Neoplasms Commons^™

Conditional Risks Of Biochemical Failure And Prostate Cancer-Specific Death In Patients Undergoing External Beam Radiotherapy: A Secondary Analysis Of 2 Randomized Clinical Trials, Gregory S. Alexander, Rebecca F Krc, James W Assif, Kai Sun, Jason K Molitoris, Phuoc Tran, Zaker Rana, Søren M Bentzen, Mark V Mishra

Department of Radiation Oncology Faculty Papers

IMPORTANCE: As patients achieve years of survival after treatment for prostate cancer, the risk of biochemical failure (BF) or prostate cancer-specific death (PCSD) may evolve over time, with clinical relevance to both patients and clinicians.

OBJECTIVE: To determine conditional BF-free survival, PSCD, and overall survival estimates for patients with low- or intermediate-risk prostate cancer enrolled in the Radiation Therapy Oncology Group (RTOG) 0126 and RTOG 0415 clinical trials. A secondary objective was to determine whether prognostic factors at diagnosis remain relevant at later points in follow-up.

DESIGN, SETTING, AND PARTICIPANTS: A pooled secondary analysis of patients treated with external-beam radiotherapy …

Genetic Susceptibility To Cognitive Decline Following Craniospinal Irradiation For Pediatric Central Nervous System Tumors, Austin L Brown, Pagna Sok, Kimberly P Raghubar, Philip J Lupo, Melissa A Richard, Alanna C Morrison, Jun J Yang, Clinton F Stewart, Mehmet Fatih Okcu, Murali M Chintagumpala, Amar Gajjar, Lisa S Kahalley, Heather Conklin, Michael E Scheurer

Faculty, Staff and Student Publications

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.

METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups.

RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

Carm1 Arginine Methyltransferase As A Therapeutic Target For Cancer, Margarida Santos, Jee Won Hwang, Mark T Bedford

Faculty, Staff and Student Publications

Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that posttranslationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators of transcription, and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely. CARM1 is ubiquitously expressed, and its KO is less detrimental in …

Characteristics And Clinical Outcomes Of Patients With Acute Myeloid Leukemia With Inv(3)(Q21q262) Or T(3; 3)(Q21; Q262), Guillaume Richard-Carpentier, Caitlin R Rausch, Koji Sasaki, Danielle Hammond, Kiyomi Morita, Koichi Takahashi, Guilin Tang, Rashmi Kanagal-Shamanna, Kapil Bhalla, Courtney D Dinardo, Gautam Borthakur, Naveen Pemmaraju, Elizabeth J Shpall, Amin Alousi, Naval G Daver, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission …

Anesthesia Care Provider Sedation Versus Conscious Sedation For Endoscopic Ultrasound-Guided Tissue Acquisition: A Retrospective Cohort Study, Sneha Shaha, Yinglin Gao, Jiahao Peng, Kendrick Che, John J Kim, Wasseem Skef

Faculty, Staff and Students Publications

BACKGROUND/AIMS: We aimed to study the effects of sedation on endoscopic ultrasound-guided tissue acquisition.

METHODS: We conducted a retrospective study evaluating the role of sedation in endoscopic ultrasound-guided tissue acquisition by comparing two groups: anesthesia care provider (ACP) sedation and endoscopist-directed conscious sedation (CS).

RESULTS: Technical success was achieved in 219/233 (94.0%) in the ACP group and 114/136 (83.8%) in the CS group (p=0.0086). In multivariate analysis, the difference in technical success between the two groups was not significant (adjusted odds ratio [aOR], 0.5; 95% confidence interval [CI], 0.234-1.069; p=0.0738). A successful diagnostic yield was present in 146/196 (74.5%) in …

Screening People On Standing Balance With Romberg Testing And Walking Balance With Tandem Walking, Helen S Cohen

Faculty, Staff and Students Publications

The goal of this protocol is to inform readers about the exact procedures to use to perform two screening tests for vestibular disorders: tandem walking (TW) with eyes closed, also known as heel-toe walking, and the Clinical Test of Sensory Integration and Balance (CTSIB), which is also known as the modified Romberg. The study describes the steps for performing each test and each of the three CTSIB subtests so that the reader will be able to replicate the test conditions for use in the clinic, in the clinical laboratory, or in any other situation needing valid and reliable screening for …

Risks Factors And Outcomes For Isolated Catheter-Related Deep Venous Thrombosis In Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation, Jonathan Avery, Danielle Guffey, Shengling Ma, Ryan Basom, Stephanie J Lee, David Garcia, Cristhiam M Rojas Hernandez, Ang Li, Kylee L Martens

Faculty, Staff and Students Publications

INTRODUCTION: Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) require indwelling central venous catheters. The comparative incidence, risk, and outcome of isolated catheter-related deep venous thrombosis (CR-DVT) versus pulmonary embolism/lower-extremity DVT (PE/LE-DVT) remains unclear.

MATERIALS AND METHODS: We conducted a retrospective cohort study for patients undergoing allo-HSCT from 2006 to 2019. CR-DVT and PE/LE-DVT outcomes were screened using ICD codes and radiology reports and confirmed by medical record reviews. Cox regression models were used to assess the association between thrombotic outcomes and pertinent baseline and time-varying covariates. The impact of thrombotic events within 1-year post-transplant (time-varying) on overall mortality was …

Detection Method Has Independent Prognostic Significance In The Plco Lung Screening Trial, James P Long, Yu Shen

Faculty, Staff and Student Publications

Prognostic models in cancer use patient demographic and tumor characteristics to predict survival and dynamic disease prognosis. Past work in breast cancer has shown that cancer detection method, screen-detected or symptom-detected, has prognostic significance. We investigate this phenomenon in the lung component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. Patients were randomized to intervention, receiving four annual chest x-rays (CXRs), or to control, receiving usual care. Patients were followed for a total of approximately 13 years. In PLCO, lung cancer detection method has independent prognostic value exceeding that of variables commonly used in lung cancer prognostic models, …

Proteogenomic Data And Resources For Pan-Cancer Analysis, Yize Li, Yongchao Dou, Felipe Da Veiga Leprevost, Yifat Geffen, Anna P Calinawan, François Aguet, Yo Akiyama, Shankara Anand, Chet Birger, Song Cao, Rekha Chaudhary, Padmini Chilappagari, Marcin Cieslik, Antonio Colaprico, Daniel Cui Zhou, Corbin Day, Marcin J Domagalski, Myvizhi Esai Selvan, David Fenyö, Steven M Foltz, Alicia Francis, Tania Gonzalez-Robles, Zeynep H Gümüş, David Heiman, Michael Holck, Runyu Hong, Yingwei Hu, Eric J Jaehnig, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Robert J Klein, Jonathan T Lei, Wen-Wei Liang, Yuxing Liao, Caleb M Lindgren, Weiping Ma, Lei Ma, Michael J Maccoss, Fernanda Martins Rodrigues, Wilson Mckerrow, Ngoc Nguyen, Robert Oldroyd, Alexander Pilozzi, Pietro Pugliese, Boris Reva, Paul Rudnick, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Deepak Singhal, Xiaoyu Song, Erik Storrs, Nadezhda V Terekhanova, Ratna R Thangudu, Mathangi Thiagarajan, Liang-Bo Wang, Joshua M Wang, Ying Wang, Bo Wen, Yige Wu, Matthew A Wyczalkowski, Yi Xin, Lijun Yao, Xinpei Yi, Hui Zhang, Qing Zhang, Maya Zuhl, Gad Getz, Li Ding, Alexey I Nesvizhskii, Pei Wang, Ana I Robles, Bing Zhang, Samuel H Payne

Faculty, Staff and Students Publications

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry …

Nivolumab And Ipilimumab In Combination With Radiotherapy In Patients With High-Risk Locally Advanced Squamous Cell Carcinoma Of The Head And Neck., Jennifer Johnson, Ioannis A. Vathiotis, Larry Harshyne, Ayesha Ali, Voichita Bar-Ad, Rita S. Axelrod, Emily Lorber, Joseph Curry, David Cognetti, Adam J. Luginbuhl, Madalina Tuluc, Scott W Keith, M.G. Mahoney, Athanassios Argiris

Department of Medical Oncology Faculty Papers

BACKGROUND: The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN).

METHODS: Patients with newly diagnosed, stage IVA-IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary …

Reduction In Racial And Ethnic Disparity In Survival Following Liver Transplant For Hepatocellular Carcinoma In The Direct-Acting Antiviral Era, Anjiya Shaikh, Karthik Goli, Tzu-Hao Lee, Nicole E Rich, Jihane N Benhammou, Stephanie Keeling, Donghee Kim, Aijaz Ahmed, John Goss, Abbas Rana, Amit G Singal, Fasiha Kanwal, George Cholankeril

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Black patients with hepatocellular cancer (HCC), often attributed to hepatitis C virus (HCV) infection, have suboptimal survival following liver transplant (LT). We evaluated the impact of direct-acting antiviral (DAA) availability on racial and ethnic disparities in wait list burden post-LT survival for candidates with HCC.

METHODS: Using the United Network for Organ Sharing registry, we identified patients with HCC who were listed and/or underwent LT from 2009 to 2020. Based on date of LT, patients were categorized into 2 era-based cohorts: the pre-DAA era (LT between 2009 and 2011) and DAA era (LT between 2015 and 2017, …

Real-World Perspectives And Practices For Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use In Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer, Hope S Rugo, Christine L Crossno, Yaron B Gesthalter, Kristen Kelley, Heather B Moore, Mothaffar F Rimawi, Kelly E Westbrook, Saundra S Buys

Faculty, Staff and Students Publications

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8%

Venous Thromboembolism Risk In Cancer Patients Receiving First-Line Immune Checkpoint Inhibitor Versus Chemotherapy, Ang Li, Sarah B May, Jennifer La, Kylee L Martens, Christopher I Amos, Christopher R Flowers, Nhan V Do, Mary T Brophy, Vipul Chitalia, Katya Ravid, John Michael Gaziano, Nathanael R Fillmore

Faculty, Staff and Students Publications

It remains unclear if immune checkpoint inhibitor (ICI) therapy is associated with higher rate of venous thromboembolism (VTE) compared with cytotoxic chemotherapy (chemo) in patients with comparable cancer type, staging, and comorbidities. Using the national Veterans Affairs healthcare system database from 2016 to 2021, we performed a propensity score (PS)-weighted retrospective cohort study to compare the incidence of VTE in patients with selected stage III/IV cancer receiving first-line ICI versus chemo. The PS model utilized overlap weights to balance age, sex, race, treatment year, VTE history, paralysis/immobilization, prolonged hospitalization, cancer type, staging, time between diagnosis and treatment, and National Cancer …

Preclinical Evaluation Of Anti-Cd38 Therapy In Mature T-Cell Neoplasms, Colleen Isabelle, William Johnson, Kathleen Mcconnell, Ashley Vogel, Jonathan Brammer, Amy Boles, Robyn Keller, Paola Sindaco, Liam Nisenfeld, Guldeep Uppal, Neda Nikbakht, Bruno Calabretta, Patrizia Porazzi, Jerald Gong, Nitin Chakravarti, Pierluigi Porcu, Anjali Mishra

Kimmel Cancer Center Faculty Papers

No abstract provided.

Conditional Metastasis Of Uveal Melanoma In 8091 Patients Over Half-Century (51 Years) By Age Group: Assessing The Entire Population And The Extremes Of Age, Carol L. Shields, Annika Samuelson, Glenn Oh, Joseph D. Desimone, Zaynab Sajjadi, Zeynep Bas, Nicholas E Kalafatis, Sara E. Lally, Jerry A. Shields, Philip W. Dockery

Wills Eye Hospital Papers

PURPOSE: To evaluate cumulative incidence of metastasis at specific timepoints after treatment of uveal melanoma in a large cohort of patients and to provide comparison of conditional outcomes in the youngest and oldest cohorts (extremes of age).

METHODS: Retrospective analysis of 8091 consecutive patients with uveal melanoma at a single center over a 51-year period. The patients were categorized by age at presentation (0-29 years [n = 348, 4%], 30-59 years [n = 3859, 48%], 60-79 years [n = 3425, 42%], 80 to 99 years [n = 459, 6%]) and evaluated for nonconditional (from presentation date) and conditional (from specific …

Interferon Signaling Promotes Tolerance To Chromosomal Instability During Metastatic Evolution In Renal Cancer, Luigi Perelli, Federica Carbone, Li Zhang, Justin K Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M T Mohamed, Jianhua Zhang, Kanishka Sircar, Alessandro Sgambato, Jianjun Gao, Eric Jonasch, Giulio F Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G Di Natale, A Ari Hakimi, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Christopher A Bristow, Nizar M Tannir, Alessandro Carugo, Giannicola Genovese

Faculty, Staff and Student Publications

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect …

Transcriptional Profiling And Consensus Molecular Subtype Assignment To Understand Response And Resistance To Anti-Epidermal Growth Factor Receptor Therapy In Colorectal Cancer, Saikat Chowdhury, Ria Gupta, Joshua Millstein, Kangyu Lin, Valsala Haridas, Mohammad A Zeineddine, Christine Parseghian, Heinz-Josef Lenz, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti–epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy.

MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes.

RESULTS: Restricting to RASWT patients, …

External Validation Of A Novel Electronic Risk Score For Cancer-Associated Thrombosis In A Comprehensive Cancer Center, Ang Li, Giordana De Las Pozas, Clark R Andersen, Chijioke C Nze, Katy M Toale, Emily M Milner, Nathanael R Fillmore, Elizabeth Yu Chiao, Cristhiam Rojas Hernandez, Michael H Kroll, Kelly W Merriman, Christopher R Flowers

Faculty, Staff and Students Publications

Venous thromboembolism (VTE) is a significant complication for cancer patients undergoing systemic therapy. We performed an independent external validation for a recently derived and validated a novel electronic health record (EHR) VTE risk score in a comprehensive cancer center. Adult patients with incident cancer diagnoses were identified from MD Anderson Cancer Center Tumor Registry 1/2017-1/2021. Baseline covariates extracted at the time of first-line systemic therapy included demographics, cancer site/histology, stage, treatment, complete blood count, body mass index, recent prolonged hospitalization, and history of VTE or paralysis. VTE was ascertained using an institution-specific natural language processing radiology algorithm (positive predictive value …

G Protein-Coupled Receptor-Targeting Antibody-Drug Conjugates: Current Status And Future Directions, Peyton High, Kendra S Carmon

Faculty, Staff and Student Publications

In recent years, antibody-drug conjugates (ADCs) have emerged as promising anti-cancer therapeutic agents with several having already received market approval for the treatment of solid tumor and hematological malignancies. As ADC technology continues to improve and the range of indications treatable by ADCs increases, the repertoire of target antigens has expanded and will undoubtedly continue to grow. G protein-coupled receptors (GPCRs) are well-characterized therapeutic targets implicated in many human pathologies, including cancer, and represent a promising emerging target of ADCs. In this review, we will discuss the past and present therapeutic targeting of GPCRs and describe ADCs as therapeutic modalities. …

Tumor Biology And Immune Infiltration Define Primary Liver Cancer Subsets Linked To Overall Survival After Immunotherapy, Anuradha Budhu, Erica C Pehrsson, Aiwu He, Lipika Goyal, Robin Kate Kelley, Hien Dang, Changqing Xie, Cecilia Monge, Mayank Tandon, Lichun Ma, Mahler Revsine, Laura Kuhlman, Karen Zhang, Islam Baiev, Ryan Lamm, Keyur Patel, David E Kleiner, Stephen M Hewitt, Bao Tran, Jyoti Shetty, Xiaolin Wu, Yongmei Zhao, Tsai-Wei Shen, Sulbha Choudhari, Yuliya Kriga, Kris Ylaya, Andrew C Warner, Elijah F Edmondson, Marshonna Forgues, Tim F Greten, Xin Wei Wang

Kimmel Cancer Center Faculty Papers

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. …

Scutellaria Baicalensis Enhances 5-Fluorouracil-Based Chemotherapy Via Inhibition Of Proliferative Signaling Pathways, Haizhou Liu, Hui Liu, Zhiyi Zhou, Jessica Chung, Guojing Zhang, Jin Chang, Robert A Parise, Edward Chu, John C Schmitz

Abington Jefferson Health Papers

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

5s Rrna Pseudogene Transcripts Are Associated With Interferon Production And Inflammatory Responses In Alcohol-Associated Hepatitis, Jianguo Wu, Adam Kim, Xiaoqin Wu, Semanti Ray, Daniela S Allende, Nicole Welch, Annette Bellar, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH.

APPROACH AND RESULTS: Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver …

Targeting Glutaminase Is Therapeutically Effective In Ibrutinib-Resistant Mantle Cell Lymphoma, Lingzhi Li, Lei Nie, Alexa Jordan, Qingsong Cai, Yang Liu, Yijing Li, Yuxuan Che, Jovanny Vargas, Zhihong Chen, Angela Leeming, Wei Wang, Yixin Yao, Michael Wang, Vivian Changying Jiang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced …

Derivation And Validation Of A Clinical Risk Assessment Model For Cancer-Associated Thrombosis In Two Unique Us Health Care Systems, Ang Li, Jennifer La, Sarah B May, Danielle Guffey, Wilson L Da Costa, Christopher I Amos, Raka Bandyo, Emily M Milner, Karen M Kurian, Daniel C R Chen, Nhan V Do, Carolina Granada, Nimrah Riaz, Mary T Brophy, Vipul Chitalia, J Michael Gaziano, David A Garcia, Marc Carrier, Christopher R Flowers, Neil A Zakai, Nathanael R Fillmore

Faculty, Staff and Students Publications

PURPOSE: Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy.

METHODS: Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using …

Epidemiology Of Cancer-Associated Venous Thromboembolism In Patients With Solid And Hematologic Neoplasms In The Veterans Affairs Health Care System, Kylee L Martens, Ang Li, Jennifer La, Sarah B May, Kaitlin N Swinnerton, Hannah Tosi, Danne C Elbers, Nhan V Do, Mary T Brophy, J Michael Gaziano, Saran Lotfollahzadeh, Vipul Chitalia, Katya Ravid, Nathanael R Fillmore

Faculty, Staff and Students Publications

IMPORTANCE: Identifying changes in epidemiologic patterns of the incidence and risk of cancer-associated thrombosis (CAT), particularly with evolving cancer-directed therapy, is essential for risk stratification.

OBJECTIVE: To assess the incidence of CAT over time and to determine pertinent patient-specific, cancer-specific, and treatment-specific factors associated with its risk.

DESIGN, SETTING, AND PARTICIPANTS: This longitudinal, retrospective cohort study was conducted from 2006 to 2021. Duration of follow-up was from the date of diagnosis until first venous thromboembolism (VTE) event, death, loss of follow-up (defined as a 90-day gap without clinical encounters), or administrative censoring on April 1, 2022. The study took place …

Zinc Treatment Reverses And Anti-Zn-Regulated Mirs Suppress Esophageal Carcinomas In Vivo, Louise Fong, Kay Huebner, Ruiyan Jing, Karl Smalley, Christopher R Brydges, Oliver Fiehn, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …