Digital Commons Network^™

Nrg/Rtog 0837: Randomized, Phase Ii, Double-Blind, Placebo-Controlled Trial Of Chemoradiation With Or Without Cediranib In Newly Diagnosed Glioblastoma, Tracy T. Batchelor, Minhee Won, Arnab Chakravarti, Costas G. Hadjipanayis, Wenyin Shi, Lynn S. Ashby, Volker W. Stieber, H. Ian Robins, Heidi J. Gray, Alfredo Voloschin, John B. Fiveash, Clifford G. Robinson, Ushasree Chamarthy, Young Kwok, Terrence P. Cescon, Anand K. Sharma, Rekha Chaudhary, Mei-Yin Polley, Minesh P. Mehta

Department of Radiation Oncology Faculty Papers

BACKGROUND: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma.

METHODS: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided …

The Inherited Kras-Variant As A Biomarker Of Cetuximab Response In Nsclc, Joanne Weidhaas, Chen Hu, Ritsuko Komaki, Gregory Masters, George Blumenschein, Joe Chang, Bo Lu, Adam Dicker, Jeffrey Bogart, Yolanda Garces, Samir Narayan, Clifford Robinson, Vivek Kavadi, Joel S Greenberger, Christopher Koprowski, James Welsh, Elizabeth Gore, Robert Macrae, Rebecca Paulus, Jeffrey Bradley

Department of Radiation Oncology Faculty Papers

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617.

EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression …

Usp1 Promotes Cholangiocarcinoma Progression By Deubiquitinating Parp1 To Prevent Its Proteasomal Degradation, Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu

Faculty, Staff and Student Publications

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin …

Polygenic Prediction Across Populations Is Influenced By Ancestry, Genetic Architecture, And Methodology, Ying Wang, Masahiro Kanai, Taotao Tan, Mireille Kamariza, Kristin Tsuo, Kai Yuan, Wei Zhou, Yukinori Okada, Biobank Japan Project, Hailiang Huang, Patrick Turley, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

Polygenic risk scores (PRSs) developed from multi-ancestry genome-wide association studies (GWASs), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulti compared with PRSs constructed from single-ancestry GWASs (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmulti overall outperformed PRSsingle in understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Furthermore, integrating PRSs based on local ancestry-informed GWASs and large-scale, European-based PRSs improved predictive performance in understudied African populations, …

Functional Analysis Reveals Driver Cooperativity And Novel Mechanisms In Endometrial Carcinogenesis, Matthew Brown, Alicia Leon, Katarzyna Kedzierska, Charlotte Moore, Hayley L Belnoue-Davis, Susanne Flach, John P Lydon, Francesco J Demayo, Annabelle Lewis, Tjalling Bosse, Ian Tomlinson, David N Church

Faculty, Staff and Students Publications

High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten …

Integrated Molecular Characterization Of Intraductal Papillary Mucinous Neoplasms: An Nci Cancer Moonshot Precancer Atlas Pilot Project, Alexander Semaan, Vincent Bernard, Justin Wong, Yuki Makino, Daniel B Swartzlander, Kimal I Rajapakshe, Jaewon J Lee, Adam Officer, Christian Max Schmidt, Howard H Wu, Courtney L Scaife, Kajsa E Affolter, Daniela Nachmanson, Matthew A Firpo, Michele Yip-Schneider, Andrew M Lowy, Olivier Harismendy, Subrata Sen, Anirban Maitra, Yasminka A Jakubek, Paola A Guerrero

Faculty, Staff and Student Publications

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with …

First-In-Human, Phase I Dose-Escalation And Dose-Expansion Study Of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan In Non-Small-Cell Lung Cancer: Tropion-Pantumor01, Toshio Shimizu, Jacob Sands, Kiyotaka Yoh, Alexander Spira, Edward B Garon, Satoru Kitazono, Melissa L Johnson, Funda Meric-Bernstam, Anthony W Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E Lisberg, Rebecca S Heist

Faculty, Staff and Student Publications

PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. …

Inducing Mitotic Catastrophe As A Therapeutic Approach To Improve Outcomes In Ewing Sarcoma., Soumya M. Turaga, Vikalp Vishwakarma, Stacey L. Hembruff, Benjamin K. Gibbs, Priya Sabu, Rajni V. Puri, Harsh B. Pathak, Glenson Samuel, Andrew K. Godwin

Manuscripts, Articles, Book Chapters and Other Papers

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given …

Bronchial Epithelial Gene Expression And Interstitial Lung Abnormalities, Aravind A Menon, Minyi Lee, Xu Ke, Rachel K Putman, Takuya Hino, Jonathan A Rose, Fenghai Duan, Samuel Y Ash, Michael H Cho, George T O'Connor, Josée Dupuis, Hiroto Hatabu, Marc E Lenburg, Ehab S Billatos, Gary M Hunninghake, Decamp Investigators

Faculty, Staff and Student Publications

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis.

METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using …

The Significant Impacts Of Interleukin-8 Genotypes On The Risk Of Colorectal Cancer In Taiwan, Chia-Wen Tsai, Wen-Shin Chang, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Mei-Due Yang, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, …

Nasal Iodophor Antiseptic Vs Nasal Mupirocin Antibiotic In The Setting Of Chlorhexidine Bathing To Prevent Infections In Adult Icus: A Randomized Clinical Trial, Susan S Huang, Edward J Septimus, Ken Kleinman, Lauren T Heim, Julia A Moody, Taliser R Avery, Laura Mclean, Syma Rashid, Katherine Haffenreffer, Lauren Shimelman, Whitney Staub-Juergens, Caren Spencer-Smith, Selsebil Sljivo, Ed Rosen, Russell E Poland, Micaela H Coady, Chi Hyun Lee, Eunice J Blanchard, Kimberly Reddish, Mary K Hayden, Robert A Weinstein, Brandon Carver, Kimberly Smith, Jason Hickok, Karen Lolans, Nadia Khan, S Gwynn Sturdevant, Sujan C Reddy, John A Jernigan, Kenneth E Sands, Jonathan B Perlin, Richard Platt

Faculty, Staff and Student Publications

IMPORTANCE: Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization.

OBJECTIVE: To compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing.

DESIGN, SETTING, AND PARTICIPANTS: Two-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Opposing Roles For The Α Isoform Of The Catalytic Subunit Of Protein Phosphatase 1 In Inside-Out And Outside-In Integrin Signaling In Murine Platelets, Tanvir Khatlani, Subhashree Pradhan, Kimberly Langlois, Deepika Subramanyam, Rolando E Rumbaut, K Vinod Vijayan

Faculty, Staff and Students Publications

Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside–out and integrin αIIbβ3-initiated outside–in signaling via protein kinases and phosphatases. Pharmacological inhibitor studies suggest that the serine/threonine protein phosphatase 1 (PP1) promotes platelet activation. However, since phosphatase inhibitors block all the isoforms of the catalytic subunit of PP1 (PP1c), the role of specific PP1c isoform in platelet signaling remains unclear. Here, we employed a platelet-specific PP1cα−/− mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1cα moderately decreased activation of integrin αIIbβ3, binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and …

Characteristics And Prognostic Impact Of Idh Mutations In Aml: A Cog, Swog, And Ecog Analysis., Sara Zarnegar-Lumley, Todd A. Alonzo, Robert B. Gerbing, Megan Othus, Zhuoxin Sun, Rhonda E. Ries, Jim Wang, Amanda Leonti, Matthew A. Kutny, Fabiana Ostronoff, Jerald P. Radich, Frederick R. Appelbaum, Era L. Pogosova-Agadjanyan, Kristen O'Dwyer, Martin S. Tallman, Mark Litzow, Ehab Atallah, Todd M. Cooper, Richard A. Aplenc, Omar Abdel-Wahab, Alan S. Gamis, Selina Luger, Harry Erba, Ross Levine, E Anders Kolb, Derek L. Stirewalt, Soheil Meshinchi, Katherine Tarlock

Manuscripts, Articles, Book Chapters and Other Papers

Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged betweenChildren's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): …

Paired Liver:Plasma Pfas Concentration Ratios From Adolescents In The Teen-Labs Study And Derivation Of Empirical And Mass Balance Models To Predict And Explain Liver Pfas Accumulationn, Brittney O Baumert, Fabian C Fischer, Flemming Nielsen, Philippe Grandjean, Scott Bartell, Nikos Stratakis, Douglas I Walker, Damaskini Valvi, Rohit Kohli, Thomas Inge, Justin Ryder, Todd Jenkins, Stephanie Sisley, Stavra Xanthakos, Sarah Rock, Michele A La Merrill, David Conti, Rob Mcconnell, Lida Chatzi

Faculty, Staff and Students Publications

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity, however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentrations ratios were perfectly explained (r2 > 0.99) in a multi-linear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this …

Clinical Characteristics Of Monkeypox Vaccine Injection Site Reactions: A Cohort Of Seven Patients, Anthony A. Gaspari

Department of Dermatology and Cutaneous Biology Faculty Papers

Background

Monkeypox (Mpox) infections are considered a public health emergency, prompting the need for the administration of a preventative vaccine to high-risk individuals.

Objectives

To describe the clinical course of dermatologic reactions to Mpox vaccine over time.

Methods

Seven recipients of the Mpox vaccine, administered via intradermal injection, were observed over time, and the dermatologic reactions to this vaccine were recorded.

Results

All seven recipients experienced mild to moderate localized reactions to Mpox vaccine to either the primary or booster injections. These reactions were characterized by erythema, induration and pruritus. These reactions eventually healed without any sustained reactions, eschar or …

Mathematical Modeling Of Radiotherapy: Impact Of Model Selection On Estimating Minimum Radiation Dose For Tumor Control, Achyudhan R Kutuva, Jimmy J Caudell, Kosj Yamoah, Heiko Enderling, Mohammad U Zahid

Faculty, Staff and Student Publications

INTRODUCTION: Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose.

METHODS: In this study, we evaluate the mathematical implications and biological effects of 2 …

Znf683 Marks A Cd8+ T Cell Population Associated With Anti-Tumor Immunity Following Anti-Pd-1 Therapy For Richter Syndrome, Erin M Parry, Camilla K Lemvigh, Stephanie Deng, Nathan Dangle, Neil Ruthen, Binyamin A Knisbacher, Julien Broséus, Sébastien Hergalant, Romain Guièze, Shuqiang Li, Wandi Zhang, Connor Johnson, Jaclyn M Long, Shanye Yin, Lillian Werner, Annabelle Anandappa, Noelia Purroy, Satyen Gohil, Giacomo Oliveira, Pavan Bachireddy, Sachet A Shukla, Teddy Huang, Joseph D Khoury, Beenu Thakral, Michael Dickinson, Constantine Tam, Kenneth J Livak, Gad Getz, Donna Neuberg, Pierre Feugier, Peter Kharchenko, William Wierda, Lars Rønn Olsen, Nitin Jain, Catherine J Wu

Faculty, Staff and Student Publications

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Faculty, Staff and Student Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …

Enzyme-Mediated Depletion Of Methylthioadenosine Restores T Cell Function In Mtap-Deficient Tumors And Reverses Immunotherapy Resistance, Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone

Faculty, Staff and Student Publications

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of …

Blood-Based Transcriptomic Biomarkers Are Predictive Of Neurodegeneration Rather Than Alzheimer's Disease, Artur Shvetcov, Shannon Thomson, Jessica Spathos, Ann-Na Cho, Heather M Wilkins, Shea J Andrews, Fabien Delerue, Timothy A Couttas, Jasmeen Kaur Issar, Finula Isik, Simranpreet Kaur, Eleanor Drummond, Carol Dobson-Stone, Shantel L Duffy, Natasha M Rogers, Daniel Catchpoole, Wendy A Gold, Russell H Swerdlow, David A Brown, Caitlin A Finney

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as …

Sox7-Positive Endothelial Progenitors Establish Coronary Arteries And Govern Ventricular Compaction, Ivy Kn Chiang, David Humphrey, Richard J Mills, Peter Kaltzis, Shikha Pachauri, Matthew Graus, Diptarka Saha, Zhijian Wu, Paul Young, Choon Boon Sim, Tara Davidson, Andres Hernandez-Garcia, Chad A Shaw, Alexander Renwick, Daryl A Scott, Enzo R Porrello, Emily S Wong, James E Hudson, Kristy Red-Horse, Gonzalo Del Monte-Nieto, Mathias Francois

Faculty, Staff and Students Publications

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, …

A Small De Novo Cnv Deletion Of The Paternal Copy Of Foxf1, Leaving Lncrna Fendrr Intact, Provides Insight Into Their Bidirectional Promoter Region, Przemyslaw Szafranski, Paweł Stankiewicz

Faculty, Staff and Students Publications

Pathogenic single-nucleotide variants (SNVs) and copy-number variant (CNV) deletions involving the FOXF1 transcription factor gene or CNV deletions of its distant lung-specific enhancer are responsible for alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a rarely diagnosed lethal lung developmental disorder in neonates. In contrast to SNVs within FOXF1 and CNV deletions involving only the FOXF1 enhancer, larger-sized deletions involving FOXF1 and the adjacent, oppositely oriented lncRNA gene FENDRR have additionally been associated with hypoplastic left heart syndrome and single umbilical artery (SUA). Here, in an ACDMPV infant without any congenital heart defect or SUA, we identified a small …

Influence Of Macrophages On Vascular Invasion Of Inflammatory Breast Cancer Emboli Measured Using An In Vitro Microfluidic Multi-Cellular Platform, Manasa Gadde, Melika Mehrabi-Dehdezi, Bisrat G Debeb, Wendy A Woodward, Marissa Nichole Rylander

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this …

The Neuroimmune Regulation And Potential Therapeutic Strategies Of Optic Pathway Glioma, Khushboo Irshad, Yu-Kai Huang, Paul Rodriguez, Jung Lo, Benjamin E Aghoghovwia, Yuan Pan, Kun-Che Chang

Faculty, Staff and Student Publications

Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration.

Early Season Monitoring Of Tarnished Plant Bug, Lygus Lineolaris, In Wild Hosts Using Pheromone Traps, Justin George, James P Glover, Gadi V P Reddy, Chris Johnson, David R Hall

Faculty, Staff and Student Publications

Simple Summary

The tarnished plant bug, Lygus lineolaris (Hemiptera: Miridae), is a polyphagous pest and causes severe economic damage to cotton crops. Managing the weedy field edges is important in preventing early-season infestations of L. lineolaris in cotton to prevent damage to the squares and other fruiting structures. Scouting fields for L. lineolaris is time- and labor-intensive, and end-user variability associated with field sampling can lead to inaccuracies. Insect traps that combine visual cues and pheromones are more accurate, sustainable, and economically feasible in contrast to traditional insect detection methods. In this study, we investigated the application of red or …

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Sunyoung S Lee, Zishuo Ian Hu, Eugene J Koay, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

Contact With Caregivers Is Associated With Composition Of The Infant Gastrointestinal Microbiome In The First 6 Months Of Life, Kyle S. Wiley, Andrew M. Gregg, Molly M. Fox, Venu Lagishetty, Curt A. Sandman, Jonathan P. Jacobs, Laura M. Glynn

Psychology Faculty Articles and Research

Objectives

Little is known about how physical contact at birth and early caregiving environments influence the colonization of the infant gastrointestinal microbiome. We investigated how infant contact with caregivers at birth and within the first 2 weeks of life relates to the composition of the gastrointestinal microbiome in a sample of U.S. infants (n = 60).

Methods

Skin-to-skin and physical contact with caregivers at birth and early caregiving environments were surveyed at 2 weeks postpartum. Stool samples were collected from infants at 2 weeks, 2, 6, and 12 months of age and underwent 16S rRNA sequencing as a proxy …

Super-Enhancer Hijacking Drives Ectopic Expression Of Hedgehog Pathway Ligands In Meningiomas, Mark W Youngblood, Zeynep Erson-Omay, Chang Li, Hinda Najem, Süleyman Coșkun, Evgeniya Tyrtova, Julio D Montejo, Danielle F Miyagishima, Tanyeri Barak, Sayoko Nishimura, Akdes Serin Harmancı, Victoria E Clark, Daniel Duran, Anita Huttner, Timuçin Avşar, Yasar Bayri, Johannes Schramm, Julien Boetto, Matthieu Peyre, Maximilien Riche, Roland Goldbrunner, Nduka Amankulor, Angeliki Louvi, Kaya Bilgüvar, M Necmettin Pamir, Koray Özduman, Türker Kilic, James R Knight, Matthias Simon, Craig Horbinski, Michel Kalamarides, Marco Timmer, Amy B Heimberger, Ketu Mishra-Gorur, Jennifer Moliterno, Katsuhito Yasuno, Murat Günel

Faculty, Staff and Students Publications

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin …

Extracellular Vesicles In Triple–Negative Breast Cancer: Immune Regulation, Biomarkers, And Immunotherapeutic Potential, Kaushik Das, Subhojit Paul, Arnab Ghosh, Saurabh Gupta, Tanmoy Mukherjee, Prem Shankar, Anshul Sharma, Shiva Keshava, Subhash C. Chauhan, Vivek Kumar Kashyap

School of Medicine Publications

Triple–negative breast cancer (TNBC) is an aggressive subtype accounting for ~10–20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile and limited targeted therapies, TNBC treatment poses significant challenges. Unlike other BC subtypes, TNBC lacks specific molecular targets, rendering endocrine therapies and HER2–targeted treatments ineffective. The chemotherapeutic regimen is the predominant systemic treatment modality for TNBC in current clinical practice. However, the efficacy of chemotherapy in TNBC is variable, with response rates varying between a wide range …