Digital Commons Network^™

A Public Health Perspective On Mitigating The Global Burden Of Chronic Liver Disease, Maya Balakrishnan, Jürgen Rehm

Faculty, Staff and Students Publications

Chronic liver disease is a significant global health problem. Epidemiological trends do not show improvement in chronic liver disease incidence but rather a shift in etiologies, with steatotic liver disease (SLD) from metabolic dysfunction and alcohol becoming increasingly important causes. Consequently, there is a pressing need to develop a comprehensive public health approach for SLD. To that end, we propose a public health framework for preventing and controlling SLD. The framework is anchored on evidence linking physical inactivity, unhealthy dietary patterns, alcohol use, and obesity with both incidence and progression of SLD. Guided by the framework, we review examples of …

Metabolism, Fibrosis, And Apoptosis: The Effect Of Lipids And Their Derivatives On Keloid Formation, Chen-Yu Li, Ru-Xin Xie, Shi-Wei Zhang, Jiao Yun, Ai Zhong, Ying Cen, Jun-Jie Chen

Faculty, Staff and Student Publications

Keloids, pathological scars resulting from skin trauma, have traditionally posed significant clinical management challenges due to their persistence and high recurrence rates. Our research elucidates the pivotal roles of lipids and their derivatives in keloid development, driven by underlying mechanisms of abnormal cell proliferation, apoptosis, and extracellular matrix deposition. Key findings suggest that abnormalities in arachidonic acid (AA) synthesis and non-essential fatty acid synthesis are integral to keloid formation. Further, a complex interplay exists between lipid derivatives, notably butyric acid (BA), prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and the regulation of hyperfibrosis. Additionally, combinations of docosahexaenoic acid (DHA) with BA …

Anatomy Of The Female Reproductive Tract Organs Of The Brown Anole (Anolis Sagrei), Bonnie K Kircher, Edward L Stanley, Richard R Behringer

Faculty, Staff and Student Publications

Female reproduction in squamate reptiles (lizards and snakes) is highly diverse and mode of reproduction, clutch size, and reproductive tract morphology all vary widely across this group of ~11,000 species. Recently, CRISPR genome editing techniques that require manipulation of the female reproductive anatomy have been developed in this group, making a more complete understanding of this anatomy essential. We describe the adult female reproductive anatomy of the model reptile the brown anole (Anolis sagrei). We show that the brown anole female reproductive tract has three distinct anterior-to-posterior regions, the infundibulum, the glandular uterus, and the nonglandular uterus. The infundibulum has …

Proteome Analysis For Inflammation Related To Acute And Convalescent Infection, Tara K Sigdel, Swastika Sur, Patrick Boada, Suzanne M Mcdermott, Cecilia S Lindestam Arlehamn, Kristy O Murray, Linda K Bockenstedt, Maggie Kerwin, Elaine F Reed, Eva Harris, Ken Stuart, Bjoern Peters, Ana Sesma, Ruth R Montgomery, Minnie M Sarwal

Faculty, Staff and Students Publications

Infectious diseases are a significant burden in global healthcare. Pathogens engage with different host defense mechanisms. However, it is currently unknown if there are disease-specific immune signatures and/or if different pathogens elicit common immune-associated molecular entities to common therapeutic interventions. We studied patients enrolled through the Human Immunology Project Consortium (HIPC), which focuses on immune responses to various infections. Blood samples were collected and analyzed from patients during infection and follow-up time points at the convalescent stage. The study included samples from patients with Lyme disease (LD), tuberculosis (TB), malaria (MLA), dengue virus (DENV), and West Nile virus (WNV), as …

Preparing Community Health Workers To Empower Latino(A)S With Diabetes: A Real-World Implementation Study, Laura Porterfield, Zuleica Santiago Delgado, Premal G Patel, Michael L Goodman, Kendall M Campbell, Elizabeth M Vaughan

Faculty, Staff and Students Publications

Purpose: The purpose of the study was to evaluate the delivery of diabetes self-management education (DSME) to Latino(a) adults by community health workers (CHWs).

Methods: Investigators developed an evidence-based, bilingual (Spanish/English) diabetes education curriculum and trained 10 CHWs on its content. CHWs then implemented the curriculum in 6-month diabetes group visit programs for low-income Latino(a)s with type 2 diabetes in nonacademic 501(c)3 community clinics. Investigators evaluated efficacy of the training through successful implementation, measured by participant group visit acceptance and attendance.

Results: Participants (n = 70) reported high levels of program satisfaction (3.8/4.0), improvement in quality of life (9.7/10), meeting …

Novel Hemizygous Single-Nucleotide Duplication In Rpgr In A Patient With Retinal Dystrophy And Sensorineural Hearing Loss, Ryan J German, Blake Vuocolo, Liesbeth Vossaert, Nichole Owen, Richard A Lewis, Lisa Saba, Texome Project, Michael F Wangler, Sandesh Nagamani

Duncan NRI Faculty and Staff Publications

Background: The RPGR gene has been associated with X-linked cone-rod dystrophy. This report describes a variant in RPGR detected with exome sequencing (ES). Genes like RPGR have not always been included in panel-based testing and thus genome-wide tests such as ES may be required for accurate diagnosis.

Methods: The Texome Project is studying the impact of ES in medically underserved patients who are in need of genomic testing to guide diagnosis and medical management. The hypothesis is that ES could uncover diagnoses not made by standard medical care.

Results: A 58-year-old male presented with retinitis pigmentosa, sensorineural hearing loss, and …

Matr3 Pathogenic Variants Differentially Impair Its Cryptic Splicing Repression Function, Mashiat Khan, Xiao Xiao Lily Chen, Michelle Dias, Jhune Rizsan Santos, Sukhleen Kour, Justin You, Rebekah Van Bruggen, Mohieldin M M Youssef, Ying-Wooi Wan, Zhandong Liu, Jill A Rosenfeld, Qiumin Tan, Udai Bhan Pandey, Hari Krishna Yalamanchili, Jeehye Park

Duncan NRI Faculty and Staff Publications

Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research …

Distribution Of P2y And P2x Purinergic Receptor Expression Within The Intestine, Kristen A Engevik, Francesca J Scribano, J Thomas Gebert, Jacob L Perry, Sue E Crawford, Joseph M Hyser

Faculty, Staff and Students Publications

Nucleotides are potent extracellular signaling molecules during homeostasis, infection, and injury due to their ability to activate purinergic receptors. The nucleotide ATP activates P2X receptors (P2RXs), whereas the nucleotides ADP, ATP, UTP, and UDP-glucose selectively activate different P2Y receptors (P2RYs). Several studies have established crucial roles for P2 receptors during intestinal inflammatory and infectious diseases, yet the most extensive characterization of purinergic signaling has focused on immune cells and the central and enteric nervous systems. As epithelial cells serve as the first barrier against irritants and infection, we hypothesized that the gut epithelium may express multiple purinergic receptors that respond …

Study Design And Methods: Us Study To Protect Brain Health Through Lifestyle Intervention To Reduce Risk (Us Pointer), Laura D Baker, Heather M Snyder, Mark A Espeland, Rachel A Whitmer, Miia Kivipelto, Nancy Woolard, Jeffrey Katula, Kathryn V Papp, Jennifer Ventrelle, Sarah Graef, Marcus A Hill, Scott Rushing, Julia Spell, Laura Lovato, Deborah Felton, Benjamin J Williams, Mina Ghadimi Nouran, Rema Raman, Tiia Ngandu, Alina Solomon, Sharon Wilmoth, Maryjo L Cleveland, Jeff D Williamson, Katherine L Lambert, Sarah Tomaszewski Farias, Claire E Day, Christy C Tangney, Darren R Gitelman, Olivia Matongo, Terrianne Reynolds, Valory N Pavlik, Melissa M Yu, Ashley S Alexander, Richard Elbein, Ann Marie Mcdonald, Stephen Salloway, Rena R Wing, Susan Antkowiak, Martha Clare Morris, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans.

METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER.

RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and …

Pluripotency Of A Founding Field: Rebranding Developmental Biology, Crystal D Rogers, Chris Amemiya, Swathi Arur, Leslie Babonis, Michael Barresi, Madelaine Bartlett, Richard Behringer, Blair Benham-Pyle, Dominique Bergmann, Ben Blackman, C Titus Brown, Bill Browne, Jasmin Camacho, Chiswili Yves Chabu, Ida Chow, Ondine Cleaver, Jonah Cool, Megan Y Dennis, Alexandra Jazz Dickinson, Stefano Di Talia, Margaret Frank, Stewart Gillmor, Eric S Haag, Iswar Hariharan, Richard Harland, Aman Husbands, Loydie Jerome-Majewska, Kristen Koenig, Carole Labonne, Michael Layden, Chris Lowe, Madhav Mani, Megan Martik, Katelyn Mckown, Cecilia Moens, Christian Mosimann, Joyce Onyenedum, Robert Reed, Ajna Rivera, Dan Rokhsar, Loic Royer, Flora Rutaganira, Rachel Shahan, Neelima Sinha, Billie Swalla, Jaimie M Van Norman, Daniel E Wagner, Athula Wikramanayake, Sophia Zebell, Siobhán M Brady

Faculty, Staff and Student Publications

The field of developmental biology has declined in prominence in recent decades, with off-shoots from the field becoming more fashionable and highly funded. This has created inequity in discovery and opportunity, partly due to the perception that the field is antiquated or not cutting edge. A 'think tank' of scientists from multiple developmental biology-related disciplines came together to define specific challenges in the field that may have inhibited innovation, and to provide tangible solutions to some of the issues facing developmental biology. The community suggestions include a call to the community to help 'rebrand' the field, alongside proposals for additional …

Ipsc-Derived Microglia Carrying The Trem2 R47h/+ Mutation Are Proinflammatory And Promote Synapse Loss, Jay Penney, William T Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, Hannah Woolf, Li-Huei Tsai

Faculty, Staff and Students Publications

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and …

Boarding Of Older Adults: A Concerning Trend In The Emergency Department, Julie Van Baardwijk, Eric Tharmathurai, Ariba Khan

Journal of Geriatric Emergency Medicine

Emergency department (ED) boarding (EDB) is the practice of holding admitted patients in the ED due to a lack of hospital beds. We identified one ED in our health system with a high rate of EDB. We sought to identify factors associated with EDB in this hospital by comparing it to a similar hospital in our health care system.

Methods: We conducted a retrospective study comparing two community hospitals in our healthcare system. Boarding was defined as a patient waiting ≥8 hours in ED for disposition. One hospital, located in a rural area with 55beds was chosen as it was …

Feasibility And Clinical Utility Of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified In Research Germline Sequencing: A Prospective Interventional Study, Megan L. Hutchcraft, Shulin Zhang, Nan Lin, Justine C. Pickarski, Elizabeth Belcher, Sainan Wei, Therese J. Bocklage, Rachel W. Miller, John L. Villano, Michael J. Cavnar, Joseph Kim, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

PURPOSE

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant sec- ondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.

METHODS

This prospective, interventional cohort study enrolled Total Cancer Care par- ticipants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic anal- ysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College …

More Physicians Alone Won’T Solve Rural America’S Health Care Problems, Atul Grover

Marshall Journal of Medicine

Policymakers have voiced their hope that locating family doctors and other primary care physicians within rural communities would, by itself, improve the health status of rural residents. However, access does not necessarily translate to better health. Rural populations face disproportionately worse health outcomes and inequities compared to urban populations. To improve the health care of rural America, it is critical to define—and periodically reassess—the problem and identify varying targeted policies.

Women’S Comfort With Mobile Applications For Menstrual Cycle Self-Monitoring Following The Overturning Of Roe V. Wade, Gabrielle M. Salvatore, Iris Bercovitz, Danielle Arigo

College of Science & Mathematics Departmental Research

Background: The overturning of Roe v. Wade in June 2022 has many implications for American women of reproductive age, as well as for researchers focused on women’s health in the United States (U.S.). Personal reproductive health data, such as information collected by menstrual cycle (MC) tracking applications (apps), can now be bought, sold, or accessed by law enforcement to enforce limits on abortion. American women have grown concerned about data privacy and have even deleted MC tracking apps following the overturning of Roe v. Wade. This concern is problematic as these apps may advance our understanding of women’s MC experiences …

Myd88 In Myofibroblasts Enhances Nonalcoholic Fatty Liver Disease-Related Hepatocarcinogenesis Via Promoting Macrophage M2 Polarization, Yu Liu, Haiqiang Chen, Xuanxuan Yan, Jie Zhang, Zhenzhong Deng, Maosheng Huang, Jianchun Gu, Jinhua Zhang

Faculty, Staff and Student Publications

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown.

Results: Myofibroblast MyD88-deficient (SMAMyD88-/-) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on …

Patient-Derived Models Of Cancer In The Nci Pdmc Consortium: Selection, Pitfalls, And Practical Recommendations, Amber N Habowski, Deepthi P Budagavi, Sandra D Scherer, Arin B Aurora, Giuseppina Caligiuri, William F Flynn, Ellen M Langer, Jonathan R Brody, Rosalie C Sears, Giorgia Foggetti, Anna Arnal Estape, Don X Nguyen, Katerina A Politi, Xiling Shen, David S Hsu, Donna M Peehl, John Kurhanewicz, Renuka Sriram, Milagros Suarez, Sophie Xiao, Yuchen Du, Xiao-Nan Li, Nora M Navone, Estefania Labanca, Christopher D Willey

Faculty, Staff and Student Publications

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as …

Reconstitution Of Human Pdac Using Primary Cells Reveals Oncogenic Transcriptomic Features At Tumor Onset, Yi Xu, Michael H Nipper, Angel A Dominguez, Zhenqing Ye, Naoki Akanuma, Kevin Lopez, Janice J Deng, Destiny Arenas, Ava Sanchez, Francis E Sharkey, Colin M Court, Aatur D Singhi, Huamin Wang, Martin E Fernandez-Zapico, Lu-Zhe Sun, Siyuan Zheng, Yidong Chen, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the …

Tetravalent Sars-Cov-2 S1 Subunit Protein Vaccination Elicits Robust Humoral And Cellular Immune Responses In Siv-Infected Rhesus Macaque Controllers, Rachel C Vanderkruik, Craig Ferguson, Lauren A Kobylski, Joseph J Locascio, Gabriella E Hamlett, Parker C Killenberg, Robert Lewis, Noah Jones, Ella T Rossa, Hannah Dineen, Rosalind Picard, Lee S Cohen

Faculty, Staff and Student Publications

BACKGROUND: Depression during pregnancy is increasingly recognized as a worldwide public health problem. If untreated, there can be detrimental outcomes for the mother and child. Anxiety is also often comorbid with depression. Although effective treatments exist, most women do not receive treatment. Technology is a mechanism to increase access to and engagement in mental health services.

OBJECTIVE: The Guardians is a mobile app, grounded in behavioral activation principles, which seeks to leverage mobile game mechanics and in-game rewards to encourage user engagement. This study seeks to assess app satisfaction and engagement and to explore changes in clinical symptoms of depression …

Bacterial Contamination Of Platelet Products, Michael R Jacobs, Bowen Zhou, Aditi Tayal, Robert W Maitta

Faculty, Staff and Student Publications

Transfusion of bacterially contaminated platelets, although rare, is still a major cause of mortality and morbidity despite the introduction of many methods to limit this over the past 20 years. The methods used include improved donor skin disinfection, diversion of the first part of donations, use of apheresis platelet units rather than whole-blood derived pools, primary and secondary testing by culture or rapid test, and use of pathogen reduction. Primary culture has been in use the US since 2004, using culture 24 h after collection of volumes of 4-8 mL from apheresis collections and whole-blood derived pools inoculated into aerobic …

Interplay Between Atrx And Idh1 Mutations Governs Innate Immune Responses In Diffuse Gliomas, Seethalakshmi Hariharan, Benjamin T Whitfield, Christopher J Pirozzi, Matthew S Waitkus, Michael C Brown, Michelle L Bowie, David M Irvin, Kristen Roso, Rebecca Fuller, Janell Hostettler, Sharvari Dharmaiah, Emiley A Gibson, Aaron Briley, Avani Mangoli, Casey Fraley, Mariah Shobande, Kevin Stevenson, Gao Zhang, Prit Benny Malgulwar, Hannah Roberts, Martin Roskoski, Ivan Spasojevic, Stephen T Keir, Yiping He, Maria G Castro, Jason T Huse, David M Ashley

Faculty, Staff and Student Publications

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes …

Intratumoral Biosynthesis Of Gold Nanoclusters By Pancreatic Cancer To Overcome Delivery Barriers To Radiosensitization, Aaron S Schwartz-Duval, Yuri Mackeyev, Iqbal Mahmud, Philip L Lorenzi, Mihai Gagea, Sunil Krishnan, Konstantin V Sokolov

Faculty, Staff and Student Publications

Nanoparticle delivery to solid tumors is a prime challenge in nanomedicine. Here, we approach this challenge through the lens of biogeochemistry, the field that studies the flow of chemical elements within ecosystems as manipulated by living cellular organisms and their environments. We leverage biogeochemistry concepts related to gold cycling against pancreatic cancer, considering mammalian organisms as drivers for gold nanoparticle biosynthesis. Sequestration of gold nanoparticles within tumors has been demonstrated as an effective strategy to enhance radiotherapy; however, the desmoplasia of pancreatic cancer impedes nanoparticle delivery. Our strategy overcomes this barrier by applying an atomic-scale agent, ionic gold, for intratumoral …

Building Research Capacity In Low- And Middle-Income Countries And Pandemic Preparedness: Lessons Learned And Future Directions, Peter H. Kilmarx, Karen A. Goralesk, Erum Khan, John F. Lindo, Nancy Gore Saravia

Department of Pathology and Laboratory Medicine

Research capacity is a critical component of pandemic preparedness, as highlighted by the challenges faced during the Ebola outbreak in West Africa. Recent global initiatives, such as the Research & Development Task Force of the Global Health Security Agenda and the World Health Assembly's resolution on strengthening clinical trials, emphasize the need for robust research capabilities. This Perspective discusses the experiences of leaders in infectious disease research and capacity building in low- and middle-income countries, focusing on Colombia, Jamaica, and Pakistan. These case studies underscore the importance of collaborative efforts, interdisciplinary training, and global partnerships in pandemic response. The experiences …

Crispr Screening Identifies Bet And Mtor Inhibitor Synergy In Cholangiocarcinoma Through Serine Glycine One Carbon, Yan Zhu, Dengyong Zhang, Pooja Shukla, Young-Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A Copland, Lin Tan, Philip L Lorenzi, Milind Javle, Jason T Huse, Jason Roszik, Traver Hart, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged …

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk In Myeloproliferative Neoplasms, Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider

Faculty, Staff and Student Publications

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a …

Multivalent Epigraph Hemagglutinin Vaccine Protects Against Influenza B Virus In Mice, Erika M. Petro-Turnquist, Brigette Corder Kampfe, Amber Gadeken, Matthew J. Pekarek, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Influenza B virus is a respiratory pathogen that contributes to seasonal epidemics, accounts for approximately 25% of global influenza infections, and can induce severe disease in young children. While vaccination is the most commonly used method of preventing influenza infections, current vaccines only induce strain-specific responses and have suboptimal efficacy when mismatched from circulating strains. Further, two influenza B virus lineages have been described, B/Yamagatalike and B/Victoria-like, and the limited cross-reactivity between the two lineages provides an additional barrier in developing a universal influenza B virus vaccine. Here, we report a novel multivalent vaccine using computationally designed Epigraph hemagglutinin proteins …

Intratumoral Biosynthesis Of Gold Nanoclusters By Pancreatic Cancer To Overcome Delivery Barriers To Radiosensitization, Aaron S Schwartz-Duval, Yuri Mackeyev, Iqbal Mahmud, Philip L Lorenzi, Mihai Gagea, Sunil Krishnan, Konstantin V Sokolov

Faculty, Staff and Student Publications

Nanoparticle delivery to solid tumors is a prime challenge in nanomedicine. Here, we approach this challenge through the lens of biogeochemistry, the field that studies the flow of chemical elements within ecosystems as manipulated by living cellular organisms and their environments. We leverage biogeochemistry concepts related to gold cycling against pancreatic cancer, considering mammalian organisms as drivers for gold nanoparticle biosynthesis. Sequestration of gold nanoparticles within tumors has been demonstrated as an effective strategy to enhance radiotherapy; however, the desmoplasia of pancreatic cancer impedes nanoparticle delivery. Our strategy overcomes this barrier by applying an atomic-scale agent, ionic gold, for intratumoral …

Unexpected Inhibition Of The Lipid Kinase Pikfyve Reveals An Epistatic Role For P38 Mapks In Endolysosomal Fission And Volume Control, Daric J Wible, Zalak Parikh, Eun Jeong Cho, Miao-Der Chen, Collene R Jeter, Somshuvra Mukhopadhyay, Kevin N Dalby, Shankar Varadarajan, Shawn B Bratton

Faculty, Staff and Student Publications

p38 mitogen-activated protein kinases (MAPKs) participate in autophagic signaling; and previous reports suggest that pyridinyl imidazole p38 MAPK inhibitors, including SB203580 and SB202190, induce cell death in some cancer cell-types through unrestrained autophagy. Subsequent studies, however, have suggested that the associated cytoplasmic vacuolation resulted from off-target inhibition of an unidentified enzyme. Herein, we report that SB203580-induced vacuolation is rapid, reversible, and relies on the class III phosphatidylinositol 3-kinase (PIK3C3) complex and the production of phosphatidylinositol 3-phosphate [PI(3)P] but not on autophagy per se. Rather, vacuolation resulted from the accumulation of Rab7 on late endosome and lysosome (LEL) membranes, combined with …

Extracellular Carriers Control Lipid-Dependent Secretion, Delivery, And Activity Of Wnt Morphogens, Taciani De Almeida Magalhaes, Jingjing Liu, Charlene Chan, Kleiton Silva Borges, Jiuchun Zhang, Andrew J Kane, Bradley M Wierbowski, Yunhui Ge, Zhiwen Liu, Prabhath Mannam, Daniel Zeve, Ron Weiss, David T Breault, Pengxiang Huang, Adrian Salic

Faculty, Staff and Students Publications

WNT morphogens trigger signaling pathways fundamental for embryogenesis, regeneration, and cancer. WNTs are modified with palmitoleate, which is critical for binding Frizzled (FZD) receptors and activating signaling. However, it is unknown how WNTs are released and spread from cells, given their strong lipid-dependent membrane attachment. We demonstrate that secreted FZD-related proteins and WNT inhibitory factor 1 are WNT carriers, potently releasing lipidated WNTs and forming active soluble complexes. WNT release occurs by direct handoff from the membrane protein WNTLESS to the carriers. In turn, carriers donate WNTs to glypicans and FZDs involved in WNT reception and to the NOTUM hydrolase, …

Occupational Therapy’S Opportunity To Impact Care At The End Of Life, Macey Genzlinger, Mackenzie L. Feldhacker

Student Journal of Occupational Therapy

Navigating and managing the end of life can be difficult. The focus of occupational therapy in care at the end of life is to aid the patient and caregiver through these challenges by facilitating improved safety, comfort, and quality of life through the participation in meaningful occupations. Despite the ways that occupational therapy benefits these patients, occupational therapy involvement in care at the end of life is misunderstood, under-researched, and underutilized. There is a general lack of awareness regarding this topic and a stigma that occupational therapy focuses only on rehabilitation and therefore does not belong in care at the …