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Article ; Online: Proteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders.

Liu, Zhonglin / Remsberg, Jarrett R / Li, Haoxin / Njomen, Evert / DeMeester, Kristen E / Tao, Yongfeng / Xia, Guoqin / Hayward, Rachel E / Yoo, Minjin / Nguyen, Tracey / Simon, Gabriel M / Schreiber, Stuart L / Melillo, Bruno / Cravatt, Benjamin F

Journal of the American Chemical Society

2024 Volume 146, Issue 15, Page(s) 10393–10406

Abstract: Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the ... ...

Abstract	Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the analysis of these electrophilic "stereoprobes" in human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared to structurally related azetidine acrylamide stereoprobes, the spirocycle acrylamides preferentially liganded specific cysteines on diverse protein classes. One compound termed ZL-12A promoted the degradation of the TFIIH helicase ERCC3. Interestingly, ZL-12A reacts with the same cysteine (C342) in ERCC3 as the natural product triptolide, which did not lead to ERCC3 degradation but instead causes collateral loss of RNA polymerases. ZL-12A and triptolide cross-antagonized one another's protein degradation profiles. Finally, we provide evidence that the antihypertension drug spironolactone─previously found to promote ERCC3 degradation through an enigmatic mechanism─also reacts with ERCC3_C342. Our findings thus describe monofunctional degraders of ERCC3 and highlight how covalent ligands targeting the same cysteine can produce strikingly different functional outcomes.
MeSH term(s)	Humans ; Acrylamide ; Cysteine/chemistry ; Proteomics ; Diterpenes ; Epoxy Compounds ; Phenanthrenes
Chemical Substances	triptolide (19ALD1S53J) ; Acrylamide (20R035KLCI) ; Cysteine (K848JZ4886) ; Diterpenes ; Epoxy Compounds ; Phenanthrenes
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c13448
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Article ; Online: Organ-on-a-Chip Systems for Modeling Pathological Tissue Morphogenesis Associated with Fibrosis and Cancer.

Hayward, Kristen L / Kouthouridis, Sonya / Zhang, Boyang

ACS biomaterials science & engineering

2020 Volume 7, Issue 7, Page(s) 2900–2925

Abstract: Tissue building does not occur exclusively during development. Even after a whole body is built from a single cell, tissue building can occur to repair and regenerate tissues of the adult body. This confers resilience and enhanced survival to ... ...

Abstract	Tissue building does not occur exclusively during development. Even after a whole body is built from a single cell, tissue building can occur to repair and regenerate tissues of the adult body. This confers resilience and enhanced survival to multicellular organisms. However, this resiliency comes at a cost, as the potential for misdirected tissue building creates vulnerability to organ deformation and dysfunction-the hallmarks of disease. Pathological tissue morphogenesis is associated with fibrosis and cancer, which are the leading causes of morbidity and mortality worldwide. Despite being the priority of research for decades, scientific understanding of these diseases is limited and existing therapies underdeliver the desired benefits to patient outcomes. This can largely be attributed to the use of two-dimensional cell culture and animal models that insufficiently recapitulate human disease. Through the synergistic union of biological principles and engineering technology, organ-on-a-chip systems represent a powerful new approach to modeling pathological tissue morphogenesis, one with the potential to yield better insights into disease mechanisms and improved therapies that offer better patient outcomes. This Review will discuss organ-on-a-chip systems that model pathological tissue morphogenesis associated with (1) fibrosis in the context of injury-induced tissue repair and aging and (2) cancer.
MeSH term(s)	Animals ; Fibrosis ; Humans ; Lab-On-A-Chip Devices ; Morphogenesis ; Neoplasms ; Tissue Engineering
Language	English
Publishing date	2020-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.0c01089
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Article ; Online: Practice Analysis and Determining the Knowledge and Skills Expected of a Pediatric Rheumatologist.

Brucia, Robert C / Hayward, Kristen / Brunner, Hermine I / Lopez-Pena, Maricarmen / Shenoi, Susan / Soybilgic, Arzu / Nocton, James J

ACR open rheumatology

2023 Volume 5, Issue 11, Page(s) 619–623

Abstract: Objective: The scope of clinical practice of pediatric rheumatology has been difficult to define. The lack of definition prevents an accurate understanding of the knowledge and skills required of practicing pediatric rheumatologists. A practice analysis ...

Abstract	Objective: The scope of clinical practice of pediatric rheumatology has been difficult to define. The lack of definition prevents an accurate understanding of the knowledge and skills required of practicing pediatric rheumatologists. A practice analysis process was used with the goal of establishing a precise definition of clinical pediatric rheumatology practice. The definition of practice will improve training and the creation of relevant certification examinations. Methods: A practice analysis approach used meetings with a representative panel of pediatric rheumatologists to create a practice analysis document (PAD) and a test content outline (TCO). Panel experience, entrustable professional activities, and the current TCO were used to guide the process. Surveys were administered to fellowship program directors (PDs) and a broader group of practicing pediatric rheumatologists to revise and validate the content of the documents. Results: A PAD was created, including 14 categories of conditions diagnosed or managed by pediatric rheumatologists and eight domains of practice, with the tasks, knowledge, and skills required to perform these tasks. The survey of PDs (n = 10) indicated that the PAD content is important and useful. A TCO was created and consists of 18 domains used to define content areas to be assessed on certifying examinations. The survey of practicing pediatric rheumatologists (n = 127) indicated that the TCO domains are relevant. Conclusion: A practice analysis process produced valuable resources for defining the clinical practice of pediatric rheumatology. The PAD and TCO can be used to develop more specific training curricula and to create relevant certification examinations.
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article
ISSN	2578-5745
ISSN (online)	2578-5745
DOI	10.1002/acr2.11613
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Article: Longitudinal program evaluation of an inter-institutional mentorship network for pediatric rheumatology using a quality improvement framework.

Hayward, Kristen / Grom, Alexi / Muscal, Eyal / Nigrovic, Peter A / Rouster-Stevens, Kelly A / Ardalan, Kaveh / Hiraki, Linda / Moorthy, L Nandini

Research square

2023

Abstract: Background: The American College of Rheumatology (ACR)/Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mentoring Interest Group (AMIGO) is an inter-institutional mentorship program launched to target mentorship gaps within pediatric ... ...

Abstract	Background: The American College of Rheumatology (ACR)/Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mentoring Interest Group (AMIGO) is an inter-institutional mentorship program launched to target mentorship gaps within pediatric rheumatology. Initial program evaluation indicated increased mentorship access. Given the small size of the pediatric rheumatology workforce, maintaining a consistent supply of mentors was a potential threat to the longevity of the network. Our aims were to: (i) describe the sustainability of AMIGO over the period 2011-2018, (ii) highlight ongoing benefits to participants, and (iii) describe challenges in the maintenance of a mentorship network. Methods: A mixed-methods approach centered on a quality improvement framework was used to report on process and outcomes measures associated with AMIGO annual cycles. Results: US and Canada Pediatric rheumatology workforce surveys identified 504 possible participants during the time period. As of fall 2018, 331 unique individuals had participated in AMIGO as a mentee, mentor or both for a program response rate of 66% (331/504). Survey of mentees indicated high satisfaction with impact on general career development, research/scholarship and work-life balance. Mentors indicated increased sense of connection to the community and satisfaction with helping mentees despite minimal perceived benefit to their academic portfolios. Based on AMIGO's success, a counterpart program, Creating Adult Rheumatology Mentorship in Academia (CARMA), was launched in 2018. Conclusions: Despite the challenges of a limited workforce, AMIGO continues to provide consistent access to mentorship opportunities for the pediatric rheumatology community. This experience can inform approaches to mentorship gaps in other academic subspecialties.
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3717708/v1
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Article ; Online: Online Resources for Enhancing Clinical Knowledge and Skills.

Curran, Megan L / Hayward, Kristen / Mehta, Jay

Rheumatic diseases clinics of North America

2019 Volume 46, Issue 1, Page(s) 37–60

Abstract: E-learning" refers to instruction occurring via digital media and ideally uses an engaging and learner-centered approach. Advantages of e-learning methods include (1) they can enable consistent messages, (2) they may use novel instructional methods, and ...

Abstract	"E-learning" refers to instruction occurring via digital media and ideally uses an engaging and learner-centered approach. Advantages of e-learning methods include (1) they can enable consistent messages, (2) they may use novel instructional methods, and (3) they enable documentation of usage and assessment. This article discusses principles for and challenges to developing e-learning materials. The authors provide a collection of available e-learning materials used to teach adult and pediatric rheumatology developed by individuals, professional societies, and private companies. Finally, they discuss challenges to using e-learning materials.
MeSH term(s)	Clinical Competence/standards ; Education, Distance/standards ; Education, Medical, Graduate/methods ; Education, Medical, Graduate/standards ; Health Knowledge, Attitudes, Practice ; Humans ; Internet ; Rheumatology/education ; Rheumatology/standards
Language	English
Publishing date	2019-11-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	92118-x
ISSN	1558-3163 ; 0889-857X
ISSN (online)	1558-3163
ISSN	0889-857X
DOI	10.1016/j.rdc.2019.09.011
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Article ; Online: Bacterial infections in a pediatric cohort of primary and acquired complement deficiencies.

Al-Shaikhly, Taha / Hayward, Kristen / Basiaga, Matthew L / Allenspach, Eric J

Pediatric rheumatology online journal

2020 Volume 18, Issue 1, Page(s) 74

Abstract: Background: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with ... ...

Abstract	Background: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. Methods: We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. Results: Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. Conclusion: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.
MeSH term(s)	Administration, Intravenous ; Adolescent ; Anti-Bacterial Agents/therapeutic use ; Bacterial Infections/drug therapy ; Bacterial Infections/epidemiology ; Bacterial Infections/immunology ; Child ; Child, Preschool ; Cohort Studies ; Complement C3/deficiency ; Complement C3/immunology ; Female ; Hereditary Complement Deficiency Diseases/epidemiology ; Hereditary Complement Deficiency Diseases/immunology ; Hospitalization/statistics & numerical data ; Humans ; Immunocompromised Host ; Immunosuppressive Agents/therapeutic use ; Lupus Erythematosus, Systemic/drug therapy ; Lupus Erythematosus, Systemic/epidemiology ; Lupus Erythematosus, Systemic/immunology ; Lupus Nephritis/epidemiology ; Lupus Nephritis/immunology ; Male ; Retrospective Studies ; Severity of Illness Index
Chemical Substances	Anti-Bacterial Agents ; Complement C3 ; Immunosuppressive Agents
Language	English
Publishing date	2020-09-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2279468-2
ISSN	1546-0096 ; 1546-0096
ISSN (online)	1546-0096
ISSN	1546-0096
DOI	10.1186/s12969-020-00467-0
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Article: The Use of Extracorporeal Life Support in Children With Immune-Mediated Diseases.

Barreto, Jessica A / Mehta, Amit / Thiagarajan, Ravi R / Hayward, Kristen N / Brogan, Adrian / Brogan, Thomas V

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

2021 Volume 23, Issue 1, Page(s) e60–e65

Abstract: Objectives: To describe the use and outcomes of extracorporeal membrane oxygenation support among children with immune-mediated conditions.: Design: Retrospective cohort study.: Setting: The Extracorporeal Life Support Organization registry.: ... ...

Abstract	Objectives: To describe the use and outcomes of extracorporeal membrane oxygenation support among children with immune-mediated conditions. Design: Retrospective cohort study. Setting: The Extracorporeal Life Support Organization registry. Patients: Patients 1 month to 18 years old with International Classification of Diseases, 9th Edition and International Classification of Diseases, 10th Edition codes for immune-mediated conditions from 1989 to 2018. Interventions: None. Measurements and main results: During the study period, 207 patients with an immune-mediated condition received extracorporeal membrane oxygenation, and 50% survived to discharge. Most patients (63%) received extracorporeal membrane oxygenation for respiratory support with 53% survival, 21% received cardiac support (55% survival), and 15% received extracorporeal cardiopulmonary resuscitation (34% survival). The most common diagnosis among nonsurvivors was hemophagocytic lymphohistiocytosis/macrophage activation syndrome with 37% survival. Patients with juvenile idiopathic arthritis (23%) and dermatomyositis (25%) had the lowest survival. Nonsurvivors had a higher frequency of infections, neurologic complications, and renal replacement therapy use. Use of preextracorporeal membrane oxygenation corticosteroids was associated with mortality. Conclusions: Children with immune-mediated conditions can be successfully supported with extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation use has increased over time, and survival varies considerably by diagnosis.
MeSH term(s)	Cardiopulmonary Resuscitation ; Child ; Extracorporeal Membrane Oxygenation ; Humans ; Registries ; Retrospective Studies
Language	English
Publishing date	2021-07-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2052349-X
ISSN	1947-3893 ; 1529-7535
ISSN (online)	1947-3893
ISSN	1529-7535
DOI	10.1097/PCC.0000000000002801
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Article: Single cell spatial transcriptomic profiling of childhood-onset lupus nephritis reveals complex interactions between kidney stroma and infiltrating immune cells.

Danaher, Patrick / Hasle, Nicholas / Nguyen, Elizabeth D / Hayward, Kristen / Rosenwasser, Natalie / Alpers, Charles E / Reed, Robyn C / Okamura, Daryl M / Baxter, Sarah K / Jackson, Shaun W

bioRxiv : the preprint server for biology

2023

Abstract: Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, ...

Abstract	Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single cell resolution atlas of kidney tissue (>400,000 cells) from eight cLN patients and two controls. Annotated cells were assigned to 35 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localize to specific regions in cLN kidneys, including myeloid cells trafficking to inflamed glomeruli and B cells clustering within tubulointerstitial immune hotspots. Notably, gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Finally, we identified modules of spatially-correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. In summary, single cell spatial transcriptomics allows unprecedented insights into the molecular heterogeneity of cLN, paving the way towards more targeted and personalized treatment approaches.
Language	English
Publishing date	2023-11-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.09.566503
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Article ; Online: A 2200-year record of Andean Condor diet and nest site usage reflects natural and anthropogenic stressors.

Duda, Matthew P / Grooms, Christopher / Sympson, Lorenzo / Blais, Jules M / Dagodzo, Daniel / Feng, Wenxi / Hayward, Kristen M / Julius, Matthew L / Kimpe, Linda E / Lambertucci, Sergio A / Layton-Matthews, Daniel / Lougheed, Stephen C / Massaferro, Julieta / Michelutti, Neal / Pufahl, Peir K / Vuletich, April / Smol, John P

Proceedings. Biological sciences

2023 Volume 290, Issue 1998, Page(s) 20230106

Abstract: Understanding how animals respond to large-scale environmental changes is difficult to achieve because monitoring data are rarely available for more than the past few decades, if at all. Here, we demonstrate how a variety of palaeoecological proxies (e.g. ...

Abstract	Understanding how animals respond to large-scale environmental changes is difficult to achieve because monitoring data are rarely available for more than the past few decades, if at all. Here, we demonstrate how a variety of palaeoecological proxies (e.g. isotopes, geochemistry and DNA) from an Andean Condor (
MeSH term(s)	Humans ; Animals ; Cattle ; Sheep ; Anthropogenic Effects ; Deer ; Falconiformes ; Birds ; Diet
Language	English
Publishing date	2023-05-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209242-6
ISSN	1471-2954 ; 0080-4649 ; 0962-8452 ; 0950-1193
ISSN (online)	1471-2954
ISSN	0080-4649 ; 0962-8452 ; 0950-1193
DOI	10.1098/rspb.2023.0106
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Article ; Online: Relationship between cognitive functioning, mood, and other patient factors on quality of life in metastatic brain cancer.

Marotta, Dario / Tucker, Zachary / Hayward, Emily N / Gerstenecker, Adam / Gammon, Meredith / Mason, Matthew / Willhelm, Gabrielle / Bae, Helen / Triebel, Kristen

Psycho-oncology

2020 Volume 29, Issue 7, Page(s) 1174–1184

Abstract: Objective: Neurocognitive functioning (NCF), mood disturbances, physical functioning, and social support all share a relationship with health-related quality of life (HRQOL). However, investigations into these relationships have not been conducted in ... ...

Abstract	Objective: Neurocognitive functioning (NCF), mood disturbances, physical functioning, and social support all share a relationship with health-related quality of life (HRQOL). However, investigations into these relationships have not been conducted in persons with brain metastases (BM). Patients and methods: Ninety-three newly diagnosed persons with BM were administered various cognitive batteries. Data were collected across a wide range of categories (ie, cognitive, demographic, disease/treatment, mood, social support, physical functioning). The Functional Assessment of Cancer Treatment (FACT) scale was used to measure HRQOL. Results: Mood and physical function correlated with lower HRQOL in every measured domain. Verbal learning and memory correlated with every FACT subscale except emotional quality of life. Social support also correlated with several HRQOL domains. Stepwise linear regression revealed that mood predicted general well-being and several FACT subscales, including physical, emotional and cognitive well-being. Social support and physical health were predictive of general well-being. Verbal learning and memory predicted cognitive well-being. Conclusion: HRQOL is a complex construct affected by numerous variables. In particular, mood, physical functioning, and learning and memory were important predictors of HRQOL, and clinicians are encouraged to obtain information in these areas during baseline assessments in persons with BM.
MeSH term(s)	Adult ; Affect ; Brain Neoplasms/psychology ; Brain Neoplasms/secondary ; Cognition/physiology ; Emotions ; Female ; Humans ; Male ; Middle Aged ; Quality of Life/psychology ; Social Support ; Surveys and Questionnaires
Language	English
Publishing date	2020-05-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1118536-3
ISSN	1099-1611 ; 1057-9249
ISSN (online)	1099-1611
ISSN	1057-9249
DOI	10.1002/pon.5401
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