Digital Commons Network^™

Advances In Molecular Imaging Of Vegfrs: Innovations In Imaging And Therapeutics, Hanieh Karimi, Sarah Lee, Wenqi Xu, Sigrid A. Langhans, David K. Johnson, Erik Stauff, Heidi H. Kecskemethy, Lauren W. Averill, Xuyi Yue

Department of Radiology Faculty Papers

Vascular endothelial growth factor receptors (VEGFRs) are key regulators of angiogenesis, lymphangiogenesis, and vascular permeability, playing essential roles in both physiological and pathological processes. The VEGFR family, including VEGFR-1, VEGFR-2, and VEGFR-3, interacts with structurally related VEGF ligands (VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor [PlGF]), activating downstream signaling pathways that mediate critical cellular processes, including proliferation, migration, and survival. Dysregulation of VEGFR signaling has been implicated in numerous diseases, such as cancer, cardiovascular conditions, and inflammatory disorders. Targeting VEGFRs with radiopharmaceuticals, such as radiolabeled peptides, antibodies, and specific tracers like 64Cu-bevacizumab and 89Zr-ramucirumab, has emerged as a powerful …

Importance Of Outbreak Response Research In Bridging Knowledge Gaps On Emerging Infectious Diseases, Robert F Breiman, David Wang, Michael Diamond, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

An important outcome of the devastating 2014 West African Ebola virus disease outbreak and the 2020 COVID-19 pandemic has been the growing promotion of conducting research during outbreaks of emerging infectious diseases (EIDs) as a valuable and acceptable process of acquiring knowledge to enhance our ability to better prevent and control these diseases in the future. Recognising the unique opportunity during outbreaks to leverage increases in cases over a short time interval and in a circumscribed area, we articulate a systematic process of conducting EID outbreak response research, highlighting knowledge gaps that should be prioritised, and measures that can be …

177lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality In Solid Tumors, Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC …

Eph Receptors Activate Myeloid Checkpoint Receptor Lilrb5 To Support Tumor Development, Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Xing Yang, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid …

Mutant P53 Gain Of Function: Why Many See It, Why Some Do Not, Guillermina Lozano, Carol Prives, Kanaga Sabapathy

Faculty, Staff and Student Publications

Mutations in the TP53 tumor-suppressor gene in human cancer are unique in that 60% to 70% are of the missense variety, resulting in a full-length protein that is often highly expressed in patients' tumors. These missense mutant proteins often exhibit pro-oncogenic activities (referred to as gain of function) in mouse models and human cell lines and correlate with poor cancer prognosis in some cases.

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map Of The Human Kidney Across The Lifespan, Liam Mclaughlin, Bo Zhang, Siddharth Sharma, Amanda L Knoten, Madhurima Kaushal, Jeffrey M Purkerson, Heidie L Huyck, Gloria S Pryhuber, Joseph P Gaut, Sanjay Jain

2020-Current year OA Pubs

The human kidney maintains homeostasis through a complex network of up to a million nephrons, its fundamental tissue units. Using innovative tissue processing and light sheet fluorescence microscopy, we mapped the 3D neurovascular connectivity of nephrons to understand how their structural organization enables coordinated functions like filtration, absorption, and blood pressure regulation. Our analysis revealed developmental changes in glomerular orientation, density, volume, and innervation from birth through aging. We discovered an extensive nerve network connecting different nephron segments and organizing glomeruli into distinct communities. These communities are linked through "mother glomeruli" that serve as control centers, creating a repeating pattern …

A Multimodal Therapeutic Strategy For Inflammatory Bowel Disease Using Microrna-146a Mimic Encapsulated In Lipid Nanoparticles., Kanika Suri, Vishnu Hosur, Rohit Panchakshari, Mansoor M Amiji

Faculty Research 2025

Dysregulated microRNAs (miRNAs) have significant potential as diagnostic tools for various chronic diseases; however, their therapeutic applications remain largely unexplored. Given their capacity to regulate multiple pathways, miRNAs are promising candidates for treating pleiotropic diseases, such as inflammatory bowel disease (IBD). In our study, we conducted a comprehensive review of the literature of miRNA-146 levels in the inflamed tissues of IBD patients and murine colitis models. Initially, we quantified the expression of miRNA-146a and miRNA-146b in the colons of mice using the dextran sodium sulfate (DSS)-inducedacute model of IBD. We selected miRNA-146a for further study due to its anti-inflammatory properties …

Irx2 And Nptx1 Differential Regulation Of Β-Catenin Underlies Mek-Mediated Proliferation In Human Neuroglial Cells, Alexander Chen, Hannah Wang, Xuanwei Li, Corina Anastasaki, David H Gutmann

2020-Current year OA Pubs

The two major genomic alterations in pediatric pilocytic astrocytoma (PA) are

Drosha: A New Tumor Suppressor In Pineoblastoma, Zhixuan Huang, Xueli Ren, Jian Hu

Faculty, Staff and Student Publications

In this Outlook, Huang et al. discuss a study in this issue of Genes & Development by Fraire et al. that shows that a deficiency in miRNA processors Drosha and Dicer and consequent cell cycle gene derepression promote pineoblastoma development. The authors highlight the heterogeneity of pineoblastoma's pathogenic mechanisms and its implications for therapeutic interventions in the clinic.

Longitudinal Outcomes Of The Covid-19 Pandemic On Youth Physical Fitness, Jizyah Injil

Faculty, Staff and Student Publications

Importance: The COVID-19 pandemic led to a decline in physical activity levels among youths, which could have a negative impact on their fitness.

Objective: To examine longitudinal changes in cardiorespiratory fitness (CRF) and musculoskeletal fitness (MSF) among students at schools participating in a school-based physical activity program during fall 2019 through spring 2023.

Design, setting, and participants: This longitudinal cohort study included US schools reporting CRF and MSF data at least once during the pandemic (fall 2020 to fall 2021) and at least 1 additional time before or after. In a subset of schools for which learning modality data was …

Multicenter Validation Of A Machine Learning Model For Surgical Transfusion Risk At 45 Us Hospitals, Sunny S Lou, Sayantan Kumar, Charles W Goss, Michael S Avidan, Sachin Kheterpal, Thomas Kannampallil, Multicenter Perioperative Outcomes Group

2020-Current year OA Pubs

IMPORTANCE: Accurate estimation of surgical transfusion risk is important for perioperative planning and effective resource allocation. Most machine learning models in health care are not validated or perform poorly in external settings.

OBJECTIVE: To externally validate a publicly available machine learning algorithm (Surgical Personalized Anticipation of Transfusion Hazard [S-PATH]) to estimate red cell transfusion during surgery within a national sample of hospitals.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study evaluated all surgical cases performed in 2020 or 2021 at 45 US hospitals participating in the Multicenter Perioperative Outcomes Group. Obstetric and nonoperative cases were excluded. Data analysis was performed …

Deriving A Mammogram-Based Risk Score From Screening Digital Breast Tomosynthesis For 5-Year Breast Cancer Risk Prediction, Shu Jiang, Debbie L Bennett, Graham A Colditz

2020-Current year OA Pubs

Screening digital breast tomosynthesis (DBT) aims to identify breast cancer early when treatment is most effective, leading to reduced mortality. In addition to early detection, the information contained within DBT images may also inform subsequent risk stratification and guide risk-reducing management. Using transfer learning, we refined a model in the Joanne Knight Breast Health Cohort at Washington University, a cohort of 5,066 women with DBT screening (mean age, 54.6), among whom 105 were diagnosed with breast cancer (26 ductal carcinoma in situ). We applied the model to external data from the Emory Breast Imaging Dataset, a cohort of 7,017 women …

Validation Of A Dynamic Risk Prediction Model Incorporating Prior Mammograms In A Diverse Population, Shu Jiang, Debbie L Bennett, Graham A Colditz

2020-Current year OA Pubs

IMPORTANCE: For breast cancer risk prediction to be clinically useful, it must be accurate and applicable to diverse groups of women across multiple settings.

OBJECTIVE: To examine whether a dynamic risk prediction model incorporating prior mammograms, previously validated in Black and White women, could predict future risk of breast cancer across a racially and ethnically diverse population in a population-based screening program.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included women aged 40 to 74 years with 1 or more screening mammograms drawn from the British Columbia Breast Screening Program from January 1, 2013, to December 31, 2019, with follow-up …

Switching On The Evolutionary Potential Of Pancreatic Cancer: The Tumor Suppressor Functions Of Pbrm1, Luigi Perelli, Giannicola Genovese

Faculty, Staff and Student Publications

Cell plasticity is a hallmark of cancer, enabling tumor cells to acquire multiple phenotypes responsible for tumor progression, metastasis, and therapy resistance. In this issue of the JCI, Kawai and colleagues leveraged genetically engineered mouse models (GEMM) of pancreatic ductal adenocarcinoma (PDAC) to demonstrate that loss of Pbrm1, a member of the SWI/SNF complex, drives dedifferentiation and aggressive tumor features. Pbrm1 loss activated a program of epithelial-to-mesenchymal transition (EMT) and allowed the emergence of poorly differentiated histologies that are commonly associated with high recurrence rate and dismal prognosis. These findings reveal the role of the SWI/SNF complex during PDAC evolution …

Mutation Of Smarca4 Induces Cancer Cell-Intrinsic Defects In The Enhancer Landscape And Resistance To Immunotherapy, Yawen Wang, Ismail M Meraz, Md Qudratullah, Sasikumar Kotagiri, Yanyan Han, Jing Wang, Jack A Roth, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and …

A Sumo-Interacting Motif In The Guanine Nucleotide Exchange Factor Epac1 Is Required For Subcellular Targeting And Function, Wenli Yang, Fang Mei, Wei Lin, Jason E Lee, Si Nie, Christopher J Bley, André Hoelz, Xiaodong Cheng

The Brown Foundation: Institute of Molecular Medicine

Exchange protein directly activated by cAMP (EPAC1), a multifunctional intracellular cAMP receptor, dynamically localizes to various cellular loci, engaging with diverse molecular partners to maintain cellular homeostasis. The study investigates the role of the SUMO-interacting motif (SIM) in the subcellular targeting and cellular functions of EPAC1. It reveals that the SIM is a critical structural element for EPAC1's association with RanBP2/nucleoporin 358, a nucleoporin of the cytoplasmic filament component of the nuclear pore complex. Mutational disruption of EPAC1 SIM interferes with EPAC1's ability to activate its canonical effectors, small GTPases, Rap1 and Rap2, and noncanonical functions, such as the formation …

Linking Symptom Inventories Using Semantic Textual Similarity, Kelly S Peterson, Kristen Dams O'Connor, Ronak Agarwal, Houshang H Amiri, Raeda K Andersen, Talin Babikian, David A Baron, Erin D Bigler, Karen Caeyenberghs, Lisa Delano-Wood, Seth G Disner, Ekaterina Dobryakova, Blessen C Eapen, Rachel M Edelstein, Carrie Esopenko, Helen M Genova, Elbert Geuze, Naomi J Goodrich-Hunsaker, Jordan Grafman, Asta K Håberg, Cooper B Hodges, Kristen R Hoskinson, Elizabeth S Hovenden, Andrei Irimia, Neda Jahanshad, Ruchira M Jha, Finian Keleher, Kimbra Kenney, Inga K Koerte, Spencer W Liebel, Abigail Livny, Marianne Løvstad, Sarah L Martindale, Jeffrey E Max, Andrew R Mayer, Timothy B Meier, Deleene S Menefee, Abdalla Z Mohamed, Stefania Mondello, Martin M Monti, Rajendra A Morey, Virginia Newcombe, Mary R Newsome, Alexander Olsen, Nicholas J Pastorek, Mary Jo Pugh, Adeel Razi, Jacob E Resch, Jared A Rowland, Kelly Russell, Nicholas P Ryan, Randall S Scheibel, Adam T Schmidt, Gershon Spitz, Jaclyn A Stephens, Assaf Tal, Leah D Talbert, Maria Carmela Tartaglia, Brian A Taylor, Sophia I Thomopoulos, Maya Troyanskaya, Eve M Valera, Harm Jan Van Der Horn, John D Van Horn, Ragini Verma, Benjamin S C Wade, Willian C Walker, Ashley L Ware, J Kent Werner, Keith Owen Yeates, Ross D Zafonte, Michael M Zeineh, Brandon Zielinski, Paul M Thompson, Frank G Hillary, David F Tate, Elisabeth A Wilde, Emily L Dennis

Faculty, Staff and Students Publications

An extensive library of symptom inventories has been developed over time to measure clinical symptoms of traumatic brain injury (TBI), but this variety has led to several long-standing issues. Most notably, results drawn from different settings and studies are not comparable. This creates a fundamental problem in TBI diagnostics and outcome prediction, namely that it is not possible to equate results drawn from distinct tools and symptom inventories. Here, we present an approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories by ranking item text similarities according to their conceptual likeness. We tested …

Biomolecular Condensates In Immune Cell Fate, Yun Huang, Bruno Di Stefano

Faculty, Staff and Students Publications

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins. Findings have established a link between condensate formation and the gene regulatory networks that ensure the proper development of immune cells. Conversely, condensate dysregulation has been linked to impaired immune cell fates, including ageing and malignant transformation. This Review …

Cumulative Effect Of Targeted Interventions On Radiologist Recommendations For Additional Imaging, Jeffrey P Guenette, Sonali Desai, David Lucier, Sanjay Saini, Rachel Sisodia, Ali S Raja, David W Bates, Ramin Khorasani

Faculty, Staff and Students Publications

Background Ambiguous or unnecessary radiologist recommendations for additional imaging (RAIs) can lead to excessive imaging use and diagnostic errors. Purpose To determine the cumulative impacts of multifaceted technology-enabled interventions aimed at optimizing RAI on RAI rate, actionability, and resolution over an 8-year period. Materials and Methods In this retrospective cohort study, conducted from January 2015 to December 2022, radiology reports from two tertiary hospitals (study site and control site) were analyzed. A series of quality improvement interventions, including radiologist education, electronic communication tools for tracking RAIs, and performance reports, were implemented at the study site but not at the control …

Evolution Of The Family Medicine Clerkship: A Cera Secondary Analysis., Bryce A Ringwald, David Banas, Allison Macerollo, Ericka Bruce, Matthew Farrell

Medical Education Articles

BACKGROUND AND OBJECTIVES: The family medicine clerkship has been found to influence medical students' decision-making regarding specialty choice. Understanding how the family medicine clerkship has changed over the past decade may assist in recruitment efforts. Our study explored trends in family medicine clerkship design, length, and format and correlated these characteristics with high proportions of medical school graduates choosing family medicine.

METHODS: We performed a secondary analysis of the Council of Academic Family Medicine Educational Research Alliance annual family medicine clerkship director surveys from 2012 to 2023. We analyzed standard family medicine clerkship structure questions that were asked in each …

Rna Interference In Protozoan Parasites And Its Application, Lon-Fye Lye, Deborah E Dobson, Stephen M Beverley, Min-Che Tung

2020-Current year OA Pubs

RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression, via small RNA triggers derived from double-stranded RNA that can target specific genes; it is a natural process that plays a role in both the regulation of protein synthesis and in immunity. Discovery of RNAi by Fire and Mello in 1998 had a profound impact on unraveling novel aspects of eukaryotic biology. RNA interference (RNAi) has proven to be an immensely useful tool for studying gene function and validation of potential drug targets in almost all organisms. A great advance in …

Cysteine Depletion Triggers Adipose Tissue Thermogenesis And Weight Loss, Aileen H Lee, Irina Shchukina, Prabhakar Sairam Andhey, Maxim N Artyomov, Et Al.

2020-Current year OA Pubs

Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via …

International Multidisciplinary Consensus Recommendations On Clinical Application Of Three-Dimensional Visualization In Precision Surgery For Pediatric Liver Tumors, Mary T Austin, Chengli Liu, Hiroki Ishibashi, Karthik K Tappa, Huanmin Wang, Chuandong Sun, Yuntao Ma, Hongwei Xi, Jian Wang, Jianghua Zhan, Kyong Ihn, Mitsuo Shimada, Mingman Zhang, Mary E Brindle, Patrick B Thomas, Shigehisa Fumino, Tao Liu, Thom Lobe, Udo Rolle, Shan Wang, Xiaowen Zhai, Yoshinori Koga, Yoshiaki Kinoshita, Yuzuo Bai, Zhaozhu Li, Zhe Wen, Weikang Pan, Krysta M Sutyak, Pier C Giulianotti

Faculty, Staff and Student Publications

Background: Pediatric liver tumors are predominantly primary malignant tumors, and complete tumor resection with sufficient preservation of liver tissue is crucial for improving prognosis. However, due to the delicate anatomical structure of the pediatric liver and the relatively large size of the tumors, especially in difficult cases, the surgical challenges are substantial. While precision liver surgery are widely applied in clinical practice, pediatric cases require more customized approaches. The application of three-dimensional (3D) visualization technology is crucial for enhancing surgical accuracy, allowing for precise preoperative planning and intraoperative guidance.

Methods: This consensus was collaboratively developed by 36 experts from eight …

Nlrp3 Inflammasome Activation Expands The Immunosuppressive Myeloid Stroma And Antagonizes The Therapeutic Benefit Of Sting Activation In Glioblastoma, Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Inés Lopez Del Castillo

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects …

Glutamatergic Regulation Of Mirna-Containing Intraluminal Vesicle Trafficking And Extracellular Vesicle Secretion From Cortical Neurons, Rashed Alananzeh, Jiaqian Wu, Yongjie Yang

Faculty, Staff and Student Publications

Neuronal extracellular vesicles (microvesicles and exosomes) are emerging secreted vesicular signals that play important roles in the CNS. Currently, little is known about how glutamatergic signalling affects the subcellular localisation of exosome precursor intraluminal vesicles (ILVs), microRNA (miR) packaging into ILVs and in vivo spreading of neuronal EVs. By selectively labelling ILVs and exosomes (but not plasma membrane-derived MVs) with GFP-tagged human CD63 (hCD63-GFP) in cortical neurons, we found that glutamate stimulation significantly redistributes subcellular localisation of hCD63-GFP+ ILVs, especially decreasing its co-localisation with multi-vesicular body (MVB) marker Rab7 while substantially promoting EV secretion. Interestingly, glutamate stimulation only modestly alters …

Egfr Controls Transcriptional And Metabolic Rewiring In Krasg12d Colorectal Cancer, Dana Krauß, Veronica Moreno-Viedma, Emi Adachi-Fernandez, Cristiano De Sá Fernandes, Jakob-Wendelin Genger, Bernadette Blauensteiner, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia

Faculty, Staff and Student Publications

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size …

Bispecific Antibodies In Hematologic And Solid Tumors: Current Landscape And Therapeutic Advances, Lorenzo Guidi, Julian Etessami, Carmine Valenza, Augusto Valdivia, Funda Meric-Bernstam, Giuseppe Curigliano

Faculty, Staff and Student Publications

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. …

Association Of Sirt6 Expression With Risk Of Pneumonitis Induced By Radiotherapy In Cancer Patients, Fengyuan Yu, Zheng Gong, Yuan Li, Danial F Naseem, Chen Li, Bingying Zhao, Shanshan Zhang, Rukun Zang, Ailu Wu, Qingxin Han, Shuhui Wu, Hongwei Li, Yipeng Song

Faculty, Staff and Student Publications

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients …

A Gut-On-A-Chip Incorporating Human Faecal Samples And Peristalsis Predicts Responses To Immune Checkpoint Inhibitors For Melanoma, Mattia Ballerini, Serena Galiè, Punit Tyagi, Carlotta Catozzi, Hariam Raji, Angeli D G Macandog, Bianca Ionela Slivinschi, Karol K Kugiejko, Martina Freisa, Paola Occhetta, Jennifer A Wargo, Pier F Ferrucci, Emilia Cocorocchio, Nicola Segata, Andrea Vignati, Andrey Morgun, Michela Deleidi, Teresa Manzo, Marco Rasponi, Luigi Nezi

Faculty, Staff and Student Publications

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human …