Medical Specialties Commons^™

Atoh1 Drives The Heterogeneity Of The Pontine Nuclei Neurons And Promotes Their Differentiation, Sih-Rong Wu, Jessica C Butts, Matthew S Caudill, Jean-Pierre Revelli, Ryan S Dhindsa, Mark A Durham, Huda Y Zoghbi

Faculty, Staff and Students Publications

Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex andthe cerebellum to refine skilled motor functions. Prior studies showed that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss of Atoh1 function in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell state–specific functions of Atoh1 during PN development and …

Twenty-Year Survival Following Lung Transplantation, John James Miggins, Ross M Reul, Spencer Barrett, Abbas Rana, Ahmed Alnajar, Jordan Dunson, Alexis Shafii, Puneet Garcha, John Goss, Gabriel Loor

Faculty, Staff and Students Publications

BACKGROUND: Lung transplantation median survival has seen improvements due to recognition of short-term survival factors but continues to trail behind other solid organs due to limited understanding of long-term survivorship. Given the creation of the United Network for Organ Sharing (UNOS) database in 1986, it was difficult to accrue data on long-term survivors until recently. This study characterizes factors impacting lung transplant survival beyond 20 years, conditional to 1-year survival.

METHODS: Lung transplant recipients listed in UNOS from 1987 to 2002 who survived to 1 post-transplant year were reviewed. Kaplan-Meier and adjusted Cox regression analyses were performed at 20 and …

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 …

Immune Cells Localize To Sites Of Corneal Erosions In C57bl/6 Mice., Phuong M. Le, Sonali Pal-Ghosh, A. Menko, Mary Ann Stepp

Computational Medicine Center Faculty Papers

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the …

Use Of Electronic Ecological Momentary Assessment Methodologies In Physical Activity, Sedentary Behavior, And Sleep Research In Young Adults: Systematic Review, Kimberly R. Hartson, Luz Huntington-Moskos, Clara G. Sears, Gina Genova, Cara Mathis, Wessly Ford, Ryan E. Rhodes

Faculty and Staff Scholarship

Background: Recent technological advances allow for the repeated sampling of real-time data in natural settings using electronic ecological momentary assessment (eEMA). These advances are particularly meaningful for investigating physical activity, sedentary behavior, and sleep in young adults who are in a critical life stage for the development of healthy lifestyle behaviors.

Objective: This study aims to describe the use of eEMA methodologies in physical activity, sedentary behavior, and sleep research in young adults.

Methods: The PubMed, CINAHL, PsycINFO, Embase, and Web of Science electronic databases were searched through August 2022. Inclusion criteria were use of eEMA; sample of young adults …

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, …

Withaferin A And Immune Checkpoint Blocker Therapy For The Treatment Of Non-Small Cell Lung Cancer, Roukiah Khalil

USF Tampa Graduate Theses and Dissertations

Lung cancer is the first cause of cancer-related deaths in both men and women with an overall five-year survival rate of 28%. Although immune checkpoint blockers (ICBs) are currently FDA-approved for the treatment of non-small cell lung cancer (NSCLC), only 17-20% of patients achieve durable responses by the induction of immunologic memory. The lack of response in most patients can be attributed to the tumor-intrinsic or tumor-extrinsic immune resistance mechanisms. A biomarker of importance is the Programmed Death Ligand-1 (PD-L1), as higher PD-L1 expression is usually associated with a better response to ICBs. Although studies have attempted to combine ICBs …

Anesthetic Considerations For Cardiac Tamponade After Internal Jugular Central Line Placement During Trauma Resuscitation: A Case Report, Kevin M Chen, Jamal Hasoon, Anvinh Nguyen

Faculty, Staff and Students Publications

Numerous complications are associated with central venous catheters. Among them, cardiac tamponade is a rare but well-documented catastrophic complication. A 22-year-old healthy male presented with Code 1 trauma resulting from gunshot wounds in the abdomen. Upon examination, he was found to have a large pericardial fluid collection, a large right supraclavicular hematoma, and significant amount of bilateral pleural effusions secondary to extraluminal placement of the right internal jugular central line during resuscitation. After repairing the internal jugular injury and draining the pericardial fluid, the patient was transferred from the intensive care unit to the regular hospital floor. However, 15 days …

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 …

Downregulation Of Fkbp5 Promotes Atrial Arrhythmogenesis, Xiaolei Wang, Jia Song, Yue Yuan, Luge Li, Issam Abu-Taha, Jordi Heijman, Liang Sun, Shokoufeh Dobrev, Markus Kamler, Liang Xie, Xander H T Wehrens, Frank T Horrigan, Dobromir Dobrev, Na Li

Faculty, Staff and Students Publications

BACKGROUND: Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of

METHODS: Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding

RESULTS: FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca

CONCLUSIONS: This is the first study to …

Drugging Evolution Of Antibiotic Resistance At A Regulatory Network Hub, Yin Zhai, John P Pribis, Sean W Dooling, Libertad Garcia-Villada, P J Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M Fitzgerald, Christophe Herman, P J Hastings, Mauro Costa-Mattioli, Susan M Rosenberg

Faculty, Staff and Students Publications

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the

Dual Functions Of Tet1 In Germ Layer Lineage Bifurcation Distinguished By Genomic Context And Dependence On 5-Methylcytosine Oxidation, Bernard K Van Der Veer, Lehua Chen, Colin Custers, Paraskevi Athanasouli, Mariana Schroiff, Riet Cornelis, Jonathan Sai-Hong Chui, Richard H Finnell, Frederic Lluis, Kian Peng Koh

Faculty, Staff and Students Publications

Gastrulation begins when the epiblast forms the primitive streak or becomes definitive ectoderm. During this lineage bifurcation, the DNA dioxygenase TET1 has bipartite functions in transcriptional activation and repression, but the mechanisms remain unclear. By converting mouse embryonic stem cells (ESCs) into neuroprogenitors, we defined how Tet1-/- cells switch from neuroectoderm fate to form mesoderm and endoderm. We identified the Wnt repressor Tcf7l1 as a TET1 target that suppresses Wnt/β-catenin and Nodal signalling. ESCs expressing catalytic dead TET1 retain neural potential but activate Nodal and subsequently Wnt/β-catenin pathways to generate also mesoderm and endoderm. At CpG-poor distal enhancers, TET1 maintains …

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 …

An Improved Reporter Identifies Ruxolitinib As A Potent And Cardioprotective Camkii Inhibitor, Oscar E Reyes Gaido, Nikoleta Pavlaki, Jonathan M Granger, Olurotimi O Mesubi, Bian Liu, Brian L Lin, Alan Long, David Walker, Joshua Mayourian, Kate L Schole, Chantelle E Terrillion, Lubika J Nkashama, Mohit M Hulsurkar, Lauren E Dorn, Kimberly M Ferrero, Richard L Huganir, Frank U Müller, Xander H T Wehrens, Jun O Liu, Elizabeth D Luczak, Vassilios J Bezzerides, Mark E Anderson

Faculty, Staff and Students Publications

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and …

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. …

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 …