Genetic Phenomena Commons^™

Comb-Boin12: A Utility-Based Bayesian Optimal Interval Design For Dose Optimization In Cancer Drug-Combination Trials, Mengyi Lu, Jingyi Zhang, Ying Yuan, Ruitao Lin

Faculty, Staff and Student Publications

Drug combinations are increasingly utilized in cancer treatment to enhance drug effectiveness through synergistic therapeutic effects. However, determining the optimal biological dose combination (OBDC) in small-scale drug combination trials presents challenges due to the increased complexity of the dose space. To effectively optimize the dose combination of combined drugs, we propose a model-assisted design by extending the single-agent Bayesian optimal interval phase I/II (BOIN12) design. Our approach incorporates a utility function to balance the trade-off between risk and benefit and directly models the utility of each dose by constructing a quasi-beta-binomial model. A key advantage of our design is the …

Consolidation Alk Tyrosine Kinase Inhibitors Versus Durvalumab Or Observation After Chemoradiation In Unresectable Stage Iii Alk-Positive Nsclc, Amin H Nassar, Ritujith Jayakrishnan, Jamie Feng, Frances Shepherd, Elio Adib, Justin M Cheung, Jessica J Lin, Yufei Liu, Steven H Lin, Kaushal Parikh, Arthi Sridhar, Purnima Shakya, Thomas J Dilling, David Kaldas, Jhanelle E Gray, Anastasiya Lobachov, Jair Bar, Heike Luders, Christian Grohe, Shruti Gupta, Ticiana Leal, Bailey Fitzgerald, Fionnuala Crowley, Yu Fujiwara, Thomas U Marron, Molly Wilgucki, Joshua Reuss, Luxi Chen, Kamya Sankar, Jacqueline V Aredo, Joel W Neal, Heather A Wakelee, Rohit Thummalapalli, Helena Yu, Ryan Whitaker, Ana Velazquez, Meera Ragavan, Alessio Cortellini, David J Kwiatkowski, Abdul Rafeh Naqash, Sarah B Goldberg, So Yeon Kim

Faculty, Staff and Student Publications

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.

Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related …

Correlation Of Pancreatic Laminin Alpha 5 Expression With Clinical Outcomes In Total Pancreatectomy With Islet Autotransplantation, Jayachandra Kuncha, Carly M Darden, Yang Liu, Michael Lawrence, J Sebastian Danobeitia, Bashoo Naziruddin

Faculty, Staff and Student Publications

This study examines extracellular matrix (ECM) protein (ECM) expression in chronic pancreatitis (CP) patients and its correlation with graft function after total pancreatectomy with islet autologous transplantation (TPIAT). Pancreatic sections from 29 CP patients undergoing TPIAT were analyzed for ECM including pan-laminin, laminin alpha 5 (LAMA5), collagen IV, and Perlecan by immunohistochemistry and scored by the percentage positive staining area within the whole tissue area. Graft function was monitored by blood glucose and C-peptide levels. Laminin alpha 5 levels in blood plasma were greater in CP. Laminin alpha 5 expression was significantly higher in all CP patient etiological categories including …

Stim1 And Lipid Interactions At Er-Pm Contact Sites, Yuepeng Ke, Ritchel Gannaban, Junchen Liu, Yubin Zhou

Faculty, Staff and Student Publications

Store-operated calcium (Ca2+) entry (SOCE) represents a major route of Ca2+ permeation across the plasma membrane (PM) in non-excitable cells, which plays an indispensable role in maintaining intracellular Ca2+ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca2+ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca2+ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to translocation of STIM1-containing ER membrane towards the PM. This movement is facilitated by the physical interaction between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, …

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

Purpose

To combine deep learning and biology-based modeling to predict the response of locally advanced, triple-negative breast cancer before initiating neoadjuvant chemotherapy (NAC).

Materials and Methods

In this retrospective study, a biology-based mathematical model of tumor response to NAC was constructed and calibrated on a patient-specific basis using imaging data from patients enrolled in the MD Anderson A Robust TNBC Evaluation FraMework to Improve Survival trial (ARTEMIS; ClinicalTrials.gov registration no. NCT02276443) between April 2018 and May 2021. To relate the calibrated parameters in the biology-based model and pretreatment MRI data, a convolutional neural network (CNN) was employed. The CNN …

Early Diagnosis Of Vascular Ehlers-Danlos Syndrome Through Ai-Powered Facial Analysis: Results From The Montalcino Aortic Consortium, David R Murdock, Adarsh Suresh, Ernesto Calderon Martinez, Isabella Marin, Frances Marin, Alan C Braverman, Angela T Yetman, Shaine A Morris, Dianna M Milewicz

Faculty, Staff and Student Publications

Purpose: Vascular Ehlers-Danlos syndrome (vEDS), which is caused by COL3A1 pathogenic variants, is a rare heritable aortic and arterial disorder associated with early mortality, mainly due to spontaneous vascular dissections and ruptures. Improved methods for diagnosing vEDS are needed for guideline-based management to be initiated for preventing deadly complications and differentiating vEDS from overlapping conditions, such as hypermobile EDS (hEDS).

Methods: We implemented an artificial intelligence (AI) facial analysis model based on the PhenoScore framework using a support vector machine trained on facial images of 30 individuals, aged 6 to 65 years, with vEDS from the Montalcino Aortic Consortium, control …

Integrative Multi-Omics Approach For Improving Causal Gene Identification, Austin King, Chong Wu

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWAS) have been widely used to identify thousands of likely causal genes for diseases and complex traits using predicted expression models. However, most existing TWAS methods rely on gene expression alone and overlook other regulatory mechanisms of gene expression, including DNA methylation and splicing, that contribute to the genetic basis of these complex traits and diseases. Here we introduce a multi-omics method that integrates gene expression, DNA methylation, and splicing data to improve the identification of associated genes with our traits of interest. Through simulations and by analyzing genome-wide association study (GWAS) summary statistics for 24 complex …

Chronic Circadian Misalignment Accelerates Sarcopenia Progression In Mice, Takashi Seya, Nobuya Koike, Naoki Okubo, Yasuhiro Umemura, Yoshiki Tsuchiya, Kazuya Yabumoto, Yasuhiro Endo, Kanako Iinuma, Akiyo Kakibuchi, Akira Sugimoto, Kenji Takahashi, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Introduction: In today's 24/7 society, circadian misalignment caused by environmental and lifestyle factors is associated with various adverse health consequences. Understanding tissue-specific pathology is required to counter this growing public health challenge. A potential association of environmental circadian misalignment with sarcopenia, or accelerated loss of skeletal muscle strength and mass, is poorly documented.

Methods: 14-week-old wild-type C57BL/6J male mice were exposed to a chronic jet lag (CJL) paradigm consisting of an 8-h phase advance every 4 days (the ADV group) or a fixed light-dark cycle (the LD group) for 64 weeks. Grip strength was measured during the experiment, and hindlimb …

Editorial: Immunoregulation By Adenosine Signaling In Infection And Inflammation, Xiangsheng Huang, Weidong Zhao, Tingting Mills, Lei Shi, Xiaoyi Yuan

Faculty, Staff and Student Publications

No abstract provided.

Peripheral Administration Of Blood From Tau Transgenic Animals Exacerbates Brain Tau-Associated Pathology, Laura Vegas-Gomez, Matias Pizarro, Jesus Garcia-Martin, Maria Angeles Arredondo-Alcala, Bianca Bustamante, Carolina Gonzalez-Silva, Soledad Matus, Rodrigo Diaz-Espinoza, Antonia Gutierrez, Rodrigo Morales, Claudia Duran-Aniotz, Ines Moreno-Gonzalez

Faculty, Staff and Student Publications

The accumulation of amyloid plaques and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD). While amyloid-beta propagation through prion-like mechanisms has been extensively studied in both central and peripheral pathways, the potential spreading of tau aggregates in the periphery remains largely unexplored. Emerging evidence suggests that hyperphosphorylated tau (ptau) aggregates may propagate beyond the central nervous system, as they have been detected in peripheral tissues and biological fluids from humans and mouse models of tauopathies. However, whether peripheral ptau aggregates or other factors associated to its accumulation contribute to brain pathology remains unclear. In this study, we investigate the …

Distribution Of Chronic Wasting Disease (Cwd) Prions In Tissues From Experimentally Exposed Coyotes (Canis Latrans), Nancy Ho, Reece Mcginn, Paulina Soto, Terry R Spraker, Justin Fischer, Kurt Vercauteren, Tracy Nichols, Rodrigo Morales

Faculty, Staff and Student Publications

Cervids susceptible to chronic wasting disease (CWD) are sympatric with multiple other animal species that can interact with infectious prions. Several reports have described the susceptibility of other species to CWD prions, or their potential to transport them. One of these species is the coyote (Canis latrans), which has been previously shown to pass transmission-relevant prion titers in their feces for at least three days after ingesting prion-positive brain material. The current study followed up on these findings and evaluated the distribution of prions in multiple tissues from the same coyotes. Our results show that prions persist in the digestive …

Identification Of Prothrombin Belgrade Variant In A Mexican-American Family With Recurrent Deep Vein Thrombosis, Émile Moura Coelho Da Silva, Natalie Montanez, Miguel Escobar

Faculty, Staff and Student Publications

A rare prothrombin variant (c.1787G > A, p.Arg596Gln), also known as the prothrombin Belgrade variant, has been associated with an increased predisposition to thrombosis through resistance to antithrombin. This variant has been previously reported in individuals from Serbia, Japan, China, and India. In this case report, we described the first reported case of heterozygosity for the prothrombin Belgrade variant in a Mexican-American family. Affected individuals had negative results on standard hypercoagulable studies; however, they exhibited a history of early-onset and recurrent venous thromboembolism (VTE). Although rare, the prothrombin Belgrade variant-and other prothrombin variants associated with antithrombin resistance-may be underrecognized in patients …

Novel Volumetric Modulated Arc Therapy Approach For Lattice Radiation Therapy For Bulky Liver Tumors, Christine V Chung, Saurabh S Nair, Meena S Khan, Callistus I Nguyen, Rachael M Martin-Paulpeter, Ethan B Ludmir, Laurence E Court, Joshua S Niedzielski

Faculty, Staff and Student Publications

Purpose: Lattice radiation therapy (LRT) is a type of spatially fractionated radiation therapy that has emerged as an effective treatment approach for bulky solid tumors. RapidArc Dynamic (RAD) is a novel beam delivery approach that may be advantageous for LRT. The purpose of this in silico study was to evaluate and compare a novel RAD-based LRT approach (RAD-LRT) with conventional volumetric modulated arc therapy (VMAT)-based LRT (VMAT-LRT).

Methods: Twenty patients with bulky liver tumors treated with RT were retrospectively identified. VMAT-LRT and RAD-LRT plans were generated for all patients. Lattice spheres were placed in a standardized hexagonal pattern with alternating …

Accumulated Seizure Burden Predicts Neurodevelopmental Outcome At 36 Months Of Age In Patients With Tuberous Sclerosis Complex, S Katie Z Ihnen, Samuel Alperin, Jamie K Capal, Alexander L Cohen, Jurriaan M Peters, E Martina Bebin, Hope A Northrup, Mustafa Sahin, Darcy A Krueger

Faculty, Staff and Student Publications

Objective: Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.

Methods: Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of …

Real-World Outcomes Of Upfront Autologous Hematopoietic Stem Cell Transplantation In Patients With Newly Diagnosed Multiple Myeloma With Deletion 17p, Curtis Marcoux, Oren Pasvolsky, Denái R Milton, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Amna Ahmed, Yosra Aljawai, Sheeba K Thomas, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Despite tremendous advancements in multiple myeloma (MM) therapeutics, outcomes remain heterogeneous, heavily influenced by clinical and cytogenetic factors. Among these, deletion of the short arm of chromosome 17 (del(17p)) is a strong predictor of poor prognosis. The aim of this study was to evaluate real-world outcomes in patients with newly diagnosed MM (NDMM) with del(17p) undergoing upfront autologous hematopoietic stem cell transplantation (auto-HCT). We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-HCT at MD Anderson Cancer Center between 2008 and 2018. Primary endpoints were progression-free survival (PFS) and overall survival (OS), with secondary endpoints being …

Exacerbation Of Paclitaxel-Induced Neuropathic Pain Behaviors In Breast Tumor-Bearing Mice, Hee Kee Kim, Juping Xing, Youn-Sang Jung, Jae-Il Park, Hee Young Kim, Jimin Kim, Salahadin Abdi

Faculty, Staff and Student Publications

Background: Chronic pain and cancer interact bidirectionally, with pain enhancing sensory peptides and potentially promoting tumor growth. Despite this, most chemotherapy-induced neuropathic pain (CIPN) studies overlook the contribution of cancer itself to neuropathy, focusing instead on chemotherapy-induced mechanisms. Animal models of chemotherapy-induced neuropathic pain (CINP) have been developed by injecting chemotherapeutic drugs such as paclitaxel into normal animals without cancer. This study aimed to develop a new model in mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mice, a widely used breast cancer model with normal immune function.

Results: The percentage of positive response (PPR) of paclitaxel-injected MMTV-PyMT mice increased …

A New, Early Cretaceous Carettochelyid Turtle From South Korea Provides Insights Into Softshell Evolution And Aquatic Ecology, Minguk Kim, Jongyun Jung, Walter G Joyce, Jae-Il Park, Hye-Yeon Jung, Hyemin Jo, Min Huh

Faculty, Staff and Student Publications

Here, we present a new Cretaceous carettochelyid turtle, Byeoljubuchelys yeosuensis gen. et sp. nov., from the Lower Cretaceous Hasandong Formation of Yeosu, Korea. A nearly complete shell and select elements of the girdles and limbs provide crucial insight into the evolution and aquatic adaptation of this family. Phylogenetic analyses place Byeoljubuchelys yeosuensis at the most basal position within Carettochelyidae. The mid-sized plastron of Byeoljubuchelys yeosuensis appears to be plesiomorphic for the group. The expansion of the plastron during carettochelyid evolution, especially during the Paleogene, may be an evolutionary response to increasing body size or the threat of mammalian predators. …

Practical Application Of Multivendor Mri-Based R2* Mapping For Liver Iron Quantification At 15 T And 30 T, Gregory Simchick, Ruiyang Zhao, Qing Yuan, Mounes Aliyari Ghasabeh, Stefan Ruschke, Dimitrios C Karampinos, David T Harris, Raphael Do Vale Souza, Ryan J Mattison, Michael R Jeng, Ivan Pedrosa, Ihab R Kamel, Shreyas Vasanawala, Takeshi Yokoo, Scott B Reeder, Diego Hernando

Faculty, Staff and Student Publications

Background: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear.

Purpose: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions.

Study type: Prospective.

Subjects: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers.

Field strength/sequence: Standardized multiecho spoiled gradient echo sequence at 1.5 T and …

Development Of Microcystoid Macular Degeneration In The Retina Of Nonhuman Primates: Time-Course And Associated Pathologies, Thomas C M Lavery, Carol A Rasmussen, Alexander W Katz, Charlene B Y Kim, James N Ver Hoeve, Paul E Miller, Peter J Sonnentag, Brian J Christian, Christopher J Murphy, David R Piwnica-Worms, Seth T Gammon, Xudong Qiu, Paul L Kaufman, T Michael Nork

Faculty, Staff and Student Publications

Purpose: Microcystoid macular degeneration (MMD) is a condition where cystoid vacuoles develop within the inner nuclear layer of the retina in humans in a variety of disorders. Here we report the occurrence of MMD in non-human primates (NHPs) with various retinal ganglion cell (RGC) pathologies and evaluate the hypothesis that MMD does not precede RGC loss but follows it.

Methods: Morphological studies were performed of the retinas of NHPs, specifically both rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis), in which MMD was identified after induction of experimental glaucoma (EG), hemiretinal endodiathermy axotomy (HEA), and spontaneous …

Deep Brain Stimulation Of The Medial Forebrain Bundle: Effects On Anhedonia And Behavioral Activation In Treatment-Resistant Depression, Andrea Boscutti, Bashar Asir, Isabela Moura, Albert Fenoy, João Quevedo, Jair C Soares

Faculty, Staff and Student Publications

No abstract provided.