Digital Commons Network^™

Informed Consent For Placebo-Controlled Trials: Do Ethics And Science Conflict?, Hope A Feldman, James A Feldman, Charles C Miller, Garrett Walsh, Jon E Tyson

Faculty, Staff and Student Publications

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled …

Pivoting The Biosafety Program In Response To Covid-19: Recommendations Of Key Services And Tasks To Consider For The Next Pandemic, Robert J Emery, Scott J Patlovich, Kristin G King, Janelle Rios

Faculty, Staff and Student Publications

INTRODUCTION: With the onset of the COVID-19 pandemic, a rapid adjustment of work tasks was necessary for many biosafety programs (and other safety programs) to address drastic shifts in workload demands amid pandemic-related shutdowns and subsequent needs for supporting COVID-19-related safe work protocols, diagnostic testing, research, vaccine development, and so forth. From a program management standpoint, evaluating and understanding these tasks were critically important to ensure that appropriate support and resources were in place, especially during such unprecedented times of rapid change and significant impact to normal life and routine.

METHODS: Described here are examples of how the biosafety program …

Hic2 Controls Developmental Hemoglobin Switching By Repressing Bcl11a Transcription, Peng Huang, Scott A Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A Keller, Belinda Giardine, Henry W Bell, Xianjiang Lan, Malini Sharma, John R Horton, Osheiza Abdulmalik, Stella T Chou, Junwei Shi, Merlin Crossley, Ross C Hardison, Xiaodong Cheng, Gerd A Blobel

Faculty, Staff and Student Publications

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, …

Multidimensional Single-Cell Analysis Identifies A Role For Cd2-Cd58 Interactions In Clinical Antitumor T Cell Responses, Gabrielle Romain, Paolo Strati, Ali Rezvan, Mohsen Fathi, Irfan N Bandey, Jay R T Adolacion, Darren Heeke, Ivan Liadi, Mario L Marques-Piubelli, Luisa M Solis, Ankit Mahendra, Francisco Vega, Laurence Jn Cooper, Harjeet Singh, Mike Mattie, Adrian Bot, Sattva S Neelapu, Navin Varadarajan

Faculty, Staff and Student Publications

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with …

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 …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Tatiana V Karpinets, Xiaogang Wu, Travis Solley, Molly B El Alam, Travis T Sims, Kyoko Yoshida-Court, Erica Lynn, Mustapha Ahmed-Kaddar, Greyson Biegert, Jingyan Yue, Xingzhi Song, Huandong Sun, Joseph F Petrosino, Melissa P Mezzari, Pablo Okhuysen, Patricia J Eifel, Anuja Jhingran, Lilie L Lin, Kathleen M Schmeler, Lois Ramondetta, Nadim Ajami, Robert R Jenq, Andrew Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi …

Reproductive Health Perspectives Of Young Women With Perinatally And Behaviourally Acquired Hiv: A Qualitative Study, Lizelle Comfort, Dana Watnick, Melissa Peskin, Julie Gutierrez, Jacob Abadi, Jessica Atrio

Faculty, Staff and Student Publications

INTRODUCTION: The aim of this study was to describe the sexual and reproductive goals of female adolescents with human immunodeficiency virus (HIV) in an urban cohort and decipher if they vary depending on the mode of HIV acquisition.

METHODS: We conducted in-depth qualitative interviews with 25 Black and/or Hispanic/Latinx female adolescents living with HIV (14 perinatally, 11 behaviourally acquired) aged 17-25 years who have access to care and antiretroviral therapy at an urban public hospitals (NYC, NY). Interviews were transcribed, coded and analysed using thematic analysis.

RESULTS: Interviews demonstrated that access to antiretroviral therapy and HIV disclosure to a sexual …

Epigenetic Grimage Acceleration And Cognitive Impairment In Bipolar Disorder, Camila N C Lima, Robert Suchting, Giselli Scaini, Valeria A Cuellar, Alexandra Del Favero-Campbell, Consuelo Walss-Bass, Jair C Soares, Joao Quevedo, Gabriel R Fries

Faculty, Staff and Student Publications

Bipolar disorder (BD) has been previously associated with clinical signs of premature aging, including accelerated epigenetic aging in blood and brain, and a steeper age-related decline in cognitive function. However, the clinical drivers and cognitive correlates of epigenetic aging in BD are still unknown. We aimed to investigate the relationship between multiple measures of epigenetic aging acceleration with clinical, functioning, and cognitive outcomes in patients with BD and controls. Blood genome-wide DNA methylation levels were measured in BD patients (n = 153) and matched healthy controls (n = 50) with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic age estimates were calculated …

National Network Of Depression Centers' Recommendations On Harmonizing Clinical Documentation Of Electroconvulsive Therapy, Peter P Zandi, Michael Morreale, Irving M Reti, Daniel F Maixner, William M Mcdonald, Paresh D Patel, Eric Achtyes, Mahendra T Bhati, Brent R Carr, Susan K Conroy, Mario Cristancho, Marc J Dubin, Andrew Francis, Kara Glazer, Wendy Ingram, Khurshid Khurshid, Shawn M Mcclintock, Omar F Pinjari, Kevin Reeves, Nelson F Rodriguez, Shirlene Sampson, Stephen J Seiner, Salih Selek, Yvette Sheline, Roy W Smetana, Takahiro Soda, Nicholas T Trapp, Jesse H Wright, Mustafa Husain, Richard D Weiner

Faculty, Staff and Student Publications

Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best …

Revisiting Sex Differences In The Acquisition And Extinction Of Threat Conditioning In Humans, Zhenfu Wen, Jamie Fried, Edward F Pace-Schott, Sara W Lazar, Mohammed R Milad

Faculty, Staff and Student Publications

Findings pertaining to sex differences in the acquisition and extinction of threat conditioning, a paradigm widely used to study emotional homeostasis, remain inconsistent, particularly in humans. This inconsistency is likely due to multiple factors, one of which is sample size. Here, we pooled functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) data from multiple studies in healthy humans to examine sex differences during threat conditioning, extinction learning, and extinction memory recall. We observed increased functional activation in males, relative to females, in multiple parietal and frontal (medial and lateral) cortical regions during acquisition of threat conditioning and extinction …

Efficacy And Safety Of Topical Hypericin Photodynamic Therapy For Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The Flash Phase 3 Randomized Clinical Trial, Ellen J Kim, Aaron R Mangold, Jennifer A Desimone, Henry K Wong, Lucia Seminario-Vidal, Joan Guitart, James Appel, Larisa Geskin, Edward Lain, Neil J Korman, Nathalie Zeitouni, Neda Nikbakht, Kenneth Dawes, Oleg Akilov, Joi Carter, Michi Shinohara, Timothy M Kuzel, Warren Piette, Neal Bhatia, Amy Musiek, David Pariser, Youn H Kim, Dirk Elston, Erin Boh, Madeleine Duvic, Auris Huen, Theresa Pacheco, Jeffrey P Zwerner, Seung Tae Lee, Michael Girardi, Christiane Querfeld, Kimberly Bohjanen, Elise Olsen, Gary S Wood, Adam Rumage, Oreola Donini, Andrea Haulenbeek, Christopher J Schaber, Richard Straube, Christopher Pullion, Alain H Rook, Brian Poligone

Faculty, Staff and Student Publications

IMPORTANCE: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).

OBJECTIVES: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL.

DESIGN, SETTINGS, AND PARTICIPANTS: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 …

Informed Consent For Placebo-Controlled Trials: Do Ethics And Science Conflict?, Hope A Feldman, James A Feldman, Charles C Miller, Garrett Walsh, Jon E Tyson

Faculty, Staff and Student Publications

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled …

Distinguishing Intrathyroid Parathyroid Adenoma From Colloid Nodules And Papillary Thyroid Carcinomas Using Multiphasic Multidetector Computed Tomography, J Matthew Debnam, T Linda Chi, Michael Kwon, Jia Sun, Dawid Schellingerhout, Brandon T Golant, Salmaan Ahmed, Nancy D Perrier, Thinh Vu

Faculty, Staff and Student Publications

OBJECTIVE: The aim of the study is to determine whether multiphase multidetector computed tomography (4D-MDCT) can differentiate between intrathyroid parathyroid adenomas (ITPAs), colloid nodules, and papillary thyroid carcinoma (PTC).

METHODS: We studied 22 ITPAs, 22 colloid nodules, and 11 PTCs in 55 patients. Hounsfield unit (HU) values of the nodules were measured on 4D-MDCT in the precontrast, arterial, venous, and delayed phases. Raw HU values, phase with peak enhancement, and washout percentages between the phases were evaluated.

RESULTS: Regardless of size, all ITPAs (22/22) showed peak enhancement in the arterial phase, which was significantly greater than both colloid nodules (15/22) …

Amphotericin B Resistance In Leishmania Mexicana: Alterations To Sterol Metabolism And Oxidative Stress Response, Edubiel A Alpizar-Sosa, Nur Raihana Binti Ithnin, Wenbin Wei, Andrew W Pountain, Stefan K Weidt, Anne M Donachie, Ryan Ritchie, Emily A Dickie, Richard J S Burchmore, Paul W Denny, Michael P Barrett

Faculty, Staff and Student Publications

Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of …

Mass Transport Model Of Radiation Response: Calibration And Application To Chemoradiation For Pancreatic Cancer, Charles X Wang, Dalia Elganainy, Mohamed M Zaid, Joseph D Butner, Anshuman Agrawal, Sara Nizzero, Bruce D Minsky, Emma B Holliday, Cullen M Taniguchi, Grace L Smith, Albert C Koong, Joseph M Herman, Prajnan Das, Anirban Maitra, Huamin Wang, Robert A Wolff, Matthew H G Katz, Christopher H Crane, Vittorio Cristini, Eugene J Koay

Faculty, Staff and Student Publications

PURPOSE: The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).

METHODS AND MATERIALS: We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the …

A New Pathogenic Polg Variant, S Nicholas Russo, Ekta G Shah, William C Copeland, Mary Kay Koenig

Faculty, Staff and Student Publications

POLG gene mutations are the most common causes of inherited mitochondrial disorders. The enzyme produced by this gene is responsible for the replication and repair of mitochondrial DNA. To date, around 300 pathogenic variants have been described in this gene. The resulting clinical outcomes of POLG mutations are widely variable in both phenotype and severity. There is considerable overlap in the phenotype of the so-called POLG syndromes with no clear genotype-phenotype correlation. Here we describe a newly discovered pathogenic variant in the POLG gene in a 7-year-old male that died of uncontrollable refractory status epilepticus. Genetic epilepsy panel sequencing identified …

Addressing Patient Heterogeneity In Disease Predictive Model Development, Xu Gao, Weining Shen, Jing Ning, Ziding Feng, Jianhua Hu

Faculty, Staff and Student Publications

This paper addresses patient heterogeneity associated with prediction problems in biomedical applications. We propose a systematic hypothesis testing approach to determine the existence of patient subgroup structure and the number of subgroups in patient population if subgroups exist. A mixture of generalized linear models is considered to model the relationship between the disease outcome and patient characteristics and clinical factors, including targeted biomarker profiles. We construct a test statistic based on expectation maximization (EM) algorithm and derive its asymptotic distribution under the null hypothesis. An important computational advantage of the test is that the involved parameter estimates under the complex …

Bintrafusp Alfa, An Anti-Pd-L1:Tgf-Β Trap Fusion Protein, In Patients With Ctdna-Positive, Liver-Limited Metastatic Colorectal Cancer, Van K Morris, Michael J Overman, Michael Lam, Christine M Parseghian, Benny Johnson, Arvind Dasari, Kanwal Raghav, Bryan K Kee, Ryan Huey, Robert A Wolff, John Paul Shen, June Li, Isabel Zorrilla, Ching-Wei D Tzeng, Hop S Tran Cao, Yun Shin Chun, Timothy E Newhook, Nicolas Vauthey, Dzifa Duose, Raja Luthra, Cara Haymaker, Scott Kopetz

Faculty, Staff and Student Publications

Background: Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) CRC, increased TGF-β signaling results in exclusion of anti-tumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor ("TGF-β trap") and anti-PD-L1 antibody.

Methods: Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1200 mg of BA intravenously every 14 days …

Coronary-To-Coronary Bypass Grafting In Aortoarteritis: A Case Report, Immaneni Sathyamurthy, Narra Lavanya, Kanthallu Narayanamoorthy Srinivasan, Maligail Ramkrishna Girinath

Faculty, Staff and Student Publications

Takayasu's arteritis (TA) is an idiopathic vasculitis affecting the aorta and its major branches. In TA, coronary artery involvement is rare and it mainly consists of stenosis or occlusion of the coronary ostia. In TA, as the arterial tree is diseased, often, arterial grafts are unsuitable for grafting so the saphenous vein grafts (SVG) are commonly used. We present a case of a young female with TA with an ostial left main stenosis who has undergone a right coronary-to-left anterior descending artery SVG and put on immunosuppression and steroids. She was asymptomatic with a patent graft during 7 years follow-up.

Apoptotic Brown Adipocytes Enhance Energy Expenditure Via Extracellular Inosine, Birte Niemann, Saskia Haufs-Brusberg, Laura Puetz, Martin Feickert, Michelle Y Jaeckstein, Anne Hoffmann, Jelena Zurkovic, Markus Heine, Eva-Maria Trautmann, Christa E Müller, Anke Tönjes, Christian Schlein, Azin Jafari, Holger K Eltzschig, Thorsten Gnad, Matthias Blüher, Natalie Krahmer, Peter Kovacs, Joerg Heeren, Alexander Pfeifer

Faculty, Staff and Student Publications

Brown adipose tissue (BAT) dissipates energy

Membrane-Anchored And Tumor-Targeted Il12 (Attil12)-Pbmc Therapy For Osteosarcoma, Qing Yang, Jiemiao Hu, Zhiliang Jia, Qi Wang, Jing Wang, Long Hoang Dao, Wendong Zhang, Sheng Zhang, Xueqing Xia, Richard Gorlick, Shulin Li

Faculty, Staff and Student Publications

Purpose: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.

Experimental design: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.

Results: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. …

Estrogen-Related Receptor Alpha Is An Ampk-Regulated Factor That Promotes Ischemic Muscle Revascularization And Recovery In Diet-Induced Obese Mice, Danesh H Sopariwala, Andrea S Rios, Mi Kyung Park, Min Sup Song, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Obesity and type II diabetes are leading causes of peripheral arterial disease (PAD), which is characterized by vascular insufficiency and ischemic damage in the limb skeletal muscle. Glycemic control is not sufficient to prevent progression of PAD, and molecular targets that can promote muscle neo-angiogenesis in obesity and diabetes remain poorly defined. Here, we have investigated whether nuclear receptor estrogen-related receptor alpha (ERRα) can promote ischemic revascularization in the skeletal muscles of diet-induced obese (DIO) mice. Using muscle-specific ERRα transgenic mice, we found that ERRα overexpression promotes revascularization, marked by increased capillary staining and muscle perfusion in DIO mice after …

Hepatic Circadian And Differentiation Factors Control Liver Susceptibility For Fatty Liver Disease And Tumorigenesis, Baharan Fekry, Aleix Ribas-Latre, Rachel Van Drunen, Rafael Bravo Santos, Samay Shivshankar, Yulin Dai, Zhongming Zhao, Seung-Hee Yoo, Zheng Chen, Kai Sun, Frances M Sladek, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased …

Mir-486 Is Essential For Muscle Function And Suppresses A Dystrophic Transcriptome, Adrienne Samani, Rylie M Hightower, Andrea L Reid, Katherine G English, Michael A Lopez, J Scott Doyle, Michael J Conklin, David A Schneider, Marcas M Bamman, Jeffrey J Widrick, David K Crossman, Min Xie, David Jee, Eric C Lai, Matthew S Alexander

Faculty, Staff and Student Publications

miR-486 is a muscle-enriched microRNA, or “myomiR,” that has reduced expression correlated with Duchenne muscular dystrophy (DMD). To determine the function of miR-486 in normal and dystrophin-deficient muscles and elucidate miR-486 target transcripts in skeletal muscle, we characterized mir-486 knockout mice (mir-486 KO). mir-486 KO mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects were exacerbated in mir-486 KO:mdx5cv (DKO) mice. To identify direct in vivo miR-486 muscle target transcripts, we integrated RNA sequencing and chimeric miRNA eCLIP sequencing to identify key transcripts and pathways that contribute towards mir-486 …

Dockopathies: A Systematic Review Of The Clinical Pathologies Associated With Human Dock Pathogenic Variants, Adrienne Samani, Katherine G English, Michael A Lopez, Camille L Birch, Donna M Brown, Gurpreet Kaur, Elizabeth A Worthey, Matthew S Alexander

Faculty, Staff and Student Publications

The Dedicator of Cytokinesis (DOCK) family (DOCK1-11) of genes are essential mediators of cellular migration, growth, and fusion in a variety of cell types and tissues. Recent advances in whole-genome sequencing of patients with undiagnosed genetic disorders have identified several rare pathogenic variants in DOCK genes. We conducted a systematic review and performed a patient database and literature search of reported DOCK pathogenic variants that have been identified in association with clinical pathologies such as global developmental delay, immune cell dysfunction, muscle hypotonia, and muscle ataxia among other categories. We then categorized these pathogenic DOCK variants and their associated clinical …

Informed Consent For Placebo-Controlled Trials: Do Ethics And Science Conflict?, Hope A Feldman, James A Feldman, Charles C Miller, Garrett Walsh, Jon E Tyson

Faculty, Staff and Student Publications

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled …

The Effect Of Body Mass Index On Therapeutic Response To Bacterial Vaginosis In Pregnancy, Kevin P Lee, Misha V Koshelev, D3code Team, Omar Pacha

Faculty, Staff and Student Publications

No abstract provided.

Repeatability And Reproducibility Assessment Of The Apparent Diffusion Coefficient In The Prostate: A Trial Of The Ecog-Acrin Research Group (Acrin 6701), Michael A Boss, Bradley S Snyder, Eunhee Kim, Dena Flamini, Sarah Englander, Karthik M Sundaram, Naveen Gumpeni, Suzanne L Palmer, Haesun Choi, Adam T Froemming, Thorsten Persigehl, Matthew S Davenport, Dariya Malyarenko, Thomas L Chenevert, Mark A Rosen

Faculty, Staff and Student Publications

Background: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.

Purpose: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting.

Study type: Prospective multi-institutional.

Subjects: Twenty-nine males, ages 53 to 80 (median 63) …

Patient-Reported Bowel And Urinary Function In Long-Term Survivors Of Squamous Cell Carcinoma Of The Anus Treated With Definitive Intensity Modulated Radiation Therapy And Concurrent Chemotherapy, Brian De, Kelsey L Corrigan, Michael K Rooney, Ethan B Ludmir, Prajnan Das, Grace L Smith, Cullen M Taniguchi, Bruce D Minsky, Eugene J Koay, Albert Koong, Van K Morris, Craig A Messick, Y Nancy You, George J Chang, O Lenaine Westney, Graciela M Nogueras Gonzalez, Emma B Holliday

Faculty, Staff and Student Publications

Purpose: Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs).

Methods and materials: We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). …

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 …