Digital Commons Network^™

Real-World Evidence For Pembrolizumab Gemcitabine Vinorelbine And Liposomal Doxorubicin In Classical Hodgkin Lymphoma, Grace Baek, Nancy L Bartlett, Marcus Watkins, Et Al.

2020-Current year OA Pubs

No abstract provided.

Inflammaging In Aged Tissues Drives Remodeling Of The Cd8+ T Cell Compartment, Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Rachael L Field, Tran H Nguyen, Quazim A Alayo, Christopher G Huckstep, Barbora Vander Wielen, Jonathan R Brestoff, Sheila A Stewart, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov

2020-Current year OA Pubs

Aging strongly impacts CD8

Efficacy And Safety Of Avapritinib In Advanced Systemic Mastocytosis: 4-Year Follow-Up Of The Pathfinder Study, Jason Gotlib, Stephen T Oh, Et Al.

2020-Current year OA Pubs

Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHNs; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200 mg once daily, starting dose) with >4 years follow-up from the fully enrolled PATHFINDER study. End points included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population …

Isg15 Negatively Regulates Ripk3-Mediated Cell Death And Viral Pathogenesis, Yi-Chieh Perng, Jessica M C Warsaw, Sachendra S Bais, Bradley E Hiller, Marissa C Locke, David J Morales-Heil, Chaoqun Li, Alissa R Young, Kristen J Monte, Robert E Schmidt, Douglas R Green, Yi-Nan Gong, Deborah J Lenschow

2020-Current year OA Pubs

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated …

Regulation Of Pfh1 Helicase Activity By Nucleic Acid Interactions And Mitochondrial Ssb, María Ortiz-Rodríguez, Saurabh P Singh, Francisco J Cao-García, Roberto Galletto, Borja Ibarra

2020-Current year OA Pubs

Pif1-family helicases are essential for proper nuclear and mitochondrial genome maintenance, yet the regulation of their activities remains incompletely understood. Here, we use single-molecule manipulation and visualization techniques to dissect the real-time mechanochemical behavior of Pfh1, the sole Pif1-family helicase in

Comprehensive Mass Spectrometry Screening-Derived Atlas Of Hdac Inhibitors Reveals Histone-Specific Acetylation Changes, Rashmi Karki, Francisca N De Luna Vitorino, Richard M Searfoss, Joanna K Lempiäinen, Cheryl H Arrowsmith, Benjamin A Garcia

2020-Current year OA Pubs

Histone deacetylase inhibitors (HDACis) have emerged as valuable therapeutics for cancer and other diseases; however, their effects on histone post-translational modification remain poorly characterized. Here, we applied quantitative mass spectrometry and high-throughput sequencing to systematically profile site-specific changes in histone modifications in response to a panel of HDACis. This platform enabled mapping of histone modification changes across hundreds of sites, including low-abundance histone marks. Furthermore, an integrative analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) data identified genome-wide binding sites for the low-abundance histone modification of H2A.Z acetylation in HeLa and MDA-MB-231 breast cancer cells, highlighting the …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek

2020-Current year OA Pubs

BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Generalizability Of An Ai-Based Mammogram Risk Score (Mrs) For Breast Cancer Among Diverse Populations Of Women, Shu Jiang, Debbie L Bennett, Peter Kraft, Graham A Colditz

2020-Current year OA Pubs

Conventional prediction models incorporating genetic and clinical factors including breast density underperform in non-European populations. We investigated an artificial intelligence-derived mammogram risk score (MRS), a summary of texture features that captures intrinsic breast-tissue characteristics-the substrate for cancer development. This study leveraged data from two North American screening cohorts totaling >226,000 women, including non-Hispanic white, non-Hispanic Black, East Asian, South Asian, and Indigenous women. MRS distributions showed nonsignificant shifts (and similar SDs) between cohorts and across race and ethnic subgroups. MRS increased with age and was significantly associated with breast cancer risk, with hazard ratios per SD ranging from 2.24 [95% …

Co-Occurring Clonal Hematopoiesis Exhibits Strong Selection And High Leukemia Risk, Kara M Barnao, Irenaeus C C Chan, Duc Tran, Yin Cao, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have …

Target Ii Data Portal: A Multi-Omics Resource For Environmental Toxicant Studies In Mice, Prashant K Kuntala, Benpeng Miao, Deepak Purushotham, Bo Zhang, Daofeng Li, Ting Wang

2020-Current year OA Pubs

The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) program is a multiphase program that aims to understand how environmental factors contribute to disease susceptibility using toxicant-exposed mouse models. Here, we present the TaRGET II Data Portal ( https://data.targetepigenomics.org/ ), a comprehensive repository of multi-omics datasets generated from mice exposed to a range of environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di(2-ethylhexyl) phthalate (DEHP), tetrachlorodibenzo-p-dioxin (TCDD), and ambient air pollution (PM2.5). Epigenomic profiling assays capturing alterations in chromatin accessibility, DNA methylation, gene expression, and histone modifications were produced across multiple research …

Decoding Spatial Transcriptomics Across Multicellular And Subcellular Resolutions, Chongyue Zhao, Hanqiu Zhao, Zhiyu Dai, Et Al.

2020-Current year OA Pubs

Current whole-genome spatial transcriptomics (ST) platforms, which range from multicellular (e.g., Visium) to subcellular resolution (e.g., Visium HD, Stereo-seq), face significant challenges in accurately decomposing or aggregating spots into single cells-the fundamental units of biological activity. To date, most existing computational methods operate at the spot level, and no method has effectively reconstructed transcriptomes at single-cell resolution. In this study, we present STARS (Spatial Transcriptomics across Resolutions for Single Cells). Leveraging Vision Transformer model and contrastive learning, STARS combines high-resolution histology images with spot-level transcriptomics data to reconstruct single-cell-level gene expression from multicellular and subcellular platforms. We demonstrate the advantage …

Harnessing Mechanobiology Of Resident Stem Cells To Refine Cell Based Therapeutics, Dakota R. Kamm

WUSM Theses and Dissertations – All Programs

Mesenchymal stem cells (MSCs) are resident cells residing with many adult tissues such as adipose tissue and bone marrow that have the potency for multiple lineage differentiation as well as the capacity to secrete a litany of beneficial factors to maintain homeostasis and promote tissue repair. Since 1995, MSCs have been used therapeutically to treat a variety of conditions from osteoarthritis to heart disease to muscle pathologies. Great leaps have been made in improving MSC-based therapies through optimization of culture methods and select enrichment of cellular subpopulations. More recently, the physical microenvironment of tissue in vivo and culture conditions in …

Improving The Assessment And Treatment Of People With Low Back Pain, Kayla Krueger

WUSM Theses and Dissertations – All Programs

Low back pain (LBP) is a significant and continually growing public health problem. While some people recover from an initial episode, a proportion will develop chronic or recurrent LBP that limits their ability to perform daily functional activities. The variable and often function-limiting course of LBP underscores the clear need for improved methods of assessment and treatment. One way to improve the assessment and treatment of LBP is to develop a more comprehensive understanding of factors that contribute to LBP. In this dissertation, we investigated two categories of factors that may contribute to a person’s LBP: (1) spinal movement impairments …

Examining The Association Of Nurse Staffing Levels With Delayed Antibiotic And Insulin Administration: A Mixed Methods Study, Mikie Desyana Rachman

WUSM Theses and Dissertations – All Programs

Background: Recent reports indicated that medication errors contributed to 10% of preventable harm among hospitalized patients with over half occurring during the administration stage. Despite emerging research using EHR data to examine care processes and clinical outcomes, limited studies have integrated objective and subjective nursing staffing measures to evaluate how nursing staffing levels could be associated with delays in care delivery.

Method: A parallel convergent mixed-methods study was conducted in four adult medical-surgical units at a Midwestern Academic Medical Center from January 1 – March 31, 2025. Quantitative data of insulin and IV antibiotic administration records, laboratory results, and nurse …

Neurodiversity Among Nurses: Consequences For Wellbeing And Burnout, Megan Pohlmann

WUSM Theses and Dissertations – All Programs

Background/Introduction – Current research highlights three critical aspects of nurse wellbeing: the subjective personal perspective, multifaceted complexity, and variation across individuals. A particular gap in past research is a lack of understanding of how neurodivergence may impact nurses’ workplace wellbeing. Neurodiversity is the variation in human minds and neurocognitive functioning, and neurodivergence is the divergence from what society would consider the norm. Like wellbeing, it is difficult to capture, recognize, and define, which causes confusion among neurodivergent individuals and employers alike. With up to 20% of individuals displaying neurodivergent traits in the workplace, it is important to recognize that those …

Longitudinal Changes In Cognition And Brain Imaging In Persons With Human Immunodeficiency Virus, James Kennedy, Sarah A Cooley, June Roman Fox, Kalen J Petersen, Elizabeth Westerhaus, Pat Reid, Linet Lopez, Beau M Ances

2020-Current year OA Pubs

BACKGROUND: As persons with human immunodeficiency virus (PWH) live longer, interactions between human immunodeficiency virus (HIV), aging, and structural brain integrity become increasingly vital for understanding cognitive disorders. This study analyzed the effects of aging, HIV serostatus, and viral load on cognition and brain volumes in a large cohort of persons without HIV (PWOH), PWH with undetectable virus (PWHU) (HIV RNA ≤50 copies/mL), and PWH with detectable virus (PHWD) (HIV RNA >50 copies/mL). Cross-sectional and longitudinal data were included.

METHODS: Cognitive composites (NPZ4) and brain volumes were obtained from 259 PWOH, 264 PWHU, and 84 PWHD with a total of …

Quantification Of Sarm1 Nadase Activity In Human Peripheral Blood Mononuclear Cells, Lila F Dabill, Ivana R Shen, Jennifer M Brazill, Alicia Neiner, Yo Sasaki, Erica L Scheller

2020-Current year OA Pubs

SARM1 (sterile α and TIR motif-containing protein-1) is an NADase enzyme that serves as the central executioner of Wallerian axon degeneration. Given this, SARM1 is of high interest as a candidate therapeutic target, and SARM1 inhibitors are currently in clinical trials for treatment of neurodegeneration. Beyond neuroscience, emerging studies reveal that SARM1 may also drive aspects of bone fragility, liver pathology, adipose expansion, and insulin resistance in metabolic disease. However, we lack methods to quantify SARM1 activation in humans to better define patients at high risk of SARM1-mediated tissue damage. Unlike neurons, peripheral blood mononuclear cells (PBMCs) represent an easily …

Subclinical Neuropsychiatric Trait Variation In Parents Of Children With Autism Spectrum Disorder: A Cohort Study, Lindsay J Mullin, Carolyn Lasch, Natasha Marrus, Et Al.

2020-Current year OA Pubs

BACKGROUND: Many neuropsychiatric conditions share overlapping features underpinned by shared genetics. In this study, we examined the co-aggregation of sub-threshold variation in neuropsychiatric phenotypes in biological parents of autistic children to provide insights into the intergenerational transmission of genetic liability for autism.

METHODS: Autistic, neuropsychiatric (i.e., anxiety, depression, ADHD), and cognitive traits were characterized in biological parents of children enrolled in a longitudinal developmental study: 189 families of autistic children and 100 families with no autistic children were included. Families were further characterized as having only one (simplex) or more than one (multiplex) autistic child. Maternal and paternal traits were …

Hierarchical Small Molecule Inhibition Of Myst Acetyltransferases, Xuemin Chen, Alexandra Castroverde, Minervo Perez, Ronald Holewinski, Kiall F Suazo, Rashmi Karki, Thorkell Andresson, Benjamin A Garcia, Jordan L Meier

2020-Current year OA Pubs

MYST lysine acetyltransferases (KATs) are a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in preclinical models as well as in clinical trials of breast cancer. Understanding the specificity of these molecules is critical for their effective use as chemical probes. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This reveals dose-dependent engagement …

Abl Kinases Regulate Fgf Signaling Independent Of Crk Phosphorylation To Prevent Peters Anomaly Type Ii, Hao Wu, Yingyu Mao, Qian Wang, Honglian Yu, Michael Bouaziz, Neoklis Makrides, Enpeng Wang, Zhipeng Ding, Anthony J Koleske, Glenn L Radice, Jerry Hsu, Xin Zhang

2020-Current year OA Pubs

Peters anomaly is an anterior segment dysgenesis and a leading cause of congenital corneal opacity. Here, we show that loss of ABL kinases restores lens induction in the absence of FGF signaling but induces Peters anomaly type II independently of ERK signaling, a phenotype also observed with elevated FGF-Ras activity. This defect is rescued by allelic deletion of the ABL substrates CRK and CRKL. Contrary to prevailing models, ABL kinases do not act through direct phosphorylation of CRK proteins; instead, they phosphorylate PTPN12, suppressing p130CAS phosphorylation and CRK recruitment required for RHO GTPase activation. ABL kinase deficiency reduces actomyosin contractility …

Mosunetuzumab Monotherapy Is Active And Tolerable In Patients With Relapsed/Refractory Richter Transformation, Katharine L Lewis, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

Richter transformation (RT) to diffuse large B-cell lymphoma is an aggressive lymphoma that arises from underlying chronic lymphocytic leukemia or small lymphocytic lymphoma. RT is often chemorefractory, resulting in poor clinical outcomes with standard chemoimmunotherapy. Mosunetuzumab, a bispecific CD20/CD3 T-cell-engaging antibody, was investigated in a cohort of 20 patients with relapsed/refractory RT. Cytokine release syndrome occurred in 65% of patients, almost exclusively grade 1 (20%) or grade 2 (40%), and occurring during the first treatment cycle. Other adverse events included infections, neutropenia, thrombocytopenia, tumor flare, and low-grade neurotoxicity, with no adverse events leading to treatment discontinuation. Mosunetuzumab resulted in an …

Simultaneous Multielectrode Recordings Along The Human Scala Tympani: Evidence For Level-Dependent Place Coding, Amit Walia, Matthew A Shew, Shannon M Lefler, Amanda J Ortmann, Patrick Ioerger, Jordan Varghese, Jacques A Herzog, Craig A Buchman

2020-Current year OA Pubs

The cochlea systematically encodes sound frequency and intensity via a precisely organized tonotopic map, in which traveling waves peak at specific cochlear locations. A fundamental but incompletely understood aspect of auditory coding involves how stimulus intensity shapes this tonotopic organization. In animal models, increasing intensity shifts the cochlear traveling wave peak basally; however, physiological evidence for such intensity-dependent shifts in human cochlear processing is limited. Here, we performed simultaneous multielectrode electrocochleography recordings along the human scala tympani to characterize how cochlear place coding varies as a function of stimulus intensity. In subjects with preserved cochlear mechanics, including individuals with auditory …

Making Process Evaluations More Explanatory - Key Opportunities To Advance Implementation Research, Michel Wensing, Elvin H Geng

2020-Current year OA Pubs

Process evaluation of implementation strategies is increasingly common, but a review by Bracci et al. showed that room for improvement exists. In this contribution, we complement their recommendations by ideas on the design of process evaluations. Process evaluations are meant to provide explanations for why implementation strategies were effective, or not effective. Therefore, they are best guided by theory or frameworks, but the frequent focus on intervention acceptability reflects a lack of imagination on moderators and mediators that influence outcomes. Intervention fidelity is relevant in all process evaluations. Meaningful synthesis of process evaluation studies requires a homogeneous outcome, such as …

Exposure To Agent Orange And Association With Myelodysplastic Syndromes, Mikkael A Sekeres, Matthew J Walter, Et Al.

2020-Current year OA Pubs

No abstract provided.

Feasibility Of Decentralized Real-World Monitoring Of Sars-Cov-2 Booster Vaccines And Covid-19 Outcomes In Myeloma, William A Wood, Mark A Schroeder, Ravi Vij, Et Al.

2020-Current year OA Pubs

Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated …

Developmental Origins Of Exceptional Health And Survival: A Four-Generation Family Cohort Study, Matthew Thomas Keys, Søren Netra, Dorthe Almind Pedersen, Pernille Stemann Larsen, Alexander Kulminski, Mary F Feitosa, Mary Wojczynski, Michael Province, Kaare Christensen

2020-Current year OA Pubs

Descendants of longevity-enriched sibships demonstrate a broad health and survival advantage throughout the life course. However, little is known about manifestations during very early life. Here we show a pattern of lower risk of adverse early-life outcomes in third-generation grandchildren (N = 5637) of Danish longevity-enriched sibships compared to the general population, including infant mortality (Hazard Ratio = 0.53, 95% CI [0.36, 0.77]) and a range of neonatal health indicators. These associations in fourth-generation great-grandchildren (N = 14,908) were attenuated and less consistent (e.g., infant mortality, Hazard Ratio = 0.90, [0.70, 1.17]). Dilatory patterns across successive generations were independent of …

Tunable Tripcides Suppress Virulence Factor Secretion During Staphylococcus Aureus Infection And Kill Dormant Cells, Hasan Tükenmez, Taylor M Nye, Suzanne Hickerson, Chloe L P Obernuefemann, Jerome S Pinkner, Karen W Dodson, Michael G Caparon, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Antimicrobial resistance (AMR) in common bacterial pathogens, including methicillin-resistant

Inflammatory Markers In The Emergency Department And Ptsd Symptoms In The Aurora Study: A Longitudinal Cohort Study, Kristen Nishimi, Stacey L House, Et Al.

2020-Current year OA Pubs

BACKGROUND: Systemic inflammation is hypothesized to contribute to post-traumatic stress disorder (PTSD) vulnerability. Few studies have examined inflammation shortly after trauma as a predictor of later PTSD symptoms. We examined whether inflammation from the emergency department (ED) post-trauma is associated with PTSD symptom severity over the following 6 months.

METHODS: Our sample included 742 AURORA participants, a longitudinal cohort of patients in 29 EDs across the United States after a traumatic stressor, followed up to 6 months. Plasma cytokines were assessed from a study blood draw in the ED: an inflammatory index (standardized sum of generally pro-inflammatory markers interleukin [IL]-6, …

Nivolumab Plus Ipilimumab For Chemotherapy-Refractory Metastatic Castration-Resistant Prostate Cancer: Results From The Randomized Portion Of The Phase 2 Checkmate 650 Trial, Padmanee Sharma, Russell K Pachynski, Et Al.

2020-Current year OA Pubs

We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare …

Cellular And Molecular Basis Of Pfcoronin Function In Artemisinin Resistance In Plasmodium Falciparum, Imran Ullah, Eva S Istvan, Et Al.

2020-Current year OA Pubs

Artemisinin combination therapies are central to malaria control, but their efficacy is threatened by the emergence of resistant Plasmodium falciparum strains. While the role of Pfkelch13 mutations is well established, mutations in Pfcoronin have also been implicated in treatment failure, revealing layers of resistance complexity. Here, we define the cellular mechanism of Pfcoronin‑mediated artemisinin resistance. PfCoronin interacts with PfActin and localizes to the parasite plasma membrane, the digestive vacuole membrane, and small vesicles containing host cell material. Mutations in PfCoronin disrupt its localization and perturb PfActin homeostasis, altering the distribution of ring‑stage morphologies, including a reduced proportion of parasites adopting …