Digital Commons Network^™

Her3-Targeted Therapeutic Antibodies And Antibody–Drug Conjugates In Non-Small Cell Lung Cancer Refractory To Egfr-Tyrosine Kinase Inhibitors, Margaret E. Larsen, Hui Lyu, Bolin Liu

School of Medicine Faculty Publications

Human epidermal growth factor receptor 3 (HER3) is a unique member of the human epidermal growth factor receptor (HER/EGFR) family, since it has negligible kinase activity. Therefore, HER3 must interact with a kinase-proficient receptor to form a heterodimer, leading to the activation of signaling cascades. Overexpression of HER3 is observed in various human cancers, including non-small cell lung cancer (NSCLC), and correlates with poor clinical outcomes in patients. Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers. Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase …

Advances And Emerging Medical Applications Of Direct Mass Spectrometry Technologies For Tissue Analysis, Mary E King, Monica Lin, Meredith Spradlin, Livia S Eberlin

Faculty, Staff and Students Publications

Offering superb speed, chemical specificity, and analytical sensitivity, direct mass spectrometry (MS) technologies are highly amenable for the molecular analysis of complex tissues to aid in disease characterization and help identify new diagnostic, prognostic, and predictive markers. By enabling detection of clinically actionable molecular profiles from tissues and cells, direct MS technologies have the potential to guide treatment decisions and transform sample analysis within clinical workflows. In this review, we highlight recent health-related developments and applications of direct MS technologies that exhibit tangible potential to accelerate clinical research and disease diagnosis, including oncological and neurodegenerative diseases and microbial infections. We …

Targeting Brd4 In The Treatment Of Pleural Fibrosis, Joy Adewumi

Biotechnology Theses

Pleural fibrosis (PF) is a respiratory disorder that refers to the thickening and scarring of the pleura. Currently, there is a lack of pharmaceutic treatment options for PF. Pleural mesothelial to mesenchymal transition (MesoMT) is a critical process that contributes to the development of PF. Bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, has recently been implicated in a wide range of lung injuries. However, whether BRD4 is involved in regulating MesoMT and the development of PF remains unclear and was explored in this study. Primary human pleural mesothelial cells (HPMCs) were used to test the role of BRD4 …

Eganelisib, A First-In-Class Pi3kγ Inhibitor, In Patients With Advanced Solid Tumors: Results Of The Phase 1/1b Mario-1 Trial, David S Hong, Michael Postow, Bartosz Chmielowski, Ryan Sullivan, Amita Patnaik, Ezra E W Cohen, Geoffrey Shapiro, Conor Steuer, Martin Gutierrez, Heather Yeckes-Rodin, Robert Ilaria, Brenda O'Connell, Joanna Peng, Guangbin Peng, Nora Zizlsperger, Anthony Tolcher, Jedd D Wolchok

Faculty, Staff and Student Publications

Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.

Patients and methods: Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).

Results: …

Biological Mechanism Of Sex Difference In Stroke Manifestation And Outcomes, Wi-Sun Ryu, Jinyong Chung, Dawid Schellingerhout, Sang-Wuk Jeong, Hang-Rai Kim, Jung E Park, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Hong-Kyun Park, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Man Seok Park, Kang-Ho Choi, Juneyoung Lee, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Female patients tend to have greater disability and worse long-term outcomes after stroke than male patients. To date, the biological basis of sex difference in ischemic stroke remains unclear. We aimed to (1) assess sex differences in clinical manifestation and outcomes of acute ischemic stroke and (2) investigate whether the sex disparity is due to different infarct locations or different impacts of infarct in the same location.

METHODS: This MRI-based multicenter study included 6,464 consecutive patients with acute ischemic stroke (<7 >days) from 11 centers in South Korea (May 2011-January 2013). Multivariable statistical and brain mapping methods …

Application Of Natural Polysaccharides And Their Novel Dosage Forms In Gynecological Cancers: Therapeutic Implications From The Diversity Potential Of Natural Compounds, Yi Li, Chuanlong Zhang, Lu Feng, Qian Shen, Fudong Liu, Xiaochen Jiang, Bo Pang

Faculty, Staff and Student Publications

Cancer is one of the most lethal diseases. Globally, the number of cancers is nearly 10 million per year. Gynecological cancers (for instance, ovarian, cervical, and endometrial), relying on hidden diseases, misdiagnoses, and high recurrence rates, have seriously affected women's health. Traditional chemotherapy, hormone therapy, targeted therapy, and immunotherapy effectively improve the prognosis of gynecological cancer patients. However, with the emergence of adverse reactions and drug resistance, leading to the occurrence of complications and poor compliance of patients, we have to focus on the new treatment direction of gynecological cancers. Because of the potential effects of natural drugs in regulating …

Ngr1 Binding To Reovirus Reveals An Unusual Bivalent Interaction And A New Viral Attachment Protein, Danica M Sutherland, Michael Strebl, Melanie Koehler, Olivia L Welsh, Xinzhe Yu, Liya Hu, Rita Dos Santos Natividade, Jonathan J Knowlton, Gwen M Taylor, Rodolfo A Moreno, Patrick Wörz, Zachery R Lonergan, Pavithra Aravamudhan, Camila Guzman-Cardozo, Sukhleen Kour, Udai Bhan Pandey, David Alsteens, Zhao Wang, B V Venkataram Prasad, Thilo Stehle, Terence S Dermody

Faculty, Staff and Students Publications

Nogo-66 receptor 1 (NgR1) binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding to NgR1 and subsequent signaling can improve neuron outgrowth, making NgR1 an important therapeutic target for diverse neurological conditions such as spinal crush injuries and Alzheimer's disease. Human NgR1 serves as a receptor for mammalian orthoreovirus (reovirus), but the mechanism of virus-receptor engagement is unknown. To elucidate how NgR1 mediates cell binding and entry of reovirus, we defined the affinity of interaction between virus and receptor, determined the structure of the virus-receptor complex, and identified …

Neurocognitive Dysfunction With Neuronal Injury In People With Hiv On Long-Duration Antiretroviral Therapy, Cynthia Mcmahan, Devon K Dietrich, Elizabeth F Horne, Erin Kelly, Katrina Geannopoulos, Peter Selim Siyahhan Julnes, Lillian Ham, Ulisses Santamaria, Chuen-Yen Lau, Tianxia Wu, Hsing-Chuan Hsieh, Anuradha Ganesan, Catherine Berjohn, Suad Kapetanovic, Daniel S Reich, Govind Nair, Joseph Snow, Brian K Agan, Avindra Nath, Bryan R Smith

Staff and Researcher Publications

Background and objectives: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses.

Methods: Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was …

Clinical Significance And Biology Of Circulating Tumor Dna In High-Risk Early-Stage Her2-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy, Mark Jesus M Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L Hirst, Christina Yau, Denise M Wolf, Wen Li, Amy L Delson, Smita Asare, Minetta C Liu, Kathy Albain, A Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W Fraser Symmans, Douglas Yee, Nola M Hylton, Laura J Esserman, Angela M Demichele, Hope S Rugo, Laura J Van 'T Veer

Faculty, Staff and Student Publications

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival …

Single Cell Clonotypic And Transcriptional Evolution Of Multiple Myeloma Precursor Disease, Minghao Dang, Ruiping Wang, Hans C Lee, Krina K Patel, Melody R Becnel, Guangchun Han, Sheeba K Thomas, Dapeng Hao, Yanshuo Chu, Donna M Weber, Pei Lin, Zuzana Lutter-Berka, David A Berrios Nolasco, Mei Huang, Hima Bansal, Xingzhi Song, Jianhua Zhang, Andrew Futreal, Luz Yurany Moreno Rueda, David E Symer, Michael R Green, Cristhiam M Rojas Hernandez, Michael Kroll, Vahid Afshar-Khargan, Libere J Ndacayisaba, Peter Kuhn, Sattva S Neelapu, Robert Z Orlowski, Linghua Wang, Elisabet E Manasanch

Faculty, Staff and Student Publications

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of …

Tumor Microenvironment As A Therapeutic Target In Melanoma Treatment, Naji Kharouf, Thomas W. Flanagan, Sofie Yasmin Hassan, Hosam Shalaby, Marla Khabaz, Sarah Lilly Hassan, Mosaad Megahed, Youssef Haikel, Simeon Santourlidis, Mohamed Hassan

School of Graduate Studies Faculty Publications

The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic …

Paleoamerican Exploitation Of Extinct Megafauna Revealed Through Immunological Blood Residue And Microwear Analysis, North And South Carolina, Usa, Christopher R Moore, Larry R Kimball, Albert C Goodyear, Mark J Brooks, I Randolph Daniel, Allen West, Sean G Taylor, Kiersten J Weber, John L Fagan, Cam M Walker

Faculty, Staff and Student Publications

Previous immunological studies in the eastern USA have failed to establish a direct connection between Paleoamericans and extinct megafauna species. The lack of physical evidence for the presence of extinct megafauna begs the question, did early Paleoamericans regularly hunt or scavenge these animals, or were some megafauna already extinct? In this study of 120 Paleoamerican stone tools from across North and South Carolina, we investigate this question using crossover immunoelectrophoresis (CIEP). We find immunological support for the exploitation of extant and extinct megafauna, including Proboscidea, Equidae, and Bovidae (possibly Bison antiquus), on Clovis points and scrapers, as well as possible …

Mycobacterium Avium Subsp. Paratuberculosis Candidate Vaccine Strains Are Pro-Apoptotic In Raw264.7murinemacrophages, Raul G. Barletta, John P. Bannantine, Judith R. Stabel, Ezhumalai Muthukrishnan, Dirk Anderson, Enakshy Dutta, Vamsi Manthena, Mostafa Hanafy, Denise K. Zinniel

School of Veterinary and Biomedical Sciences: Faculty Publications

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne’s disease, a severe gastroenteritis of ruminants. This study developed a model cell culture system to rapidly screen MAP mutants with vaccine potential for apoptosis. Two wild-type strains, a transposon mutant, and two deletion mutant MAP strains (MOI of 10 with 1.2 × 10⁶ CFU) were tested in murine RAW 264.7 macrophages to determine if they induce apoptosis and/or necrosis. Both deletion mutants were previously shown to be attenuated and immunogenic in primary bovine macrophages. All strains had similar growth rates, but cell morphology indicated that both deletion mutants …

Whole Genome Analysis For 163 Grnas In Cas9-Edited Mice Reveals Minimal Off-Target Activity, Kevin A Peterson, Sam Khalouei, Nour Hanafi, Joshua A Wood, Denise G Lanza, Lauri G Lintott, Brandon J Willis, John R Seavitt, Robert E Braun, Mary E Dickinson, Jacqueline K White, K C Kent Lloyd, Jason D Heaney, Stephen A Murray, Arun Ramani, Lauryl M J Nutter

Faculty, Staff and Students Publications

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 …

Effects Of Interleukin-22 (Il-22) On Necroptosis, Inflammatory Responses, And Metabolism Of Mycobacterium Tuberculosis Stimulated Type 2 Diabetes Mellitus Mouse Macrophages, Bismark Owusu-Afriyie

Biotechnology Theses

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes nearly 1.3 million deaths per year. Limited information is available about the immune responses during Mtb infection in type 2 diabetic hosts. Our laboratory developed an experimentally induced type 2 diabetes (T2DM) model in wild-type C57BL/6 mice and found that IL-22 and type 3 innate lymphoid cells (ILC3s) reduce inflammation and mortality of Mtb-infected T2DM mice. Our laboratory also found that Mtb-infected alveolar macrophages (AMs) from T2DM mice undergo necroptosis compared to Mtb-infected AMs of non-T2DM mice. In the current study, we determined whether …

Viral Dna Accumulation Regulates Replication Efficiency Of Chlorovirus Osy-Ne5 In Two Closely Related Chlorella Variabilis Strains, Ahmed Esmael, Irina V. Agarkova, David D. Dunigan, You Zhou, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Many chloroviruses replicate in Chlorella variabilis algal strains that are ex-endosymbionts isolated from the protozoan Paramecium bursaria, including the NC64A and Syngen 2-3 strains. We noticed that indigenous water samples produced a higher number of plaque-forming viruses on C. variabilis Syngen 2-3 lawns than on C. variabilis NC64A lawns. These observed differences led to the discovery of viruses that replicate exclusively in Syngen 2-3 cells, named Only Syngen (OSy) viruses. Here, we demonstrate that OSy viruses initiate infection in the restricted host NC64A by synthesizing some early virus gene products and that approximately 20% of the cells produce a …

A Novel Bioactive Peptide, T14, Selectively Activates Mtorc1 Signalling: Therapeutic Implications For Neurodegeneration And Other Rapamycin-Sensitive Applications, Sanskar Ranglani, Anna Ashton, Kashif Mahfooz, Joanna Komorowska, Alexandru Graur, Nadine Kabbani, Sara Garcia-Rates, Susan Greenfield

Faculty, Staff and Student Publications

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer's disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer. T14 is a product of the longer 30mer-T30. Recent work shows that T30 drives neurite growth in the human SH-SY5Y cell line via the mTOR pathway. Here, we demonstrate that T30 induces an …

Repair Of Noise-Induced Damage To Stereocilia F-Actin Cores Is Facilitated By Xirp2 And Its Novel Mechanosensor Domain, Elizabeth L Wagner, Jun-Sub Im, Stefano Sala, Maura I Nakahata, Terence E Imbery, Sihan Li, Daniel Chen, Katherine Nimchuk, Yael Noy, David W Archer, Wenhao Xu, George Hashisaki, Karen B Avraham, Patrick W Oakes, Jung-Bum Shin

Faculty, Staff and Student Publications

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat …

The Axis Of Complement C1 And Nucleolus In Antinuclear Autoimmunity, Shan Wu, Junjie Chen, Boon Heng Dennis Teo, Seng Yin Kelly Wee, Ming Hui Millie Wong, Jianzhou Cui, Jinmiao Chen, Khai Pang Leong, Jinhua Lu

Faculty, Staff and Student Publications

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. …

Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of …

Bone Growth Induction In Mucopolysaccharidosis Iva Mouse, Estera Rintz, Angélica María Herreño-Pachón, Betul Celik, Fnu Nidhi, Shaukat Khan, Eliana Benincore-Flórez, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) enzyme, leading to the accumulation of glycosaminoglycans (GAG), keratan sulfate (KS) and chondroitin-6-sulfate (C6S), mainly in cartilage and bone. This lysosomal storage disorder (LSD) is characterized by severe systemic skeletal dysplasia. To this date, none of the treatment options for the MPS IVA patients correct bone pathology. Enzyme replacement therapy with elosulfase alpha provides a limited impact on bone growth and skeletal lesions in MPS IVA patients. To improve bone pathology, we propose a novel gene therapy with a small peptide as a growth-promoting …

Chronic Basal Forebrain Activation Improves Spatial Memory, Boosts Neurotrophin Receptor Expression, And Lowers Bace1 And Aβ42 Levels In The Cerebral Cortex In Mice, Jacob Kumro, Ashutosh Tripathi, Yun Lei, Jeremy Sword, Patrick Callahan, Alvin Terry, Xin-Yun Lu, Sergei A Kirov, Anilkumar Pillai, David T Blake

Faculty, Staff and Student Publications

The etiology of Alzheimer’s dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer’s model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2–3-fold increases in frontal cortex …

Early Postpartum Hba1c After Hyperglycemia First Detected In Pregnancy-Imperfect But Not Without Value, Ankia Coetzee, David R Hall, Mari Van De Vyver, Magda Conradie

Faculty, Staff and Student Publications

BACKGROUND: South African women of childbearing age are disproportionally affected by obesity and at significant risk of Type 2 Diabetes Mellitus (T2DM). Unless pregnant, they do not readily undergo screening for T2DM. With a local focus on improved antenatal care, hyperglycemia is often first detected in pregnancy (HFDP). This may erroneously be attributed to Gestational Diabetes Mellitus (GDM) in all without considering T2DM. Glucose evaluation following pregnancy is essential for early detection and management of women with T2DM in whom persistent hyperglycemia is to be expected. Conventional testing with an oral glucose tolerance test (OGTT) is cumbersome, prompting investigation for …

Genome-Wide Analyses Characterize Shared Heritability Among Cancers And Identify Novel Cancer Susceptibility Regions, Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, Breast Cancer Association Consortium (Bcac), Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, Colorectal Transdisciplinary Study (Corect), Colon Cancer Family Registry Study (Ccfr), Genetics And Epidemiology Of Colorectal Cancer Consortium (Gecco), Immaculata De Vivo, Tracy A O'Mara, Amanda B Spurdle, Ian Tomlinson, Endometrial Cancer Association Consortium (Ecac), Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David C Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, International Lung Cancer Consortium (Ilcco), D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, Ovarian Cancer Association Consortium (Ocac), Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, Pancreatic Cancer Cohort Consortium (Panscan), Alison Klein, Gloria Petersen, Harvey Risch, Pancreatic Cancer Case-Control Consortium (Panc4), The Practical Consortium, Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft

Faculty, Staff and Student Publications

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel …

Microcalcification Crystallography As A Potential Marker Of Dcis Recurrence, Sarah B Gosling, Emily L Arnold, Samantha K Davies, Hannah Cross, Ihssane Bouybayoune, Doriana Calabrese, Jayakrupakar Nallala, Sarah E Pinder, Liping Fu, Esther H Lips, Lorraine King, Jeffrey Marks, Allison Hall, Lars J Grimm, Thomas Lynch, Donna Pinto, Hilary Stobart, E Shelley Hwang, Jelle Wesseling, Kalotina Geraki, Nicholas Stone, Iain D Lyburn, Charlene Greenwood, Keith D Rogers, Grand Challenge Precision Consortium

Faculty, Staff and Student Publications

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite …

Identification Of Key Elements In Prostate Cancer For Ontology Building Via A Multidisciplinary Consensus Agreement, Amy Moreno, Abhishek A Solanki, Tianlin Xu, Ruitao Lin, Jatinder Palta, Emily Daugherty, David Hong, Julian Hong, Sophia C Kamran, Evangelia Katsoulakis, Kristy Brock, Mary Feng, Clifton Fuller, Charles Mayo

Faculty, Staff and Student Publications

BACKGROUND: Clinical data collection related to prostate cancer (PCa) care is often unstructured or heterogeneous among providers, resulting in a high risk for ambiguity in its meaning when sharing or analyzing data. Ontologies, which are shareable formal (i.e., computable) representations of knowledge, can address these challenges by enabling machine-readable semantic interoperability. The purpose of this study was to identify PCa-specific key data elements (KDEs) for standardization in clinic and research.

METHODS: A modified Delphi method using iterative online surveys was performed to report a consensus agreement on KDEs by a multidisciplinary panel of 39 PCa specialists. Data elements were divided …

Germline Genetic Variants And Pediatric Rhabdomyosarcoma Outcomes: A Report From The Children’S Oncology Group, Bailey A Martin-Giacalone, Melissa A Richard, Michael E Scheurer, Javed Khan, Pagna Sok, Priya B Shetty, Stephen J Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T Mcevoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J Lupo

Faculty, Staff and Student Publications

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.

METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical …

Decoding The Regulatory Roles Of Non-Coding Rnas In Cellular Metabolism And Disease, Yuru Zong, Xuliang Wang, Bing Cui, Xiaowei Xiong, Andrew Wu, Chunru Lin, Yaohua Zhang

Faculty, Staff and Student Publications

Non-coding RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms and takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. We also summarize the therapeutic advances for non-coding …

Plumbing Mysterious Rnas In “Dark Genome” For The Conquest Of Human Diseases, Lisa A Huang, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

Next-generation sequencing has revealed that less than 2% of transcribed genes are translated into proteins, with a large portion transcribed into noncoding RNAs (ncRNAs). Among these, long noncoding RNAs (lncRNAs) represent the largest group and are pervasively transcribed throughout the genome. Dysfunctions in lncRNAs have been found in various diseases, highlighting their potential as therapeutic, diagnostic, and prognostic targets. However, challenges, such as unknown molecular mechanisms and nonspecific immune responses, and issues of drug specificity and delivery present obstacles in translating lncRNAs into clinical applications. In this review, we summarize recent publications that have explored lncRNA functions in human diseases. …

Genome Editing For Cystic Fibrosis, Guoshun Wang

School of Medicine Faculty Publications

Cystic fibrosis (CF) is a monogenic recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator gene (CFTR). Remarkable progress in basic research has led to the discovery of highly effective CFTR modulators. Now ~90% of CF patients are treatable. However, these modulator therapies are not curative and do not cover the full spectrum of CFTR mutations. Thus, there is a continued need to develop a complete and durable therapy that can treat all CF patients once and for all. As CF is a genetic disease, the ultimate therapy would be in-situ repair of the genetic lesions in the …