Medicine and Health Sciences Commons^™

Improving Laboratory Animal Genetic Reporting: Lag-R Guidelines, Lydia Teboul, James Amos-Landgraf, Fernando J Benavides, Marie-Christine Birling, Steve D M Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe De Angelis, Kevin C Kent Lloyd, Terry R Magnuson, Lluis Montoliu, Stephen A Murray, Ki-Hoan Nam, Lauryl M J Nutter, Eric Pailhoux, Fernando Pardo Manuel De Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, Celphedia Infrastructure, Infrafrontier Consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society For Transgenic Technologies, Mutant Mouse Resource And Research Centers, Phenomics Australia, Rrrc- Rat Resource And Research Center, Guillaume Pavlovic

Faculty, Staff and Student Publications

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

The Use Of Apparent Diffusion Coefficient Values For Differentiating Bevacizumab-Related Cytotoxicity From Tumor Recurrence And Radiation Necrosis In Glioblastoma, Kamand Khalaj, Michael A Jacobs, Jay-Jiguang Zhu, Yoshua Esquenazi, Sigmund Hsu, Nitin Tandon, Alireza Akhbardeh, Xu Zhang, Roy Riascos, Arash Kamali

Faculty, Staff and Student Publications

OBJECTIVES: Glioblastomas (GBM) are the most common primary invasive neoplasms of the brain. Distinguishing between lesion recurrence and different types of treatment related changes in patients with GBM remains challenging using conventional MRI imaging techniques. Therefore, accurate and precise differentiation between true progression or pseudoresponse is crucial in deciding on the appropriate course of treatment. This retrospective study investigated the potential of apparent diffusion coefficient (ADC) map values derived from diffusion-weighted imaging (DWI) as a noninvasive method to increase diagnostic accuracy in treatment response.

METHODS: A cohort of 21 glioblastoma patients (mean age: 59.2 ± 11.8, 12 Male, 9 Female) …

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …

Influence Of Polypyrrole On Phosphorus- And Tio2-Based Anode Nanomaterials For Li-Ion Batteries, Chiwon Kang, Kibum Song, Seungho Ha, Yujin Sung, Yejin Kim, Keun-Young Shin, Byung Hyo Kim

Faculty, Staff and Student Publications

Phosphorus (P) and TiO2 have been extensively studied as anode materials for lithium-ion batteries (LIBs) due to their high specific capacities. However, P is limited by low electrical conductivity and significant volume changes during charge and discharge cycles, while TiO2 is hindered by low electrical conductivity and slow Li-ion diffusion. To address these issues, we synthesized organic–inorganic hybrid anode materials of P–polypyrrole (PPy) and TiO2–PPy, through in situ polymerization of pyrrole monomer in the presence of the nanoscale inorganic materials. These hybrid anode materials showed higher cycling stability and capacity compared to pure P and TiO2. The enhancements are attributed …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Assessment Of Patient-Derived Xenograft Growth And Antitumor Activity: The Nci Pdxnet Consensus Recommendations, Funda Meric-Bernstam, Michael W Lloyd, Soner Koc, Yvonne A Evrard, Lisa M Mcshane, Michael T Lewis, Kurt W Evans, Dali Li, Lawrence Rubinstein, Alana Welm, Dennis A Dean, Anuj Srivastava, Jeffrey W Grover, Min J Ha, Huiqin Chen, Xuelin Huang, Kaushik Varadarajan, Jing Wang, Jack A Roth, Bryan Welm, Ramaswamy Govinden, Li Ding, Salma Kaochar, Nicholas Mitsiades, Luis Carvajal-Carmona, Meenhard Herylyn, Michael A Davies, Geoffrey I Shapiro, Ryan Fields, Jose G Trevino, Joshua C Harrell, Nci Pdxnet Consortium, James H Doroshow, Jeffrey H Chuang, Jeffrey A Moscow

Faculty, Staff and Student Publications

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification …

Towards Environmentally Sustainable Preservation Of Heritage Buildings, Rozal Rozal Yousef Hanna1, Ayman Gamal El-Din Abd El- Tawab2, Walaa Abou El- Haggag Mehanna3

Journal of Engineering Research

The construction industry, characterized by its intricate processes and extensive stakeholder networks, stands at the cusp of a digital revolution. The adoption of blockchain-smart contract (BCSC) technology is at the heart of this transformation. This research delves deep into the BCSC within the construction arena to provide comprehensive insight into its probable applications, inherent challenges, and potential future trajectories. Leveraging the PRISMA analysis technique, a curated collection of relevant academic research articles was assembled, shedding light on the existing body of knowledge regarding the application of BCSC technology in construction. The authors developed an innovative user interface tool customized to …

Review: Protection Of Wooden Structures With Nano-Titanium Dioxide Coating, Zienab Zienab A. Ahmed1*, And M. M. Mosallem2

Journal of Engineering Research

Wood is widely used for various purposes with good performance. Wood works as the main material for furniture, monuments, decorations and constructions. which has the close relationship with human. Durability of wood is important in ensuring an appropriate life for the structure being designed. Wooden construction deteriorates easily due to UV radiation and weather conditions. Many of wood types need a preservative treatment. Several compounds are available for chemical protection, but not all are completely safe for human health. New technologies with low environmental impact and economically feasible are developed, which improves the life cycle of wood. Titanium dioxide is …

Urbanism Strategies For Linking Existing And New Cities, Naglaa J. Q. Mo’Men Abdel-Qader Ebrahim1, Mohsen Bayad2

Journal of Engineering Research

New cities, designed for urban growth outside existing metropolitan regions, face challenges in street infrastructure due to rapid expansion. Efficient control of mobility is crucial as cities grow. Sustainable transportation involves factors like infrastructure, public transit, delivery networks, affordability, efficiency, air quality, health, and reduced emissions. Commuting between established and new urban areas is common, leading to issues like urban sprawl, longer travel times, and congestion in developing countries. The challenge is to improve accessibility while addressing air quality, traffic, congestion, noise, built environment, emissions, and sprawl. This study aims to explore factors influencing mobility choices in Egypt, focusing on …

Multi-Omic Single-Cell Integration For Understanding T Cell Responses In Acute Myeloid Leukemia, Poonam Desai

Dissertations and Theses (Open Access)

In recent years, translational initiatives have gained significant traction within the medical community. Clinical parameters alone have been insufficient to fully understand the intricate mechanisms governing patient responses to disease and therapy. Additionally, single-cell technologies have rapidly advanced to a point where generation of large patient-based datasets is financially and logistically feasible. The integration of clinical information with multi-omic single-cell technologies enables the formation of data-driven hypotheses pertaining to the mechanisms of disease progression and therapeutic resistance. Acute Myeloid Leukemia (AML) is a rapidly-progressing cancer of the bone marrow with poor prognoses and dismal outcomes. Of the adult patients that …

Improving Distributed Health Information Technology Integration Through Enriched Context In Sociotechnical System Components, Jeritt Thayer

Dissertations and Theses (Open Access)

The design and architecture of health information technology (HIT) are in the process of a transformative shift. Monolithic code bases, which are several systems intertwined into a single program, are being split into multiple distributed programs that communicate across information networks. Thus far, only sparse knowledge exists about the challenges of distributed HIT, and the interaction of these architectures with other factors of the sociotechnical system, such as clinical content, is not well understood. Existing sociotechnical models describe the components within a healthcare system and the connections between components, but the types of relationships between each component are underspecified. Within …

Designing Recommendation Systems For Identification And Reduction Of Unnecessary Blood Tests, Tongtong Huang

Dissertations and Theses (Open Access)

Blood testing is an indispensable tool to check the patient's health status. However, the overutilization of lab tests in healthcare settings is a prevalent issue that can lead to redundant information, increased patient risk, and financial strain on healthcare resources. This dissertation presents novel approaches to optimizing lab test utilization by applying deep learning models. The primary objective is to develop and validate methods that accurately predict and reduce unnecessary blood tests.

The study introduces a “selective” mechanism that quantifies the predictability of future lab tests, allowing for the selective reduction of unnecessary tests in the context of specific clinical …

Discret: Synthesizing Faithful Explanations For Treatment Effect Estimation, Yinjun Wu, Mayank Keoliya, Kan Chen, Neelay Velingker, Ziyang Li, Emily J Getzen, Qi Long, Mayur Naik, Ravi B Parikh, Eric Wong

Faculty, Staff and Student Publications

Designing faithful yet accurate AI models is challenging, particularly in the field of individual treatment effect estimation (ITE). ITE prediction models deployed in critical settings such as healthcare should ideally be (i) accurate, and (ii) provide faithful explanations. However, current solutions are inadequate: state-of-the-art black-box models do not supply explanations, post-hoc explainers for black-box models lack faithfulness guarantees, and self-interpretable models greatly compromise accuracy. To address these issues, we propose DISCRET, a self-interpretable ITE framework that synthesizes faithful, rule-based explanations for each sample. A key insight behind DISCRET is that explanations can serve dually as database queries to identify similar …

Fedgmmat: Federated Generalized Linear Mixed Model Association Tests, Wentao Li, Han Chen, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

Increasing genetic and phenotypic data size is critical for understanding the genetic determinants of diseases. Evidently, establishing practical means for collaboration and data sharing among institutions is a fundamental methodological barrier for performing high-powered studies. As the sample sizes become more heterogeneous, complex statistical approaches, such as generalized linear mixed effects models, must be used to correct for the confounders that may bias results. On another front, due to the privacy concerns around Protected Health Information (PHI), genetic information is restrictively protected by sharing according to regulations such as Health Insurance Portability and Accountability Act (HIPAA). This limits data sharing …

Ultrapotent Broadly Neutralizing Human-Llama Bispecific Antibodies Against Hiv-1, Jianliang Xu, Tongqing Zhou, Krisha Mckee, Baoshan Zhang, Cuiping Liu, Alexandra F Nazzari, Amarendra Pegu, Chen-Hsiang Shen, Jordan E Becker, Michael F Bender, Payton Chan, Anita Changela, Ridhi Chaudhary, Xuejun Chen, Tal Einav, Young Do Kwon, Bob C Lin, Mark K Louder, Jonah S Merriam, Nicholas C Morano, Sijy O'Dell, Adam S Olia, Reda Rawi, Ryan S Roark, Tyler Stephens, I-Ting Teng, Emily Tourtellott-Fogt, Shuishu Wang, Eun Sung Yang, Lawrence Shapiro, Yaroslav Tsybovsky, Nicole A Doria-Rose, Rafael Casellas, Peter D Kwong

Faculty, Staff and Student Publications

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM …

Effect Of Medicaid Expansion On Cancer Treatment And Survival Among Medicaid Beneficiaries And The Uninsured, Kristin M Primm, Hui Zhao, Naomi N Adjei, Charlotte C Sun, Alen Haas, Larissa A Meyer, Shine Chang

Faculty, Staff and Student Publications

BACKGROUND: The Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.

METHODS: Medicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences …

Identification Of Immune-Associated Biomarkers Of Diabetes Nephropathy Tubulointerstitial Injury Based On Machine Learning: A Bioinformatics Multi-Chip Integrated Analysis, Lin Wang, Jiaming Su, Zhongjie Liu, Shaowei Ding, Yaotan Li, Baoluo Hou, Yuxin Hu, Zhaoxi Dong, Jingyi Tang, Hongfang Liu, Weijing Liu

Faculty, Staff and Student Publications

BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN.

METHODS: The …

A Deep Catalogue Of Protein-Coding Variation In 983,578 Individuals, Kathie Y Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan Maxwell, George Mitra, Alexander Gorovits, Adam Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E Locke, Liron Ganel, Alicia Hawes, Michael D Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berumen, Roberto Tapia-Conyer, Pablo Kuri-Morales, Jason Torres, Jonathan Emberson, Rory Collins, Regeneron Genetics Center, Rgc-Me Cohort Partners; Michael Cantor, Michael Cantor, Timothy Thornton, Hyun Min Kang, John D Overton, Alan R Shuldiner, M Laura Cremona, Mona Nafde, Aris Baras, Gonçalo Abecasis, Jonathan Marchini, Jeffrey G Reid, William Salerno, Suganthi Balasubramanian

Faculty, Staff and Student Publications

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of …

Targeting Of Cyp2e1 By Mirnas In Alcohol-Induced Intestine Injury, Hyejin Mun, Sungyul Lee, Suyoung Choi, Ji-Hoon Jeong, Seungbeom Ko, Yoo Lim Chun, Benjamin Deaton, Clay T Yeager, Audrey Boyette, Juliana Palmera, London Newman, Ping Zhou, Soona Shin, Dong-Chan Kim, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Jaeyul Kwon, Junyang Jung, Jeong Ho Chang, Je-Hyun Yoon

Faculty, Staff and Student Publications

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression …

Ghcu, A Molecular Chaperone, Regulates Leaf Curling By Modulating The Distribution Of Kngh1 In Cotton, Yihao Zang, Chenyu Xu, Lishan Yu, Longen Ma, Lisha Xuan, Sunyi Yan, Yayao Zhang, Yiwen Cao, Xiaoran Li, Zhanfeng Si, Jieqiong Deng, Tianzhen Zhang, Yan Hu

Faculty, Staff and Student Publications

Leaf shape is considered to be one of the most significant agronomic traits in crop breeding. However, the molecular basis underlying leaf morphogenesis in cotton is still largely unknown. In this study, through genetic mapping and molecular investigation using a natural cotton mutant cu with leaves curling upward, the causal gene GHCU is successfully identified as the key regulator of leaf flattening. Knockout of GHCU or its homolog in cotton and tobacco using CRISPR results in abnormal leaf shape. It is further discovered that GHCU facilitates the transport of the HD protein KNOTTED1-like (KNGH1) from the adaxial to the abaxial …

Genetic Analysis Of Seven Patients With Inherited Ichthyosis And Nagashima-Type Palmoplantar Keratoderma, Jing Zhang, Yue Yao, Ya Tan, Hua-Ying Hu, Lin-Xi Zeng, Guo-Qiang Zhang

Faculty, Staff and Student Publications

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole-exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis-like but distinct clinical manifestations. …

Change In Trust In Us Government Health Agencies For Cancer Information In The Covid-19 Era, Onyema G Chido-Amajuoyi, Rajesh Talluri, Henry K Onyeaka, Itunu Sokale, Gideon T Dosunmu, Noelle Loconte, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study assesses changes in levels of public trust in US government health agencies providing cancer information.

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

Fc Engineering By Monoclonal Mammalian Cell Display For Improved Affinity And Selectivity Towards Fcγrs, Zening Wang, Minhyo Kang, Afshin Ebrahimpour, Chuan Chen, Xin Ge

Faculty, Staff and Student Publications

Fc optimization can significantly enhance therapeutic efficacy of monoclonal antibodies. However, existing Fc engineering approaches are sub-optimal with noted limitations, such as inappropriate glycosylation, polyclonal libraries, and utilizing fragment but not full-length IgG display. Applying cell cycle arrested recombinase-mediated cassette exchange, this study constructed high-quality monoclonal Fc libraries in CHO cells, displayed full-length IgG on cell surface, and preformed ratiometric fluorescence activated cell sorting (FACS) with the antigen and individual FcγRs. Identified Fc variants were quantitatively evaluated by flow cytometry, ELISA, kinetic and steady-state binding affinity measurements, and cytotoxicity assays. An error-prone Fc library focusing on the hinge-CH2 region was …

Epigenetic Regulation Of Heart Failure, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

Purpose of review: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure.

Recent findings: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as …

50-Nm Gas-Filled Protein Nanostructures To Enable The Access Of Lymphatic Cells By Ultrasound Technologies, Qionghua Shen, Zongru Li, Yixian Wang, Matthew D Meyer, Marc T De Guzman, Janie C Lim, Han Xiao, Richard R Bouchard, George J Lu

Faculty, Staff and Student Publications

Ultrasound imaging and ultrasound-mediated gene and drug delivery are rapidly advancing diagnostic and therapeutic methods; however, their use is often limited by the need for microbubbles, which cannot transverse many biological barriers due to their large size. Here, the authors introduce 50-nm gas-filled protein nanostructures derived from genetically engineered gas vesicles(GVs) that are referred to as

Neighborhood-Level Social Determinants Of Health Burden Among Adolescent And Young Adult Cancer Patients And Impact On Overall Survival, Elizabeth R Rodriguez, Tori Tonn, Midhat Jafry, Sairah Ahmed, Branko Cuglievan, J Andrew Livingston, Christopher R Flowers, Gregory J Aune, Karen H Albritton, Michael E Roth, Qian Xiao, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

BACKGROUND: Neighborhood socioeconomic deprivation has been linked to adverse health outcomes, yet it is unclear whether neighborhood-level social determinants of health (SDOH) measures affect overall survival in adolescent and young adult patients with cancer.

METHODS: This study used a diverse cohort of adolescent and young adult patients with cancer (N = 10 261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI values representing worse SDOH.

RESULTS: ADI was statistically significantly worse (P < .050) for Black (61.7) and Hispanic (65.3) patients than for White patients (51.2). Analysis of ADI by cancer type showed statistically significant differences, mainly driven by worse ADI in patients with cervical cancer (62.3) than with other cancers. In multivariable models including sex, age at diagnosis, cancer diagnosis, and race and ethnicity, risk of shorter survival for people residing in neighborhoods with the least favorable ADI quartile was greater than for individuals in the most favorable ADI quartile (hazard ratio = 1.09, 95% confidence interval = 1.00 to 1.19, P = .043).

CONCLUSION: Adolescent and young adult patients with cancer and the worst ADI …

Evaluating Automatically Generated Normal Tissue Contours For Safe Use In Head And Neck And Cervical Cancer Treatment Planning, Raphael Douglas, Adenike Olanrewaju, Raymond Mumme, Lifei Zhang, Beth M Beadle, Laurence Edward Court

Faculty, Staff and Student Publications

Purpose: Volumetric-modulated arc therapy (VMAT) is a widely accepted treatment method for head and neck (HN) and cervical cancers; however, creating contours and plan optimization for VMAT plans is a time-consuming process. Our group has created an automated treatment planning tool, the Radiation Planning Assistant (RPA), that uses deep learning models to generate organs at risk (OARs), planning structures and automates plan optimization. This study quantitatively evaluates the quality of contours generated by the RPA tool.

Methods: For patients with HN (54) and cervical (39) cancers, we retrospectively generated autoplans using the RPA. Autoplans were generated using deep-learning and RapidPlan …