Medical Specialties Commons^™

Somatic Mutational Landscape Of Hereditary Hematopoietic Malignancies Caused By Germline Variants In Runx1, Gata2, And Ddx41, Claire C Homan, Michael W Drazer, Kai Yu, David M Lawrence, Jinghua Feng, Luis Arriola-Martinez, Matthew J Pozsgai, Kelsey E Mcneely, Thuong Ha, Parvathy Venugopal, Peer Arts, Sarah L King-Smith, Jesse Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B Cantor, Mario Cazzola, Erin Degelman, Courtney D Dinardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Georges Natsoulis, Carolyn Owen, Keyur P Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Erika Kim, Raman Sood, Amy P Hsu, Steven M Holland, Kerry Phillips, Nicola K Poplawski, Milena Babic, Andrew H Wei, Cecily Forsyth, Helen Mar Fan, Ian D Lewis, Julian Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra Hiwase, Belinda Phipson, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul Liu, Lucy A Godley, Anna L Brown, Nisc Comparative Sequencing Program

Faculty, Staff and Student Publications

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high …

Targeted Therapy With Nanatinostat And Valganciclovir In Recurrent Ebv-Positive Lymphoid Malignancies: A Phase 1b/2 Study, Bradley Haverkos, Onder Alpdogan, Robert Baiocchi, Jonathan E. Brammer, Tatyana A. Feldman, Marcelo Capra, Elizabeth A. Brem, Santosh Nair, Phillip Scheinberg, Juliana Pereira, Leyla Shune, Erel Joffe, Patricia Young, Susan Spruill, Afton Katkov, Robert Mcrae, Ivor Royston, Douglas V. Faller, Lisa Rojkjaer, Pierluigi Porcu

Department of Medical Oncology Faculty Papers

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine …

White Matter Integrity Abnormalities In Healthy Overweight Individuals Revealed By Whole Brain Meta-Analysis Of Diffusion Tensor Imaging Studies, Xiaodong Cheng, Wenchang Wang, Chen Sun, Yana Sun, Cong Zhou

Faculty, Staff and Student Publications

OBJECTIVE: This study aimed to conduct a coordinate-based meta-analysis (CBMA) to investigate white matter (WM) abnormalities in healthy individuals with overweight or obesity.

METHODS: A systematic literature search using Web of Science and PubMed datasets was performed. Original investigations that used diffusion tensor imaging (DTI) to explore fractional anisotropy (FA) differences between healthy overweight/obese individuals and normal weight controls were collected. The meta-analysis was conducted using the seed-based

RESULTS: The analysis included five studies comprising 232 overweight/obese individuals and 219 healthy normal weight controls. The findings showed that overweight/obese individuals exhibited reduced fractional anisotropy (FA) in specific regions, namely, the …

Mutual-Information Based Optimal Experimental Design For Hyperpolarized [Formula: See Text]C-Pyruvate Mri, Prashant K Jha, Christopher Walker, Drew Mitchell, J Tinsley Oden, Dawid Schellingerhout, James A Bankson, David T Fuentes

Faculty, Staff and Student Publications

A key parameter of interest recovered from hyperpolarized (HP) MRI measurements is the apparent pyruvate-to-lactate exchange rate, [Formula: see text], for measuring tumor metabolism. This manuscript presents an information-theory-based optimal experimental design approach that minimizes the uncertainty in the rate parameter, [Formula: see text], recovered from HP-MRI measurements. Mutual information is employed to measure the information content of the HP measurements with respect to the first-order exchange kinetics of the pyruvate conversion to lactate. Flip angles of the pulse sequence acquisition are optimized with respect to the mutual information. A time-varying flip angle scheme leads to a higher parameter optimization …

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted …

Research Progress On The Regulation And Mechanism Of Borneol On The Blood-Brain Barrier In Pathological States: A Narrative Review Focused On Ischemic Stroke And Cerebral Glioma, Xinghua Tan, Ke Zhang, Wenyin Shi, Zhihu Tang

Department of Radiation Oncology Faculty Papers

Background and Objective: The blood-brain barrier (BBB) serves as a dynamic, selective shield, safeguarding the central nervous system (CNS) by separating the brain from circulating blood, preserving its microenvironment, and ensuring stability. However, in the presence of brain pathology, drug delivery across the BBB and blood-tumor barrier (BTB) becomes challenging, hindering effective treatments. Borneol exhibits promise in bidirectionally modulating the BBB under pathological conditions, suggesting at potential clinical applications for related diseases. Our primary goal in this review is to investigate borneol’s potential clinical utility in bidirectionally regulating the BBB under pathological conditions.

Methods: The PubMed database, CNKI (China National …

Identification Of Dual Strn-Ntrk2 Rearrangements In A High Grade Sarcoma, With Good Clinical Response To First-Line Larotrectinib Therapy, Ruihe Lin, Atrayee Basu Mallick, Zi-Xuan Wang, Phd, Scot Andrew Brown, Bo Lu, Md, Wei Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA.

CASE PRESENTATION: We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass …

Re-Stratification Of Patients With Copy-Number Low Endometrial Cancer By Clinicopathological Characteristics, Li Liwei, Li He, Dai Yibo, Zhao Luyang, Shen Zhihui, Kang Nan, Shen Danhua, Wang Junzhu, Wang Zhiqi, Wang Jianliu

Faculty, Staff and Student Publications

Objective: To stratify patients with copy-number low (CNL) endometrial cancer (EC) by clinicopathological characteristics.

Methods: EC patients who underwent surgery between June 2018 and June 2022 at Peking University People's Hospital were included and further classified according to TCGA molecular subtyping: POLE ultramutated, microsatellite instability high (MSI-H), CNL, and copy-number high (CNH). Clinicopathological characteristics and prognosis of CNL patients were retrospectively reviewed. The Cox proportional hazards regression model was applied to perform univariate and multivariate analysis, and independent risk factors were identified. Differentially expressed genes (DEGs) according to overall survival (OS) were screened based on the transcriptome of CNL cases …

Xaluritamig, A Steap1 × Cd3 Xmab 2+1 Immune Therapy For Metastatic Castration-Resistant Prostate Cancer: Results From Dose Exploration In A First-In-Human Study, William K. Kelly, Daniel C. Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J. Ward, Andrew J. Armstrong, David Pook, Miso Kim, Tanya B. Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G. Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M. Smith, Jamie N. Connarn, Hweixian L. Penny, Julia Stieglmaier, Leonard J. Appleman

Kimmel Cancer Center Faculty Papers

ABSTRACT : Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during …

Age-Associated Spinal Stenosis In The Turquoise Killifish, Su-Hyeon Cho, Seongsin Lee, Jae-Il Park, Yoon La Yang, Song-Rae Kim, Juhee Ahn, Hoibin Jeong, Hye-Yeon Jung, Nayoung Gwak, Kil-Nam Kim, Yumi Kim

Faculty, Staff and Student Publications

Aging triggers spinal degeneration, including common spinal stenosis, which causes back and leg pain in older individuals, significantly impacting their quality of life. Here, we explored aging traits in turquoise killifish spines, potentially offering a model for age-linked spinal stenosis in humans. Aged turquoise killifish exhibited body shape deformation and increased vertebral collapse, which was further accelerated by spawning. High-resolution CT scans revealed suppressed cortical bone thickness and hemal arch area in vertebrae due to spawning, and osteophyte formation was observed in both aged and breeding fish populations. Scale mineralization mirrored these changes, increasing with age but being suppressed by …

Actinide-Lanthanide Single Electron Metal-Metal Bond Formed In Mixed-Valence Di-Metallofullerenes, Yingjing Yan, Laura Abella, Rong Sun, Yu-Hui Fang, Yannick Roselló, Yi Shen, Meihe Jin, Antonio Rodríguez-Fortea, Coen De Graaf, Qingyu Meng, Yang-Rong Yao, Luis Echegoyen, Bing-Wu Wang, Song Gao, Josep M Poblet, Ning Chen

Faculty, Staff and Student Publications

Understanding metal-metal bonding involving f-block elements has been a challenging goal in chemistry. Here we report a series of mixed-valence di-metallofullerenes, ThDy@C2n (2n = 72, 76, 78, and 80) and ThY@C2n (2n = 72 and 78), which feature single electron actinide-lanthanide metal-metal bonds, characterized by structural, spectroscopic and computational methods. Crystallographic characterization unambiguously confirmed that Th and Y or Dy are encapsulated inside variably sized fullerene carbon cages. The ESR study of ThY@D3h(5)-C78 shows a doublet as expected for an unpaired electron interacting with Y, and a SQUID magnetometric study of ThDy@ …

Restructuring And Serving Web-Accessible Streamflow Data From The Noaa National Water Model Historic Simulations, J Michael Johnson, David L Blodgett, Keith C Clarke, Jon Pollak

Faculty, Staff and Student Publications

In 2016, the National Oceanic and Atmospheric Administration deployed the first iteration of an operational National Water Model (NWM) to forecast the water cycle in the continental United States. With many versions, an hourly, multi-decadal historic simulation is made available to the public. In all released to date, the files containing simulated streamflow contain a snapshot of model conditions across the entire domain for a single timestep which makes accessing time series a technical and resource-intensive challenge. In the most recent release, extracting a complete streamflow time series for a single location requires managing 367,920 files (~16.2 TB). In this …

Focalizing Regions Of Biomarker Relevance Facilitates Biomarker Prediction On Histopathological Images, Jiefeng Gan, Hanchen Wang, Hui Yu, Zitong He, Wenjuan Zhang, Ke Ma, Lianghui Zhu, Yutong Bai, Zongwei Zhou, Alan Yullie, Xiang Bai, Mingwei Wang, Dehua Yang, Yanyan Chen, Guoan Chen, Joan Lasenby, Chao Cheng, Jia Wu, Jianjun Zhang, Xinggang Wang, Yaobing Chen, Guoping Wang, Tian Xia

Faculty, Staff and Student Publications

Image-based AI has thrived as a potentially revolutionary tool for predicting molecular biomarker statuses, which aids in categorizing patients for appropriate medical treatments. However, many methods using hematoxylin and eosin-stained (H&E) whole-slide images (WSIs) have been found to be inefficient because of the presence of numerous uninformative or irrelevant image patches. In this study, we introduced the region of biomarker relevance (ROB) concept to identify the morphological areas most closely associated with biomarkers for accurate status prediction. We actualized this concept within a framework called saliency ROB search (SRS) to enable efficient and effective predictions. By evaluating various lung adenocarcinoma …

Liposome Synthesis And Evaluation In The Hek-293 Cell Line, Christine Skibinski

Harrisburg University Research Symposium: Highlighting Research, Innovation, & Creativity

Liposomes were synthesized using the thin film method. A lyophilized power of egg-derived phosphatidylcholine, stearylamine, and cholesterol were added to ethanol and dried under argon to form a lipid cake. The lipid cake was rehydrated with dPBS and sonicated at 60°C forming a heterogenous batch of liposomes. Our results revealed the average size of the liposomes, determined by Dynamic Light Scattering, was approximately 223.1nm, while demonstrating a weakly positive zeta-potential of 1.9± 8.07mv. Next, we tested the antitumor action of the liposomes in the HEK-293 cell line via an MTT assay. We observed that the liposomes were able to inhibit …

Tumor-Resident Lactobacillus Iners Confer Chemoradiation Resistance Through Lactate-Induced Metabolic Rewiring, Lauren E. Colbert, Molly B. El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J. Lynn, Timothy A. Harris, Jacob H. Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K. Bronk, Julie Sammouri, Ananta V. Yanamandra, Adilene V. Olvera, Lily G. Carlin, Travis Sims, Andrea Y. Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O. Abana, Hannah X. Li, Patricia J. Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M. Ramondetta, Andrew M. Futreal

School of Medicine Faculty Publications

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other …

Adaptive Design Of Mrna-Loaded Extracellular Vesicles For Targeted Immunotherapy Of Cancer, Shiyan Dong, Xuan Liu, Ye Bi, Yifan Wang, Abin Antony, Daeyong Lee, Kristin Huntoon, Seongdong Jeong, Yifan Ma, Xuefeng Li, Weiye Deng, Benjamin R Schrank, Adam J Grippin, Jonghoon Ha, Minjeong Kang, Mengyu Chang, Yarong Zhao, Rongze Sun, Xiangshi Sun, Jie Yang, Jiayi Chen, Sarah K Tang, L James Lee, Andrew S Lee, Lirong Teng, Shengnian Wang, Lesheng Teng, Betty Y S Kim, Zhaogang Yang, Wen Jiang

Faculty, Staff and Student Publications

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock …

Exploring Breast Cancer Systemic Drug Therapy Patterns In Real-World Data, Julia O'Rourke, Jeff Warnick, John Doole, Luc De Keyser, Zuzanna Drebert, Olivia Wan, Courtney N Thompson, Jack W. London, Karen Fairchild, Matvey B. Palchuk

Kimmel Cancer Center Faculty Papers

PURPOSE: To explore medications and their administration patterns in real-world patients with breast cancer.

METHODS: A retrospective study was performed using TriNetX, a federated network of deidentified, Health Insurance Portability and Accountability Act-compliant data from 21 health care organizations across North America. Patients diagnosed with breast cancer between January 1, 2013, and May 31, 2022, were included. We investigated a rule-based and unsupervised learning algorithm to extract medications and their administration patterns. To group similar administration patterns, we used three features in k-means clustering: total number of administrations, median number of days between administrations, and standard deviation of the days …

Braf D594a Mutation Defines A Unique Biological And Immuno-Modulatory Subgroup Associated With Functional Cd8+ T Cell Infiltration In Colorectal Cancer, Wenjing Li, Chenyi Zhao, Wenhui Li, Yang Gong, Kaili Ma, Yujie Lu, Xiaowei Liu, Lianjun Zhang, Feng Guo

Faculty, Staff and Student Publications

BACKGROUND: BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells.

METHODS: BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 …

Preoperative Hematocrit Levels And Postoperative Mortality In Patients Undergoing Craniotomy For Brain Tumors, Yangchun Xiao, Xin Cheng, Lu Jia, Yixin Tian, Jialing He, Miao He, Lvlin Chen, Pengfei Hao, Tiangui Li, Weelic Chong, Yang Hai, Chao You, Liyuan Peng, Fang Fang, Yu Zhang

Department of Medicine Faculty Papers

BACKGROUND: Abnormal hematocrit values, including anemia and polycythemia, are common in patients undergoing craniotomy, but the extent to which preoperative anemia or polycythemia independently increases the risk of mortality is unclear. This retrospective cohort study aimed to examine the association between preoperative anemia and polycythemia and postoperative mortality in patients who underwent craniotomy for brain tumor resection.

METHODS: We retrospectively analyzed data from 12,170 patients diagnosed with a brain tumor who underwent cranial surgery at West China Hospital between January 2011 and March 2021. The preoperative hematocrit value was defined as the last hematocrit value within 7 days before the …

Repurposing The Fda-Approved Anthelmintic Pyrvinium Pamoate For Pancreatic Cancer Treatment: Study Protocol For A Phase I Clinical Trial In Early-Stage Pancreatic Ductal Adenocarcinoma, Francesca M. Ponzini, Christopher W. Schultz, Benjamin E. Leiby, Shawnna Cannaday, T. Yeo, James Posey, Wilbur B. Bowne, Charles Yeo, Jonathan R. Brody, Harish Lavu, Avinoam Nevler

Department of Surgery Faculty Papers

BACKGROUND: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.

METHODS AND ANALYSIS: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will …

Clinical Characteristics, Racial Inequities, And Outcomes In Patients With Breast Cancer And Covid-19: A Covid-19 And Cancer Consortium (Ccc19) Cohort Study, Gayathri Nagaraj, Shaveta Vinayak, Ali Raza Khaki, Tianyi Sun, Nicole M. Kuderer, David M. Aboulafia, Jared D. Acoba, Joy Awosika, Ziad Bakouny, Nicole B. Balmaceda, Ting Bao, Babar Bashir, Stephanie Berg, Mehmet A. Bilen, Poorva Bindal, Sibel Blau, Brianne E. Bodin, Hala T. Borno, Cecilia Castellano, Horyun Choi, John Deeken, Aakash Desai, Natasha Edwin, Lawrence E. Feldman, Daniel B. Flora, Christopher R. Friese, Matthew D. Galsky, Cyndi J. Gonzalez, Petros Grivas, Shilpa Gupta, Marcy Haynam, Hannah Heilman, Dawn L. Hershman, Clara Hwang, Chinmay Jani, Sachin R. Jhawar, Monika Joshi, Virginia Kaklamani, Elizabeth J. Klein, Natalie Knox, Vadim S. Koshkin, Amit A. Kulkarni, Daniel H. Kwon, Chris Labaki, Philip E. Lammers, Kate I. Lathrop, Mark A. Lewis, Xuanyi Li, Gilbert De Lima Lopes, Gary H. Lyman, Della F. Makower, Abdul-Hai Mansoor, Merry-Jennifer Markham, Sandeep H. Mashru, Rana R. Mckay, Ian Messing, Vasil Mico, Rajani Nadkarni, Swathi Namburi, Ryan H. Nguyen, Taylor Kristian Nonato, Tracey Lynn O'Connor, Orestis A. Panagiotou, Kyu Park, Jaymin M. Patel, Kanishka Gopikabimal Patel, Jeffrey Peppercorn, Hyma Polimera, Matthew Puc, Yuan James Rao, Pedram Razavi, Sonya A. Reid, Jonathan W. Riess, Donna R. Rivera, Mark Robson, Suzanne J. Rose, Atlantis D. Russ, Lidia Schapira, Pankil K. Shah, M Kelly Shanahan, Lauren C. Shapiro, Melissa Smits, Daniel G. Stover, Mitrianna Streckfuss, Lisa Tachiki, Michael A. Thompson, Sara M. Tolaney, Lisa B. Weissmann, Grace Wilson, Michael T. Wotman, Elizabeth M. Wulff-Burchfield, Sanjay Mishra, Benjamin French, Jeremy L. Warner, Maryam B. Lustberg, Melissa K. Accordino, Dimpy P. Shah

Department of Medical Oncology Faculty Papers

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.

METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.

RESULTS: …

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Faculty, Staff and Student Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Oncolytic Virus M1 Functions As A Bifunctional Checkpoint Inhibitor To Enhance The Antitumor Activity Of Dc Vaccine, Jia Dan, Jing Cai, Yingqian Zhong, Chaoqun Wang, Shanyu Huang, Ying Zeng, Zhen Fan, Cuiying Xu, Linyi Hu, Jiayu Zhang, Jun Hu, Ying Liu, Xingwen Su, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Yuan Lin

Faculty, Staff and Student Publications

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can …

Emotional Barriers And Facilitators Of Deprescribing For Older Adults With Cancer And Polypharmacy: A Qualitative Study, Erika Ramsdale, Arul Malhotra, Holly M Holmes, Lisa Zubkoff, Jinjiao Wang, Supriya Mohile, Sally A Norton, Paul R Duberstein

Faculty, Staff and Student Publications

Purpose: To describe emotional barriers and facilitators to deprescribing (the planned reduction or discontinuation of medications) in older adults with cancer and polypharmacy.

Methods: Virtual focus groups were conducted over Zoom with 5 key informant groups: oncologists, oncology nurses, primary care physicians, pharmacists, and patients. All groups were video- and audio-recorded and transcribed verbatim. Focus group transcripts were analyzed using inductive content analysis, and open coding was performed by two coders. A codebook was generated based on the initial round of open coding and updated throughout the analytic process. Codes and themes were discussed for each transcript until consensus was …

Author Correction: Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

No abstract provided.

Dna2 Nuclease Inhibition Confers Synthetic Lethality In Cancers With Mutant P53 And Synergizes With Parp Inhibitors, Helena Folly-Kossi, Joshua D Graves, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

UNLABELLED: The tumor suppressor p53 promotes tumor-suppressive activities including cell-cycle inhibition, apoptosis, senescence, autophagy, and DNA repair. However, somatic mutations in the TP53 gene are one of the most common alterations in human cancers. We previously showed that mutant p53 (mutp53) can bind TopBP1, an ATR activator, to attenuate its ATR-activating function. A partially defective ATR function caused by mutp53 makes cancer cells more vulnerable to inhibitors of other TopBP1-independent ATR activators, such as DNA2. DNA2 plays a role in homologous recombination (HR) repair by resecting DNA ends in double-strand breaks and preparing them for invasion of homologous duplex. Here …

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

Faculty, Staff and Student Publications

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Sptan1/Numb Axis Senses Cell Density To Restrain Cell Growth And Oncogenesis Through Hippo Signaling, Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou

Faculty, Staff and Student Publications

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and …

Possible Delayed Foreign Body Reactions Against Titanium Clips And Coating Materials After Unruptured Cerebral Aneurysm Surgery, Ryota Tatezawa, Taku Sugiyama, Shuho Gotoh, Takafumi Shindo, Hiroshi Ikeda, Masaaki Hokari, Katsumi Takizawa, Naoki Nakayama, Miki Fujimura

Faculty, Staff and Student Publications

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid …

Associations Between Birth Defects And Childhood And Adolescent Germ Cell Tumors According To Sex, Histologic Subtype, And Site, Jeremy M Schraw, Pagna Sok, Tania A Desrosiers, Amanda E Janitz, Peter H Langlois, Mark A Canfield, A Lindsay Frazier, Sharon E Plon, Philip J Lupo, Jenny N Poynter

Faculty, Staff and Students Publications

BACKGROUND: Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.

METHODS: Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and …