Medical Specialties Commons^™

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …

Multitrait Genome-Wide Analyses Identify New Susceptibility Loci And Candidate Drugs To Primary Sclerosing Cholangitis, Younghun Han, Jinyoung Byun, Catherine Zhu, Ryan Sun, Julia Y Roh, Heather J Cordell, Hyun-Sung Lee, Vikram R Shaw, Sung Wook Kang, Javad Razjouyan, Matthew A Cooley, Manal M Hassan, Katherine A Siminovitch, Trine Folseraas, David Ellinghaus, Annika Bergquist, Simon M Rushbrook, Andre Franke, Tom H Karlsen, Konstantinos N Lazaridis, Kathryn A. Mcglynn, Katherine A Mcglynn, Lewis R Roberts, Christopher I Amos, International Psc Study Group

Faculty, Staff and Students Publications

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug …

Banking On Virus-Specific T Cells To Fulfill The Need For Off-The-Shelf Cell Therapies, David H Quach, Premal Lulla, Cliona M Rooney

Faculty, Staff and Students Publications

Adoptively transferred virus-specific T cells (VSTs) have shown remarkable safety and efficacy for the treatment of virus-associated diseases and malignancies in hematopoietic stem cell transplant (HSCT) recipients, for whom VSTs are derived from the HSCT donor. Autologous VSTs have also shown promise for the treatment of virus-driven malignancies outside the HSCT setting. In both cases, VSTs are manufactured as patient-specific products, and the time required for procurement, manufacture, and release testing precludes their use in acutely ill patients. Further, Good Manufacturing Practices-compliant products are expensive, and failures are common in virus-naive HSCT donors and patient-derived VSTs that are rendered anergic …

Developing A Standardized But Extendable Framework To Increase The Findability Of Infectious Disease Datasets, Ginger Tsueng, Marco A Alvarado Cano, José Bento, Candice Czech, Mengjia Kang, Lars Pache, Luke V Rasmussen, Tor C Savidge, Justin Starren, Qinglong Wu, Jiwen Xin, Michael R Yeaman, Xinghua Zhou, Andrew I Su, Chunlei Wu, Liliana Brown, Reed S Shabman, Laura D Hughes

Faculty, Staff and Students Publications

Biomedical datasets are increasing in size, stored in many repositories, and face challenges in FAIRness (findability, accessibility, interoperability, reusability). As a Consortium of infectious disease researchers from 15 Centers, we aim to adopt open science practices to promote transparency, encourage reproducibility, and accelerate research advances through data reuse. To improve FAIRness of our datasets and computational tools, we evaluated metadata standards across established biomedical data repositories. The vast majority do not adhere to a single standard, such as Schema.org, which is widely-adopted by generalist repositories. Consequently, datasets in these repositories are not findable in aggregation projects like Google Dataset Search. …

Natural Killer T Cells And Other Innate-Like T Lymphocytes As Emerging Platforms For Allogeneic Cancer Cell Therapy, Amy N Courtney, Gengwen Tian, Leonid S Metelitsa

Faculty, Staff and Students Publications

T cells expressing chimeric antigen receptors (CARs) have achieved major clinical success in patients with hematologic malignancies. However, these treatments remain largely ineffective for solid cancers and require significant time and resources to be manufactured in an autologous setting. Developing alternative immune effector cells as cancer immunotherapy agents that can be employed in allogeneic settings is crucial for the advancement of cell therapy. Unlike T cells, Vα24-invariant natural killer T cells (NKTs) are not alloreactive and can therefore be generated from allogeneic donors for rapid infusion into numerous patients without the risk of graft-versus-host disease. Additionally, NKT cells demonstrate inherent …

Addressing Barriers In Fair Data Practices For Biomedical Data, Laura D Hughes, Ginger Tsueng, Jack Digiovanna, Thomas D Horvath, Luke V Rasmussen, Tor C Savidge, Thomas Stoeger, Serdar Turkarslan, Qinglong Wu, Chunlei Wu, Andrew I Su, Lars Pache, Niaid Systems Biology Data Dissemination Working Group

Faculty, Staff and Students Publications

No abstract provided.

Macroh2a Histone Variants Modulate Enhancer Activity To Repress Oncogenic Programs And Cellular Reprogramming, Wazim Mohammed Ismail, Amelia Mazzone, Flavia G Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S Bagwell, Stephanie L Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A Leach, Luis F Duarte, Chandandeep S Nagi, Saul Carcamo, Chi-Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong-Heon Lee, Fergus J Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia

Faculty, Staff and Students Publications

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at …

Prenatal Detection Of A Foxf1 Deletion In A Fetus With Acdmpv And Hydronephrosis, Katarzyna Bzdęga, Anna Kutkowska-Kaźmierczak, Gail H Deutsch, Izabela Plaskota, Marta Smyk, Magdalena Niemiec, Artur Barczyk, Ewa Obersztyn, Jan Modzelewski, Iwona Lipska, Paweł Stankiewicz, Marzena Gajecka, Małgorzata Rydzanicz, Rafał Płoski, Tomasz Szczapa, Justyna A Karolak

Faculty, Staff and Students Publications

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by the arrest of fetal lung formation, resulting in neonatal death due to acute respiratory failure and pulmonary arterial hypertension. Heterozygous single-nucleotide variants or copy-number variant (CNV) deletions involving the FOXF1 gene and/or its lung-specific enhancer are found in the vast majority of ACDMPV patients. ACDMPV is often accompanied by extrapulmonary malformations, including the gastrointestinal, cardiac, or genitourinary systems. Thus far, most of the described ACDMPV patients have been diagnosed post mortem, based on histologic evaluation of the lung tissue and/or genetic testing. Here, …

Intellectual Disability Related To De Novo Germline Loss Of The Distal End Of The P-Arm Of Chromosome 17: A Case Report, Eden Pope, Matthew Huertas, Amar Paul, Braden Cunningham, Matthew Jennings, Ryan Perry, Stephanie Chavez, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

Hypothesis/Purpose: In this report we present a case of a 20-year-old female with congenital intellectual disability, stunted growth, and hypothyroidism. Competitive genetic hybridization (CHG) revealed a loss of 17p13.3, and the deletion was not present in either parent. This deletion has not previously been characterized, but mutations on the p-arm of chromosome 17 are responsible for Miller-Dieker Syndrome and Isolated Lissencephaly Sequence, both of which share symptoms in common with the patient.

Methods: Peripheral mononuclear cells (PBMCs) were used for karyotyping and competitive genetic hybridization (CHG). Bioinformatic analysis was carried out using the Genome Data Viewer (ncbi.nlm.nih.gov/genome/gdv).

Results: Karyotype was …

The Impact Of Procalcitonin In Assessing Outcomes In Pediatrics Severe Trauma Cases: A Three-Year Experience From A Tertiary Hospital, Waleed H. Albuali

BioMedicine

Background Although procalcitonin levels are raised in patients with systemic inflammation, its usage in pediatric patients, particularly those in the intensive care unit who are most susceptible to sepsis. Methods It is a retrospective research study that included pediatric patients aged more than two weeks who were brought to the King Fahd Hospital of the University's PICU owing to serious trauma or post-acute postoperative occurrences from January 2017 to December 2019. At 24 hours after admission, data such as age, gender, comorbidities, trauma severity as measured by the Injury Severity Score, and PRISM III score were collected. Results Following a …

Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney …

A Scanning-To-Incision Switch In Tfiih-Xpg Induced By Dna Damage Licenses Nucleotide Excision Repair, Amer Bralić, Muhammad Tehseen, Mohamed A Sobhy, Chi-Lin Tsai, Lubna Alhudhali, Gang Yi, Jina Yu, Chunli Yan, Ivaylo Ivanov, Susan E Tsutakawa, John A Tainer, Samir M Hamdan

Faculty, Staff and Student Publications

Nucleotide excision repair (NER) is critical for removing bulky DNA base lesions and avoiding diseases. NER couples lesion recognition by XPC to strand separation by XPB and XPD ATPases, followed by lesion excision by XPF and XPG nucleases. Here, we describe key regulatory mechanisms and roles of XPG for and beyond its cleavage activity. Strikingly, by combing single-molecule imaging and bulk cleavage assays, we found that XPG binding to the 7-subunit TFIIH core (coreTFIIH) stimulates coreTFIIH-dependent double-strand (ds)DNA unwinding 10-fold, and XPG-dependent DNA cleavage by up to 700-fold. Simultaneous monitoring of rates for coreTFIIH single-stranded (ss)DNA translocation and dsDNA unwinding …

Hyperprogression Of Cutaneous T Cell Lymphoma After Anti-Pd-1 Treatment, Yumei Gao, Simeng Hu, Ruoyan Li, Shanzhao Jin, Fengjie Liu, Xiangjun Liu, Yingyi Li, Yicen Yan, Weiping Liu, Jifang Gong, Shuxia Yang, Ping Tu, Lin Shen, Fan Bai, Yang Wang

Faculty, Staff and Student Publications

BACKGROUND

Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin’s lymphoma (T-NHL), but some patients with T-NHL have experienced hyperprogression with undetermined mechanisms upon anti–PD-1 therapy.

METHODS

Single-cell RNA-Seq, whole-genome sequencing, whole-exome sequencing, and functional assays were performed on primary malignant T cells from a patient with advanced cutaneous T cell lymphoma who experienced hyperprogression upon anti–PD-1 treatment.

RESULTS

The patient was enrolled in a clinical trial of anti–PD-1 therapy and experienced disease hyperprogression. Single-cell RNA-Seq revealed that PD-1 blockade elicited a remarkable activation and proliferation of the CD4+ malignant T cells, which showed functional PD-1 expression and …

Evofosfamide For The Treatment Of Human Papillomavirus-Negative Head And Neck Squamous Cell Carcinoma, Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D Mckee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P Mcivor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter

Faculty, Staff and Student Publications

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × …

Alternative Splicing Mediates The Compensatory Upregulation Of Mbnl2 Upon Mbnl1 Loss-Of-Function, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Lathan Lucas, Thomas A Cooper

Faculty, Staff and Students Publications

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while …

Asprosin Promotes Feeding Through Sk Channel-Dependent Activation Of Agrp Neurons, Bing Feng, Hesong Liu, Ila Mishra, Clemens Duerrschmid, Peiyu Gao, Pingwen Xu, Chunmei Wang, Yanlin He

Faculty, Staff and Students Publications

Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRPARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRPARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRPARH neurons, respectively. AgRPARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRPARH neurons) blocked asprosin-induced …

Investigating Respiratory Simplification Caused By Prenatal Rage Upregulation, Paul Reynolds

Annual Research Symposium

No abstract provided.

Potential Role For Rage In The Development Of Secondhand Smoke-Induced Chronic Sinusitis, Paul Reynolds

Annual Research Symposium

No abstract provided.

Rage Inhibition Reduces Timp And Decreases Cell Invasion In Cigarette Smoke Extract (Cse) Treated Oral Squamous Carcinoma Cells, Paul Reynolds

Annual Research Symposium

No abstract provided.

Inflammatory Cytokine Elaboration Following Secondhand Smoke Exposure Is Mediated In Part By Rage Signaling, Paul Reynolds

Annual Research Symposium

No abstract provided.

Rage Availability Lessens The Degree Of Dysfunctional Mitochondrial Bioenergetics Following Chronic Secondhand Smoke Exposure, Paul Reynolds

Annual Research Symposium

No abstract provided.

Gestational Dependent Responses To Second Hand Smoke (Shs) In Mouse Pregnancies, Paul Reynolds

Annual Research Symposium

No abstract provided.

Change In Basic Pulmonary Function With Change In Altitude, Jaden Arnold, Mindy Cook, Bivash Neupane, Erika Noonan Md, Rex Ripplinger Md

Annual Research Symposium

No abstract provided.

Reversible Emerging Neuropsychological Pattern In Chronic Intractable Migraine, Tanner Williford, Pooja Chemiti, Mason Allen, Brandon Burrell, Stephanie Chavez, Jude Emego, Bridger Gunter, Matthew Huertas, Matthew Jennings, Roshni Jogin, Paulo Kelly, Laura Minor, Steven Salazar, Jameson Williams, David W. Sant, John A. Kriak, Kyle B. Bills

Annual Research Symposium

No abstract provided.

Fixitfelix: Improving Genomic Analysis By Fixing Reference Errors, Sairam Behera, Jonathon Lefaive, Peter Orchard, Medhat Mahmoud, Luis F Paulin, Jesse Farek, Daniela C Soto, Stephen C J Parker, Albert V Smith, Megan Y Dennis, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The current version of the human reference genome, GRCh38, contains a number of errors including 1.2 Mbp of falsely duplicated and 8.04 Mbp of collapsed regions. These errors impact the variant calling of 33 protein-coding genes, including 12 with medical relevance. Here, we present FixItFelix, an efficient remapping approach, together with a modified version of the GRCh38 reference genome that improves the subsequent analysis across these genes within minutes for an existing alignment file while maintaining the same coordinates. We showcase these improvements over multi-ethnic control samples, demonstrating improvements for population variant calling as well as eQTL studies.

Promoting Health Equity: Identifying Parent And Child Reactions To A Culturally-Grounded Obesity Prevention Program Specifically Designed For Black Girls Using Community-Engaged Research, Haley Allen, Chishinga Callender, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

The Butterfly Girls (BFG) Study is a culturally and developmentally appropriate online obesity prevention program for 8-10-year-old Black girls designed with key stakeholders in the Black community. This multi-methods investigation, conducted with parent-child dyads who participated in an outcome evaluation of the intervention, aimed to understand parent and child reactions to the program. We were particularly interested in understanding perceptions regarding its cultural and developmental appropriateness, relevance and acceptability. Program participation and survey data (demographics, parent and child write-in comments on process evaluation surveys) were analyzed. Participation data demonstrated high adherence in treatment and comparison groups. Descriptive statistics were calculated …

Predicting Patient-Specific Tumor Dynamics: How Many Measurements Are Necessary?, Isha Harshe, Heiko Enderling, Renee Brady-Nicholls

Faculty, Staff and Student Publications

Acquiring sufficient data is imperative to accurately predict tumor growth dynamics and effectively treat patients. The aim of this study was to investigate the number of volume measurements necessary to predict breast tumor growth dynamics using the logistic growth model. The model was calibrated to tumor volume data from 18 untreated breast cancer patients using a varying number of measurements interpolated at clinically relevant timepoints with different levels of noise (0-20%). Error-to-model parameters and the data were compared to determine the sufficient number of measurements needed to accurately determine growth dynamics. We found that without noise, three tumor volume measurements …

Emerging Treatments For Myelodysplastic Syndromes: Biological Rationales And Clinical Translation, Juan Jose Rodriguez-Sevilla, Vera Adema, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients' only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS …

Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer

Faculty, Staff and Student Publications

Nontyphoidal salmonellosis is one of the most significant foodborne diseases in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics are available to treat complicated cases of the disease. However, antibiotic resistance is on the rise and new therapeutics are needed. We previously identified the Salmonella fraB gene, that mutation of causes attenuation of fitness in the murine gastrointestinal tract. The FraB gene product is encoded in an operon responsible for the uptake and utilization of fructose-asparagine (F-Asn), an Amadori product found in several human foods. Mutations in …

A Cryptic Oxidoreductase Safeguards Oxidative Protein Folding In Corynebacterium Diphtheriae, Melissa E Reardon-Robinson, Minh Tan Nguyen, Belkys C Sanchez, Jerzy Osipiuk, Christian Rückert, Chungyu Chang, Bo Chen, Rahul Nagvekar, Andrzej Joachimiak, Andreas Tauch, Asis Das, Hung Ton-That

Faculty, Staff and Student Publications

In many gram-positive Actinobacteria, including Actinomyces oris and Corynebacterium matruchotii, the conserved thiol-disulfide oxidoreductase MdbA that catalyzes oxidative folding of exported proteins is essential for bacterial viability by an unidentified mechanism. Intriguingly, in Corynebacterium diphtheriae, the deletion of mdbA blocks cell growth only at 37 °C but not at 30 °C, suggesting the presence of alternative oxidoreductase enzyme(s). By isolating spontaneous thermotolerant revertants of the mdbA mutant at 37 °C, we obtained genetic suppressors, all mapped to a single T-to-G mutation within the promoter region of tsdA, causing its elevated expression. Strikingly, increased expression of tsdA—via …