehabilitation, Georgetown University Medical Center, Washington, DC, USA.

It has been argued that individuals with logopenic variant primary progressive aphasia (lvPPA) have an impairment of the phonological loop, which is a component of the short-term memory (STM) system. In contrast, this type of impairment is not thought to be present in mild typical Alzheimer's disease (AD). Thus, one would predict that people with lvPPA would score significantly lower than a matched AD group on tasks that require phonological STM. In the current study, an lvPPA group was compared with a mild AD group that was matched on age, education, and general cognitive functioning. For a subset of the tasks that involved pseudowords, the AD and lvPPA groups were compared to a healthy control group that was matched on age and education. The lvPPA group was more impaired than the AD group on all of the tasks that required phonological STM, including the pseudoword tasks, but there were no significant differences between these groups on tasks that required visuospatial STM. Compared to the healthy controls, the lvPPA group performed significantly worse on the repetition and reading of pseudowords, while the AD group did not differ significantly from the controls on these tasks. These findings are consistent with the hypothesis that phonological STM is impaired in lvPPA.
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http://dx.doi.org/10.1016/j.cortex.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521400PMC
October 2015

Selectivity in subunit composition of Ena/VASP tetramers.

Biosci Rep 2015 Jul 28;35(5). Epub 2015 Jul 28.

The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, MA 02139, U.S.A. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.

The members of the actin regulatory family of Ena/VASP proteins form stable tetramers. The vertebrate members of the Ena/VASP family, VASP, Mena and EVL, have many overlapping properties and expression patterns, but functional and regulatory differences between paralogues have been observed. The formation of mixed oligomers may serve a regulatory role to refine Ena/VASP activity. While it has been assumed that family members can form mixed oligomers, this possibility has not been investigated systematically. Using cells expressing controlled combinations of VASP, Mena and EVL, we evaluated the composition of Ena/VASP oligomers and found that VASP forms oligomers without apparent bias with itself, Mena or EVL. However, Mena and EVL showed only weak hetero-oligomerization, suggesting specificity in the association of Ena/VASP family members. Co-expression of VASP increased the ability of Mena and EVL to form mixed oligomers. Additionally, we found that the tetramerization domain (TD) at the C-termini of Ena/VASP proteins conferred the observed selectivity. Finally, we demonstrate that replacement of the TD with a synthetic tetramerizing coiled coil sequence supports homo-oligomerization and normal VASP subcellular localization.
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http://dx.doi.org/10.1042/BSR20150149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721544PMC
July 2015

Metastatic breast cancer in patients with schizophrenia.

Mol Clin Oncol 2013 Mar 27;1(2):359-364. Epub 2012 Nov 27.

Saint Louis University, St. Louis, MO; ; St. Louis VA Medical Center, St. Louis, MO;

Breast cancer is a major health problem worldwide. The median survival duration for patients with metastatic breast cancer is two to three years. Approximately 1% of populations worldwide have schizophrenia. The manner in which schizophrenic patients fare when diagnosed with metastatic breast carcinoma (MBC) was evaluated. We queried the National Department of Veterans Affairs (DVA) datasets using computer codes for a pre-existing diagnosis of schizophrenia and a later diagnosis of breast carcinoma. Chart-based data concerning the identified subjects were then requested. Previously determined inclusion and exclusion criteria were applied to select evaluable patients from the medical records, prior to extracting demographic details and data concerning the treatment course in each subject. Ten patients had distant metastases at initial diagnosis, while seven developed MBC following prior curative-intent treatment. Two patients refused therapy. Ten did not comply with recommended management. Five harmed or threatened physicians, other caregivers or themselves. Schizophrenic patients with MBC often fail to understand the nature of their illnesses. Often they do not accept palliative treatment, while a number of them do not comply with therapy, once initiated. They often exhibit behaviors that are detrimental to themselves or others. Formal psychiatric consultation is therefore necessary in patients. Several detrimental behaviors may be predicted reliably by history alone.
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http://dx.doi.org/10.3892/mco.2012.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956275PMC
March 2013