Digital Commons Network^™

Standardisation Of Protocols Can Be Crucial In Long Non-Coding Rna Research, Kinga Németh, George A Calin

Faculty, Staff and Student Publications

In this issue, Traversa et al. [1] reviewed our current knowledge about the role of circular and linear forms of PVT1 non-coding RNA in cancer and human diseases. They highlighted the technical challenges of these studies and raised a potential bias in the publications, which require more attention from researchers.

Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable With Isolated Isochromosome 17q Represents A Distinct Clinico-Biologic Subset: A Multi-Institutional Collaborative Study From The Bone Marrow Pathology Group, Rashmi Kanagal-Shamanna, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Kaaren Reichard, Eric D Hsi, Adam Bagg, Heesun Joyce Rogers, Julia Geyer, Faezeh Darbaniyan, Kim-Anh Do, Kyle M Devins, Olga Pozdnyakova, Tracy I George, Paola Dal Cin, Patricia T Greipp, Mark J Routbort, Keyur Patel, Guillermo Garcia-Manero, Srdan Verstovsek, L Jeffrey Medeiros, Sa A Wang, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated …

Pgc1Α/Β Expression Predicts Therapeutic Response To Oxidative Phosphorylation Inhibition In Ovarian Cancer, Carmen Ghilardi, Catarina Moreira-Barbosa, Laura Brunelli, Paola Ostano, Nicolò Panini, Monica Lupi, Alessia Anastasia, Fabio Fiordaliso, Monica Salio, Laura Formenti, Massimo Russo, Edoardo Arrigoni, Ferdinando Chiaradonna, Giovanna Chiorino, Giulio Draetta, Joseph R Marszalek, Christopher P Vellano, Roberta Pastorelli, Mariarosa Bani, Alessandra Decio, Raffaella Giavazzi

Faculty, Staff and Student Publications

Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1β (PGC1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling …

Camk2/Camkii Activates Mlkl In Short-Term Starvation To Facilitate Autophagic Flux, Qionghui Zhan, Jaepyo Jeon, Ying Li, Yu Huang, Jian Xiong, Qiaochu Wang, Tian-Le Xu, Yong Li, Fu-Hai Ji, Guangwei Du, Michael X Zhu

Faculty, Staff and Student Publications

MLKL (mixed lineage kinase domain like pseudokinase) is a well-known core component of necrosome that executes necroptotic cell death upon phosphorylation by RIPK3 (receptor interacting serine/threonine kinase 3). Recent studies also implicate a role of MLKL in endosomal trafficking, which is not always dependent on RIPK3. Using mouse Neuro-2a and L929 as well as human HEK293 and HT29 cells, we show here that MLKL is phosphorylated in response to serum and amino acid deprivation from the culture medium, in a manner that depends on CAMK2/CaMKII (calcium/calmodulin dependent protein kinase II) but not RIPK3. The starvation-induced increase in MLKL phosphorylation was …

Alterations Of The Mdm2 C-Terminus Differentially Impact Its Function In Vivo, Vinod Pant, Neeraj K Aryal, Shunbin Xiong, Gilda P Chau, Natalie W Fowlkes, Guillermina Lozano

Faculty, Staff and Student Publications

Murine double minute 2 (Mdm2) is the principal E3-ubiquitin ligase for p53 and contains a C2H2C4 type RING domain wherein the last cysteine residue is followed by an evolutionarily conserved 13 amino acid C-terminal tail. Previous studies have indicated that integrity of the C-terminal tail is critical for Mdm2 function. Recently, a mutation extending the MDM2 length by five amino acids was identified and associated with enhanced p53 response in fibroblasts and premature aging in a human patient. To investigate the importance of the conserved Mdm2 C-terminal length on p53 regulatory function in vivo, we engineered three novel mouse alleles …

Β-Adrenergic Signaling In Skin Cancer, Jennifer Batalla-Covello, Shahrukh Ali, Tongxin Xie, Moran Amit

Faculty, Staff and Student Publications

Activation of the sympathetic nervous system releases catecholamines that can interact with β-adrenergic receptors on tumor cells. Preclinical models have shown that the signaling processes initiated by activation of β-adrenergic receptors increase tumorigenesis, stimulate cell proliferation, and inhibit apoptosis. Indeed, preclinical studies have also shown that β-adrenergic blockade can decrease tumor burden. Researchers have been studying the effects of β-adrenergic receptor blockers on tumor cells and how they may slow the progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Moreover, clinical data have shown improved prognosis in patients with skin cancer who take β-blockers. This review discusses the …

Inhibition Of Bcl2a1 By Stat5 Inactivation Overcomes Resistance To Targeted Therapies Of Flt3-Itd/D835 Mutant Aml, Kotoko Yamatani, Tomohiko Ai, Kaori Saito, Koya Suzuki, Atsushi Hori, Sonoko Kinjo, Kazuho Ikeo, Vivian Ruvolo, Weiguo Zhang, Po Yee Mak, Bogumil Kaczkowski, Hironori Harada, Kazuhiro Katayama, Yoshikazu Sugimoto, Jered Myslinski, Takashi Hato, Takashi Miida, Marina Konopleva, Yoshihide Hayashizaki, Bing Z Carter, Yoko Tabe, Michael Andreeff

Faculty, Staff and Student Publications

Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and …

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses, Andrew Fedoriw, Leilei Shi, Shane O'Brien, Kimberly N Smitheman, Yunfei Wang, Jiakai Hou, Christian Sherk, Satyajit Rajapurkar, Jenny Laraio, Leila J Williams, Chunyu Xu, Guangchun Han, Qin Feng, Mark T Bedford, Linghua Wang, Olena Barbash, Ryan G Kruger, Patrick Hwu, Helai P Mohammad, Weiyi Peng

Faculty, Staff and Student Publications

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I …

Comparative Molecular Genomic Analyses Of A Spontaneous Rhesus Macaque Model Of Mismatch Repair-Deficient Colorectal Cancer, Nejla Ozirmak Lermi, Stanton B Gray, Charles M Bowen, Laura Reyes-Uribe, Beth K Dray, Nan Deng, R Alan Harris, Muthuswamy Raveendran, Fernando Benavides, Carolyn L Hodo, Melissa W Taggart, Karen Colbert Maresso, Krishna M Sinha, Jeffrey Rogers, Eduardo Vilar

Faculty, Staff and Student Publications

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Effect Of Perfluorocarbon Composition On Activation Of Phase-Changing Ultrasound Contrast Agents, Trevor M Mitcham, Dmitry Nevozhay, Yunyun Chen, Linh D Nguyen, Gianmarco F Pinton, Stephen Y Lai, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

BACKGROUND: While microbubble contrast agents (MCAs) are commonly used in ultrasound (US), they are inherently limited to vascular targets due to their size. Alternatively, phase-changing nanodroplet contrast agents (PNCAs) can be delivered as nanoscale agents (i.e., small enough to extravasate), but when exposed to a US field of sufficient mechanical index (MI), they convert to MCAs, which can be visualized with high contrast using nonlinear US.

PURPOSE: To investigate the effect of perfluorocarbon (PFC) core composition and presence of cholesterol in particle coatings on stability and image contrast generated from acoustic activation of PNCAs using high-frequency US suitable for clinical …

Notch-Induced Mdsc Recruitment After Ohsv Virotherapy In Cns Cancer Models Modulates Antitumor Immunotherapy, Yoshihiro Otani, Ji Young Yoo, Cole T Lewis, Samantha Chao, Jessica Swanner, Toshihiko Shimizu, Jin Muk Kang, Sara A Murphy, Kimberly Rivera-Caraballo, Bangxing Hong, Joseph C Glorioso, Hiroshi Nakashima, Sean E Lawler, Yeshavanth Banasavadi-Siddegowda, John D Heiss, Yuanqing Yan, Guangsheng Pei, Michael A Caligiuri, Zhongming Zhao, E Antonio Chiocca, Jianhua Yu, Balveen Kaur

Faculty, Staff and Student Publications

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy.

EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.

RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Citation Analysis Of The Most Influential Ependymoma Research Articles Illustrates Improved Knowledge Of The Molecular Biology Of Ependymoma, Nolan J Brown, Bayard Wilson, Brian V Lien, Alexander Himstead, Ali R Tafreshi, Shane Shahrestani, Jack Birkenbeuel, Katelynn Tran, David Horton, Anushka Paladugu, Lydia R Kirillova, Chen Yi Yang, Seth C Ransom, Ronald Sahyouni, Isaac Yang

Faculty, Staff and Student Publications

The history of academic research on ependymoma is expansive. This review summarizes its history with a bibliometric analysis of the 100 most cited articles on ependymoma. In March 2020, we queried the Web of Science database to identify the most cited articles on ependymoma using the terms "ependymoma" or "ependymal tumors," yielding 3145 publications. Results were arranged by the number of times each article was cited in descending order. The top 100 articles spanned across nearly a century; the oldest article was published in 1924, while the most recent was in 2017. These articles were published in 35 unique journals, …

Predictive Radiation Oncology - A New Nci-Doe Scientific Space And Community, Jeffrey C Buchsbaum, David A Jaffray, Demba Ba, Lynn L Borkon, Christine Chalk, Caroline Chung, Matthew A Coleman, C Norman Coleman, Maximilian Diehn, Kelvin K Droegemeier, Heiko Enderling, Michael G Espey, Emily J Greenspan, Christopher M Hartshorn, Thuc Hoang, H Timothy Hsiao, Cynthia Keppel, Nathan W Moore, Fred Prior, Eric A Stahlberg, Georgia Tourassi, Karen E Willcox

Faculty, Staff and Student Publications

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, …

Enzymatic Characterization Of Mrna Cap Adenosine-N6 Methyltransferase Pcif1 Activity On Uncapped Rnas, Dan Yu, Nan Dai, Eric J Wolf, Ivan R Corrêa, Jujun Zhou, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

The phosphorylated RNA polymerase II CTD interacting factor 1 (PCIF1) is a methyltransferase that adds a methyl group to the N6-position of 2′O-methyladenosine (Am), generating N6, 2′O-dimethyladenosine (m6Am) when Am is the cap-proximal nucleotide. In addition, PCIF1 has ancillary methylation activities on internal adenosines (both A and Am), although with much lower catalytic efficiency relative to that of its preferred cap substrate. The PCIF1 preference for 2′O-methylated Am over unmodified A nucleosides is due mainly to increased binding affinity for Am. Importantly, it was recently reported that PCIF1 can methylate viral RNA. Although some viral RNA can be translated in …

An Efficient Magnetic Resonance Image Data Quality Screening Dashboard, Evan D H Gates, Adrian Celaya, Dima Suki, Dawid Schellingerhout, David Fuentes

Faculty, Staff and Student Publications

Purpose: Complex data processing and curation for artificial intelligence applications rely on high-quality data sets for training and analysis. Manually reviewing images and their associated annotations is a very laborious task and existing quality control tools for data review are generally limited to raw images only. The purpose of this work was to develop an imaging informatics dashboard for the easy and fast review of processed magnetic resonance (MR) imaging data sets; we demonstrated its ability in a large-scale data review.

Methods: We developed a custom R Shiny dashboard that displays key static snapshots of each imaging study and its …

Cell Type-Specific Roles Of Stat3 Signaling In The Pathogenesis And Progression Of K-Ras Mutant Lung Adenocarcinoma, Michael J Clowers, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of K-ras and/or its cooperating pathways. Tumor-promoting inflammation, an enabling hallmark of cancer, strongly participates in the development and progression of KM-LUAD. However, our knowledge of the dynamic inflammatory mechanisms, immunomodulatory pathways, and cell-specific molecular signals mediating K-ras-induced lung tumorigenesis is substantially deficient. Nevertheless, within this signaling complexity, an inflammatory pathway is emerging as a druggable target: signal …

Prmt7 Ablation Stimulates Anti-Tumor Immunity And Sensitizes Melanoma To Immune Checkpoint Blockade, Nivine Srour, Oscar D Villarreal, Swanand Hardikar, Zhenbao Yu, Samuel Preston, Wilson H Miller, Magdelena M Szewczyk, Dalia Barsyte-Lovejoy, Han Xu, Taiping Chen, Sonia V Del Rincón, Stéphane Richard

Faculty, Staff and Student Publications

Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression of genes in the interferon pathway, antigen presentation, and chemokine signaling. PRMT7 deficiency or inhibition with SGC3027 in B16.F10 melanoma results in reduced DNMT expression, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs) …

Wwox Binding To The Murine Brca1-Brct Domain Regulates Timing Of Brip1 And Ctip Phospho-Protein Interactions With This Domain At Dna Double-Strand Breaks, And Repair Pathway Choice, Dongju Park, Mehdi Gharghabi, Colleen R Reczek, Rebecca Plow, Charles Yungvirt, C Marcelo Aldaz, Kay Huebner

Faculty, Staff and Student Publications

Wwox-deficient human cells show elevated homologous recombination, leading to resistance to killing by double-strand break-inducing agents. Human Wwox binds to the Brca1 981-PPLF-984 Wwox-binding motif, likely blocking the pChk2 phosphorylation site at Brca1-S988. This phosphorylation site is conserved across mammalian species; the PPLF motif is conserved in primates but not in rodents. We now show that murine Wwox does not bind Brca1 near the conserved mouse Brca1 phospho-S971 site, leaving it open for Chk2 phosphorylation and Brca1 activation. Instead, murine Wwox binds to Brca1 through its BRCT domain, where pAbraxas, pBrip1, and pCtIP, of the A, B, and C binding …

Anti-Tumor Activity Of Cetuximab Plus Avelumab In Non-Small Cell Lung Cancer Patients Involves Innate Immunity Activation: Findings From The Cave-Lung Trial, Carminia Maria Della Corte, Morena Fasano, Vincenza Ciaramella, Flora Cimmino, Robert Cardnell, Carl M Gay, Kavya Ramkumar, Lixia Diao, Raimondo Di Liello, Giuseppe Viscardi, Vincenzo Famiglietti, Davide Ciardiello, Giulia Martini, Stefania Napolitano, Concetta Tuccillo, Teresa Troiani, Erika Martinelli, Jing Wang, Lauren Byers, Floriana Morgillo, Fortunato Ciardiello

Faculty, Staff and Student Publications

BACKGROUND: We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab.

METHODS: We report long-term clinical follow-up and additional …

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation For B-Lineage Acute Lymphoblastic Leukemia, Mahmoud R Gaballa, Pinaki Banerjee, Denái R Milton, Xianli Jiang, Christina Ganesh, Sajad Khazal, Vandana Nandivada, Sanjida Islam, Mecit Kaplan, May Daher, Rafet Basar, Amin Alousi, Rohtesh Mehta, Gheath Alatrash, Issa Khouri, Betul Oran, David Marin, Uday Popat, Amanda Olson, Priti Tewari, Nitin Jain, Elias Jabbour, Farhad Ravandi, Hagop Kantarjian, Ken Chen, Richard Champlin, Elizabeth Shpall, Katayoun Rezvani, Partow Kebriaei

Faculty, Staff and Student Publications

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the …

Temperature Changes During Implant Osteotomy Preparations In Fresh Human Cadaver Tibiae, Comparing Straight With Tapered Drills, Nikolaos Soldatos, Laura Nelson-Rabe, Nathan Palanker, Nikola Angelov, Georgios Romanos, Robin Weltman

Faculty, Staff and Student Publications

The success of osseointegration depends on many factors. With temperatures beyond a 47 °C threshold over 1 min, bone survival may be impaired. The purpose of the study was to evaluate, in fresh human cadaver tibiae, the temperature changes during osteotomy preparations using two straight and two tapered implant systems' drills, external irrigation, and varying revolutions per minute (RPM). The tibiae from a fresh female cadaver were harvested bilaterally. Two tapered and two straight design drills were assessed. Two-hundred and forty osteotomies were prepared at 6 mm depth following the drill sequence of the manufacturers' protocol for each drilling speed. …

Micrornas In Leukemias: A Clinically Annotated Compendium, Aleksander Turk, George A Calin, Tanja Kunej

Faculty, Staff and Student Publications

Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved …

Targeted Dual-Modal Pet/Spect-Nir Imaging: From Building Blocks And Construction Strategies To Applications, Syed Muhammad Usama, Sierra C Marker, Servando Hernandez Vargas, Solmaz Aghaamiri, Sukhen C Ghosh, Naruhiko Ikoma, Hop S Tran Cao, Martin J Schnermann, Ali Azhdarinia

Faculty, Staff and Student Publications

Molecular imaging is an emerging non-invasive method to qualitatively and quantitively visualize and characterize biological processes. Among the imaging modalities, PET/SPECT and near-infrared (NIR) imaging provide synergistic properties that result in deep tissue penetration and up to cell-level resolution. Dual-modal PET/SPECT-NIR agents are commonly combined with a targeting ligand (e.g., antibody or small molecule) to engage biomolecules overexpressed in cancer, thereby enabling selective multimodal visualization of primary and metastatic tumors. The use of such agents for (i) preoperative patient selection and surgical planning and (ii) intraoperative FGS could improve surgical workflow and patient outcomes. However, the development of targeted dual-modal …

Fusionai, A Dna-Sequence-Based Deep Learning Protocol Reduces The False Positives Of Human Fusion Gene Prediction, Pora Kim, Hua Tan, Jiajia Liu, Himansu Kumar, Xiaobo Zhou

Faculty, Staff and Student Publications

Even though there were many tool developments of fusion gene prediction from NGS data, too many false positives are still an issue. Wise use of the genomic features around the fusion gene breakpoints will be helpful to identify reliable fusion genes efficiently. For this aim, we developed FusionAI, a deep learning pipeline predicting human fusion gene breakpoints from DNA sequence. FusionAI is freely available via https://compbio.uth.edu/FusionGDB2/FusionAI. For complete details on the use and execution of this protocol, please refer to Kim et al. (2021b).

Proteomic Profiling Based Classification Of Cll Provides Prognostication For Modern Therapy And Identifies Novel Therapeutic Targets, Ti'ara L Griffen, Fieke W Hoff, Yihua Qiu, James W Lillard, Alessandra Ferrajoli, Philip Thompson, Endurance Toro, Kevin Ruiz, Jan Burger, William Wierda, Steven M Kornblau

Faculty, Staff and Student Publications

Protein expression for 384 total and post-translationally modified proteins was assessed in 871 CLL and MSBL patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteomics identified six recurrent signatures that were highly prognostic of survival and time to first or second treatment at three levels: individual proteins, when grouped into 40 functionally related groups (PFGs), and systemically in signatures (SGs). A novel SG characterized by hairy cell leukemia like proteomics but poor therapy response was discovered. SG membership superseded other prognostic factors (Rai Staging, …

Bigmouth: Development And Maintenance Of A Successful Dental Data Repository, Muhammad F Walji, Heiko Spallek, Krishna Kumar Kookal, Jane Barrow, Britta Magnuson, Tamanna Tiwari, Udochukwu Oyoyo, Michael Brandt, Brian J Howe, Gary C Anderson, Joel M White, Elsbeth Kalenderian

Faculty, Staff and Student Publications

Few clinical datasets exist in dentistry to conduct secondary research. Hence, a novel dental data repository called BigMouth was developed, which has grown to include 11 academic institutions contributing Electronic Health Record data on over 4.5 million patients. The primary purpose for BigMouth is to serve as a high-quality resource for rapidly conducting oral health-related research. BigMouth allows for assessing the oral health status of a diverse US patient population; provides rationale and evidence for new oral health care delivery modes; and embraces the specific oral health research education mission. A data governance framework that encouraged data sharing while controlling …

Synergy Of Venetoclax And 8-Chloro-Adenosine In Aml: The Interplay Of Rrna Inhibition And Fatty Acid Metabolism, Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen

Faculty, Staff and Student Publications

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado …

Elucidating Mechanisms Of Genetic Cross-Disease Associations At The Procr Vascular Disease Locus, David Stacey, Lingyan Chen, Paulina J Stanczyk, Joanna M M Howson, Amy M Mason, Stephen Burgess, Stephen Macdonald, Jonathan Langdown, Harriett Mckinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S De Vries, Nicholas L Smith, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Nilesh J Samani, Shu Ye, Charlotte Summers, Edwin R Chilvers, John Danesh, Dirk S Paul

Faculty, Staff and Student Publications

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, …

Analysis Of The Circrna And T-Ucr Populations Identifies Convergent Pathways In Mouse And Human Models Of Rett Syndrome, Edilene Siqueira, Aida Obiols-Guardia, Olga C Jorge-Torres, Cristina Oliveira-Mateos, Marta Soler, Deepthi Ramesh-Kumar, Fernando Setién, Daniëlle Van Rossum, Ainhoa Pascual-Alonso, Clara Xiol, Cristina Ivan, Masayoshi Shimizu, Judith Armstrong, George A Calin, R Jeroen Pasterkamp, Manel Esteller, Sonia Guil

Faculty, Staff and Student Publications

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key …