Genetic Phenomena Commons^™

High-Dose Chemotherapy And Autologous Stem Cell Transplantation For Relapsed Or Refractory Primary Mediastinal Large B-Cell Lymphoma, Hanan Alkhaldi, Alec Reinhardt, Melissa Barnett, Suprateek Kundu, Chitra Hosing, Jeremy Ramdial, Neeraj Saini, Samer Srour, Amin Alousi, Partow Kebriaei, Uday Popat, Muzaffar Qazilbash, Richard Champlin, Elizabeth J Shpall, Allison Gulbis, Terri Lynn Shigle, Bouthaina Dabaja, Chelsea Pinnix, Sairah Ahmed, Raphael Steiner, Borje S Andersson, Yago Nieto

Faculty, Staff and Student Publications

Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy with or without radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC), with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. The 60 study patients received either rituximab-BEAM (n = 37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) with or without vorinostat (n = 23), followed by ASCT. Forty-six patients received mediastinal RT, …

Exosomes Modified With Anti-Mek1 Sirna Lead To An Effective Silencing Of Triple Negative Breast Cancer Cells, Débora Ferreira, Cátia Santos-Pereira, Marta Costa, Julieta Afonso, Sujuan Yang, Janine Hensel, Kathleen M Mcandrews, Adhemar Longatto-Filho, Rui Fernandes, Joana B Melo, Fátima Baltazar, João N Moreira, Raghu Kalluri, Ligia R Rodrigues

Faculty, Staff and Student Publications

Triple negative breast cancer (TNBC) is a highly heterogenous disease not sensitive to endocrine or HER2 therapy and standardized treatment regimens are still missing. Therefore, development of novel TNBC treatment approaches is of utmost relevance. Herein, the potential of MAPK/ERK downregulation by RNAi-based therapeutics in a panel of mesenchymal stem-like TNBC cell lines was uncovered. Our data revealed that suppression of one of the central nodes of this signaling pathway, MEK1, affects proliferation, migration, and invasion of TNBC cells, that may be explained by the reversion of the epithelial-mesenchymal transition phenotype, which is facilitated by the MMP-2/MMP-9 downregulation. Moreover, an …

Care After Premenopausal Risk-Reducing Salpingo-Oophorectomy In High-Risk Women: Scoping Review And International Consensus Recommendations, Denise R Nebgen, Susan M Domchek, Joanne Kotsopoulos, Joanne A De Hullu, Emma J Crosbie, Vincent Singh Paramanandam, Monique M A Brood-Van Zanten, Barbara M Norquist, Theresa Guise, Serge Rozenberg, Allison W Kurian, Holly J Pederson, Nese Yuksel, Rachel Michaelson-Cohen, Sharon L Bober, Agnaldo Lopes Da Silva Filho, Nora Johansen, F Guidozzi, D Gareth Evans, Usha Menon, Sheryl A Kingsberg, C Bethan Powell, Giovanni Grandi, Claudia Marchetti, Michelle Jacobson, Donal J Brennan, Martha Hickey

Faculty, Staff and Student Publications

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Opioid-Free Discharge After Pancreatic Resection Through A Learning Health System Paradigm, Artem Boyev, Anish J Jain, Timothy E Newhook, Laura R Prakash, Yi-Ju Chiang, Morgan L Bruno, Elsa M Arvide, Whitney L Dewhurst, Michael P Kim, Jessica E Maxwell, Naruhiko Ikoma, Rebecca A Snyder, Jeffrey E Lee, Matthew H G Katz, Ching-Wei D Tzeng

Faculty, Staff and Student Publications

Importance: Postoperative opioid overprescribing leads to persistent opioid use and excess pills at risk for misuse and diversion. A learning health system paradigm using risk-stratified pancreatectomy clinical pathways (RSPCPs) may lead to reduction in inpatient and discharge opioid volume.

Objective: To analyze the outcomes of 2 iterative RSPCP updates on inpatient and discharge opioid volumes.

Design, setting, and participants: This cohort study included 832 consecutive adult patients at an urban comprehensive cancer center who underwent pancreatic resection between October 2016 and April 2022, comprising 3 sequential pathway cohorts (version [V] 1, October 1, 2016, to January 31, 2019 [n = …

Supportive Care For Dual Caregivers Who Care For Their Partner With Cancer And Their Young Children, Sujin Ann-Yi, Kathrin Milbury, Morgan Jones, Victoria Necroto, Meagan Whisenant, Yisheng Li, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Advanced cancer patients and their spouses who parent minor children report parenting concerns and increased psychological distress. This single-arm trial examined the feasibility and initial evidence for efficacy of a novel parent support program.

Methods: Patients with a metastatic solid malignancy and their spouses completed self-reported assessments of psychological distress (HADS), parenting concerns (PCQ) and efficacy (CaPSE) at baseline. Both patients and spouses jointly attended the first two sessions addressing illness communication and family routines. Spouses individually attended two additional sessions focusing on caregiver support and death preparedness. All four sessions were delivered via videoconference by a licensed psychological …

Engineering Cannabidiol Synergistic Carbon Monoxide Nanocomplexes To Enhance Cancer Therapy Via Excessive Autophagy, Chang Xiao, Yue Sun, Jialong Fan, William Nguyen, Simin Chen, Ying Long, Wei Chen, Aiguo Zhu, Bin Liu

Faculty, Staff and Student Publications

Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H2O2) to disintegrate into CO and Mn2+. The comprehensive effect of CO/Mn2+ and CBD can induce ROS-mediated cell apoptosis. In addition, …

Model-Informed Drug Development Of Autologous Car-T Cell Therapy: Strategies To Optimize Car-T Cell Exposure Leveraging Cell Kinetic/Dynamic Modeling, Anna M Mc Laughlin, Peter A Milligan, Cassian Yee, Martin Bergstrand

Faculty, Staff and Student Publications

Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other …

Style Transfer-Assisted Deep Learning Method For Kidney Segmentation At Multiphase Mri, Junyu Guo, Manu Goyal, Yin Xi, Lauren Hinojosa, Gaelle Haddad, Emin Albayrak, Ivan Pedrosa

Faculty, Staff and Student Publications

Purpose: To develop and validate a semisupervised style transfer-assisted deep learning method for automated segmentation of the kidneys using multiphase contrast-enhanced (MCE) MRI acquisitions.

Materials and methods: This retrospective, Health Insurance Portability and Accountability Act-compliant, institutional review board-approved study included 125 patients (mean age, 57.3 years; 67 male, 58 female) with renal masses. Cohort 1 consisted of 102 coronal T2-weighted MRI acquisitions and 27 MCE MRI acquisitions during the corticomedullary phase. Cohort 2 comprised 92 MCE MRI acquisitions (23 acquisitions during four phases each, including precontrast, corticomedullary, early nephrographic, and nephrographic phases). The kidneys were manually segmented on T2-weighted images. …

Texas Youth Depression And Suicide Research Network (Tx-Ydsrn) Research Registry And Learning Healthcare Network: Rationale, Design, And Baseline Characteristics, Madhukar H Trivedi, Abu Minhajuddin, Holli Slater, Regina Baronia, Joseph C Blader, Jamon Blood, Ryan Brown, Cynthia Claassen, Melissa Defilippis, David Farmer, Cynthia Garza, Jennifer L Hughes, Beth D Kennard, Israel Liberzon, Sarah Martin, Taryn L Mayes, Jair C Soares, Cesar A Soutullo, Eric A Storch, Sarah M Wakefield

Faculty, Staff and Student Publications

Background: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants.

Methods: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality …

Cardiac Muscle-Restricted Partial Loss Of Nos1ap Expression Has Limited But Significant Impact On Electrocardiographic Features, Alexa Smith, Dallas Auer, Morgan Johnson, Ernesto Sanchez, Holly Ross, Christopher Ward, Aravinda Chakravarti, Ashish Kapoor

Faculty, Staff and Student Publications

Genome-wide association studies have identified sequence polymorphisms in a functional enhancer of the NOS1AP gene as the most common genetic regulator of QT interval and human cardiac NOS1AP gene expression in the general population. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have also demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT …

Interobserver Variability And Challenges In Intraoperative Frozen Section Evaluation Of Pancreatic Margins In Pancreatectomy Specimens, Sadhna Dhingra, Melissa W Taggart, Wai Chin Foo, Asif Rashid, Maria Luisa Machado Heredia, Sarah B May, George Van Buren, William E Fisher, Huamin Wang

Faculty, Staff and Student Publications

Objective: Frozen-section evaluation of the pancreatic margin is challenging. We aimed to determine interobserver variability among gastrointestinal pathologists for the assessment of frozen sections of pancreatic margins with marked chronic pancreatitis and to determine the challenging histological features in discrepant cases.

Methods: We identified 45 patients who underwent pancreas resection for pancreatic ductal adenocarcinoma and showed marked chronic pancreatitis at pancreatic margin. Deidentified first levels of frozen-sections of the pancreatic margins from all cases were independently reviewed by 5 experienced gastrointestinal pathologists for the presence of carcinoma and/or high-grade dysplasia.

Results: Interobserver agreement among pathologists was calculated as kappa coefficients …

Dicarboxylic Acylcarnitine Biomarkers In Peroxisome Biogenesis Disorders, Michael F Wangler, Barbara Lesko, Rejwi Dahal, Sharayu Jangam, Pradnya Bhadane, Theodore E Wilson, Molly Mcpheron, Marcus J Miller

Duncan NRI Faculty and Staff Publications

The peroxisome is an essential eukaryotic organelle with diverse metabolic functions. Inherited peroxisomal disorders are associated with a wide spectrum of clinical outcomes and are broadly divided into two classes, those impacting peroxisome biogenesis (PBD) and those impacting specific peroxisomal factors. Prior studies have indicated a role for acylcarnitine testing in the diagnosis of some peroxisomal diseases through the detection of long chain dicarboxylic acylcarnitine abnormalities (C16-DC and C18-DC). However, there remains limited independent corroboration of these initial findings and acylcarnitine testing for peroxisomal diseases has not been widely adopted in clinical laboratories. To explore the utility of acylcarnitine testing …

The Influence Of Obesity On Outcomes With Immune Checkpoint Blockade: Clinical Evidence And Potential Biological Mechanisms, Andrew W Hahn, Neha Venkatesh, Pavlos Msaouel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we …

Correction: Microrna 603 Acts As A Tumor Suppressor And Inhibits Triple-Negative Breast Cancer Tumorigenesis By Targeting Elongation Factor 2 Kinase, Recep Bayraktar, Martin Pichler, Pinar Kanlikilicer, Cristina Ivan, Emine Bayraktar, Nermin Kahraman, Burcu Aslan, Serpil Oguztuzun, Mustafa Ulasli, Ahmet Arslan, George Calin, Gabriel Lopez-Berestein, Bulent Ozpolat

Faculty, Staff and Student Publications

No abstract provided.

The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao

Faculty, Staff and Student Publications

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in …

Irf1 Regulates Self-Renewal And Stress Responsiveness To Support Hematopoietic Stem Cell Maintenance, Alexandra J S Rundberg Nilsson, Hongxu Xian, Shabnam Shalapour, Jörg Cammenga, Michael Karin

Faculty, Staff and Student Publications

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in …

Rna-Based Translation Activators For Targeted Gene Upregulation, Yang Cao, Huachun Liu, Shannon S Lu, Krysten A Jones, Anitha P Govind, Okunola Jeyifous, Christine Q Simmons, Negar Tabatabaei, William N Green, Jimmy L Holder, Soroush Tahmasebi, Alfred L George, Bryan C Dickinson

Duncan NRI Faculty and Staff Publications

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. …

Decoding Meningioma Heterogeneity And Neoplastic Cell-Macrophage Interaction Through Single-Cell Transcriptome Profiling Across Pathological Grades, Hailang Fan, Lairong Song, Jian Fan, Junpeng Ma, Xiaojie Li, Junting Zhang, Jian Hu, Zhen Wu, Dake Zhang, Liang Wang

Faculty, Staff and Student Publications

Background: Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment.

Methods: We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, …

Methyl-Branched Liposomes As A Depot For Sustained Drug Delivery, Yang Li, Rachelle Shao, Claire A Ostertag-Hill, Matthew Torre, Ran Yan, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Inadequate drug loading and control of payload leakage limit the duration of the effect of liposomal drug carriers and may cause toxicity. Here, we report a liposome system as a depot for sustained drug delivery whose design is inspired by the low permeability of Archaeal membranes to protons and solutes. Incorporating methyl-branched phospholipids into lipid bilayers decreased payload diffusion across liposomal membranes, thereby enhancing the drug load capacity by 10-16% and reducing the release of small molecules in the first 24 h by 40-48%. The in vivo impact of this approach was demonstrated by injection at the sciatic nerve. Methyl-branched …

Uracil-Dna Glycosylase Of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently Of Its Catalytic Residues, Kyle R Smith, Somnath Paul, Qiwen Dong, Orchi Anannya, Darby G Oldenburg, J Craig Forrest, Kevin M Mcbride, Laurie T Krug

Faculty, Staff and Student Publications

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional …