Medical Specialties Commons^™

Evaluation Of Methotrexate Pharmacogenomic Variation To Predict Acute Neurotoxicity In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, M Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

BACKGROUND: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.

METHODS: This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance …

Designing And Implementing Solution-Oriented Team Science Initiatives-A Chronic Pain Example, Nele A Haelterman, Armen N Akopian, Kyle D Allen, Yenisel Cruz-Almeida, Christopher R Donnelly, Brendan Lee, Rebecca Lenzi, Anne-Marie Malfait, Marie Mancini, Maryann E Martone, Joost B Wagenaar, Kim C Worley

Faculty, Staff and Students Publications

Large, collaborative projects that combine researchers from multiple scientific disciplines have become an integral part of the scientific endeavor. While transdisciplinary team science projects hold great potential, they also come with a unique set of challenges compared to monodisciplinary projects. The Science of Team Science (SciTS) field has developed multiple conceptual models and frameworks that guide the design, implementation, and evaluation of team science initiatives to maximize their potential for making breakthrough discoveries and creating solutions for complex problems. While these conceptual models contain a trove of valuable information for successful team science, guidance on how to effectively implement them …

Nanoparticle Contrast Agents For Photon-Counting Computed Tomography: Recent Developments And Future Opportunities, Laxman Devkota, Rohan Bhavane, Cristian T Badea, Eric A Tanifum, Ananth V Annapragada, Ketan B Ghaghada

Faculty, Staff and Students Publications

The clinical availability of photon-counting computed tomography (PCCT) has ushered in a new era of CT imaging. Spectral imaging coupled with superior contrast resolution, and ultrahigh spatial resolution (200 μm) offered by PCCT has the potential to revolutionize value-driven imaging. The potential of multicolor PCCT has generated excitement, and renewed interest, in novel contrast agent development for comprehensive disease interrogation, prediction and monitoring of treatment outcomes. Nanoparticles provide a versatile and powerful platform for the development of next generation contrast agents for spectral PCCT. In this article, we review recent developments and use of nanoparticle contrast agents for PCCT. We …

Assessing The Cardioprotective Effects Of Exercise In Apoe Mouse Models Using Deep Learning And Photon-Counting Micro-Ct, Alex J Allphin, Rohan Nadkarni, Zay Y Han, Darin P Clark, Ketan B Ghaghada, Alexandra Badea, Cristian T Badea

Faculty, Staff and Students Publications

Background: The allelic variations of the apolipoprotein E (APOE) gene play a critical role in regulating lipid metabolism and significantly impact cardiovascular disease risk (CVD). This study aimed to evaluate the impact of exercise on cardiac structure and function in mouse models expressing different APOE genotypes using photon-counting computed tomography (PCCT) and deep learning-based segmentation.

Methods: A total of 140 mice were grouped based on APOE genotype (APOE2, APOE3, APOE4), sex, and exercise regimen. All mice were maintained on a controlled diet to isolate the effects of exercise. Low dose cardiac photon counting micro-CT imaging with intrinsic gating was performed …

Sex Differences In Beneficial And Pathogenic Bacteria In People With Hiv (Pwh) With A History Of Heavy Alcohol Drinking, Aakarsha V Rao, Smita S Ghare, Vasuk Gautam, Kristi L Hoffman, Joseph Petrosino, Kaku So-Armah, Jeffrey H Samet, Gregory J Patts, Debbie M Cheng, Elena Blokhina, Evgeny M Krupitsky, Dmitry Lioznov, Edwin Zvartau, Craig J Mcclain, Hillary Tindle, Matthew S Freiberg, Shirish S Barve

Faculty, Staff and Students Publications

BACKGROUND: HIV-1 infection and hazardous levels of alcohol consumption have been independently linked to gut dysbiosis affecting beneficial butyrate-producing bacteria. However, sex-based differences in the composition and function of gut microbiome of People With HIV (PWH) with a history of heavy alcohol drinking remain undetermined, which is the focus of this study.

METHODS: Cross-sectional study examining structural and functional features of the gut microbiome in PWH between men and women with a history of hazardous alcohol drinking recruited at St. Petersburg, Russia. 16S rDNA sequencing information was used for metataxonomic, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2) …

The Association Of Human Milk Intake And Outcomes In Biliary Atresia, Mary Elizabeth M Tessier, Jeremy M Schraw, Stacey Beer, Sanjiv Harpavat, M Kyle Jensen, John C Magee, Vicky Ng, Michael E Scheurer, Sarah A Taylor, Benjamin L Shneider

Faculty, Staff and Students Publications

Objectives: Human milk intake has many benefits which could influence outcomes in biliary atresia (BA). However, the role of human milk in BA has not been examined. We hypothesized that human milk intake would be associated with improved outcomes in BA.

Methods: We assessed the impact of any human milk (AHM) as compared to formula only (FO) intake before Kasai portoenterostomy (KP) on outcomes in 447 infants with BA using the PROBE database (NCT00061828) post hoc. The primary outcome was clearance of jaundice (COJ = total bilirubin (TB) < 2 mg/dL by 3 months post-KP). Secondary outcomes included 2-year survival with native liver (SNL), bilirubin levels, cholangitis, ascites, and growth. We assessed the fecal microbiome (n = 8) comparing AHM versus FO.

Results: At baseline, 211 infants received AHM and 215 received …

A Multifunctional Theranostic Ultrasound Platform For Remote Magnetogenetics And Expanded Blood-Brain Barrier Opening, Alec J Batts, Fotios N Tsitsos, Jeannette Ingabire, Guillaume Duret, Samantha L Gorman, Deny Tsakri, Rebecca L Noel, Robin Ji, Nancy Kwon, Quoc-Khanh Pham, Linlin Zhang, Gang Bao, Jacob T Robinson, Elisa E Konofagou

Faculty, Staff and Students Publications

Introduction: Brain stimulation techniques are critical for unraveling the innerworkings of complex neuronal pathways governing both normal physiological function and pathologic states in neurological disorders. Focused ultrasound (FUS) is an emerging technique poised to significantly alter central nervous system (CNS) drug delivery and neuroscience research through non-invasive means. Magnetogenetics is a brain stimulation technique which may benefit from FUS technology in that alternating magnetic fields (AMF), like FUS, can pass through the skull without requiring surgery.

Methodology: Magnetogenetics involves the deposition of superparamagnetic iron-oxide nanoparticles (SPIONs) and overexpression of thermoreceptor transmembrane proteins (e.g. TRPV1 and TRPA1) in the brain. When …

Placentas From Sars-Cov-2 Infection During Pregnancy Exhibit Foci Of Oxidative Stress And Dna Damage, Guilherme M Nobrega, Eliza R Mccoll, Arthur Antolini-Tavares, Renato T Souza, José Guilherme Cecatti, Maria Laura Costa, Indira U Mysorekar

Faculty, Staff and Students Publications

Problem: COVID-19 during pregnancy is linked to increased maternal morbidity and a higher incidence of preterm births (PTBs), yet the underlying mechanisms remain unclear. Cellular senescence, characterized by the irreversible cessation of cell division, is a critical process in placental function, and its dysregulation has been implicated in pregnancy complications like PTB. Senescence can be induced by various stressors, including oxidative stress, DNA damage, and viral infections.

Method of study: In this study, we determined whether COVID-19 had an impact on placental senescence. We examined placentas from women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 10 …

Establishing Standardized Transthoracic Echocardiography Reference Ranges For Mouse Models: Insights Into The Impact Of Anesthesia, Sex, And Age, Manuela A Oestereicher, Christopher S Ward, Elida Schneltzer, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Ghina Bou About, Mohammed Selloum, Hamid Meziane, Michelle Stewart, Lydia Teboul, Clare Norris, Dale Pimm, Marina Kan, Federico López Gómez, Robert Wilson, Mayra Monroy, Sheraz Pasha, Eva Zabrodska, Jan Prochazka, David Pajuelo Reguera, Zuzana Nichtova, Yann Herault, Sara Wells, Helen Parkinson, Jason D Heaney, Radislav Sedlacek, Xiang Gao, Martin Hrabe De Angelis, Nadine Spielmann

Faculty, Staff and Students Publications

Introduction: Mouse models play a critical role in cardiology research, offering valuable insights into the molecular mechanisms, genetics, and potential treatments for cardiovascular diseases. However, the ability to transfer findings in mice between studies is limited by the absence of standardized protocols and valid reference values for the assessment of normal cardiac function in mice. This study aims to establish comprehensive transthoracic echocardiography (TTE) reference ranges for mice, particularly focusing on C57BL/6N wild-type controls.

Methods: The study, which includes data from over 15,000 mice through the International Mouse Phenotyping Consortium (IMPC), highlights how variables such as sex, age, body weight, …

Mutations In Retinal Cyclic Nucleotide-Gated Channels Identified In Familial Cases Of Inherited Retinal Dystrophies From Pakistan, Zainab Akhtar, Kiran Afshan, Yumei Li, Sumaira Altaf, Aleesha Asghar, Ume Sughra, Wajid Ali Khan, Haiba Kaul, Rui Chen, Sabika Firasat

Faculty, Staff and Students Publications

Purpose: Cyclic nucleotide-gated (CNG) channels are ligand-gated ion channels that transduce light signals into electrical signals in the retinal photoreceptors. Pathogenic variants in CNG channel genes are reported to cause inherited retinal dystrophies (IRDs). The current study used targeted panel sequencing to describe the mutational spectrum of CNG channel genes in familial cases of IRDs from eight consanguineous Pakistani families.

Methods: The current study included consanguineous Pakistani families with at least two affected members. DNA was extracted from whole blood samples by the phenol-chloroform method. Two affected members from each family were initially analyzed using targeted panel sequencing of 344 …

Exercise Mitigates High-Fat Diet-Induced Cardiac Dysfunction Via Apoe Genotype- And Immune-Dependent Mechanisms: A Photon-Counting Ct Study In Adult Mice, Rohan Nadkarni, Alex J Allphin, Darin P Clark, Yi Qi, Zay Yar Han, Ketan B Ghaghada, Alexandra Badea, Cristian T Badea

Faculty, Staff and Students Publications

Background: Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation.

Methods: This study included 251 male and female mice in mid-to-late life of APOE2, APOE3, and APOE4 genotypes with variation in humanized NOS2 (HN) mediated innate immune response, exercise status (exercised vs. sedentary) and …

Biallelic Variation In The Choline And Ethanolamine Transporter Flvcr1 Underlies A Severe Developmental Disorder Spectrum, Daniel G Calame, Jovi Huixin Wong, Puravi Panda, Dat Tuan Nguyen, Nancy C P Leong, Riccardo Sangermano, Sohil G Patankar, Mohamed S Abdel-Hamid, Lama Alabdi, Sylvia Safwat, Kyle P Flannery, Zain Dardas, Jawid M Fatih, Chaya Murali, Varun Kannan, Timothy E Lotze, Isabella Herman, Farah Ammouri, Brianna Rezich, Stephanie Efthymiou, Shahryar Alavi, David Murphy, Zahra Firoozfar, Mahya Ebrahimi Nasab, Amir Bahreini, Majid Ghasemi, Nourelhoda A Haridy, Hamid Reza Goldouzi, Fatemeh Eghbal, Ehsan Ghayoor Karimiani, Amber Begtrup, Houda Elloumi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Haowei Du, Shalini N Jhangiani, Zeynep Coban-Akdemir, Dana Marafi, Lance Rodan, Sedat Isikay, Jill A Rosenfeld, Subhadra Ramanathan, Michael Staton, Kerby C Oberg, Robin D Clark, Catharina Wenman, Sam Loughlin, Ramy Saad, Tazeen Ashraf, Alison Male, Shereen Tadros, Reza Boostani, Ghada M H Abdel-Salam, Maha Zaki, Ali Mardi, Farzad Hashemi-Gorji, Ebtesam Abdalla, M Chiara Manzini, Davut Pehlivan, Jennifer E Posey, Richard A Gibbs, Henry Houlden, Fowzan S Alkuraya, Kinga Bujakowska, Reza Maroofian, James R Lupski, Long N Nguyen

Faculty, Staff and Students Publications

Purpose: FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.

Methods: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.

Results: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly …

Targeted Analysis Of Dyslexia-Associated Regions On Chromosomes 6, 12 And 15 In Large Multigenerational Cohorts, Nicola H Chapman, Patrick A Navas, Michael O Dorschner, Michele Mehaffey, Karen G Wigg, Kaitlyn M Price, Oxana Y Naumova, Elizabeth N Kerr, Sharon L Guger, Maureen W Lovett, Elena L Grigorenko, Virginia Berninger, Cathy L Barr, Ellen M Wijsman, Wendy H Raskind

Faculty, Staff and Students Publications

Dyslexia is a common learning impairment with a genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date have investigated only limited genomic variation within each locus with no confirmed pathogenic variants identified. Our study is the first to comprehensively sequence both coding and cis-acting regulatory regions of such genes in a large study sample. In a collection of >2000 participants in families from three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate risk genes (DNAAF4, CYP19A1, DCDC2, …

Efficacy Of Nampt Inhibition In T-Cell Acute Lymphoblastic Leukemia, Chelsea Vrana, Matthew Zhang, Max Rochette, Michelle Alozie, Hailey Oviedo, Alan Gonzalez, Jaden Sherman, Barry Zorman, Pavel Sumazin, Karen R Rabin, Jacob J Junco

Faculty, Staff and Students Publications

Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a KrasLSL-G12D/+.Mb1Cre/+ murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 in vivo in PDX mouse models of T-ALL, and found that it significantly reduced the …

Mapping The Functional Network Of Human Cancer Through Machine Learning And Pan-Cancer Proteogenomics, Zhiao Shi, Jonathan T Lei, John M Elizarraras, Bing Zhang

Faculty, Staff and Students Publications

Large-scale omics profiling has uncovered a vast array of somatic mutations and cancer-associated proteins, posing substantial challenges for their functional interpretation. Here we present a network-based approach centered on FunMap, a pan-cancer functional network constructed using supervised machine learning on extensive proteomics and RNA sequencing data from 1,194 individuals spanning 11 cancer types. Comprising 10,525 protein-coding genes, FunMap connects functionally associated genes with unprecedented precision, surpassing traditional protein-protein interaction maps. Network analysis identifies functional protein modules, reveals a hierarchical structure linked to cancer hallmarks and clinical phenotypes, provides deeper insights into established cancer drivers and predicts functions for understudied cancer-associated …

Longitudinal Host Transcriptional Responses To Sars-Cov-2 Infection In Adults With Extremely High Viral Load, Vasanthi Avadhanula, Chad J Creighton, Laura Ferlic-Stark, Divya Nagaraj, Yiqun Zhang, Richard Sucgang, Erin G Nicholson, Anubama Rajan, Vipin Kumar Menon, Harshavardhan Doddapaneni, Donna Marie Muzny, Ginger A Metcalf, Sara Joan Javornik Cregeen, Kristi Louise Hoffman, Richard A Gibbs, Joseph F Petrosino, Pedro A Piedra

Faculty, Staff and Students Publications

Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes …

An Evaluation Of Genetic Predisposition To Congenital Anomalies And Pediatric Cancer Supports, Hyunjung Gu, Yao Yu, Saumya Dushyant Sisoudiya, Pamela Mishra, He Li, Jeremy M Schraw, Michael E Scheurer, Donna M Muzny, Danielle Mitchell, Olga Taylor, Shalini N Jhangiani, Shannon Dugan-Perez, Yifan Wu, Harsha Doddapaneni, Sravya Venkata Bhamidipati, Marie-Claude Gingras, Jennifer E Posey, Richard A Gibbs, Chad D Huff, Sharon E Plon, Philip J Lupo, Aniko Sabo

Faculty, Staff and Students Publications

Purpose: Although congenital anomalies are among the strongest risk factors for developing pediatric cancer, the genetic underpinnings remain unclear. Therefore, we evaluated germline susceptibility in children with congenital anomalies and cancer.

Methods: Through the Genetic Overlap Between Anomalies and Cancer in Kids Study, we recruited 47 participants with anomalies and cancer, along with their biological families. Genome sequencing was performed, focusing on single-nucleotide variants, indels, and structural variants. Pathogenic or likely pathogenic variants were identified by the American College of Medical Genetics and Genomics classification.

Results: We identified pathogenic or likely pathogenic variants in 23.4% (11 of 47) of participants. …

Nanoparticle Contrast-Enhanced Computed Tomography Of Sporadic Aortic Aneurysm And Dissection: Effect Of Nanoparticle Size And Contrast Agent Dose, Laxman Devkota, Chen Zhang, Deborah Vela, Poonam Sarkar, Prajwal Bhandari, Zbigniew Starosolski, Renuka Menon, Dianna M Milewicz, Ying H Shen, Scott A Lemaire, Ketan B Ghaghada

Faculty, Staff and Students Publications

Background: Aortopathies, such as aortic aneurysm and dissection (AAD), are associated with enhanced aortic wall permeability and endothelial dysfunction. We previously demonstrated that nanoparticle contrast-enhanced computed tomography (nCECT), which detects enhanced aortic wall permeability, could enable non-invasive detection of early AAD before its progresses to fatal aortic rupture. This study investigated the effect of nanoparticle contrast agent (NPCA) size and dose on detection of aortopathy by nCECT.

Methods: In vivo studies were performed in a mouse model of sporadic AAD induced by challenging animals with high fat diet (5 weeks) and angiotensin II infusion (last one week). The effects …

Structural Dynamics And Binding Of Caenorhabditis Elegans Lifespan-Extending Lipid Binding Protein-3 To Polyunsaturated Fatty Acids, André R Cuevas, Matthew C Tillman, Meng C Wang, Eric A Ortlund

Faculty, Staff and Students Publications

Intracellular lipid binding proteins (iLBPs) play crucial roles in lipid transport and cellular metabolism across the animal kingdom. Recently, a fat‐to‐neuron axis was described in Caenorhabditis elegans, in which lysosomal activity in the fat liberates polyunsaturated fatty acids (PUFAs) that signal to neurons and extend lifespan with durable fecundity. In this study, we investigate the structure and binding mechanisms of a lifespan‐extending lipid chaperone, lipid binding protein‐3 (LBP‐3), which shuttles dihomo‐γ‐linolenic (DGLA) acid from intestinal fat to neurons. We present the first high‐resolution crystal structure of LBP‐3, which reveals a classic iLBP fold with an unexpected and unique homodimeric …

Overview Of The Head And Neck Tumor Segmentation For Magnetic Resonance Guided Applications (Hnts-Mrg) 2024 Challenge, Kareem A Wahid, Cem Dede, Dina M El-Habashy, Serageldin Kamel, Michael K Rooney, Yomna Khamis, Moamen R A Abdelaal, Sara Ahmed, Kelsey L Corrigan, Enoch Chang, Stephanie O Dudzinski, Travis C Salzillo, Brigid A Mcdonald, Samuel L Mulder, Lucas Mccullum, Qusai Alakayleh, Carlos Sjogreen, Renjie He, Abdallah S R Mohamed, Stephen Y Lai, John P Christodouleas, Andrew J Schaefer, Mohamed A Naser, Clifton D Fuller

Faculty, Staff and Student Publications

Magnetic resonance (MR)-guided radiation therapy (RT) is enhancing head and neck cancer (HNC) treatment through superior soft tissue contrast and longitudinal imaging capabilities. However, manual tumor segmentation remains a significant challenge, spurring interest in artificial intelligence (AI)-driven automation. To accelerate innovation in this field, we present the Head and Neck Tumor Segmentation for MR-Guided Applications (HNTS-MRG) 2024 Challenge, a satellite event of the 27th International Conference on Medical Image Computing and Computer Assisted Intervention. This challenge addresses the scarcity of large, publicly available AI-ready adaptive RT datasets in HNC and explores the potential of incorporating multi-timepoint data to enhance RT …

Disruption Of Distal Appendage Protein Cep164 Causes Skeletal Malformation In Mice, Hiroyuki Yamaguchi, Megumi Kitami, Margaret Li, Sowmya Swaminathan, Radbod Darabi, Ken-Ichi Takemaru, Yoshihiro Komatsu

Faculty, Staff and Student Publications

The primary cilium is a cellular antenna to orchestrate cell growth and differentiation. Deficient or dysfunctional cilia are frequently linked to skeletal abnormalities. Previous research demonstrated that ciliary proteins regulating axoneme elongation are essential for skeletogenesis. However, the role of the ciliary proteins responsible for initiating cilium assembly in skeletal development remains unknown. Here, we investigate the function of centrosomal protein of 164 kDa (CEP164), a key ciliogenesis regulator that localizes at the distal appendages of the mother centriole, during skeletal development in mice. Interestingly, the mesodermal cell-specific Cep164 deletion resulted in severe bone defects and osteoblast-specific deletion of Cep164 …

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. …

Neurofilament Light Chain In Serum Of Cancer Patients With Acute Neurological Complications, Amulya Gottiparthy, Keng Lam, Suprateek Kundu, Zixi Yang, Ivo Tremont-Lukats, Sudhakar Tummala

Faculty, Staff and Student Publications

Aim: Neurofilament light chain (NfL) is a nonspecific sensitive biomarker of axonal damage.

Methods: This case series identified cancer patients with neurological complications who had serum NfL measurements and paired these results to outcomes.

Results: NfL serum levels were available in 15 patients with hematological malignancies or solid tumors. The neurological complications studied were immune effector cell-associated neurotoxicity syndrome, immune checkpoint inhibitor-related encephalopathy, anoxic brain injury, Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis, transverse myelitis, paraneoplastic syndrome, central nervous system demyelinating disorder and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. All patients but one with serum NfL >900 pg/ml died …

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 …

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 …

Stem Cell Activity-Coupled Suppression Of Endogenous Retrovirus Governs Adult Tissue Regeneration, Ying Lyu, Soo Jin Kim, Ericka S Humphrey, Richa Nayak, Yinglu Guan, Qingnan Liang, Kun Hee Kim, Yukun Tan, Jinzhuang Dou, Huandong Sun, Xingzhi Song, Priyadharsini Nagarajan, Kamryn N Gerner-Mauro, Kevin Jin, Virginia Liu, Rehman H Hassan, Miranda L Johnson, Lisa P Deliu, Yun You, Anurag Sharma, H Amalia Pasolli, Yue Lu, Jianhua Zhang, Vakul Mohanty, Ken Chen, Youn Joo Yang, Taiping Chen, Yejing Ge

Faculty, Staff and Student Publications

Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair …