Medical Specialties Commons^™

An Epithelial-Immune Circuit Amplifies Inflammasome And Il-6 Responses To Sars-Cov-2, Katherine C Barnett, Yuying Xie, Takanori Asakura, Dingka Song, Kaixin Liang, Sharon A Taft-Benz, Haitao Guo, Shuangshuang Yang, Kenichi Okuda, Rodney C Gilmore, Jennifer F Loome, Thomas H Oguin Iii, Gregory D Sempowski, Scott H Randell, Mark T Heise, Yu Leo Lei, Richard C Boucher, Jenny P-Y Ting

Faculty, Staff and Student Publications

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, …

Incidence And Clearance Of Anal Human Papillomavirus Infection In 16 164 Individuals, According To Human Immunodeficiency Virus Status, Sex, And Male Sexuality: An International Pooled Analysis Of 34 Longitudinal Studies, Feixue Wei, Marc T Goodman, Ningshao Xia, Jun Zhang, Anna R Giuliano, Gypsyamber D'Souza, Nancy A Hessol, Maarten F Schim Van Der Loeff, Jianghong Dai, Karin Neukam, Alexandra De Pokomandy, I Mary Poynten, Ronald B Geskus, Joaquin Burgos, Isabelle Etienney, Anna-Barbara Moscicki, Maria Gabriella Donà, Maura L Gillison, Alan G Nyitray, Rebecca G Nowak, Evy Yunihastuti, Huachun Zou, Carmen Hidalgo-Tenorio, Nittaya Phanuphak, Jean-Michel Molina, Alice M Schofield, Stephen Kerr, Song Fan, Yong Lu, Jason J Ong, Admire T Chikandiwa, Sirinya Teeraananchai, Nicola Squillace, Dorothy J Wiley, Joel M Palefsky, Damien Georges, Catharina J Alberts, Gary M Clifford

Faculty, Staff and Student Publications

Background: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized.

Methods: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their …

Life-Threatening Complications Of Influenza Vs Coronavirus Disease 2019 (Covid-19) In Us Children, Natasha B Halasa, Andrew J Spieker, Cameron C Young, Samantha M Olson, Margaret M Newhams, Justin Z Amarin, Kristin L Moffitt, Mari M Nakamura, Emily R Levy, Vijaya L Soma, Rana Talj, Scott L Weiss, Julie C Fitzgerald, Elizabeth H Mack, Aline B Maddux, Jennifer E Schuster, Bria M Coates, Mark W Hall, Stephanie P Schwartz, Adam J Schwarz, Michele Kong, Philip C Spinella, Laura L Loftis, Gwenn E Mclaughlin, Charlotte V Hobbs, Courtney M Rowan, Melania M Bembea, Ryan A Nofziger, Christopher J Babbitt, Cindy Bowens, Heidi R Flori, Shira J Gertz, Matt S Zinter, John S Giuliano, Janet R Hume, Natalie Z Cvijanovich, Aalok R Singh, Hillary A Crandall, Neal J Thomas, Melissa L Cullimore, Manish M Patel, Adrienne G Randolph, Pediatric Intensive Care Influenza, Overcoming Covid-19 Investigators

Faculty, Staff and Student Publications

Background: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.

Methods: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.

Results: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 …

Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting Pd-L1 And Tgf-Β, In Patients With Pretreated Colorectal Cancer: Results From A Phase I Trial, Alexander Spira, Michael S Wertheim, Edward J Kim, Benjamin Tan, Heinz-Josef Lenz, Petros Nikolinakos, Patricia L Rich, Genevieve Jehl, Andreas Machl, Rena Ito, James L Gulley, Scott Kopetz

Faculty, Staff and Student Publications

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor β (TGF-β) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received …

Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Testing And Detection During Peripartum Hospitalizations Among A Multicenter Cohort Of Pregnant Persons: March 2020-February 2021, Miranda J Delahoy, Flor Munoz, De-Kun Li, Carmen Sofia Arriola, Nanette Lee Bond, Michael Daugherty, Jeannette Ferber, Nickolas Ferguson, Louise Hadden, Jillian T Henderson, Stephanie A Irving, Mary Juergens, Venkatesh Kancharla, Mara Greenberg, Roxana Odouli, Gabriella Newes-Adeyi, Erin G Nicholson, Lawrence Reichle, Momodou Sanyang, Margaret Snead, Fatimah S Dawood, Allison L Naleway

Faculty, Staff and Students Publications

BACKGROUND: Identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections during peripartum hospitalizations is important to guide care, implement prevention measures, and understand infection burden.

METHODS: This cross-sectional analysis used electronic health record data from hospitalizations during which pregnancies ended (peripartum hospitalizations) among a cohort of pregnant persons at 3 US integrated healthcare networks (sites 1-3). Maternal demographic, medical encounter, SARS-CoV-2 testing, and pregnancy and neonatal outcome information was extracted for persons with estimated delivery and pregnancy end dates during March 2020-February 2021 and ≥1 antenatal care record. Site-stratified multivariable logistic regression was used to identify factors associated with testing …

Acute High-Fat Diet Impairs Macrophage-Supported Intestinal Damage Resolution, Andrea A Hill, Myunghoo Kim, Daniel F Zegarra-Ruiz, Lin-Chun Chang, Kendra Norwood, Adrien Assié, Wan-Jung H Wu, Michael C Renfroe, Hyo Wong Song, Angela M Major, Buck S Samuel, Joseph M Hyser, Randy S Longman, Gretchen E Diehl

Faculty, Staff and Students Publications

Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure …

Production Of A Monoclonal Antibody For The Detection Of Forchlorfenuron: Application In An Indirect Enzyme-Linked Immunosorbent Assay And Immunochromatographic Strip, Xingmei Lei, A M Abd El-Aty, Lingyuan Xu, Jing Zhao, Jia Li, Song Gao, Yun Zhao, Yongxin She, Fen Jin, Jing Wang, Lufei Zheng, Maojun Jin, Bruce D Hammock

Faculty, Staff and Student Publications

In this study, a monoclonal antibody (mAb) specific to forchlorfenuron (CPPU) with high sensitivity and specificity was produced and designated (9G9). To detect CPPU in cucumber samples, an indirect enzyme-linked immunosorbent assay (ic-ELISA) and a colloidal gold nanobead immunochromatographic test strip (CGN-ICTS) were established using 9G9. The half-maximal inhibitory concentration (IC50) and the LOD for the developed ic-ELISA were determined to be 0.19 ng/mL and 0.04 ng/mL in the sample dilution buffer, respectively. The results indicate that the sensitivity of the antibodies prepared in this study (9G9 mAb) was higher than those reported in the previous literature. On the other …

Modeling And Analysis Of The Intrinsic Cardiac Nervous System In Closed-Loop Cardiovascular Control, Michelle M. Gee, Abraham M. Lenhoff, James S. Schwaber, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating nerve activity between the brainstem and the heart. The computational model by Park et al. (2020) is the most recent iteration in our exploration of the system. However, the contributions of”the little brain of the heart”, the intrinsic cardiac nervous system (ICN), to local control of the heart and to the integration of sensory information is unknown and has been overlooked in previous models. We have incorporated a high-fidelity representation of the ICN into a model of the baroreceptor reflex based on anatomical, …

Evaluation Of Apparent Diffusion Coefficient Repeatability And Reproducibility For Preclinical Mris Using Standardized Procedures And A Diffusion-Weighted Imaging Phantom, Dariya Malyarenko, Ghoncheh Amouzandeh, Stephen Pickup, Rong Zhou, Henry Charles Manning, Seth T Gammon, Kooresh I Shoghi, James D Quirk, Renuka Sriram, Peder Larson, Michael T Lewis, Robia G Pautler, Paul E Kinahan, Mark Muzi, Thomas L Chenevert

Faculty, Staff and Students Publications

Relevant to co-clinical trials, the goal of this work was to assess repeatability, reproducibility, and bias of the apparent diffusion coefficient (ADC) for preclinical MRIs using standardized procedures for comparison to performance of clinical MRIs. A temperature-controlled phantom provided an absolute reference standard to measure spatial uniformity of these performance metrics. Seven institutions participated in the study, wherein diffusion-weighted imaging (DWI) data were acquired over multiple days on 10 preclinical scanners, from 3 vendors, at 6 field strengths. Centralized versus site-based analysis was compared to illustrate incremental variance due to processing workflow. At magnet isocenter, short-term (intra-exam) and long-term (multiday) …

Targeted Protein Degradation Via Lysosomes, Rishi R Paudel, Dong Lu, Sandipan Roy Chowdhury, Erika Y Monroy, Jin Wang

Faculty, Staff and Students Publications

In the scope of targeted protein degradation (TPD), proteolysis-targeting chimeras (PROTACs), leveraging the ubiquitin-proteasome system, have been extensively studied. However, they are limited to the degradation of soluble and membrane proteins, excluding the aggregated and extracellular proteins and dysfunctional organelles. As an alternative protein degradation pathway, lysosomes serve as a feasible tool for accessing these untouched proteins and/or organelles by proteosomes. Here, we focus on reviewing the emerging lysosome-mediated TPD, such as AUTAC, ATTEC, AUTOTAC, LYTAC, and MoDE-A. Intracellular targets, such as soluble and aggregated proteins and organelles, can be degraded via the autophagy-lysosome pathway. Extracellular targets, such as membrane …

Post-Transcriptional Regulation In Cranial Neural Crest Cells Expands Developmental Potential, Rachel A Keuls, Young Sun Oh, Ivanshi Patel, Ronald J Parchem

Faculty, Staff and Students Publications

Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm, yet give rise to both ectodermal derivatives of the peripheral nervous system and ectomesenchymal bone and cartilage. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility. We profile the spatiotemporal emergence of premigratory neural crest and find evidence of lineage bias toward either a neuronal or ectomesenchymal fate, with each expressing distinct factors from earlier stages …

Assessment Of Response To Neoadjuvant Systemic Treatment In Triple-Negative Breast Cancer Using Functional Tumor Volumes From Longitudinal Dynamic Contrast-Enhanced Mri, Bikash Panthi, Beatriz E Adrada, Rosalind P Candelaria, Mary S Guirguis, Clinton Yam, Medine Boge, Huiqin Chen, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Deanna L Lane, Huong C Le-Petross, Jessica W T Leung, Jennifer K Litton, Rania M Mohamed, Benjamin C Musall, Sanaz Pashapoor, Miral M Patel, Frances Perez, Jong Bum Son, Alastair Thompson, Vicente Valero, Peng Wei, Jason White, Zhan Xu, Lawrence Pinsky, Debu Tripathy, Wei Yang, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Early assessment of neoadjuvant systemic therapy (NAST) response for triple-negative breast cancer (TNBC) is critical for patient care in order to avoid the unnecessary toxicity of an ineffective treatment. We assessed functional tumor volumes (FTVs) from dynamic contrast-enhanced (DCE) MRI after 2 cycles (C2) and 4 cycles (C4) of NAST as predictors of response in TNBC. A group of 100 patients with stage I-III TNBC who underwent DCE MRI at baseline, C2, and C4 were included in this study. Tumors were segmented on DCE images of 1 min and 2.5 min post-injection. FTVs were measured using the optimized percentage enhancement …

Dynamic Cone-Beam Ct Reconstruction Using Spatial And Temporal Implicit Neural Representation Learning (Stinr), You Zhang, Hua-Chieh Shao, Tinsu Pan, Tielige Mengke

Faculty, Staff and Student Publications

Objective. Dynamic cone-beam CT (CBCT) imaging is highly desired in image-guided radiation therapy to provide volumetric images with high spatial and temporal resolutions to enable applications including tumor motion tracking/prediction and intra-delivery dose calculation/accumulation. However, dynamic CBCT reconstruction is a substantially challenging spatiotemporal inverse problem, due to the extremely limited projection sample available for each CBCT reconstruction (one projection for one CBCT volume).

Approach. We developed a simultaneous spatial and temporal implicit neural representation (STINR) method for dynamic CBCT reconstruction. STINR mapped the unknown image and the evolution of its motion into spatial and temporal multi-layer perceptrons (MLPs), and …

Patient-Reported Symptoms At Discharge And Risk Of Complications After Gynecologic Surgery, Xin Shelley Wang, Pedro T Ramirez, Qiuling Shi, Mona Kamal, Araceli Garcia-Gonzalez, Maria D Iniesta, Charles S Cleeland, Larissa A Meyer

Faculty, Staff and Student Publications

Objective: Current gaps in knowledge limit clinicians from fully implementing patient-reported outcomes in routine post-operative care.

Methods: This prospective study assessed symptoms via the gynecologic module of the MD Anderson Symptom Inventory (MDASI-PeriOp-GYN) in patients who underwent open laparotomy.

Results: At discharge, patient-reported moderate to severe (≥4 on a 0-10 scale) abdominal bloating or abdominal cramping, combined with length of stay of ≥4 days, were found to be associated with a higher risk of 30-day post-operative grade II-IV complications by the Clavien-Dindo system (all p values < 0.01). Also, length of stay of ≥4 days and moderate to severe urinary urgency at discharge were found to be associated with the need for re-admission (all p values < 0.01).

Conclusion: This study defined the clinically meaningful symptoms that related to the risk of …

Short-Term Pi3k Inhibition Prevents Breast Cancer In Preclinical Models, Amy T Ku, Adelaide I J Young, Ahmed Atef Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C Williams, Bryant Lee Mccue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li

Faculty, Staff and Students Publications

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a …

Bone Metastasis Initiation Is Coupled With Bone Remodeling Through Osteogenic Differentiation Of Ng2+ Cells, Weijie Zhang, Zhan Xu, Xiaoxin Hao, Tiancheng He, Jiasong Li, Yichao Shen, Kai Liu, Yang Gao, Jun Liu, David G Edwards, Aaron M Muscarella, Ling Wu, Liqun Yu, Longyong Xu, Xi Chen, Yi-Hsuan Wu, Igor L Bado, Yunfeng Ding, Sergio Aguirre, Hai Wang, Zbigniew Gugala, Robert L Satcher, Stephen T C Wong, Xiang H-F Zhang

Faculty, Staff and Students Publications

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when …

Loci On Chromosome 12q132 Encompassing Erbb3, Pa2g4 And Rab5b Are Associated With Polycystic Ovary Syndrome, R Alan Harris, Kellie J Archer, Mark O Goodarzi, Timothy P York, Jeffrey Rogers, Andrea Dunaif, Jan M Mcallister, Jerome F Strauss

Faculty, Staff and Students Publications

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. We report significant association of androgen production with 15 single nucleotide variants (SNVs) identified by exome sequencing of theca cells from women with PCOS and normal ovulatory women. Ten SNVs are located within a 150 kbp region on 12q13.2 which encompasses loci identified in PCOS genome-wide association studies (GWAS) and contains PCOS candidate genes ERBB3 and RAB5B. The region also contains PA2G4 which encodes a transcriptional corepressor of androgen receptor and androgen receptor-regulated genes. PA2G4 has not previously been recognized as related to PCOS in published …

Long And Short Duration Exposures To The Selective Serotonin Reuptake Inhibitors (Ssris) Fluoxetine, Paroxetine And Sertraline At Environmentally Relevant Concentrations Lead To Adverse Effects On Zebrafish Behaviour And Reproduction, Ananda Baskaran Venkatachalam, Bailey Levesque, John C Achenbach, Jane J Pappas, Lee D Ellis

Faculty, Staff and Student Publications

Selective serotonin reuptake inhibitors (SSRIs) are currently the most prescribed class of psychotropic medications. Their increased global manufacture and use have become growing concerns for aquatic toxicologists and environmental biologists, who assess both the direct and indirect effects of substances on the environment and on human health. In order to assess the potential impact of environmentally relevant levels of SSRIs on fish development, behaviour and reproduction, we exposed juvenile and adult zebrafish to a select group of SSRIs using two separate exposure paradigms. In the first paradigm, juvenile zebrafish were exposed to Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft) or a …

3,3'-Diindolylmethane Augments 5-Fluorouracil-Inducedgrowth Suppression In Gastric Cancer Cells Through Suppression Of The Akt/Gsk-3Β And Wnt/Beta-Catenin, Cong Shan Li, Thi Van Nguyen, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Soo Mi Kim

Faculty, Staff and Student Publications

Gastric cancer (GC) is one of the most lethal cancers in South Korea, and it is a cancer of concern worldwide. 5-fluorouracil (5-Fu) is commonly used as the first-line therapy for advanced GC; however, its side effects often limit the dosage range and impair patients' quality of life. Due to the limitations of current chemotherapy, new anticancer therapies are urgently needed. 3,3'-diindolylmethane (DIM) has been reported to have the ability to protect against various types of cancer. Our study aimed to elucidate the anticancer effect of DIM in GC when treated with the chemotherapeutic agent 5-Fu. In our results, combined …

Factors For Poor Oral Health In Long-Term Childhood Cancer Survivors, Tushar Patni, Chun-Teh Lee, Yimei Li, Sue Kaste, Liang Zhu, Ryan Sun, Melissa M Hudson, Kirsten K Ness, Ana Neumann, Leslie L Robison

Faculty, Staff and Student Publications

Background: Survivors of childhood cancer are at risk for therapy-related dental diseases. The purpose of the study was to investigate the associations between clinical, socioeconomic, and demographic factors and oral diseases in the St. Jude Lifetime Cohort (SJLIFE) participants.

Methods: We performed a retrospective medical chart review and evaluated longitudinal self-reported dental outcomes in 4856 childhood cancer survivors and 591 community controls participating in the St. Jude Lifetime Cohort (SJLIFE) study. Univariate and multivariable logistic regression models were used to assess the impact of socioeconomic factors, treatment exposures and patient demographics on dental outcomes.

Results: Cancer survivors were more likely …

Hmgb1/Gpc3 Dual Targeting Vaccine Induces Dendritic Cells-Mediated Cd8+T Cell Immune Response And Elicits Potential Therapeutic Effect In Hepatocellular Carcinoma, Xiaoqing Shi, Jiage Ding, Yanyan Zheng, Jiawei Wang, Navid Sobhani, Praveen Neeli, Gang Wang, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) is a fatal malignant tumor, but effective clinical interventions are limited. PLGA/PEI-mediated DNA vaccine encoding the dual targets of high-mobility group box 1 (HMGB1) or GPC3 was developed for HCC treatment. Compared with PLGA/PEI-GPC3 immunization, PLGA/PEI-HMGB1/GPC3 co-immunization significantly inhibited the subcutaneous tumor growth, while increasing the infiltration of CD8

Long-Lasting Chews Elicit Positive Emotional States In Dogs During Short Periods Of Social Isolation, Hannah E Flint, Megan Atkinson, James Lush, Alysia B G Hunt, Tammie King

Faculty, Staff and Students Publications

Dogs may experience negative emotional states when isolated from human caregivers and conspecifics. This study aimed to evaluate how dogs interact with different enrichments during a short period of social isolation, as a first step towards identifying methods for improving their emotional wellbeing. Using a cross-over design, dogs (n = 20) at the Waltham Petcare Science Institute were exposed to four different food-based enrichments while left alone in a familiar room for 20 min: long-lasting chew (Chew), kibble in a treat-dispensing toy (Toy), and kibble dispensed through a smart treat-dispensing device with (Device + Voice) and without (Device) a …

Response To: What Is Missing From The 2022 Practice Recommendation Updates From The World Consensus Conference On Bia-Alcl?, Fabio Santanelli Di Pompeo, Mark W Clemens, Michael Atlan, Giovanni Botti, Peter G Cordeiro, Daphne De Jong, Arianna Di Napoli, Dennis Hammond, Cara L Haymaker, Steven M Horwitz, Kelly Hunt, Peter Lennox, Patrick Mallucci, Roberto N Miranda, Alexandre M Munhoz, Demosthenes Panagiotakos, Eric C Swanson, Suzanne D Turner, Guido Firmani, Michail Sorotos

Faculty, Staff and Student Publications

No abstract provided.

Spatial Regulation Of The Glycocalyx Component Podocalyxin Is A Switch For Prometastatic Function, Alvaro Román-Fernández, Mohammed A Mansour, Fernanda G Kugeratski, Jayanthi Anand, Emma Sandilands, Laura Galbraith, Kai Rakovic, Eva C Freckmann, Erin M Cumming, Ji Park, Konstantina Nikolatou, Sergio Lilla, Robin Shaw, David Strachan, Susan Mason, Rachana Patel, Lynn Mcgarry, Archana Katoch, Kirsteen J Campbell, Colin Nixon, Crispin J Miller, Hing Y Leung, John Le Quesne, James C Norman, Sara Zanivan, Karen Blyth, David M Bryant

Faculty, Staff and Student Publications

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within …

Spatially Resolved Single-Cell Assessment Of Pancreatic Cancer Expression Subtypes Reveals Co-Expressor Phenotypes And Extensive Intratumoral Heterogeneity, Hannah L Williams, Andressa Dias Costa, Jinming Zhang, Srivatsan Raghavan, Peter S Winter, Kevin S Kapner, Scott P Ginebaugh, Sara A Väyrynen, Juha P Väyrynen, Chen Yuan, Andrew W Navia, Junning Wang, Annan Yang, Timothy L Bosse, Radha L Kalekar, Kristen E Lowder, Mai Chan Lau, Dalia Elganainy, Vicente Morales-Oyarvide, Douglas A Rubinson, Harshabad Singh, Kimberly Perez, James M Cleary, Thomas E Clancy, Jiping Wang, Joseph D Mancias, Lauren K Brais, Emma R Hill, Margaret M Kozak, David C Linehan, Richard F Dunne, Daniel T Chang, Albert C Koong, Aram F Hezel, William C Hahn, Alex K Shalek, Andrew J Aguirre, Jonathan A Nowak, Brian M Wolpin

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed …

Immunogenetic Determinants Of Susceptibility To Head And Neck Cancer In The Million Veteran Program Cohort, Yanhong Liu, Jennifer R Kramer, Vlad C Sandulache, Robert Yu, Guojun Li, Liang Chen, Zenab I Yusuf, Yunling Shi, Saiju Pyarajan, Spyros Tsavachidis, Li Jiao, Michelle L Mierzwa, Elizabeth Chiao, Yvonne M Mowery, Andrew Shuman, Sanjay Shete, Andrew G Sikora, Donna L White

Faculty, Staff and Student Publications

Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and …

Tumor-Associated Nonmyelinating Schwann Cell-Expressed Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Chengcao Sun, Youqiong Ye, Zhi Tan, Yuan Liu, Yajuan Li, Wei Hu, Ke Liang, Sergey D Egranov, Lisa Angela Huang, Zhao Zhang, Yaohua Zhang, Jun Yao, Tina K Nguyen, Zilong Zhao, Andrew Wu, Jeffrey R Marks, Abigail S Caudle, Aysegul A Sahin, Jianjun Gao, Seth T Gammon, David Piwnica-Worms, Jian Hu, Paul J Chiao, Dihua Yu, Mien-Chie Hung, Michael A Curran, George A Calin, Haoqiang Ying, Leng Han, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (

Lef1 Drives A Central Memory Program And Supports Antitumor Activity Of Natural Killer T Cells, Ho Ngai, Gabriel A Barragan, Gengwen Tian, Julien C Balzeau, Chunchao Zhang, Amy N Courtney, Linjie Guo, Xin Xu, Michael S Wood, Janice M Drabek, Thorsten Demberg, Caroline M Sands, Cynthia N Chauvin-Fleurence, Erica J Di Pierro, Jeffrey M Rosen, Leonid S Metelitsa

Faculty, Staff and Students Publications

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L- cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression …

Association Between P2y12 Inhibitor Reloading And In-Hospital Outcomes For Patients With Non-St-Segment Elevation Acute Coronary Syndrome Already On Chronic P2y12 Receptor Inhibitors Therapy In China: Findings From The Ccc-Acs (Improving Care For Cardiovascular Disease In China-Acute Coronary Syndrome) Project, Yintang Wang, Yu Geng, Ou Zhang, Qin Xu, Yajun Xue, Boda Zhou, Ping Zhang

Faculty, Staff and Student Publications

BACKGROUND: The association between P2Y12 receptor inhibitors reloading and in-hospital outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients who were on chronic P2Y12 receptor inhibitors therapy remained underdetermined.

METHODS: The Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS project) is a national registry active from November 2014 to December 2019. 4790 NSTEACS patients on chronic P2Y12 receptor inhibitors therapy were included. Cox proportional hazard models, Kaplan-Meier curves, and subgroup analyses were conducted.

RESULTS: The NSTEACS patients who received reloading of P2Y12 receptor inhibitors were younger and had fewer comorbid conditions. The reloading group had a lower risk …

Effective Treatment Of Low-Risk Acute Gvhd With Itacitinib Monotherapy, Aaron Etra, Alexandra Capellini, Amin Alousi, Monzr M Al Malki, Hannah Choe, Zachariah Defilipp, William J Hogan, Carrie L Kitko, Francis Ayuk, Janna Baez, Isha Gandhi, Stelios Kasikis, Sigrun Gleich, Elizabeth Hexner, Matthias Hoepting, Urvi Kapoor, Steven Kowalyk, Deukwoo Kwon, Amelia Langston, Marco Mielcarek, George Morales, Umut Özbek, Muna Qayed, Ran Reshef, Wolf Rösler, Nikolaos Spyrou, Rachel Young, Yi-Bin Chen, James L M Ferrara, John E Levine

Faculty, Staff and Student Publications

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those …