Medical Specialties Commons^™

Therapeutic Potential Of Salicylamide Derivatives For Combating Viral Infections, Jimin Xu, Yu Xue, Andrew A Bolinger, Jun Li, Mingxiang Zhou, Haiying Chen, Hongmin Li, Jia Zhou

Faculty, Staff and Student Publications

Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. …

Venetoclax Consolidation In High-Risk Cll Treated With Ibrutinib For ≥1 Year Achieves A High Rate Of Undetectable Mrd, Philip A Thompson, Michael J Keating, Alessandra Ferrajoli, Nitin Jain, Christine B Peterson, Naveen Garg, Sa A Wang, Jeffrey L Jorgensen, Tapan M Kadia, Prithviraj Bose, Naveen Pemmaraju, Nicholas J Short, William G Wierda

Faculty, Staff and Student Publications

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10−4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were …

Characterization Of The Oral Microbiota Among Middle-Aged Men With And Without Human Papillomavirus Infection, Kristina R Dahlstrom, Andrew G Sikora, Yanhong Liu, Chia-Chi Chang, Peng Wei, Erich M Sturgis, Guojun Li

Faculty, Staff and Student Publications

OBJECTIVES: To characterize the oral microbiota among middle-aged men and identify differences between men with a prevalent oral high-risk (oncogenic) HPV infection and those without.

MATERIALS AND METHODS: This was a case-control study nested within a prospective screening study for HPV-related cancers among middle-aged men. 16S rRNA sequencing was used to characterize the oral microbiota and the cobas HPV Test was used to detect presence of oral high-risk HPV types. We determined the overall composition of the oral microbiota and assessed differences in relative abundance of bacterial taxa as well as alpha and beta diversity among men with a prevalent …

Single-Cell Profiling Of Tumor Immune Microenvironment Reveals Immune Irresponsiveness In Gastric Signet-Ring Cell Carcinoma, Jing Chen, Kuai Liu, Yikai Luo, Muxing Kang, Jun Wang, Guofeng Chen, Jia Qi, Wenxuan Wu, Beidi Wang, Yaxuan Han, Le Shi, Kefan Wang, Xiaying Han, Xiaojing Ma, Wei Liu, Yuan Ding, Liangjing Wang, Han Liang, Lie Wang, Jian Chen

Faculty, Staff and Student Publications

Background & aims: Gastric cancer (GC) is a major cancer type characterized by high heterogeneity in both tumor cells and the tumor immune microenvironment (TIME). One intractable GC subtype is gastric signet-ring cell carcinoma (GSRCC), which is associated with poor prognosis. However, it remains unclear what the GSRCC TIME characteristics are and how these characteristics may contribute to clinical outcomes.

Methods: We enrolled 32 patients with advanced GC of diverse subtypes and profiled their TIME using an immune-targeted single-cell profiling strategy, including (1) immune-targeted single-cell RNA sequencing (n = 20 patients) and (2) protein expression profiling by a targeted antibody …

Identification Of Unique Α4 Chain Structure And Conserved Antiangiogenic Activity Of Α3nc1 Type Iv Collagen In Zebrafish, Valerie S Lebleu, Jianli Dai, Susan Tsutakawa, Brian A Macdonald, Joseph L Alge, Malin Sund, Liang Xie, Hikaru Sugimoto, John Tainer, Leonard I Zon, Raghu Kalluri

Faculty, Staff and Student Publications

BACKGROUND: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1-α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied.

RESULTS: We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in …

Proteogenomic Approaches For The Identification Of Nf1/Neurofibromin-Depleted Estrogen Receptor-Positive Breast Cancers For Targeted Treatment, Beom-Jun Kim, Ze-Yi Zheng, Jonathan T Lei, Matthew V Holt, Anran Chen, Jianheng Peng, Diana Fandino, Purba Singh, Hilda Kennedy, Yongchao Dou, María Del Rosario Chica-Parrado, Emmanuel Bikorimana, Dan Ye, Yunguan Wang, Ariella B Hanker, Nada Mohamed, Susan G Hilsenbeck, Bora Lim, Jaya Ruth Asirvatham, Arun Sreekumar, Bing Zhang, George Miles, Meenakshi Anurag, Matthew J Ellis, Eric C Chang

Faculty, Staff and Student Publications

NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA …

Predicting Benefit From Immune Checkpoint Inhibitors In Patients With Non-Small-Cell Lung Cancer By Ct-Based Ensemble Deep Learning: A Retrospective Study, Maliazurina B Saad, Lingzhi Hong, Muhammad Aminu, Natalie I Vokes, Pingjun Chen, Morteza Salehjahromi, Kang Qin, Sheeba J Sujit, Xuetao Lu, Elliana Young, Qasem Al-Tashi, Rizwan Qureshi, Carol C Wu, Brett W Carter, Steven H Lin, Percy P Lee, Saumil Gandhi, Joe Y Chang, Ruijiang Li, Michael F Gensheimer, Heather A Wakelee, Joel W Neal, Hyun-Sung Lee, Chao Cheng, Vamsidhar Velcheti, Yanyan Lou, Milena Petranovic, Waree Rinsurongkawong, Xiuning Le, Vadeerat Rinsurongkawong, Amy Spelman, Yasir Y Elamin, Marcelo V Negrao, Ferdinandos Skoulidis, Carl M Gay, Tina Cascone, Mara B Antonoff, Boris Sepesi, Jeff Lewis, Ignacio I Wistuba, John D Hazle, Caroline Chung, David Jaffray, Don L Gibbons, Ara Vaporciyan, J Jack Lee, John V Heymach, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

BACKGROUND: Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context.

METHODS: In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from …

Development Of Photo-Polymerization-Type 3d Printer For High-Viscosity Ceramic Resin Using Cnn-Based Surface Defect Detection, Jin-Kyo Chung, Jeong-Seon Im, Min-Soo Park

Faculty, Staff and Student Publications

Due to the high hardness and brittleness of ceramic materials, conventional cutting methods result in poor quality and machining difficulties. Additive manufacturing has also been tried in various ways, but it has many limitations. This study aims to propose a system to monitor surface defects that occur during the printing process based on high-viscosity composite resin that maximizes ceramic powder content in real time using image processing and convolutional neural network (CNN) algorithms. To do so, defects mainly observed on the surface were classified into four types by form: pore, minor, critical, and error, and the effect of each defect …

Co-Targeting Fasn And Mtor Suppresses Uveal Melanoma Growth, Anna Han, Dzmitry Mukha, Vivian Chua, Timothy J Purwin, Manoela Tiago, Bhavik Modasia, Usman Baqai, Jenna L Aumiller, Nelisa Bechtel, Emily Hunter, Meggie Danielson, Mizue Terai, Philip B Wedegaertner, Takami Sato, Solange Landreville, Michael A Davies, Stefan Kurtenbach, J William Harbour, Zachary T Schug, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, …

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. …

Role Of Glucose Metabolic Reprogramming In Breast Cancer Progression And Drug Resistance, Pan Lei, Wenzhou Wang, Marisela Sheldon, Yutong Sun, Fan Yao, Li Ma

Faculty, Staff and Student Publications

The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges …

Hdac1 Regulates The Chromatin Landscape To Control Transcriptional Dependencies In Chronic Lymphocytic Leukemia, Tzung-Huei Lai, Hatice Gulcin Ozer, Pierluigi Gasparini, Giovanni Nigita, Rosario Distefano, Lianbo Yu, Janani Ravikrishnan, Selen Yilmaz, Juan Gallegos, Sachet Shukla, Vinay Puduvalli, Jennifer Woyach, Rosa Lapalombella, James Blachly, John C Byrd, Deepa Sampath

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome-wide occupancy of HDAC1, BRD4, H3K27Ac, and H3K9Ac signals with chromatin accessibility, Pol2 occupancy, and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression …

Spatial Single-Cell Sequencing Of Meiosis I Arrested Oocytes Indicates Acquisition Of Maternal Transcripts From The Soma, Kenneth A Trimmer, Peisen Zhao, Jacob Seemann, Shin-Yu Chen, Sudip Mondal, Adela Ben-Yakar, Swathi Arur

Faculty, Staff and Student Publications

Maternal RNAs are stored from minutes to decades in oocytes throughout meiosis I arrest in a transcriptionally quiescent state. Recent reports, however, propose a role for nascent transcription in arrested oocytes. Whether arrested oocytes launch nascent transcription in response to environmental or hormonal signals while maintaining the meiosis I arrest remains undetermined. We test this by integrating single-cell RNA sequencing, RNA velocity, and RNA fluorescence in situ hybridization on C. elegans meiosis I arrested oocytes. We identify transcripts that increase as the arrested meiosis I oocyte ages, but rule out extracellular signaling through ERK MAPK and nascent transcription as a …

Hyperphosphorylation Of The Group A Streptococcal Control Of Virulence Regulator Increases Promoter Occupancy Specifically At Virulence Factor-Encoding Genes, Nicola Horstmann, Chau Nguyen Tran, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The control of virulence two-component gene regulatory system (CovRS) is critical to the pathogenesis of many medically important streptococci. In emm1 group A streptococci (GAS), CovR directly binds the promoters of numerous GAS virulence factor-encoding genes. Elimination of CovS phosphatase activity increases CovR phosphorylation (CovR~P) levels and abrogates GAS virulence. Given the emm type-specific diversity of CovRS function, in this study we used chromatin immunoprecipitation sequencing (ChIP-seq) to define global CovR DNA occupancy in the wild-type emm3 strain MGAS10870 (medium CovR~P) and its CovS phosphatase-negative derivative 10870-CovS-T284A (high CovR~P). In the wild-type emm3 strain, 89% of the previously identified emm1 …

The Long Non-Coding Rna Neat1 Is A Δnp63 Target Gene Modulating Epidermal Differentiation, Claudia Fierro, Veronica Gatti, Veronica La Banca, Sara De Domenico, Stefano Scalera, Giacomo Corleone, Maurizio Fanciulli, Francesca De Nicola, Alessandro Mauriello, Manuela Montanaro, George A Calin, Gerry Melino, Angelo Peschiaroli

Faculty, Staff and Student Publications

The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting …

Effect Of Ishophloroglucin A Isolated From Ishige Okamurae On In Vitro Osteoclastogenesis And Osteoblastogenesis, Su-Hyeon Cho, Hyun-Soo Kim, Hye-Yeon Jung, Jae-Il Park, You-Jee Jang, Juhee Ahn, Kil-Nam Kim

Faculty, Staff and Student Publications

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the bone remodeling process. This study aimed to investigate the effect of Ishophloroglucin A (IPA) isolated from Ishige okamurae on the function of osteoclasts and osteoblasts in vitro. First, we demonstrated the effect of IPA on osteoclastogenesis in receptor activator of nuclear factor κB ligand (RANKL)-induced RAW 264.7 cells. IPA inhibited the tartrate-resistant acid phosphatase (TRAP) activity and osteoclast differentiation in RANKL-induced RAW 264.7 cells. Moreover, it inhibited the RANKL-induced osteoclast-related factors, such as TRAP, matrix metalloproteinase-9 (MMP-9), and calcitonin receptor (CTR), and transcription factors, such as nuclear factor …

Diagnostic Accuracy Of Whole Heart Coronary Magnetic Resonance Angiography: A Systematic Review And Meta-Analysis, Shingo Kato, Mai Azuma, Naoki Nakayama, Kazuki Fukui, Masanori Ito, Naka Saito, Nobuyuki Horita, Daisuke Utsunomiya

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this meta-analysis was to comprehensively investigate the diagnostic ability of 1.5 T and 3.0 T whole heart coronary angiography (WHCA) to detect significant coronary artery disease (CAD) on X-ray coronary angiography.

METHODS: A literature search of electronic databases, including PubMed, Web of Science Core Collection, Cochrane advanced search, and EMBASE, was performed to retrieve and integrate articles showing significant CAD detectability of 1.5 and 3.0 T WHCA.

RESULTS: Data from 1899 patients from 34 studies were included in the meta-analysis. 1.5 T WHCA had a summary area under ROC of 0.88 in the patient-based analysis, 0.90 …

Mdm2/P53 Levels In Bone Marrow Mesenchymal Stromal Cells Are Essential For Maintaining The Hematopoietic Niche In Response To Dna Damage, Rasoul Pourebrahim, Rafael Heinz Montoya, Zoe Alaniz, Lauren Ostermann, Patrick P Lin, Bin Liu, Edward Ayoub, Jared K Burks, Michael Andreeff

Faculty, Staff and Student Publications

Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for the maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo. We demonstrate that Mdm2 is essential for the emergence, maintenance, and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress-associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected …

Small Molecule Rbi2 Disrupts Ribosome Biogenesis Through Pre-Rrna Depletion, Catherine E Scull, Guy Twa, Yinfeng Zhang, Naiheng J Yang, Robert N Hunter, Corinne E Augelli-Szafran, David A Schneider

Faculty, Staff and Student Publications

Cancer cells are especially sensitive to perturbations in ribosome biogenesis as they rely on finely tuned protein homeostasis to facilitate their rapid growth and proliferation. While ribosome synthesis and cancer have a well-established relationship, ribosome biogenesis has only recently drawn interest as a cancer therapeutic target. In this study, we exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor, RBI2 (Ribosome Biogenesis Inhibitor 2), to perturb cancer cell growth and viability. We demonstrate herein that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 …

Normal Saline Remodels The Omentum And Stimulates Its Receptivity For Transcoelomic Metastasis, Hironari Akasaka, Wonjae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

The omentum contains immune cell structures called milky spots that are niches for transcoelomic metastasis. It is difficult to remove the omentum completely, and there are no effective strategies to minimize the risk of colonization of preserved omental tissues by cancer cells that circulate in the peritoneal fluid. Normal saline is commonly administered into the peritoneal cavity for diagnostic and intraoperative lavage. Here we show that normal saline, when administered into the peritoneal cavity of mice, is prominently absorbed by the omentum, exfoliates its mesothelium, and induces expression of CX3CL1, the ligand for CX3CR1, within and surrounding the omental vasculature. …

Nanoparticle-Enhanced Proton Beam Immunoradiotherapy Drives Immune Activation And Durable Tumor Rejection, Yun Hu, Sébastien Paris, Narayan Sahoo, Genevieve Bertolet, Qi Wang, Qianxia Wang, Hampartsoum B Barsoumian, Jordan Da Silva, Ailing Huang, Denaha J Doss, David P Pollock, Ethan Hsu, Nanez Selene, Claudia S Kettlun Leyton, Tiffany A Voss, Fatemeh Masrorpour, Shonik Ganjoo, Carola Leuschner, Jordan T Pietz, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of …

Slc7a11 Expression Level Dictates Differential Responses To Oxidative Stress In Cancer Cells, Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show …

Predictive Roles Of Baseline Stromal Tumor-Infiltrating Lymphocytes And Ki-67 In Pathologic Complete Response In An Early-Stage Triple-Negative Breast Cancer Prospective Trial, Nour Abuhadra, Ryan Sun, Clinton Yam, Gaiane M Rauch, Qingqing Ding, Bora Lim, Alastair M Thompson, Elizabeth A Mittendorf, Beatriz E Adrada, Senthil Damodaran, Kiran Virani, Jason White, Elizabeth Ravenberg, Jia Sun, Jaihee Choi, Rosalind Candelaria, Banu Arun, Naoto T Ueno, Lumarie Santiago, Sadia Saleem, Sausan Abouharb, Rashmi K Murthy, Nuhad Ibrahim, Aysegul Sahin, Vicente Valero, William Fraser Symmans, Jennifer K Litton, Debu Tripathy, Stacy Moulder, Lei Huo

Faculty, Staff and Student Publications

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for …

Creating And Activating An Implementation Community To Drive Hpv Vaccine Uptake In Texas: The Role Of An Nci-Designated Cancer Center, Rosalind S Bello, Michael T Walsh, Blake Harper, Charles E Amos, Katherine Oestman, Stephanie Nutt, Marcita Galindez, Kaitlyn Block, Ruth Rechis, Erica M Bednar, Jennifer Tektiridis, Lewis Foxhall, Mark Moreno, Sanjay Shete, Ernest Hawk

Faculty, Staff and Student Publications

The University of Texas MD Anderson Cancer Center, a comprehensive cancer center designated by the National Cancer Institute (NCI), defines its service population area as the State of Texas (29.1 M), the second most populous state in the country and the state with the greatest number of uninsured residents in the United States. Consistent with a novel and formal commitment to prevention as part of its core mission, alongside clear opportunities in Texas to drive vaccine uptake, MD Anderson assembled a transdisciplinary team to develop an institutional Framework to increase adolescent HPV vaccination and reduce HPV-related cancer burden. The Framework …

Arginine Depletion Attenuates Renal Cystogenesis In Tuberous Sclerosis Complex Model, Athar Amleh, Hadass Pri Chen, Lana Watad, Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Iddo Z Ben-Dov, Morris Nechama, Oded Volovelsky

Faculty, Staff and Student Publications

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in …

Long-Term Outcomes And Molecular Correlates Of Sotorasib Efficacy In Patients With Pretreated Kras G12c-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis Of Codebreak 100, Grace K Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S Falchook, Antoine Italiano, Jürgen Wolf, Adrian G Sacher, Toshiaki Takahashi, Suresh S Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, Bob T Li

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

In the longest follow-up, to our knowledge, for a KRAS^G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non–small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical …

Wdr5 Facilitates Recruitment Of N-Myc To Conserved Wdr5 Gene Targets In Neuroblastoma Cell Lines, Leigh A Bumpous, Kylie C Moe, Jing Wang, Logan A Carver, Alexandria G Williams, Alexander S Romer, Jesse D Scobee, Jack N Maxwell, Cheyenne A Jones, Dai H Chung, William P Tansey, Qi Liu, April M Weissmiller

Faculty, Staff and Student Publications

Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC-cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 …

Comparative Analyses Of The Clinicopathologic Features Of Short-Term And Long-Term Survivors Of Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Therapy And Pancreatoduodenectomy, Tom Z Liang, Matthew H G Katz, Laura R Prakash, Deyali Chatterjee, Hua Wang, Michael Kim, Ching-Wei D Tzeng, Naruhiko Ikoma, Robert A Wolff, Dan Zhao, Eugene J Koay, Anirban Maitra, Suprateek Kundu, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant therapy (NAT) is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often show heterogenous responses to NAT with variable clinical outcomes, and the clinicopathologic parameters associated with these variable outcomes remain unclear. In this study, we systematically examined the clinicopathologic characteristics of 60 short-term survivors (overall survival < 15 months) and 149 long-term survivors (overall survival > 60 months) and compared them to 352 intermediate-term survivors (overall survival: 15-60 months) of PDAC who received NAT and pancreatoduodenectomy. We found that the short-term survivor group was associated with male gender (p = 0.03), tumor resectability prior to NAT (p = 0.04), poorly differentiated …