Digital Commons Network^™

Stereotactic Body Radiotherapy With Or Without Selective Dismutase Mimetic In Pancreatic Adenocarcinoma: An Adaptive, Randomised, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial, Cullen M Taniguchi, Jessica M Frakes, Todd A Aguilera, Manisha Palta, Brian Czito, Manoop S Bhutani, Lauren E Colbert, Joseph Abi Jaoude, Vincent Bernard, Shubham Pant, Ching-Wei D Tzeng, Dae Won Kim, Mokenge Malafa, James Costello, Geena Mathew, Neal Rebueno, Eugene J Koay, Prajnan Das, Ethan B Ludmir, Matthew H G Katz, Robert A Wolff, Sam Beddar, Gabriel O Sawakuchi, Shalini Moningi, Rebecca S Slack Tidwell, Ying Yuan, Peter F Thall, Robert A Beardsley, Jon Holmlund, Joseph M Herman, Sarah E Hoffe

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma.

METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six …

Multipar: Supervised Irregular Tensor Factorization With Multi-Task Learning For Computational Phenotyping, Yifei Ren, Jian Lou, Li Xiong, Joyce C Ho, Xiaoqian Jiang, Sivasubramanium Venkatraman Bhavani

Faculty, Staff and Student Publications

Tensor factorization has received increasing interest due to its intrinsic ability to capture latent factors in multi-dimensional data with many applications including Electronic Health Records (EHR) mining. PARAFAC2 and its variants have been proposed to address irregular tensors where one of the tensor modes is not aligned, e.g., different patients in EHRs may have different length of records. PARAFAC2 has been successfully applied to EHRs for extracting meaningful medical concepts (phenotypes). Despite recent advancements, current models' predictability and interpretability are not satisfactory, which limits its utility for downstream analysis. In this paper, we propose MULTIPAR: a supervised irregular tensor factorization …

Larotrectinib Efficacy And Safety In Adult Patients With Tropomyosin Receptor Kinase Fusion Sarcomas, Shivaani Kummar, Lin Shen, David S Hong, Ray Mcdermott, Vicki L Keedy, Michela Casanova, George D Demetri, Afshin Dowlati, Soledad Gallego Melcón, Ulrik N Lassen, Serge Leyvraz, Tianshu Liu, Victor Moreno, Jyoti Patel, Tejas Patil, Atrayee Basu Mallick, Nuno Sousa, Makoto Tahara, David S Ziegler, Ricarda Norenberg, Pierre Arvis, Nicoletta Brega, Alexander Drilon, Daniel S W Tan

Faculty, Staff and Student Publications

Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas.

Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021.

Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M Kurimchak, Isabella V Trachtenberg, Timothy J Purwin, Jelan I Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A Davies, J Silvio Gutkind, Jeffrey L Benovic, James S Duncan, Andrew E Aplin

Faculty, Staff and Student Publications

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Localization, Tissue Biology, And T Cell State — Implications For Cancer Immunotherapy, Jason M Schenkel, Kristen E Pauken

Faculty, Staff and Student Publications

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this …

Enhanced Tp53 Reactivation Disrupts Myc Transcriptional Program And Overcomes Venetoclax Resistance In Acute Myeloid Leukemias, Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B Ostermann, Muharrem Muftuoglu, Vivian R Ruvolo, Tallie Patsilevas, Darah A Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z Carter, Steffen Boettcher, Benjamin L Ebert, Naval G Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff

Faculty, Staff and Student Publications

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a …

Huntington Study Group's Neuropsychology Working Group: Implementing Non-Motor Diagnostic Criteria, Ciaran M Considine, M Agustina Rossetti, Victor A Del Bene, Kendra Anderson, Sharlet A Anderson, Andrea S Celka, Mary C Edmondson, Amelia L Nelson-Sheese, Adam Piccolino, Antonio L Teixeira, Julie C Stout

Faculty, Staff and Student Publications

Background: The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD-consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non-motor diagnostic criteria for HD.

Objectives: To provide (1) a recommended clinical approach toward non-motor diagnostic criteria in persons with HD …

Relapse Recovery In Relapsing-Remitting Multiple Sclerosis: An Analysis Of The Combirx Dataset, Marcus W Koch, Ester Moral, Luis Brieva, Jop Mostert, Eva Mm Strijbis, Jacynthe Comtois, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Gary Cutter

Faculty, Staff and Student Publications

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery.

OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS).

METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to …

Systematic Review And Meta-Analysis Of The Association Between Radiation Therapy Treatment Volume And Patient Outcomes, Jerry Ye Aung Kyaw, Alice Rendall, Erin F Gillespie, Tom Roques, Laurence Court, Yolande Lievens, Alison C Tree, Chris Frampton, Ajay Aggarwal

Faculty, Staff and Student Publications

Purpose: Evidence of a volume-outcome association in cancer surgery has shaped the centralization of cancer services; however, it is unknown whether a similar association exists for radiation therapy. The objective of this study was to determine the association between radiation therapy treatment volume and patient outcomes.

Methods and materials: This systematic review and meta-analysis included studies that compared outcomes of patients who underwent definitive radiation therapy at high-volume radiation therapy facilities (HVRFs) versus low-volume facilities (LVRFs). The systematic review used Ovid MEDLINE and Embase. For the meta-analysis, a random effects model was used. Absolute effects and hazard ratios (HRs) were …

An Update On The Management Of Advanced Phase Chronic Myeloid Leukemia, Nicholas J Short, Jayastu Senapati, Elias Jabbour

Faculty, Staff and Student Publications

Purpose of review: While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management.

Recent findings: Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of …

Evaluation Of Potential Role Of R-Loop And G-Quadruplex Dna In The Fragility Of C-Myc During Chromosomal Translocation Associated With Burkitt's Lymphoma, Nitu Kumari, Kohal Das, Shivangi Sharma, Sumedha Dahal, Sagar Sanjiv Desai, Urbi Roy, Anju Sharma, Meghana Manjunath, Vidya Gopalakrishnan, S T Retheesh, Saniya M Javadekar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness …

The Risk Index As A Basis For Risk/Benefit Analyses And Protocol Optimization In Diagnostic Nuclear Imaging, Juan C Ocampo Ramos, Lukas M Carter, Justin L Brown, Harry Marquis, Carlos F Uribe, Pat B Zanzonico, Wesley E Bolch, Adam L Kesner

Faculty, Staff and Student Publications

Background: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex.

Purpose: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure …

Droid: Dose-Ranging Approach To Optimizing Dose In Oncology Drug Development, Beibei Guo, Ying Yuan

Faculty, Staff and Student Publications

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to …

Radiation-Induced Innate Neutrophil Response In Tumor Is Mediated By The Cxcls/Cxcr2 Axis, Faya Zhang, Oscar Mulvaney, Erica Salcedo, Subrata Manna, James Z Zhu, Tao Wang, Chul Ahn, Laurentiu M Pop, Raquibul Hannan

Faculty, Staff and Student Publications

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24-48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune …

Recurrent Oropharyngeal Squamous Cell Carcinomas Maintain Anti-Tumor Immunity And Multinucleation Levels Following Completion Of Radiation, Patricia Castro, Germán Corredor, Can Koyuncu, Luke A Nordstrom, Michelle Tiji, Taylor Leavitt, James S Lewis, Anant Madabhushi, Mitchell J Frederick, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology.

METHODS: We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms.

RESULTS: Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors …

Benefits And Concerns Of Expanded Carrier Screening: What Do Pregnant Latina Women In Texas Think?, Embedzayi Madhiri, Haocen Wang, Melodie Tedross, Victoria Vidal, Christine Young, Denise Martinez, Wei-Ju Chen, Patricia Robbins-Furman, Robin Page, Nora Montalvo-Liendo, Lei-Shih Chen

Faculty, Staff and Students Publications

The American College of Medical Genetics and Genomics (ACMG) recommends carrier screening for all pregnant women regardless of race or ethnicity. In recent years, the ACMG broadened the guidelines to include expanded carrier screening (ECS) which can screen for 112 conditions. This study seeks to explore the perceptions of pregnant Latina women about the benefits and concerns related to ECS use. Partnering with prenatal clinics in Texas, we conducted semi-structured qualitative interviews with 32 pregnant Latina women in their second or third trimester of pregnancy. NVivo 8 was used to conduct content analysis and emergent coding of the data. Participants …

Modulating A Prebiotic Food Source Influences Inflammation And Immune-Regulating Gut Microbes And Metabolites: Insights From The Be Gone Trial, Xiaotao Zhang, Ehsan Irajizad, Kristi L Hoffman, Johannes F Fahrmann, Fangyu Li, Yongwoo David Seo, Gladys J Browman, Jennifer B Dennison, Jody Vykoukal, Pamela N Luna, Wesley Siu, Ranran Wu, Eunice Murage, Nadim J Ajami, Jennifer L Mcquade, Jennifer A Wargo, James P Long, Kim-Anh Do, Johanna W Lampe, Karen M Basen-Engquist, Pablo C Okhuysen, Scott Kopetz, Samir M Hanash, Joseph F Petrosino, Paul Scheet, Carrie R Daniel

Faculty, Staff and Student Publications

BACKGROUND: Accessible prebiotic foods hold strong potential to jointly target gut health and metabolic health in high-risk patients. The BE GONE trial targeted the gut microbiota of obese surveillance patients with a history of colorectal neoplasia through a straightforward bean intervention.

METHODS: This low-risk, non-invasive dietary intervention trial was conducted at MD Anderson Cancer Center (Houston, TX, USA). Following a 4-week equilibration, patients were randomized to continue their usual diet without beans (control) or to add a daily cup of study beans to their usual diet (intervention) with immediate crossover at 8-weeks. Stool and fasting blood were collected every 4 …

Type 2 Diabetes Modifies The Association Of Cad Genomic Risk Variants With Subclinical Atherosclerosis, Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S De Vries

Faculty, Staff and Student Publications

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 …

Whole-Genome Sequencing Uncovers Two Loci For Coronary Artery Calcification And Identifies Arse As A Regulator Of Vascular Calcification, Paul S De Vries, Matthew P Conomos, Kuldeep Singh, Christopher J Nicholson, Deepti Jain, Natalie R Hasbani, Wanlin Jiang, Sujin Lee, Christian L Lino Cardenas, Sharon M Lutz, Doris Wong, Xiuqing Guo, Jie Yao, Erica P Young, Catherine Tcheandjieu, Austin T Hilliard, Joshua C Bis, Lawrence F Bielak, Michael R Brown, Shaila Musharoff, Shoa L Clarke, James G Terry, Nicholette D Palmer, Lisa R Yanek, Huichun Xu, Nancy Heard-Costa, Jennifer Wessel, Margaret Sunitha Selvaraj, Rebecca H Li, Xiao Sun, Adam W Turner, Adrienne M Stilp, Alyna Khan, Anne B Newman, Asif Rasheed, Barry I Freedman, Brian G Kral, Caitlin P Mchugh, Chani Hodonsky, Danish Saleheen, David M Herrington, David R Jacobs, Deborah A Nickerson, Eric Boerwinkle, Fei Fei Wang, Gerardo Heiss, Goo Jun, Greg L Kinney, Haakon H Sigurslid, Harshavardhan Doddapaneni, Ira M Hall, Isabela M Bensenor, Jai Broome, James D Crapo, James G Wilson, Jennifer A Smith, John Blangero, Jose D Vargas, Jose Verdezoto Mosquera, Joshua D Smith, Karine A Viaud-Martinez, Kathleen A Ryan, Kendra A Young, Kent D Taylor, Leslie A Lange, Leslie S Emery, Marcio S Bittencourt, Matthew J Budoff, May E Montasser, Miao Yu, Michael C Mahaney, Mohammed S Mahamdeh, Myriam Fornage, Nora Franceschini, Paulo A Lotufo, Pradeep Natarajan, Quenna Wong, Rasika A Mathias, Richard A Gibbs, Ron Do, Roxana Mehran, Russell P Tracy, Ryan W Kim, Sarah C Nelson, Scott M Damrauer, Sharon L R Kardia, Stephen S Rich, Valentin Fuster, Valerio Napolioni, Wei Zhao, Wenjie Tian, Xianyong Yin, Yuan-I Min, Alisa K Manning, Gina Peloso, Tanika N Kelly, Christopher J O'Donnell, Alanna C Morrison, Joanne E Curran, Warren M Zapol, Donald W Bowden, Lewis C Becker, Adolfo Correa, Braxton D Mitchell, Bruce M Psaty, John Jeffrey Carr, Alexandre C Pereira, Themistocles L Assimes, Nathan O Stitziel, John E Hokanson, Cecelia A Laurie, Jerome I Rotter, Ramachandran S Vasan, Wendy S Post, Patricia A Peyser, Clint L Miller, Rajeev Malhotra

Faculty, Staff and Student Publications

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying …

Estradiol Mediates Colonic Epithelial Protection In Aged Mice After Stroke And Is Associated With Shifts In The Gut Microbiome, Juneyoung Lee, Pedram Peesh, Victoria Quaicoe, Chunfeng Tan, Anik Banerjee, Patrick Mooz, Bhanu P Ganesh, Joseph Petrosino, Robert M Bryan, Louise D Mccullough, Venugopal Reddy Venna

Faculty, Staff and Student Publications

The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young …

Ezh2 Cooperates With Brd4-Nut To Drive Nut Carcinoma Growth By Silencing Key Tumor Suppressor Genes, Yeying Huang, R Taylor Durall, Nhi M Luong, Hans J Hertzler, Julianna Huang, Prafulla C Gokhale, Brittaney A Leeper, Nicole S Persky, David E Root, Praju V Anekal, Paula D L M Montero Llopis, Clement N David, Jeffery L Kutok, Alejandra Raimondi, Karan Saluja, Jia Luo, Cynthia A Zahnow, Biniam Adane, Kimberly Stegmaier, Catherine E Hawkins, Christopher Ponne, Quan Le, Geoffrey I Shapiro, Madeleine E Lemieux, Kyle P Eagen, Christopher A French

Faculty, Staff and Student Publications

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple …

Crispr-Cas9-Based Functional Interrogation Of Unconventional Translatome Reveals Human Cancer Dependency On Cryptic Non-Canonical Open Reading Frames, Caishang Zheng, Yanjun Wei, Peng Zhang, Kangyu Lin, Dandan He, Hongqi Teng, Ganiraju Manyam, Zhao Zhang, Wen Liu, Hye Rin Lindsay Lee, Ximing Tang, Wei He, Nelufa Islam, Antrix Jain, Yulun Chiu, Shaolong Cao, Yarui Diao, Sherita Meyer-Gauen, Magnus Höök, Anna Malovannaya, Wenbo Li, Ming Hu, Wenyi Wang, Han Xu, Scott Kopetz, Yiwen Chen

Faculty, Staff and Student Publications

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a …

Nonsense Variant Prdm16-Q187x Causes Impaired Myocardial Development And Tgf-Β Signaling Resulting In Noncompaction Cardiomyopathy In Humans And Mice, Bo Sun, Omid M T Rouzbehani, Ryan J Kramer, Rajeshwary Ghosh, Robin M Perelli, Sage Atkins, Amir Nima Fatahian, Kathryn Davis, Marta W Szulik, Michael A Goodman, Marissa A Hathaway, Ellenor Chi, Tarah A Word, Hari Tunuguntla, Susan W Denfield, Xander H T Wehrens, Kevin J Whitehead, Hala Y Abdelnasser, Junco S Warren, Mingfu Wu, Sarah Franklin, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans.

METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated …

Differentiating Desquamating Skin Lesions: A Case Of Methotrexate Epidermal Necrosis, Sahifah Ansari, Dina H Zamil, Edgar Rodriguez, Carly Dunn, Soo Jung Kim

Faculty, Staff and Students Publications

Desquamating skin lesions are a non-specific finding that requires urgent evaluation given the life-threatening severity of one of the potential causes, Stevens-Johnson syndrome (SJS). Methotrexate toxicity, also known in its cutaneous form as methotrexate epidermal necrosis (MEN), is another entity that presents similarly to SJS and is described here in a patient with increased risk due to his age, chronic kidney disease, and increased dose of methotrexate. His diagnosis was complicated by other historical risk factors, including antibiotic use, but was eventually elucidated when he was noted to have bone marrow suppression. Given the pathophysiology of SJS, a T-cell mediated …

Elevating The Educational Mission Of "Full-Service" Core Facilities Through Formal Biotechnology Workshops, Emily Ricco, Stacy Nguyen, Victoria Rodriguez, Kieu Pham, Esmanur Tokcan, Sherita Love, Alana Newell, Daniel C Kraushaar

Faculty, Staff and Students Publications

Core facility laboratories are an essential part of the successful research enterprise of many universities around the world. Core facilities provide state-of-the-art instrumentation and technologies to support research of all faculty, postdocs, and students on a fee-for-service basis. Academic next-generation sequencing cores are typically "full service" facilities, and access to and training on their instrumentation is limited to core staff. To address these limitations, we provided graduate students with technical training at our core facility. We developed a 1-week noncredit-bearing workshop and recruited 6 graduate students (N = 6) as part of a pilot program. The program involved online teaching, …

Steroid Receptor Coactivator-2 Drives Epithelial Reprogramming That Enables Murine Embryo Implantation, Vineet K Maurya, Maria M Szwarc, David M Lonard, Ramakrishna Kommagani, San Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Although we have shown that steroid receptor coactivator-2 (SRC-2), a member of the p160/SRC family of transcriptional coregulators, is essential for decidualization of both human and murine endometrial stromal cells, SRC-2’s role in the earlier stages of the implantation process have not been adequately addressed. Using a conditional SRC-2 knockout mouse (SRC-2 ^d/d) in timed natural pregnancy studies, we show that endometrial SRC-2 is required for embryo attachment and adherence to the luminal epithelium. Implantation failure is associated with the persistent expression of Mucin 1 and E-cadherin on the apical surface and basolateral adherens junctions of the SRC-2 …

A Multisociety Delphi Consensus Statement On New Fatty Liver Disease Nomenclature, Mary E Rinella, Jeffrey V Lazarus, Vlad Ratziu, Sven M Francque, Arun J Sanyal, Fasiha Kanwal, Diana Romero, Manal F Abdelmalek, Quentin M Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher D Byrne, Graciela E Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna R Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D Guy, Stephen A Harrison, Seung Up Kim, Bart G Koot, Marko Korenjak, Kris V Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R Morgan, Elisabeth E Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C Sookoian, C Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N Newsome, Nafld Nomenclature Consensus Group

Faculty, Staff and Students Publications

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 …

Trajectories Of Egfr And Risk Of Albuminuria In Youth With Type 2 Diabetes: Results From The Today Cohort Study, Laure El Ghormli, Hui Wen, Diane Uschner, Morey W Haymond, Kara S Hughan, Katherine Kutney, Lori Laffel, Sherida E Tollefsen, Elia N Escaname, Jane Lynch, Petter Bjornstad, Today Study Group

Faculty, Staff and Students Publications

BACKGROUND: We conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

METHODS: Annual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories.

RESULTS: At baseline, participants' mean age …

Radiographic And Clinical Outcomes With Particle Or Liquid Embolic Agents For Middle Meningeal Artery Embolization Of Nonacute Subdural Hematomas, Jonathan P Scoville, Evan Joyce, Daniel A Tonetti, Michael T Bounajem, Ajith Thomas, Christopher S Ogilvy, Justin M Moore, Howard A Riina, Omar Tanweer, Elad I Levy, Alejandro M Spiotta, Bradley A Gross, Brian T Jankowitz, C Michael Cawley, Alexander A Khalessi, Aditya S Pandey, Andrew J Ringer, Ricardo Hanel, Rafael A Ortiz, David Langer, Michael R Levitt, Mandy Binning, Philipp Taussky, Peter Kan, Ramesh Grandhi

Faculty, Staff and Students Publications

BACKGROUND: Middle meningeal artery (MMA) embolization is an apparently efficacious minimally invasive treatment for nonacute subdural hematomas (NASHs), but how different embolisates affect outcomes remains unclear. Our objective was to compare radiographic and clinical outcomes after particle or liquid MMA embolization.

METHODS: Patients who had MMA embolization for NASH were retrospectively identified from a multi-institution database. The primary radiographic and clinical outcomes-50% NASH thickness reduction and need for surgical retreatment within 90 days, respectively-were compared for liquid and particle embolizations in patients treated 1) without surgical intervention (upfront), 2) after recurrence, or 3) with concomitant surgery (prophylactic).

RESULTS: The upfront, …

Chimeric Antigen Receptor T Cells In Hodgkin And T-Cell Lymphomas, Ibrahim N Muhsen, Laquisa C Hill, Carlos A Ramos

Faculty, Staff and Students Publications

The authors review the current use of chimeric antigen receptor (CAR)-transduced T cells (CAR-T) in Hodgkin lymphoma (HL) and T-cell lymphomas (TCL) and discuss the data on CD30-targeting CAR-T cells, which seem to be safe and effective in HL. In addition, the authors examine the use of CAR-T cells targeting CD30, CD5, or CD7 in TCL, while highlighting the unique challenges of their use in this subset of lymphomas. Furthermore, the authors present future directions and ongoing trials investigating the use of CAR-T cells in TCL and HL.