Digital Commons Network^™

Best Practices For Delivering Neoadjuvant Therapy In Pancreatic Ductal Adenocarcinoma, Jordan M Cloyd, Angela Sarna, Matthew J Arango, Susan E Bates, Manoop S Bhutani, Mark Bloomston, Vincent Chung, Efrat Dotan, Cristina R Ferrone, Patricia F Gambino, Ajit H Goenka, Karyn A Goodman, William A Hall, Jin He, Melissa E Hogg, Shiva Jayaraman, Avinash Kambadakone, Matthew H G Katz, Alok A Khorana, Andrew H Ko, Eugene J Koay, David A Kooby, Somashekar G Krishna, Liliana K Larsson, Richard T Lee, Anirban Maitra, Nader N Massarweh, Sameh Mikhail, Mahvish Muzaffar, Eileen M O'Reilly, Manisha Palta, Maria Q B Petzel, Philip A Philip, Marsha Reyngold, Daniel Santa Mina, Davendra P S Sohal, Tilak K Sundaresan, Susan Tsai, Kea L Turner, Timothy J Vreeland, Steve Walston, M Kay Washington, Terence M Williams, Jennifer Y Wo, Rebecca A Snyder

Faculty, Staff and Student Publications

Importance: Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined.

Objective: To develop consensus best practices for delivering NT to patients with localized PDAC.

Design, setting, and participants: This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature …

Advancing Diagnostic Accuracy And Quality Of Patient Care Through The Implementation Of A Flow Cytometry Quality Assurance Program, Dylan Wang, Hong Fang, Chi Young Ok, Jeffrey L Jorgensen, L Jeffrey Medeiros, Wei Wang, Sa A Wang

Faculty, Staff and Student Publications

Context.—: Flow cytometry immunophenotypic analysis plays an important role in the diagnosis, classification, and disease monitoring of hematologic neoplasms. The interpretation of flow cytometry testing can be challenging.

Objective.—: To explore ways to improve diagnostic accuracy and in turn enhance the quality of patient care.

Design.—: A flow cytometry quality assurance (QA) program was developed. Cases from various complex flow cytometry panels were randomly selected and cross-reviewed. The outcomes of the QA review were categorized into 3 groups: complete agreement, minor discrepancy, and major discrepancy. Each discrepancy underwent a process of documentation, discussion, and resolution. Here we summarize our 3 …

Decoding Cancer Etiology With Cellular Reprogramming, Mo-Fan Huang, Megan E Fisher, Trinh T T Phan, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

Cancer research remains clinically unmet in many areas due to limited access to patient samples and the lack of reliable model systems that truly reflect human cancer biology. The emergence of patient-derived induced pluripotent stem cells and engineered human pluripotent stem cells (hPSCs) has helped overcome these challenges, offering a versatile alternative platform for advancing cancer research. These hPSCs are already proving to be valuable models for studying specific cancer driver mutations, offering insights into cancer origins, pathogenesis, tumor heterogeneity, clonal evolution, and facilitating drug discovery and testing. This article reviews recent progress in utilizing hPSCs for clinically relevant cancer …

Chemoresistance-Motility Signature Of Molecular Evolution To Chemotherapy In Non-Muscle-Invasive Bladder Cancer And Its Clinical Implications, Mi-So Jeong, Seung-Woo Baek, Gi-Eun Yang, Jeong-Yeon Mun, Jeong Ah Kim, Tae-Nam Kim, Jong-Kil Nam, Yung-Hyun Choi, Ju-Seog Lee, In-Sun Chu, Sun-Hee Leem

Faculty, Staff and Student Publications

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature …

Imaging Lung Tumor Motion Using Integrated-Mode Proton Radiography-A Phantom Study Towards Tumor Tracking In Proton Radiotherapy, Ryan Fullarton, Mikaël Simard, Lennart Volz, Allison Toltz, Savanna Chung, Christoph Schuy, Daniel G Robertson, Gary Royle, Sam Beddar, Colin Baker, Christian Graeff, Charles-Antoine Collins-Fekete

Faculty, Staff and Student Publications

BACKGROUND: Motion of lung tumors during radiotherapy leads to decreased accuracy of the delivered dose distribution. This is especially true for proton radiotherapy due to the finite range of the proton beam. Methods for mitigating motion rely on knowing the position of the tumor during treatment.

PURPOSE: Proton radiography uses the treatment beam, at an energy high enough to traverse the patient, to produce a radiograph. This work shows the first results of using an integrated-mode proton radiography system to track the position of moving objects in an experimental phantom study; demonstrating the potential of using this method for measuring …

A Randomized, Double-Blind, Placebo-Controlled Trial Of Daxibotulinumtoxina For Injection For The Treatment Of Upper Limb Spasticity In Adults After Stroke Or Traumatic Brain Injury, Atul T Patel, Michael C Munin, Ziyad Ayyoub, Gerard E Francisco, Rashid Kazerooni, Todd M Gross

Faculty, Staff and Student Publications

Background: Intramuscular injection of botulinum toxin type A is a first-line pharmacotherapy for adults with upper limb spasticity (ULS). However, reemergence of symptoms within 12 weeks of treatment is common and longer-lasting treatments are needed.

Objective: To evaluate the efficacy and safety of three doses of DaxibotulinumtoxinA for Injection (DAXI) for treatment of ULS in adults with stroke or traumatic brain injury.

Intervention: Intramuscular injections of placebo (N = 24), DAXI 250 U (N = 22), DAXI 375 U (N = 19), or DAXI 500 U (N = 18) to the suprahypertonic muscle (SMG) and other muscle groups.

Design: Randomized, …

Comparing One Stage, Chromogenic Assay Results And Discrepancies With Bleeding Phenotype And Genetic Variants In Females With Hemophilia A, Lakshmi Srivaths, Joanna Larson, Sepideh Saroukhani, Mohammed Said, Deborah Brown, Nidra Rodriguez, Neethu Menon, Miguel Escobar

Faculty, Staff and Student Publications

Background: Increasing evidence in females with hemophilia A has shown significant bleeding symptoms. Accurate factor (F) VIII activity (FVIII:C) measurement is essential to assign correct diagnosis and severity. Assay discrepancies reported in male patients with hemophilia A are not well studied in females.

Objectives: Our research sought to assess the association of FVIII:C levels by one-stage versus chromogenic assays and the assay discrepancy with bleeding phenotype and genetic mutation in females with hemophilia A.

Methods: Data from 64 females with hemophilia A from our center were reviewed with center's institutional review board approval. Descriptive statistics, chi-squared, Fisher's exact, and Bland-Altman …

Melanoma Risk In Turner Syndrome: A Case-Control Study In Surveillance, Epidemiology, And End Results-Medicare, Gabriella V Alvarez, Kai-Ping Liao, Mackenzie R Wehner, Megan N Rogge

Faculty, Staff and Student Publications

No abstract provided.

All Three Supersystems-Nervous, Vascular, And Immune-Contribute To The Cortical Infarcts After Subarachnoid Hemorrhage, Jens P Dreier, Alexander Joerk, Hiroki Uchikawa, Viktor Horst, Coline L Lemale, Helena Radbruch, Devin W Mcbride, Peter Vajkoczy, Ulf C Schneider, Ran Xu

Faculty, Staff and Student Publications

The recently published DISCHARGE-1 trial supports the observations of earlier autopsy and neuroimaging studies that almost 70% of all focal brain damage after aneurysmal subarachnoid hemorrhage are anemic infarcts of the cortex, often also affecting the white matter immediately below. The infarcts are not limited by the usual vascular territories. About two-fifths of the ischemic damage occurs within ~ 48 h; the remaining three-fifths are delayed (within ~ 3 weeks). Using neuromonitoring technology in combination with longitudinal neuroimaging, the entire sequence of both early and delayed cortical infarct development after subarachnoid hemorrhage has recently been recorded in patients. Characteristically, cortical …

Psychiatric Manifestations Of Encephalitis, Paris Bean, Ashley Heck, Ralph Habis, Swathi Sowmitran, Zoe Cartaina, Rajesh Gupta, John Probasco, Rodrigo Hasbun, Arun Venkatesan

Faculty, Staff and Student Publications

Objective: Encephalitis is a serious and potentially life-threatening condition of infectious or autoimmune cause. We aim to characterize the frequency and clinical spectrum of presenting psychiatric symptoms in encephalitis in order to inform earlier recognition and initiation of treatment.

Methods: This was a retrospective study of adult patients who met the 2013 International Encephalitis Consortium (IEC) and/or 2016 Graus criteria between February 2005 and February 2023. The study included two hospital systems in Houston, Texas, and Baltimore, Maryland and included a total of 642 patients. Psychiatric manifestations were grouped into five high-level categories: behavior, psychosis, mood, sleep disturbances, and catatonia. …

Protein Arginine Methyltransferases As Regulators Of Cellular Stress, Julia Zaccarelli-Magalhães, Cristiane Teresinha Citadin, Julia Langman, Drew James Smith, Luiz Henrique Matuguma, Hung Wen Lin, Mariana Sayuri Berto Udo

Faculty, Staff and Student Publications

Arginine modification can be a "switch" to regulate DNA transcription and a post-translational modification via methylation of a variety of cellular targets involved in signal transduction, gene transcription, DNA repair, and mRNA alterations. This consequently can turn downstream biological effectors "on" and "off". Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs 1-9) in both the nucleus and cytoplasm, and is thought to be involved in many disease processes. However, PRMTs have not been well-documented in the brain and their function as it relates to metabolism, circulation, functional learning and memory are understudied. In this review, we provide a comprehensive …

Management Of Isolated Partial Acl Tears: A Survey Of International Acl Surgeons, Christopher S Frey, Kinsley J Pierre, Nicole S Pham, Geoffrey D Abrams, Seth L Sherman, Tim Spalding, Marc R Safran

Faculty, Staff and Student Publications

Background: Partial anterior cruciate ligament (ACL) tears, particularly injuries detected with magnetic resonance imaging (MRI) but stable on ligamentous examination, appear to be recognized more frequently; however, there remains no consensus management for this complex pathology.

Purpose: To present the results of a survey of a group of international ACL experts on the management of partial ACL injuries.

Study design: Survey study; Level of evidence, 5.

Methods: The ACL Study Group is an international group of orthopaedic surgeons with a special interest in the ACL. There are 169 members overall, with 135 clinically active surgeons. A branching logic survey was …

Deformity Considerations In Cervical Laminoplasty: A Narrative Review, Joseph P Drain, Paul Alvarez, William Ryan Spiker, Elizabeth Yu

Faculty, Staff and Student Publications

Objectives: We discuss the incidence of postoperative kyphosis following laminoplasty and its impact on outcomes, as well as critical radiographic parameters, intraoperative technical factors, and postoperative protocols that can be used to improve results.

Summary of background data: When appropriately selected, cervical laminoplasty is a motion-sparing treatment option for cervical myelopathy and is a valid alternative to laminectomy and fusion procedures. However, like other posterior-based cervical decompression techniques, laminoplasty can cause postoperative kyphosis.

Methods: A PubMed search was performed to gather articles that focus on cervical deformity in the context of cervical laminoplasty.

Results: The reported conversion rates of lordotic …

Non-Invasive Prenatal Screening: Testing Motivations And Decision Making In The Low-Risk Population, Jenna K Lea, Blair K Stevens, Shannon Mulligan, Syed S Hashmi, Rebecca Lunstroth, Meagan G Choates

Faculty, Staff and Student Publications

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) …

Hemodynamic Response Of The Aortic Valve During Dobutamine Onset Then Progressive Aortic Banding, Rob Eerdekens, Philipos K Gebremedhin, Daniel T Johnson, Richard L Kirkeeide, Gretchen L Howe, Richard W Smalling, K Lance Gould, Pim A L Tonino, Nils P Johnson

Faculty, Staff and Student Publications

An increasing number of procedures over the past two decades for aortic stenosis (AS) reflects the combination of an aging population and less invasive transcatheter options. As a result, the hemodynamics of the aortic valve (AV) have gained renewed interest to understand its behavior and to optimize patient selection. We studied the hemodynamic relationship between pressure loss (ΔP) and transvalvular flow (Q) of the normal AV as well as the impact of a variable supravalvular stenosis. Our mechanistic study included 11 healthy swine monitored during dobutamine stress and followed by acute aortic banding to simulate AS. Hemodynamics were continuously recorded, …

Acquired Hepatocerebral Degeneration In A Septic Patient: Hospital Course And Mri Findings, Ethan L Porter, Alexandria R Koney, Alexia R Jauregui, Emelie N Mcquitty, Courtney T Huynh, Rita B Khouri, Alisha Kashyap, Matthew T Wong

Faculty, Staff and Student Publications

Acquired hepatocerebral degeneration (AHD) is a rare neuropsychiatric disorder affecting cirrhotic patients, often presenting with neuropsychiatric symptoms triggered by a precipitating factor. Magnetic resonance imaging (MRI) showing T1 hyperintensities in the globus pallidus is diagnostic. In this case report, a 40-year-old female patient with alcoholic cirrhosis presented with generalized swelling, jaundice, fever, and signs of septic shock. After stabilization, changes in cognition while this patient was hospitalized prompted the management of several different factors, including the underlying infection, hypernatremia, vitamin deficiency, alcohol withdrawal, and hyperammonemia. Infectious disease consultation helped determine the antibiotic selection and dosage for bacteremia and later concerns …

Respiratory Outcomes Of Infants Born Extremely Preterm In The Necrotizing Enterocolitis Surgery Trial, Sara B Demauro, Erik A Jensen, Scott A Mcdonald, Susan Hintz, Jon Tyson, David K Stevenson, Martin L Blakely

Faculty, Staff and Student Publications

The multicenter Necrotizing Enterocolitis Surgery Trial compared initial peritoneal drainage with laparotomy among infants with extremely low birth weight and surgical necrotizing enterocolitis or intestinal perforation. In this post hoc analysis of trial data, initial drainage was associated with adverse respiratory outcomes, both in hospital and through 2 years corrected age.

On The Acceptance, Commissioning, And Quality Assurance Of Electron Flash Units, Allison Palmiero, Kevin Liu, Julie Colnot, Nitish Chopra, Denae Neill, Luke Connell, Brett Velasquez, Albert C Koong, Steven H Lin, Peter Balter, Ramesh Tailor, Charlotte Robert, Jean-François Germond, Patrik Gonçalves Jorge, Reiner Geyer, Sam Beddar, Raphael Moeckli, Emil Schüler

Faculty, Staff and Student Publications

Background and purpose: FLASH or ultra-high dose rate (UHDR) radiation therapy (RT) has gained attention in recent years for its ability to spare normal tissues relative to conventional dose rate (CDR) RT in various preclinical trials. However, clinical implementation of this promising treatment option has been limited because of the lack of availability of accelerators capable of delivering UHDR RT. Commercial options are finally reaching the market that produce electron beams with average dose rates of up to 1000 Gy/s. We established a framework for the acceptance, commissioning, and periodic quality assurance (QA) of electron FLASH units and present an …

Refining Diagnostic Subtypes Of Peripheral T-Cell Lymphoma Using A Multiparameter Approach, Catalina Amador, Dennis D Weisenburger, Ana Gomez, Alyssa Bouska, Ahmad Alshomrani, Sunandini Sharma, Ab Rauf Shah, Timothy C Greiner, Francisco Vega, Andreas Rosenwald, German Ott, Andrew L Feldman, Elaine S Jaffe, Neval Ozkaya, Sarah L Ondrejka, James R Cook, Philipp W Raess, Kerry J Savage, Graham W Slack, Joo Y Song, David W Scott, Elias Campo, Lisa M Rimsza, Joseph D Khoury, Louis M Staudt, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

Peripheral T-cell lymphoma (PTCL) is a heterogeneous category, and many cases are unclassifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated two prognostic subtypes within PTCL-NOS, PTCL-TBX21, and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including TFH biomarkers) and GEP analyses, separating them into PTCL-NOS (n=63) and PTCL-TFH (a.k.a. nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n=38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n=22; 34%) …

A Statistical Framework For Multi-Trait Rare Variant Analysis In Large-Scale Whole-Genome Sequencing Studies, Xihao Li, Han Chen, Margaret Sunitha Selvaraj, Eric Van Buren, Hufeng Zhou, Yuxuan Wang, Ryan Sun, Zachary R Mccaw, Zhi Yu, Min-Zhi Jiang, Daniel Dicorpo, Sheila M Gaynor, Rounak Dey, Donna K Arnett, Emelia J Benjamin, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, April P Carson, Jenna C Carlson, Nathalie Chami, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Myriam Fornage, Nora Franceschini, Barry I Freedman, Charles Gu, Nancy L Heard-Costa, Jiang He, Lifang Hou, Yi-Jen Hung, Marguerite R Irvin, Robert C Kaplan, Sharon L R Kardia, Tanika N Kelly, Iain Konigsberg, Charles Kooperberg, Brian G Kral, Changwei Li, Yun Li, Honghuang Lin, Ching-Ti Liu, Ruth J F Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Kari E North, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alexander P Reiner, Stephen S Rich, Colleen M Sitlani, Jennifer A Smith, Kent D Taylor, Hemant K Tiwari, Ramachandran S Vasan, Satupa'itea Viali, Zhe Wang, Jennifer Wessel, Lisa R Yanek, Bing Yu, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Josée Dupuis, James B Meigs, Paul L Auer, Laura M Raffield, Alisa K Manning, Kenneth M Rice, Jerome I Rotter, Gina M Peloso, Pradeep Natarajan, Zilin Li, Zhonghua Liu, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple …

Ligand Distances As Key Predictors Of Pathogenicity And Function In Nmda Receptors, Ludovica Montanucci, Tobias Brünger, Nisha Bhattarai, Christian M Boßelmann, Sukhan Kim, James P Allen, Jing Zhang, Chiara Klöckner, Ilona Krey, Piero Fariselli, Patrick May, Johannes R Lemke, Scott J Myers, Hongjie Yuan, Stephen F Traynelis, Dennis Lal

Faculty, Staff and Student Publications

Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by …

Overcoming Cd226-Related Immune Evasion In Acute Myeloid Leukemia With Cd38 Car-Engineered Nk Cells, Luciana Melo Garcia, Achintyan Gangadharan, Pinaki Banerjee, Ye Li, Andy G X Zeng, Hind Rafei, Paul Lin, Bijender Kumar, Sunil Acharya, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Gabriel Dominguez, Jeong Min Park, Francia Reyes Silva, Ana Karen Nunez Cortes, Rafet Basar, Nadima Uprety, Mayra Shanley, Mecit Kaplan, Enli Liu, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 …

A Morphometric Signature To Identify Ductal Carcinoma In Situ With A Low Risk Of Progression, Marcelo Sobral-Leite, Simon P Castillo, Shiva Vonk, Hendrik A Messal, Xenia Melillo, Noomie Lam, Brandi De Bruijn, Yeman B Hagos, Myrna Van Den Bos, Joyce Sanders, Mathilde Almekinders, Lindy L Visser, Emma J Groen, Petra Kristel, Caner Ercan, Leyla Azarang, Jacco Van Rheenen, E Shelley Hwang, Yinyin Yuan, Renee Menezes, Esther H Lips, Jelle Wesseling

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) may progress to ipsilateral invasive breast cancer (iIBC), but often never will. Because DCIS is treated as early breast cancer, many women with harmless DCIS face overtreatment. To identify features associated with progression, we developed an artificial intelligence-based DCIS morphometric analysis pipeline (AIDmap) on hematoxylin-eosin-stained (H&E) tissue sections. We analyzed 689 digitized H&Es of pure primary DCIS of which 226 were diagnosed with subsequent iIBC and 463 were not. The distribution of 15 duct morphological measurements was summarized in 55 morphometric variables. A ridge regression classifier with cross validation predicted 5-years-free of iIBC with an …

Erk Activation Dynamics In Maturing Oocyte Controls Embryonic Nuclear Divisions In Caenorhabditis Elegans, Han Bit Baek, Debabrata Das, Shin-Yu Chen, Hongyuan Li, Swathi Arur

Faculty, Staff and Student Publications

ERK activity oscillates between sustained activation during oocyte formation and transient inactivation during oocyte maturation, fertilization, and early embryogenesis. Consequences of ectopic ERK activity upon oocyte maturation and in early embryogenesis are unknown. We show, in Caenorhabditis elegans, that ectopic ERK activity upon oocyte maturation (metaphase I oocytes) results in embryos with abnormalities in nuclear divisions leading to embryonic death. We uncover that ERK directly phosphorylates Polo-like kinase I (PLK-1), on Serine 404, to inhibit nuclear envelope breakdown (NEBD) in early embryogenesis. The RAS/ERK/PLK-1 pathway poisons zygotic NEBD and inhibits the merging of parental genomes, underlining the importance of turning …

Statistical Identification Of Cell Type-Specific Spatially Variable Genes In Spatial Transcriptomics, Lulu Shang, Peijun Wu, Xiang Zhou

Faculty, Staff and Student Publications

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real …

Correlates Of Inaccuracy In Reporting Of Energy Intake Among Persons With Multiple Sclerosis, Stephanie L Silveira, Brenda Jeng, Barbara A Gower, Gary R Cutter, Robert W Motl

Faculty, Staff and Student Publications

BACKGROUND/OBJECTIVES: Persons with multiple sclerosis (MS) are interested in diet as a second-line approach for disease management. This study examined potential variables that correlate with inaccuracy of self-reported energy intake (EI) in adults with MS.

METHODS: Twenty-eight participants completed two assessment appointments within a 14-day period that included a standard doubly labeled water (DLW) protocol for estimating total energy expenditure (TEE). The participants reported their EI using the Automated Self-Administered 24 h (ASA24) Dietary Assessment Tool. The primary variables of interest for explaining the discrepancy between TEE and ASA24 EI (i.e., inaccuracy) included cognition (processing speed, visuospatial memory, and verbal …

Urine Proteomics Defines An Immune Checkpoint-Associated Nephritis Signature, James P Long, Shailbala Singh, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish …

A Paper-Based Hpv E7 Oncoprotein Assay For Cervical Precancer Detection At The Point Of Care, Chelsey A Smith, Sai Paul, Karen E Haney, Sonia G Parra, Meaghan Bond, Leticia López, Mauricio Maza, Juan Felix, Preetha Ramalingam, Pablo Escobar, Philip E Castle, Kathleen M Schmeler, Rebecca R Richards-Kortum

Faculty, Staff and Student Publications

Cervical cancer, while preventable through screening and treatment of cervical precancer, remains a global challenge with a disproportionately high burden of disease in resource-limited settings, especially in low- and middle-income countries (LMICs). Lack of affordable, easy-to-use screening and diagnostic tests contributes to this disparity. Most commercially available tests are not appropriate for use in LMICs due to resource constraints. Specifically, HPV mRNA and oncoprotein tests that have high specificity for cervical precancer and cancer require complex sample preparation protocols and expensive instrumentation. To address these limitations, an HPV E7 oncoprotein assay for HPV16, 18, and 45 was developed that is …

Reduced Autoimmunity Associated With Deletion Of Host Cd73, Beanna Okeugo, Shabba A Armbrister, Rhea C Daniel, Zeina M Saleh, Jessica Wang, Salomea Giorgberidze, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

CD73 is ubiquitously expressed and regulates critical functions across multiple organ systems. The sequential actions of CD39 and CD73 accomplish the conversion of adenosine triphosphate to adenosine and shift the adenosine triphosphate-driven proinflammatory immune cell milieu toward an anti-inflammatory state. This immunological switch is a major mechanism by which regulatory T (Treg) cells control inflammation. Foxp3 engages in Treg development and function. Foxp3 mutations result in the scurfy (SF) mouse phenotype and a rapidly lethal lymphoproliferative syndrome. We generated double knockout (KO) mouse (CD73KOSF) by breeding heterozygous Foxp3sf/J females to CD73KO male mice to remove host CD73. We initially aimed …

A Deconvolution Framework That Uses Single-Cell Sequencing Plus A Small Benchmark Data Set For Accurate Analysis Of Cell Type Ratios In Complex Tissue Samples, Shuai Guo, Xiaoqian Liu, Xuesen Cheng, Yujie Jiang, Shuangxi Ji, Qingnan Liang, Andrew Koval, Yumei Li, Leah A Owen, Ivana K Kim, Ana Aparicio, Sanghoon Lee, Anil K Sood, Scott Kopetz, John Paul Shen, John N Weinstein, Margaret M Deangelis, Rui Chen, Wenyi Wang

Faculty, Staff and Student Publications

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we utilize an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using this well-matched, that is, benchmark, data. Built upon a novel weighted nonnegative least-squares framework, DeMixSC identifies and adjusts genes with high technological discrepancy and aligns the benchmark data with large patient cohorts of matched-tissue-type for large-scale deconvolution. Our results using two benchmark data sets of healthy retinas and …