Digital Commons Network^™

Structural Heart Imaging Using 3-Dimensional Intracardiac Echocardiography: Jacc: Cardiovascular Imaging Position Statement, Gilbert H L Tang, Syed Zaid, Rebecca T Hahn, Vratika Aggarwal, Mohamad Alkhouli, Edris Aman, Sergio Berti, Y S Chandrashekhar, Scott M Chadderdon, Andreina D'Agostino, Neil P Fam, Edwin C Ho, Chad Kliger, Susheel K Kodali, Parasuram Krishnamoorthy, Azeem Latib, Stamatios Lerakis, D Scott Lim, Vaikom S Mahadevan, Devi G Nair, Jagat Narula, Patrick T O'Gara, Douglas L Packer, Fabien Praz, Jason H Rogers, Tobias F Ruf, Carlos E Sanchez, Alok Sharma, Gagan D Singh, Nicolas M Van Mieghem, Mani A Vannan, Pradeep K Yadav, Lina Ya'qoub, Firas E Zahr, Ralph Stephan Von Bardeleben

Faculty, Staff and Students Publications

3-dimensional (3D) intracardiac echocardiography (ICE) is emerging as a promising complement and potential alternative to transesophageal echocardiography for imaging guidance in structural heart interventions. To establish standardized practices, our multidisciplinary expert position statement serves as a comprehensive guide for the appropriate indications and utilization of 3D-ICE in various structural heart procedures. The paper covers essential aspects such as the fundamentals of 3D-ICE imaging, basic views, and workflow recommendations specifically tailored for ICE-guided structural heart procedures, such as transeptal puncture, device closure of intracardiac structures, and transcatheter mitral and tricuspid valve interventions. Current challenges, future directions, and training requirements to ensure …

Igf-1 Impacts Neocortical Interneuron Connectivity In Epileptic Spasm Generation And Resolution, Carlos J Ballester-Rosado, John T Le, Trang T Lam, Anne E Anderson, James D Frost, John W Swann

Faculty, Staff and Students Publications

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients' brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. …

Zic1 Is A Context-Dependent Medulloblastoma Driver In The Rhombic Lip, John J Y Lee, Ran Tao, Zhen You, Parthiv Haldipur, Anders W Erickson, Hamza Farooq, Liam D Hendriske, Namal Abeysundara, Cory M Richman, Evan Y Wang, Neha Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M G Cavalli, Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raul Suarez, Bryn G Livingston, Miao Liu, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J French, Johan M Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce De León, Mario Perezpeña-Diazconti, Boleslaw Lach, Sheila K Singh, Sarah E S Leary, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji-Yeoun Lee, Teiji Tominaga, William A Weiss, Joanna J Phillips, Shizhong Dai, Gelareh Zadeh, Ali G Saad, László Bognár, Almos Klekner, Ian F Pollack, Ronald L Hamilton, Young-Shin Ra, Wieslawa A Grajkowska, Marta Perek-Polnik, Reid C Thompson, Anna M Kenney, Michael K Cooper, Stephen C Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L Suva, Hiromichi Suzuki, Kathleen J Millen, L Frank Huang, Paul A Northcott, Michael D Taylor

Faculty, Staff and Students Publications

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma …

The Dna Demethylase Tet1 Modifies The Impact Of Maternal Folic Acid Status On Embryonic Brain Development, Lehua Chen, Bernard K Van Der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh

Faculty, Staff and Students Publications

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1−/− embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/− offspring and to …

Dfcp1 Is A Regulator Of Starvation-Driven Atgl-Mediated Lipid Droplet Lipolysis, Victoria A Ismail, Meg Schuetz, Zak N Baker, Jean A Castillo-Badillo, Teri V Naismith, David J Pagliarini, David J Kast

2020-Current year OA Pubs

Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that …

Diagnostic And Prognostic Value Of Cystatin C In Acute Coronary Syndrome: An Up-To-Date Meta-Analysis, Michal Pruc, Damian Swieczkowski, Basar Cander, Milosz J Jaguszewski, Sagar Galwankar, Salvatore Di Somma, Fatimah Lateef, Indrani Sardesai, Ayman El-Menyar, Michal Zembala, Jacek Kubica, Togay Evrin, Burak Katipoglu, Zubaid Rafique, Frank William Peacock, Lukasz Szarpak

Faculty, Staff and Students Publications

Background: The role of Cystatin C (CysC) in the diagnosis and prognosis of cardiovascular disease, particularly acute coronary syndrome (ACS), is increasingly significant. The goal of this meta-analysis was to assess the diagnostic and prognostic value of CysC in patients with ACS, as well as its association with major adverse cardiovascular events (MACE), defined as mortality, myocardial infarction, heart failure, and stroke.

Methods: The present study is a systematic review and meta-analysis. Using PubMed, Web of Science, Cochrane Library, and Embase, a literature review of cohort and case control studies reporting MACE and using the terms ACS and Cystatin C …

Prognostic Value Of The Monocyte-To-High-Density Lipoprotein-Cholesterol Ratio In Acute Coronary Syndrome Patients: A Systematic Review And Meta-Analysis, Michał Pruc, Jacek Kubica, Maciej Banach, Damian Świeczkowski, Zubaid Rafique, William Frank Peacock, Zbigniew Siudak, Stanisław Surma, Prabath Nanayakkara, Krzysztof Kurek, Anne Lepetit, Łukasz Szarpak

Faculty, Staff and Students Publications

Background: Globally, diseases of the cardiovascular system stand as principal contributors to mortality and are expected to show an upward trajectory. The occurrence of acute coronary syndrome (ACS) has been linked to underlying inflammatory processes. The monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) has garnered significant attention as a prognostic biomarker, encapsulating the synergistic roles of inflammation and lipid metabolism in the pathophysiology of cardiovascular diseases, including ACS.

Aims: This meta-analysis examines the prognostic MHR ratio in ACS patients.

Methods: We systematically searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library databases to identify the relevant meta-analyses published before February 26, …

Mice With Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs That Model An Autoimmune Emphysema Phenotype Of Copd, Barbara Summers, Kihwan Kim, Anjali Trivedi, Tyler M Lu, Sean Houghton, Jade Palmer-Johnson, Joselyn Rojas-Quintero, Juan Cala-Garcia, Tania Pannellini, Francesca Polverino, Raphaël Lis, Hasina Outtz Reed

Faculty, Staff and Students Publications

We have previously shown that mice with a loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development …

Mutations In Retinal Cyclic Nucleotide-Gated Channels Identified In Familial Cases Of Inherited Retinal Dystrophies From Pakistan, Zainab Akhtar, Kiran Afshan, Yumei Li, Sumaira Altaf, Aleesha Asghar, Ume Sughra, Wajid Ali Khan, Haiba Kaul, Rui Chen, Sabika Firasat

Faculty, Staff and Students Publications

Purpose: Cyclic nucleotide-gated (CNG) channels are ligand-gated ion channels that transduce light signals into electrical signals in the retinal photoreceptors. Pathogenic variants in CNG channel genes are reported to cause inherited retinal dystrophies (IRDs). The current study used targeted panel sequencing to describe the mutational spectrum of CNG channel genes in familial cases of IRDs from eight consanguineous Pakistani families.

Methods: The current study included consanguineous Pakistani families with at least two affected members. DNA was extracted from whole blood samples by the phenol-chloroform method. Two affected members from each family were initially analyzed using targeted panel sequencing of 344 …

Exercise Mitigates High-Fat Diet-Induced Cardiac Dysfunction Via Apoe Genotype- And Immune-Dependent Mechanisms: A Photon-Counting Ct Study In Adult Mice, Rohan Nadkarni, Alex J Allphin, Darin P Clark, Yi Qi, Zay Yar Han, Ketan B Ghaghada, Alexandra Badea, Cristian T Badea

Faculty, Staff and Students Publications

Background: Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation.

Methods: This study included 251 male and female mice in mid-to-late life of APOE2, APOE3, and APOE4 genotypes with variation in humanized NOS2 (HN) mediated innate immune response, exercise status (exercised vs. sedentary) and …

Towards A Map Of The Immune System Manipulation Network By Trypanosoma Cruzi, Juan Cruz Gamba, Ana Rosa Pérez, Carolina Verónica Poncini, Cristina Poveda, Iván Marcipar, Gabriel Cabrera

Faculty, Staff and Students Publications

No abstract provided.

A Multifunctional Theranostic Ultrasound Platform For Remote Magnetogenetics And Expanded Blood-Brain Barrier Opening, Alec J Batts, Fotios N Tsitsos, Jeannette Ingabire, Guillaume Duret, Samantha L Gorman, Deny Tsakri, Rebecca L Noel, Robin Ji, Nancy Kwon, Quoc-Khanh Pham, Linlin Zhang, Gang Bao, Jacob T Robinson, Elisa E Konofagou

Faculty, Staff and Students Publications

Introduction: Brain stimulation techniques are critical for unraveling the innerworkings of complex neuronal pathways governing both normal physiological function and pathologic states in neurological disorders. Focused ultrasound (FUS) is an emerging technique poised to significantly alter central nervous system (CNS) drug delivery and neuroscience research through non-invasive means. Magnetogenetics is a brain stimulation technique which may benefit from FUS technology in that alternating magnetic fields (AMF), like FUS, can pass through the skull without requiring surgery.

Methodology: Magnetogenetics involves the deposition of superparamagnetic iron-oxide nanoparticles (SPIONs) and overexpression of thermoreceptor transmembrane proteins (e.g. TRPV1 and TRPA1) in the brain. When …

The Role Of Complement In Normal Pregnancy And Preeclampsia, Richard M Burwick, Anuja Java, Jean F Regal

2020-Current year OA Pubs

Preeclampsia affects 3-4% of pregnancies with adverse effects for both mother and child. Minimal therapeutic options are available, and biomarkers are urgently needed to identify those at greatest risk early in the pregnancy. Both the innate and adaptive immune systems are well regulated during normal pregnancy including the complement system. A functioning complement system with some degree of complement activation participates in proper placental development, ensuring a healthy pregnancy and assisting with host defense. However, aberrant complement activation can lead to adverse pregnancy outcomes such as preeclampsia. An overview of the complement system will be presented, along with review of …

Th9 Cells Provide Protective Tb Immunity, Mei Xia, Azra Blazevic, Huan Ning, Christopher S Eickhoff, Chad E Storer, Richard D Head, Jianguo Liu, Jessica Jarvela, David Stoeckel, Erin Rakey, Jan Tennant, Daniel L Miller, Kathleen R Holloway, Richard F Silver, Daniel F Hoft

2020-Current year OA Pubs

INTRODUCTION: CD4+ Th9 cells have been associated with inflammatory and allergic diseases. IL-9/Th9 can function as both positive and negative immune regulators, but their protective effects against

METHODS: To study TB-specific Th9 protective effects, we generated Th9 cells from ESAT6-specific TCR transgenic mice and healthy human donors.

RESULTS: Both murine and human Th9 cells significantly inhibited intracellular mycobacterial growth. In both

DISCUSSION: Th9 cells can provide important protection against Mtb infection, and should be targeted with future TB vaccine strategies. Furthermore, Th9 cells appear to utilize a novel protective mechanism independent from Th1-mediated protective responses.

Endogenous Self-Peptides Guard Immune Privilege Of The Central Nervous System, Min Woo Kim, Wenqing Gao, Cheryl F Lichti, Xingxing Gu, Taitea Dykstra, Jay Cao, Igor Smirnov, Pavle Boskovic, Denis Kleverov, Andrea F M Salvador, Antoine Drieu, Kyungdeok Kim, Susan Blackburn, Clair Crewe, Maxim N Artyomov, Emil R Unanue, Jonathan Kipnis

2020-Current year OA Pubs

Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system

Alternative Approaches For Monitoring And Evaluation Of Lymphatic Filariasis Following Mass Drug Treatment With Ivermectin, Diethylcarbamazine And Albendazole In East New Britain Province, Papua New Guinea, Krufinta Bun, Benedict Mode, Melinda Susapu, Joyceline Salo, Catherine Bjerum, Michael Payne, Daniel Tisch, Makoto Sekihara, Emanuele Giorgi, Gary J. Weil, Peter U. Fischer, Leanne Robinson, Moses Laman, Christopher L. King

2020-Current year OA Pubs

BACKGROUND: WHO recommends two annual rounds of mass drug administration (MDA) with ivermectin, diethylcarbamazine, and albendazole (IDA) for lymphatic filariasis (LF) elimination in treatment naïve areas that are not co-endemic for onchocerciasis such as Papua New Guinea (PNG). Whether two rounds of MDA are necessary or sufficient and the optimal sampling strategies and endpoints for stopping MDA remain undefined.

METHODS AND FINDINGS: Two cross-sectional studies were conducted at baseline (N = 49 clusters or villages) and 12 months after mass drug administration (MDA) with IDA (N = 47 villages) to assess lymphatic filariasis (LF) by circulating filarial antigenemia (CFA) and …

De Novo Lipid Synthesis In Cardiovascular Tissue And Disease, Tariq J Khan, Clay F Semenkovich, Mohamed A Zayed

2020-Current year OA Pubs

Most tissues have the capacity for endogenous lipid synthesis. A crucial foundational pathway for lipid synthesis is de novo lipid synthesis (DNL), a ubiquitous and complex metabolic process that occurs at high levels in the liver, adipose and brain tissue. Under normal physiological conditions, DNL is vital in converting excess carbohydrates into fatty acids. DNL is linked to other pathways, including the endogenous synthesis of phospholipids and sphingolipids. However, abnormal lipid synthesis can contribute to various pathologies and clinical conditions. Experimental studies involving dietary restriction and in vivo genetic modifications provide compelling evidence demonstrating the significance of lipid synthesis in …

Rethinking Immune Check Point Inhibitors Use In Liver Transplantation: Implications And Resistance, Vivian Ortiz, Emilien Loeuillard

2020-Current year OA Pubs

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression …

Molecular Regulation And Therapeutic Targeting Of Vldl Production In Cardiometabolic Disease, Kendall H Burks, Nathan O Stitziel, Nicholas O Davidson

2020-Current year OA Pubs

There exists a complex relationship between steatotic liver disease (SLD) and atherosclerotic cardiovascular disease (CVD). CVD is a leading cause of morbidity and mortality among individuals with SLD, particularly those with metabolic dysfunction-associated SLD (MASLD), a significant proportion of whom also exhibit features of insulin resistance. Recent evidence supports an expanded role of very low-density lipoprotein (VLDL) in the pathogenesis of CVD in patients, both with and without associated metabolic dysfunction. VLDL represents the major vehicle for exporting neutral lipid from hepatocytes, with each particle containing one molecule of apolipoproteinB100 (APOB100). VLDL production becomes dysregulated under conditions characteristic of MASLD …

Recombinant Human Alpha-N-Acetylglucosamine-6-Sulfatase Delivered To Sanfilippo D Mice With Repeated Intracerebroventricular Injections Corrects Cns Pathology, Grant L. Austin, Feng Wang, Steven Q. Le, Alexander Sorensen, Shan Li, Lai C. Foong, Srikanth Singamsetty, Jill Wood, Tsui-Fen Chou, Patricia I. Dickson

2020-Current year OA Pubs

Mucopolysaccharidosis type IIID (MPS IIID; Sanfilippo D) is caused by biallelic pathogenic variants in N-acetylglucosamine-6-sulfatase (GNS), which participates in catabolism of heparan sulfate (HS) glycosaminoglycans. Characterization of MPS IIID disease at a cellular level has not been robustly achieved. We used unbiased quantitative proteomics to establish a cellular phenotype for MPS IIID mice. Recombinant human GNS (rhGNS), a variant of which previously demonstrated single dose efficacy in MPS IIID human fibroblasts and in MPS IIID neonatal mice, was used to establish a repeat dosing schedule to treat MPS IIID mice. Adult Gns KO mice or heterozygous carriers were treated via …

Bronchus-Associated Lymphoid Tissue In Lung Transplantation: A Facilitator Of Rejection Or Regulator Of Tolerance?, Alexander N Wein, Charles R Liu, Daniel Kreisel

2020-Current year OA Pubs

The role of bronchus-associated lymphoid tissue (BALT) in the regulation of immune responses to transplanted lungs remains an area of interest and controversy. Early studies in a rat pulmonary transplant model suggested BALT may accelerate rejection of grafts by inducing a local and systemic inflammatory response. Such observations were corroborated in intrapulmonary tracheal transplant models in the rat. While some human studies have described the presence of BALT in grafts that have been chronically rejected, others did not observe an association between induction of BALT and adverse outcomes. More recent investigations have found that BALT, enriched in immunoregulatory cell populations, …

The Perfect Storm: Unraveling The Interplay Of Genetic Predisposition And Viral Triggers In Type 1 Diabetes Pathogenesis, Daniel A Veronese-Paniagua, Jeffrey R Millman

2020-Current year OA Pubs

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the T cell-mediated destruction of insulin-secreting pancreatic β cells, leaving patients reliant on exogenous insulin to establish normoglycemia. Despite advancements in glucose management, the precise pathological mechanisms linking genetic predisposition and environmental triggers to the loss of immune tolerance remain incompletely understood, hindering the development of preventative therapies. This comprehensive review synthesizes clinical, experimental, and epidemiological data to detail the intricate pathogenesis of T1D, focusing on the convergence of autoimmunity, high-risk genetics, and enteroviral infection. We discuss how T1D is fundamentally a disease caused by failures in central and …

Linking Transcriptome And Morphology In Bone Cells At Cellular Resolution With Generative Ai, Lu Lu, Noriaki Ono, Joshua D Welch

Faculty, Staff and Student Publications

Recent advancements in deep learning (DL) have revolutionized the capability of artificial intelligence (AI) by enabling the analysis of large-scale, complex datasets that are difficult for humans to interpret. However, large amounts of high-quality data are required to train such generative AI models successfully. With the rapid commercialization of single-cell sequencing and spatial transcriptomics platforms, the field is increasingly producing large-scale datasets such as histological images, single-cell molecular data, and spatial transcriptomic data. These molecular and morphological datasets parallel the multimodal text and image data used to train highly successful generative AI models for natural language processing and computer vision. …

Saponin Tql1055 Adjuvant-Containing Vaccine Confers Protection Upon Mycobacterium Tuberculosis Challenge In Mice, Mushtaq Ahmed, Eric Farris, Rosemary V Swanson, Shibali Das, Yan Yang, Tyler Martin, Shabaana A Khader

2020-Current year OA Pubs

Tuberculosis (TB), caused by the intracellular pathogen

The Significance Of Aldehyde Dehydrogenase 1 In Cancers, Anh L. Nguyen, Caroline O. B. Facey, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular …

Nos Inhibition Sensitizes Metaplastic Breast Cancer To Pi3k Inhibition And Taxane Therapy Via C-Jun Repression, Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang

Faculty, Staff and Student Publications

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH

Dlk-Dependent Axonal Mitochondrial Fission Drives Degeneration After Axotomy, Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon

Faculty, Staff and Students Publications

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related …

Parp Inhibition Radiosensitizes Brca1 Wildtype And Mutated Breast Cancer To Proton Therapy, Mariam Ben Kacem, Scott J Bright, Emma Moran, David B Flint, David K J Martinus, Broderick X Turner, Ilsa Qureshi, Rishab Kolachina, Mandira Manandhar, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons …

Cancer Organoids As Reliable Disease Models To Drive Clinical Development Of Novel Therapies, Giovanni Blandino, Ronit Satchi-Fainaro, Ingeborg Tinhofer, Giovanni Tonon, Sarah C Heilshorn, Yong-Jun Kwon, Ana Pestana, Carlotta Frascolla, Luca Pompili, Aurora Puce, Sara Iachettini, Annalisa Tocci, Sofia Karkampouna, Marianna Kruithof-De Julio, Piera Tocci, Nicla Porciello, Klizia Maccaroni, Daniela Rutigliano, Xiling Shen, Gennaro Ciliberto

Faculty, Staff and Student Publications

On September 23-24 (2024) the 6th Workshop IRE on Translational Oncology, titled "Cancer Organoids as Reliable Disease Models to Drive Clinical Development of Novel Therapies," took place at the IRCCS Regina Elena Cancer Institute in Rome. This prominent international conference focused on tumor organoids, bringing together leading experts from around the world.A central challenge in precision oncology is modeling the dynamic tumor ecosystem, which encompasses numerous elements that evolve spatially and temporally. Patient-derived 3D culture models, including organoids, explants, and engineered or bioprinted systems, have recently emerged as sophisticated tools capable of capturing the complexity and diversity of cancer cells …

Visualizing Parcel-Level Lead Risk Using An Exterior Housing-Based Index., Neal J. Wilson, Ryan Allenbrand, Elizabeth Friedman, Kevin Kennedy, Amy Roberts, Stephen Simon

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric lead poisoning remains a persistent public health problem. Children in the US spend the preponderance of their time at home; thus, housing is an important social determinant of health. Improving health outcomes derived from housing-based sources involves differentiating the risks posed by the existing housing stock. In this paper, we developed a parcel-level lead risk index (LRI) based on external housing conditions and the year of home construction. The purpose of this study was to introduce a housing-based lead risk index (LRI), developed using retrospective data, to estimate parcel-by-parcel variation in housing-based lead risk. We described how the LRI …