Medical Specialties Commons^™

Magnetic Resonance Biomarkers In Radiation Oncology: The Report Of Aapm Task Group 294, Kiaran P Mcgee, Ken-Pin Hwang, Daniel C Sullivan, John Kurhanewicz, Yanle Hu, Jihong Wang, Wen Li, Josef Debbins, Eric Paulson, Jeffrey R Olsen, Chia-Ho Hua, Lizette Warner, Daniel Ma, Eduardo Moros, Neelam Tyagi, Caroline Chung

Faculty, Staff and Student Publications

A magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) …

Genetic Variation And Recurrent Haplotypes On Chromosome 6q23-25 Risk Locus In Familial Lung Cancer, Anthony M Musolf, Claire L Simpson, Bilal A Moiz, Claudio W Pikielny, Candace D Middlebrooks, Diptasri Mandal, Mariza De Andrade, Michael D Cole, Colette Gaba, Ping Yang, Ming You, Yafang Li, Elena Y Kupert, Marshall W Anderson, Ann G Schwartz, Susan M Pinney, Christopher I Amos, Joan E Bailey-Wilson

Faculty, Staff and Students Publications

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 …

A Novel Biomarker Panel For The Early Detection And Risk Assessment Of Hepatocellular Carcinoma In Patients With Cirrhosis, Ilvira M Khan, Donjeta Gjuka, Jingjing Jiao, Xiaoling Song, Ying Wang, Jing Wang, Peng Wei, Hashem B El-Serag, Jorge A Marrero, Laura Beretta

Faculty, Staff and Students Publications

Novel biomarkers for hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis are urgently needed. We previously identified osteopontin (OPN) as a promising biomarker for the early detection of HCC. This study is to further validate the performance of OPN and identify fatty acids (FA) that could improve OPN's performance in HCC risk assessment in patients with cirrhosis. To that end, we selected 103 patients with cirrhosis under surveillance. Among them, 40 patients developed HCC during follow-up. We investigated in these 103 patients, the association between HCC incidence and prediagnostic serum levels of AFP, OPN, and 46 FAs. OPN performance was …

Plasma Adenosine Deaminase (Ada)-1 And -2 Demonstrate Robust Ontogeny Across The First Four Months Of Human Life., Oludare A. Odumade, Alec L. Plotkin, Jensen Pak, Olubukola T. Idoko, Matthew A. Pettengill, Tobias R. Kollmann, Al Ozonoff, Beate Kampmann, Ofer Levy, Kinga K. Smolen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Human adenosine deaminases (ADAs) modulate the immune response: ADA1

Methods: In a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated to ADA concentrations.

Results: ADA2 demonstrated a steady rise across the first months of life, while ADA1 concentration significantly decreased 0.79-fold …

A Metabolomic Endotype Of Bioenergetic Dysfunction Predicts Mortality In Critically Ill Patients With Acute Respiratory Failure, Raymond J. Langley, Marie E. Migaud, Lori Flores, J. Will Thompson, Elizabeth A. Kean, Murphy M. Mostellar, Matthew Mowry, Patrick Luckett, Lina D. Purcell, James Lovato, Sheetal Gandotra, Ryan Benton, D. Clark Files, Kevin S. Harrod, Mark N. Gillespie, Peter E. Morris

Internal Medicine Faculty Publications

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. …

Intracranial Vcam1 At Time Of Mechanical Thrombectomy Predicts Ischemic Stroke Severity, Benton Maglinger, Madison Sands, Jacqueline A. Frank, Christopher J. Mclouth, Amanda L. Trout, Jill M. Roberts, Stephen Grupke, Jadwiga Turchan-Cholewo, Ann M. Stowe, Justin F. Fraser, Keith R. Pennypacker

Behavioral Science Faculty Publications

BACKGROUND: Emergent large vessel occlusion (ELVO) strokes are devastating ischemic vascular events for which novel treatment options are needed. Using vascular cell adhesion molecule 1 (VCAM1) as a prototype, the objective of this study was to identify proteomic biomarkers and network signaling functions that are potential therapeutic targets for adjuvant treatment for mechanical thrombectomy.

METHODS: The blood and clot thrombectomy and collaboration (BACTRAC) study is a continually enrolling tissue bank and registry from stroke patients undergoing mechanical thrombectomy. Plasma proteins from intracranial (distal to clot) and systemic arterial blood (carotid) were analyzed by Olink Proteomics for N=42 subjects. Statistical …

Upregulation Of Inflammatory Cytokines In Pulmonary Embolism Using Biochip-Array Profiling., Emily Bontekoe, Yevgeniy Brailovsky, Debra Hoppensteadt, Jack Bontekoe, Fakiha Siddiqui, Joshua Newman, Omer Iqbal, Trent Reed, Jawed Fareed, Amir Darki

Department of Medicine Faculty Papers

The complex pathophysiology of pulmonary embolism (PE) involves hemostatic activation, inflammatory processes, cellular dysfunction, and hemodynamic derangements. Due to the heterogeneity of this disease, risk stratification and diagnosis remains challenging. Biochip-array technology provides an integrated high throughput method for analyzing blood plasma samples for the simultaneous measurement of multiple biomarkers for potential risk stratification. Using biochip-array method, this study aimed to quantify the inflammatory biomarkers such as interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and epidermal growth factor (EGF) in 109 clinically …

Soluble Angiotensin-Converting Enzyme 2, Cardiac Biomarkers, Structure, And Function, And Cardiovascular Events (From The Atherosclerosis Risk In Communities Study), Aliza Hussain, Olive Tang, Caroline Sun, Xiaoming Jia, Elizabeth Selvin, Vijay Nambi, Aaron Folsom, Gerardo Heiss, Faiez Zannad, Thomas Mosley, Salim S Virani, Josef Coresh, Eric Boerwinkle, Bing Yu, Jonathan W Cunningham, Amil M Shah, Scott D Solomon, James A De Lemos, Ron C Hoogeveen, Christie M Ballantyne

Faculty, Staff and Students Publications

Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin-angiotensin-aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels …

Coronavirus Disease-19 And Cardiovascular Disease: A Risk Factor Or A Risk Marker?, Jing Liu, Salim S Virani, Mahboob Alam, Ali E Denktas, Ihab Hamzeh, Umair Khalid

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus-2 causes the clinical syndrome of coronavirus disease of 2019 (COVID-19) which has become a global pandemic resulting in significant morbidity and mortality. While the virus primarily affects the respiratory system, it also causes a wide variety of complex cardiac manifestations such as acute myopericarditis, acute coronary syndrome, congested heart failure, cardiogenic shock and cardiac arrhythmias. There are numerous proposed mechanisms of cardiac injury, including direct cellular injury, pro-inflammatory cytokine storm, myocardial oxygen-demand mismatch, and systemic inflammation causing multi-organ failure. Additionally, medications commonly used to treat COVID-19 patients have various cardiovascular side effects. We aim to …

Coronavirus Disease-19 And Cardiovascular Disease: A Risk Factor Or A Risk Marker?, Jing Liu, Salim S Virani, Mahboob Alam, Ali E Denktas, Ihab Hamzeh, Umair Khalid

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus-2 causes the clinical syndrome of coronavirus disease of 2019 (COVID-19) which has become a global pandemic resulting in significant morbidity and mortality. While the virus primarily affects the respiratory system, it also causes a wide variety of complex cardiac manifestations such as acute myopericarditis, acute coronary syndrome, congested heart failure, cardiogenic shock and cardiac arrhythmias. There are numerous proposed mechanisms of cardiac injury, including direct cellular injury, pro-inflammatory cytokine storm, myocardial oxygen-demand mismatch, and systemic inflammation causing multi-organ failure. Additionally, medications commonly used to treat COVID-19 patients have various cardiovascular side effects. We aim to …

N-3 Fatty Acid Biomarkers And Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project Of 20 Prospective Cohort Studies, Frank Qian, Andres V Ardisson Korat, Fumiaki Imamura, Matti Marklund, Nathan Tintle, Jyrki K Virtanen, Xia Zhou, Julie K Bassett, Heidi Lai, Yoichiro Hirakawa, Kuo-Liong Chien, Alexis C Wood, Maria Lankinen, Rachel A Murphy, Cecilia Samieri, Kamalita Pertiwi, Vanessa D De Mello, Weihua Guan, Nita G Forouhi, Nick Wareham, Interact Consortium Frank B Hu, Ulf Riserus, Lars Lind, William S Harris, Aladdin H Shadyab, Jennifer G Robinson, Lyn M Steffen, Allison Hodge, Graham G Giles, Toshiharu Ninomiya, Matti Uusitupa, Jaakko Tuomilehto, Jaana Lindström, Markku Laakso, David S Siscovick, Catherine Helmer, Johanna M Geleijnse, Jason H Y Wu, Amanda Fretts, Rozenn N Lemaitre, Renata Micha, Dariush Mozaffarian, Qi Sun

Children’s Nutrition Research Center Staff Publications

Objective: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.

Research design and methods: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed …

Predictive Factors For Success Of Awake Proning In Hypoxemic Respiratory Failure Secondary To Covid-19: A Retrospective Cohort Study, Sujith V Cherian, Chang Li, Brad Roche, Stephan A Reyes, Siddharth Karanth, Aditya P Lal, Gabriel M Aisenberg, Rosa M Estrada-Y-Martin

Faculty, Staff and Student Publications

BACKGROUND: Awake prone positioning has been recommended as an adjunctive measure in spontaneously breathing patients with hypoxemic respiratory failure during the COVID-19 pandemic. It remains uncertain as to how long this should be implemented, what variables to follow and who would be the ideal candidates for this adjunctive therapy.

METHODS: A retrospective chart review of patients admitted from April to August 2020 within our institution with multifocal pneumonia and hypoxemic respiratory failure secondary to COVID-19 who underwent awake-proning for at least 3 hours was conducted.

RESULTS: Improvement in respiratory parameters including ROX (SpO2/Fio2/ Respiratory Rate) indices and inflammatory markers within …

Proteomic Investigation Of Glyceraldehyde-Derived Intracellular Ages And Their Potential Influence On Pancreatic Ductal Cells, Lakmini Senavirathna, Cheng Ma, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, …

The Context-Dependent Impact Of Integrin-Associated Cd151 And Other Tetraspanins On Cancer Development And Progression: A Class Of Versatile Mediators Of Cellular Function And Signaling, Tumorigenesis And Metastasis, Sonia F. Erfani, Hui Hua, Yueyin Pan, Binhua P. Zhou, Xiuwei H. Yang

Molecular and Cellular Biochemistry Faculty Publications

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition …

Obstructive Sleep Apnea And Dementia-Common Gene Associations Through Network-Based Identification Of Common Driver Genes, Hyun-Hwan Jeong, Arvind Chandrakantan, Adam C Adler

Faculty, Staff and Students Publications

BACKGROUND: Obstructive Sleep Apnea (OSA) occurs in 7% of the adult population. The relationship between neurodegenerative diseases such as dementia and sleep disorders have long attracted clinical attention; however, no comprehensive data exists elucidating common gene expression between the two diseases. The objective of this study was to (1) demonstrate the practicability and feasibility of utilizing a systems biology approach called network-based identification of common driver genes (NICD) to identify common genomic features between two associated diseases and (2) utilize this approach to identify genes associated with both OSA and dementia.

METHODS: This study utilized 2 public databases (PCNet, DisGeNET) …

Real World Clinicopathologic Observations Of Patients With Metastatic Solid Tumors Receiving Immune Checkpoint Inhibitor Therapy: Analysis From Kentucky Cancer Registry, Aasems Jacob, Jianrong Wu, Jill M. Kolesar, Eric B. Durbin, Aju Mathew, Susanne Arnold, Aman Chauhan

Biostatistics Faculty Publications

The state of Kentucky has the highest cancer incidence and mortality in the United States. High‐risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution.

Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure …

Gauging Working Memory Capacity From Differential Resting Brain Oscillations In Older Individuals With A Wearable Device, Soheil Borhani, Xiaopeng Zhao, Margaret R. Kelly, Karah E. Gottschalk, Fengpei Yuan, Gregory A. Jicha, Yang Jiang

Sanders-Brown Center on Aging Faculty Publications

Working memory is a core cognitive function and its deficits is one of the most common cognitive impairments. Reduced working memory capacity manifests as reduced accuracy in memory recall and prolonged speed of memory retrieval in older adults. Currently, the relationship between healthy older individuals’ age-related changes in resting brain oscillations and their working memory capacity is not clear. Eyes-closed resting electroencephalogram (rEEG) is gaining momentum as a potential neuromarker of mild cognitive impairments. Wearable and wireless EEG headset measuring key electrophysiological brain signals during rest and a working memory task was utilized. This research’s central hypothesis is that rEEG …

5Th Generation Vs 4Th Generation Troponin T In Predicting Major Adverse Cardiovascular Events And All-Cause Mortality In Patients Hospitalized For Non-Cardiac Indications: A Cohort Study, Vedant Gupta, Marc Paranzino, Talal Alnabelsi, Karam Ayoub, Joshua Eason, Andin Mullis, John R. Kotter, Andrew Parks, Levi May, Sethabhisha Nerusu, Chen Dai, Daniel Cleland, Steve W. Leung, Vincent L. Sorrell

Gill Heart & Vascular Institute Faculty Publications

OBJECTIVE: The frequency and implications of an elevated cardiac troponin (4^th or 5^th generation TnT) in patients outside of the emergency department or presenting with non-cardiac conditions is unclear.

METHODS: Consecutive patients aged 18 years or older admitted for a primary non-cardiac condition who had the 4^th generation TnT drawn had the 5^th generation TnT run on the residual blood sample. Primary and secondary outcomes were all-cause mortality (ACM) and major adverse cardiovascular events (MACE) respectively at 1 year.

RESULTS: 918 patients were included (mean age 59.8 years, 55% male) in the cohort. 69% had elevated …

Association Of Nt-Probnp, Blood Pressure, And Cardiovascular Events: The Aric Study, Aliza Hussain, Wensheng Sun, Anita Deswal, James A De Lemos, John W Mcevoy, Ron C Hoogeveen, Kunihiro Matsushita, David Aguilar, Biykem Bozkurt, Salim S Virani, Amil M Shah, Elizabeth Selvin, Chiadi Ndumule, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

BACKGROUND: Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk.

OBJECTIVES: This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories.

METHODS: Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, …

Hyperlipasemia And Potential Pancreatic Injury Patterns In Covid-19: A Marker Of Severity Or Innocent Bystander?, Hemant Goyal, Sonali Sachdeva, Abhilash Perisetti Md, Rupinder Mann, Sumant Inamdar, Benjamin Tharian

Other Specialties

No abstract provided.

Links Between Thrombosis And Inflammation In Traumatic Brain Injury, W Brad Hubbard, Jing-Fei Dong, Miguel A Cruz, Rolando E Rumbaut

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI. Despite advances in the links between thrombosis and inflammation, there is a …

Hemoglobin A1c Threshold For Reduction In Bone Turnover In Men With Type 2 Diabetes Mellitus, Sabaa Joad, Elliot Ballato, Fnu Deepika, Giulia Gregori, Alcibiades Leonardo Fleires-Gutierrez, Georgia Colleluori, Lina Aguirre, Rui Chen, Vittoria Russo, Virginia Carolina Fuenmayor Lopez, Clifford Qualls, Dennis T Villareal, Reina Armamento-Villareal

Faculty, Staff and Students Publications

BACKGROUND: Emerging data suggest that type 2 diabetes mellitus (T2D) is associated with an increased risk for fractures despite relatively normal or increased bone mineral density (BMD). Although the mechanism for bone fragility in T2D patients is multifactorial, whether glycemic control is important in generating this impairment in bone metabolism remains unclear. The purpose of our study is to identify a hemoglobin A1c (A1c) threshold level by which reduction in bone turnover begins in men with T2D.

METHOD: A cross-sectional analysis of baseline data was obtained from 217 men, ages 35-65, regardless of the presence or absence of hypogonadism or …

A Semiparametric Modeling Approach For Analyzing Clinical Biomarkers Restricted To Limits Of Detection, Sandipan Dutta, Susan Halabi

Mathematics & Statistics Faculty Publications

Before biomarkers can be used in clinical trials or patients' management, the laboratory assays that measure their levels have to go through development and analytical validation. One of the most critical performance metrics for validation of any assay is related to the minimum amount of values that can be detected and any value below this limit is referred to as below the limit of detection (LOD). Most of the existing approaches that model such biomarkers, restricted by LOD, are parametric in nature. These parametric models, however, heavily depend on the distributional assumptions, and can result in loss of precision under …

Rapid Induction Of The Unfolded Protein Response And Apoptosis By Estrogen Mimic Ttc-352 For The Treatment Of Endocrine-Resistant Breast Cancer, Balkees Abderrahman, Philipp Y Maximov, Ramona F Curpan, Sean W Fanning, Jay S Hanspal, Ping Fan, Charles E Foulds, Yue Chen, Anna Malovannaya, Antrix Jain, Rui Xiong, Geoffrey L Greene, Debra A Tonetti, Gregory R J Thatcher, V Craig Jordan

Faculty, Staff and Students Publications

Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEMs) BMI-135 and TTC-352, and the naturally-occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared to 17β-estradiol (E2), for the treatment of endocrine-resistant BC. TTC-352 and E4 are being evaluated in BC clinical trials. …

Mir15a/Mir16-1 Cluster And Its Novel Targeting Molecules Negatively Regulate Cardiac Hypertrophy., Hongchang Guo, Ke Ma, Wenjing Hao, Yao Jiao, Ping Li, Jing Chen, Chen Xu, Fu-Jian Xu, Wayne Bond Lau, Jie Du, Xin-Liang Ma, Yulin Li

Department of Emergency Medicine Faculty Papers

In response to pathological stimuli, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. miRNAs are increasingly recognized as pathogenic factors, clinically relevant biomarkers, and potential therapeutic targets. We identified that mir15a/mir16-1 cluster was negatively correlated with hypertrophic severity in patients with hypertrophic cardiomyopathy. The mir15a/mir16-1 expression was enriched in cardiomyocytes (CMs), decreased in hypertrophic human hearts, and decreased in mouse hearts after transverse aortic constriction (TAC). CM-specific mir15a/mir16-1 knockout promoted cardiac hypertrophy and dysfunction after TAC. CCAAT/enhancer binding protein (C/EBP)β was responsible for the downregulation of mir15a/mir16-1 cluster transcription. Mechanistically, mir15a/mir16-1 cluster attenuated the insulin/IGF1 …

Investigation Of The Functional Impact Of Anti-Pd-1 On Tumor-Infiltrating Lymphocytes (Til) And Mapping Of Tumor Genomic Features Relevant For Response To Til Therapy, Caitlin Creasy

Dissertations and Theses (Open Access)

With the growing use of both cellular and antibody-based immunotherapies, it has become more important to uncover biomarkers to predict patient response to therapy and ideally aid in patient selection for specific therapeutics, thereby enhancing treatment outcome. At MD Anderson, we have a 43% response rate to therapy when treating metastatic melanoma patients with adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), but it is unknown what makes the other 57% of patients not respond to therapy. It is further unknown how particularly early doses of checkpoint inhibitors, like anti-PD-1, attribute to TIL functionality, adding another confounding factor in determining …

High Molecular Weight Adiponectin Levels Are Inversely Associated With Adiposity In Pediatric Brain Tumor Survivors., Rebecca Ronsley, Shahrad Rod Rassekh, Adam Fleming, Brianna Empringham, William Jennings, Carol Portwine, Sarah Burrow, Shayna Zelcer, Donna L Johnston, Lehana Thabane, M Constantine Samaan

Paediatrics Publications

While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin's profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) …

Redefining Cardiac Biomarkers In Predicting Mortality Of Inpatients With Covid-19, Juan-Juan Qin, Xu Cheng, Feng Zhou, Fang Lei, Gauri Akolkar, Jingjing Cai, Xiao-Jing Zhang, Alice Blet, Jing Xie, Peng Zhang, Ye-Mao Liu, Zizhen Huang, Ling-Ping Zhao, Lijin Lin, Meng Xia, Ming-Ming Chen, Xiaohui Song, Liangjie Bai, Ze Chen, Xingyuan Zhang, Da Xiang, Jing Chen, Qingbo Xu, Xin-Liang Ma, Rhian M Touyz, Chen Gao, Haitao Wang, Liming Liu, Weiming Mao, Pengcheng Luo, Youqin Yan, Ping Ye, Manhua Chen, Guohua Chen, Lihua Zhu, Zhi-Gang She, Xiaodong Huang, Yufeng Yuan, Bing-Hong Zhang, Yibin Wang, Peter P Liu, Hongliang Li

Department of Emergency Medicine Faculty Papers

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

Canakinumab To Reduce Deterioration Of Cardiac And Respiratory Function In Sars-Cov-2 Associated Myocardial Injury With Heightened Inflammation (Canakinumab In Covid-19 Cardiac Injury: The Three C Study), Calvin C Sheng, Debasis Sahoo, Siddharth Dugar, Robier Aguillon Prada, Tom Kai Ming Wang, Ossama K Abou Hassan, Danielle Brennan, Daniel A Culver, Prabalini Rajendram, Abhijit Duggal, A Michael Lincoff, Steven E Nissen, Venu Menon, Paul C Cremer

Faculty, Staff and Student Publications

BACKGROUND: In patients with Covid-19, myocardial injury and increased inflammation are associated with morbidity and mortality. We designed a proof-of-concept randomized controlled trial to evaluate whether treatment with canakinumab prevents progressive respiratory failure and worsening cardiac dysfunction in patients with SARS-CoV2 infection, myocardial injury, and high levels of inflammation.

HYPOTHESIS: The primary hypothesis is that canakiumab will shorten time to recovery.

METHODS: The three C study (canakinumab in Covid-19 Cardiac Injury, NCT04365153) is a double-blind, randomized controlled trial comparing canakinumab 300 mg IV, 600 mg IV, or placebo in a 1:1:1 ratio in hospitalized Covid-19 patients with elevations in troponin …

Serially Assessed Bisphenol A And Phthalate Exposure And Association With Kidney Function In Children With Chronic Kidney Disease In The Us And Canada: A Longitudinal Cohort Study., Melanie H. Jacobson, Yinxiang Wu, Mengling Liu, Teresa M. Attina, Mrudula Naidu, Rajendiran Karthikraj, Kurunthachalam Kannan, Bradley A. Warady, Susan Furth, Suzanne Vento, Howard Trachtman, Leonardo Trasande

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD.

METHODS AND FINDINGS: Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) …