Digital Commons Network^™

Pressing Issues For Oral Care Quality Improvement: Findings From The Eu Deliver Project, Paulo Melo, Leonor Frey-Furtado, Daniela Correia, Stefan Listl, Michael Lorenz, Nagihan Bostanci, Álvaro Azevedo, Maria Lurdes Pereira

Faculty, Staff and Student Publications

BACKGROUND: While oral health often takes a backseat to other health domains, it silently affects nearly half of the Worldwide population. The DELIVER project, funded by the EU's Horizon Europe program, seeks to develop a blueprint model for improving the quality of oral health care for everyone.

METHODS: Applying the Nominal Group Technique (NGT), 17 stakeholders from various backgrounds participated in identifying pressing issues for oral care quality improvement across practice, community, and policy levels.

RESULTS: The results revealed significant differences at the different levels, with accessibility emerging as a prominent issue, encompassing affordability, availability, and acceptability of oral healthcare …

Interleukin-21 Engineering Enhances Nk Cell Activity Against Glioblastoma Via Cebpd, Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as …

Mif/Nr3c2 Axis Regulates Glucose Metabolism Reprogramming In Pancreatic Cancer Through Mapk-Erk And Ap-1 Pathways, Shouhui Yang, Wei Tang, Azadeh Azizian, Jochen Gaedcke, Yuuki Ohara, Helen Cawley, Nader Hanna, Michael Ghadimi, Trisha Lal, Subrata Sen, Chad J Creighton, Jianjun Gao, Nagireddy Putluri, Stefan Ambs, Perwez Hussain

Faculty, Staff and Student Publications

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth …

A Social Media Game To Increase Physical Activity Among Older Adult Women: Protocol Of A Randomized Controlled Trial To Evaluate Challenge, Michael C Robertson, Maria Chang Swartz, Karen M Basen-Engquist, Yisheng Li, Kristofer Jennings, Debbe Thompson, Tom Baranowski, Elena Volpi, Elizabeth J Lyons

Faculty, Staff and Student Publications

BACKGROUND: Older adult women often do not engage in sufficient physical activity (PA) and can encounter biological changes that exacerbate the negative effects of inadequate activity. Wearable activity monitors can facilitate PA initiation, but evidence of sustained behavior change is lacking. Supplementing wearable technologies with intervention content that evokes enjoyment, interest, meaning, and personal values associated with PA may support long term adherence. In this paper, we present the protocol of an NIA-funded study designed to evaluate the efficacy of CHALLENGE for increasing step count and motivation for PA in insufficiently active older women (Challenges for Healthy Aging: Leveraging Limits …

Personalized Neoantigen Vaccines As Early Intervention In Untreated Patients With Lymphoplasmacytic Lymphoma: A Non-Randomized Phase 1 Trial, Szymon J Szymura, Lin Wang, Tiantian Zhang, Soung-Chul Cha, Joo Song, Zhenyuan Dong, Aaron Anderson, Elizabeth Oh, Vincent Lee, Zhe Wang, Sapna Parshottam, Sheetal Rao, Jasper B Olsem, Brandon N Crumpton, Hans C Lee, Elisabet E Manasanch, Sattva Neelapu, Larry W Kwak, Sheeba K Thomas

Faculty, Staff and Student Publications

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. …

Infratubercle Anterior Closing Wedge Osteotomy Corrects Sagittal Alignment Without Affecting Coronal Alignment Or Patellar Height, Shintaro Onishi, Youngji Kim, Hiroshi Nakayama, Alfred A Mansour, Walter R Lowe, Matthieu Ollivier

Faculty, Staff and Student Publications

Background: Excessive posterior tibial slope (PTS) has been associated with a higher risk of graft failure after anterior cruciate ligament reconstruction (ACLR). Although anterior closing wedge osteotomy (ACWO) can reduce the PTS, it may also change the coronal alignment and patellar height. Purpose: To elucidate the radiological outcomes after infratubercle ACWO, specifically to evaluate its influence on perioperative changes in patellar height.

Methods: Patients who underwent infratubercle ACWO with combined ACLR with a minimum follow-up of 3 months were included. Surgery was indicated when the PTS was greater than 12°. Radiological evaluation included measurements of the hip-knee-ankle angle (HKA), PTS, …

Creation Of A Predictive Calculator To Determine Adequacy Of Occlusion Of The Woven Endobridge (Web) Device In Intracranial Aneurysms-A Retrospective Analysis Of The Worldwide Web Consortium Database, Basel Musmar, Nimer Adeeb, Julian Gendreau, Melanie Alfonzo Horowitz, Hamza Adel Salim, Praveen Sanmugananthan, Assala Aslan, Nolan J Brown, Nicole M Cancelliere, Rachel M Mclellan, Oktay Algin, Sherief Ghozy, Mahmoud Dibas, Atakan Orscelik, Yigit Can Senol, Sovann V Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Panagiotis Mastorakos, Kareem El Naamani, Eimad Shotar, Kevin Premat, Markus Möhlenbruch, Michael Kral, Omer Doron, Charlotte Chung, Mohamed M Salem, Ivan Lylyk, Paul M Foreman, Jay A Vachhani, Hamza Shaikh, Vedran Župančić, Muhammad U Hafeez, Joshua Catapano, Muhammad Waqas, Vincent M Tutino, Yuce Gokhan, Cetin Imamoglu, Ahmet Bayrak, James D Rabinov, Yifan Ren, Clemens M Schirmer, Mariangela Piano, Anna L Kühn, Caterina Michelozzi, Stéphanie Elens, Robert M Starke, Ameer E Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marie T Nawka, Marios Psychogios, Christian Ulfert, Jose Danilo Bengzon Diestro, Bryan Pukenas, Jan-Karl Burkhardt, Thien Huynh, Juan Carlos Martinez-Gutierrez, Muhammed Amir Essibayi, Sunil A Sheth, Gary Spiegel, Rabih Tawk, Boris Lubicz, Pietro Panni, Ajit S Puri, Guglielmo Pero, Erez Nossek, Eytan Raz, Monika Killer-Oberfalzer, Christoph J Griessenauer, Hamed Asadi, Adnan Siddiqui, Allan L Brook, David Altschul, Andrew F Ducruet, Felipe C Albuquerque, Robert W Regenhardt, Christopher J Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Mohammad A Aziz-Sultan, Stavropoula I Tjoumakaris, Frédéric Clarençon, Nicola Limbucci, Mohamad Bydon, David Hasan, Hugo H Cuellar-Saenz, Pascal M Jabbour, Vitor Mendes Pereira, Aman B Patel, Adam A Dmytriw

Faculty, Staff and Student Publications

Background: Endovascular treatment with the woven endobridge (WEB) device has been widely utilized for managing intracranial aneurysms. However, predicting the probability of achieving adequate occlusion (Raymond-Roy classification 1 or 2) remains challenging.

Objective: Our study sought to develop and validate a predictive calculator for adequate occlusion using the WEB device via data from a large multi-institutional retrospective cohort.

Methods: We used data from the WorldWide WEB Consortium, encompassing 356 patients from 30 centers across North America, South America, and Europe. Bivariate and multivariate regression analyses were performed on a variety of demographic and clinical factors, from which predictive factors were …

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …

Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular …

3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea

Faculty, Staff and Student Publications

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion …

Novel Il-4/Hb-Egf-Dependent Crosstalk Between Eosinophils And Macrophages Controls Liver Regeneration After Ischaemia And Reperfusion Injury, Yang Yang, Long Xu, Constance Atkins, Lily Kuhlman, Jie Zhao, Jong-Min Jeong, Yankai Wen, Nicolas Moreno, Kang Ho Kim, Yu A An, Fenfen Wang, Steve Bynon, Vincenzo Villani, Bin Gao, Frank Brombacher, Raymond Harris, Holger K Eltzschig, Elizabeth Jacobsen, Cynthia Ju

Faculty, Staff and Student Publications

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair.

DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding …

Multifocal Mycotic Aneurysms And Pseudoaneurysms, Camilo Perdomo, Catalina Jaramillo, Laura Ocacio, Emma Ferguson, Daniel Ocazionez

Faculty, Staff and Student Publications

Mycotic aneurysms and pseudoaneurysms, though rare, present significant diagnostic and therapeutic challenges. The case follows a 74-year-old male with a history of bladder cancer who developed multifocal mycotic aneurysms and pseudoaneurysms following sepsis. Initially misdiagnosed as a Pancoast tumor, imaging revealed an extensive disease involving the right subclavian artery, proximal descending thoracic aorta, infrarenal abdominal aorta, and right common iliac artery. This case highlights the importance of considering mycotic aneurysms in the differential diagnosis of patients with a history of infection and highlights the role of Computed Tomography Angiography in early diagnosis.

Cefiderocol Heteroresistance Associated With Mutations In Tonb-Dependent Receptor Genes In Pseudomonas Aeruginosa Of Clinical Origin, Stephanie L Egge, Samie A Rizvi, Shelby R Simar, Manuel Alcalde, Jose R W Martinez, Blake M Hanson, An Q Dinh, Rodrigo P Baptista, Truc T Tran, Samuel A Shelburne, Jose M Munita, Cesar A Arias, Morgan Hakki, William R Miller

Faculty, Staff and Student Publications

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa …

Video And Phone Visit Use Differed By Language Preference Among Us Latino And Chinese Adults During The First 9 Months Of The Covid-19 Pandemic: A Cross-Sectional Electronic Health Record Study, Nancy P Gordon, Teresa Y Lin, Antonia Torreblanca, Mary E Reed

Faculty, Staff and Student Publications

BACKGROUND: During the first nine months of the COVID-19 emergency, patients were encouraged to use virtual versus clinic visits if in-person care was not deemed necessary by clinical staff. This study examined the association of spoken language preference and ethnicity with use of video versus phone virtual visits by US Latino and Chinese adult patients who got care in the same healthcare system.

METHODS: We analyzed electronic health record data for four groups of adults aged 26-85y who had ≥ 1 primary or specialty care outpatient clinician visits during April-December 2020: 80,869 Latino adults preferring Spanish (LEP Latino); 214,765 Latino …

Pathophysiology In Brain Arteriovenous Malformations: Focus On Endothelial Dysfunctions And Endothelial-To-Mesenchymal Transition, Jae Yeong Jeong, Adrian E Bafor, Bridger H Freeman, Peng R Chen, Eun S Park, Eunhee Kim

Faculty, Staff and Student Publications

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to …

Enhancing Clinical Relevance Of Pretrained Language Models Through Integration Of External Knowledge: Case Study On Cardiovascular Diagnosis From Electronic Health Records, Qiuhao Lu, Andrew Wen, Thien Nguyen, Hongfang Liu

Faculty, Staff and Student Publications

Background: Despite their growing use in health care, pretrained language models (PLMs) often lack clinical relevance due to insufficient domain expertise and poor interpretability. A key strategy to overcome these challenges is integrating external knowledge into PLMs, enhancing their adaptability and clinical usefulness. Current biomedical knowledge graphs like UMLS (Unified Medical Language System), SNOMED CT (Systematized Medical Nomenclature for Medicine-Clinical Terminology), and HPO (Human Phenotype Ontology), while comprehensive, fail to effectively connect general biomedical knowledge with physician insights. There is an equally important need for a model that integrates diverse knowledge in a way that is both unified and compartmentalized. …

Intermittent Clearance Of P21-Highly-Expressing Cells Extends Lifespan And Confers Sustained Benefits To Health And Physical Function, Binsheng Wang, Lichao Wang, Nathan S Gasek, Chia-Ling Kuo, Jia Nie, Taewan Kim, Pengyi Yan, Junyu Zhu, Blake L Torrance, Yueying Zhou, Lisa C Flores, Colton Allen, Allison M Andrade, Chun Guo, Rachel L Cohn, Evan R Jellison, Jenna M Bartley, George A Kuchel, Sheng Li, Tamar Pirtskhalava, Tamar Tchkonia, Sumit Yadav, Laura Haynes, James L Kirkland, Yuji Ikeno, Ming Xu

Faculty, Staff and Student Publications

A key challenge in aging research is to extend lifespan in tandem with slowing down functional decline so that the life with good health (healthspan) can be extended. Here, we show that monthly clearance of a small number of cells, which highly express p21Cip1 (p21high), starting from 20 months improves cardiac and metabolic function, and extends both median and maximum lifespan in mice. Importantly, by assessing health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Whole Genome Sequencing Based Analysis Of Inflammation Biomarkers In The Trans-Omics For Precision Medicine (Topmed) Consortium, Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Inflammation Working Group

Faculty, Staff and Student Publications

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant …

Disability In Cluster Headache Is More Than Attack Frequency – Results From And Validation Of The English Version Of The Cluster Headache Impact Questionnaire (Chiq), Katharina Kamm, Andreas Straube, Mark Burish, Ruth Ruscheweyh

Faculty, Staff and Student Publications

BACKGROUND: Cluster headache (CH) is associated with high disability. The Cluster Headache Impact Questionnaire (CHIQ) is a short, disease-specific disability questionnaire first developed and validated in German. Here, we validated the English version of this questionnaire.

METHODS: The CHIQ was assessed together with nonspecific headache-related disability questionnaires in CH patients from a tertiary headache center and an American self-help group.

RESULTS: 155 active episodic and chronic CH patients were included. The CHIQ showed good internal consistency (Cronbach's α = 0.91) and test-retest reliability (ICC = 0.93, n = 44). Factor analysis identified a single factor. Convergent validity was shown by …

Adjuvant External Beam Radiotherapy Combined With Brachytherapy For Intermediate-Risk Cervical Cancer, Nuria Agusti, David Viveros-Carreño, Alexander Melamed, Rene Pareja, Alexa Kanbergs, Chi-Fang Wu, Roni Nitecki, Lauren Colbert, Jose Alejandro Rauh-Hain

Faculty, Staff and Student Publications

Objective: Patients with intermediate-risk cervical cancer receive external beam radiotherapy (EBRT) as adjuvant treatment. It is commonly administered with brachytherapy without proven benefits. Therefore, we evaluated the frequency of brachytherapy use, the doses for EBRT administered alone or with brachytherapy, and the overall survival impact of brachytherapy in patients with intermediate-risk, early-stage cervical cancer.

Methods: This retrospective cohort study was performed using data collected from the National Cancer Database. Patients diagnosed with cervical cancer from 2004 to 2019 who underwent a radical hysterectomy and lymph node staging and had disease limited to the cervix but with tumors larger than 4 …

Women In Stem Becoming Independent: Our Shared Motivation And Enthusiasm Are Our Driving Force, Liudmila Andreeva, Lidia Bosurgi, Shu Zhen Chong, Coco Chu, Yejing Ge, Esther Hoste, Kellie A Jurado, Jette Lengefeld, Archita Mishra, Stefanie Wculek, Arabella Young

Faculty, Staff and Student Publications

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

Tumour-Intrinsic Endomembrane Trafficking By Arf6 Shapes An Immunosuppressive Microenvironment That Drives Melanomagenesis And Response To Checkpoint Blockade Therapy, Yinshen Wee, Junhua Wang, Emily C Wilson, Coulson P Rich, Aaron Rogers, Zongzhong Tong, Evelyn Degroot, Y N Vashisht Gopal, Michael A Davies, H Atakan Ekiz, Joshua K H Tay, Chris Stubben, Kenneth M Boucher, Juan M Oviedo, Keke C Fairfax, Matthew A Williams, Sheri L Holmen, Roger K Wolff, Allie H Grossmann

Faculty, Staff and Student Publications

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

Population-Level Trends In Self-Reported Healthcare Utilization Among Older Adults In Mexico With And Without Cognitive Impairment, José Eduardo Cabrero Castro, Rebeca Wong, Rafael Samper Ternent, Brian Downer

Faculty, Staff and Student Publications

BACKGROUND: Older adults with cognitive impairment exhibit different patterns of healthcare utilization compared to their cognitively healthy counterparts. Despite extensive research in high-income countries, similar studies in low- and middle-income countries are lacking. This study aims to investigate the population-level patterns in healthcare utilization among older adults with and without cognitive impairment in Mexico.

METHODS: Data came from five waves (2001-2018) of the Mexican Health and Aging Study. We used self-reported measures for one or more over-night hospital stays, doctor visits, visits to homeopathic doctors, and dental visits in the past year; seeing a pharmacist in the past year; and …

Kinesin Facilitates Phenotypic Targeting Of Therapeutic Resistance In Advanced Prostate Cancer, Maddison Archer, Diane Begemann, Edgar Gonzalez-Kozlova, Prerna R Nepali, Estefania Labanca, Peter Shepherd, Navneet Dogra, Nora Navone, Natasha Kyprianou

Faculty, Staff and Student Publications

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial-mesenchymal transition to mesenchymal-epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential …

Brca1-Mediated Dual Regulation Of Ferroptosis Exposes A Vulnerability To Gpx4 And Parp Co-Inhibition In Brca1-Deficient Cancers, Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, Mingjian James You, Helen Piwnica-Worms, Boyi Gan

Faculty, Staff and Student Publications

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i …

Rosiglitazone And Trametinib Exhibit Potent Anti-Tumor Activity In A Mouse Model Of Muscle Invasive Bladder Cancer, Sakina A Plumber, Tiffany Tate, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Merve Basar, Chao Lu, Aaron Viny, Ekatherina Batourina, Jiaqi Li, Kristjan Gretarsson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, Byron Hing Lung Lee, James Mckiernan, David J Mcconkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn

Faculty, Staff and Student Publications

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. …

Prognostic Factors On Preoperative Mri For Patient-Reported Outcomes After Posterior Medial Meniscus Root Repair, Sergio E Flores, Rawee Manatrakul, Christopher Anigwe, Chotigar Ngarmsrikam, Brian T Feeley, C Benjamin Ma, Thomas M Link, Drew A Lansdown

Faculty, Staff and Student Publications

Background: Repair of posterior medial meniscus root (PMMR) tears has demonstrated favorable outcomes and may prevent rapid progression of knee osteoarthritis; however, there is a paucity of data regarding prognostic factors affecting postoperative outcomes.

Purpose/hypothesis: The purpose of this study was to identify factors on preoperative magnetic resonance imaging (MRI) that predict postoperative outcomes after PMMR repair. It was hypothesized that patients with increasing levels of degenerative changes as evaluated through semiquantitative preoperative MRI scans would have worse postoperative patient-reported outcome (PRO) scores.

Study design: Cohort study; Level of evidence, 3.

Methods: Patients who underwent PMMR repair between 2012 and …