Digital Commons Network^™

Safety And Efficacy Of Hsp90 Inhibitor Ganetespib For Neoadjuvant Treatment Of Stage Ii/Iii Breast Cancer, Julie E Lang, Andres Forero-Torres, Douglas Yee, Christina Yau, Denise Wolf, John Park, Barbara A Parker, A Jo Chien, Anne M Wallace, Rashmi Murthy, Kathy S Albain, Erin D Ellis, Heather Beckwith, Barbara B Haley, Anthony D Elias, Judy C Boughey, Rachel L Yung, Claudine Isaacs, Amy S Clark, Hyo S Han, Rita Nanda, Qamar J Khan, Kristen K Edmiston, Erica Stringer-Reasor, Elissa Price, Bonnie Joe, Minetta C Liu, Lamorna Brown-Swigart, Emanuel F Petricoin, Julia D Wulfkuhle, Meredith Buxton, Julia L Clennell, Ashish Sanil, Scott Berry, Smita M Asare, Amy Wilson, Gillian L Hirst, Ruby Singhrao, Adam L Asare, Jeffrey B Matthews, Michelle Melisko, Jane Perlmutter, Hope S Rugo, W Fraser Symmans, Laura J Van 'T Veer, Nola M Hylton, Angela M Demichele, Donald A Berry, Laura J Esserman

Faculty, Staff and Student Publications

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to …

Identifying Missing Is-A Relations In Orphanet Rare Disease Ontology, Maryamsadat Mohtashamian, Rashmie Abeysinghe, Xubing Hao, Licong Cui

Faculty, Staff and Student Publications

The Orphanet Rare Disease Ontology (ORDO) provides a structured vocabulary encapsulating rare diseases. Downstream applications of ORDO depend on its accuracy to effectively perform their tasks. In this paper, we implement an automated quality assurance pipeline to identify missing is-a relations in ORDO. We first obtain lexical features from concept names. Then we generate related and unrelated feature sharing concept-pairs, where a feature sharing concept-pair can further generate derived term-pairs. If an unrelated and related feature sharing concept-pair generate the same derived term-pair, then we suggest a potential missing is-a relation between the unrelated feature sharing concept-pair. Applying this approach …

Structural Variants Drive Context-Dependent Oncogene Activation In Cancer, Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C Akdemir, Selene Tyndale, P Andrew Futreal, Graham Mcvicker, Geoffrey M Wahl, Jesse R Dixon

Faculty, Staff and Student Publications

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific …

Pan-Cancer Landscape Of Aid-Related Mutations, Composite Mutations, And Their Potential Role In The Ici Response, Isaias Hernández-Verdin, Kadir C Akdemir, Daniele Ramazzotti, Giulio Caravagna, Karim Labreche, Karima Mokhtari, Khê Hoang-Xuan, Matthieu Peyre, Franck Bielle, Mehdi Touat, Ahmed Idbaih, Alex Duval, Marc Sanson, Agustí Alentorn

Faculty, Staff and Student Publications

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome, or targeted sequencing. AID mutations are present at pan-cancer level with higher frequency in hematological cancers and higher presence at transcriptionally active TAD domains. AID synergizes initial hotspot mutations by a second composite mutation. AID mutational load was found to be independently associated with …

Spinal Metastases And The Evolving Role Of Molecular Targeted Therapy, Chemotherapy, And Immunotherapy, Elena I Fomchenko, James C Bayley, Christopher Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved …

Germline Variants Associated With Toxicity To Immune Checkpoint Blockade, Stefan Groha, Sarah Abou Alaiwi, Wenxin Xu, Vivek Naranbhai, Amin H Nassar, Ziad Bakouny, Talal El Zarif, Renee Maria Saliby, Guihong Wan, Ahmad Rajeh, Elio Adib, Pier V Nuzzo, Andrew L Schmidt, Chris Labaki, Biagio Ricciuti, Joao Victor Alessi, David A Braun, Sachet A Shukla, Tanya E Keenan, Eliezer Van Allen, Mark M Awad, Michael Manos, Osama Rahma, Leyre Zubiri, Alexandra-Chloe Villani, Benjamin Fairfax, Christian Hammer, Zia Khan, Kerry Reynolds, Yevgeniy Semenov, Deborah Schrag, Kenneth L Kehl, Matthew L Freedman, Toni K Choueiri, Alexander Gusev

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

Mildly Dysplastic Oral Lesions With Optically-Detectable Abnormalities Share Genetic Similarities With Severely Dysplastic Lesions, David R Brenes, Allison J Nipper, Melody T Tan, Frederico O Gleber-Netto, Richard A Schwarz, Curtis R Pickering, Michelle D Williams, Nadarajah Vigneswaran, Ann M Gillenwater, Andrew G Sikora, Rebecca R Richards-Kortum

Faculty, Staff and Student Publications

OBJECTIVE: Optical imaging studies of oral premalignant lesions have shown that optical markers, including loss of autofluorescence and altered morphology of epithelial cell nuclei, are predictive of high-grade pathology. While these optical markers are consistently positive in lesions with moderate/severe dysplasia or cancer, they are positive only in a subset of lesions with mild dysplasia. This study compared the gene expression profiles of lesions with mild dysplasia (stratified by optical marker status) to lesions with severe dysplasia and without dysplasia.

MATERIALS AND METHODS: Forty oral lesions imaged in patients undergoing oral surgery were analyzed: nine without dysplasia, nine with severe …

Learning From The Past: A Century Of Accuracy, Aspirations, And Aspersions In Brachytherapy, Christopher S Melhus, Samantha J Simiele, Manik Aima, Susan Richardson

Faculty, Staff and Student Publications

The oldest form of radiation therapy, brachytherapy, has been investigated and reported in the scientific and medical literature for well over a century. Known by many names over the years, radium-based, empirical practices evolved over decades to contemporary practice. This includes treatment at various dose rates using multiple radionuclides or even electrically generated photon sources. Predictions or prognostications of what may happen in the future enjoy a history that spans centuries, e.g. those by Nostradamus in the 1500s. In this review article, publications from several eras of past practice between the early 1900s and the late 2010s where the authors …

Biobehavioral Factors Predict An Exosome Biomarker Of Ovarian Carcinoma Disease Progression, Susan K Lutgendorf, Premal H Thaker, Michael J Goodheart, Jesusa M G Arevalo, Mamur A Chowdhury, Alyssa E Noble, Laila Dahmoush, George M Slavich, Frank J Penedo, Anil K Sood, Steven W Cole

Faculty, Staff and Student Publications

BACKGROUND: Biobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors.

METHODS: Exosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were …

Distinct Germline Genetic Susceptibility Profiles Identified For Common Non-Hodgkin Lymphoma Subtypes, Sonja I Berndt, Joseph Vijai, Yolanda Benavente, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Karin E Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F Skibola, Lindsay M Morton, Angela R Brooks-Wilson, Lauren R Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C Anderson, Stephen M Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M Birmann, Paolo Boffetta, Paige M Bracci, Paul Brennan, Elizabeth E Brown, Laurie Burdett, Lisa A Cannon-Albright, Ellen T Chang, Brian C H Chiu, Charles C Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V Conti, David G Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W Ryan Diver, Ahmet Dogan, Christopher K Edlund, Lenka Foretova, Joseph F Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M Habermann, Christopher A Haiman, Corinne Haioun, Jonathan N Hofmann, Theodore R Holford, Elizabeth A Holly, Amy Hutchinson, Aalin Izhar, Rebecca D Jackson, Ruth F Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K Link, Corrado Magnani, Marc Maynadie, James Mckay, Mads Melbye, Lucia Miligi, Roger L Milne, Thierry J Molina, Alain Monnereau, Rebecca Montalvan, Kari E North, Anne J Novak, Kenan Onel, Mark P Purdue, Kristin A Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W Sborov, Richard K Severson, Tait D Shanafelt, Martyn T Smith, Alexandra Smith, Kevin W Song, Lei Song, Melissa C Southey, John J Spinelli, Anthony Staines, Deborah Stephens, Heather J Sutherland, Kaitlyn Tkachuk, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Ruth C Travis, Jenny Turner, Celine M Vachon, Claire M Vajdic, Anke Van Den Berg, David J Van Den Berg, Roel C H Vermeulen, Paolo Vineis, Sophia S Wang, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R Cerhan, Stephen J Chanock, Susan L Slager, Nathaniel Rothman

Faculty, Staff and Student Publications

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9,505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P<5 >× 10−8) for subsets of NHL subtypes, …

Soy Isoflavones Decrease Fibroglandular Breast Tissue Measured By Magnetic Resonance Imaging In Premenopausal Women: A 2-Year Randomized Double-Blind Placebo Controlled Clinical Trial, Lee-Jane W Lu, Nai-Wei Chen, Donald G Brunder, Fatima Nayeem, Manubai Nagamani, Thomas K Nishino, Karl E Anderson, Tuenchit Khamapirad

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast cancer, but the mechanisms are unclear. We tested the hypothesis that soy isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer.

METHODS: Premenopausal women (age 30-42 years) were randomized to consume isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5 days per week up to 2 years, and changes in breast composition measured by magnetic resonance imaging at baseline and yearly intervals were compared after square root transformation using linear …

Targeted Ablation Of Fn14 Receptor Improves Exercise Capacity And Inhibits Neurogenic Muscle Atrophy, Meiricris Tomaz Da Silva, Aniket S Joshi, Tatiana E Koike, Anirban Roy, Kavya Mathukumalli, Danesh H Sopariwala, Vihang A Narkar, Ashok Kumar

Faculty, Staff and Student Publications

Skeletal muscle atrophy is a prevalent complication in multiple chronic diseases and disuse conditions. Fibroblast growth factor-inducible 14 (Fn14) is a member of the TNF receptor superfamily and a bona fide receptor of the TWEAK cytokine. Accumulating evidence suggests that Fn14 levels are increased in catabolic conditions as well as during exercise. However, the role of Fn14 in the regulation of skeletal muscle mass and function remains poorly understood. In this study, through the generation of novel skeletal muscle-specific Fn14-knockout mice, we have investigated the muscle role of Fn14 in the regulation of exercise capacity and denervation-induced muscle atrophy. Our …

Uncloaking Cell-Impermeant Gold Nanorods Via Tumor Microenvironmental Cathepsin B Facilitates Cancer Cell Penetration And Potent Radiosensitization, Subhiksha Raghuram, Yuri Mackeyev, Jessica Symons, Yasmin Zahra, Valeria Gonzalez, Krishnan K Mahadevan, Katherinne I Requejo, Anton Liopo, Paul Derry, Eugene Zubarev, Onur Sahin, Joseph Byung-Kyu Kim, Pankaj K Singh, Sang Hyun Cho, Sunil Krishnan

Faculty, Staff and Student Publications

Major impediments to conveyance of intravenously administered drugs to tumors are biofouling, opsonization, and rapid clearance from the circulation by macrophages and reticuloendothelial phagocytes. Cloaking nanoparticles with stealth epilayers partly overcomes these hurdles but it also foils interactions with tumor cells. Here, we describe the synthesis, characterization, and validation of smart gold nanorods (GNRs) that spontaneously transform from inert passengers in the blood stream to active cell-penetrating nanoparticles within tumors to potently sensitize tumors to radiation therapy. Intrinsically cationic and cell-penetrating GNRs were shielded from phagocytosis with a cloaking polyethylene glycol epilayer containing an intervening cleavable peptide. In the absence …

Randomization, Design And Analysis For Interdependency In Aging Research: No Person Or Mouse Is An Island, Daniella E Chusyd, Steven N Austad, Stephanie L Dickinson, Keisuke Ejima, Gary L Gadbury, Lilian Golzarri-Arroyo, Richard J Holden, Yasaman Jamshidi-Naeini, Doug Landsittel, Tapan Mehta, J Michael Oakes, Arthur H Owora, Greg Pavela, Javier Rojo, Michael W Sandel, Daniel L Smith, Colby J Vorland, Pengcheng Xun, Roger Zoh, David B Allison

Children’s Nutrition Research Center Staff Publications

Investigators traditionally use randomized designs and corresponding analysis procedures to make causal inferences about the effects of interventions, assuming independence between an individual's outcome and treatment assignment and the outcomes of other individuals in the study. Often, such independence may not hold. We provide examples of interdependency in model organism studies and human trials and group effects in aging research and then discuss methodologic issues and solutions. We group methodologic issues as they pertain to (1) single-stage individually randomized trials; (2) cluster-randomized controlled trials; (3) pseudo-cluster-randomized trials; (4) individually randomized group treatment; and (5) two-stage randomized designs. Although we present …

Clinical And Demographic Factors Contributing To Asparaginase-Associated Toxicities In Children With Acute Lymphoblastic Leukemia, Priyadarshani Dharia, Michael D Swartz, M Brooke Bernhardt, Han Chen, M Monica Gramatges, Philip J Lupo, Austin L Brown, Michael E Scheurer

Center for Medical Ethics and Health Policy Staff Publications

A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age >10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; …

Social Networks, High-Risk Anal Hpv And Coinfection With Hiv In Young Sexual Minority Men, Kayo Fujimoto, Alan G Nyitray, Jacky Kuo, Jing Zhao, Lu-Yu Hwang, Elizabeth Chiao, Anna R Giuliano, John A Schneider, Aditya Khanna

Faculty, Staff and Student Publications

OBJECTIVES: Young sexual minority men (SMM) exhibit a high prevalence and incidence of high-risk genotypes of human papillomavirus (hrHPV) anal infections and a confluence of a high prevalence of HIV and rectal STIs. Social determinants of health (SDOHs) are linked to social network contexts that generate and maintain racial disparities in HIV and STIs. A network perspective was provided to advance our knowledge of drivers of genotype-specific hrHPV infection and coinfection with HIV. The study also examined whether socially connected men are infected with the same high-risk HPV genotypes and, if so, whether this tendency is conditioned on coinfection with …

Understanding And Targeting The Immunosuppressive Tumor Microenvironment, Li Cai, Li Cai

Dissertations and Theses (Open Access)

Immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, have shown impressive antitumor efficacy by improving the activity of T cells. While these inhibitors work in many patients with various cancer types, they have minimal or no effect in many more patients. Mounting evidence indicates that, besides current known immune checkpoints, other immunosuppressive components in the tumor microenvironment (TME) need to be targeted to elicit the full immune responses.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive myeloid cells that are involved in cancer progression and therapeutic resistance. In this work, we demonstrated the essential role of MDSCs …

Redox Sensing By Yeast Hsp70 Facilitates Modulation Of Protein Quality Control And The Cytoprotective Response, Alec Santiago

Dissertations and Theses (Open Access)

Neurodegenerative disease affects millions of Americans every year, through diagnoses such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. One factor linked to formation of these aggregates is damage sustained to proteins by oxidative stress. Cellular protein homeostasis (proteostasis) relies on the ubiquitous Hsp70 chaperone family. Hsp70 activity has been previously shown to be modulated by modification of two key cysteines in the ATPase domain by oxidizing or thiol-modifying compounds. To investigate the biological consequences of cysteine modification on the Hsp70 Ssa1 in budding yeast, I generated cysteine null (cysteine to serine) and oxidomimetic (cysteine to aspartic acid) mutant variants of both …

The Adar-Mavs Pathway Is A Critical Mediator Of The Innate Immune System In Pancreatic Development And Cancer, Dhwani Rupani

Dissertations and Theses (Open Access)

Adenosine deaminase acting on RNA (ADAR) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing is an important post-transcriptional mechanism to prevent recognition of endogenous RNA by MDA5, a cytosolic RNA sensor. Activation of MDA5 by viral RNA can stimulate the innate immune system. Thus, ADAR-mediated RNA editing is crucial to distinguish “self” from “non-self”. ADAR has an important role in gene regulation as A-to-I editing alters RNA processing affecting both RNA and protein abundance. Given its importance in regulating innate immunity and transcript abundance, aberrations in Adar expression are implicated in developmental deformities and carcinogenesis. …

Bayesian Adaptive Clinical Trial Design, Mengyi Lu

Dissertations and Theses (Open Access)

The landscape of drug development in oncology has changed from conventional chemotherapies to molecular targeted therapies and immunotherapies, which provide innovative therapeutic modalities for treating cancers. These novel therapeutic agents work through mechanisms that fundamentally differ from standard chemotherapeutic agents, making the conventional trial design paradigm inefficient and dysfunctional. Specifically, the focus of dose-finding trials has shifted from finding the maximum tolerated dose (MTD) to the optimal biological dose (OBD), defined as the dose that optimizes the risk–benefit tradeoff. How to accurately identify the OBD and its dosing schedule is of great importance to maximize efficacy and safety of targeted …

Risk-Factor Induced Changes In The Breast Microenvironment Facilitate Inflammatory Breast Cancer Progression And Lymphovascular Invasion, Wintana Balema, Wintana Balema

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) is a rapidly progressing, rare and highly lethal form of breast cancer. IBC is a clinical diagnosis, requiring >1/3 involvement on the affected breast and/or skin by erythema, and disease onset of < 6 months. The clinical symptoms of IBC vary in severity and presentation, these include redness, warmth, skin thickening and bruised or pink/purple discoloration appearance and skin changes such as peau d’orange. These skin symptoms are not attributed to inflammation, rather IBC is characterized by florid lymphovascular tumor emboli clogging dermal lymphatics. This leads to “classic” symptoms of breast swelling and skin edema or discoloration. To date, unique genomic drivers which differentiate IBC from non-IBC invasive breast cancers have not been identified highlighting a role for the microenvironment. Several epidemiological studies have unveiled subtype-specific risk factors associated with IBC that are known to alter the microenvironment. Obesity is an established risk factor for all subtypes of IBC. Never-breastfeeding increases risk for developing the most aggressive, triple-negative IBC. Further, never breastfeeding is associated with later clinical stage and worse outcomes. We worked to model these overlapping risk factors to understand microenvironment changes that may lead to the lymphatic change’s indicative of IBC.

First, we investigated the association of a “classic” triad of clinical IBC signs with overall survival among patients to demonstrate the most overt clinical findings of lymphatic involvement were impacting prognosis. We evaluated a triad of IBC signs, including swollen involved breast, nipple change, and diffuse skin change, using breast medical photographs from patients enrolled on a prospective IBC registry. We reported that the …

Genetic Analysis Of Rna Exosome Complex Cofactors, Luisa Orlando

Dissertations and Theses (Open Access)

The RNA exosome complex is known to process and/or degrade many classes of RNA, including mRNA, rRNA, tRNA and snRNA, through its 3’-to-5’ exoribonuclease catalytic activity. The RNA exosome complex comprises a 9-unit core (exo-9), with six proteins making up a PH-Ring barrel and three proteins making up a S1-KH cap. The RNA exosome complex exo-9 core is inactive by itself and requires different cofactors in the nucleus and cytoplasm to perform different localized functions. This exo-9 core can associate with one or two catalytic subunits, including Rrp44/Dis3 and Rrp6 in yeast and DIS3 or DIS3L and RRP6/EXOSC10 in humans. …

Concomitant Inhibition Of Flt3 And Mcl-1 In Flt3 Mutated Acute Myeloid Leukemia, Paul Panis

Dissertations and Theses (Open Access)

The MCL-1 inhibitor S63845 synergizes with the FLT3 inhibitor midostaurin for potent anti-leukemic effect in preclinical human models of FLT3-ITD mutated acute myeloid leukemia (AML). Acute Myeloid leukemia (AML) is a neoplastic blood disorder defined by a characteristically rapid growth rate and altered behavior of myeloid cells in the bone marrow. The FLT3 receptor is responsible for the upstream regulation of many key processes in hematopoietic cells. FLT3 internal tandem duplication (ITD) mutations are common in leukemia and have been observed in up to a third of newly diagnosed AML patients. FLT3-ITD have been implicated as a driver mutation partly …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations and Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

Innate Lymphoid Cells In Depression: Current Status And Perspectives, Amit Kumar Madeshiya, Anilkumar Pillai

Faculty, Staff and Student Publications

The recent discovery of innate lymphoid cells (ILCs) has provided new insights into our understanding of the pathogenesis of many disease conditions with immune dysregulation. Type 1 innate lymphoid cells (ILC1s) induce type I immunity and are characterized by the expression of signature cytokine IFN-γ and the master transcription factor T-bet; ILC2s stimulate type II immune responses and are defined by the expression of signature cytokines IL-5 and IL-13, and transcription factors ROR-α and GATA3; ILC3s requires the transcription factor RORγt and produce IL-22 and IL-17. ILCs are largely tissue-resident and are enriched at barrier surfaces of the mammalian body. …

Clinical And Patient-Reported Outcomes After Recession Coverage Using Modified Vestibular Incision Subperiosteal Tunnel Access With A Volume-Stable Collagen Matrix As Compared To A Coronally Advanced Flap With A Subepithelial Connective Tissue Graft, Chun-Teh Lee, Marlena Lange, Alain Jureidini, Nurit Bittner, Ulrike Schulze-Späte

Faculty, Staff and Student Publications

Purpose: Coronally advanced split-or full-thickness (CAST or CAFT) flaps in combination with subepithelial connective tissue grafts (SCTGs) are commonly used in root-coverage procedures despite postoperative pain and bleeding from the graft donor site. Therefore, the modified vestibular incision subperiosteal tunnel access procedure (VISTAX) uses a novel collagen matrix (VCMX) instead of autogenous tissue to address the limitations associated with autogenous tissue grafting. This retrospective study compared the clinical outcomes of VISTAX to the results obtained after using a CAST or CAFT flap in combination with SCTG for root coverage.

Methods: Patients with single or multiple adjacent recession I/II defects were …

Genetic Diversity Fuels Gene Discovery For Tobacco And Alcohol Use, Gretchen R B Saunders, Xingyan Wang, Fang Chen, Seon-Kyeong Jang, Mengzhen Liu, Chen Wang, Shuang Gao, Yu Jiang, Chachrit Khunsriraksakul, Jacqueline M Otto, Clifton Addison, Masato Akiyama, Christine M Albert, Fazil Aliev, Alvaro Alonso, Donna K Arnett, Allison E Ashley-Koch, Aneel A Ashrani, Kathleen C Barnes, R Graham Barr, Traci M Bartz, Diane M Becker, Lawrence F Bielak, Emelia J Benjamin, Joshua C Bis, Gyda Bjornsdottir, John Blangero, Eugene R Bleecker, Jason D Boardman, Eric Boerwinkle, Dorret I Boomsma, Meher Preethi Boorgula, Donald W Bowden, Jennifer A Brody, Brian E Cade, Daniel I Chasman, Sameer Chavan, Yii-Der Ida Chen, Zhengming Chen, Iona Cheng, Michael H Cho, Hélène Choquet, John W Cole, Marilyn C Cornelis, Francesco Cucca, Joanne E Curran, Mariza De Andrade, Danielle M Dick, Anna R Docherty, Ravindranath Duggirala, Charles B Eaton, Marissa A Ehringer, Tõnu Esko, Jessica D Faul, Lilian Fernandes Silva, Edoardo Fiorillo, Myriam Fornage, Barry I Freedman, Maiken E Gabrielsen, Melanie E Garrett, Sina A Gharib, Christian Gieger, Nathan Gillespie, David C Glahn, Scott D Gordon, Charles C Gu, Dongfeng Gu, Daniel F Gudbjartsson, Xiuqing Guo, Jeffrey Haessler, Michael E Hall, Toomas Haller, Kathleen Mullan Harris, Jiang He, Pamela Herd, John K Hewitt, Ian Hickie, Bertha Hidalgo, John E Hokanson, Christian Hopfer, Joukejan Hottenga, Lifang Hou, Hongyan Huang, Yi-Jen Hung, David J Hunter, Kristian Hveem, Shih-Jen Hwang, Chii-Min Hwu, William Iacono, Marguerite R Irvin, Yon Ho Jee, Eric O Johnson, Yoonjung Y Joo, Eric Jorgenson, Anne E Justice, Yoichiro Kamatani, Robert C Kaplan, Jaakko Kaprio, Sharon L R Kardia, Matthew C Keller, Tanika N Kelly, Charles Kooperberg, Tellervo Korhonen, Peter Kraft, Kenneth Krauter, Johanna Kuusisto, Markku Laakso, Jessica Lasky-Su, Wen-Jane Lee, James J Lee, Daniel Levy, Liming Li, Kevin Li, Yuqing Li, Kuang Lin, Penelope A Lind, Chunyu Liu, Donald M Lloyd-Jones, Sharon M Lutz, Jiantao Ma, Reedik Mägi, Ani Manichaikul, Nicholas G Martin, Ravi Mathur, Nana Matoba, Patrick F Mcardle, Matt Mcgue, Matthew B Mcqueen, Sarah E Medland, Andres Metspalu, Deborah A Meyers, Iona Y Millwood, Braxton D Mitchell, Karen L Mohlke, Matthew Moll, May E Montasser, Alanna C Morrison, Antonella Mulas, Jonas B Nielsen, Kari E North, Elizabeth C Oelsner, Yukinori Okada, Valeria Orrù, Nicholette D Palmer, Teemu Palviainen, Anita Pandit, S Lani Park, Ulrike Peters, Annette Peters, Patricia A Peyser, Tinca J C Polderman, Nicholas Rafaels, Susan Redline, Robert M Reed, Alex P Reiner, John P Rice, Stephen S Rich, Nicole E Richmond, Carol Roan, Jerome I Rotter, Michael N Rueschman, Valgerdur Runarsdottir, Nancy L Saccone, David A Schwartz, Aladdin H Shadyab, Jingchunzi Shi, Suyash S Shringarpure, Kamil Sicinski, Anne Heidi Skogholt, Jennifer A Smith, Nicholas L Smith, Nona Sotoodehnia, Michael C Stallings, Hreinn Stefansson, Kari Stefansson, Jerry A Stitzel, Xiao Sun, Moin Syed, Ruth Tal-Singer, Amy E Taylor, Kent D Taylor, Marilyn J Telen, Khanh K Thai, Hemant Tiwari, Constance Turman, Thorarinn Tyrfingsson, Tamara L Wall, Robin G Walters, David R Weir, Scott T Weiss, Wendy B White, John B Whitfield, Kerri L Wiggins, Gonneke Willemsen, Cristen J Willer, Bendik S Winsvold, Huichun Xu, Lisa R Yanek, Jie Yin, Kristin L Young, Kendra A Young, Bing Yu, Wei Zhao, Wei Zhou, Sebastian Zöllner, Luisa Zuccolo, 23andme Research Team, Biobank Japan Project, Chiara Batini, Andrew W Bergen, Laura J Bierut, Sean P David, Sarah A Gagliano Taliun, Dana B Hancock, Bibo Jiang, Marcus R Munafò, Thorgeir E Thorgeirsson, Dajiang J Liu, Scott Vrieze

Faculty, Staff and Student Publications

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power …

Leveraging Pleiotropy To Discover And Interpret Gwas Results For Sleep-Associated Traits, Sung Chun, Sebastian Akle, Athanasios Teodosiadis, Brian E Cade, Heming Wang, Tamar Sofer, Daniel S Evans, Katie L Stone, Sina A Gharib, Sutapa Mukherjee, Lyle J Palmer, David Hillman, Jerome I Rotter, Craig L Hanis, John A Stamatoyannopoulos, Susan Redline, Chris Cotsapas, Shamil R Sunyaev

Faculty, Staff and Student Publications

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations …

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

Reorganization Of The Functional Connectome From Rest To A Visual Perception Task In Schizophrenia And Bipolar Disorder, Philipp Riedel, Junghee Lee, Christopher G Watson, Amy M Jimenez, Eric A Reavis, Michael F Green

Faculty, Staff and Student Publications

Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited …