Medical Specialties Commons^™

A Phase 1 Study Of Idh305 In Patients With Idh1 R132-Mutant Acute Myeloid Leukemia Or Myelodysplastic Syndrome, Courtney D Dinardo, Andreas Hochhaus, Mark G Frattini, Karen Yee, Thomas Zander, Alwin Krämer, Xueying Chen, Yan Ji, Nehal S Parikh, Joanne Choi, Andrew H Wei

Faculty, Staff and Student Publications

Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Methods: IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting …

Impact Of High Neutrophil-To-Lymphocyte Ratio On Survival In Hospitalized Cancer Patients With Covid-19, Fernando A Díaz-Couselo, Santiago Flagel, Carla Nicolini, Sebastián Halac, Natalia Manzano, Marina Aguirre, Juan Rébora, Sandra Valle, Laura Noro, Chirayu Mohindroo, Florencia Mcallister, Marcelo Zylberman

Faculty, Staff and Student Publications

Neutrophil-to-lymphocyte ratio (NLR) has been studied as a prognostic factor for mortality in COVID-19 patients. Our study aimed to evaluate the association between NLR at COVID-19 diagnosis and survival during the following 90 days in hospitalized patients with solid cancer. Between May 2020 and June 2021, 120 patients were included in a retrospective cohort study. Univariable analysis showed patients with an NLR > 8.3 were associated with an increased risk of death (HR: 4.34; 95% CI: 1.74-10.84) compared to patients with NLR < 3.82 and with NLR ≥3.82 and ≤8.30 (HR: 2.89; 95% CI: 1.32-6.36). Furthermore, on multivariable analysis, NLR > 8.30 independently correlated with increased mortality. In patients with solid malignancies with COVID-19, an NLR > 8.3 is associated with …

Electrophysiological Normative Responses To Emotional, Neutral, And Cigarette-Related Images, Francesco Versace, Nicola Sambuco, Menton M Deweese, Paul M Cinciripini

Faculty, Staff and Student Publications

To create reproducible emotional probes, affective scientists rely on sets of standardized pictures that are normed using subjective ratings of valence and emotional arousal. However, when emotional responses are investigated using neurophysiological measures, it might be more appropriate to select pictures integrating information from normative subjective reports and normative neurophysiological responses. Here, we provide electrophysiological normative responses for 323 emotional pictures (215 from the IAPS) covering a wide range of categories (erotica, romantic, appetizing foods, landscapes, people engaged in mundane activities, household objects, disgusting objects, accidents, sad people, violence, mutilations, and cigarette-related contents). Event-related potentials (ERPs) and subjective ratings of …

Dosimetric Response Of Gafchromic™ Ebt-Xd Film To Therapeutic Protons, Fada Guan, Xiaochun Wang, Ming Yang, Emily Draeger, Dae Han, Kiminori Iga, Fanqing Guo, Luis Perles, Yuting Li, Narayan Sahoo, Radhe Mohan, Zhe Chen

Faculty, Staff and Student Publications

The EBT-XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared with its predecessor models. This characteristic has made EBT-XD films suitable for high-dose applications, such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra-high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT-XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot-scanning proton beam was used to study LET dependence at three dose-averaged LET values of 1.0 keV/μm, 3.6 keV/μm, and 7.6 …

The Effect Direction Should Be Taken Into Account When Assessing Small-Study Effects, Zhuo Meng, Chong Wu, Lifeng Lin

Faculty, Staff and Student Publications

OBJECTIVE: Studies with statistically significant results are frequently more likely to be published than those with non-significant results. This phenomenon leads to publication bias or small-study effects and can seriously affect the validity of the conclusion from systematic reviews and meta-analyses. Small-study effects typically appear in a specific direction, depending on whether the outcome of interest is beneficial or harmful, but this direction is rarely taken into account in conventional methods.

METHODS: We propose to use directional tests to assess potential small-study effects. The tests are built on a one-sided testing framework based on the existing Egger's regression test. We …

Mutant Npm1 Hijacks Transcriptional Hubs To Maintain Pathogenic Gene Programs In Acute Myeloid Leukemia, Xue Qing David Wang, Dandan Fan, Qinyu Han, Yiman Liu, Hongzhi Miao, Xinyu Wang, Qinglan Li, Dong Chen, Haley Gore, Pamela Himadewi, Gerd P Pfeifer, Tomasz Cierpicki, Jolanta Grembecka, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang

Faculty, Staff and Student Publications

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes—HOXA/B cluster genes and MEIS1. NPM1c sustains …

18f-Fdg Pet/Ct Prediction Of Treatment Outcomes In Human Papillomavirus–Positive, Locally Advanced Oropharyngeal Cancer Patients Receiving Deintensified Therapy: Results From Nrg-Hn002, Rathan M Subramaniam, Lyudmila Demora, Min Yao, Sue S Yom, Maura Gillison, Jimmy J Caudell, John Waldron, Ping Xia, Christine H Chung, Minh Tam Truong, Michelle Echevarria, Jason W Chan, Jessica L Geiger, Loren Mell, Samantha Seaward, Wade L Thorstad, Jonathan Jay Beitler, Khalil Sultanem, Diagjin Blakaj, Quynh-Thu Le

Faculty, Staff and Student Publications

The purpose of this study was to determine the negative predictive value (NPV) of a 12- to 14-wk posttreatment PET/CT for 2-y progression-free survival (PFS) and locoregional control (LRC) in patients with p16-positive locoregionally advanced oropharyngeal cancer (LA-OPC). Study was a secondary endpoint in NRG-HN002, a noncomparative phase II trial in p16-positive LA-OPC, stage T1-T2, N1-N2b or T3, N0-N2b, and ≤10 pack-year smoking. Patients were randomized in a 1:1 ratio to reduced-dose intensity-modulated radiotherapy (IMRT) with or without cisplatin. Methods: PET/CT scans were reviewed centrally. Tumor response evaluations for the primary site, right neck, and left neck were performed using …

Medicaid Expansion And Postoperative Mortality In Women With Gynecologic Cancer: A Difference-In-Difference Analysis, Sarah P Huepenbecker, Shuangshuang Fu, Charlotte C Sun, Hui Zhao, Kristin M Primm, Sharon H Giordano, Larissa A Meyer

Faculty, Staff and Student Publications

BACKGROUND: The association between Medicaid expansion and postoperative mortality after surgery for gynecologic cancer is unknown. Our objective was to compare 30- and 90-day postoperative mortality after gynecologic cancer surgery before and after 2014 in states that did and did not expand Medicaid.

METHODS: We searched the National Cancer Database for women aged 40-64 years old between 2010 and 2016 who underwent surgery for a primary gynecologic malignancy. We used pre/post and quasi-experimental difference-in-difference (DID) multivariable logistic regressions to evaluate mortality pre-2014 (2010-2013) and post-2014 (2014-2016) for states that did and did not expand Medicaid in January 2014. We completed …

Deep Learning-Based Pathology Image Analysis Predicts Cancer Progression Risk In Patients With Oral Leukoplakia, Xinyi Zhang, Frederico O Gleber-Netto, Shidan Wang, Roberta Rayra Martins-Chaves, Ricardo Santiago Gomez, Nadarajah Vigneswaran, Arunangshu Sarkar, William N William, Vassiliki Papadimitrakopoulou, Michelle Williams, Diana Bell, Doreen Palsgrove, Justin Bishop, John V Heymach, Ann M Gillenwater, Jeffrey N Myers, Renata Ferrarotto, Scott M Lippman, Curtis Rg Pickering, Guanghua Xiao

Faculty, Staff and Student Publications

BACKGROUND: Oral leukoplakia (OL) is associated with an increased risk for oral cancer (OC) development. Prediction of OL cancer progression may contribute to decreased OC morbidity and mortality by favoring early intervention. Current OL progression risk assessment approaches face large interobserver variability and is weakly prognostic. We hypothesized that convolutional neural networks (CNN)-based histology image analyses could accelerate the discovery of better OC progression risk models.

METHODS: Our CNN-based oral mucosa risk stratification model (OMRS) was trained to classify a set of nondysplastic oral mucosa (OM) and a set of OC H&E slides. As a result, the OMRS model could …

On Target Methods To Induce Abscopal Phenomenon For Off-Target Effects: From Happenstance To Happenings, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Although the "abscopal phenomenon" has been described several decades ago, this phenomenon lately has been obtaining momentous traction with the dawn of immune-based therapies. There has been increased cross talk among radiation oncologists, oncologists and immunologists and consequently a surge in the number of prospective clinical trials. This must be coupled with translation work from these clinical trials to aid in eventual identification of patients who may benefit. Abscopal effects may be induced by local and systemic methods, conventional radiotherapy, particle radiation, radionucleotide methods, cryoablation and brachytherapy. These approaches have all been reported to be stimulate abscopal effect. Immune induction …

Evaluating Bone Marrow Dosimetry With The Addition Of Bone Marrow Structures To The Medical Internal Radiation Dose Phantom, Kristine L Ferrone, Charles E Willis, Fada Guan, Jingfei Ma, Leif E Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Background: Reliable estimates of radiation dose to bone marrow are critical to understanding the risk of radiation-induced cancers. Although the medical internal radiation dose phantom is routinely used for dose estimation, bone marrow is not defined in the phantom. Consequently, methods of indirectly estimating bone marrow dose have been implemented based on dose to surrogate volumes or average dose to soft tissue.

Methods: In this study, new bone marrow structures were implemented and evaluated to the medical internal radiation dose phantom in geant4, offering improved fidelity. The dose equivalent to the bone marrow was calculated across medical, occupational, and space …

Frontline Combination Of Ponatinib And Hyper-Cvad In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: 80-Months Follow-Up Results, Hagop Kantarjian, Nicholas J Short, Nitin Jain, Koji Sasaki, Xuelin Huang, Fadi G Haddad, Issa Khouri, Courtney D Dinardo, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Partow Kebriaei, Rebecca Garris, Sanam Loghavi, Jeffrey Jorgensen, Monica Kwari, Susan O'Brien, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

Background:

The combination of ponatinib, a third generation BCR::ABL1 tyrosine kinase inhibitor (TKI), with Hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for SCT in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients followed with longer follow-up would establish this regimen as a new standard of care.

Methods:

Adults with newly diagnosed Ph-positive ALL were treated with the Hyper-CVAD regimen. Ponatinib was added as 45 mg daily x 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily …

Disruption Of Gcn2 Pathway Aggravates Vascular And Parenchymal Remodeling During Pulmonary Fibrosis, Diana Santos-Ribeiro, Marylène Lecocq, Michèle De Beukelaer, Stijn Verleden, Caroline Bouzin, Jérôme Ambroise, Peter Dorfmuller, Yousef Yakoub, François Huaux, Rozenn Quarck, Harry Karmouty-Quintana, Maria-Rosa Ghigna, Juliette Bignard, Sophie Nadaud, Florent Soubrier, Sandrine Horman, Frederic Perros, Laurent Godinas, Charles Pilette

Faculty, Staff and Student Publications

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the …

Customizable Landmark-Based Field Aperture Design For Automated Whole-Brain Radiotherapy Treatment Planning, Yao Xiao, Carlos Cardenas, Dong Joo Rhee, Tucker Netherton, Lifei Zhang, Callistus Nguyen, Raphael Douglas, Raymond Mumme, Stephen Skett, Tina Patel, Chris Trauernicht, Caroline Chung, Hannah Simonds, Ajay Aggarwal, Laurence Court

Faculty, Staff and Student Publications

Purpose: To develop and evaluate an automated whole-brain radiotherapy (WBRT) treatment planning pipeline with a deep learning-based auto-contouring and customizable landmark-based field aperture design.

Methods: The pipeline consisted of the following steps: (1) Auto-contour normal structures on computed tomography scans and digitally reconstructed radiographs using deep learning techniques, (2) locate the landmark structures using the beam's-eye-view, (3) generate field apertures based on eight different landmark rules addressing different clinical purposes and physician preferences. Two parallel approaches for generating field apertures were developed for quality control. The performance of the generated field shapes and dose distributions were compared with the original …

Clinical Outcomes Of Combined Cervical And Transthoracic Surgical Approaches In Patients With Advanced Thyroid Cancer, Jared A Shenson, Mark E Zafereo, Mark Lee, Kevin J Contrera, Lei Feng, Mongkol Boonsripitayanon, Neil Gross, Ryan Goepfert, Anastasios Maniakas, Jennifer Rui Wang, Libby Grubbs, Ara Vaporciyan, Wayne Hofstetter, Stephen Swisher, Reza Mehran, David Rice, Boris Sepesi, Mara Antonoff, Maria Cabanillas, Naifa Busaidy, Ramona Dadu, Natalie L Silver

Faculty, Staff and Student Publications

Background: Advanced thyroid disease involving the mediastinum may be managed surgically with a combined transcervical and transthoracic approach. Contemporary analysis of this infrequently encountered cohort will aid the multidisciplinary team in personalizing treatment approaches.

Methods: Retrospective review of patients undergoing combined transcervical and transthoracic surgery for thyroid cancer at a single high-volume institution from 1994 to 2015.

Results: Thirty-eight patients with median age 59 years (range 28-76) underwent surgery without perioperative mortality. Most patients had primary disease. A majority had distant metastases outside the mediastinum but had locoregionally curable disease. Common complications were temporary (39%) and permanent (18%) hypoparathyroidism, and …

Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth And Metabolic Reprogramming Leading To Chemoresistance, Sumeet Solanki, Katherine Sanchez, Varun Ponnusamy, Vasudha Kota, Hannah N Bell, Chun-Seok Cho, Allison H Kowalsky, Michael Green, Jun Hee Lee, Yatrik M Shah

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid-sensing GTPase activity towards Rags (GATOR). The role of amino acid-sensing pathways in CRC is unclear.

METHODS: Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic …

An Extension Of Estimating Equations To Model Longitudinal Medical Cost Trajectory With Medicare Claims Data Linked To Seer Cancer Registry, Shikun Wang, Jing Ning, Ying Xu, Ya-Chen Tina Shih, Y U Shen, Liang Li

Faculty, Staff and Student Publications

Insurance claims data is an increasingly important health policy research resource, given its longitudinal assessment of cancer care clinical outcomes. Population-level information on medical cost trajectory from disease diagnosis to terminal events, such as death, specifically interests policy makers. Estimating the mean cost trajectory has statistical challenges. The shape of the trajectory is usually highly nonlinear with varying durations, depending on the diagnosis-to-death population time distribution. The terminal event may be right censored, resulting in missing subsequent costs. Medical costs often have skewed distributions with zero-inflation and heteroscedasticity, which may not fit well with the commonly used parametric family of …

Adding The X-Ray Bragg Reflection Physical Process In Crystal To The Geant4 Monte Carlo Simulation Toolkit, Part I: Reflection From A Crystal Slab, Fada Guan, Makoto Asai, Dirk A Bartkoski, Michael Kleckner, Ze'ev Harel, Mohammad Salehpour

Faculty, Staff and Student Publications

X-ray diffraction from a solid crystal shows the wave nature of photons. It is an important electromagnetic (EM) physics process when X-ray photons interact with a crystal. Bragg diffraction, often called Bragg reflection, is a special case of the general form of X-ray diffraction, known as Laue diffraction. When the Bragg's law is met, the incident photon beam is reflected from the crystal plane behaving as a specular reflection at the Bragg angle. However, the Bragg reflection physical process has not been integrated into the general-purpose Monte Carlo simulation toolkit Geant4 for particle physics. In the current study, we developed …

Surgical Results Of The Lung Cancer Mutation Consortium 3 Trial: A Phase Ii Multicenter Single-Arm Study To Investigate The Efficacy And Safety Of Atezolizumab As Neoadjuvant Therapy In Patients With Stages Ib-Select Iiib Resectable Non-Small Cell Lung Cancer, Valerie W Rusch, Alan Nicholas, G Alexander Patterson, Salama N Waqar, Eric M Toloza, Eric B Haura, Dan J Raz, Karen L Reckamp, Robert E Merritt, Dwight H Owen, David J Finley, Ciaran J Mcnamee, Justin D Blasberg, Edward B Garon, John D Mitchell, Robert C Doebele, Frank Baciewicz, Misako Nagasaka, Harvey I Pass, Katja Schulze, Ann Johnson, Paul A Bunn, Bruce E Johnson, Mark G Kris, David J Kwiatkowski, Ignacio I Wistuba, Jamie E Chaft, David P Carbone, Jay M Lee

Faculty, Staff and Student Publications

Objective: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.

Methods: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was …

Systemic Lupus Erythematosus And Mortality In Elderly Patients With Early Breast Cancer, Sebastian Bruera, Xiudong Lei, Xerxes Pundole, Hui Zhao, Sharon H Giordano, Surabhi Vinod, Maria E Suarez-Almazor

Faculty, Staff and Student Publications

Objective: Patients with cancer and systemic lupus erythematosus (SLE) may have worse outcomes than those without SLE, given their comorbidities. We examined survival in elderly women with breast cancer (BC) and SLE and hypothesized that survival would be decreased compared with women with BC but without SLE.

Methods: We identified patients with BC and SLE and patients with BC without SLE in the Texas Cancer Registry and Surveillance, Epidemiology, and End Results, linked to Medicare claims. Overall survival (OS) was estimated after matching (age and cancer stage) and in multivariable Cox proportional hazards models adjusting for other cancer characteristics, treatment, …

Longitudinal Evaluation Of Serum Micrornas As Biomarkers For Neuroblastoma Burden And Therapeutic P53 Reactivation, Alan Van Goethem, Jill Deleu, Nurten Yigit, Celine Everaert, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Fjoralba Zeka, Fleur Demuynck, Eveline Barbieri, Frank Speleman, Pieter Mestdagh, Jason Shohet, Jo Vandesompele, Tom Van Maerken

Faculty, Staff and Students Publications

Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed …

High Molecular Diagnostic Yields And Novel Phenotypic Expansions Involving Syndromic Anorectal Malformations, Raymond Belanger Deloge, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% …

Interaction Between Tumor Cell Tnfr2 And Monocyte Membrane-Bound Tnf-Α Triggers Tumorigenic Inflammation In Neuroblastoma, Julie A Tomolonis, Xin Xu, Kshiti H Dholakia, Chunchao Zhang, Linjie Guo, Amy N Courtney, Siyue Wang, Julien Balzeau, Gabriel A Barragán, Gengwen Tian, Erica J Di Pierro, Leonid S Metelitsa

Faculty, Staff and Students Publications

BACKGROUND: Tumor progression and resistance to therapy in children with neuroblastoma (NB), a common childhood cancer, are often associated with infiltration of monocytes and macrophages that produce inflammatory cytokines. However, the mechanism by which tumor-supportive inflammation is initiated and propagated remains unknown. Here, we describe a novel protumorigenic circuit between NB cells and monocytes that is triggered and sustained by tumor necrosis factor alpha (TNF-α).

METHODS: We used NB knockouts (KOs) of TNF-α and

RESULTS: We found that NB expression of TNFR2 and monocyte membrane-bound tumor necrosis factor alpha is required for monocyte activation and interleukin (IL)-6 production, while NB …

Immune Checkpoint Gene Vsir Predicts Patient Prognosis In Acute Myeloid Leukemia And Myelodysplastic Syndromes, Kevin Yao, Emily Zhou, Evelien Schaafsma, Baoyi Zhang, Chao Cheng

Faculty, Staff and Students Publications

Background: Immune checkpoint proteins play critical functions during the immune response to cancer and have been targeted by immune checkpoint blockade therapy. V-domain Ig suppressor of T cell activation (VSIR) is one of these immune checkpoint genes and has been investigated extensively in recent years due to its conflicting roles in cancer immunity. Specifically, in acute myeloid leukemia (AML), the prognostic value of VSIR is debated.

Results: In both patient tumor samples and cancer cell lines we find that VSIR has the highest expression in AML out of all cancer types and, in AML, has the highest expression out of …

Phase Separation In Biology And Disease; Current Perspectives And Open Questions, Steven Boeynaems, Shasha Chong, Jörg Gsponer, Liam Holt, Dragomir Milovanovic, Diana M Mitrea, Oliver Mueller-Cajar, Bede Portz, John F Reilly, Christopher D Reinkemeier, Benjamin R Sabari, Serena Sanulli, James Shorter, Emily Sontag, Lucia Strader, Jeanne Stachowiak, Stephanie C Weber, Michael White, Huaiying Zhang, Markus Zweckstetter, Shana Elbaum-Garfinkle, Richard Kriwacki

Faculty, Staff and Students Publications

In the past almost 15 years, we witnessed the birth of a new scientific field focused on the existence, formation, biological functions, and disease associations of membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories [reviewed in [1–3]] supported a model wherein biomolecular condensates associated with diverse biological processes form through the process of phase separation. These and other findings that followed have revolutionized our understanding of how biomolecules are organized in space and time within cells to perform myriad biological functions, including cell fate determination, signal transduction, endocytosis, regulation …

Novel And Replicated Clinical And Genetic Risk Factors For Toxicity From High-Dose Methotrexate In Pediatric Acute Lymphoblastic Leukemia, Mark Zobeck, M Brooke Bernhardt, Kala Y Kamdar, Karen R Rabin, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

STUDY OBJECTIVE: Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.

DESIGN: We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m

MAIN RESULTS: Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance.

CONCLUSIONS: These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

Determinants And Mechanisms Of The Low Fusogenicity And High Dependence On Endosomal Entry Of Omicron Subvariants, Panke Qu, John P Evans, Chaitanya Kurhade, Cong Zeng, Yi-Min Zheng, Kai Xu, Pei-Yong Shi, Xuping Xie, Shan-Lu Liu

Faculty, Staff and Student Publications

The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced …

Allosteric Autoregulation Of Dna Binding Via A Dna-Mimicking Protein Domain: A Biophysical Study Of Znf410-Dna Interaction Using Small Angle X-Ray Scattering, Gundeep Kaur, Ren Ren, Michal Hammel, John R Horton, Jie Yang, Yu Cao, Chenxi He, Fei Lan, Xianjiang Lan, Gerd A Blobel, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (ZFs), surrounded by uncharacterized N- and C-terminal regions. Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of the isolated DNA binding ZF array, both in vitro and in cells. AlphaFold predicts a partially-folded N-terminal subdomain that includes a 30-residue long helix, preceded by a hairpin loop rich in acidic (aspartate/glutamate) and serine/threonine residues. This hairpin loop is predicted by AlphaFold to …

Jaml Immunotherapy Targets Recently Activated Tumor-Infiltrating Cd8+ T Cells, Simon Eschweiler, Alice Wang, Ciro Ramírez-Suástegui, Adrian Von Witzleben, Yingcong Li, Serena J Chee, Hayley Simon, Monalisa Mondal, Matthew Ellis, Gareth J Thomas, Vivek Chandra, Christian H Ottensmeier, Pandurangan Vijayanand

Faculty, Staff and Student Publications

Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly …

Prognostic Significance Of Acellular Mucin In Patients Undergoing Cytoreductive Surgery And Hyperthermic Intraperitoneal Chemotherapy (Crs/Hipec) For Appendiceal Neoplasms, Derek J Erstad, Kristen A Robinson, Karen Beaty, Safia Rafeeq, Yi-Ju Chiang, Kanwal Raghav, John P Shen, Michael J Overman, Wai Chin Foo, Melissa W Taggart, Paul F Mansfield, Richard E Royal, Keith F Fournier, Christopher P Scally

Faculty, Staff and Student Publications

Introduction: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients.

Methods: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed.

Results: Median age was 51 years, 70% were female, …