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Article ; Online: Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing.

Young, Colin C / Horton, Carolyn / Grzybowski, Jessica / Abualkheir, Nelly / Ramirez Castano, Jesus / Molparia, Bhuvan / Karam, Rachid / Chao, Elizabeth / Richardson, Marcy E

JCO precision oncology

2024 Volume 8, Page(s) e2300404

Abstract: Purpose: Patients with germline pathogenic variants (PVs) in : Methods: We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel : Results: Three ... ...

Abstract	Purpose: Patients with germline pathogenic variants (PVs) in Methods: We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel Results: Three novel Conclusion: Here, we describe how paired DNA-RNA MGPT can be used to solve missing heritability in FAP families, which can have important implications in family planning and treatment decisions for patients and their families.
MeSH term(s)	Humans ; Retrospective Studies ; Adenomatous Polyposis Coli/diagnosis ; Adenomatous Polyposis Coli/genetics ; Adenomatous Polyposis Coli/pathology ; Genetic Testing ; Colorectal Neoplasms/genetics ; DNA
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.23.00404
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Article: Nanomechanics of Aggrecan: A New Perspective on Cartilage Biomechanics, Disease and Regeneration.

Wang, Chao / Kahle, Elizabeth R / Li, Qing / Han, Lin

Advances in experimental medicine and biology

2023 Volume 1402, Page(s) 69–82

Abstract: Articular cartilage is a hydrated macromolecular composite mainly composed of type II collagen fibrils and the large proteoglycan, aggrecan. Aggrecan is a key determinant of the load bearing and energy dissipation functions of cartilage. Previously, ... ...

Abstract	Articular cartilage is a hydrated macromolecular composite mainly composed of type II collagen fibrils and the large proteoglycan, aggrecan. Aggrecan is a key determinant of the load bearing and energy dissipation functions of cartilage. Previously, studies of cartilage biomechanics have been primarily focusing on the macroscopic, tissue-level properties, which failed to elucidate the molecular-level activities that govern cartilage development, function, and disease. This chapter provides a brief summary of Dr. Alan J. Grodzinsky's seminal contribution to the understanding of aggrecan molecular mechanics at the nanoscopic level. By developing and applying a series of atomic force microscopy (AFM)-based nanomechanical tools, Grodzinsky and colleagues revealed the unique structural and mechanical characteristics of aggrecan at unprecedented resolutions. In this body of work, the "bottle-brush"-like ultrastructure of aggrecan was directly visualized for the first time. Meanwhile, molecular mechanics of aggrecan was studied using a physiological-like 2D biomimetic assembly of aggrecan on multiple fronts, including compression, dynamic loading, shear, and adhesion. These studies not only generated new insights into the development, aging, and disease of cartilage, but established a foundation for designing and evaluating novel cartilage regeneration strategies. For example, building on the scientific foundation and methodology infrastructure established by Dr. Grodzinsky, recent studies have elucidated the roles of other proteoglycans in mediating cartilage integrity, such as decorin and perlecan, and evaluated the therapeutic potential of biomimetic proteoglycans in improving cartilage regeneration.
MeSH term(s)	Aggrecans/analysis ; Aggrecans/chemistry ; Aggrecans/ultrastructure ; Biomechanical Phenomena ; Proteoglycans/chemistry ; Cartilage, Articular ; Extracellular Matrix Proteins ; Lectins, C-Type
Chemical Substances	Aggrecans ; Proteoglycans ; Extracellular Matrix Proteins ; Lectins, C-Type
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-031-25588-5_5
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Article ; Online: Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG).

Chao, Elizabeth C / Astbury, Caroline / Deignan, Joshua L / Pronold, Melissa / Reddi, Honey V / Weitzel, Jeffrey N

Genetics in medicine : official journal of the American College of Medical Genetics

2021 Volume 23, Issue 7, Page(s) 1179–1184

MeSH term(s)	Genetic Testing ; Genetics, Medical ; Genome, Human ; Genomics ; Germ Cells ; Humans ; United States
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1038/s41436-021-01138-5
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Article: A genotype-first approach identifies high incidence of

Safonov, Anton / Nomakuchi, Tomoki T / Chao, Elizabeth / Horton, Carrie / Dolinsky, Jill S / Yussuf, Amal / Richardson, Marcy / Speare, Virginia / Li, Shuwei / Bogus, Zoe C / Bonanni, Maria / Raper, Anna / Kallish, Staci / Ritchie, Marylyn D / Nathanson, Katherine L / Drivas, Theodore G

medRxiv : the preprint server for health sciences

2023

Abstract: Loss of function variants in ... ...

Abstract	Loss of function variants in the
Language	English
Publishing date	2023-08-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.08.23293676
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Article: Hydration-induced Void-containing Hydrogels for Encapsulation and Sustained Release of Small Hydrophilic Molecules.

Li, Qi / Li, Xiaosi / Bury, Elizabeth / Koh, Amanda / Lackey, Kimberly / Wesselmann, Ursula / Yaksh, Tony / Zhao, Chao

Advanced functional materials

2023 Volume 33, Issue 34

Abstract: ... is incubated overnight at 4 °C in the drug solution, it is hydrated into a hydrogel containing micron ...

Abstract	Efficient encapsulation and sustained release of small hydrophilic molecules from traditional hydrogel systems have been challenging due to the large mesh size of 3D networks and high water content. Furthermore, the encapsulated molecules are prone to early release from the hydrogel prior to use, resulting in a short shelf life of the formulation. Here, we present a hydration-induced void-containing hydrogel (HVH) based on hyperbranched polyglycerol-poly(propylene oxide)-hyperbranched polyglycerol (HPG-PPG-HPG) as a robust and efficient delivery system for small hydrophilic molecules. Specifically, after the HPG-PPG-HPG is incubated overnight at 4 °C in the drug solution, it is hydrated into a hydrogel containing micron-sized voids, which could encapsulate hydrophilic drugs and achieve 100% drug encapsulation efficiency. In addition, the voids are surrounded by a densely packed polymer matrix, which restricts drug transport to achieve sustained drug release. The hydrogel/drug formulation can be stored for several months without changing the drug encapsulation and release properties. HVH hydrogels are injectable due to shear thinning properties. In rats, a single injection of the HPG-PPG-HPG hydrogel containing 8 μg of tetrodotoxin (TTX) produced sciatic nerve block lasting up to 10 hours without any TTX-related systemic toxicity nor local toxicity to nerves and muscles.
Language	English
Publishing date	2023-05-05
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2039420-2
ISSN	1616-3028 ; 1616-301X
ISSN (online)	1616-3028
ISSN	1616-301X
DOI	10.1002/adfm.202301025
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Article: Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.

Chao, Cara W / Sprouse, Kaitlin R / Miranda, Marcos C / Catanzaro, Nicholas J / Hubbard, Miranda L / Addetia, Amin / Stewart, Cameron / Brown, Jack T / Dosey, Annie / Valdez, Adian / Ravichandran, Rashmi / Hendricks, Grace G / Ahlrichs, Maggie / Dobbins, Craig / Hand, Alexis / Treichel, Catherine / Willoughby, Isabelle / Walls, Alexandra C / McGuire, Andrew T /

Leaf, Elizabeth M / Baric, Ralph S / Schäfer, Alexandra / Veesler, David / King, Neil P

bioRxiv : the preprint server for biology

2024

Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and ... ...

Abstract	Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.13.584735
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Article ; Online: Diagnostic Outcomes of Concurrent DNA and RNA Sequencing in Individuals Undergoing Hereditary Cancer Testing.

Horton, Carolyn / Hoang, Lily / Zimmermann, Heather / Young, Colin / Grzybowski, Jessica / Durda, Kate / Vuong, Huy / Burks, David / Cass, Ashley / LaDuca, Holly / Richardson, Marcy E / Harrison, Steven / Chao, Elizabeth C / Karam, Rachid

JAMA oncology

2023 Volume 10, Issue 2, Page(s) 212–219

Abstract: Importance: Personalized surveillance, prophylaxis, and cancer treatment options for individuals with hereditary cancer predisposition are informed by results of germline genetic testing. Improvements to genomic technology, such as the availability of ... ...

Abstract	Importance: Personalized surveillance, prophylaxis, and cancer treatment options for individuals with hereditary cancer predisposition are informed by results of germline genetic testing. Improvements to genomic technology, such as the availability of RNA sequencing, may increase identification of individuals eligible for personalized interventions by improving the accuracy and yield of germline testing. Objective: To assess the cumulative association of paired DNA and RNA testing with detection of disease-causing germline genetic variants and resolution of variants of uncertain significance (VUS). Design, setting, and participants: Paired DNA and RNA sequencing was performed on individuals undergoing germline testing for hereditary cancer indication at a single diagnostic laboratory from March 2019 through April 2020. Demographic characteristics, clinical data, and test results were curated as samples were received, and changes to variant classification were assessed over time. Data analysis was performed from May 2020 to June 2023. Main outcomes and measures: Main outcomes were increase in diagnostic yield, decrease in VUS rate, the overall results by variant type, the association of RNA evidence with variant classification, and the corresponding predicted effect on cancer risk management. Results: A total of 43 524 individuals were included (median [range] age at testing, 54 [2-101] years; 37 373 female individuals [85.7%], 6224 male individuals [14.3%], and 2 individuals of unknown sex [<0.1%]), with 43 599 tests. A total of 2197 (5.0%) were Ashkenazi Jewish, 1539 (3.5%) were Asian, 3077 (7.1%) were Black, 2437 (5.6%) were Hispanic, 27 793 (63.7%) were White, and 2049 (4.7%) were other race, and for 4507 individuals (10.3%), race and ethnicity were unknown. Variant classification was impacted in 549 individuals (1.3%). Medically significant upgrades were made in 97 individuals, including 70 individuals who had a variant reclassified from VUS to pathogenic/likely pathogenic (P/LP) and 27 individuals who had a novel deep intronic P/LP variant that would not have been detected using DNA sequencing alone. A total of 93 of 545 P/LP splicing variants (17.1%) were dependent on RNA evidence for classification, and 312 of 439 existing splicing VUS (71.1%) were resolved by RNA evidence. Notably, the increase in positive rate (3.1%) and decrease in VUS rate (-3.9%) was higher in Asian, Black, and Hispanic individuals combined compared to White individuals (1.6%; P = .02; and -2.5%; P < .001). Conclusions and relevance: Findings of this diagnostic study demonstrate that the ability to perform RNA sequencing concurrently with DNA sequencing represents an important advancement in germline genetic testing by improving detection of novel variants and classification of existing variants. This expands the identification of individuals with hereditary cancer predisposition and increases opportunities for personalization of therapeutics and surveillance.
MeSH term(s)	Humans ; Male ; Female ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Genetic Testing/methods ; Neoplasms/genetics ; Genetic Predisposition to Disease ; Sequence Analysis, RNA ; RNA
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ISSN	2374-2445
ISSN (online)	2374-2445
DOI	10.1001/jamaoncol.2023.5586
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Article ; Online: Impact of Medicaid Expansion on the Diagnosis, Treatment, and Outcomes of Stage II and III Rectal Cancer Patients.

Lin, Mayin / O'Guinn, Makayla / Zipprer, Elizabeth / Hsieh, John C / Dardon, Arturo Torices / Raman, Shankar / Foglia, Christopher M / Chao, Steven Y

Journal of the American College of Surgeons

2022 Volume 234, Issue 1, Page(s) 54–63

Abstract: Background: Insurance status has been associated with disparities in stage at cancer diagnosis. We examined how Medicaid expansion (ME) impacted diagnoses, surgical treatment, use of neoadjuvant therapies (NCRT), and outcomes for Stage II and III rectal ...

Abstract	Background: Insurance status has been associated with disparities in stage at cancer diagnosis. We examined how Medicaid expansion (ME) impacted diagnoses, surgical treatment, use of neoadjuvant therapies (NCRT), and outcomes for Stage II and III rectal cancer. Study design: We used 2010-2017 American College of Surgeons National Cancer Database (NCDB) to identify patients ages 18-65, with Medicaid as primary form of payment, and were diagnosed with Stage II or III rectal cancer. Patients were stratified based on Census bureau division's ME adoption rates of High, Medium, Low. Overall trends were examined, and patient characteristics and outcomes were compared before and after ME date of 1/1/2014. Results: Over 8 years of NCDB data examined, there was an increasing trend of Stage II and III rectal cancer diagnoses, surgical resection, and use of NCRT for Medicaid patients. We observed an increase in age, proportion of White Medicaid patients in Low ME divisions, and proportion of fourth income quartile patients in High ME divisions. Univariate analysis showed decreased use of open surgery for all 3 categories after ME, but adjusted odds ratios (aOR) were not significant based on multivariate analysis. NCRT utilization increased after ME for all 3 ME adoption categories and aOR significantly increased for Low and High ME divisions. ME significantly decreased 90-day mortality. Conclusions: Medicaid expansion had important impacts on increasing Stage II and III rectal cancer diagnoses, use of NCRT, and decreased 90-day mortality for patients with Medicaid. Our study supports increasing health insurance coverage to improve Medicaid patient outcomes in rectal cancer care.
MeSH term(s)	Adolescent ; Adult ; Aged ; Humans ; Insurance Coverage ; Medicaid ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Staging ; Patient Protection and Affordable Care Act ; Rectal Neoplasms/diagnosis ; Rectal Neoplasms/surgery ; United States ; Young Adult
Language	English
Publishing date	2022-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1181115-8
ISSN	1879-1190 ; 1072-7515
ISSN (online)	1879-1190
ISSN	1072-7515
DOI	10.1097/XCS.0000000000000010
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Article ; Online: Inter-organ steroid hormone signaling promotes myoblast fusion via direct transcriptional regulation of a single key effector gene.

Ruan, Zhi-Rong / Yu, Ze / Xing, Chao / Chen, Elizabeth H

Current biology : CB

2024 Volume 34, Issue 7, Page(s) 1438–1452.e6

Abstract: Steroid hormones regulate tissue development and physiology by modulating the transcription of a broad spectrum of genes. In insects, the principal steroid hormones, ecdysteroids, trigger the expression of thousands of genes through a cascade of ... ...

Abstract	Steroid hormones regulate tissue development and physiology by modulating the transcription of a broad spectrum of genes. In insects, the principal steroid hormones, ecdysteroids, trigger the expression of thousands of genes through a cascade of transcription factors (TFs) to coordinate developmental transitions such as larval molting and metamorphosis. However, whether ecdysteroid signaling can bypass transcriptional hierarchies to exert its function in individual developmental processes is unclear. Here, we report that a single non-TF effector gene mediates the transcriptional output of ecdysteroid signaling in Drosophila myoblast fusion, a critical step in muscle development and differentiation. Specifically, we show that the 20-hydroxyecdysone (commonly referred to as "ecdysone") secreted from an extraembryonic tissue, amnioserosa, acts on embryonic muscle cells to directly activate the expression of antisocial (ants), which encodes an essential scaffold protein enriched at the fusogenic synapse. Not only is ants transcription directly regulated by the heterodimeric ecdysone receptor complex composed of ecdysone receptor (EcR) and ultraspiracle (USP) via ecdysone-response elements but also more strikingly, expression of ants alone is sufficient to rescue the myoblast fusion defect in ecdysone signaling-deficient mutants. We further show that EcR/USP and a muscle-specific TF Twist synergistically activate ants expression in vitro and in vivo. Taken together, our study provides the first example of a steroid hormone directly activating the expression of a single key non-TF effector gene to regulate a developmental process via inter-organ signaling and provides a new paradigm for understanding steroid hormone signaling in other developmental and physiological processes.
MeSH term(s)	Animals ; DNA-Binding Proteins/metabolism ; Ecdysone ; Ecdysteroids ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Receptors, Steroid/genetics ; Receptors, Steroid/metabolism ; Molting/physiology ; Drosophila/physiology ; Gene Expression Regulation, Developmental
Chemical Substances	DNA-Binding Proteins ; Ecdysone (3604-87-3) ; Ecdysteroids ; Drosophila Proteins ; Receptors, Steroid
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2024.02.056
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Article ; Online: A pilot randomized controlled trial of liraglutide 3.0 mg for binge eating disorder.

Allison, Kelly C / Chao, Ariana M / Bruzas, Maija B / McCuen-Wurst, Courtney / Jones, Elizabeth / McAllister, Cooper / Gruber, Kathryn / Berkowitz, Robert I / Wadden, Thomas A / Tronieri, Jena S

Obesity science & practice

2022 Volume 9, Issue 2, Page(s) 127–136

Abstract: Objective: To assess the efficacy of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist, for binge eating disorder (BED).: Methods: Adults with a body mass index (BMI) ≥ 27 kg/m: Results: Participants (: Conclusion: ... ...

Abstract	Objective: To assess the efficacy of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist, for binge eating disorder (BED). Methods: Adults with a body mass index (BMI) ≥ 27 kg/m Results: Participants ( Conclusion: Participants in both groups reported reductions in OBEs, with the liraglutide group showing clinically meaningful weight loss. A pharmacy medication dispensing error was a significant limitation of this study. Further research on liraglutide and other GLP-1 agonists for BED is warranted.
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2836381-4
ISSN	2055-2238 ; 2055-2238
ISSN (online)	2055-2238
ISSN	2055-2238
DOI	10.1002/osp4.619
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