Medical Specialties Commons^™

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …

A Pilot Study Of The Cd38 Antagonist Daratumumab In Patients With Metastatic Renal Cell Carcinoma Or Muscle-Invasive Bladder Cancer, Matthew T Campbell, Amishi Y Shah, Pavlos Msaouel, Nizar M Tannir, Arlene O Siefker-Radtke, Ashish M Kamat, Neema Navai, Colin P N Dinney, Priya Rao, Charles C Guo, Rahul A Sheth, Aradhana M Venkatesan, Rebecca S Tidwell, Shalini S Yadav, Aidi Gu, Hong Chen, Marc Macaluso, Fei Duan, Sreyashi Basu, Sonali Jindal, Padmanee Sharma

Faculty, Staff and Student Publications

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC).

EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring …

Mechanisms That Clear Mutations Drive Field Cancerization In Mammary Tissue, Marta Ciwinska, Hendrik A Messal, Hristina R Hristova, Catrin Lutz, Laura Bornes, Theofilos Chalkiadakis, Rolf Harkes, Nathalia S M Langedijk, Stefan J Hutten, Renée X Menezes, Jos Jonkers, Stefan Prekovic, Grand Challenge Precision Consortium, Benjamin D Simons, Colinda L G J Scheele, Jacco Van Rheenen

Faculty, Staff and Student Publications

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1-3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1-/-;Trp53-/- cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to …

Neoadjuvant Talazoparib In Patients With Germline Brca1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Exploration Of Tumor Brca Mutational Status, Melinda L Telli, Jennifer K Litton, J Thaddeus Beck, Jason M Jones, Jay Andersen, Lida A Mina, Raymond Brig, Michael Danso, Yuan Yuan, William F Symmans, Julia F Hopkins, Lee A Albacker, Antonello Abbattista, Kay Noonan, Marielena Mata, A Douglas Laird, Joanne L Blum

Faculty, Staff and Student Publications

BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study.

METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne

RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with …

Understanding, Diagnosing, And Treating Pancreatic Cancer From The Perspective Of Telomeres And Telomerase, Songting Shou, Yuanliang Li, Jiaqin Chen, Xing Zhang, Chuanlong Zhang, Xiaochen Jiang, Fudong Liu, Li Yi, Xiyuan Zhang, En Geer, Zhenqing Pu, Bo Pang

Faculty, Staff and Student Publications

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase …

Beneficial Effects Of Lactobacillus Plantarum On Growth Performance, Immune Status, Antioxidant Function And Intestinal Microbiota In Broilers, Xiao Xiao, Tiantian Cui, Songke Qin, Tao Wang, Jinsong Liu, Lihan Sa, Yanping Wu, Yifan Zhong, Caimei Yang

Faculty, Staff and Student Publications

Lactobacillus plantarum (L. plantarum) has been globally regarded as antibiotic alternative in animal farming in the past few years. However, the potential function of L. plantarum in broilers has not been systemically explored. In this study, a total of 560 one-day-old yellow-feathered broilers were randomly divided into 3 groups, fed with basal diet and drank with L. plantarum HJZW08 (LP) at the concentration of 0 (CON), 1000 × 10^5 (LP1000), and 2000 × 10^5 CFU/L (LP2000) for 70 d. Results showed that the body weight (BW), average daily …

Smyd5 Is A Ribosomal Methyltransferase That Catalyzes Rpl40 Lysine Methylation To Enhance Translation Output And Promote Hepatocellular Carcinoma, Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu, Xiang Li, Kun Chen, Jinkai Wan, Shenghui Xing, Lingnan Ren, Zhennan Shi, Shengnan Liu, Yajun Hu, Jiajia Chen, Yanyan Yu, Lijian Feng, Natasha M Flores, Zhihui Liang, Xinyi Xu, Ruoxin Wang, Jian Zhou, Jia Fan, Bin Xiang, En Li, Yuanhui Mao, Jingdong Cheng, Kehao Zhao, Pawel K Mazur, Jiabin Cai, Fei Lan

Faculty, Staff and Student Publications

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma …

Mechanical Thrombectomy Versus Intravenous Thrombolysis In Distal Medium Vessel Acute Ischemic Stroke: A Multinational Multicenter Propensity Score-Matched Study, Hamza Adel Salim, Vivek Yedavalli, Basel Musmar, Nimer Adeeb, Muhammed Amir Essibayi, Kareem El Naamani, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kühn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Benjamin Y Q Tan, Benjamin Pulli, Jeremy J Heit, Robert W Regenhardt, Nicole M Cancelliere, Joshua D Bernstock, Aymeric Rouchaud, Jens Fiehler, Sunil Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Xavier Barreau, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Razvan Alexandru Radu, Thomas R Marotta, Julian Spears, Takahiro Ota, Ashkan Mowla, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor R Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Mohammad Ali Aziz-Sultan, Constantin Hecker, Hamza Shaikh, David S Liebeskind, Alessandro Pedicelli, Andrea M Alexandre, Illario Tancredi, Tobias D Faizy, Erwah Kalsoum, Boris Lubicz, Aman B Patel, Vitor Mendes Pereira, Adrien Guenego, Adam A Dmytriw, Mad Mt Investigators

Faculty, Staff and Student Publications

Background and purpose: The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone.

Methods: This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures …

Artificial Intelligence-Based Segmentation Of Residual Pancreatic Cancer In Resection Specimens Following Neoadjuvant Treatment (Isgpp-2): International Improvement And Validation Study, Boris V Janssen, Bart Oteman, Mahsoem Ali, Pieter A Valkema, Volkan Adsay, Olca Basturk, Deyali Chatterjee, Angela Chou, Stijn Crobach, Michael Doukas, Paul Drillenburg, Irene Esposito, Anthony J Gill, Seung-Mo Hong, Casper Jansen, Mike Kliffen, Anubhav Mittal, Jas Samra, Marie-Louise F Van Velthuysen, Aslihan Yavas, Geert Kazemier, Joanne Verheij, Ewout Steyerberg, Marc G Besselink, Huamin Wang, Caroline Verbeke, Arantza Fariña, Onno J De Boer, Pancreatobiliary And Hepatic Artificial Intelligence Research (Phair) Consortium, International Study Group Of Pancreatic Pathologists (Isgpp);

Faculty, Staff and Student Publications

Neoadjuvant therapy (NAT) has become routine in patients with borderline resectable pancreatic cancer. Pathologists examine pancreatic cancer resection specimens to evaluate the effect of NAT. However, an automated scoring system to objectively quantify residual pancreatic cancer (RPC) is currently lacking. Herein, we developed and validated the first automated segmentation model using artificial intelligence techniques to objectively quantify RPC. Digitized histopathological tissue slides were included from resected pancreatic cancer specimens from 14 centers in 7 countries in Europe, North America, Australia, and Asia. Four different scanner types were used: Philips (56%), Hamamatsu (27%), 3DHistech (10%), and Leica (7%). Regions of interest …

Hydrops And Congenital Diaphragmatic Hernia: Reported Incidence And Postnatal Outcomes Analysis Of The Congenital Diaphragmatic Hernia Study Group Registry, Carmen Mesas Burgos, Ashley H Ebanks, Anna Löf-Granström, Kylie I Holden, Anthony Johnson, Peter Conner, Matthew T Harting, Congenital Diaphragmatic Hernia Study Group

Faculty, Staff and Student Publications

Objective: Congenital Diaphragmatic Hernia (CDH) associated with hydrops is rare. The aim of this study was to describe the incidence of this combination of anomalies and the postnatal outcomes from a large database for CDH.

Study design: Data from the multicenter, multinational database on infants with prenatally diagnosed CDH (CDHSG Registry) born from 2015 to 2021 were analyzed.

Results: A total of 3985 patients were entered in the registry during the study period, 3156 were prenatally diagnosed and 88 were reported to have associated fluid in at least 1 compartment, representing 2.8% of all prenatally diagnosed CDH cases in the …

Ataxia Telangiectasia And Rad3-Related (Atr) Inhibitor Camonsertib Dose Optimization In Patients With Biomarker-Selected Advanced Solid Tumors (Tresr Study), Elisa Fontana, Ezra Rosen, Elizabeth K Lee, Martin Højgaard, Niharika B Mettu, Stephanie Lheureux, Benedito A Carneiro, Gregory M Cote, Louise Carter, Ruth Plummer, Devalingam Mahalingam, Adrian J Fretland, Joseph D Schonhoft, Ian M Silverman, Marisa Wainszelbaum, Yi Xu, Danielle Ulanet, Maria Koehler, Timothy A Yap

Faculty, Staff and Student Publications

BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects.

METHODS: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of …

Identification Of Hypoxia-Alcamhigh Macrophage- Exhausted T Cell Axis In Tumor Microenvironment Remodeling For Immunotherapy Resistance, Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Faculty, Staff and Student Publications

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM

Unraveling The Role Of Mir-181 In Skin Fibrosis Pathogenesis By Targeting Nudt21, Tingting W Mills, Minghua Wu, Jerry Alonso, Hydia Puente, Julio Charles, Zheng Chen, Seung-Hee Yoo, Maureen D Mayes, Shervin Assassi

Faculty, Staff and Student Publications

Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by widespread fibrosis in the skin and several internal organs. Nudix Hydrolase 21 (NUDT2 or CFIm25) downregulation in fibroblasts is known to play detrimental roles in both skin and lung fibrosis. This study aims to investigate the upstream mechanisms that lead to NUDT21 repression in skin fibrosis. We identified transforming growth factor β (TGFβ1) as the primary cytokine that downregulated NUDT21 in normal skin fibroblasts. In the bleomycin-induced dermal fibrosis model, consistent with the peak activation of TGFβ1 at the late fibrotic stage, NUDT21 was downregulated at this stage, and delayed …

Target Engagement And Immunogenicity Of An Active Immunotherapeutic Targeting Pathological Α-Synuclein: A Phase 1 Placebo-Controlled Trial, Pepijn Eijsvogel, Pinaki Misra, Luis Concha-Marambio, Justin D Boyd, Shuang Ding, Lauren Fedor, Yueh-Ting Hsieh, Yu Shuang Sun, Madeline M Vroom, Carly M Farris, Yihua Ma, Marieke L De Kam, Igor Radanovic, Maurits F J M Vissers, Dario Mirski, Ghazal Shareghi, Mohammad Shahnawaz, Wolfgang Singer, Philip Kremer, Geert Jan Groeneveld, Hui Jing Yu, Jean-Cosme Dodart

Faculty, Staff and Student Publications

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks …

Lysophospholipid Remodeling Mediated By The Lplt And Aas Protein Complex In The Bacterial Envelope, Wei Niu, Trung Vu, Guangwei Du, Mikhail Bogdanov, Lei Zheng

Faculty, Staff and Student Publications

Lysophospholipid transporter LplT and acyltransferase Aas consist of a lysophospholipid-remodeling system ubiquitously found in gram-negative microorganisms. LplT flips lysophospholipid across the inner membrane which is subsequently acylated by Aas on the cytoplasmic membrane surface. Our previous study showed that the proper functioning of this system is important to protecting Escherichia coli from phospholipase-mediated host attack by maintaining the integrity of the bacterial cell envelope. However, the working mechanism of this system is still unclear. Herein, we report that LplT and Aas form a membrane protein complex in E. coli which allows these two enzymes to cooperate efficiently to move lysophospholipids …

Use Of Long Spinal Board Post-Application Of Protocol For Spinal Motion Restriction For Spinal Cord Injury, Amber D Rice, Philipp L Hannan, Memu-Iye Kamara, Joshua B Gaither, Robyn Blust, Vatsal Chikani, Franco Castro-Marin, Gail Bradley, Bentley J Bobrow, Rachel Munn, Mary Knotts, Justin Lara

Faculty, Staff and Student Publications

Introduction: Historically, prehospital care of trauma patients has included nearly universal use of a cervical collar (C-collar) and long spine board (LSB). Due to recent evidence demonstrating harm in using LSBs, implementation of new spinal motion restriction (SMR) protocols in the prehospital setting should reduce LSB use, even among patients with spinal cord injury. Our goal in this study was to evaluate the rates of and reasons for LSB use in high-risk patients-those with hospital-diagnosed spinal cord injury (SCI)-after statewide implementation of SMR protocols.

Methods: Applying data from a state emergency medical services (EMS) registry to a state hospital discharge …

A Guideline On The Molecular Ecosystem Regulating Ferroptosis, Enyong Dai, Xin Chen, Andreas Linkermann, Xuejun Jiang, Rui Kang, Valerian E Kagan, Hülya Bayir, Wan Seok Yang, Ana J Garcia-Saez, Maria S Ioannou, Tobias Janowitz, Qitao Ran, Wei Gu, Boyi Gan, Dmitri V Krysko, Xiaofeng Zhu, Jiayi Wang, Stefan Krautwald, Shinya Toyokuni, Yangchun Xie, Florian R Greten, Qing Yi, Joel Schick, Jiao Liu, Dmitry I Gabrilovich, Jinbao Liu, Herbert J Zeh, Donna D Zhang, Minghua Yang, Juan Iovanna, Manfred Kopf, Timon E Adolph, Jen-Tsan Chi, Changfeng Li, Hidenori Ichijo, Michael Karin, Vijay G Sankaran, Weiping Zou, Lorenzo Galluzzi, Ashley I Bush, Binghui Li, Gerry Melino, Eric H Baehrecke, Michael T Lotze, Daniel J Klionsky, Brent R Stockwell, Guido Kroemer, Daolin Tang

Faculty, Staff and Student Publications

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Ibrutinib And Venetoclax In Combination For Chronic Lymphocytic Leukemia: Synergy In Practice, Natalia Timofeeva, Nitin Jain, Varsha Gandhi

Faculty, Staff and Student Publications

The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)-driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and …

Three-Year Overall Survival Outcomes And Correlative Analyses In Patients With Nsclc And High (50%-89%) Versus Very High (≥90%) Programmed Death-Ligand 1 Expression Treated With First-Line Pembrolizumab Or Cemiplimab, Biagio Ricciuti, Arielle Elkrief, Jessica Lin, Jianjun Zhang, Joao V Alessi, Giuseppe Lamberti, Malini Gandhi, Alessandro Di Federico, Federica Pecci, Xinan Wang, Maisam Makarem, Cassio Murilo Hidalgo Filho, Teresa Gorria, Arushi Saini, Cindy Pabon, James Lindsay, Kathleen L Pfaff, Emma L Welsh, Mizuki Nishino, Lynette M Sholl, Scott Rodig, Saadettin Kilickap, Petra Rietschel, Debra Ag Mcintyre, Jean-Francois Pouliot, Mehmet Altan, Justin F Gainor, John V Heymach, Adam J Schoenfeld, Mark M Awad

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Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to …

Landmark-Based Auto-Contouring Of Clinical Target Volumes For Radiotherapy Of Nasopharyngeal Cancer, Carlos Sjogreen, Tucker J Netherton, Anna Lee, Moaaz Soliman, Skylar S Gay, Callistus Nguyen, Raymond Mumme, Ivan Vazquez, Dong Joo Rhee, Carlos E Cardenas, Mary K Martel, Beth M Beadle, Laurence Edward Court

Faculty, Staff and Student Publications

Background: The delineation of clinical target volumes (CTVs) for radiotherapy for nasopharyngeal cancer is complex and varies based on the location and extent of disease.

Purpose: The current study aimed to develop an auto-contouring solution following one protocol guidelines (NRG-HN001) that can be adjusted to meet other guidelines, such as RTOG-0225 and the 2018 International guidelines.

Methods: The study used 2-channel 3-dimensional U-Net and nnU-Net framework to auto-contour 27 normal structures in the head and neck (H&N) region that are used to define CTVs in the protocol. To define the CTV-Expansion (CTV1 and CTV2) and CTV-Overall (the outer envelope of …

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A Curran, Hao Zhu, Li Ma

Faculty, Staff and Student Publications

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 …

Calcium Rescues Streptococcus Pneumoniae D39 Δmnte Manganese-Sensitive Growth Phenotype, Reuben Opoku, Edgar Carrasco, Nicholas R De Lay, Julia E Martin

Faculty, Staff and Student Publications

Calcium (Ca2+) functions as a universal signal messenger in eukaryotes but in bacteria, the physiological roles for Ca2+ are limited. Here, we examine the role of Ca2+ in Streptococcus pneumoniae during manganese (Mn2+) intoxication. S. pneumoniae mntE mutants, lacking the Mn2+ efflux transporter, exhibit impaired growth due to accumulation of Mn2+ when exposed to elevated exogenous Mn2+. This Mn2+-sensitive growth defect is restored to wild-type growth level by exogenous Ca2+, in a Ca2+-dependent manner. Despite growth restoration of the mntE mutant to wild-type levels, cellular Mn2+ remains elevated in this strain. Bacterial capsule production is also increased for the mntE …

Ablative Margin Quantification Using Deformable Versus Rigid Image Registration In Colorectal Liver Metastasis Thermal Ablation: A Retrospective Single-Center Study, Yuan-Mao Lin, Iwan Paolucci, Jessica Albuquerque Marques Silva, Caleb S O'Connor, Jun Hong, Ketan Y Shah, Mohamed E Abdelsalam, Peiman Habibollahi, Kyle A Jones, Kristy K Brock, Bruno C Odisio

Faculty, Staff and Student Publications

Purpose: To investigate the correlation of minimal ablative margin (MAM) quantification using biomechanical deformable (DIR) versus intensity-based rigid image registration (RIR) with local outcomes following colorectal liver metastasis (CLM) thermal ablation.

Methods: This retrospective single-institution study included consecutive patients undergoing thermal ablation between May 2016 and October 2021. Patients who did not have intraprocedural pre- and post-ablation contrast-enhanced CT images for MAM quantification or follow-up period less than 1 year without residual tumor or local tumor progression (LTP) were excluded. DIR and RIR methods were used to quantify the MAM. The registration accuracy was compared using Dice similarity coefficient (DSC). …

Small Molecules Targeting Micrornas: New Opportunities And Challenges In Precision Cancer Therapy, Ancuta Jurj, Beatrice Fontana, Gabriele Varani, George A Calin

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Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential …

Proteomic Analysis Of Ferroptosis Pathways Reveals A Role Of Cept1 In Suppressing Ferroptosis, Xiaoguang Liu, Zhen Chen, Yuelong Yan, Fereshteh Zandkarimi, Litong Nie, Qidong Li, Amber Horbath, Kellen Olszewski, Lavanya Kondiparthi, Chao Mao, Hyemin Lee, Li Zhuang, Masha Poyurovsky, Brent R Stockwell, Junjie Chen, Boyi Gan

Faculty, Staff and Student Publications

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

Inferring Super-Resolution Tissue Architecture By Integrating Spatial Transcriptomics With Histology, Daiwei Zhang, Amelia Schroeder, Hanying Yan, Haochen Yang, Jian Hu, Michelle Y Y Lee, Kyung S Cho, Katalin Susztak, George X Xu, Michael D Feldman, Edward B Lee, Emma E Furth, Linghua Wang, Mingyao Li

Faculty, Staff and Student Publications

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.

Quantitative Evaluation Of 90y-Pet/Ct And 90y-Spect/Ct-Based Dosimetry Following Yttrium-90 Radioembolization, Srinivas Cheenu Kappadath, Eric Courtney Henry, Benjamin P Lopez, Armeen Mahvash

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Background: Following yttrium-90 radioembolization (90Y-RE), 90Y-PET/CT and 90Y-SPECT/CT imaging provide the means to calculate the voxelized absorbed dose distribution. Given the widespread use of the two imaging modalities and lack of well-established standardized dosimetry protocols for 90Y-RE, there is a clinical need to systematically investigate and evaluate differences in the performance of voxel-based dosimetry between 90Y-PET/CT and 90Y-SPECT/CT.

Purpose: To quantitatively analyze and compare 90Y-PET/CT and 90Y-SPECT/CT-based dosimetry following 90Y-RE.

Methods: 90Y-PET/CT and 90Y-SPECT/CT imaging was acquired for 35 patients following 90Y-RE with TheraSphere for the treatment of unresectable hepatocellular carcinoma. Dosimetry was performed using the local deposition method with …

Resin-Based 90 Y Tumor Dose As A Predictor Of Duration Of Response And Survival In Patients With Surgically Unresectable Hepatocellular Carcinoma : A Prospective Single-Arm Study, Nima Kokabi, Linzi A Webster, Howard Dabbous, Anand Shah, David Brandon, James Galt, Minzhi Xing, Alexander Villalobos, Amir Davarpanahfakhr, S Cheenu Kappadath, David M Schuster

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Background: Personalized dosimetry improves overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with glass 90 Y radioembolization. This study evaluated personalized tumor dose (TD) as a predictor of OS, progression-free survival (PFS), and local duration of response (DOR) in patients with surgically unresectable HCC treated with resin 90 Y radioembolization.

Patients and methods: This prospective, single-center, single-arm clinical trial (NCT04172714) evaluated the efficacy of scout activity of resin 90 Y versus 99m Tc-MAA for treatment planning. A secondary aim of this study was to evaluate personalized dosimetry as a predictor of OS, PFS, and DOR. Partition …

Radiation Therapy Quality Assurance Analysis Of Alliance A021501: Preoperative Mfolfirinox Or Mfolfirinox Plus Hypofractionated Radiation Therapy For Borderline Resectable Adenocarcinoma Of The Pancreas, Leila T Tchelebi, Diana Segovia, Koren Smith, Qian Shi, T J Fitzgerald, Michael D Chuong, Tyler J Zemla, Eileen M O'Reilly, Jeffrey A Meyerhardt, Eugene J Koay, Jessica Lowenstein, Ardaman Shergill, Matthew H G Katz, Joseph M Herman

Faculty, Staff and Student Publications

Purpose: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered.

Methods and materials: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable …

Magnetic Particle Imaging Enables Nonradioactive Quantitative Sentinel Lymph Node Identification: Feasibility Proof In Murine Models, Olivia C Sehl, Kelvin Guo, Abdul Rahman Mohtasebzadeh, Petrina Kim, Benjamin Fellows, Marcela Weyhmiller, Patrick W Goodwill, Max Wintermark, Stephen Y Lai, Paula J Foster, Joan M Greve

Faculty, Staff and Student Publications

Background: Sentinel lymph node biopsy (SLNB) is an important cancer diagnostic staging procedure. Conventional SLNB procedures with 99mTc radiotracers and scintigraphy are constrained by tracer half-life and, in some cases, insufficient image resolution. Here, we explore an alternative magnetic (nonradioactive) image-guided SLNB procedure.

Purpose: To demonstrate that magnetic particle imaging (MPI) lymphography can sensitively, specifically, and quantitatively identify and map sentinel lymph modes (SLNs) in murine models in multiple regional lymphatic basins.

Materials and methods: Iron oxide nanoparticles were administered intradermally to healthy C57BL/6 mice (male, 12-week-old, n = 5). The nanoparticles (0.675 mg Fe/kg) were injected into the tongue, …