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Functions Of The Trna Splicing Endonuclease And Other Adventures In Rna Processing, Jennifer Hurtig, Ambro Van Hoof

Dissertations and Theses (Open Access)

The tRNA splicing endonuclease (TSEN), has been studied for over three decades for its function in tRNA splicing. However, this enzyme has other functions that are just beginning to be characterized. Mutations in TSEN cause the neuronal disease pontocerebellar hypoplasia (PCH) that is characterized by atrophy of the cerebellum and pons, overall developmental failure, and usually results in death before adolescence. How mutations in TSEN cause these neuronal defects and disease is not understood. In yeast, TSEN has another essential function that is independent of tRNA splicing and is still unknown. In this thesis I strived to understand the other …

Regulation And Function Of Zeb1 Acetylation In Lung Adenocarcinoma Progression And Metastasis, Mabel Perez-Oquendo

Dissertations and Theses (Open Access)

Lung cancer metastasis is leading the causes of cancer-related mortality in the United States and worldwide. Epithelial-to-mesenchymal transition (EMT) is a model for metastasis that results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. Zinc finger E-box-binding homeobox 1 (ZEB1) recognizes and binds to E-boxes of epithelial gene promoters to repress its transcription. ZEB1 has inconsistent molecular weights, which have been attributed to post-translational modifications (PTMs). In the presented dissertation, I specifically addressed the gap in the molecular mechanisms by which PTMs of ZEB1 regulate its ability to induce EMT and how its activity might …

Sex Differences In The Inflammatory Response To Stroke, Muhammad Bilal Tariq, Juneyoung Lee, Louise D Mccullough

Faculty, Staff and Student Publications

Ischemic stroke is a leading cause of morbidity and mortality and disproportionally affects women, in part due to their higher longevity. Older women have poorer outcomes after stroke with high rates of cognitive deficits, depression, and reduced quality of life. Post-stroke inflammatory responses are also sexually dimorphic and drive differences in infarct size and recovery. Factors that influence sex-specific immune responses can be both intrinsic and extrinsic. Differences in gonadal hormone exposure, sex chromosome compliment, and environmental/social factors can drive changes in transcriptional and metabolic profiles. In addition, how these variables interact, changes across the lifespan. After the onset of …

Updated Analysis To Reject The Laboratory-Engineering Hypothesis Of Sars-Cov-2, Fuqing Wu

Faculty, Staff and Student Publications

A clear understanding of the origin of SARS-CoV-2 is important for future pandemic preparedness. Here, I provided an updated analysis of the type IIS endonuclease maps in genomes of alphacoronavirus, betacoronavirus, and SARS-CoV-2. Scenarios to engineer SARS-CoV-2 in the laboratory and the associated workload was also discussed. The analysis clearly shows that the endonuclease fingerprint does not indicate a synthetic origin of SARS-CoV-2 and engineering a SARS-CoV-2 virus in the laboratory is extremely challenging both scientifically and financially. On the contrary, current scientific evidence does support the animal origin of SARS-CoV-2.

Ros-Mediated Srms Activation Confers Platinum Resistance In Ovarian Cancer, Yunhan Jiang, Lina Song, Yizhu Lin, Pawel Nowialis, Qiongmei Gao, Tao Li, Bin Li, Xiaobo Mao, Qianqian Song, Chengguo Xing, Guangrong Zheng, Shuang Huang, Lingtao Jin

Faculty, Staff and Student Publications

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and …

One Immune System Plays Many Parts: The Dynamic Role Of The Immune System In Chronic Pain And Opioid Pharmacology, Sanam Mustafa, Juliana E Bajic, Benjamin Barry, Samuel Evans, Kariel R Siemens, Mark R Hutchinson, Peter M Grace

Faculty, Staff and Student Publications

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront. As a highly dynamic and versatile network of cells, tissues and organs, the immune system is perfectly positioned at the microscale level to alter nociception and drive structural adaptations that underpin chronic pain and opioid use. In this review, …

Higher Hippocampal Diffusivity Values In Welders Are Associated With Greater R2* In The Red Nucleus And Lower Psychomotor Performance, Eun-Young Lee, Juhee Kim, Janina Manzieri Prado-Rico, Guangwei Du, Mechelle M Lewis, Lan Kong, Byoung-Gwon Kim, Young-Seoub Hong, Jeff D Yanosky, Richard B Mailman, Xuemei Huang

Faculty, Staff and Student Publications

INTRODUCTION: Chronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences.

METHODS: Study includes 42 welders and 31 controls without a welding history. Welding-related structural differences were assessed by volume and diffusion tensor imaging (DTI) metrics in basal ganglia, red nucleus (RN), and hippocampus. Metal exposure was estimated by both exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by R1 (for Mn) and R2* (for Fe). Neurobehavioral status was assessed by standard …

Apoptotic Cell Death In Disease-Current Understanding Of The Nccd 2023, Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion Macfarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia Von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi

Faculty, Staff and Student Publications

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. …

Long Noncoding Rna 01534 Maintains Cancer Stemness By Downregulating Endoplasmic Reticulum Stress Response In Colorectal Cancer, Momoko Ichihara, Hidekazu Takahashi, Naohiro Nishida, Cristina Ivan, Daisuke Okuzaki, Yuhki Yokoyama, Masahisa Ohtsuka, Norikatsu Miyoshi, Mamoru Uemura, Shinji Tanaka, George Adrian Calin, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hirofumi Yamamoto

Faculty, Staff and Student Publications

Background: Studies have shown that cancer stemness and the endoplasmic reticulum (ER) stress response are inversely regulated in colorectal cancer (CRC), but the mechanism has not been fully clarified. Long noncoding RNAs (lncRNAs) play key roles in cancer progression and metastasis. In this study we investigated lncRNA 01534 (LINC01534) as a possible modulator between cancer stemness and ER stress response.

Methods: In vitro experiments using CRC cell lines were performed to explore a possible role of LINC01534. The expression of LINC01534 in clinical CRC samples was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization.

Results: Silencing …

Disclosing Quantitative Rt-Pcr Raw Data During Manuscript Submission: A Call For Action, Andreas Untergasser, Jan Hellemans, Michael W Pfaffl, Jan M Ruijter, Maurice J B Van Den Hoff, Mihnea P Dragomir, Douglas Adamoski, Sandra Martha Gomes Dias, Rui Manuel Reis, Manuela Ferracin, Emmanuel Dias-Neto, Ian Marsh, Mikael Kubista, Muller Fabbri, Ajay Goel, Ondřej Slabý, Erik Knutsen, Baoqing Chen, Massimo Negrini, Koshi Mimori, Martin Pichler, Maria Papatriantafyllou, Simone Anfossi, Thomas D Schmittgen, Jim Huggett, Stephen Bustin, Jo Vandesompele, George A Calin, Heroic (The Initiative Group On Qrt Disclosure) Consortium

Faculty, Staff and Student Publications

Accuracy and transparency of scientific data are becoming more and more relevant with the increasing concern regarding the evaluation of data reproducibility in many research areas. This concern is also true for quantifying coding and noncoding RNAs, with the remarkable increase in publications reporting RNA profiling and sequencing studies. To address the problem, we propose the following recommendations: (a) accurate documentation of experimental procedures in Materials and methods (and not only in the supplementary information, as many journals have a strict mandate for making Materials and methods as visible as possible in the main text); (b) submission of RT‐qPCR raw …

Potent Antitumor Activity Of Ensartinib In Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer, Yang Xia, Rui Jin, Miao Li, Fen Lan, Hao Zhu, Yinghui Yu, Da Miao, Qiyuan Wang, Yi Zhou, Giovanni Selvaggi, Songmin Ying, Jianjun Zhang, Huahao Shen, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of …

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Unlocking The Promise Of Systemic Sting Agonist For Cancer Immunotherapy, Xiaoqi Sun, Xingwu Zhou, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING …

Redox Phospholipidomics Discovers Pro-Ferroptotic Death Signals In A375 Melanoma Cells In Vitro And In Vivo, Yulia Y Tyurina, Alexandr A Kapralov, Vladimir A Tyurin, Galina Shurin, Andrew A Amoscato, Dhivyaa Rajasundaram, Hua Tian, Yuri L Bunimovich, Yulia Nefedova, William G Herrick, Ralph E Parchment, James H Doroshow, Hulya Bayir, Apurva K Srivastava, Valerian E Kagan

Faculty, Staff and Student Publications

Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them - ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis. Ferroptosis is accompanied by peroxidation of polyunsaturated species of phosphatidylethanolamine (PE) to hydroperoxy- (-OOH) derivatives, which act as death signals. We demonstrate that RSL3-induced death of A375 melanoma cells in vitro was fully preventable by ferrostatin-1, suggesting their high susceptibility to ferroptosis. Treatment of A375 cells with RSL3 caused a significant …

Enhancing Oral Delivery Of Plant-Derived Vesicles For Colitis, Yuan Liu, Adrian Lankenau Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M Sebastian, Htet Khant, Natalia De Val, Nazende Nur Bayram, Guodong Zhang, Thanh Chung Vu, Zuliang Jie, Nicholas B Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Ermias, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K Sood

Faculty, Staff and Student Publications

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the …

Quantitative Dual-Energy Ct Image Guidance For Thermochemical Ablation: In Vivo Results In The Rabbit Vx2 Model, Emily A Thompson, Natalie W Fowlkes, Megan C Jacobsen, Rick R Layman, Erik N K Cressman

Faculty, Staff and Student Publications

PURPOSE: To evaluate the feasibility of using dual-energy computed tomography (CT) and theranostic cesium hydroxide (CsOH) for image guidance of thermochemical ablation (TCA) in a rabbit VX2 tumor model.

MATERIALS AND METHODS: In vivo experiments were performed on New Zealand white rabbits, where VX2 tumor fragments (0.3 mL) were inoculated into the right and left flanks (n = 16 rabbits, 32 tumors). Catheters were placed in the approximate center of 1- to 2-cm diameter tumors under ultrasound guidance. TCA was delivered in 1 of 3 treatment groups: untreated control, 5-M TCA, or 10-M TCA. The TCA base reagent was doped …

Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Mauro Di Pilato, Yun Gao, Yi Sun, Amina Fu, Carina Grass, Thomas Seeholzer, Regina Feederle, Irina Mazo, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller

Faculty, Staff and Student Publications

Introduction

Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods

We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to …

Interleukin-33 Facilitates Liver Regeneration Through Serotonin-Involved Gut-Liver Axis, Yankai Wen, Christoph Emontzpohl, Long Xu, Constance L Atkins, Jong-Min Jeong, Yang Yang, Kangho Kim, Chuan Wu, Shizuo Akira, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms.

APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be …

Major Differences In Transcriptional Alterations In Dorsal Root Ganglia Between Spinal Cord Injury And Peripheral Neuropathic Pain Models, Raquel Cuevas-Diaz Duran, Yong Li, Anibal Garza Carbajal, Yanan You, Carmen W Dessauer, Jiaqian Wu, Edgar T Walters

Faculty, Staff and Student Publications

Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs …

Therapeutic Potential Of Tumor Treating Fields For Malignant Brain Tumors, Youyou Zhou, Xiaoqing Xing, Jinyun Zhou, Han Jiang, Peili Cen, Chentao Jin, Yan Zhong, Rui Zhou, Jing Wang, Mei Tian, Hong Zhang

Faculty, Staff and Student Publications

BACKGROUND: Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate-frequency and low-intensity electric field and can lead to the development of novel therapeutic options.

RECENT FINDINGS: A series of biological processes induced by TTFields to exert anti-cancer effects have been identified. Recent studies have shown that TTFields can alter the bioelectrical state of macromolecules and organelles involved in cancer biology. Massive alterations in cancer cell proteomics and transcriptomics caused by TTFields …

One Immune System Plays Many Parts: The Dynamic Role Of The Immune System In Chronic Pain And Opioid Pharmacology, Sanam Mustafa, Juliana E Bajic, Benjamin Barry, Samuel Evans, Kariel R Siemens, Mark R Hutchinson, Peter M Grace

Faculty, Staff and Student Publications

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront. As a highly dynamic and versatile network of cells, tissues and organs, the immune system is perfectly positioned at the microscale level to alter nociception and drive structural adaptations that underpin chronic pain and opioid use. In this review, …

Alendronate Conjugate For Targeted Delivery To Bone-Forming Prostate Cancer, Jossana A Damasco, Guoyu Yu, Ajay Kumar, Joy Perez, Rio Carlo M Lirag, Elizabeth M Whitley, Sue-Hwa Lin, Marites P Melancon

Faculty, Staff and Student Publications

Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, …

Molecular Identity Changes Of Tumor-Associated Macrophages And Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Mouse Glioblastoma Model, Yanrong Zhang, Jing Wang, Sara Natasha Ghobadi, Haiyan Zhou, Ai Huang, Marco Gerosa, Qingyi Hou, Olivier Keunen, Anna Golebiewska, Frezghi G Habte, Gerald A Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

An orthotopically allografted mouse GL26 glioma model (Ccr2^RFP/wt-Cx3cr1^GFP/wt) was used to evaluate the effect of transient, focal opening of the Blood Brain Barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB Opening was induced by Magnetic Resonance Imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not show significant changes in cell numbers when compared to tumors in animals not receiving FUS. However, tumors that received two or three sessions …

Pirtobrutinib And Venetoclax Combination Overcomes Resistance To Targeted And Chimeric Antigen Receptor T-Cell Therapy In Aggressive Mantle Cell Lymphoma, Yang Liu, Fangfang Yan, Vivian Changying Jiang, Yijing Li, Yuxuan Che, Joseph Mcintosh, Alexa Jordan, Ian Hou, Lei Nie, Jingling Jin, Wei Wang, Heng-Huan Lee, Yixin Yao, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

Vestigial-Like 1 (Vgll1): An Ancient Co-Transcriptional Activator Linking Wing, Placenta, And Tumor Development, Heather M Sonnemann, Barbara Pazdrak, Dinler A Antunes, Jason Roszik, Gregory Lizée

Faculty, Staff and Student Publications

Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as …

A Model For Gastrointestinal Tract Motility In A 4d Imaging Phantom Of Human Anatomy, Ergys Subashi, Paul Segars, Harini Veeraraghavan, Joseph Deasy, Neelam Tyagi

Faculty, Staff and Student Publications

BACKGROUND: Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in radiation therapy for abdominal targets. Models for GI motility can improve the assessment of delivered dose and contribute to the development, testing, and validation of deformable image registration (DIR) and dose-accumulation algorithms.

PURPOSE: To implement GI tract motion in the 4D extended cardiac-torso (XCAT) digital phantom of human anatomy.

MATERIALS AND METHODS: Motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery were identified based on …

Meta-Analysis Of The Association Between Atrial Fibrillation, Hypertension, Sleep-Disordered Breathing, And Wake-Up Stroke, Jin Zhou, Jing Xu, Aijuan Cheng, Yimiti Kadier, Xiaoli Liang, Maimaitijiang Mutailipu, Shan Sun

The Texas Heart Institute Journal

BACKGROUND: The occurrence of atrial fibrillation, circadian fluctuation in blood pressure, and oxygen desaturation at night is likely associated with the pathophysiology of wake-up stroke. Whether patients who experience wake-up strokes are candidates for thrombolysis treatment is a serious dilemma. The aim is to investigate the association between risk factors and wake-up stroke and to determine variations that are associated with the pathophysiology of wake-up stroke.

METHODS: Five major electronic databases were searched using a fitted search strategy to identify relevant studies. Odds ratios with 95% CIs were used to calculate estimates, and the Quality Assessment for Diagnostic Accuracy Studies-2 …

Closed Mitral Valvotomy: Celebrating 100 Years Of Surgical History, Uberto Bortolotti, Igor Vendramin, Aldo Domenico Milano, Ugolino Livi

The Texas Heart Institute Journal

The year 2023 marks the 100th anniversary of the first successful valvotomy for mitral valve stenosis by Elliott C. Cutler in 1923. Closed-chest mitral valve commissurotomy developed further before being replaced by an open procedure after the advent of the heart-lung machine. Currently, because of the almost complete disappearance of rheumatic disease in the Western World, mitral commissurotomies are infrequently performed in those countries, although the procedure-either closed or open-is still performed in developing countries and select patients. This review retraces the 100-year journey from a historic operation to the current era-a milestone in the treatment of patients with mitral …

Functional Screening Of Lysosomal Storage Disorder Genes Identifies Modifiers Of Alpha-Synuclein Neurotoxicity, Meigen Yu, Hui Ye, Ruth B De-Paula, Carl Grant Mangleburg, Timothy Wu, Tom V Lee, Yarong Li, Duc Duong, Bridget Phillips, Carlos Cruchaga, Genevera I Allen, Nicholas T Seyfried, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA …

Cascade Testing After Exome Sequencing: Retrospective Analysis Of Linked Family Data At 2 Us Laboratories, Julie Stefka, Haley Streff, Pengfei Liu, Meghan Towne, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications.

Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and …