Medical Specialties Commons^™

Inactivation Of Lats1/2 Drives Luminal-Basal Plasticity To Initiate Basal-Like Mammary Carcinomas, Joseph G Kern, Andrew M Tilston-Lunel, Anthony Federico, Boting Ning, Amy Mueller, Grace B Peppler, Eleni Stampouloglou, Nan Cheng, Randy L Johnson, Marc E Lenburg, Jennifer E Beane, Stefano Monti, Xaralabos Varelas

Faculty, Staff and Student Publications

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of Krt14 and Sox9-expressing basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Gene expression analyses of …

Amplification Of The Plag-Family Genes-Plagl1 And Plagl2-Is A Key Feature Of The Novel Tumor Type Cns Embryonal Tumor With Plagl Amplification, Michaela-Kristina Keck, Martin Sill, Andrea Wittmann, Piyush Joshi, Damian Stichel, Pengbo Beck, Konstantin Okonechnikow, Philipp Sievers, Annika K. Wefers, Nasir Uddin

Department of Pathology and Laboratory Medicine

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal …

Interventions For Preventing And Ameliorating Cognitive Deficits In Adults Treated With Cranial Irradiation, Matthew A Kirkman, Julia Day, Karin Gehring, Karolis Zienius, David Grosshans, Martin Taphoorn, Jing Li, Paul D Brown

Faculty, Staff and Student Publications

BACKGROUND: Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.

OBJECTIVES: To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.

SEARCH METHODS: For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 …

Oxphos Promotes Apoptotic Resistance And Cellular Persistence In Th17 Cells In The Periphery And Tumor Microenvironment, Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis

Faculty, Staff and Student Publications

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to …

A Retrospective Comparative Study Of Sodium Fluoride Na18f-Pet/Ct And 68ga-Psma-11 Pet/Ct In The Bone Metastases Of Prostate Cancer Using A Volumetric 3-D Radiomic Analysis, Kalevi Kairemo, Aki Kangasmäki, Srinivasan Cheenu Kappadath, Timo Joensuu, Homer A Macapinlac

Faculty, Staff and Student Publications

Bone is the most common metastatic site in prostate cancer (PCa). 68Ga-PSMA-11 (or gozetotide) and sodium fluoride-18 (Na18F) are rather new radiopharmaceuticals for assessing PCa-associated bone metastases. Gozetotide uptake reflects cell membrane enzyme activity and the sodium fluoride uptake measures bone mineralization in advanced PCa. Here, we aim to characterize this difference and possibly provide a new method for patient selection in targeted therapies. Methods: The study consisted of 14 patients with advanced PCa (M group > 5 lesions), who had had routine PET/CT both with PSMA and NaF over consecutive days, and 12 PCa patients with no skeletal metastases (N). …

Coating Formulation Change Leads To Inferior Performance Of Long-Lasting Insecticidal Nets In Papua New Guinea, Nakei Bubun, Evodia Anetul, Melanie Koinari, Timothy W Freeman, Stephan Karl

Faculty, Staff and Student Publications

BACKGROUND: Long-lasting insecticidal nets (LLINs) play a key role in reducing malaria transmission in endemic countries. In a previous study, the authors demonstrated a substantial decrease in the bioefficacy of LLINs for malaria prevention delivered to Papua New Guinea (PNG) between 2013 and 2019. This coincided with a rise in malaria cases in the country. The present study was aimed at determining the underlying cause of the reduced bioefficacy observed in these LLINs. The main hypothesis was that a change in the coating formulation of the respective LLIN product was responsible, and had led to significantly altered product properties and …

The Innate Immune System In Cardiovascular Diseases And Its Role In Doxorubicin-Induced Cardiotoxicity, Anchit Bhagat, Pradeep Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Spatially Aware Dimension Reduction For Spatial Transcriptomics, Lulu Shang, Xiang Zhou

Faculty, Staff and Student Publications

Spatial transcriptomics are a collection of genomic technologies that have enabled transcriptomic profiling on tissues with spatial localization information. Analyzing spatial transcriptomic data is computationally challenging, as the data collected from various spatial transcriptomic technologies are often noisy and display substantial spatial correlation across tissue locations. Here, we develop a spatially-aware dimension reduction method, SpatialPCA, that can extract a low dimensional representation of the spatial transcriptomics data with biological signal and preserved spatial correlation structure, thus unlocking many existing computational tools previously developed in single-cell RNAseq studies for tailored analysis of spatial transcriptomics. We illustrate the benefits of SpatialPCA for …

Epigenetic Regulation In Chromium-, Nickel- And Cadmium-Induced Carcinogenesis, Lei Zhao, Ranakul Islam, Yifang Wang, Xiujuan Zhang, Ling-Zhi Liu

Department of Medical Oncology Faculty Papers

Environmental and occupational exposure to heavy metals, such as hexavalent chromium, nickel, and cadmium, are major health concerns worldwide. Some heavy metals are well-documented human carcinogens. Multiple mechanisms, including DNA damage, dysregulated gene expression, and aberrant cancer-related signaling, have been shown to contribute to metal-induced carcinogenesis. However, the molecular mechanisms accounting for heavy metal-induced carcinogenesis and angiogenesis are still not fully understood. In recent years, an increasing number of studies have indicated that in addition to genotoxicity and genetic mutations, epigenetic mechanisms play critical roles in metal-induced cancers. Epigenetics refers to the reversible modification of genomes without changing DNA sequences; …

Triple Blockade Of Ido-1, Pd-L1 And Mek As A Potential Therapeutic Strategy In Nsclc, Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, Floriana Morgillo

Faculty, Staff and Student Publications

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and …

Low Rates Of Structured Advance Care Planning Documentation In Electronic Health Records: Results Of A Single-Center Observational Study, Adela Wu, Robert J Huang, Gabriela Ruiz Colón, Chris Zembrzuski, Chirag B Patel

Faculty, Staff and Student Publications

BACKGROUND: Proper advance care planning (ACP) documentation both improves patient care and is increasingly seen as a marker of high quality by governmental payers. The transition of most medical documentation to electronic health records (EHR) allows for ACP documents to be rapidly disseminated across diverse ambulatory practice settings. At the same time, the complexity and heterogeneity of the EHR, as well as the multiple potential storage locations for documentation, may lead to confusion and inaccessibility. There has been movement to promote structured ACP (S-ACP) documentation within the EHR.

METHODS: We performed a retrospective cohort study at a single, large university …

Clinical Impact Of Number Of Lymph Nodes Dissected On Postoperative Survival In Node-Negative Small Cell Lung Cancer, Shinkichi Takamori, Takefumi Komiya Md, Emily Powell Phd

PCI Publications and Projects

Objectives: Small cell lung cancer (SCLC) is a lethal histologic subtype of lung cancer. Although the Commission on Cancer recommends pathological examination of at least 10 lymph nodes dissected (LNDs) for resected early-stage non-small cell lung cancer, its survival benefit of LNDs in patients with early-stage SCLC is unknown.

Methods: The National Cancer Database was queried for SCLC patients with clinical stage I-II and clinical N0, NX disease per AJCC 7th edition who had undergone lobectomy between 2004 and 2017. Overall survival of SCLC patients by the number of LNDs was compared using Log-rank tests. Univariate and multivariable Cox proportional …

Phase Ii Study Of Venetoclax Added To Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine In Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Tapan M Kadia, Patrick K Reville, Xuemei Wang, Caitlin R Rausch, Gautam Borthakur, Naveen Pemmaraju, Naval G Daver, Courtney D Dinardo, Koji Sasaki, Ghayas C Issa, Maro Ohanian, Guillermo Montalban-Bravo, Nicholas J Short, Nitin Jain, Alessandra Ferrajoli, Kapil N Bhalla, Elias Jabbour, Koichi Takahashi, Rashmi Malla, Kelly Quagliato, Rashmi Kanagal-Shamanna, Uday R Popat, Michael Andreeff, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

PURPOSE: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.

METHODS: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with …

Bob: Bayesian Optimal Design For Biosimilar Trials With Co-Primary Endpoints, Xiaohan Chi, Zhangsheng Yu, Ruitao Lin

Faculty, Staff and Student Publications

For regulatory approval of a biosimilar product, extensive evaluations should be performed by rigorous clinical trials to establish the similarity between the reference product and the proposed biosimilar in terms of both efficacy and safety. Existing designs for biosimilar trials often use a single primary efficacy endpoint in trial monitoring, and then separately evaluate the safety of the biosimilar product in a secondary analysis at the trial completion. However, ignoring the safety endpoint and the correlation between safety and efficacy in trial monitoring may lead to a high false positive rate, or it may delay the termination of the trial …

New Insights Into Avian Infectious Bronchitis Virus In Colombia From Whole-Genome Analysis, Gloria Ramirez-Nieto, Daiana Mir, Diego Almansa-Villa, Geovanna Cordoba-Argotti, Magda Beltran-Leon, Nelida Rodriguez-Osorio, Jone Garai, Jovanny Zabaleta, Arlen P. Gomez

School of Medicine Faculty Publications

Infectious Bronchitis (IB) is a respiratory disease caused by a highly variable Gammacoronavirus, which generates a negative impact on poultry health worldwide. GI-11 and GI-16 lineages have been identified in South America based on Infectious Bronchitis virus (IBV) partial S1 sequences. However, full genome sequence information is limited. In this study we report, for the first time, the whole-genome sequence of IBV from Colombia. Seven IBV isolates obtained during 2012 and 2013 from farms with respiratory disease compatible with IB were selected and the complete genome sequence was obtained by NGS. According to S1 sequence phylogenetic analysis, six isolates belong …

Reducing Liver Cancer Risk Through Dietary Change: Positive Results From A Community-Based Educational Initiative In Three Racial/Ethnic Groups, Lin Zhu, Ellen Jaeson Kim, Evelyn González, Marilyn A. Fraser, Steven Zhu, Nathaly Rubio-Torio, Grace X. Ma, Ming-Chin Yeh, Yin Tan

Publications and Research

Dietary behaviors and alcohol consumption have been linked to liver disease and liver cancer. So far, most of the liver cancer awareness campaigns and behavioral interventions have focused on preventive behaviors such as screening and vaccination uptake, while few incorporated dietary aspects of liver cancer prevention. We implemented a community-based education initiative for liver cancer prevention among the African, Asian, and Hispanic populations within the Greater Philadelphia and metropolitan New York City areas. Data from the baseline and the 6-month follow-up surveys were used for the assessment of changes in dietary behaviors and alcohol consumption among participants. In total, we …

Fine-Tuned Local Coordination Environment Of Pt Single Atoms On Ceria Controls Catalytic Reactivity, Wei Tan, Shaohua Xie, Duy Le, Weijian Diao, Meiyu Wang, Ke-Bin Low, Dave Austin, Sampyo Hong, Fei Gao, Lin Dong, Lu Ma, Steven N Ehrlich, Talat S Rahman, Fudong Liu

Faculty, Staff and Student Publications

Constructing single atom catalysts with fine-tuned coordination environments can be a promising strategy to achieve satisfactory catalytic performance. Herein, via a simple calcination temperature-control strategy, CeO2 supported Pt single atom catalysts with precisely controlled coordination environments are successfully fabricated. The joint experimental and theoretical analysis reveals that the Pt single atoms on Pt1/CeO2 prepared at 550 °C (Pt/CeO2-550) are mainly located at the edge sites of CeO2 with a Pt-O coordination number of ca. 5, while those prepared at 800 °C (Pt/CeO2-800) are predominantly located at distorted Ce substitution sites on CeO2 terrace with a Pt-O coordination number of ca. …

Chronic Exposure To Carbon Black Ultrafine Particles Reprograms Macrophage Metabolism And Accelerates Lung Cancer, Cheng-Yen Chang, Ran You, Dominique Armstrong, Ashwini Bandi, Yi-Ting Cheng, Philip M Burkhardt, Luis Becerra-Dominguez, Matthew C Madison, Hui-Ying Tung, Zhimin Zeng, Yifan Wu, Lizhen Song, Patricia E Phillips, Paul Porter, John M Knight, Nagireddy Putluri, Xiaoyi Yuan, Daniela C Marcano, Emily A Mchugh, James M Tour, Andre Catic, Laure Maneix, Bryan M Burt, Hyun-Sung Lee, David B Corry, Farrah Kheradmand

Faculty, Staff and Student Publications

Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A-dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non-small cell lung cancers. Adoptive transfer of lung APCs …

Intervening On Impostor Phenomenon: Prospective Evaluation Of A Workshop For Health Science Students Using A Mixed-Method Design, Shine Chang, Hwa Young Lee, Cheryl Anderson, Kava Lewis, Devasmita Chakraverty, Melinda Yates

Faculty, Staff and Student Publications

BACKGROUND: Unaddressed impostor feelings that impede developing interest in science and self-efficacy in conducting research have a dispiriting effect that perpetuates unsatisfactory diversity in the health science workforce when such feelings are experienced more by those historically underrepresented in the workforce. This warrants effective interventions to reduce the impact of impostor feelings and related factors that diminish career resilience. We examined the effects of a 90-minute workshop on impostor perceptions and growth mindset to raise awareness of impostor phenomenon (IP) and develop skills to manage IP successfully for students attending a 10-week summer research experience program.

METHODS: Using a convergent …

Response To Chen Et. Al, Albert Stuart Reece, Gary Kenneth Hulse

Research outputs 2022 to 2026

Whilst our paper was published in three parts to assist with readability it is essentially a single report. Our analysis moves logically from continuous and categorical bivariate studies to inverse probability weighted multivariate (IPWM) and then geospatiotemporal analysis and finally statistical analysis of geospatiotemporal models. Context is important. As stated by Chen and colleagues IPWM models are very powerful and present compelling conclusions and have the effect of transforming ecological into pseudo-randomized studies from which it is entirely proper to draw causal conclusions. That this report follows similar earlier IPWM and geotemporospatial reports on the commonest cancer in adults and …

Environmental Drivers Of The First Major Animal Extinction Across The Ediacaran White Sea-Nama Transition, Scott D Evans, Chenyi Tu, Adriana Rizzo, Rachel L Surprenant, Phillip C Boan, Heather Mccandless, Nathan Marshall, Shuhai Xiao, Mary L Droser

Faculty, Staff and Student Publications

The Ediacara Biota-the oldest communities of complex, macroscopic fossils-consists of three temporally distinct assemblages: the Avalon (ca. 575-560 Ma), White Sea (ca. 560-550 Ma), and Nama (ca. 550-539 Ma). Generic diversity varies among assemblages, with a notable decline at the transition from White Sea to Nama. Preservation and sampling biases, biotic replacement, and environmental perturbation have been proposed as potential mechanisms for this drop in diversity. Here, we compile a global database of the Ediacara Biota, specifically targeting taphonomic and paleoecological characters, to test these hypotheses. Major ecological shifts in feeding mode, life habit, and tiering level accompany an increase …

Diet-Derived Metabolites And Mucus Link The Gut Microbiome To Fever After Cytotoxic Cancer Treatment, Zaker I Schwabkey, Diana H Wiesnoski, Chia-Chi Chang, Wen-Bin Tsai, Dung Pham, Saira S Ahmed, Tomo Hayase, Miriam R Ortega Turrubiates, Rawan K El-Himri, Christopher A Sanchez, Eiko Hayase, Annette C Frenk Oquendo, Takahiko Miyama, Taylor M Halsey, Brooke E Heckel, Alexandria N Brown, Yimei Jin, Mathilde Raybaud, Rishika Prasad, Ivonne Flores, Lauren Mcdaniel, Valerie Chapa, Philip L Lorenzi, Marc O Warmoes, Lin Tan, Alton G Swennes, Stephanie Fowler, Margaret Conner, Kevin Mchugh, Tyler Graf, Vanessa B Jensen, Christine B Peterson, Kim-Anh Do, Liangliang Zhang, Yushu Shi, Yinghong Wang, Jessica R Galloway-Pena, Pablo C Okhuysen, Carrie R Daniel-Macdougall, Yusuke Shono, Marina Burgos Da Silva, Jonathan U Peled, Marcel R M Van Den Brink, Nadim Ajami, Jennifer A Wargo, Pavan Reddy, Raphael H Valdivia, Lauren Davey, Gabriela Rondon, Samer A Srour, Rohtesh S Mehta, Amin M Alousi, Elizabeth J Shpall, Richard E Champlin, Samuel A Shelburne, Jeffrey J Molldrem, Mohamed A Jamal, Jennifer L Karmouch, Robert R Jenq

Faculty, Staff and Student Publications

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction …

Transposon Mutagenesis Reveals Rbms3 Silencing As A Promoter Of Malignant Progression Of Brafv600e-Driven Lung Tumorigenesis, Aria Vaishnavi, Joseph Juan, Maebh Jacob, Christopher Stehn, Eric E Gardner, Michael T Scherzer, Sophia Schuman, J Edward Van Veen, Brandon Murphy, Christopher S Hackett, Adam J Dupuy, Steven A Chmura, Louise Van Der Weyden, Justin Y Newberg, Annie Liu, Karen Mann, Alistair G Rust, William A Weiss, Conan G Kinsey, David J Adams, Allie Grossmann, Michael B Mann, Martin Mcmahon

Faculty, Staff and Student Publications

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a …

Preclinical Evaluation Of Combination Nemtabrutinib And Venetoclax In Chronic Lymphocytic Leukemia, Elizabeth M Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A Rogers, John C Byrd, Jennifer A Woyach

Faculty, Staff and Student Publications

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and …

A Polyamine-Centric, Blood-Based Metabolite Panel Predictive Of Poor Response To Car-T Cell Therapy In Large B Cell Lymphoma, Johannes F Fahrmann, Neeraj Y Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael Jain, Robert Jenq, Christoph K Stein-Thoeringer, Marion Subklewe, Sattva S Neelapu, Sam Hanash

Faculty, Staff and Student Publications

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified …

Effect Of Selective Decontamination Of The Digestive Tract On Hospital Mortality In Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial, The Suddicu Investigators For The Australian And New Zealand Intensive Care Society Clinical Trials Group, John A Myburgh, Ian M Seppelt, Fiona Goodman, Laurent Billot, Maryam Correa, Joshua S Davis, Anthony C Gordon, Naomi E Hammond, Jon Iredell, Qiang Li, Sharon Micallef, Jennene Miller, Jayanthi Mysore, Colman Taylor, Paul J Young, Brian H Cuthbertson, Simon R Finfer

Faculty, Staff and Student Publications

IMPORTANCE: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.

OBJECTIVE: To determine whether SDD reduces in-hospital mortality in critically ill adults.

DESIGN, SETTING, AND PARTICIPANTS: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.

INTERVENTIONS: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a …

Is There A Role For Allogeneic Hematopoietic Stem Cell Transplantation For Refractory Follicular Lymphoma?, Yang Yang, Xia Bi, Mia Gergis, Usama Gergis

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

No abstract provided.

Longitudinal Survival Outcomes In Allogeneic Stem Cell Transplantation: An Institutional Experience., Justin Jiang, Audrey M Sigmund, Qiuhong Zhao, Patrick Elder, Don M Benson, Sumithira Vasu, Samantha Jaglowski, Alice Mims, Hannah Choe, Karilyn Larkin, Jonathan E Brammer, Sarah Wall, Nicole Grieselhuber, Ayman Saad, Sam Penza, Yvonne A Efebera, Nidhi Sharma

Oncology Articles

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for many hematological disorders, but is often complicated by relapse of the underlying disease, graft-versus-host disease (GVHD), and infectious complications. We conducted a retrospective analysis on patients undergoing allo-SCT from 1984 to 2018 to better understand how survival has changed longitudinally with therapeutic advancements made to mitigate these complications. Method: We analyzed data from 1943 consecutive patients who received allo-SCT. Patients were divided into groups (gps) based on the year (yr) of transplant. Primary endpoints were overall survival (OS), progression free survival (PFS), and GVHD-free relapse-free survival (GRFS). Secondary …

Tumor-Intrinsic Sirpa Promotes Sensitivity To Checkpoint Inhibition Immunotherapy In Melanoma, Zhicheng Zhou, Mei-Ju May Chen, Yikai Luo, Kamalika Mojumdar, Xin Peng, Hu Chen, Shweta V Kumar, Rehan Akbani, Yiling Lu, Han Liang

Faculty, Staff and Student Publications

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture …