Digital Commons Network^™

Distribution Pattern Of Antibiotic Resistance Genes In Escherichia Coli Isolated From Colibacillosis Cases In Broiler Farms Of Egypt, Mona A A Abdel-Rahman, Engy A Hamed, May F Abdelaty, Hend K Sorour, Heba Badr, Wafaa M Hassan, Azhar G Shalaby, Ahmed Abd-Elhalem Mohamed, Mohamed A Soliman, Heba Roshdy

Faculty, Staff and Student Publications

BACKGROUND AND AIM: Multidrug resistance (MDR) of

MATERIALS AND METHODS: Samples from 938 broiler farms were bacteriologically examined for

RESULTS:

CONCLUSION: The study showed a high prevalence of

Psychotic Symptom, Mood, And Cognition-Associated Multimodal Mri Reveal Shared Links To The Salience Network Within The Psychosis Spectrum Disorders, Chuang Liang, Godfrey Pearlson, Juan Bustillo, Peter Kochunov, Jessica A Turner, Xuyun Wen, Rongtao Jiang, Zening Fu, Xiao Zhang, Kaicheng Li, Xijia Xu, Daoqiang Zhang, Shile Qi, Vince D Calhoun

Faculty, Staff and Student Publications

Schizophrenia (SZ), schizoaffective disorder (SAD), and psychotic bipolar disorder share substantial overlap in clinical phenotypes, associated brain abnormalities and risk genes, making reliable diagnosis among the three illness challenging, especially in the absence of distinguishing biomarkers. This investigation aims to identify multimodal brain networks related to psychotic symptom, mood, and cognition through reference-guided fusion to discriminate among SZ, SAD, and BP. Psychotic symptom, mood, and cognition were used as references to supervise functional and structural magnetic resonance imaging (MRI) fusion to identify multimodal brain networks for SZ, SAD, and BP individually. These features were then used to assess the ability …

Inhibiting Androgen Receptor Splice Variants With Cysteine-Selective Irreversible Covalent Inhibitors To Treat Prostate Cancer, Thirumagal Thiyagarajan, Suriyan Ponnusamy, Dong-Jin Hwang, Yali He, Sarah Asemota, Kirsten L Young, Daniel L Johnson, Vera Bocharova, Weidong Zhou, Abhinav K Jain, Emanuel F Petricoin, Zheng Yin, Lawrence M Pfeffer, Duane D Miller, Ramesh Narayanan

Faculty, Staff and Student Publications

Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a …

Radiofrequency Ablation Remodels The Tumor Microenvironment And Promotes Neutrophil-Mediated Abscopal Immunomodulation In Pancreatic Cancer, Erika Y Faraoni, Baylee J O'Brien, Lincoln N Strickland, Baron K Osborn, Victoria Mota, Jarod Chaney, Constance Lynn Atkins, Putao Cen, Julie Rowe, Jessica Cardenas, Kyle L Poulsen, Curtis J Wray, Nirav C Thosani, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong …

Subtype And Site Specific-Induced Metabolic Vulnerabilities In Prostate Cancer, Federica Mossa, Daniele Robesti, Ramachandran Sumankalai, Eva Corey, Mark Titus, Yuqi Kang, Jianhua Zhang, Alberto Briganti, Francesco Montorsi, Christopher P Vellano, Joseph R Marszalek, Daniel E Frigo, Christopher J Logothetis, Taranjit S Gujral, Eleonora Dondossola

Faculty, Staff and Student Publications

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward …

Evaluation Of Proton Therapy Reirradiation For Patients With Recurrent Head And Neck Squamous Cell Carcinoma, Anna Lee, Robbie Woods, Amgad Mahfouz, Sarin Kitpanit, Olivia Cartano, Nader Mohamed, Irini Youssef, Kathryn Marqueen, Kevin Sine, Dennis Mah, Brian Neal, Kaveh Zakeri, Jung J Kang, Nadeem Riaz, Yao Yu, Sean M Mcbride, Linda D Chen, C Jillian Tsai, Daphna Y Gelblum, Robert H Press, Loren S Michel, Eric J Sherman, David Pfister, Lara A Dunn, Alan L Ho, James Fetten, Richard J Wong, Jay O Boyle, Bhuvanesh Singh, Jennifer R Cracchiolo, Ian Ganly, Marc A Cohen, Nancy Y Lee

Faculty, Staff and Student Publications

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret.

Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma.

Design, setting, and participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and …

Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms And Sleep In Juvenile And Adult Mouse Models Of Angelman Syndrome, Dongwon Lee, Wu Chen, Heet Naresh Kaku, Xinming Zhuo, Eugene S Chao, Armand Soriano, Allen Kuncheria, Stephanie Flores, Joo Hyun Kim, Armando Rivera, Frank Rigo, Paymaan Jafar-Nejad, Arthur L Beaudet, Matthew S Caudill, Mingshan Xue

Faculty, Staff and Students Publications

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we …

Mitochondrial Dysfunction Reactivates Α-Fetoprotein Expression That Drives Copper-Dependent Immunosuppression In Mitochondrial Disease Models, Kimberly A Jett, Zakery N Baker, Amzad Hossain, Aren Boulet, Paul A Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John Decoteau, Karen Mochoruk, George N Ioannou, Christopher Savard, Sai Yuan, Osama Hmh Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J Battersby, Vishal M Gohil, Scot C Leary

Faculty, Staff and Students Publications

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative …

Increased Camkk2 Expression Is An Adaptive Response That Maintains The Fitness Of Tumor-Infiltrating Natural Killer Cells, Patrick K Juras, Luigi Racioppi, Debarati Mukherjee, Sandeep Artham, Xia Gao, Laura Akullian D'Agostino, Ching-Yi Chang, Donald P Mcdonnell

Faculty, Staff and Students Publications

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) …

Vista Targeting Of T-Cell Quiescence And Myeloid Suppression Overcomes Adaptive Resistance, Evelien Schaafsma, Walburga Croteau, Mohamed Eltanbouly, Elizabeth C Nowak, Nicole C Smits, Jie Deng, Aurelien Sarde, Cecilia A Webber, Dina Rabadi, Chao Cheng, Randolph Noelle, J Louise Lines

Faculty, Staff and Students Publications

VISTA is a premier target for cancer treatment due to its broad expression in many cancer types and enhanced expression upon development of adaptive immune checkpoint resistance. In the CT26 colorectal cancer model, monotherapy of small tumors with anti-VISTA resulted in slowed tumor growth. In a combination therapy setting, large CT26 tumors showed complete adaptive resistance to anti-PD-1/CTLA-4, but inclusion of anti-VISTA led to rejection of half the tumors. Mechanisms of enhanced anti-tumor immunity were investigated using scRNA-seq, multiplex image analysis and flow cytometry of the tumor immune infiltrate. In both treatment models, anti-VISTA upregulated stimulated antigen-presentation pathways and reduced …

Follistatin Regulates The Specification Of The Apical Cochlea Responsible For Low-Frequency Hearing In Mammals, Hei Yeun Koo, Min-A Kim, Hyehyun Min, Jae Yeon Hwang, Meenakshi Prajapati-Dinubila, Kwan Soo Kim, Martin M Matzuk, Juw Won Park, Angelika Doetzlhofer, Un-Kyung Kim, Jinwoong Bok

Faculty, Staff and Students Publications

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in …

The Phytophthora Sojae Nuclear Effector Psavh110 Targets A Host Transcriptional Complex To Modulate Plant Immunity, Xufang Qiu, Liang Kong, Han Chen, Yachun Lin, Siqun Tu, Lei Wang, Zhiyuan Chen, Mengzhu Zeng, Junhua Xiao, Peiguo Yuan, Min Qiu, Yan Wang, Wenwu Ye, Kaixuan Duan, Suomeng Dong, Yuanchao Wang

Faculty, Staff and Student Publications

Plants have evolved sophisticated immune networks to restrict pathogen colonization. In response, pathogens deploy numerous virulent effectors to circumvent plant immune responses. However, the molecular mechanisms by which pathogen-derived effectors suppress plant defenses remain elusive. Here, we report that the nucleus-localized RxLR effector PsAvh110 from the pathogen Phytophthora sojae, causing soybean (Glycine max) stem and root rot, modulates the activity of a transcriptional complex to suppress plant immunity. Soybean like-heterochromatin protein 1-2 (GmLHP1-2) and plant homeodomain finger protein 6 (GmPHD6) form a transcriptional complex with transcriptional activity that positively regulates plant immunity against Phytophthora infection. To suppress plant immunity, the …

Fn14-Directed Dart Nanoparticles Selectively Target Neoplastic Cells In Preclinical Models Of Triple-Negative Breast Cancer Brain Metastasis, Christine P Carney, Anshika Kapur, Pavlos Anastasiadis, Rodney M Ritzel, Chixiang Chen, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) patients with brain metastasis (BM) face dismal prognosis due to the limited therapeutic efficacy of the currently available treatment options. We previously demonstrated that paclitaxel-loaded PLGA−PEG nanoparticles (NPs) directed to the Fn14 receptor, termed “DARTs”, are more efficacious than Abraxane—an FDA-approved paclitaxel nanoformulation—following intravenous delivery in a mouse model of TNBC BM. However, the precise basis for this difference was not investigated. Here, we further examine the utility of the DART drug delivery platform in complementary xenograft and syngeneic TNBC BM models. First, we demonstrated that, in comparison to nontargeted NPs, DART NPs exhibit preferential association …

S-Acylation Is A Key Regulator Of Orai1/Stim1-Mediated Store-Operated Calcium Entry In T Cells, Savannah J. West Diaz

Dissertations and Theses (Open Access)

Orai1 and STIM1 proteins are the essential components of the Ca²⁺ release activated Ca²⁺ (CRAC) channel which is required for store-operated Ca²⁺ entry (SOCE) in T cells and subsequent signaling events leading to T cell activation, proliferation, and differentiation. Plasma membrane (PM)-localized Orai1 is the pore-forming subunit of the CRAC channel, and STIM1 is the Ca²⁺ sensor localized to the endoplasmic reticulum (ER) membrane in quiescent T cells. T cell receptor (TCR) stimulation leads to depletion of ER Ca²⁺ stores resulting in Ca²⁺ no longer being bound to STIM1. This activates STIM1 by triggering …

Oral/Oropharyngeal “Selfies” In Gay And Bisexual Men: A Pilot Study Exploring Oropharyngeal Screening For Hpv-Related Possible Malignancies, Michael W Ross, Sarah L Bennis, C Mark Nichols, I Niles Zoschke, J Michael Wilkerson, B R Simon Rosser, Cyndee L Stull, Alan G Nyitray, Charlene Flash, Samir S Khariwala

Faculty, Staff and Student Publications

Objectives: This study aims to determine the potential uptake and quality of oropharyngeal "selfies" taken by gay/bisexual men as a screening approach for HPV-associated oropharyngeal cancer.

Methods: From 1,699 gay/bisexual men in the US, surveyed about knowledge and attitudes to HPV-associated oropharyngeal cancer, a random sample of 320 men were invited to take an oropharyngeal "selfie" by smartphone and send it to the study website: 113 (35.5%) did so. Images were rated for quality by three healthcare professional raters blinded to each other's rating, with an otolaryngologist as the gold standard. In the second wave, those whose images were rated …

Serum Neurofilament Light-Chain Levels And Long-Term Treatment Outcomes In Relapsing-Remitting Multiple Sclerosis Patients: A Post Hoc Analysis Of The Randomized Combirx Trial, Gary Cutter, Richard A Rudick, Carl De Moor, Carol M Singh, Elizabeth Fisher, Thijs Koster, Fred D Lublin, Jerry S Wolinsky, Henry Mcfarland, Steven Jacobson, Maria L Naylor

Faculty, Staff and Student Publications

BACKGROUND: CombiRx was a randomized, double-blind, placebo-controlled phase 3 trial in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients randomized to intramuscular interferon beta-1a (IM IFN beta-1a), glatiramer acetate (GA), or both therapies.

OBJECTIVE: This analysis investigated changes in serum neurofilament light-chain (sNfL) levels in response to treatment and assessed baseline sNfL as a predictor of relapse.

METHODS: RRMS patients treated with IM IFN beta-1a 30 µg weekly + placebo (n = 159), GA 20 mg/mL daily + placebo (n = 172), or IM IFN beta-1a + GA (n = 344) were included. A linear mixed model compared sNfL values over time. …

High-Definition Transcranial Direct Current Stimulation For Upper Extremity Rehabilitation In Moderate-To-Severe Ischemic Stroke: A Pilot Study, Jordan N Williamson, Shirley A James, Dorothy He, Sheng Li, Evgeny V Sidorov, Yuan Yang

Faculty, Staff and Student Publications

Introduction: Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract (CST) and hyperexcitability of the contralesional cortico-reticulospinal tract (CRST). This proof-of-concept study aims to develop a non-invasive brain stimulation protocol that facilitates the lesioned CST and inhibits the contralesional CRST to improve upper extremity rehabilitation in individuals with moderate-to-severe motor impairments post-stroke.

Methods: Fourteen individuals (minimum 3 months post ischemic stroke) consented. Physician decision of the participants baseline assessment qualified eight to continue in a randomized, double-blind cross-over pilot trial (ClinicalTrials.gov Identifier: NCT05174949) with: (1) anodal high-definition transcranial direct stimulation (HD-tDCS) over …

Researching Covid To Enhance Recovery (Recover) Pregnancy Study: Rationale, Objectives And Design, Torri D Metz, Rebecca G Clifton, Richard Gallagher, Rachel S Gross, Leora I Horwitz, Vanessa L Jacoby, Susanne P Martin-Herz, Myriam Peralta-Carcelen, Harrison T Reeder, Carmen J Beamon, James Chan, A Ann Chang, Maged M Costantine, Megan L Fitzgerald, Andrea S Foulkes, Kelly S Gibson, Nick Güthe, Mounira Habli, David N Hackney, Matthew K Hoffman, M Camille Hoffman, Brenna L Hughes, Stuart D Katz, Victoria Laleau, Gail Mallett, Hector Mendez-Figueroa, Vanessa Monzon, Anna Palatnik, Kristy T S Palomares, Samuel Parry, Christian M Pettker, Beth A Plunkett, Athena Poppas, Uma M Reddy, Dwight J Rouse, George R Saade, Grecio J Sandoval, Shannon M Schlater, Frank C Sciurba, Hyagriv N Simhan, Daniel W Skupski, Amber Sowles, Tanayott Thaweethai, Gelise L Thomas, John M Thorp, Alan T Tita, Steven J Weiner, Samantha Weigand, Lynn M Yee, Valerie J Flaherman

Faculty, Staff and Student Publications

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads.

METHODS: RECOVER-Pregnancy cohort is a …

Machine Learning-Driven Exploration Of Drug Therapies For Triple-Negative Breast Cancer Treatment, Aman Chandra Kaushik, Zhongming Zhao

Faculty, Staff and Student Publications

Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have different morphologies and there is heterogeneity even among people who have the same type of tumor. Several staging and classifying systems have been developed due to the variability of different types of breast cancer. Due to high heterogeneity, personalized treatment has become a new strategy. Out of all breast cancer subtypes, triple-negative breast cancer (TNBC) comprises ∼10%-15%. TNBC refers to the subtype of breast cancer where cells do not express estrogen receptors, …

Covidanno, Covid-19 Annotation In Human, Yuzhou Feng, Mengyuan Yang, Zhiwei Fan, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 19 (COVID-19), has caused a global health crisis. Despite ongoing efforts to treat patients, there is no universal prevention or cure available. One of the feasible approaches will be identifying the key genes from SARS-CoV-2-infected cells. SARS-CoV-2-infected in vitro model, allows easy control of the experimental conditions, obtaining reproducible results, and monitoring of infection progression. Currently, accumulating RNA-seq data from SARS-CoV-2 in vitro models urgently needs systematic translation and interpretation. To fill this gap, we built COVIDanno, COVID-19 annotation in humans, available at http://biomedbdc.wchscu.cn/COVIDanno/. The aim …

Towards Fair Patient-Trial Matching Via Patient-Criterion Level Fairness Constraint, Chia-Yuan Chang, Jiayi Yuan, Sirui Ding, Qiaoyu Tan, Kai Zhang, Xiaoqian Jiang, Xia Hu, Na Zou

Faculty, Staff and Student Publications

Clinical trials are indispensable in developing new treatments, but they face obstacles in patient recruitment and retention, hindering the enrollment of necessary participants. To tackle these challenges, deep learning frameworks have been created to match patients to trials. These frameworks calculate the similarity between patients and clinical trial eligibility criteria, considering the discrepancy between inclusion and exclusion criteria. Recent studies have shown that these frameworks outperform earlier approaches. However, deep learning models may raise fairness issues in patient-trial matching when certain sensitive groups of individuals are underrepresented in clinical trials, leading to incomplete or inaccurate data and potential harm. To …

The Kynurenine Pathway In Alzheimer’S Disease: A Meta-Analysis Of Central And Peripheral Levels, Brisa S Fernandes, Mehmet Enes Inam, Nitesh Enduru, Joao Quevedo, Zhongming Zhao

Faculty, Staff and Student Publications

OBJECTIVE: Changes in the kynurenine pathway are recognized in psychiatric disorders, but their role in Alzheimer's disease (AD) is less clear. We aimed to conduct a systematic review and meta-analysis to determine whether tryptophan and kynurenine pathway metabolites are altered in AD.

METHODS: We performed a systematic review and random-effects meta-analyses. Inclusion criteria were studies that compared AD and cognitively normal (CN) groups and assessed tryptophan or kynurenine pathway metabolites in cerebrospinal fluid or peripheral blood.

RESULTS: Twenty-two studies with a total of 1,356 participants (664 with AD and 692 CN individuals) were included. Tryptophan was decreased only in peripheral …

Premature Senescence And Cardiovascular Disease Following Cancer Treatments: Mechanistic Insights, Ashita Jain, Diego Casanova, Alejandra Valdivia Padilla, Angelica Paniagua Bojorges, Sivareddy Kotla, Kyung Ae Ko, Venkata S K Samanthapudi, Khanh Chau, Minh T H Nguyen, Jake Wen, Selina L Hernandez Gonzalez, Shaefali P Rodgers, Elizabeth A Olmsted-Davis, Dale J Hamilton, Cielito Reyes-Gibby, Sai-Ching J Yeung, John P Cooke, Joerg Herrmann, Eduardo N Chini, Xiaolei Xu, Syed Wamique Yusuf, Momoko Yoshimoto, Philip L Lorenzi, Brain Hobbs, Sunil Krishnan, Efstratios Koutroumpakis, Nicolas L Palaskas, Guangyu Wang, Anita Deswal, Steven H Lin, Jun-Ichi Abe, Nhat-Tu Le

The Brown Foundation: Institute of Molecular Medicine

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain …

Predictive Digital Twin For Optimizing Patient-Specific Radiotherapy Regimens Under Uncertainty In High-Grade Gliomas, Anirban Chaudhuri, Graham Pash, David A Hormuth, Guillermo Lorenzo, Michael Kapteyn, Chengyue Wu, Ernesto A B F Lima, Thomas E Yankeelov, Karen Willcox

Faculty, Staff and Student Publications

We develop a methodology to create data-driven predictive digital twins for optimal risk-aware clinical decision-making. We illustrate the methodology as an enabler for an anticipatory personalized treatment that accounts for uncertainties in the underlying tumor biology in high-grade gliomas, where heterogeneity in the response to standard-of-care (SOC) radiotherapy contributes to sub-optimal patient outcomes. The digital twin is initialized through prior distributions derived from population-level clinical data in the literature for a mechanistic model's parameters. Then the digital twin is personalized using Bayesian model calibration for assimilating patient-specific magnetic resonance imaging data. The calibrated digital twin is used to propose optimal …

Integrated Clinical Genotype-Phenotype Characteristics Of Early T-Cell Precursor Acute Lymphoblastic Leukemia, Matthew T Ye, Yi Wang, Zhuang Zuo, Steliana Calin, Hua He, Zhenya Tang, Elias J Jabbour, Gautam Borthakur, Yizhuo Zhang, Yaling Yang, M James You

Faculty, Staff and Student Publications

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood.

Methods: The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL.

Results: The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), …

Ribonuclease 1 Enhances Antitumor Immunity Against Breast Cancer By Boosting T Cell Activation, Ying-Nai Wang, Heng-Huan Lee, Zhou Jiang, Li-Chuan Chan, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

The secretory enzyme human ribonuclease 1 (RNase1) is involved in innate immunity and anti-inflammation, achieving host defense and anti-cancer effects; however, whether RNase1 contributes to adaptive immune response in the tumor microenvironment (TME) remains unclear. Here, we established a syngeneic immunocompetent mouse model in breast cancer and demonstrated that ectopic RNase1 expression significantly inhibited tumor progression. Overall changes in immunological profiles in the mouse tumors were analyzed by mass cytometry and showed that the RNase1-expressing tumor cells significantly induced CD4+ Th1 and Th17 cells and natural killer cells and reduced granulocytic myeloid-derived suppressor cells, supporting that RNase1 favors an antitumor …

Sound Speed Estimation For Distributed Aberration Correction In Laterally Varying Media, Rehman Ali, Trevor M Mitcham, Melanie Singh, Marvin M Doyley, Richard R Bouchard, Jeremy J Dahl, Nebojsa Duric

Faculty, Staff and Student Publications

Spatial variation in sound speed causes aberration in medical ultrasound imaging. Although our previous work has examined aberration correction in the presence of a spatially varying sound speed, practical implementations were limited to layered media due to the sound speed estimation process involved. Unfortunately, most models of layered media do not capture the lateral variations in sound speed that have the greatest aberrative effect on the image. Building upon a Fourier split-step migration technique from geophysics, this work introduces an iterative sound speed estimation and distributed aberration correction technique that can model and correct for aberrations resulting from laterally varying …

Naproxen Chemoprevention Induces Proliferation Of Cytotoxic Lymphocytes In Lynch Syndrome Colorectal Mucosa, Charles M Bowen, Nan Deng, Laura Reyes-Uribe, Edwin Roger Parra, Pedro Rocha, Luisa M Solis, Ignacio I Wistuba, Valerie O Sepeda, Lana Vornik, Marjorie Perloff, Eva Szabo, Asad Umar, Krishna M Sinha, Powel H Brown, Eduardo Vilar

Faculty, Staff and Student Publications

BACKGROUND: Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.

METHODS: Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled 'Naproxen Study' were obtained and subjected to a tissue microarray for image mass cytometry …

A Scientific Communication Mentoring Intervention Benefits Diverse Mentees With Language Variety Related Discomfort, Carrie A Cameron, Hwa Young Lee, Cheryl B Anderson, Erin K Dahlstrom, Shine Chang

Faculty, Staff and Student Publications

We studied social-psychological effects over time of a faculty-mentor workshop intervention that addressed attitudes associated with language variety and their impact on scientific communication (SC) skill development of PhD and postdoctoral STEM research trainees (N = 274). Six months after their mentors attended the workshop, all mentees had significant gains in productivity in speaking tasks. In particular, mentees with high language discomfort rated their quality of communication with their mentor and their enthusiasm about communicating more highly (p < .05 for both measures), compared to mentees with low language discomfort. In addition, mentees raised speaking nonstandardized varieties of English reported significant reductions in discomfort related to language use (p = .003), compared to mentees raised speaking standardized English. We conclude that training mentors to understand and respond to …

Integrating Comorbidity Knowledge For Alzheimer's Disease Drug Repurposing Using Multi-Task Graph Neural Network, Ko-Hong Lin, Kang-Lin Hsieh, Xiaoqian Jiang, Yejin Kim

Faculty, Staff and Student Publications

Alzheimer's Disease (AD) is a multifactorial disease that shares common etiologies with its multiple comorbidities, especially vascular diseases. To predict repurposable drugs for AD utilizing the relatively well-investigated comorbidities' knowledge, we proposed a multi-task graph neural network (GNN)-based pipeline that incorporates the corresponding biomedical interactome of these diseases with their genetic markers and effective therapeutics. Our pipeline can accurately capture the interactions and disease classification in the network. Next, we predicted drugs that might interact with the AD module by the node embedding similarity. Our candidates are mostly BBB permeable, and literature evidence showed their potential for treating AD pathologies, …