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1. Non-Invasive microRNA Profiling in Saliva can Serve as a Biomarker of Alcohol Exposure and Its Effects in Humans

Author

Edward A. Mead, Nadia Boulghassoul-Pietrzykowska, Yongping Wang, Onaiza Anees, Noah S. Kinstlinger, Maximillian Lee, Shireen Hamza, Yaping Feng, and Andrzej Z. Pietrzykowski

Subjects
abuse, alcohol, array, microRNA, profiling, saliva, Genetics, QH426-470
Abstract

Alcohol Use Disorder (AUD) is one of the most prevalent mental disorders worldwide. Considering the widespread occurrence of AUD, a reliable, cheap, non-invasive biomarker of alcohol consumption is desired by healthcare providers, clinicians, researchers, public health and criminal justice officials. microRNAs could serve as such biomarkers. They are easily detectable in saliva, which can be sampled from individuals in a non-invasive manner. Moreover, microRNAs expression is dynamically regulated by environmental factors, including alcohol. Since excessive alcohol consumption is a hallmark of alcohol abuse, we have profiled microRNA expression in the saliva of chronic, heavy alcohol abusers using microRNA microarrays. We observed significant changes in salivary microRNA expression caused by excessive alcohol consumption. These changes fell into three categories: downregulated microRNAs, upregulated microRNAs, and microRNAs upregulated de novo. Analysis of these combinatorial changes in microRNA expression suggests dysregulation of specific biological pathways leading to impairment of the immune system and development of several types of epithelial cancer. Moreover, some of the altered microRNAs are also modulators of inflammation, suggesting their contribution to pro-inflammatory mechanisms of alcohol actions. Establishment of the cellular source of microRNAs in saliva corroborated these results. We determined that most of the microRNAs in saliva come from two types of cells: leukocytes involved in immune responses and inflammation, and buccal cells, involved in development of epithelial, oral cancers. In summary, we propose that microRNA profiling in saliva can be a useful, non-invasive biomarker allowing the monitoring of alcohol abuse, as well as alcohol-related inflammation and early detection of cancer.

Published
2022
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2. Gangrene of the Foot After Coronary Artery Bypass Graft Surgery

Author

Julia L Boland, Kristine Cueva, Jessica Pawly, Darius Shahbazi, Maximillian Lee, and Shahin Shahbazi

Subjects
Gangrene, Male, Intra-Aortic Balloon Pumping, Treatment Outcome, Myocardial Infarction, Humans, cardiovascular diseases, Constriction, Pathologic, Case Reports, General Medicine, Coronary Artery Bypass, Aged
Abstract

Coronary artery bypass grafting (CABG) is the most common surgery performed by cardiothoracic surgeons worldwide. Risks of CABG include neurological outcomes, deep vein thrombosis, renal or gastrointestinal injury, and death. Perioperatively, some patients may need intra-aortic balloon pump (IABP) use to help assist with cardiac function. In this case, a 75-year-old man presented with multivessel myocardial infarction requiring IABP for cardiac assistance prior to undergoing CABG. Eighteen days after his CABG, his toes turned black at home. A CT angiogram showed aortic atherosclerosis, right tibioperoneal trunk stenosis, mild atherosclerotic right proximal anterior tibial artery stenosis, and multifocal occlusive lesions in the right and left infrapopliteal vessels. Vascular surgery performed balloon angioplasty of the right anterior tibial artery and podiatry performed a transmetatarsal amputation of the dry gangrene. The aim of this case report is to present a rare complication of CABG with peri-operative IABP use and to highlight the need for prompt diagnosis and treatment of dry gangrene.

Published
2022
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4. Cardiovascular Toxicity of Androgen Deprivation Therapy

Author

William Choi, Jianqing Lin, Maximillian Lee, and Julia Boland

Subjects
Male, Oncology, Agonist, endocrine system, medicine.medical_specialty, Cardio-Oncology (TG Neilan, Section Editor), medicine.drug_class, Myocardial Infarction, Disease, Androgen deprivation therapy, Coronary artery disease, Gonadotropin-Releasing Hormone, Prostate cancer, Cardiovascular toxicity, Internal medicine, GnRH antagonist, medicine, Humans, Adverse effect, Stroke, business.industry, Prostatic Neoplasms, Androgen Antagonists, medicine.disease, Clinical trial, Cardio-oncology, Cardiovascular Diseases, Androgens, Cardiology and Cardiovascular Medicine, business, hormones, hormone substitutes, and hormone antagonists
Abstract

Purpose of Review Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer (PC). ADT, particularly with GnRH agonists, leads to increased risk of cardiovascular disease, including myocardial infarction, hypertension, and stroke. This review discusses the options of ADT, the mechanism of ADT-associated cardiovascular side effects, and potential benefit by using GnRH antagonists. Recent Findings GnRH antagonists have relatively less cardiovascular adverse effects compared to GnRH agonists. We highlight on a recently published phase III clinical trial on the oral GnRH antagonist, relugolix, and its comparative benefit to traditional GnRH agonist regarding development of cardiovascular disease. Summary Recent data reinforces that GnRH antagonists have a more favorable cardiovascular outcomes compared to GnRH agonists yet maintain a similar efficacy profile. From the data we reviewed, GnRH antagonists may be the preferred method of ADT for PC, but further data with primary cardiovascular outcomes are warranted.

Published
2021
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6. Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing

Author

Edward S. Boyden, Elizabeth A. Chavez, Steven S.S. Poon, Robby Becker, Wendy Greenwood, M Jafar Taghiyar, Peter Eirew, Maximillian Lee, Carl L. Hansen, Hans Zahn, Sohrab P. Shah, Mohammad Al Sa’d, Jonas Windager, Maia A. Smith, Lauren Martin, Hsuan Lee, Matt Wiens, So Ra Lee, A. Dariush, Oleg Golovko, Fergus Cafferty, Sorhab Shah, Russell Kunes, Owen Harris, Nick Chornay, Jean Fan, Samuel Aparicio, Marco A. Marra, Shankar Balasubramanian, Stephen Chia, Andrew McPherson, Farhia Kabeer, Samantha Leung, Sophia A Wild, Neil Millar, Claire Mulvey, Shahar Alon, Giorgia Battistoni, Leonardo Sepulveda Duran, Anubhav Sinha, Khanh N. Dinh, Viktoria Bojilova, Yi Cui, Nafis Abrar, Sophia Chan, Yussanne Ma, Austin Smith, Marcel Burger, Jean Hausser, Eduardo Gonzales Solares, Maurizio Callari, Bernd Bodenmiller, Dario Bressan, Aybuke Kupcu Yoldas, Tehmina Masud, Adi Steif, Colin Mar, Abigail Shea, Gregory J. Hannon, Yangguang Li, Timothy M. Chan, Christian Steidl, Cydney B. Nielsen, Flaminia Grimaldi, Eyal Fisher, Daniel J. Da Costa, Tatjana Kovacevic, Carlos Gonzalez-Fernandez, Beixi Wang, Spencer Watson, Sandra Tietscher, Teresa Ruiz, Ignacio Vázquez-García, Jessica Ngo, Amauche Emenari, Pu Zheng, Kirsty Sawicka, Carlos Caldas, Asmamaw T Wassie, Daniel Lai, Chenglong Xia, Oscar M. Rueda, Robin J.N. Coope, Andrew J. Mungall, Fiona Nugent, Marta Paez Ribes, Karen A. Gelmon, Stephen Pleasance, Simon Tavaré, Pascale Walters, Teresa Ruiz de Algara, Ciara H. O'Flanagan, Curtis Huebner, Emma Laks, T. Michael Underhill, Jazmine Brimhall, Alastair Marti, Justina Biele, R. Wilder Scott, Diljot Grewal, Fatime Qosaj, Richard D. Moore, Dan Goodwin, Laura Kuett, Nicolas A. Walton, Suvi Harris, Emmanouil D. Karagiannis, Cristina Jauset, Elena Williams, Isabella Pearsall, Sara Vogl, Alejandra Bruna, Yaniv Lubling, Jerome Ting, Ian G. Cannell, Xiaowei Zhuang, Richard Corbett, Hannah Casbolt, Giulia Lerda, Johanna A. Joyce, and Spencer Vatrt-Watts

Subjects
Genome instability, DNA Replication, Male, tumor evolution, Genotype, Cell Survival, Genomics, Computational biology, Biology, Genome, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, 03 medical and health sciences, Mice, 0302 clinical medicine, copy number, Cell Line, Tumor, tumor heterogeneity, Animals, Chromosomes, Human, Humans, Cell Shape, Phylogeny, 030304 developmental biology, cancer genomics, 0303 health sciences, Genome, Human, Cell Cycle, DNA replication, High-Throughput Nucleotide Sequencing, Cell cycle, genomic instability, Aneuploidy, Diploidy, single cell, Clone Cells, Mutation, DNA Transposable Elements, Female, Ploidy, Single-Cell Analysis, 030217 neurology & neurosurgery
Abstract

Summary Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations., Graphical Abstract, Highlights • Scaled method and resource of > 50K single-cell whole genomes from diverse cell types • Clonal merging can resolve clone specific mutations to single-nucleotide level • Image analysis of single cells permits correlation of morphology and genome features • Clonal replication states and rare aneuploidy patterns of single cells measured, A high-throughput method for amplication-free single-cell whole-genome sequencing can be scaled up to analyze tens of thousands of cells from different tissues and clinical sample types and identifies replication states, aneuploidies, and subclonal mutations.

Published
2018

7. Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Author

Kathryn J. Fowler, Nicholas Raviele, Linda D. Ferrell, Maximillian Lee, Debra King, Melissa Paiz, Puneet Puri, Michael Fuchs, Michael S. Middleton, Tarek Hassanein, Edward Doo, Danielle Brandman, Katie Gelinas, Kim M. Cecil, Ryan M. Gill, Katie Amsden, Sherry Boyett, Archana Bhatt, Melissa Young, Mangesh R. Pagadala, Carol Sargeant, Jean P. Molleston, Mark Fishbein, Averell H. Sherker, Deana Rich, Muhammad Y. Sheikh, Kumar Sandrasegaran, Jaividhya Dasarathy, Sarah E. Barlow, Cheryl Shaw, Laura R. Carucci, Randolph K. Otto, Kimberly Pfeifer, James Tonascia, Ann O. Scheimann, Kimberlee Bernstein, Karen F. Murray, Laura A. Wilson, Amy Jones, Carol Hawkins, Evelyn K. Hsu, Laura Miriel, Miriam B. Vos, Joan Siegner, Gerald Behr, Brandon Ang, Stavra A. Xanthakos, Adina Alazraki, Elizabeth M. Brunt, Michael Torbenson, Cynthia Behling, Alexander Ko, Daniel J. Podberesky, Milana Isaacson, Peter F. Whitington, Elizabeth Kirwan, Girish Subbarao, Emily R. Perito, Saeed Mohammad, Ryan Himes, Pat Osmack, Jolene Schlosser, Patrika Tsai, Kenneth A. Kraft, Patricia Ugalde-Nicalo, Ronen Arnon, Melissa J. Contos, Bimalijit Sandhu, Mariel Boyd, Cynthia D. Guy, ünalp-Arida Aynur ünalp-Arida, Elena Reynoso, Pradeep R. Atla, Ajay Jain, Oscar W. Cummings, Shetal N. Shah, Shannon Cooney, Rajesh Krisnamurthy, Srinivasan Dasarathy, Sonia Garcia, Matthew M. Yeh, Rohit Loomba, Rohit Kohli, Ruth Sargent, Patricia Belt, Patricia R. Robuck, Ivana A. Vaughn, Mandeep Singh, Marwan Ghabril, Mohhamad S. Siddiqui, Kimberly Noble, Kara Cooper, Kimberly P. Newton, Kevin P. May, Brent A. Neuschwander-Tetri, Joel E. Lavine, Rish K. Pai, Chia Wang, Stephanie H. Abrams, Velimir A. Luketic, Kris V. Kowdley, Christopher J. N. Kigongo, Arthur J. McCullough, David E. Kleiner, Jay H. Hoofnagle, Katherine P. Yates, Sandra Arroyo, Jeanne M. Clark, Erin Corless, Melanie B. White, Dawn Piercy, Yi Ping Pan, Iliana Doycheva, Camille Langlois, Philip J. Rosenthal, Ann Quinn, James E. Nelson, Ali A. Mencin, Cynthia K. Rigsby, Stephanie Buie, Nadia Ovchinsky, Tracey Pierce, Jose Derdoy, Kathleen Lake, Cynthia Fleming, Mark L. Van Natta, Asma Siddique, Arun J. Sanyal, Janis Durelle, Phirum Nguyen, Anna Mae Diehl, Crystal Slaughter, Mazen Noureddin, Leanel Maldonado, Rebekah Garcia, Nathan M. Bass, Linda Ragozzino, Jody Mooney, Smitha Marri, Claudia Ortiz Zein, Beverly Morris, Bilal Hameed, Claude B. Sirlin, Alice L. Sternberg, Jeffrey B. Schwimmer, Melissa Wagner, David L. Coy, Michele Donithan, Naga Chalasani, Heather Patton, Susan Stewart, Dana Romo, Stephanie DeVore, Manal F. Abdelmalek, Shannon Fleck, Gilman D. Grave, Saul J. Karpen, Aliya Qayyum, Ann Klipsch, Bradley E. Aouizerat, Simon Horslen, Mustafa R. Bashir, Norah A. Terrault, Lacey Siekas, Elizabeth Byam, Sarah Ackermann, Jennifer Collins, Patricia Brandt, Ben Wolford, Raj Vuppalanchi, Rebecca Cleeton, and Cathy Hurtado

Subjects
Adult, Male, Serum, medicine.medical_specialty, Interleukin-1beta, Ferroportin, Article, Body Mass Index, Young Adult, Sex Factors, Hepcidins, Non-alcoholic Fatty Liver Disease, Risk Factors, Hepcidin, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Humans, Obesity, Aged, Aged, 80 and over, Hepatology, biology, Interleukin-6, Transferrin saturation, business.industry, Racial Groups, Gastroenterology, Iron Deficiencies, Iron deficiency, Middle Aged, medicine.disease, Endocrinology, biology.protein, Female, Metabolic syndrome, business, Body mass index, Alaska
Abstract

Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency.We collected data on 675 adult subjects (18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency.One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P.0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005).Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

Published
2014
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8. Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

Author

Ju Dong Yang, Manal F. Abdelmalek, Cynthia D. Guy, Ryan M. Gill, Joel E. Lavine, Katherine Yates, Jagpal Klair, Norah A. Terrault, Jeanne M. Clark, Aynur Unalp-Arida, Anna Mae Diehl, Ayako Suzuki, Srinivasan Dasarathy, Jaividhya Dasarathy, Carol Hawkins, Arthur J. McCullough, Mangesh Pagadala, Rish Pai, Ruth Sargent, Mustafa Bashir, Stephanie Buie, Cynthia Guy, Christopher Kigongo, Yi-Ping Pan, Dawn Piercy, Naga Chalasani, Oscar W. Cummings, Samer Gawrieh, Marwan Ghabril, Smitha Marri, Linda Ragozzino, Kumar Sandrasegaran, Raj Vuppalanchi, Debra King, Pat Osmack, Joan Siegner, Susan Stewart, Brent A. Neuschwander-Tetri, Susan Torretta, Brandon Ang, Cynthia Behling, Archana Bhatt, Rohit Loomba, Michael Middleton, Heather Patton, Claude Sirlin, Bradley Aouizerat, Nathan M. Bass, Danielle Brandman, Linda D. Ferrell, Ryan Gill, Bilal Hameed, Claudia Ramos, Norah Terrault, Ashley Ungermann, Pradeep Atla, Brandon Croft, Rebekah Garcia, Sonia Garcia, Muhammad Sheikh, Mandeep Singh, Sherry Boyett, Laura Carucci, Melissa J. Contos, Kenneth Kraft, Velimir A.C. Luketic, Puneet Puri, Arun J. Sanyal, Jolene Schlosser, Mohhamad S. Siddiqui, Ben Wolford, Sarah Ackermann, Shannon Cooney, David Coy, Katie Gelinas, Kris V. Kowdley, Maximillian Lee, Tracey Pierce, Jody Mooney, James E. Nelson, Cheryl Shaw, Asma Siddique, Chia Wang, Elizabeth M. Brunt, Kathryn Fowler, David E. Kleiner, Gilman D. Grave, Edward C. Doo, Jay H. Hoofnagle, Patricia R. Robuck, Averell Sherker, Patricia Belt, Michele Donithan, Erin Hallinan, Milana Isaacson, Kevin P. May, Laura Miriel, Alice Sternberg, James Tonascia, Aynur Ünalp-Arida, Mark Van Natta, Ivana Vaughn, and Laura Wilson

Subjects
medicine.medical_specialty, Hepatology, Cross-sectional study, business.industry, Gastroenterology, Physiology, medicine.disease, Article, Menopause, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Transgender hormone therapy, Fibrosis, 030220 oncology & carcinogenesis, Internal medicine, Nonalcoholic fatty liver disease, medicine, 030211 gastroenterology & hepatology, Young adult, business, Body mass index, Hormone
Abstract

Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. We collected data from 3 large US studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. We found that pre-menopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than post-menopausal women (P

Published
2017
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