Genetic Phenomena Commons^™

Burden Of Seasonal Human Coronavirus Infections In Hematopoietic Cell Transplant Recipients, Fareed Khawaja, Terri Lynn Shigle, Layale Yaghi, May Daher, Jeremy L Ramdial, Ella Ariza-Heredia, Ying Jiang, Roy F Chemaly

Faculty, Staff and Student Publications

Background: Community respiratory viruses, such as seasonal human coronavirus (HCoV), commonly infect hematopoietic cell transplant (HCT) recipients. Recognizing the risk factors and outcomes of HCoV infections in HCT recipients is essential for the future development of potentially lifesaving therapeutics.

Methods: We performed a retrospective review of all HCoV-infected HCT recipients from September 1, 2015 to August 31, 2017, at our institution. Patients were classified with upper respiratory tract infection (URI) or lower respiratory infection (LRI) based on predefined definitions for respiratory viral infections in HCT recipients. Patient data were collected to identify risk factors for HCoV LRI, and to calculate …

Mechanical Regulation Of Macrophage Metabolism By Allograft Inflammatory Factor 1 Leads To Adverse Remodeling After Cardiac Injury, Matthew Deberge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P Sullivan, Swapna Patil, Bo Ryung Lee, Minori I Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M Van Der Laan, Hans W M Niessen, Xunrong Luo, Nicholas E S Sibinga, Edward B Thorp

Faculty, Staff and Student Publications

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of …

Continued Positive Job Search Experience For New Pathologists Seeking First Employment During The Covid-19 Pandemic (2020-2022), Julie Katz Karp, Amanda Lofgreen, Kristen Johnson, Melissa R George, Stephanie Barak, Bronwyn H Bryant, Mary P Berg, John M Childs, Barbara E C Knollman-Ritschel, Victor G Prieto, Kristie L White, Cindy B Mccloskey

Faculty, Staff and Student Publications

Context.—: As pathologists retire and leave the field, it is critical to accurately capture employment trends for new-in-practice pathologists. There is always interest in the job market for newly graduated pathology trainees and prospective pathology trainees, but it is unclear how the COVID-19 pandemic may have affected the job search experience.

Objective.—: To provide an update on trends gleaned from a survey of pathology graduates' job search experiences during the COVID-19 pandemic.

Design.—: We analyzed data from an annual job search survey sent by the College of American Pathologists Graduate Medical Education Committee between 2020 and 2022 to College of …

Partial Agonism In Heteromeric Gluk2/Gluk5 Kainate Receptor, Nabina Paudyal, Anindita Das, Elisa Carrillo, Vladimir Berka, Vasanthi Jayaraman

Faculty, Staff and Student Publications

Kainate receptors are a subtype of ionotropic glutamate receptors that form transmembrane channels upon binding glutamate. Here, we have investigated the mechanism of partial agonism in heteromeric GluK2/K5 receptors, where the GluK2 and GluK5 subunits have distinct agonist binding profiles. Using single-molecule Förster resonance energy transfer, we found that at the bi-lobed agonist-binding domain, the partial agonist AMPA-bound receptor occupied intermediate cleft closure conformational states at the GluK2 cleft, compared to the more open cleft conformations in apo form and more closed cleft conformations in the full agonist glutamate-bound form. In contrast, there is no significant difference in cleft closure …

Anti-Cd137 Agonist Antibody-Independent And Clinically Feasible Preparation Of Tumor-Infiltrating Lymphocytes From Soft Tissue Sarcoma And Osteosarcoma, Yining Jin, Zhiliang Jia, Xueqing Xia, Nancy B Gordon, Joseph A Ludwig, Neeta Somaiah, Shulin Li

Faculty, Staff and Student Publications

Background: Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors.

Methods: We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist …

Combining Biology-Based And Mri Data-Driven Modeling To Predict Response To Neoadjuvant Chemotherapy In Patients With Triple-Negative Breast Cancer, Casey E Stowers, Chengyue Wu, Zhan Xu, Sidharth Kumar, Clinton Yam, Jong Bum Son, Jingfei Ma, Jonathan I Tamir, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with limited targeted treatment options, heterogeneous treatment response, and high risk of early recurrence. Artificial intelligence (AI) has rapidly emerged as a powerful tool to address key clinical challenges in TNBC across diagnosis, treatment response assessment, and prognosis. Diagnostic and staging challenges persist due to variable imaging features in TNBC and limitations in conventional modalities, increasing the risk of delayed detection. Predicting response to neoadjuvant systemic therapy remains difficult, as patient responses are heterogeneous, and existing clinical markers provide limited early predictive value. Prognostication in TNBC is similarly constrained …

Development Of An H&E On-Block Staining Technique For Collagen Detection In Cryo-Fluorescence Tomography Imaging Of Frozen Breast Tissue Samples, Erin P Snoddy, Tien T Tang, Natalie Fowlkes, Thomas Huynh, Kari J Brewer Savannah, Alejandro Contreras, Gregory Reece, Kristy K Brock

Faculty, Staff and Student Publications

Hematoxylin and eosin (H&E) staining is widely considered to be the gold-standard diagnostic tool for histopathology evaluation. However, the fatty nature of some tissue types, such as breast tissue, presents challenges with cryo-sectioning, often resulting in artifacts that can make histopathologic interpretation and correlation with other imaging modalities virtually impossible. We present an optimized on-block H&E staining technique that improves contrast for identifying collagenous stroma during cryo-fluorescence tomography (CFT) sectioning. In this prospective study, we embedded four breast specimens with confirmed ligaments from a bilateral mastopexy in an optimal cutting temperature block. Two of the samples were processed on a …

Wnt7a, Naomi M Calhoun, Richard R Behringer

Faculty, Staff and Student Publications

WNT7A regulates numerous developmental processes. It can activate canonical and non-canonical signaling depending on context. It is expressed in the developing central nervous system, limb buds, reproductive organs, and other tissues. Spontaneous and targeted Wnt7a mutations in mouse models resulted in abnormal limbs, defects in male and female reproductive tract organs, infertility, and defects in cerebellar axon remodeling. In zebrafish, wnt7aa mutants exhibited neurogenesis and angiogenesis defects in the central nervous system. In humans, recessive WNT7A missense and nonsense mutations resulted in severe limb and pelvic bone defects. Alterations in WNT7A expression correlated with multiple types of cancer.

Disparities In Breast Cancer Detection Modalities And Outcomes Among Geriatric Female Cancer Patients, Zhaoli Liu, Mathilda Nicot-Cartsonis, Biai D E Digbeu, Daoqi Gao, Sharon H Giordano, Yong-Fang Kuo

Faculty, Staff and Student Publications

This study examined racial and geographic disparities in breast cancer detection modalities (screening-, diagnostic-, or non-mammography) with cancer stage and mortality. A retrospective cohort study was conducted using Texas Cancer Registry-Medicare linkage data for geriatric women. Cancers detected through screening and diagnostic mammography had 43 % (95 % CI, 39 %-46 %, p < .0001) and 31 % (95 % CI, 27 %-35 %, p < .0001) lower all-cause mortality, and 49 % (95 % CI, 41 %-54 %, p < .0001) and 37 % (95 % CI, 32 %-43 %, p < .0001) lower cancer-specific mortality, respectively, compared to non-mammography-detected breast cancers. Patients from rural areas were 17 % (95 % CI, 1.06 - 1.29) more likely to be diagnosed with mid- (p = .0023) and advanced stage (p = .003) cancers compared to their urban counterparts. Racial or geographic disparities in cancer detection modalities with associated mortality no longer exist after adjusting for covariates. Healthcare professionals can leverage these findings to promote rural cancer health equity.

A Cytotoxic Peptide-Drug Conjugate For Tumor-Specific Delivery Of Co-Injected Molecules, Norio Miyamura, Chisato M Yamazaki, Yasuaki Anami, Kyoji Tsuchikama, Kazuki N Sugahara

Faculty, Staff and Student Publications

An ideal cancer therapy enhances anti-tumor effects while minimizing side effects. iRGD, a non-cytotoxic peptide that activates a tumor-specific molecular transport machinery, promotes the penetration of co-injected drugs into tumor tissues. Clinical trials have demonstrated its potential as a tumor-specific delivery scaffold and potentiator of anti-cancer agents. In this study, we synthesized an iRGD conjugate containing monomethyl auristatin F (MMAF), a highly toxic antimitotic agent, and characterized its dual function as a tumor-specific cytotoxic agent and co-injected drug delivery scaffold. The iRGD-MMAF conjugate internalized and killed cultured tumor cells in an αv integrin-dependent manner. When injected systemically, iRGD-MMAF homed selectively …

Integrating Multi-Omics Data To Uncover Prostate Tissue Dna Methylation Biomarkers And Target Genes For Prostate Cancer Risk, Shuai Liu, Jingjing Zhu, Dylan Green, Hua Zhong, Quan Long, Chong Wu, Liang Wang, Youping Deng, Lang Wu

Faculty, Staff and Student Publications

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. …

Three-Dimensional Deep Learning Normal Tissue Complication Probability Model To Predict Late Xerostomia In Patients With Head And Neck Cancer, Hung Chu, Suzanne P M De Vette, Hendrike Neh, Nanna M Sijtsema, Roel J H M Steenbakkers, Amy Moreno, Johannes A Langendijk, Peter M A Van Ooijen, Clifton D Fuller, Lisanne V Van Dijk

Faculty, Staff and Student Publications

Purpose: Conventional normal tissue complication probability (NTCP) models for patients with head and neck cancer are typically based on single-value variables, which, for radiation-induced xerostomia, are baseline xerostomia and mean salivary gland doses. This study aimed to improve the prediction of late xerostomia by using 3-dimensional information from radiation dose distributions, computed tomography imaging, organ-at-risk segmentations, and clinical variables with deep learning (DL).

Methods and materials: An international cohort of 1208 patients with head and neck cancer from 2 institutes was used to train and twice validate DL models (deep convolutional neural network, EfficientNet-v2, and ResNet) with 3-dimensional dose distribution, …

Reproducibility And Repeatability Of 18f-(2s, 4r)-4-Fluoroglutamine Pet Imaging In Preclinical Oncology Models, Gregory D Ayers, Allison S Cohen, Seong-Woo Bae, Xiaoxia Wen, Alyssa Pollard, Shilpa Sharma, Trey Claus, Adria Payne, Ling Geng, Ping Zhao, Mohammed Noor Tantawy, Seth T Gammon, H Charles Manning

Faculty, Staff and Student Publications

Introduction: Measurement of repeatability and reproducibility (R&R) is necessary to realize the full potential of positron emission tomography (PET). Several studies have evaluated the reproducibility of PET using 18F-FDG, the most common PET tracer used in oncology, but similar studies using other PET tracers are scarce. Even fewer assess agreement and R&R with statistical methods designed explicitly for the task. 18F-(2S, 4R)-4-fluoro-glutamine (18F-Gln) is a PET tracer designed for imaging glutamine uptake and metabolism. This study illustrates high reproducibility and repeatability with 18F-Gln for in vivo research.

Methods: Twenty mice bearing colorectal cancer cell line xenografts were injected with ~9 …

Patterns Of Loco-Regional Progression And Patient Outcomes After Definitive-Dose Radiation Therapy For Anaplastic Thyroid Cancer, Julianna K Bronk, Alexander Augustyn, Abdallah S R Mohamed, C David Fuller, Adam S Garden, Amy C Moreno, Anna Lee, William H Morrison, Jack Phan, Jay P Reddy, David I Rosenthal, Michael T Spiotto, Steven J Frank, Ramona Dadu, Naifa Busaidy, Mark Zafereo, Jennifer R Wang, Anastasios Maniakas, Renata Ferrarotto, Priyanka C Iyer, Maria E Cabanillas, G Brandon Gunn

Faculty, Staff and Student Publications

Background: The aim of this study is to characterize the patterns of loco-regional progression (LRP) and outcomes after definitive-dose intensity modulated radiation therapy (IMRT) for anaplastic thyroid cancer (ATC) with macroscopic neck disease at the time of IMRT.

Methods: Disease/treatment characteristics and outcomes for patients with unresected or incompletely resected ATC who received IMRT (≥45 Gy) were retrospectively reviewed. For those with LRP after IMRT, progressive/recurrent gross tumor volumes (rGTV) were contoured on diagnostic CTs and co-registered with initial planning CTs using deformable image registration. rGTVs were classified based on established spatial/dosimetric criteria.

Results: Forty patients treated between 2010-2020 formed …

Selective Inhibition Of Canonical Stat3 Signaling Suppresses K-Ras Mutant Lung Tumorigenesis And Reinvigorates Anti-Tumor Immunity, Michael J Clowers, Zahraa Rahal, Sung-Nam Cho, Avantika Krishna, Bo Yuan, Leticia G Hamana Zorrilla, T Kris Eckols, Moses M Kasembeli, Samuel Liu, Stephen Peng, Marco Ramos-Castaneda, Annamarie L Thompson, Carlos Ignacio Rodriguez Reyna, Katherine E Larsen, Maria T Grimaldo, Shanshan Deng, Nastaran Karimi, Cody Chou, Walter V Velasco, Melody Zarghooni, Sayan Alekseev, Luisa M Solis Soto, Edwin J Ostrin, Humam Kadara, Suhendan Ekmekcioglu, David J Tweardy, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

Introduction: K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. One of the lynchpins of chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3).

Methods: Here, we tested the anti-tumor and early immunotherapeutic efficacy of TTI-101, a selective small-molecule inhibitor of canonical STAT3 signaling, in a K-rasG12D mutant lung cancer mouse model (CC-LR).

Results: Treatment of CC-LR mice with TTI-101 resulted in reduced …

Dedifferentiated Liposarcomas Treated With Immune Checkpoint Blockade: The Md Anderson Experience, Madeline B Torres, Cheuk Hong Leung, Marianne Zoghbi, Rossana Lazcano, Davis Ingram, Khalida Wani, Emily Z Keung, M Alejandra Zarzour, Christopher P Scally, Kelly K Hunt, Anthony Conley, Andrew J Bishop, B Ashleigh Guadagnolo, Ahsan Farooqi, Devarati Mitra, Alison K Yoder, Michael S Nakazawa, Dejka Araujo, Andrew Livingston, Ravin Ratan, Shreyaskumar Patel, Vinod Ravi, Alexander J Lazar, Christina L Roland, Neeta Somaiah, Elise F Nassif Haddad

Faculty, Staff and Student Publications

Background: Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.

Methods: We conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between …

Inhibition Of Nitric Oxide Synthase Transforms Carotid Occlusion-Mediated Benign Oligemia Into De Novo Large Cerebral Infarction, Ha Kim, Jinyong Chung, Jeong Wook Kang, Dawid Schellingerhout, Soo Ji Lee, Hee Jeong Jang, Inyeong Park, Taesu Kim, Dong-Seok Gwak, Ji Sung Lee, Sung-Ha Hong, Kang-Hoon Je, Hee-Joon Bae, Joohon Sung, Eng H Lo, James Faber, Cenk Ayata, Dong-Eog Kim

Faculty, Staff and Student Publications

No abstract provided.

Heterologous Prime-Pull Mucosal Vaccination With An Adjuvanted Rbd Vaccine Elicits Robust Iga Production And Protects Against Sars-Cov-2, Allyson H Hirsch, Calder R Ellsworth, William A Lewis, Ryan Craig, Amy E Meyer, Jonatan Maldonado, Frania Ramirez Lopez, Syamala Rani Thimmiraju, James B Mclachlan, Xuebin Qin, Nicholas J Maness, Jeroen Pollet, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Lisa A Morici

Faculty, Staff and Students Publications

Despite the efficacy of approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in preventing severe disease and death, breakthrough infections continue to occur in vaccinated individuals, contributing to further viral mutation and spread. These limitations may be attributable to the poor induction of mucosal immunity by parenteral vaccination. Mucosal adjuvants, such as T-vant, can enhance vaccine-induced immune responses through the generation of antigen-specific antibodies and T cells in the respiratory tract. In this study, we evaluated the protective efficacy of adjuvanted SARS-CoV-2 receptor binding domain (RBD) subunit vaccines administered by homologous and heterologous routes. Immunized mice were challenged with …

Monoallelic Expression Can Govern Penetrance Of Inborn Errors Of Immunity, O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema Van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters …

Mixed-Methods Evaluation And Behavior Change Interventions To Improve Hand Hygiene Resources And Practices Among Healthcare Workers In Polyclinics And Health Centers In Belize, 2023, Anh N Ly, Kelsey Mcdavid, Christina Craig, Rosalva Blanco, Vickie Romero, Melissa Diaz-Musa, Francis Morey, Russell Manzanero, Gerhaldine Morazan, Makenzie Towery, Anna Impellitteri, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Background: Hand hygiene (HH) is an effective public health measure to prevent the spread of infections in healthcare settings. A previous study in Belize showed gaps in HH practices in hospitals and large polyclinics; however, there are limited national data assessing access to and use of HH resources in smaller outpatient primary care facilities, especially in rural areas.

Methods: In February 2023, facility assessments were conducted at 26 health centers and polyclinics in Belize to assess the availability of HH resources. Of these, 12 pilot healthcare facilities (HCF) were selected for additional evaluation, which included observation of HH practices, hand …

A Bayesian Pharmacokinetics Integrated Phase I-Ii Design To Optimize Dose-Schedule Regimes, Mengyi Lu, Ying Yuan, Suyu Liu

Faculty, Staff and Student Publications

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. …

Predicting Kidney Graft Function And Failure Among Kidney Transplant Recipients, Yi Yao, Brad C Astor, Wei Yang, Tom Greene, Liang Li

Faculty, Staff and Student Publications

Background: Graft loss is a major health concern for kidney transplant (KTx) recipients. It is of clinical interest to develop a prognostic model for both graft function, quantified by estimated glomerular filtration rate (eGFR), and the risk of graft failure. Additionally, the model should be dynamic in the sense that it adapts to accumulating longitudinal information, including time-varying at-risk population, predictor-outcome association, and clinical history. Finally, the model should also properly account for the competing risk by death with a functioning graft. A model with the features above is not yet available in the literature and is the focus of …

The Win Ratio Approach In Bayesian Monitoring For Two-Arm Phase Ii Clinical Trial Designs With Multiple Time-To-Event Endpoints, Xinran Huang, Jian Wang, Jing Ning

Faculty, Staff and Student Publications

To assess the preliminary therapeutic impact of a novel treatment, futility monitoring is commonly employed in Phase II clinical trials to facilitate informed decisions regarding the early termination of trials. Given the rapid evolution in cancer treatment development, particularly with new agents like immunotherapeutic agents, the focus has often shifted from objective response to time-to-event endpoints. In trials involving multiple time-to-event endpoints, existing monitoring designs typically select one as the primary endpoint or employ a composite endpoint as the time to the first occurrence of any event. However, relying on a single efficacy endpoint may not adequately evaluate an experimental …

Nos Inhibition Sensitizes Metaplastic Breast Cancer To Pi3k Inhibition And Taxane Therapy Via C-Jun Repression, Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang

Faculty, Staff and Student Publications

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH

Bayesian Nonparametric Model For Heterogeneous Treatment Effects With Zero-Inflated Data, Chanmin Kim, Yisheng Li, Ting Xu, Zhongxing Liao

Faculty, Staff and Student Publications

One goal of precision medicine is to develop effective treatments for patients by tailoring to their individual demographic, clinical, and/or genetic characteristics. To achieve this goal, statistical models must be developed that can identify and evaluate potentially heterogeneous treatment effects in a robust manner. The oft-cited existing methods for assessing treatment effect heterogeneity are based upon parametric models with interactions or conditioning on covariate values, the performance of which is sensitive to the omission of important covariates and/or the choice of their values. We propose a new Bayesian nonparametric (BNP) method for estimating heterogeneous causal effects in studies with zero-inflated …

Orthogonal And Multiplexable Genetic Perturbations With An Engineered Prime Editor And A Diverse Rna Array, Qichen Yuan, Hongzhi Zeng, Tyler C Daniel, Qingzhuo Liu, Yongjie Yang, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M Abramson, Boyang Zhang, Yong Xu, Xue Gao

Faculty, Staff and Students Publications

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation. mvGPT can precisely edit human genome via PE coupled with a prime editing guide RNA and a nicking guide RNA, activate endogenous gene expression …

Cancer Organoids As Reliable Disease Models To Drive Clinical Development Of Novel Therapies, Giovanni Blandino, Ronit Satchi-Fainaro, Ingeborg Tinhofer, Giovanni Tonon, Sarah C Heilshorn, Yong-Jun Kwon, Ana Pestana, Carlotta Frascolla, Luca Pompili, Aurora Puce, Sara Iachettini, Annalisa Tocci, Sofia Karkampouna, Marianna Kruithof-De Julio, Piera Tocci, Nicla Porciello, Klizia Maccaroni, Daniela Rutigliano, Xiling Shen, Gennaro Ciliberto

Faculty, Staff and Student Publications

On September 23-24 (2024) the 6th Workshop IRE on Translational Oncology, titled "Cancer Organoids as Reliable Disease Models to Drive Clinical Development of Novel Therapies," took place at the IRCCS Regina Elena Cancer Institute in Rome. This prominent international conference focused on tumor organoids, bringing together leading experts from around the world.A central challenge in precision oncology is modeling the dynamic tumor ecosystem, which encompasses numerous elements that evolve spatially and temporally. Patient-derived 3D culture models, including organoids, explants, and engineered or bioprinted systems, have recently emerged as sophisticated tools capable of capturing the complexity and diversity of cancer cells …

Parp Inhibition Radiosensitizes Brca1 Wildtype And Mutated Breast Cancer To Proton Therapy, Mariam Ben Kacem, Scott J Bright, Emma Moran, David B Flint, David K J Martinus, Broderick X Turner, Ilsa Qureshi, Rishab Kolachina, Mandira Manandhar, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons …

Optimizing Ewing Sarcoma And Osteosarcoma Biopsy Acquisition: A Children's Oncology Group Bone Tumor Committee Consensus Statement, Matthew S Dietz, Alyaa Al-Ibraheemi, Jessica L Davis, C Matthew Hawkins, Brian T Craig, Roshni Dasgupta, David S Geller, David S Shulman, Sarah Cohen-Gogo, Ajay Gupta, Susan L Whiteway, Emily K Slotkin, Christine M Heske, Safia K Ahmed, Daniel J Indelicato, Catherine M Albert, Nicole Montgomery, Jesse K Sandberg, Holcombe E Grier, Mark Krailo, Michael S Isakoff, Elyssa Rubin, Elizabeth R Lawlor, Steven G Dubois, Leo Mascarenhas, Patrick J Grohar, Odion Binitie, Damon Reed, Katherine Janeway, Ryan D Roberts, Kelly M Bailey

Faculty, Staff and Students Publications

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and …

High Peripheral T Cell Diversity Is Associated With Lower Risk Of Toxicity And Superior Response To Dual Immune Checkpoint Inhibitor Therapy In Patients With Metastatic Nsclc, Mehmet Altan, Ruoxing Li, Ziyi Li, Runzhe Chen, Ajay Sheshadri, Hai T Tran, Latasha Little, Joshua Baguley, Jefferson Sinson, Natalie Vokes, Saumil Gandhi, Mara B Antonoff, Stephen G Swisher, Greg Lizee, Alexandre Reuben, John V Heymach, Jianjun Zhang

Faculty, Staff and Student Publications

INTRODUCTION: Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs.

METHODS: Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869). Blood samples were systematically obtained at baseline (n=107), …