Digital Commons Network^™

Effectiveness Of Glucagon-Like Peptide 1 Receptor Agonists In The Treatment Of Heart Failure, Lisa Kristen Schloemann

SIU Journal of Medical Science Scholarly Works

ABSTRACT

Purpose: The purpose of this article is to review the use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in heart failure (HF) treatment considering the HF phenotype and comorbidities, including type 2 diabetes mellitus (DM) and obesity.

Method: A PubMed and Google Scholar literature search was conducted with search terms, HF and GLP-1 RA. Seven pertinent articles were retrieved and served as the basis for this clinical review.

Results: The efficacy of GLP-1 RA therapy in patients with heart failure with reduced ejection fractions (HFrEF) is unclear, with one study showing increased adverse cardiac events including tachyarrhythmias, and …

Prefrontal Cortex Astrocytes Modulate Distinct Neuronal Populations To Control Anxiety-Like Behavior, Eunyoung Kim, Hairuo Du, Yanqi Tan, Brandon L Brown, Yaowen Chang, Blanca Díaz-Castro, Jonathan V Sweedler, Xinzhu Yu

Faculty, Staff and Student Publications

Accumulating evidence has supported diverse regulatory functions of astrocytes in different neural circuits as well as various aspects of complex behaviors. However, little is known about how astrocytes regulate different neuronal subpopulations that are linked to specific behavioral aspects within a single brain region. Here, we show that astrocytes in the medial prefrontal cortex (mPFC) encode anxiogenic environmental cues in freely behaving mice. Silencing mPFC astrocyte Ca

Circzfr/Ythdf3 Axis Drives Lymph Node Metastasis In Cervical Cancer Via Fasn Translation, Mingyi Zhou, Yan Gao, Yong Zhang, Lian He, Bo Gao, Yue Zhang, Francois X Claret, George A Calin, Danbo Wang

Faculty, Staff and Student Publications

Background: Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.

Methods: We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression. …

Retrieval Of An Embolized Left Atrial Appendage Occluder From The Aortic Arch Using A Transcatheter Retrieval Device, Juan Siordia, Hussam Al Hennawi, Muhammad Sabri, Daniel Ice, Ronald Ross, Sheena Rastogi, Chunguang Chen, Richard Kovach, Muhammad Raza

Abington Jefferson Health Papers

BACKGROUND: Device embolization is a recognized complication of left atrial appendage occlusion (LAAO) procedures, with outcomes depending on the location of the embolized device and patient management.

CASE SUMMARY: A 70-year-old male with atrial fibrillation underwent LAAO due to high bleeding risk. Postoperative surveillance revealed an Amplatzer Amulet device embolized in the transverse arch of the aorta. The patient remained asymptomatic, and transcatheter retrieval was planned. A percutaneous approach was used with the ONOCOR system and snare devices with successful retrieval. The patient recovered without complications and remained stable at follow-up.

DISCUSSION: Device embolization often presents challenges, with clinical outcomes …

Targeted Proteomic Analysis Identifies Acvrl1 As A Marker Of Cerebral Edema In Aneurysmal Subarachnoid Hemorrhage, Bosco Seong Kyu Yang, Lena O'Keefe, Sarah Hinds, Hua Chen, Athziry Paz, Jude Savarraj, Han-Gil Jeong, Moon-Ku Han, Aaron Gusdon, Xuefang Sophie Ren, Spiros Blackburn, Huimahn Alex Choi

Faculty, Staff and Student Publications

Cerebral edema (CE) is a major component of early brain injury from aneurysmal subarachnoid hemorrhage (SAH). Despite the utility of blood-based protein markers, biomarkers targeting cerebral edema have yet to be developed. We performed a targeted proteomic search analyzing 141 proteins in plasma samples taken from 80 adult patients within 48 hours after aneurysmal rupture to identify plasma biomarkers of cerebral edema. The protein expression profiles were analyzed for associations with a higher level of the subarachnoid hemorrhage early brain edema score measured in admission computed tomography scans. Five differentially expressed proteins-brorin, ectodysplasin A2 receptor, layilin, scavenger receptor class A …

Gm-Csf Production By Immune Cells In Steady State And Autoimmune Neuroinflammation Mapped Using Fate Reporting Mice, Gholamreza Azizi, Javad Rasouli, Hamed Naziri, Michael V. Gonzalez, James Garifallou, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad M. Rostami

Department of Neurology Faculty Papers

INTRODUCTION: GM-CSF is a pro-inflammatory cytokine that promotes an inflammatory phenotype in myeloid cells. The extent and pattern of GM-CSF expression in immune cells have not been fully elucidated. Our goal was to advance this topic using novel GM-CSF reporter/fate reporter transgenic mice.

METHODS: We tracked ongoing and past GM-CSF expression in various immune cells from multiple organs, in steady-state and autoimmune inflammation of the central nervous system (CNS).

RESULTS: The GM-CSF expression patterns varied by cell type and organ, with CD4

DISCUSSION: These findings identified distinct GM-CSF cellular sources across organs, highlighting the transient nature of GM-CSF expression and …

Immunogenicity And Safety Of A Rabies-Based Highly Pathogenic Influenza A Virus H5 Vaccine In Cattle, Nir Paran, Christoph Wirblich, Catherine Olal, Alessandro Tarquinio, Kimberly H. Lohmeyer, Drishya Kurup, Stacey Schultz-Cherry, Ismaila Shittu, Gregory C. Gray, Dennis A. Bente, Pia U. Olafson, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

The circulation of highly pathogenic H5 influenza A viruses in cattle, other mammals, and wildlife threatens animal and human health. To address this, we vaccinated heifer-calves with a deactivated rabies-virus-based H5 vaccine, which was well-tolerated and elicited neutralizing antibodies against both clade-1 and clade-2.3.4.4b H5N1 viruses, comparable to naturally H5-infected and convalescing cows. The immune responses to the vaccine platform were durable for at least 200 days and unaffected by preexisting RABV immunity.

Silvestrol Inhibits Nasopharyngeal Carcinoma Cells And Synergizes With Cx‑5461: Insights From A Proteomics Study, Maelinda Daker, Munirah Ahmad, Alan Khoo, Lu Ping Tan, Siok-Fong Chin, Siaw San Hwang, Paul Neilsen

Department of Medical Oncology Faculty Papers

Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx, which is rare in Western countries but extremely prevalent in Borneo and the Southern China region. Present-day hurdles in NPC treatment that lead to poor quality of life and poor survival include distant metastasis and resistance to chemoradiotherapy. Silvestrol and its 5'''-epimer, episilvestrol, are compounds isolated from the plant Aglaia stellatopilosa, which is endemic to Borneo. Silvestrol, a protein synthesis inhibitor, preferentially inhibits the translation of cancer-associated mRNAs. CX-5461 is an inhibitor of RNA polymerase I that catalyzes rRNA synthesis. The present study sought to …

Lipid-Laden Microglia: Characterization And Roles In Diseases, Jiani Xing, Takese Mckenzie, Jian Hu

Faculty, Staff and Student Publications

Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). LLMs have been implicated in various neuroinflammatory and neurodegenerative diseases, functioning as both regulators/indicators of inflammation and potential therapeutic targets. This review summarizes the current research on LLMs, focusing on disease-specific regulators and functions, protective roles, interactions with neighboring cells, and advances in diagnostic and analytical tools. We also discuss the blurred distinction between LLMs and macrophages, …

Therapeutic Targeting Of Syndecan-1 Axis Overcomes Acquired Resistance To Kras-Targeted Therapy In Gastrointestinal Cancers, Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A Depinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao

Faculty, Staff and Student Publications

The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated …

Causes Of Symptoms And Symptom Persistence In Long Covid And Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Anthony L Komaroff, Robert Dantzer

Faculty, Staff and Student Publications

Debilitating symptoms for many years can follow acute COVID-19 ("long COVID"), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural …

Trpc4 Regulates Limbic Behavior And Neuronal Development By Stabilizing Dendrite Branches Through Actomyosin-Driven Integrin Activation, Jaepyo Jeon, Travis I Moore, Insuk So, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer, Michael X Zhu

Faculty, Staff and Student Publications

Transient Receptor Potential Canonical 4 (TRPC4) channels have been implicated in multiple neurological functions, including anxiety and sociability. TRPC4 variants were also found in patients with autism. However, the contributions of TRPC4 to neurodevelopment remain undefined. Here, we show that neurobehavioral deficits appear early in young TRPC4 knockout (Trpc4^−/−) mice immediately after weaning, manifesting as alterations in multiple, limbic-related behaviors, such as nesting, marble burying, burrowing, self-grooming, and social interactions. Hippocampal neurons of Trpc4−/− mice exhibit reduced dendritic arborization both in vivo and in vitro. Mechanistically, we found that TRPC4 expression in dendrites surged at the …

Mechano-Signal Transduction Pathways Of The Diaphragmatic Muscle And Role Of Cytoskeleton, Junaith S Mohamed, Patricia S Pardo, Aladin M Boriek

Faculty, Staff and Students Publications

Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of mechanically active tissues, such as the diaphragm-a respiratory muscle vital for breathing in mammals. In vivo, the diaphragm is subjected to transdiaphragmatic pressure, and therefore, its muscle fibers are subjected to mechanical forces not only in the direction of the muscle fibers but also in the direction transverse to the fibers. Previous research conducted in our laboratory …

Bioinspired Ruthenium-Manganese-Oxygen Complex For Biocatalytic And Radiosensitization Therapies To Eradicate Primary And Metastatic Tumors, Ruidan Li, Ting Wang, Shengdong Mu, Zhenyu Xing, Zhiying Ding, Qinlong Wen, Zhigong Wei, Xiaolin Wang, Mohsen Adeli, Shuang Li, Chong Cheng, Xingchen Peng

Faculty, Staff and Students Publications

Designing efficient, biocompatible radiation-sensitive materials to activate systemic immune responses can maximize tumoricidal effects against malignant tumors. Here, inspired by natural Mn-peroxidase, we propose the de novo design of the RuMn-oxygen complex (MnBTC-Ru) for biocatalytic and radiosensitization therapies to eradicate primary and metastatic tumors. Our results reveal that Mn-organic ligands can enhance the electron density of Ru clusters, thereby optimizing their binding to oxygen species and resulting in high reactive oxygen species and oxygen generation. Accordingly, MnBTC-Ru with radiation can enhance cell membrane and DNA damage, triggering apoptosis though oxidative damage, heightening radiosensitization, and activating CD8

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett’S Esophagus Development, Ramon U Jin, Yuanwei Xu, T Mamie Lih, Yang-Zhe Huang, Toni M Nittolo, Blake E Sells, Olivia M Dres, Jean S Wang, Qing K Li, Hui Zhang, Jason C Mills

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Lipidomic And Proteomic Insights From Extracellular Vesicles In The Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes, Chioma M Okeoma, Wasifa Naushad, Bryson C Okeoma, Carlos Gartner, Yulica Santos-Ortega, Calvin Vary, Savio Lima-Bastos, Victor Corasolla Carregari, Martin R Larsen, Alessio Noghero, Consuelo Walss-Bass, Rodrigo Grassi-Oliveira

Faculty, Staff and Student Publications

Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to reactive astrogliosis and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD patients by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmann's area 9 (BA9) from postmortem subjects. We isolated BA9-derived …

Mathematical Modeling And Association Analysis Decipher The Impact Of The Gut Microbiome On Cancer Immunotherapy, Andreas G Hadjigeorgiou, Constantinos Harkos, Aditya K Mishra, Golnaz Morad, Sarah B Johnson, Nadim J Ajami, Jennifer A Wargo, Lance L Munn, Triantafyllos Stylianopoulos, Rakesh K Jain

Faculty, Staff and Student Publications

The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, a better understanding of the underlying mechanisms by which the microbiome influences immunotherapy is needed to identify strategies to optimize outcomes. To this end, we developed a mathematical model to obtain insights into the effect of the microbiome on the immune system and immunotherapy response. This model was based on (i) gut microbiome data derived from preclinical studies, (ii) mathematical modeling of the antitumor immune response, (iii) association analysis of microbiome profiles with model-predicted immune profiles, and (iv) statistical models that correlate model parameters with …

Post-Translational Modifications Of Extracellular Matrix Domains As Prognosticators Of Hepatocellular Carcinoma Via Integrative Serum And Spatial Proteomics, Jade K. Macdonald

MUSC Theses and Dissertations

Hepatocellular carcinoma (HCC) remains a major global health challenge, with rising incidence, high mortality, and a five-year survival rate below 20%. Approximately 90% of HCC cases arise in cirrhosis, a stromal disease characterized by excessive deposition and remodeling of collagenous extracellular matrix (ECM). As HCC progresses, alterations in ECM composition and spatial distribution influence disease progression, emphasizing the potential of the ECM as a biomarker for HCC prognosis and treatment response. However, ECM proteomic analysis is challenging due to complex post-translational modifications, crosslinking, and insolubility. This dissertation molecularly and spatially characterizes the stromal landscape in and around HCC tumors in …

Transcriptional Remodeling Shapes Therapeutic Vulnerability To Necroptosis In Acute Lymphoblastic Leukemia, Anna Saorin, Anna Dehler, Bartimée Galvan, Fabio Steffen, Marine Ray, Dong Lu, Xin Yu, James Kim, Aneta Drakul, Samanta Kisele, Jin Wang, Jean-Pierre Bourquin, Beat C Bornhauser

Faculty, Staff and Students Publications

Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent …

Planetary Health: At The Crossroads Of Cvd Prevention, Tasveer Khawaja, Sanjay Rajagopalan

Faculty Scholarship

Purpose of Review: To highlight important recent findings demonstrating the interconnectedness of planetary and human health with a focus on cardiovascular disease. Recent Findings: Data continue to demonstrate a clear interconnectedness between the health of the planet and human health, with cardiovascular disease as an important outcome. The central roles of air pollution, non-optimal temperatures, water/waste management, and food/biodiversity are highlighted. We also highlight the clear opportunity for healthcare organizations to facilitate change that will yield positive environmental and patient outcomes. Summary: The undeniable interconnectedness of the health of the planet and human health serves as a call to action …

Co-Targeting Bcl-Xl With Mcl-1 Induces Lethal Mitochondrial Dysfunction In Diffuse Mesothelioma, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley

Faculty, Staff and Students Publications

Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance.

We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl …

Prenatal Diagnosis Of An Uncommon Form Of A Hypoplastic Left Heart Syndrome Variant., Anmol Goyal, Abigail Phillips, Kelsey Brattrud, Rita France, Maria Kiaffas

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Mitral valve dysplasia syndrome (MVDS) is a rare cardiac defect requiring accurate prenatal identification and appropriate counseling, delivery planning, and postnatal management.

CASE SUMMARY: A 39-year-old woman underwent fetal echocardiography at 34 weeks' gestation owing to cardiomegaly and hydrops. Biatrial enlargement, mild to moderate atrioventricular valve insufficiency, dysplastic mitral valve apparatus, biventricular dilation with systolic dysfunction, endocardial fibroelastosis, hypoplastic aortic outflow, and severely restrictive atrial septum were attributed to MVDS. The plan for critical (class IV) delivery was modified with premature onset of labor at 36 weeks' gestation, leading to urgent cesarean section. Emergent balloon atrial septostomy was performed …

Gastrointestinal Fistulas-What Gastroenterologists Need To Know In 2025, Monjur Ahmed

Division of Gastroenterology and Hepatology Faculty Papers

Gastrointestinal fistulas are increasingly being encountered in our clinical practice because of the increased burden of Crohn's disease, bariatric surgeries, interventional endoscopic procedures, nonsurgical trauma, and war and disaster zones worldwide. Presentation depends on the location and specific type of the fistula. Symptomatic ones can have a tremendous impact on social life and can cause dehydration, electrolyte imbalance, malnutrition, increased morbidity, and mortality. Different imaging studies and endoscopic procedures are done to establish the diagnosis. Treatment modalities to close the fistula depend on the underlying disease and the type of fistula. They include conservative treatment, medical therapy, endoscopic interventions, and …

Ribosome Deficiency Induces Salmonella Filamentation Within Host Cells, Zhihui Lyu, Cierra Wilson, Kalyn Weiss, Spencer Lewis, Kurt Fredrick, William Margolin, Jiqiang Ling

Faculty, Staff and Student Publications

The ribosome is the central hub for protein synthesis and is heavily targeted by antibiotics. Ribosomal mutations, antibiotic treatment, and nutrient starvation can alter translational efficiency and lead to stressed cells. Ribosome deficiency plays a critical role in stress responses and disease progression; yet, how it affects bacteria-host interactions remains poorly understood. In this study, we show that a ribosome-deficient strain exhibits a surprising morphological change from rod shape to filamentous in Salmonella cells growing inside host macrophages. Such filamentation depends on an acidic condition within macrophages and in a defined medium mimicking macrophage conditions. Further genetic analyses revealed that …

Identification Of Alkynyl Nicotinamide Hsn748 As A Ret Solvent-Front Mutant Inhibitor With Intracranial Efficacy, Ujjwol Khatri, Neetu Dayal, Kofi B Owusu, Mandeep Kaur Hunjan, Shriya Pandey, Haley Anne Harper, Carli Mcmahan, Bennett D Elzey, Tao Shen, Xueqing Hu, Kurt W Evans, Ahmed El-Sheikh, Seong Jun Jo, Frederick W Holtsberg, M Javad Aman, Funda Meric-Bernstam, Sukyung Woo, Herman O Sintim, Jie Wu

Faculty, Staff and Student Publications

RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Moreover, RET fusion-positive lung adenocarcinoma frequently metastasizes to the brain. To address these challenges, it is imperative to develop a RET TKI that is effective against solvent-front mutations and exhibits intracranial activity. We synthesized alkynyl nicotinamide-based RET TKIs and tested their efficacy in cell cultures in inhibiting selpercatinib/pralsetinib-resistant RET solvent-front mutants G810C/R/S found in cancer patients, and in BaF3/KIF5B-RET(G810C) cell-derived subcutaneous and intracranial tumors in vivo. We also evaluated alkynyl nicotinamide RET TKIs in KIF5B-RET-induced lung tumors in immune competent …

Non-Isolated Tetralogy Of Fallot (Tof+): Exome Sequencing Efficacy And Phenotypic Expansions, Julia Volpi, Xiaonan Zhao, Nichole Owen, Tia Evans, Muriel Holder-Espinasse, Nayana Lahiri, Eleanor Sherlock, Gemma Poke, Jeroen Breckpot, Koen Devriendt, Bjorn Cools, Alfredo Brusco, Giovanni Battista Ferrero, Enrico Grosso, Pradeep Vasudevan, Sara Loddo, Antonio Novelli, Maria Cristina Digilio, Aafke Engwerda, Marrit Hitzert, Alison Male, Lucy Bownass, Ruth Newbury-Ecob, Zosia Miedzybrodzka, Ruth Armstrong, Sally Ann Lynch, Gunnar Houge, Shiyi Xiong, Seema R Lalani, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Daryl A Scott

Faculty, Staff and Students Publications

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES). Here, we analyzed cES data from 131 individuals with TOF+. A definitive or probable diagnosis was made for 31 individuals, yielding a diagnostic rate of 23.6% (31/131). One individual received three diagnoses. Commercially available CHD panels …

Extracellular Vesicles For Clinical Diagnostics: From Bulk Measurements To Single-Vesicle Analysis, Hai Linh Tran, Wenshu Zheng, David A Issadore, Hyungsoon Im, Yoon-Kyoung Cho, Yuanqing Zhang, Dingbin Liu, Yang Liu, Bo Li, Fei Liu, David Tai Wai Wong, Jiashu Sun, Kun Qian, Mei He, Meihua Wan, Yong Zeng, Ke Cheng, Tony Jun Huang, Daniel T Chiu, Luke P Lee, Lei Zheng, Andrew K Godwin, Raghu Kalluri, Steven A Soper, Tony Y Hu

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) play a crucial role in intercellular communication, signaling pathways, and disease pathogenesis by transporting biomolecules such as DNA, RNA, proteins, and lipids derived from their cells of origin, and they have demonstrated substantial potential in clinical applications. Their clinical significance underscores the need for sensitive methods to fully harness their diagnostic potential. In this comprehensive review, we explore EV heterogeneity related to biogenesis, structure, content, origin, sample type, and function roles; the use of EVs as disease biomarkers; and the evolving landscape of EV measurement for clinical diagnostics, highlighting the progression from bulk measurement to single vesicle …

Hippocampal Avoidance During Prophylactic Cranial Irradiation For Patients With Small Cell Lung Cancer: Randomized Phase Ii/Iii Trial Nrg-Cc003, Vinai Gondi, Stephanie L Pugh, Minesh P Mehta, Jeffrey S Wefel, Wolfgang A Tomé, Alexander Y Sun, John Grecula, Kristin J Redmond, Shannon Fogh, Laurie Gaspar, Andre Konski, Joseph Bovi, Clifford G Robinson, Benjamin Corn, Gregory M Videtic, Benjamin H Lok, Harold A Yoon, John H Heinzerling, Albert S Denittis, Ronald C Mcgarry, Kiran Devisetty, Vijayananda Kundapur, Abraham J Wu, Edward C Mccarron, Isabelle Thibault, Edmund L Simon, Andrew M Baschnagel, Samir Narayan, Jondavid Pollock, Rebecca Paulus, Lisa A Kachnic

Faculty, Staff and Student Publications

Purpose: Hippocampal avoidance (HA) during therapeutic whole-brain radiotherapy reduces the risk of neurocognitive function (NCF) toxicity in patients with brain metastasis. This trial hypothesized that HA during prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) leads to noninferior intracranial relapse (ICR) and reduction in NCF toxicity.

Methods: This randomized phase II/III trial enrolled patients with SCLC, no brain metastases, and response to chemotherapy. The primary end points were 12-month ICR (noninferiority design, randomized phase II) and 6-month Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure (phase III). Secondary end points were failure in any NCF …

Keap1 And Stk11/Lkb1 Alterations Enhance Vulnerability To Atr Inhibition In Kras Mutant Non-Small Cell Lung Cancer, Ana Galan-Cobo, Natalie I Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G Paula, Marlese Pisegna, Daniel J Mcgrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc'h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, Gozde Kar, Caezaan Keshvani, Claudio Arrechedera, Sharia Hernandez, Katharina Schlacher, Jing Wang, Sonia Iyer, James Conway, Mohamed Reda Keddar, Marta Milo, Ilario De Toma, Susan E Critchlow, J Carl Barrett, Jan Cosaert, Alan Lau, Viia Valge-Archer, Lauren A Byers, Simon T Barry, John V Heymach

Faculty, Staff and Student Publications

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype …

Polo-Like Kinase 1 Inactivation Enhances Pi3k Inhibition-Mediated Apoptosis Of Notch1-Mutant Head And Neck Squamous Cell Carcinoma, Pooja A Shah, Tuhina Mazumdar, Soma Ghosh, Lacin Yapindi, Reid T Powell, Yong S Park, Li Shen, Anne M Fernandez, Clifford C Stephan, Jing Wang, Andrew G Sikora, Jawad Kazi, Mitchell J Frederick, Faye M Johnson

Children’s Nutrition Research Center Staff Publications

PI3K inhibition causes apoptosis selectively in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR NOTCH1-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal in vitro methods and in two HNSCC xenograft models. Compound efficacy …