Medical Specialties Commons^™

Enhancing Cyberattack Resiliency Through The Radiotherapy Backup And Recovery Dashboard Tool, Justin Pijanowski, Eric Nguyen, Yasin Abdulkadir, Justin Hink, Yevgeniy Vinogradskiy, James Lamb

Department of Radiation Oncology Faculty Papers

PURPOSE: Radiation Oncology departments impacted by recent cyberattacks were unable to access data backups or their Record and Verify (R&V) system and therefore faced challenges to resume patient treatments in a timely manner. We present a novel software tool that backs-up critical radiotherapy treatment information and displays essential information for on-treatment patients in an intuitive and accessible dashboard allowing clinics to continue radiotherapy treatments. The purpose of this report is to describe implementation details, challenges, and share open-source code to facilitate radiation oncology clinics' efforts to develop tools to improve cyberattack resiliency.

METHODS: The Radiotherapy Backup and Recovery Dashboard Tool …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

Review Of Diffusion Models And Its Applications In Biomedical Informatics, Jiawei Luo, Liren Yang, Yan Liu, Changbao Hu, Grant Wang, Yan Yang, Tie-Lin Yang, Xiaobo Zhou

Faculty, Staff and Student Publications

The diffusion model, a cutting-edge deep generative technique, is gaining traction in biomedical informatics, showcasing promising applications across various domains. This review presents an overview of the working principles, categories, and numerous applications of diffusion models in biomedical research. In medical imaging, these models, through frameworks like Denoising Diffusion Probabilistic Models (DDPMs) and Stochastic Differential Equations (SDE), offer advanced solutions for image generation, reconstruction, segmentation, and denoising. Notably, they’ve been employed in synthesizing 2D/3D medical images, MRI, and PET image reconstruction, and segmentation tasks such as labeled MRI generation. In the realm of structured Electronic Health Records (EHR) data, diffusion …

Sexually Dimorphic Sail Feathers In The Mandarin Duck As A Model For Lifelong Developmental Modulation, Pin-Chi Tang, Hsu-Chen Cheng, Gee-Way Lin, Yung-Chih Lai, Ya-Chen Liang, Ping Wu, Tzu-Chiao Lin, Chen Siang Ng, Isheng Jason Tsai, Ang Li, Wen Hsiung Li, Chih-Feng Chen, Cheng-Ming Chuong, Randall Widelitz

Faculty, Staff and Student Publications

Developmental processes extend beyond embryogenesis to support lifelong tissue adaptations. Avian feather follicles, with their resident stem cells and capacity for cyclic regeneration, provide a dynamic model for postnatal tissue remodeling. Here, we propose the Mandarin duck (Aix galericulata) as an ideal model to study lifelong developmental modulation, focusing on the sexually dimorphic "sail feather"-a secondary flight feather in males that undergoes seasonal transformation into a strikingly asymmetric, ornamented phenotype during the breeding season. We identified asymmetric morphogen expression in regenerating male sail feathers and used transcriptome and H3K27ac ChIP-seq to uncover male and female signaling pathways and regulatory elements. …

Insights, Opportunities, And Challenges Provided By Large Cell Atlases, Martin Hemberg, Federico Marini, Shila Ghazanfar, Ahmad Al Ajami, Najla Abassi, Benedict Anchang, Bérénice A Benayoun, Yue Cao, Ken Chen, Yesid Cuesta-Astroz, Zachary Debruine, Calliope A Dendrou, Iwijn De Vlaminck, Katharina Imkeller, Ilya Korsunsky, Alex R Lederer, Jessica Jingyi Li, Pieter Meysman, Clint L Miller, Kerry A Mullan, Uwe Ohler, Pratibha Panwar, Nikolaos Patikas, Jonas Schuck, Jacqueline H Y Siu, Timothy J Triche, Alex Tsankov, Sander W Van Der Laan, Masanao Yajima, Jean Yang, Fabio Zanini, Ivana Jelic

Faculty, Staff and Student Publications

The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.

Intracellular Lactate Dynamics In Drosophila Neurons, Matthew S Price, Elham Rastegari, Richa Gupta, Katie Vo, Travis I Moore, Kartik Venkatachalam

Faculty, Staff and Student Publications

Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigated the effects of nutrient deprivation on lactate dynamics in Drosophila neurons by leveraging the limiting effects of the unstirred layer, a diffusion barrier that forms around cells in culture. We found that neurons constitutively consume lactate when the availability of trehalose, a glucose disaccharide preferred by insects, is limited by the unstirred layer. Acute mechanical disruption of the unstirred layer reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates under unstirred layer …

Nucleotide Motif-Guided Selection Of Plasma Microrna Biomarkers In Trauma, Boyang Ren, Ruoxing Li, Chien-Yu Lin, Chanhee Park, Sheng Wang, Andrew O Suen, John Kessler, Shiming Yang, Rosemary Kozar, Lin Zou, Brittney Williams, Ziyi Li, Peter Hu, Wei Chao

Faculty, Staff and Student Publications

Trauma remains a leading cause of morbidity and mortality in part due to complex pathophysiological responses. Yet our abilities to predict these changes are limited. Plasma miRNAs have been proposed as DAMPs that drive immune response and organ injury. Here, we test a panel of plasma miRNAs-selected based on next-generation sequencing and nucleotide motifs identified via a machine-learning algorithm-for their abilities to predict subclinical pathophysiological injuries. We find marked and severity-dependent increases in the miRNA biomarkers following trauma, which are closely associated with various injury markers. AUROC indicates that these biomarkers possess strong diagnostic and predictive abilities in overall trauma …

Visualization Of Lysosomal Membrane Proteins By Cryo Electron Tomography, Bridget M Mcveigh, José J De Jesús-Pérez, Dirk H Siepe, Prerana Gogoi, Shrawan Kumar Mageswaran, Marian Kalocsay, Elaine M Mihelc, Vera Y Moiseenkova-Bell

Faculty, Staff and Student Publications

Lysosomes are essential organelles for cellular homeostasis and signaling, with dysfunction linked to neurological disorders, lysosomal storage diseases, and cancer. While proteomics has advanced our understanding of lysosomal composition, the structural characterization of lysosomal membrane proteins in their native environment remains a significant challenge. Here, we developed a cryo electron tomography workflow to visualize lysosomal membrane proteins within intact, native lysosomal membranes. We isolated endolysosomes by independently targeting two lysosomal membrane proteins, transient receptor potential mucolipin 1 and transmembrane protein 192, enriching organelles that exhibited the expected morphology and proteomic composition of the endolysosomal system. Sub-tomogram averaging enabled the structural …

Protocol For Isolating Patient-Derived Ascites Cells And Extracellular Vesicles From Gastric Cancer Peritoneal Metastases, Yibo Fan, Jody V Vykoukal, Shumei Song, Melissa Pool Pizzi, Gengyi Zou, Katsuhiro Yoshimura, Jiankang Jin, Hiroyuki Katayama, George A Calin, Rebecca E Waters, Qiong Gan, Linghua Wang, Samir Hanash, Shilpa S Dhar, Jaffer A Ajani

Faculty, Staff and Student Publications

Peritoneal carcinomatosis (PC) cells and extracellular vesicles (EVs) from gastric cancer ascites are valuable for studying tumor-stroma interactions. Here, we present a protocol for isolating PC cells and EVs from patient ascites. We describe steps for PC cell culture, iodixanol-based EV purification, electron microscopy, nanoparticle tracking analysis, flow cytometry, and proteomic profiling. This protocol also includes TD-139 loading into exosomes for functional assays to evaluate their role in modulating the tumor microenvironment. For complete details on the use and execution of this protocol, please refer to Fan et al.

Equal Survival For Black Americans With Multiple Myeloma When Appropriately Matched To White Americans, David E Mery, Guido Tricot, Samer Al Hadidi, Yihao Zhan, Cody Ashby, Clyde Bailey, Eric R Siegel, Daisy V Alapat, Hongwei Xu, Sandra Mattox, Caroline Schinke, Maurizio Zangari, Sharmilan Thanendrarajan, Qing Yi, Robert Z Orlowski, Frits Van Rhee, John D Shaughnessy, Fenghuang Zhan

Faculty, Staff and Student Publications

No abstract provided.

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

Molecular Determinants Of Neoadjuvant Chemotherapy Resistance In Breast Cancer: An Analysis Of Gene Expression And Tumor Microenvironment, Hedda Michelle Guevara-Nieto, Carlos A. Orozco-Castaño, Rafael Parra-Medina, Jenny Nathaly Poveda-Garavito, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba Lucia Combita

School of Graduate Studies Faculty Publications

Neoadjuvant chemotherapy (NAC) is a critical component of breast cancer treatment, but the molecular mechanisms underlying resistance remain poorly understood. This study aimed to identify transcriptomic changes associated with NAC resistance across four breast cancer subtypes: Luminal A, Luminal B/HER2-positive, Luminal B/HER2-negative, and Triple-Negative Breast Cancer (TNBC). RNA-seq analysis was performed on paired pre- and post-NAC breast cancer samples from 32 nonresponders. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were conducted. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Tumor microenvironment (TME) infiltration was estimated using deconvolution algorithms. The results revealed distinct gene expression profiles …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Landscape And Clinicopathologic Features Of Ras Pathway Mutations In Chronic Myelomonocytic Leukemia, Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney Dinardo, Tapan Kadia, Farhad Ravandi, Naval Daver, Nicholas Short, Naveen Pemmaraju, Ghayas Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos Bueso-Ramos, Ayalew Tefferi, Hagop Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik

Faculty, Staff and Student Publications

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Yx0798 Is A Highly Potent, Selective, And Orally Effective Cdk9 Inhibitor For Treating Aggressive Lymphoma, Vivian Jiang, Yu Xue, Hong Kim, Qingsong Cai, Tianci Zhang, Lei Nie, Joseph Mcintosh, Yang Liu, Haiying Chen, Jia Zhou, Michael Wang

Faculty, Staff and Student Publications

Nongenetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the heat shock protein 90 (HSP90)-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical Mantle Cell Lymphoma (MCL) models, supporting CDK9 as a valid therapeutic target for …

Characterization Of Suspicious Prostate Lesions At Multiparametric Mri With Dynamic 68 Ga-Gozetotide Pet/Ct, Daniel Parrott, Qing Yuan, Daniella Pinho, Yin Xi, Daniel N Costa, Alberto Diaz De Leon, Marianna Dakanali, Xiankai Sun, Orhan K Oz, Spencer Bowen, Neil M Rofsky, Dana Mathews, Ivan Pedrosa

Faculty, Staff and Student Publications

Background: Prostate cancer (PCa) will affect approximately 12% of US men in their lifetime and remains the 2nd most common cause of cancer-specific death. However, there is a broad spectrum of severity of PCa; some require aggressive treatment and others can "watch-and-wait". Distinction of clinically significant prostate cancer (csPCa) from indolent PCA with current imaging methods remains challenging.

Objective: This study aims to evaluate dynamic prostate specific membrane antigen (PSMA) positron emission tomography (PET/CT) in the characterization of suspicious prostate lesions identified on multiparametric MRI (mpMRI).

Methods: Prospective study of biopsy-naïve patients with at least one Prostate Imaging and Reporting …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Genetic Engineering Of Esophageal Organoids: Crispr-Based Knock-In For Cell Lineage Tracing, Kyung-Pil Ko, Jae-Il Park

Faculty, Staff and Student Publications

Esophageal organoids serve as powerful systems to study epithelial lineage hierarchies and cancer biology. Gene manipulation in these organoids has traditionally involved overexpression or knockout strategies. However, CRISPR-/Cas9-based knock-in (KI) approaches now enable precise cell lineage tracing and live imaging. Here, we describe protocols to generate fluorescent KI organoids from murine esophageal epithelium by tagging Krt13 (BFP) and Sox2 (mNeon). These dual-reporter organoids allow direct monitoring of growth dynamics and differentiation trajectories. We outline CRISPR/Cas9 design, donor construction using homology-independent approaches (CRISPaint), delivery into organoid cells, enrichment and single-clone isolation, and validation by fluorescence. For organoids, homology-directed repair (HDR) can …

Germline Determinants Of Toxicity And Efficacy In Patients With Large B-Cell Lymphoma Treated With Car T-Cell Therapy, Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.

Methods: Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was …

Comprehensive Analysis Of The Tumor Targeting Efficiency Of Functionalized Nanoparticles In An Immunocompetent Environment, Nolan Jackson, Nasry Bouzeineddine, Daniel Cecchi, Safara Holder, Katrina Gee, Wayne Beckham, Sameh Basta, Sunil Krishnan, Devika B Chithrani

Faculty, Staff and Student Publications

The success of nanoparticle-based cancer therapeutics relies on their efficient tumor uptake and retention. Given this, improving nanoparticle localization in tumors is paramount to maximize their therapeutic potential. A common approach to achieve this is to functionalize nanoparticles with active targeting moieties that bind to specific tumor-associated receptors. Among these, arginine-glycine-aspartic acid (RGD) peptides have shown a potential to promote tumor accumulation by targeting the ανβ3 integrin receptor, a receptor commonly overexpressed by tumors owing to its role in promoting angiogenesis, metastasis and proliferation. Yet, its efficacy is commonly assessed using immunocompromised mice models. While useful, these models do not …

A Plain Language Summary Publication Of Patients’ Survival With Endometrial Cancer Treated With Dostarlimab Plus Carboplatin-Paclitaxel, Matthew A. Powell, Line Bjørge, Lyndsay Willmott, Zoltán Novák, Destin Black, Lucy Gilbert, Sudarshan Sharma, Giorgio Valabrega, Lisa M. Landrum, Martina Gropp-Meier, Ashley Stuckey, Ingrid Boere, Michael A. Gold, Yakir Segev, Sarah E. Gill, Christine Gennigens, Alexandra Sebastianelli, Mark S. Shahin, Bhavana Pothuri, Bradley J. Monk, Joseph Buscema, Robert L. Coleman, Brian M. Slomovitz, Kari L. Ring, Thomas J. Herzog, Morad Marco Balas, Matthew Grimshaw, Shadi Stevens, Dominic W. Lai, Carolyn Mccourt, Mansoor Raza Mirza

Abington Jefferson Health Papers

What is the purpose of this PLS-P? The purpose of this plain language summary of publication is to help you understand recent findings from Part 1 of the RUBY study (full name ENGOT-EN6/GOG3031/RUBY trial). • Researchers sometimes study new combinations of already approved individual treatments to see if the combinations work well together and if they are safe to prescribe to patients. • In Part 1 of the RUBY study, the combination of dostarlimab with carboplatin-paclitaxel was investigated to see how well it worked for patients with primary advanced or recurrent endometrial cancer when compared with patients who were given …

Complications Of Ovarian Metastases From Well-Differentiated Small Bowel Neuroendocrine Neoplasms: A Focus On Bowel And Ureteral Obstruction, Sydney J. Wellens, Nicholas J. Skill, Kevin M. Sullivan, Mary A. Maluccio, Kristen E. Limbach

School of Medicine Faculty Publications

Ovarian metastasis from small bowel neuroendocrine neoplasms (SBNENs) was traditionally considered rare, but more recent series have suggested a higher prevalence. This case series seeks to examine the features and outcomes of patients with neuroendocrine ovarian metastases (NOM). Female patients with histologically confirmed well-differentiated SBNENs were identified using a prospectively maintained database (2014–2024). The electronic medical record was reviewed for details of diagnosis, histopathology, biomarkers, and outcomes among patients with and without NOM. 175 patients met inclusion criteria. 35 patients (20 %) had ovarian metastasis; for this group, 31.4 % had small bowel obstruction only, 5.7 % had ureteral obstruction …

Multimodal Reprogramming Of The Tumor Microenvironment By Mmr And Dual Checkpoint Blockade In Hepatocellular Carcinoma Models, Mulu Z. Tesfay, Aleksandra Cios, Khandoker Usran Ferdous, Randal S. Shelton, Bahaa Mustafa, Camila C. Simoes, Murat Gokden, Isabelle R. Miousse, Kimberly J. Krager, Marjan Boerma, Alicja Urbaniak, Anuradha Kunthur, Sri Obulareddy, Joshua M. Eichhorn, Steven R. Post, Jean Christopher Chamcheu, Omeed Moaven, Chiswili Y. Chabu, Dan G. Duda, Matteo Conti, Bruno Nardo, Rang Govindarajan, Martin E. Fernandez-Zapico, Lewis R. Roberts, Mitesh J. Borad, Martin J. Cannon, Alexei G. Basnakian, Bolni M. Nagalo

School of Graduate Studies Faculty Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, thus, there is an urgent need to develop more effective therapeutic options for this dismal condition. Tumor-infiltrating lymphocytes (TILs) are associated with improved response to immune checkpoint blockade in HCC, but their low abundance in most cases limits their therapeutic efficacy. Here, we demonstrate, in mice, that low-dose intratumoral immunovirotherapy with the trivalent measles, mumps, and rubella vaccine (MMR) induces superior tumor-growth delay and extended host survival compared to individually administered vaccines for measles, mumps, or rubella viruses. Further, our results show that MMR therapy synergizes with PD-1 and …

A Neuroimmune Cerebral Assembloid Model To Study The Pathophysiology Of Familial Alzheimer's Disease, Andrea Becerra-Calixto, Anik Banerjee, Huihui Fan, Chunfeng Tan, Eunyoung Lee, Louise D Mccullough, Juneyoung Lee

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the leading cause of dementia globally. The accumulation of amyloid and tau proteins, neuronal cell death and neuroinflammation are seen with AD progression, resulting in memory and cognitive impairment. Microglia are crucial for AD progression as they engage with neural cells and protein aggregates to regulate amyloid pathology and neuroinflammation. Recent studies indicate that microglia contribute to the propagation of amyloid beta (Aβ) via their immunomodulatory functions including Aβ phagocytosis and inflammatory cytokine production. Three-dimensional cell culture techniques provide the opportunity to study pathophysiological changes in AD in human-derived samples that are difficult to recapitulate in …

Synaptic Transmission Promotes Brain Metastatic Outgrowth In Breast Cancer, Jayanta Mondal, Patrick Nylund, Prit Benny Malgulwar, William E Johnson, Jason T Huse

Faculty, Staff and Student Publications

This work demonstrates that normal neuron-to-neuron signaling machinery is hijacked by metastasizing cancer cells during their outgrowth in the central nervous system.

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Enhanced Piezo1 Function Contributes To The Pathogenesis Of Sickle Cell Disease, Luis O Romero, Manisha Bade, Laila Elsherif, Jada D Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I Ataga, Shang Ma, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte …

A Soft-Stiff Patterned Bioengineering Model Reveals Kinase Pathways Driving Directional Cell Migration In Pulmonary Arterial Hypertension, Tamanna Islam, Jacob Hooper, Xiaojun Zhang, Clarissa Garcia, Md Mahedi Hasan, David H Drewry, Mohammad Anwar Hossain, Taslim A Al-Hilal

Faculty, Staff and Student Publications

Directional cell migration by pulmonary arterial cells (PACs) is one of the important features of diseases involving arterial remodeling, such as pulmonary arterial hypertension (PAH), a disease that is often characterized by reduced arterial compliance and increased extracellular matrix (ECM) stiffening. However, there are no therapeutics that can halt the directional cell migration of PACs in PAH. The inability to identify drug targets or drugs against the directional cell migration during PAH pathogenesis stems from an incomplete understanding of the process and a lack of effective translational models for screening of candidate small molecules. Here, for the first time, we …