Genetic Phenomena Commons^™

White Matter Abnormalities And Cognition In Aging And Alzheimer Disease, Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, T Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders

Faculty, Staff and Student Publications

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design setting and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were …

Complete Response To Trastuzumab-Deruxtecan (Enhertu, T-Dxd) In Her2-Positive Stage Ivb Uterine Carcinosarcoma, Michael Kim, Amma Asare, Jamie L Dockery, Nadia Hameed, Travis T Sims

Faculty, Staff and Student Publications

Objectives: To report a case of complete response to trastuzumab-deruxtecan (T-DXd) in a patient with HER2-positive stage IVB uterine carcinosarcoma, and to contextualize this within evolving therapy for HER2-positive gynecologic malignancies.

Methods: We present the clinical course of a 62-year-old woman with a history of multiple prior malignancies, diagnosed with stage IVB uterine carcinosarcoma exhibiting HER2 overexpression. Following optimal cytoreductive surgery and first-line carboplatin, paclitaxel, and trastuzumab, the patient developed platinum-resistant recurrence. She was subsequently treated with T-DXd, and received serial imaging and clinical monitoring.

Results: The patient achieved a partial response by cycle 4 of T-DXd, with subsequent scans …

Nanotechnology For Immuno-Oncology, Adam J Grippin, Daeyong Lee, Eileen E Parkes, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.

Consensus Statement On The Prevention And Management Of Complications Of Fully Ablative Laser Resurfacing Of The Face, Bianca Y Kang, Joel L Cohen, Roy Geronemus, Suzanne L Kilmer, Edward Victor Ross, Elizabeth L Tanzi, Jill S Waibel, Brian J F Wong, Murad Alam, Macrene Alexiades, Kenneth A Arndt, Mathew Avram, Ashish C Bhatia, Brian Stuart Biesman, Jason D Bloom, A Jay Burns, Henry H L Chan, Catherine M Digiorgio, Jeffrey S Dover, Sam Fathizadeh, Sara C Esteves, Michael H Gold, Gerald N Goldberg, Merete Haedersdal, Elika Hoss, Omar A Ibrahimi, H Ray Jalian, Kristen M Kelly, Woraphong Manuskiatti, Lisa A Marks, Girish S Munavalli, Jason N Pozner, Chris W Robb, Anthony M Rossi, Nazanin Saedi, Peter R Shumaker, Kelly Stankiewicz, Molly Wanner, Douglas C Wu, Adam J Wulkan, Arisa Ortiz

Faculty, Staff and Student Publications

Objectives: To achieve consensus among expert laser surgeons on standards for the prevention and management of adverse events from fully ablative laser resurfacing of the face.

Materials and methods: Delphi study with two rounds of ratings and revisions until consensus was achieved. The draft set of statements was developed by a steering committee based on expert clinical experience. This was followed by two rounds of rating and revisions completed by an expert panel, then a virtual consensus meeting. In both rounds, respondents rated the draft statements on a 9-point Likert scale (1 = strongly disagree; 9 = strongly agree) and …

Provider Attitudes And Perspectives On Rehabilitation For Pediatric Cancer Patients, Maria C Swartz, Eduardo Gonzalez Villarreal, Keri Schadler, Donna Kelly, Alakh P Rajan, Clark Andersen, Shiming Zhang, Stephanie J Wells, Amy Heaton, Karen M Moody

Faculty, Staff and Student Publications

PurposeTwenty percent of childhood cancer survivors experience physical function impairments, and ∼75% develop a chronic health condition. Physical and occupational therapists (PT/OTs) can mitigate these late effects, yet few children receive cancer rehabilitation (CR). This research aimed to identify provider attitudes and perspectives towards CR services for children across inpatient and outpatient settings at a cancer center.MethodsThree cardiac rehabilitation instruments were adapted to evaluate knowledge, attitudes, and perceptions regarding CR delivery. Descriptive statistics were used to summarize participant survey results.ResultsTwenty administrators, 20 physicians/advanced practice providers (APPs), and 20 PT/OTs completed surveys. All disciplines strongly agreed on the value of CR …

The Significance Of Detecting An Unusual Myeloblast Immunophenotype In A Presumptive Clinical Diagnosis Of Myelodysplastic Syndromes, Fnu Sameeta, Wei Wang, Fatima Zahra Jelloul, Okechukwu V Nwogbo, Beenu Thakral, Jie Xu, Shaoying Li, Chi Young Ok, Guilin Tang, Fuli Jia, L Jeffrey Medeiros, Sanam Loghavi, Jeffrey L Jorgensen, Sa A Wang

Faculty, Staff and Student Publications

Context.—: Blasts in myelodysplastic syndromes (MDSs) typically have a primitive myeloid immunophenotype (CD34+CD117+CD13+CD33+HLA-DR+). On rare occasions, blasts were found to be CD34 negative or minimally expressed in a presumptive MDS.

Objective.—: To investigate the occurrence of these cases, and to examine any unique molecular genetic features, and clinical relevance.

Design.—: More than 2000 flow cytometry immunophenotyping tests for MDS performed during a 5-year period were retrospectively reviewed. Chronic myelomonocytic leukemia and overt acute myeloid leukemia (AML) (≥20% blasts) were excluded.

Results.—: Approximately 800 cases had abnormal myeloblasts consistent with myeloid neoplasms; 96% of cases showed a typical primitive phenotype, but …

Bard: A Seamless Two-Stage Dose Optimization Design Integrating Backfill And Adaptive Randomization, Yixuan Zhao, Rachael Liu, Jianchang Lin, Ying Yuan

Faculty, Staff and Student Publications

One common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose, followed by a randomization stage where patients are assigned to two or more doses to further assess and compare their risk-benefit profiles to identify the optimal dose. A limitation of this approach is its requirement for a relatively large sample size. To address this challenge, we propose a seamless two-stage design, BARD (Backfill and Adaptive Randomization for Dose Optimization), which incorporates two key features to reduce sample size and shorten trial duration. The first feature is the integration of …

Gd3 Synthase Drives Resistance To P53-Induced Apoptosis In Breast Cancer By Modulating Mitochondrial Function, Vivek Anand, Fouad El-Dana, Natalia Baran, Jenny Borgman, Zheng Yin, Hong Zhao, Stephen T Wong, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

TP53 mutations are common in breast cancer (BC) and are associated with poor prognosis. GD3 synthase (GD3S/ST8SIA1), a gene associated with breast cancer stem cells, is upregulated in tumors with p53 mutations. However, the functional relationship between GD3S and p53 is unknown. Here, we show that GD3S levels are highest in breast tumors with specific p53 mutations. Functional studies revealed that wild-type (WT) p53 inhibits GD3S expression, whereas mutation in p53 enhances GD3S expression by upregulating GD3S promoter activity. Moreover, we found that GD3S inhibits wild-type p53-induced apoptosis in BC cells, while BC cells harboring gain-of-function p53 mutations are dependent …

Pparγ-Induced Upregulation Of Fatty Acid Metabolism Confers Resistance To Venetoclax And Decitabine Therapy In Aml, Kotoko Yamatani, Tatsuro Watanabe, Kaori Saito, Abdullah Khasawneh, Abhishek Maiti, Zhihong Zeng, Kala Hayes, Shinya Kimura, Courtney D Dinardo, Xiaoping Su, Shuko Nojiri, Yasushi Okazaki, Michael Andreeff, Marina Konopleva, Yoko Tabe

Faculty, Staff and Student Publications

The combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC; VEN/DEC) constitutes a primary therapeutic strategy for treating older adults with acute myeloid leukemia (AML). However, a notable subset of patients exhibits resistance to VEN/DEC, demonstrating either no disease response or relapse after initial remission. This study aimed to elucidate the molecular mechanisms underlying this resistance through analyses of gene expression and DNA methylation profiles. We conducted comprehensive RNA sequencing analysis and DNA methylation profiling on AML samples from 35 patients undergoing VEN/DEC therapy. The RNA sequencing analysis revealed that several genes related …

Dynamic Long-Term Prediction With Intermediate Event Information: A Flexible Model With Bivariate Time-Varying Coefficients, Yunyi Wang, Wen Li, Ruosha Li, Jing Ning

Faculty, Staff and Student Publications

The integration of time-to-intermediate event data and the evolving characteristics of patients to enhance long-term prediction has garnered significant interest, driven by the wealth of data generated from longitudinal cohorts. In this paper, we propose sequential/dynamic prediction rules by using regression models with time-varying coefficients. We introduce a class of dynamic models that not only incorporates intermediate event information but also leverages information across different landmark times. To address the challenge of right-censoring, we employ an inverse weighting technique in the estimation process. We establish the asymptotic properties of the estimated parameters and conduct extensive simulations to assess the finite …

Single-Cell Proteomic Analysis Reveals Multiple Myeloma Heterogeneity And The Dynamics Of The Tumor Immune Microenvironment In Precursor And Advanced States, Mohamed Kamal, Stephanie N Shishido, Jeremy Mason, Krina Patel, Elisabet E Manasanch, Robert Z Orlowski, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone …

De-Escalating Local Therapies Without Compromising Outcomes: Lessons From The Collision Trial, Jessica Albuquerque, Noreen S Siddiqi, Van K Morris, Hop Tran Cao, Iwan Paolucci, Bruno C Odisio

Faculty, Staff and Student Publications

No abstract provided.

Patient, Physician, And Assessor Blinding In Phase Iii Randomized Trials In Oncology: A Meta-Epidemiological Analysis, Gabrielle Brown, Pavlos Msaouel, Avital M Miller, Ramez Kouzy, Timothy A Lin, Joseph Abi Jaoude, Ethan B Ludmir, Alexander D Sherry

Faculty, Staff and Student Publications

Background: Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression-free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints.

Methods: Two-arm, superiority-design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double-blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety-five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic …

Management Of Aromatase Inhibitor-Associated Bone Loss (Aibl) In Women With Hormone-Sensitive Breast Cancer: An Updated Joint Position Statement Of The Iof, Cabs, Ects, Ieg, Esceo, Ims, And Siog, Peyman Hadji, Matty Aapro, Nasser Al-Dagri, Majed Alokail, Emmanuel Biver, Jean-Jacques Body, Maria Luisa Brandi, Janet Brown, Cyrille Confavreux, Bernard Cortet, Matthew Drake, Peter Ebeling, Erik Fink Eriksen, Ghada El-Hajj Fuleihan, Theresa A Guise, Nick C Harvey, Andreas Kurth, Bente Langdahl, Willem Lems, Radmila Matijevic, Eugene Mccloskey, Rossella Nappi, Santiago Palacios, Georg Pfeiler, Jean-Yves Reginster, René Rizzoli, Daniele Santini, Sansin Tuzun, Catherine Van Poznak, Tobias De Villiers, M Carola Zillikens, Robert Coleman

Faculty, Staff and Student Publications

Background: Women with hormone-responsive breast cancer who receive adjuvant endocrine treatment with aromatase inhibitors (AI) are known to be at higher fracture risk due to a marked increase in bone resorption. In 2017, several interdisciplinary cancer and bone societies involved in the management of women with AI-associated bone loss (AIBL) published a joint position statement comprising evidence-based recommendations and a practical management algorithm for the assessment of fracture risk and optimal treatment of this patient population.

Patients and methods: In order to provide updated recommendations that reflect recent advances in the assessment and management of AIBL since publication of the …

Tert Promoter Mutations And Survival Outcomes In Adult-Type Granulosa Cell Tumors, Allison L Brodsky, Alejandra Flores Legarreta, Bryan M Fellman, Deanna Glassman, Jeffrey How, Veena Vuttaradhi, Anil K Sood, Lois Michelle Ramondetta, David Gershenson, R Tyler Hillman

Faculty, Staff and Student Publications

Objectives: To evaluate survival outcomes among patients with adult-type granulosa cell tumors who have telomerase reverse transcriptase (TERT) promoter mutations.

Methods: This is a retrospective cohort study using the MD Anderson Rare Gynecologic Malignancy Registry. Patients with adult granulosa cell tumors who underwent molecular testing for TERT promoter and FOXL2 c.C402G mutations were included. We used descriptive statistics to compare demographic and clinical variables and estimated progression-free and overall survival with Kaplan-Meier curves. Cox proportional hazards regression and log-rank tests were employed for comparisons, with multivariable analyses adjusting for various factors.

Results: Among 70 patients, 28 (40%) had TERT+ tumors. …

Ppp2r1a Mutations Portend Improved Survival After Cancer Immunotherapy, Yibo Dai, Anne Knisely, Mitsutake Yano, Minghao Dang, Emily M Hinchcliff, Sanghoon Lee, Annalyn Welp, Manoj Chelvanambi, Matthew Lastrapes, Heng Liu, Zhe Yuan, Chen Wang, Hao Nie, Stephanie Jean, Luis J Montaner, Jiakai Hou, Ami Patel, Shrina Patel, Bryan Fellman, Ying Yuan, Baohua Sun, Renganayaki Krishna Pandurengan, Edwin Roger Parra Cuentas, Joseph Celestino, Yan Liu, Jinsong Liu, R Tyler Hillman, Shannon N Westin, Anil K Sood, Pamela T Soliman, Aaron Shafer, Larissa A Meyer, David M Gershenson, David Vining, Dhakshinamoorthy Ganeshan, Karen Lu, Jennifer A Wargo, Weiyi Peng, Rugang Zhang, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes1-5. Here we studied ICB response in a cohort of patients with ovarian clear cell carcinoma-a cancer type that poses considerable clinical challenges and lacks effective therapies6-8. We observed significantly prolonged overall survival and progression-free survival in patients with tumours with PPP2R1A mutations. Importantly, our findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumour biopsies demonstrated enhanced IFNγ signalling, and the presence of tertiary lymphoid structures at the baseline, …

Nature-Inspired Metaheuristics For Optimizing Dose-Finding And Computationally Challenging Clinical Trial Designs, Weng Kee Wong, Yevgen Ryeznik, Oleksandr Sverdlov, Ping-Yang Chen, Xinying Fang, Ray-Bing Chen, Shouhao Zhou, J Jack Lee

Faculty, Staff and Student Publications

Metaheuristics are commonly used in computer science and engineering to solve optimization problems, but their potential applications in clinical trial design have remained largely unexplored. This article provides a brief overview of metaheuristics and reviews their limited use in clinical trial settings. We focus on nature-inspired metaheuristics and apply one of its exemplary algorithms, the particle swarm optimization (PSO) algorithm, to find phase I/II designs that jointly consider toxicity and efficacy. As a specific application, we demonstrate the utility of PSO in designing optimal dose-finding studies to estimate the optimal biological dose (OBD) for a continuation-ratio model with four parameters …

Optimization Of Mhealth Behavioral Interventions For Patients With Chronic Lymphocytic Leukemia: The Health4cll Study, Che Young Lee, Max J Gordon, Melissa M Markofski, Emily C Lavoy, Susan K Peterson, Liang Li, Sara Fares, Miranda Baum, Margaret Pace, Danielle Walsh, Alessandra Ferrajoli, Karen Basen-Engquist

Faculty, Staff and Student Publications

Purpose: This pilot study of a diet and physical activity intervention (HEALTH4CLL) was conducted to reduce fatigue and improve physical function (PF) in patients with chronic lymphocytic leukemia (CLL).

Methods: The HEALTH4CLL study used a randomized factorial design based on the multiphase optimization strategy (MOST). Patients received diet, exercise, and body weight management instructional materials plus a Fitbit and were randomized to undergo one of 16 combinations of 4 evidence-based mHealth intervention strategies over 16 weeks. Patients' fatigue, PF, health-related quality of life, behavior changes, and program satisfaction and retention were assessed. Paired t-tests were used to examine changes in …

Film Measurements Of Kilovoltage X-Ray Percentage Depth Doses For Different Energies And Field Sizes, Tze Yee Lim, Dershan Luo, Jamshid Moradi-Kurdestany, Xin Wang, Ramesh Tailor

Faculty, Staff and Student Publications

Objectives: Kilovoltage x-ray therapy, which includes superficial x-rays and orthovoltage x-rays, is particularly suited for treatments near the skin surface. Radiation dose deposition at depth is typically characterized by percentage depth dose (PDD) curves. However, PDD data are difficult to obtain in kilovoltage x-ray therapy, hence clinics often rely on British Journal of Radiology Supplement 25 (BJR-25) archival data. This study measured PDD for different energies and field sizes on the Xstrahl 300 kilovoltage x-ray therapy unit for comparison with BJR-25 data.

Methods: We irradiated EBT3 film in water using different energy and field size combinations, then, compared the acquired …

Orp2 Regulates Free Cholesterol Accumulation In Hepatocytes During Mash, Jin Wu, Yudi Zhao, Liwen Qiu, Qiaoli Chen, Xiaowei Wang, Jingwen Gu, Yan Liang, Yingjie Zhang, Hong-Yu Wang, Yang Liu, Xiaoqin Wu, Shuai Chen, Feng-Jung Chen, Mingming Gao, Hongyuan Yang

Faculty, Staff and Student Publications

Background: Cholesterol crystals in hepatocytes are known to strongly associate with human metabolic dysfunction-associated steatohepatitis. However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation and the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from endosomal compartments.

Methods: Here, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high-fat diet.

Results: The ORP2-LKO mice developed much more severe hepatic steatosis than floxed control mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. …