Digital Commons Network^™

An Unsupervised Map Of Excitatory Neuron Dendritic Morphology In The Mouse Visual Cortex, Marissa A Weis, Stelios Papadopoulos, Laura Hansel, Timo Lüddecke, Brendan Celii, Paul G Fahey, Eric Y Wang, J Alexander Bae, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Manuel A Castro, Forrest Collman, Nuno Maçarico Da Costa, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, R Clay Reid, Casey M Schneider-Mizell, H Sebastian Seung, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-Chieh Yu, Jacob Reimer, Philipp Berens, Andreas S Tolias, Alexander S Ecker

Faculty, Staff and Students Publications

Neurons in the neocortex exhibit astonishing morphological diversity, which is critical for properly wiring neural circuits and giving neurons their functional properties. However, the organizational principles underlying this morphological diversity remain an open question. Here, we took a data-driven approach using graph-based machine learning methods to obtain a low-dimensional morphological "bar code" describing more than 30,000 excitatory neurons in mouse visual areas V1, AL, and RL that were reconstructed from the millimeter scale MICrONS serial-section electron microscopy volume. Contrary to previous classifications into discrete morphological types (m-types), our data-driven approach suggests that the morphological landscape of cortical excitatory neurons is …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

2020-Current year OA Pubs

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …

Gramd1b Is A Regulator Of Lipid Homeostasis, Autophagic Flux And Phosphorylated Tau, Diana Acosta Ingram, Jacob Marsh, Celeste M Karch, Et Al.

2020-Current year OA Pubs

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, …

Molecular Subtyping Of Hypertensive Disorders Of Pregnancy, Michal Elovitz, Elaine Gee, Nathaniel Delaney-Busch, Alison Moe, Mitsu Reddy, Arkady Khodursky, Johnny La, Ilma Abbas, Kay Mekaru, Hunter Collins, Farooq Siddiqui, Rory Nolan, Rupsa Boelig, Daniel Kiefer, Pamela Simmons, George Saade, Antonio Saad, Ebony Carter, Thomas Mcelrath, Stephen Quake, Mark Depristo, Carrie Haverty, Manfred Lee, Eugeni Namsaraev, Vincenzo Berghella, Ai-Ris Collier, Antonia Frolova, Esther Park-Hwang, Luis Pacheco, Elizabeth Sutton, Maneesh Jain, Kara Rood, William A Grobman, Joseph Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan, Morten Rasmussen

Department of Obstetrics and Gynecology Faculty Papers

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. …

Differential Antibody Response To Ebv Proteome Following Ebvst Immunotherapy In Ebv-Associated Lymphomas, Yomani D Sarathkumara, Nathan W Van Bibber, Zhiwei Liu, Helen E Heslop, Rayne H Rouce, Anna E Coghill, Cliona M Rooney, Carla Proietti, Denise L Doolan

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen–specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than …

Phase 2 Trial Of Ibrutinib And Nivolumab In Patients With Relapsed Cns Lymphomas, Dai Chihara, Raphael E Steiner, Ranjit Nair, Lei Feng, Sairah Ahmed, Paolo Strati, Luis Malpica, Donna P Griffith, Shivon A Mathew, Wirt Montinez, Gita Masand, Felipe Samaniego, Maria A Rodriguez, Fredrick B Hagemeister, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Sattva S Neelapu, Christopher R Flowers, Jason R Westin

Faculty, Staff and Student Publications

Treatment options are limited for both relapsed/refractory primary and secondary central nervous system (CNS) lymphoma and the prognosis remains poor. Previous studies have shown the activity of Bruton tyrosine kinase inhibitors and programmed death-1-targeted therapies in CNS lymphoma, and studies suggested potential synergy. Therefore, we conducted a phase 2 trial that combined ibrutinib with nivolumab for patients with relapsed/refractory CNS lymphoma. Patients received 560 mg oral ibrutinib daily with 240 mg IV nivolumab every 14 days (28 days per cycle). Patients who had partial or complete response after 6 cycles of treatment could continue therapy for up to 2 years …

Identifying The Human Olfactory And Chemosignaling Neural Networks Using Event Related Fmri And Graph Theory, Saideh Ferdowsi, Tom Foulsham, Alireza Rahmani, Dimitri Ognibene, Luca Citi, Wen Li

Faculty, Staff and Student Publications

This study aims to characterize and compare the functional neural networks associated with different olfactory stimuli, including air, non-social odours, and human body odours. We introduce a novel processing pipeline based on event-related functional magnetic resonance imaging (fMRI) and graph theory for network identification. To ensure the stability and small worldness of the characterized networks, we conduct statistical validations, network modularity assessments, and robustness measurement against local attacks. The key hypothesis is that human body odours (so-called social odours) and non-social odours engage distinct neural networks, particularly in regions responsible for social processing. We found that the posterior medial orbitofrontal …

Challenges In Transitioning From Methadone To Buprenorphine-Naloxone For Chronic Pain Management: Two Cases, Jamal Hasoon, Anvinh Nguyen, Omar Viswanath, Alaa Abd-Elsayed

Faculty, Staff and Students Publications

Background: Methadone is frequently used for chronic pain management due to its long half-life and NMDA receptor activity, making it an effective option for opioid-tolerant patients. Buprenorphine-naloxone is increasingly explored as an alternative for chronic pain and opioid use disorder, offering partial opioid agonism with a ceiling effect on respiratory depression. The transition from methadone to buprenorphine-naloxone remains clinically challenging, requiring careful management to prevent withdrawal and ensure adequate pain control.

Case descriptions: Two patients with chronic pain were transitioned from methadone to buprenorphine-naloxone. The first patient, a mid-40s female, was abruptly switched from methadone 10 mg twice daily dosing …

Molecular Subtyping Of Hypertensive Disorders Of Pregnancy, Michal A Elovitz, Antonia I Frolova, Et Al.

2020-Current year OA Pubs

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. …

Tumor-Derived Arachidonic Acid Reprograms Neutrophils To Promote Immune Suppression And Therapy Resistance In Triple-Negative Breast Cancer, Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L Chan, Bo Wei, Philip L Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, David G Edwards, Livia S Eberlin, Xiang H-F Zhang

Faculty, Staff and Students Publications

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of …

Mechanistic Insights Into The Structure-Based Design Of A Cspz-Targeting Lyme Disease Vaccine, Kalvis Brangulis, Jill Malfetano, Ashley L Marcinkiewicz, Alan Wang, Yi-Lin Chen, Jungsoon Lee, Zhuyun Liu, Xiuli Yang, Ulrich Strych, Dagnija Tupina, Inara Akopjana, Maria-Elena Bottazzi, Utpal Pal, Ching-Lin Hsieh, Wen-Hsiang Chen, Yi-Pin Lin

Faculty, Staff and Students Publications

Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YAI183Y and CspZ-YAC187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized …

Association Of Age, Sex And Education With Access To The Intravenous Thrombolysis For Acute Ischemic Stroke, Yoona Ko, Beom Joon Kim, Youngran Kim, Jong-Moo Park, Kyusik Kang, Jae Guk Kim, Jae-Kwan Cha, Tai Hwan Park, Kyungbok Lee, Jun Lee, Keun-Sik Hong, Byung-Chul Lee, Kyung-Ho Yu, Dong-Eog Kim, Joon-Tae Kim, Jay Chol Choi, Jee Hyun Kwon, Wook-Joo Kim, Kyu Sun Yum, Sung-Il Sohn, Hyungjong Park, Sang-Hwa Lee, Kwang-Yeol Park, Chi Kyung Kim, Sung Hyuk Heo, Moon-Ku Han, Anjail Z Sharrief, Sunil A Sheth, Hee-Joon Bae

Faculty, Staff and Student Publications

Background: Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients.

Methods: We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed …

Adaptations Of An Online Cognitive-Behavioral Therapy Intervention For Binge Type Eating Disorders In Publicly-Insured And Uninsured Adults: A Pilot Study, Siena S Vendlinski, Agatha A Laboe, Peyton Crest, Claire G Mcginnis, Molly F Steinhoff, Denise E Wilfley, C Barr Taylor, Ellen E Fitzsimmons-Craft, Erin C Accurso

2020-Current year OA Pubs

BACKGROUND: Publicly-insured and uninsured individuals-many of whom are marginalized because of race/ethnicity, ability status, and/or other social identities-experience barriers to accessing evidence-based interventions (EBIs) for eating disorders (EDs). Additionally, EBIs have not been developed with or for diverse populations, exacerbating poor treatment uptake. Mobile technology is well-positioned to bridge this gap and increase access to low-cost, culturally-sensitive EBIs.

METHODS: This study leverages a user-centered design approach to adapt an existing coached cognitive-behavioral therapy-based digital program and evaluate its usability in a sample of 11 participants with (sub)clinical binge type EDs who are publicly-insured (n = 10) or uninsured (n = …

Comparing Analgesic Regimen Effectiveness And Safety After Surgery (Cares): Protocol For A Pragmatic, International Multicentre Randomised Trial, Mark C Bicket, Karim Shiraz Ladha, Simon Haroutounian, Kellie Mcfarlin, Mary Neff, Rachel L Mcduffie, Jennifer F Waljee, Duminda Nalaka Wijeysundera, Chad Brummet, Yi Li, Cares Investigators

2020-Current year OA Pubs

INTRODUCTION: Acute pain is commonly experienced by millions of patients who undergo outpatient surgical procedures. Moreover, an increasing number of procedures are performed on an outpatient basis, requiring greater postoperative planning to ensure effective pain management. Analgesic approaches commonly involve prescription opioids and non-steroidal anti-inflammatory drugs (NSAIDs), but an optimal regimen that balances pain and adverse effects has not been identified. In addition, critical gaps in evidence exist regarding how opioids and NSAIDs compare as analgesic regimens after surgery.

METHODS AND ANALYSIS: The Comparing Analgesic Regimen Effectiveness and Safety after Surgery (CARES) trial is a pragmatic, international, multicentre randomised trial …

Protocol For A Multisite, Observational Clinical Study Of The Association Between Skin Colour And Pulse Oximeter Accuracy In Children Undergoing Cardiac Catheterisation (Pach Study), Halley Ruppel, Liming Huang, Christopher J Petit, Athar M Qureshi, Christopher P Bonafide, Elizabeth E Foglia, Jeffery Feldman, Meghan B Lane-Fall, Jennifer M Lynch, Anna Chien, Michelle Dunn, Michael L O'Byrne

Faculty, Staff and Students Publications

Introduction: Prospective, real-world clinical studies of the association between skin color and pulse oximeter (SpO2) accuracy in children are needed to address the limitations of previous research. Such studies are essential for generating evidence for clinicians, regulators and industry. This is the protocol for a multisite study funded by the National Heart, Lung, and Blood Institute (R01HL171313; 1 January 2024-31 December 2028).

Methods and analysis: In this pragmatic, observational study conducted in three large paediatric cardiac catheterisation centres in the USA, children undergoing cardiac catheterisation with directly measured arterial oxygen saturation will be prospectively enrolled. The outcome variable (SpO2 bias) …

A Phase Ii Trial Of Sitravatinib + Nivolumab After Progression On Immune Checkpoint Inhibitor In Patients With Metastatic Clear Cell Rcc, Andrew W Hahn, Nabil Adra, Ulka Vaishampayan, Lianchun Xiao, Nazli Dizman, Ying Yuan, Sagar S Mukhida, Matthew T Campbell, Jianjun Gao, Amado J Zurita, Eric Jonasch, Nizar M Tannir, Amishi Y Shah, Pavlos Msaouel

Faculty, Staff and Student Publications

Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to immune checkpoint inhibitors (ICI) by reducing immune-suppressive myeloid cells in metastatic clear cell RCC (ccRCC). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve clinical outcomes.

Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into 3 …

Findings From A Qualitative Analysis: Social Media Influencers Of Color As Trusted Messengers Of Hpv Vaccination Messages, Amelia Burke-Garcia, Erin Cutroneo, Dasha Afanaseva, Kayla Madden, Angela Sustaita-Ruiz, Preethi Selvan, Estefany Rivera Sanchez, Amy Leader

Department of Medical Oncology Faculty Papers

BACKGROUND: Despite HPV vaccination reducing the prevalence of cervical cancer by 90%, vaccination rates remain lower among communities of color due to vaccine hesitancy and mistrust in traditional public health messengers. The emergence of social media influencers, a newer kind of messenger, presents a unique opportunity to share immunization messages in new ways with a variety of communities. This paper reviews the qualitative findings from a study aimed at assessing influencers' perceptions of and approaches to sharing messaging about the HPV vaccine.

METHODS: Guided by several theories (Theory of Planned Behavior, Narrative Theory, and Opinion Leader Theory), the study team …

Year 1 Of Medicare's Accountable Care Organization Realizing Equity, Access, And Community Health Model, Gmerice Hammond, Sunny Lin, Sukruth A Shashikumar, R J Waken, Fengxian Wang, Khavya Avula, Vi-Anh Hoang, Kenton J Johnston, Karen Joynt Maddox

2020-Current year OA Pubs

IMPORTANCE: The US Centers for Medicare & Medicaid Services launched the Accountable Care Organization (ACO) Realizing Equity, Access, and Community Health (REACH) payment model in January 2023. In contrast to prior ACO initiatives, such as the Medicare Shared Savings Program (MSSP), ACO REACH includes equity-focused measures and payment adjustments, including an equity plan and financial risk adjustment for ACOs with higher proportions of underserved beneficiaries. However, it is unknown whether these changes have incented participation from organizations that serve beneficiaries from marginalized communities.

OBJECTIVE: To compare characteristics between participants in ACO REACH with those in MSSP and the broader pool …

Chronic Alcohol Withdrawal-Associated Increases In Vta Hcrtr1 Expression Are Associated With Heightened Nociception And Anxiety-Like Behavior In Female Rats, Shealan Cruise, Maria E. Secci, Leslie K. Kelley, Nathan M. Sharfman, Keishla Rodriguez-Graciani, Tiffany A. Wills, Nicholas W. Gilpin, Elizabeth M. Avegno

School of Medicine Faculty Publications

Alcohol withdrawal is characterized by various symptoms that include pain and negative affect in the absence of the drug. The neural underpinnings of these behaviors are not entirely understood, but orexin has emerged as a candidate target for the treatment of substance use disorders. Here, we explored changes in orexin system-related gene expression in brain regions important for mediating reward and stress, including the ventral tegmental area (VTA) and extended amygdala (including the central amygdala, nucleus accumbens shell, and bed nucleus of the stria terminalis), in adolescent and adult female Wistar rats following chronic alcohol exposure. We observed higher numbers …

Polygenic Score Analysis Identifies Distinct Genetic Risk Profiles In Alzheimer’S Disease Comorbidities, Carlos F Hernández, Camilo Villaman, Costin Leu, Dennis Lal, Ignacio Mata, Andrés D Klein, Eduardo Pérez-Palma

Faculty, Staff and Student Publications

Alzheimer’s disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients. We show that individuals with higher PGS values showed an elevated risk of developing T2D (OR 2.1, p = 1.07 × 10−11) …

De Novo Variants In Cdkl1 And Cdkl2 Are Associated With Neurodevelopmental Symptoms, Ali H Bereshneh, Jonathan C Andrews, Daniel F Eberl, Guney Bademci, Nicholas A Borja, Stephanie Bivona, Wendy K Chung, Shinya Yamamoto, Michael F Wangler, Shane Mckee, Mustafa Tekin, Hugo J Bellen, Oguz Kanca

Duncan NRI Faculty and Staff Publications

The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx …

Methylome-Wide Association Analyses Of Lipids And Modifying Effects Of Behavioral Factors In Diverse Race And Ethnicity Participants, Yao Hu, Jeff Haessler, Jessica I Lundin, Burcu F Darst, Eric A Whitsel, Megan Grove, Weihua Guan, Rui Xia, Mindy Szeto, Laura M Raffield, Scott Ratliff, Yuxuan Wang, Xuzhi Wang, Alison E Fohner, Megan T Lynch, Yesha M Patel, S Lani Park, Huichun Xu, Braxton D Mitchell, Joshua C Bis, Nona Sotoodehnia, Jennifer A Brody, Bruce M Psaty, Gina M Peloso, Michael Y Tsai, Stephen S Rich, Jerome I Rotter, Jennifer A Smith, Sharon L R Kardia, Alex P Reiner, Leslie Lange, Myriam Fornage, James S Pankow, Mariaelisa Graff, Kari E North, Charles Kooperberg, Ulrike Peters

Faculty, Staff and Student Publications

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG …

Zp4: A Novel Target For Car-T Cell Therapy In Triple Negative Breast Cancer, Lauren K Somes, Jonathan T Lei, Xinpei Yi, Diego F Chamorro, Paul Shafer, Ahmed Z Gad, Lacey E Dobrolecki, Emily Madaras, Nabil Ahmed, Michael T Lewis, Bing Zhang, Valentina Hoyos

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes. We generated 89 ZP4-specific novel monoclonal antibodies and used the …

Conformal Predictive Intervals In Survival Analysis: A Resampling Approach, Jing Qin, Jin Piao, Jing Ning, Yu Shen

Faculty, Staff and Student Publications

The distribution-free method of conformal prediction has gained considerable attention in computer science, machine learning, and statistics. Candès et al. extended this method to right-censored survival data, addressing right-censoring complexity by creating a covariate shift setting, extracting a subcohort of subjects with censoring times exceeding a fixed threshold. Their approach only estimates the lower prediction bound for type I censoring, where all subjects have available censoring times regardless of their failure status. In medical applications, we often encounter more general right-censored data, observing only the minimum of failure time and censoring time. Subjects with observed failure times have unavailable censoring …

Bone-Induced Her2 Promotes Secondary Metastasis In Hr+/Her2- Breast Cancer, Rahat Alam, Anna Reva, David G Edwards, Bree M Lege, Laura S Munoz-Arcos, Carolina Reduzzi, Swarnima Singh, Xiaoxin Hao, Yi-Hsuan Wu, Zeru Tian, Laura M Natalee, Gargi Damle, Deniz Demircioglu, Yixian Wang, Ling Wu, Elisabetta Molteni, Dan Hasson, Bora Lim, Zbigniew Gugala, Jerry E Chipuk, Julie E Lang, Joseph A Sparano, Chonghui Cheng, Massimo Cristofanilli, Han Xiao, Xiang H-F Zhang, Igor L Bado

Faculty, Staff and Students Publications

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2− status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 …

Epidemiologic Investigation Of Protozoa And Soil-Transmitted Helminths In Starr County, Texas, Lauren M Leining, Timothy A Erickson, Craig L Hanis, Cici Bauer, Maya D Murry, Eric L Brown, Rojelio Mejia, Sarah M Gunter

Faculty, Staff and Students Publications

The burden of pathogenic enteric protozoa and soil-transmitted helminths among impoverished populations living on the Texas-Mexico border is unclear. We conducted a cross-sectional study on an ongoing longitudinal cohort of 616 adults residing in Starr County, Texas. A total of 359 adults were screened for four protozoa and five soil-transmitted helminths by using real-time polymerase chain reaction. This analysis identified 48 (13.4%) participants who tested positive for Blastocystis sp., three (0.8%) who tested positive for Giardia intestinalis, and one (0.3%) who tested positive for Strongyloides stercoralis and was also coinfected with Blastocystis sp. Infection was significantly associated with age, a …

Capitalizing On Natural Language Processing (Nlp) To Automate The Evaluation Of Coach Implementation Fidelity In Guided Digital Cognitive-Behavioral Therapy (Gdcbt), Nur Hani Zainal, Regina Eckhardt, Gavin N Rackoff, Ellen E Fitzsimmons-Craft, Elsa Rojas-Ashe, Craig Barr Taylor, Burkhardt Funk, Daniel Eisenberg, Denise E Wilfley, Michelle G Newman

2020-Current year OA Pubs

BACKGROUND: As the use of guided digitally-delivered cognitive-behavioral therapy (GdCBT) grows, pragmatic analytic tools are needed to evaluate coaches' implementation fidelity.

AIMS: We evaluated how natural language processing (NLP) and machine learning (ML) methods might automate the monitoring of coaches' implementation fidelity to GdCBT delivered as part of a randomized controlled trial.

METHOD: Coaches served as guides to 6-month GdCBT with 3,381 assigned users with or at risk for anxiety, depression, or eating disorders. CBT-trained and supervised human coders used a rubric to rate the implementation fidelity of 13,529 coach-to-user messages. NLP methods abstracted data from text-based coach-to-user messages, and …

Cross-Ancestry Genome-Wide Association Study Identifies Implications Of Sorl1 In Cerebral Beta-Amyloid Deposition, Jun Pyo Kim, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

GWAS of Alzheimer's disease have been predominantly based on European ancestry cohorts with clinically diagnosed patients. Increasing the ancestral diversity of GWAS and focusing on imaging brain biomarkers for Alzheimer's disease may lead to the identification of new genetic loci. Here, we perform a GWAS on cerebral β-amyloid deposition measured by PET imaging in 3,885 East Asians and a cross-ancestry GWAS meta-analysis with data from 11,816 European participants. Our GWAS analysis replicates known loci (APOE4, CR1, and FERMT2) and identifies a novel locus near SORL1 that is significantly associated with β-amyloid deposition. Single-nucleus expression analysis shows that SORL1 is differentially …

A Prospective, Multicenter Analysis Of Recurrence-Free Survival After Sentinel Lymph Node Biopsy Decisions Influenced By The 31-Gep., J Michael Guenther, Andrew Ward, Brian J Martin, Mark Cripe, Timothy Beard, Oliver Wisco, Rohit Sharma, Stanley P Leong, Richard Essner, Joseph I Clark, John Hamner, Brenda Sickle-Santanello, Maki Yamamoto

Oncology Articles

BACKGROUND: Although most patients with cutaneous melanoma (CM) will have a negative sentinel lymph node biopsy (SLNB), up to 20%-30% of these patients will recur. The 31-gene expression profile (31-GEP) test has been prospectively validated to identify patients at low (Class 1A), intermediate (Class 1B/2A), and high (Class 2B) risk of SLN positivity and recurrence.

METHODS: DECIDE is a prospective, multicenter study to assess the effect of 31-GEP testing on SLNB performance rates in patients with T1-T2 tumors considering SLNB and to study long-term outcomes. Here, we assessed outcomes in patients with a Class 1A 31-GEP result (n = 130). …

The Relationship Between Physical Activity And Telomere Length In Women: A Systematic Review, Jeni Page, Catherine Stephens, Melissa Richard, Elizabeth Lyons, Elizabeth Baumler, M Terese Verklan, Elizabeth Lorenzo

Faculty, Staff and Student Publications

Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A …