Medical Specialties Commons^™

Prodrugs Of A 1-Hydroxy-2-Oxopiperidin-3-Yl Phosphonate Enolase Inhibitor For The Treatment Of Eno1-Deleted Cancers, Victoria C Yan, Cong-Dat Pham, Elliot S Ballato, Kristine L Yang, Kenisha Arthur, Sunada Khadka, Yasaman Barekatain, Prakriti Shrestha, Theresa Tran, Anton H Poral, Mykia Washington, Sudhir Raghavan, Barbara Czako, Federica Pisaneschi, Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Jeffrey J Ackroyd, Dimitra K Georgiou, Steven W Millward, Florian L Muller

Faculty, Staff and Student Publications

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma …

Biomarkers Beyond Brca: Promising Combinatorial Treatment Strategies In Overcoming Resistance To Parp Inhibitors, Yu-Yi Chu, Clinton Yam, Hirohito Yamaguchi, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in the treatment of tumors with deficiencies in homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) and trapping PARP1 on damaged DNA. To date, the U.S. Food and Drug Administration (FDA) has approved four PARPi for the treatment of several cancer types including ovarian, breast, pancreatic and prostate cancer. Although patients with HR-deficient tumors benefit from PARPi, majority of tumors ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers of PARPi sensitivity in …

Estimating The Optimal Linear Combination Of Predictors Using Spherically Constrained Optimization, Priyam Das, Debsurya De, Raju Maiti, Mona Kamal, Katherine A Hutcheson, Clifton D Fuller, Bibhas Chakraborty, Christine B Peterson

Faculty, Staff and Student Publications

Background: In the context of a binary classification problem, the optimal linear combination of continuous predictors can be estimated by maximizing the area under the receiver operating characteristic curve. For ordinal responses, the optimal predictor combination can similarly be obtained by maximization of the hypervolume under the manifold (HUM). Since the empirical HUM is discontinuous, non-differentiable, and possibly multi-modal, solving this maximization problem requires a global optimization technique. Estimation of the optimal coefficient vector using existing global optimization techniques is computationally expensive, becoming prohibitive as the number of predictors and the number of outcome categories increases.

Results: We propose an …

Intensive Blood Pressure Lowering In Patients With Malignant Left Ventricular Hypertrophy, Simon B Ascher, James A De Lemos, Minjae Lee, Elaine Wu, Elsayed Z Soliman, Ian J Neeland, Dalane W Kitzman, Christie M Ballantyne, Vijay Nambi, Anthony A Killeen, Joachim H Ix, Michael G Shlipak, Jarett D Berry

Faculty, Staff and Students Publications

Background: Left ventricular hypertrophy (LVH) combined with elevations in cardiac biomarkers reflecting myocardial injury and neurohormonal stress (malignant LVH) is associated with a high risk for heart failure and death.

Objectives: The aim of this study was to determine the impact of intensive systolic blood pressure (SBP) control on the prevention of malignant LVH and its consequences.

Methods: A total of 8,820 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were classified into groups based on the presence or absence of LVH assessed by 12-lead ECG, and elevations in biomarker levels (high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro-B-type …

Sex Differences In Determinants Of Covid-19 Severe Outcomes – Findings From The National Covid Cohort Collaborative (N3c), Yilin Yoshida, San Chu, Sarah Fox, Yuanhao Zu, Dragana Lovre, Joshua L. Denson, Lucio Miele, Franck Mauvais-Jarvis

School of Medicine Faculty Publications

Objective: The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have not yet been verified in population-based studies. We examined the association of comorbidities, inflammatory biomarkers, and severe outcomes in men and women hospitalized for COVID-19. Design: This is a retrospective cohort analysis based on the National COVID Cohort Collaborative (N3C). We included 574,391 adult patients admitted for COVID-19 at hospitals or emergency rooms between 01/01/2020 and 12/31/2021. Methods: We defined comorbidities at or before the first admission for COVID-19 by Charlson Comorbidity Index (CCI) and CCI components. We used the averaged lab values taken within …

Tryptophan Oxidation In Young Children With Environmental Enteric Dysfunction Classified By The Lactulose Rhamnose Ratio, Nirupama Shivakumar, Jean W Hsu, Sindhu Kashyap, Tinku Thomas, Anura V Kurpad, Farook Jahoor

Faculty, Staff and Students Publications

BACKGROUND: In young children, associations between linear growth faltering, environmental enteric dysfunction (EED), and the plasma kynurenine (Kyn)/tryptophan (Trp) ratio (KTR) have led to the proposal that higher Trp catabolism in response to intestinal/systemic inflammation limits Trp availability for protein synthesis, resulting in impaired growth.

OBJECTIVES: We sought to estimate the Trp oxidation rate and the Trp conversion rate to Kyn in young children with and without EED.

METHODS: Children aged 18-24 mo, from urban slums, were assigned to EED (n = 19) or no-EED (n = 26) groups on the basis of a urinary lactulose/rhamnose ratio (LRR) cutoff based …

Diabetes Duration And Subclinical Myocardial Injury: The Atherosclerosis Risk In Communities Study (Aric), Carine E Hamo, Justin B Echouffo-Tcheugui, Sui Zhang, Roberta Florido, James S Pankow, Erin D Michos, Ronald Goldberg, Vijay Nambi, Gary Gerstenblith, Wendy S Post, Roger S Blumenthal, Christie Ballantyne, Elizabeth Selvin, Josef Coresh, Chiadi E Ndumele

Faculty, Staff and Students Publications

Background: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT).

Methods: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used …

Allostatic Load Predicts Racial Disparities In Intracerebral Hemorrhage Cognitive Outcomes, Jennifer Harris, Amelia Boehme, Luisa Chan, Harmon Moats, Rachelle Dugue, Chigozirim Izeogu, Marykay A Pavol, Imama A Naqvi, Olajide Williams, Randolph S Marshall

Faculty, Staff and Student Publications

A large portion of stroke disparities remains unexplained, even after adjusting for demographic, comorbidity, and health care access variables. There is a critical need to close this knowledge gap by investigating novel factors that may contribute to stroke disparities. Allostatic load (AL) is the lifetime adverse physiologic impact of needing to adjust to socially structured stressors such as racism. AL has been shown to increase health vulnerability and worsen outcomes in marginalized populations. We sought to assess the differential impact of AL on cognitive outcomes post intracerebral hemorrhage (ICH) across race-ethnicity. The Intracerebral Hemorrhage Outcomes Project (ICHOP) prospectively collected data …

Immunogenomic Profiling Of Lung Adenocarcinoma Reveals Poorly Differentiated Tumors Are Associated With An Immunogenic Tumor Microenvironment, Neal Akhave, Jiexin Zhang, Erin Bayley, Meredith Frank, Shin-Heng Chiou, Carmen Behrens, Runzhe Chen, Xin Hu, Edwin Roger Parra, Won-Chul Lee, Stephen Swisher, Luisa Solis, Annikka Weissferdt, Cesar Moran, Neda Kalhor, Jianhua Zhang, Paul Scheet, Ara A Vaporciyan, Boris Sepesi, Don L Gibbons, John V Heymach, Jack J Lee, Ignacio I Wistuba, P Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Alexandre Reuben

Faculty, Staff and Student Publications

OBJECTIVES: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy.

METHODS: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including …

Systematically Higher Ki67 Scores On Core Biopsy Samples Compared To Corresponding Resection Specimen In Breast Cancer: A Multi-Operator And Multi-Institutional Study, Balazs Acs, Samuel C Y Leung, Kelley M Kidwell, Indu Arun, Renaldas Augulis, Sunil S Badve, Yalai Bai, Anita L Bane, John M S Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C Chang, Robin L Dietz, Andrew Dodson, Susan Fineberg, Cornelia M Focke, Dongxia Gao, Allen M Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M Levenson, Rustin Mahboubi-Ardakani, Mauro G Mastropasqua, Sharon Nofech-Mozes, C Kent Osborne, Frédérique M Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert Van Der Vegt, Giuseppe Viale, Lila A Zabaglo, Daniel F Hayes, Mitch Dowsett, Torsten O Nielsen, David L Rimm, International Ki67 In Breast Cancer Working Group Of The Breast International Group And North American Breast Cancer Group (Big-Nabcg)

Faculty, Staff and Students Publications

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

T1 Signal Intensity Ratio Of The Pancreas As An Imaging Biomarker For The Staging Of Chronic Pancreatitis, Temel Tirkes, Anil K Dasyam, Zarine K Shah, Evan L Fogel, Santhi Swaroop Vege, Liang Li, Shuang Li, Stephanie T Chang, Carlos A Farinas, Joseph R Grajo, Kareem Mawad, Naoki Takahashi, Sudhakar K Venkatesh, Ashley Wachsman, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Stephen K Van Den Eeden, Yunlong Yang, Mark Topazian, Dana K Andersen, Jose Serrano, Darwin L Conwell, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.

Methods: The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0-6) based on their …

A Retrospective Analysis Of Ebv-Dna Status With The Prognosis Of Lymphoma, Lihua Qiu, Junqi Si, Junnan Kang, Zehui Chen, Rexidan Nuermaimaiti, Zhengzi Qian, Lanfang Li, Shiyong Zhou, Mingjian James You, Huilai Zhang, Chen Tian

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate …

Comprehensive Multiplexed Immune Profiling Of The Ductal Carcinoma In Situ Immune Microenvironment Regarding Subsequent Ipsilateral Invasive Breast Cancer Risk, Mathilde M Almekinders, Tycho Bismeijer, Tapsi Kumar, Fei Yang, Bram Thijssen, Rianne Van Der Linden, Charlotte Van Rooijen, Shiva Vonk, Baohua Sun, Edwin R Parra Cuentas, Ignacio I Wistuba, Savitri Krishnamurthy, Lindy L Visser, Iris M Seignette, Ingrid Hofland, Joyce Sanders, Annegien Broeks, Jason K Love, Brian Menegaz, Lodewyk Wessels, Alastair M Thompson, Karin E De Visser, Erik Hooijberg, Esther Lips, Andrew Futreal, Jelle Wesseling

Faculty, Staff and Student Publications

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.

Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with …

Plasma Protein Biomarkers For Primary Graft Dysfunction After Lung Transplantation: A Single-Center Cohort Analysis, Lourdes Chacon-Alberty, Rupa S Kanchi, Shengbin Ye, Camila Hochman-Mendez, Daoud Daoud, Cristian Coarfa, Meng Li, Sandra L Grimm, Maher Baz, Ivan Rosas, Gabriel Loor

Faculty, Staff and Students Publications

The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based …

Microrna Expression Levels Change In Neonatal Patients During And After Exposure To Cardiopulmonary Bypass., Lance Hsieh, Lan N. Tu, Alison Paquette, Quanhu Sheng, Shilin Zhao, Douglas C. Bittel, James O'Brien, Kasey Vickers, Peter Pastuszko, Vishal Nigam

Manuscripts, Articles, Book Chapters and Other Papers

Background The systemic inflammation that occurs after exposure to cardiopulmonary bypass (CPB), which is especially severe in neonatal patients, is associated with poorer outcomes and is not well understood. In order to gain deeper insight into how exposure to bypass activates inflammatory responses in circulating leukocytes, we studied changes in microRNA (miRNA) expression during and after exposure to bypass. miRNAs are small noncoding RNAs that have important roles in modulating protein levels and function of cells. Methods and Results We performed miRNA-sequencing on leukocytes isolated from neonatal patients with CPB (n=5) at 7 time points during the process of CPB, …

Longitudinal Effects Of Combination Antiretroviral Therapy On Cognition And Neuroimaging Biomarkers In Treatment-Naive People With Hiv, Miriam T Weber, Alan Finkelstein, Md Nasir Uddin, Elizabeth Asiago Reddy, Roberto C Arduino, Lu Wang, Madalina E Tivarus, Jianhui Zhong, Xing Qiu, Giovanni Schifitto

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: While combination antiretroviral therapy (cART) has dramatically increased the life expectancy of people with HIV (PWH), nearly 50% develop HIV-associated neurocognitive disorders. This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication or activation from other sources, or cART-associated neurotoxicity. The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers in PWH before and after initiation of cART compared with that in HIV-negative controls (HCs) and HIV elite controllers (ECs) who remain untreated.

METHODS: We recruited 3 groups of participants from the University …

Preoperative Inflammatory Markers As Prognostic Predictors After Hepatocellular Carcinoma Resection: Data From A Western Referral Center, João Paulo Maciel Silva, Fabricio Ferreira Coelho, Alex Jones Flores Cassenote, Vagner Birk Jeismann, Gilton Marques Fonseca, Jaime Arthur Pirola Kruger, José Donizeti De Meira Júnior, Sérgio Carlos Nahas, Paulo Herman

Faculty, Staff and Student Publications

BACKGROUND: Recent studies from eastern centers have demonstrate an association between inflammatory response and long-term outcomes after hepatocellular carcinoma (HCC) resection. However, the prognostic impact of inflammatory markers in western patients, with distinct tumor and epidemiologic features, is still unknown.

AIM: To evaluate the prognostic impact of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), as well as their impact according to tumor size (< 5 cm, 5-10 cm, > 10 cm) in patients undergoing HCC resection with curative intent.

METHODS: Optimal cut-off values for NLR, PLR, and MLR were determined by plotting the receiver operator curves. Overall survival (OS) and disease-free …

Idh1 Prr32h Ctdna And D-2-Hydroxyglutarate As Csf Biomarkers In Patients With Idh-Mutant Gliomas, Yoko Fujita, Luis Nunez-Rubiano, Antonio Dono, Allison Bellman, Mauli Shah, Juan C Rodriguez, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Roy F Riascos, Jay-Jiguang Zhu, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 …

Risk Of Type 2 Diabetes Among Individuals With Excess Weight: Weight Trajectory Effects, Arthur H Owora, David B Allison, Xuan Zhang, Nana Gletsu-Miller, Kishore M Gadde

Children’s Nutrition Research Center Staff Publications

PURPOSE OF REVIEW: Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the …

Idh1 Pr132h Ctdna And D-2-Hydroxyglutarate As Csf Biomarkers In Patients With Idh-Mutant Gliomas, Yoko Fujita, Luis Nunez-Rubiano, Antonio Dono, Allison Bellman, Mauli Shah, Juan C Rodriguez, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Roy F Riascos, Jay-Jiguang Zhu, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

Changes In Apparent Diffusion Coefficient (Adc) In Serial Weekly Mri During Radiotherapy In Patients With Head And Neck Cancer: Results From The Predict-Hn Study, Sweet Ping Ng, Carlos E Cardenas, Houda Bahig, Baher Elgohari, Jihong Wang, Jason M Johnson, Amy C Moreno, Shalin J Shah, Adam S Garden, Jack Phan, G Brandon Gunn, Steven J Frank, Yao Ding, Lumine Na, Ying Yuan, Diana Urbauer, Abdallah S R Mohamed, David I Rosenthal, William H Morrison, Michael P Macmanus, Clifton D Fuller

Faculty, Staff and Student Publications

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy.

Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time.

Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that …

Occlusionchip: A Functional Microcapillary Occlusion Assay Complementary To Ektacytometry For Detection Of Small-Fraction Red Blood Cells With Abnormal Deformability, Yuncheng Man, Ran An, Karamoja Monchamp, Zoe Sekyonda, Erdem Kucukal, Chiara Federici, William J. Wulftange, Utku Goreke, Allison Bode, Umut A. Gurkan

Faculty Scholarship

Red blood cell (RBC) deformability is a valuable hemorheological biomarker that can be used to assess the clinical status and response to therapy of individuals with sickle cell disease (SCD). RBC deformability has been measured by ektacytometry for decades, which uses shear or osmolar stress. However, ektacytometry is a population based measurement that does not detect small-fractions of abnormal RBCs. A single cell-based, functional RBC deformability assay would complement ektacytometry and provide additional information. Here, we tested the relative merits of the OcclusionChip, which measures RBC deformability by microcapillary occlusion, and ektacytometry. We tested samples containing glutaraldehyde-stiffened RBCs for up …

Increased Expression Of Interferon-Induced Transmembrane 3 (Ifitm3) In Stroke And Other Inflammatory Conditions In The Brain, Elisabeth Harmon, Andrea Doan, Jesus Bautista-Garrido, Joo Eun Jung, Sean P Marrelli, Gab Seok Kim

Faculty, Staff and Student Publications

Microglia, the resident innate immune cells of the brain, become more highly reactive with aging and diseased conditions. In collaboration with other cell types in brains, microglia can contribute both to worsened outcome following stroke or other neurodegenerative diseases and to the recovery process by changing their phenotype toward reparative microglia. Recently, IFITM3 (a member of the "interferon-inducible transmembrane" family) has been revealed as a molecular mediator between amyloid pathology and neuroinflammation. Expression of IFITM3 in glial cells, especially microglia following stroke, is not well described. Here, we present evidence that ischemic stroke causes an increase in IFITM3 expression along …

Tale Of Two Cities: Narrative Review Of Oxygen, Sung-Ho Ahn, Angela Burkett, Atzhiry Paz, Jude P Savarraj, Sarah Hinds, Georgene Hergenroeder, Aaron M Gusdon, Xuefeng Ren, Jeong-Ho Hong, Huimahn A Choi

Faculty, Staff and Student Publications

BACKGROUND: Cerebral edema (CE) at admission is a surrogate marker of 'early brain injury' (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH.

METHODS: Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0-4 'subarachnoid hemorrhage early …

Charting The Proteome Landscape In Major Psychiatric Disorders: From Biomarkers To Biological Pathways Towards Drug Discovery, Brisa S Fernandes, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically …

Salivary Biomarker Evaluation Of Chronic Pancreatitis Patients Reveals Alterations In Human Proteins, Cytokines, Prostaglandin E2 Levels, And Bacterial Diversity, Richard T Waldron, Elaina K Jones, Vincent I Anani, Jolaine M Hines, Jing Zhao, Aurelia Lugea, Marcio A Diniz, Sungjin Kim, Aida Habtezion, Kristi L Hoffman, Joseph F Petrosino, William E Fisher, Liang Li, Ryan J Lennon, Ravinder Jit Singh, Santhi Swaroop Vege, Stephen J Pandol, Mark D Topazian

Faculty, Staff and Students Publications

OBJECTIVES: Chronic pancreatitis (CP) is a chronic fibroinflammatory condition of the pancreas difficult to diagnose in early stages. Novel biomarkers useful to facilitate early diagnosis or treatment responses may be found in biofluids. Although saliva can be easily and noninvasively collected from patients, useful salivary biomarkers from CP patients have not yet been identified.

METHODS: Here, we analyzed the proteome by quantitative proteomics, cytokine/chemokine levels by Luminex analysis, prostaglandin E2 (PGE2) levels by a mass spectrometry-based assay, and bacterial species diversity by 16S ribosomal ribonucleic acid sequencing in saliva samples from confirmed CP patients and healthy controls.

RESULTS: Our results …

Circulating Trophoblast Numbers As A Potential Marker For Pregnancy Complications, Brielle Crovetti, Mohamad Ali Maktabi, Hadi Erfani, Tachjaree Panchalee, Qun Wang, Liesbeth Vossaert, Ignatia Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Objective: To explore the potential of circulating trophoblasts (TBs) as a non-invasive tool to assess placental health and predict obstetric complications.

Methods: We retrospectively reviewed maternal characteristics and pregnancy outcomes of 369 women who enrolled in our original cell-based NIPT (cbNIPT) study. The number of circulating TBs recovered from the maternal blood samples was recorded and expressed as fetal cell concentration (FCC). We evaluated if FCC can be used to predict pregnancy outcomes such as hypertensive disorders of pregnancy (HDP), fetal growth restriction, placental abruption, preterm labor, and pregnancy loss.

Results: Receiver operating characteristic (ROC) analysis was performed to find …

Safety And Efficacy Of Voxelotor In Pediatric Patients With Sickle Cell Disease Aged 4 To 11 Years., Jeremie H. Estepp, Ram Kalpatthi, Gerald Woods, Sara Trompeter, Robert I. Liem, Kacie Sims, Adlette Inati, Baba P D Inusa, Andrew Campbell, Connie Piccone, Miguel R. Abboud, Kim Smith-Whitley, Sandra Dixon, Margaret Tonda, Carla Washington, Noelle M. Griffin, Clark Brown

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality.

PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization …