Medicine and Health Sciences Commons^™

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 …

Loss Of Rnf43 Accelerates Kras-Mediated Neoplasia And Remodels The Tumor Immune Microenvironment In Pancreatic Adenocarcinoma, Abdel Nasser Hosein, Gita Dangol, Takashi Okumura, Jason Roszik, Kimal Rajapakshe, Megan Siemann, Mohamed Zaid, Bidyut Ghosh, Maria Monberg, Paola A Guerrero, Aatur Singhi, Cara L Haymaker, Hans Clevers, Lotfi Abou-Elkacem, Sonja M Woermann, Anirban Maitra

Faculty, Staff and Student Publications

Background & aims: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells.

Methods: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund …

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 …

Zanubrutinib For Treatment-Naïve And Relapsed/Refractory Chronic Lymphocytic Leukaemia: Long-Term Follow-Up Of The Phase I/Ii Au-003 Study, Akash Mukherjee, Denái R Milton, Elias J Jabbour, Alison M Gulbis, Tapan Kadia, Nitin Jain, Celina Ledesma, Jan Burger, Alessandra Ferrajoli, William Wierda, L Jeffrey Medeiros, Hagop Kantarjian, Richard Champlin, Issa F Khouri

Faculty, Staff and Student Publications

We aimed to study the risks of graft-versus-host disease (GVHD), non-relapse mortality (NRM) and survival outcomes of allogeneic stem cell transplantation (alloSCT) in patients with chronic lymphocytic leukemia (n = 17), Richter's syndrome (n = 14), or lymphoma (n = 18) after small molecule inhibitors (SMIs). Patients had a median of 4 prior therapies, including ibrutinib (n = 46; 94%), venetoclax (n = 19; 39%), and idelalisib (n = 6; 12%). Twenty-one (43%) had >1 SMI. P53 mutation was detected in 58% of patients. The 3-year overall and progression-free survival rates were 68% and …

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 …

The Paradox Of Immunosuppressants And Covid-19, Guang-Shing Cheng, Scott E Evans

Faculty, Staff and Student Publications

Lessons learned from a large registry analysis show worse COVID-19 outcomes for patients previously exposed to glucocorticoids https://bit.ly/306rNrk

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 …

Pan-Methylarginine Antibody Generation Using Peg Linked Gar Motifs As Antigens, Yalong Wang, Maria D Person, Mark T Bedford

Faculty, Staff and Student Publications

Arginine methylation is a prevalent posttranslational modification which is deposited by a family of protein arginine methyltransferases (PRMTs), and is found in three different forms in mammalian cells: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Pan-methylarginine antibodies are critical for identifying proteins that are methylated on arginine residues, and are also used for evaluating signaling pathways that modulate this methyltransferase activity. Although good pan-MMA, -ADMA and -SDMA antibodies have been developed over the years, there is still room for improvement. Here we use a novel antigen approach, which involves the separation of short methylated motifs with inert polyethylene …

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, …

Metformin Bicarbonate-Mediated Efficient Rnai For Precise Targeting Of Tp53 Deficiency In Colon And Rectal Cancers, Jiangsheng Xu, Yunhua Liu, Sheng Liu, Wenquan Ou, Alisa White, Samantha Stewart, Katherine H R Tkaczuk, Lee M Ellis, Jun Wan, Xiongbin Lu, Xiaoming He

Faculty, Staff and Student Publications

Colon and rectal cancers are the leading causes of cancer-related deaths in the United States and effective targeted therapies are in need for treating them. Our genomic analyses show hemizygous deletion of TP53, an important tumor suppressor gene, is highly frequent in both cancers, and the 5-year survival of patients with the more prevalent colon cancer is significantly reduced in the patients with the cancer harboring such deletion, although such reduction is not observed for rectal cancer. Unfortunately, direct targeting TP53 has been unsuccessful for cancer therapy. Interestingly, POLR2A, a gene essential for cell survival and proliferation, is …

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, …

Targeting Protein Degradation To Uncover Novel Oncoprotein Drivers Of Acute Leukemia, Fatemeh Keramatnia

Theses and Dissertations (ETD)

Acute Lymphoblastic Leukemia (ALL), the most common childhood cancer and the second most common acute leukemia in adults, arises from clonal expansion of undifferentiated lymphoid precursor cells in bone marrow. Despite the extensive knowledge on its cytogenetic and molecular biology, ALL treatment remains highly challenging especially after relapse. Conventional chemotherapy has shown significant improvement in overall survival rates of pediatric patients up to 90%, however, treatment failure due to ALL relapse occurs in 15-20% of the cases. On the other hand, adults and elderly patients with ALL are considered difficult to treat populations with the 5-year overall survival of 30–40%. …

Developing Targeted Therapies For T-Cell Acute Lymphoblastic Leukemia, Jianzhong Hu

Theses and Dissertations (ETD)

Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and risk-adapted chemotherapies have dramatically improved the outcomes of this disease. Compared to B-cell ALL, T-cell ALL (T-ALL) is more aggressive and has worse outcomes from chemotherapy. There is a great unmet need to develop biomarkers and novel targeted therapies for this type of cancer. Working together with internal and external collaborators, we performed a large-scale pharmacotyping assay in over 300 primary ALL samples. By combining pharmacotypying and genomic profiling of these samples, we identified a substantial T-ALL population that showed strong response to dasatinib, a known ABL1 …

A Quantitative Dose Pertubation Comparison Study Between Gold And Platinum Visicoil Fiducial Markers In Proton Beam Therapy, Xuanfeng Ding, Gang Liu, Weili Zheng, Jessica Vadas, Xiaoqiang Li, Lewei Zhao, An Qin, Daniel Krauss, Di Yan

Conference Presentation Abstracts

Purpose: To quantitatively investigate the dose perturbations difference between gold and platinum VISICOILTM fiducial markers in proton beam therapy Method: Gold and platinum VISICOILTM fiducial markers with two different dimensions were tested, including 0.35 & 0.5mm in diameter and 5mm in length. Total four kinds of markers. Gafchromic EBT2 was used to measure dose perturbations along the beam path in a ‘‘sandwich’’ setup (Figure 1). Dose perturbation was reported in each depth (0.3mm, 1.65mm, 3.00mm, 5.40mm, 7.80mm, 10.20mm, 12.60mm, 18.15mm). Relative proton stopping power relative to water were calculated through National Institute of Standards and Technology database and SRIM (version …

The First Modeling Of The Spot-Scanning Proton Arc(Sparc) Delivery Sequence And Investigating Its Efficiency Improvement, Xuanfeng Ding, Gang Liu, Lewei Zhao, Rohan Deraniyagala, Craig Stevens, Di Yan, Xiaoqiang Li

Conference Presentation Abstracts

Purpose: Introduce an experimental approach to model a precise prototype arc system and quantitatively assess its efficiency improvement in the routine proton clinical operation. Methods: The SPArc delivery sequence model(DSMSPArc) includes two kinds of parameters:(1) mechanical parameters. (2) irradiation parameters. Log files and an independent gantry inclinometer were used to derive the irradiation parameters through a series of test plans. The in-house DSMSPArc was established by fitting both mechanical and irradiation parameters. Eight SPArc plans from different disease sites were used to validate the model’s accuracy. To assess the treatment efficiency improvement, the DSMSPArc was used to simulate the SPArc …

A Direct Machine-Specific Parameters Incorporated Spot-Scanning Proton Arc (Sparc) Algorithm, Gang Liu, Lewei Zhao, Di Yan, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: To address the challenges of generating a deliverable and efficient spot-scanning proton arc (SPArc) plan for a proton therapy system. We developed a novel SPArc optimization algorithm (SPArcDMSP) by directly incorporating machinespecific parameters such as mechanical constraints and delivery sequence. Method and Material: A SPArc delivery sequence model (DSMarc) was built based on the machine-specific parameters of the prototype arc delivery system IBA ProteusONEt. The SPArcDMSP resamples and adjusts each control point’s delivery speed based on the DSMarc calculation through the iterative approach (Fig1). Users could set the expected delivery time and gantry max acceleration as a mechanical constraint …

Differences In Covid-19-Related Testing And Healthcare Utilization By Race And Ethnicity In The Veterans Health Administration, Javad Razjouyan, Drew A Helmer, Ang Li, Aanand D Naik, Christopher I Amos, Venkata Bandi, Amir Sharafkhaneh

Faculty, Staff and Students Publications

IMPORTANCE: Recent reports indicate differences in COVID-19-related care and outcomes between Black and White Americans.

OBJECTIVE: We examine the COVID-19-related healthcare utilization and mortality by race and ethnicity of patients tested for SARS-CoV-2 in the Veterans Health Administration (VHA).

DESIGN: A retrospective cohort study.

SETTING: We used the VHA COVID-19 shared data resources between February 1 and June 30, 2020.

PARTICIPANTS: Veterans tested for SARS-CoV-2 virus by VHA.

EXPOSURE(S): Three racial-ethnicity groups of Black, Hispanic, and White (as reference) veterans.

MAIN OUTCOME(S) AND MEASURE(S): Main outcomes are testing rate, positivity rate, hospitalization rate, ICU admission rate, and in-hospital mortality. Controlling …

Risk Factors Associated With Patient-Reported Fatigue Among Long-Term Oropharyngeal Carcinoma Survivors, Puja Aggarwal, Katherine A Hutcheson, Ryan P Goepfert, Adam S Garden, Naveen Garg, Frank E Mott, Clifton D Fuller, Stephen Y Lai, Gary Brandon Gunn, Mark S Chambers, Ehab Y Hanna, Erich M Sturgis, Sanjay Shete

Faculty, Staff and Students Publications

BACKGROUND: The study objective is to identify risk factors associated with fatigue among long-term OPC survivors.

METHODS: This cross-sectional study included disease-free OPC survivors treated curatively between 2000 and 2013 who were surveyed from September 2015 to July 2016. The outcome variable was patient-reported fatigue. Multivariable logistic regression was used to identify factors associated with moderate to severe fatigue.

RESULTS: Among 863 OPC survivors, 17.4% reported moderate to severe fatigue. Self-reported thyroid problems (OR: 2.01; p = 0.003), current cigarette smoking at time of survey (OR: 3.85; p = 0.001), late lower cranial neuropathy (OR: 3.44; p = 0.002), and …

A Multi-Disciplinary Approach To Chronic Cough In Children, Shraddha S Mukerji, Naga Jaya Smitha Yenduri, Eric Chiou, Siby P Moonnumakal, Joshua R Bedwell

Faculty, Staff and Students Publications

OBJECTIVES: (1) To highlight the important causes of chronic and recurrent cough in children. (2) To discuss multidisciplinary approach to management of chronic/recurrent pediatric cough.

METHODS: Review of scholarly articles, guidelines, expert panels via PubMed and Google Scholar.

CONCLUSION: Chronic cough (CC) in children is mainly attributed to persistent bacterial bronchitis, asthma, nonspecific cough, and gastroesophageal reflux disease (GERD) symptoms. A multi-disciplinary approach is cost-effective and aids with earlier diagnosis and appropriate treatment. Congenital or acquired narrowing of the subglottis is the leading ENT cause for recurrent croup (RC) in children. Laryngeal cleft-type 1 is commonly seen in children with …

Targeting Delivery Of Bcl-2 Family Protein Inhibitor Has The Potential To Treat Cancer And Fibrosis, Mohammad Nurul Huda

Open Access Theses & Dissertations

Apoptosis is a naturally occurring cell death mechanism to remove the selective cell population. B-cell leukemia/lymphoma-2 (BCL-2) family protein plays a critical role in activating the upstream apoptosis signaling pathway, primarily the intrinsic apoptosis pathway. The BCL-2 family consists of both pro-and anti-apoptotic proteins, which are structurally and functionally similar, containing up to four BCL-2 homologies (BH) motifs (BH1-4). Defecting apoptosis along this signaling pathway can lead to various events, including malignant cell transformation, tumor metastasis, tissue fibrosis, and drug resistance. In fibrosis, the aberrant apoptosis signaling also activates multiple effector proteins and growth factors, such as TGF-β, CTGF, and …