Medicine and Health Sciences Commons^™

Integrative Multi-Omics Profiling Identifies Infiltrative Hepatocellular Carcinoma As An Immunotherapy-Resistant Subtype With Distinct Molecular Features, Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Young Kwon, Da-Yeon Lee, Ju-Seog Lee, Junho Park, Youngsoo Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon

Faculty, Staff and Student Publications

Background/aims: Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).

Methods: We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.

Results: Infiltrative morphology, encompassing pure and …

Engineering Mutation Clones In Mammalian Cells With Crispr/Cas9, Zijun Huo, Jian Tu, Rachel Shoemaker, Dung-Fang Lee, Ruiying Zhao

Faculty, Staff and Student Publications

CRISPR, Clustered Regularly Interspaced Short Palindromic Repeat, as a powerful genome engineering system, has been widely accepted and employed in gene editing of a vast range of cell types. Compared to zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), CRISPR shows a less complicated process and higher efficiency. With the development of different CRISPR systems, it can be used not only to knock out a gene but also to make precise modifications, activate or repress target genes with epigenetic modifications, and even for genome wide screening. Here we will describe the procedure of generating a stable cell line …

Poly(A) Probe Hcr Rna-Fish Specifically Marks Pyriform Nurse Cells In The Brown Anole Lizard Ovary, Zoe B Griffin, Bonnie K Kircher, Richard R Behringer

Faculty, Staff and Student Publications

Hybridization chain reaction RNA-fluorescent in situ hybridization (HCR RNA-FISH) is a powerful and increasingly used method for visualizing gene expression in cells and tissues. A probe set against polyadenylated RNA (poly(A)) is often used as a positive control for RNA integrity and staining quality. While optimizing this technique in the ovary of the brown anole lizard (Anolis sagrei), we found that the poly(A) probe produced a strikingly specific and intense signal in pyriform cells, a specialized lizard-specific nurse cell type. This staining pattern was found in both whole-mount samples and paraffin sections, suggesting that poly(A) signal intensity can serve as …

Uncertainty-Guided Test-Time Optimization For Personalizing Segmentation Models In Longitudinal Medical Imaging, Jaehee Chun, Austin Castelo, Mckell Woodland, Caleb O'Connor, Mais Al Taie, Mohamed Eltaher, Aashish Gupta, Bilel Daoud, Shanli Ding, Jeddy Bennett, Anirban Maitra, Matthew A Firpo, Kimberly Kirkwood, Eugene J Koay, Kristy K Brock

Faculty, Staff and Student Publications

Background: Accurate and consistent image segmentation across longitudinal scans is essential in many clinical applications, including surveillance, treatment monitoring, and adaptive interventions. While personalized model adaptation using patient-specific prior scans has shown promise, current approaches typically rely on fixed training durations and lack mechanisms to determine optimal stopping points on a per-patient basis, particularly in the absence of validation labels.

Purpose: We propose an uncertainty-guided test-time optimization (TTO) framework that dynamically adjusts the personalization duration for each patient using a validation-free stopping criterion based on predictive uncertainty.

Methods: Our framework personalizes a generalized segmentation model using patient-specific prior imaging and …

Contralateral Breast Cancer After Radiotherapy And Hormone Therapy In Two Cohorts Of Us Breast Cancer Survivors, Lene H S Veiga, Gretchen L Gierach, Susan A Smith, Rebecca M Howell, Matthew M Mille, Monjoy Saha, Rochelle E Curtis, Cody Ramin, Clara Bodelon, Heather Spencer Feigelson, Erin J Aiello Bowles, Diana S M Buist, Sheila Weinmann, Jacqueline B Vo, Choonsik Lee, Amy Berrington De Gonzalez

Faculty, Staff and Student Publications

Background: Radiotherapy increases contralateral breast cancer risk, while hormone therapy reduces it; their combined effects are unclear.

Methods: Data from two US retrospective cohort studies of 5-year breast cancer survivors (stage I-III, ages 20-84), Kaiser Permanente (KP, 1990-2012) and SEER (1990-2013), were analysed. Contralateral breast radiation doses were estimated for the KP cohort. Multivariable Poisson regression estimated relative risks (RRs) and excess relative risks per Gray (ERR/Gy), stratified by hormone therapy use.

Results: KP cohort (n = 9053) included 353 contralateral breast cancer cases (73% ER+); SEER cohort (n = 244,834) included 10,470 cases (72% ER+). Among women with ER+ …

Host Modulation Therapy In Periodontitis: From Established Therapies To Emerging Technologies, Aonjittra Phanrungsuwan, Jiaqi Huang, Neeraja Dharmaraj, Alejandra Cobos Perez, Omid Veiseh, Simon Young, Chun-Teh Lee

Faculty, Staff and Student Publications

Periodontitis is a biofilm-induced chronic inflammatory disease, characterized by gingival inflammation and alveolar bone loss. According to a national survey, approximately half of the U.S. adults are affected by periodontal disease. To effectively prevent and treat periodontitis, it is essential to address its underlying causes. The primary etiological factors include polymicrobial synergy and dysbiosis of the oral microbiota, and a dysregulated immune response. The standard therapeutic approach, mechanical removal of biofilm through debridement, sometimes demonstrates limited efficacy, particularly in cases of severe periodontitis, which may require adjunctive or additional therapy. Emerging evidence indicates that periodontal tissue destruction is initiated by …

Attf-Gnn: An Attention-Based Multi-Omics Graph Neural Network With Modality Learning For Disease Subtyping, Sovon Chakraborty, Eleni Adam, Terry Stilwell, Harold Riethman, Desh Ranjan, Pratip Rana

Computer Science Faculty Publications

We propose AttF-GNN, an attention-based graph fusion strategy for diseases classification and subtyping. In multiomics analysis, not all types of molecular data are equally relevant for disease subtyping and considering all modalities equally may obscure discriminative signals and limit the effectiveness of predictive models by overlooking modality-specific contributions. Therefore, we design an attention-based multimodal GraphSAGE framework that can automatically emphasize the modalities providing the most relevant information for classification. At first, we have constructed three graphs using mRNA, RNA-seq and DNA methylation modalities, and train each omics with individual GraphSAGE encoders. Next, a unified intersection graph is formed using an …

Chromnet: A Multi-Task Learning Framework For Cross-Cell Type Prediction Of 3d Chromatin Interactions Using Epigenetic Signals, Bin Wang, Shaokai Wang, Liqing Ding, Hongdong Li, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

The 3D organization of chromatin plays a fundamental role in gene regulation, cellular function, and disease mechanisms. However, current experimental techniques, such as Hi-C, remain costly and labor-intensive, limiting their application in large-scale and disease-related studies. To address this challenge, ChromNet is presented, a multi-task learning framework that integrates epigenetic signals across diverse cell types to enable high-precision prediction of chromatin architecture. By incorporating noise perturbation and auxiliary classification tasks, ChromNet improves the identification of topologically associating domains (TADs) and cell-type-specific chromatin structures, demonstrating superior generalization performance. Notably, ChromNet accurately predicts chromatin interactions in acute myeloid leukemia (AML) samples by …

Adaptive Self-Attention For Enhanced Segmentation Of Adult Gliomas In Multi-Modal Mri, Evan P. Savaria, Jiangwen Sun

Computer Science Faculty Publications

Every year there are an estimated 80,000–90,000 new glioma cases, highlighting the need for reliable imaging-based decision support. Although deep learning has improved tumor sub-region segmentation, many state-of-the-art models fail to fully capture complementary information across T1, T1Gd, T2, and FLAIR MRI modalities and often operate as “black boxes,” limiting physician trust when precise delineation is critical for surgical planning, radiation targeting, and treatment monitoring. To address these limitations, we propose AIMS, an Adaptive Integrated Multi-Modal Segmentation framework that maintains modality-specific feature streams and employs adaptive self-attention within a hierarchical CNN-Transformer architecture to prioritize and fuse multi-modal MRI features. We …

Chemoradiation After Chemotherapy For Metastatic Cervical Cancer Can Provide Chemo-Free Time, Spoorthi Kamepalli, Ashley Chavana, Michelle Ludwig, Madeline Flanagan, Shelly Sharma, Tracilyn Hall, Anthony Costales, Jan Sunde, Claire Hoppenot

Faculty, Staff and Students Publications

Introduction: Stage IVB cervical cancer is treated with a life-prolonging and palliative intent with systemic chemotherapy and immunotherapy. The purpose of this study was to evaluate the number of these patients who had an adequate response to chemotherapy to be eligible for consolidative radiosensitizing chemotherapy and radiation (chemoradiation) and subsequent outcomes.

Materials and methods: This is a retrospective review of metastatic cervical cancer patients treated with chemotherapy and evaluated for treatment with consolidative pelvic chemoradiation at a single safety-net hospital system from 2016 to 2024. Demographic data and clinical information were collected from electronic medical records. Stata was used for …

Gender-Specific Behavior Reductions In Spontaneous Locomotive And Rearing In A Rat Model Of Paclitaxel-Induced Peripheral Neuropathy: A Pilot Study, Serena Jiyeon Kim, Kevin Cao, Patrick M Dougherty, Kathleen E Mcdonough, Saba Javed

Faculty, Staff and Students Publications

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) from agents like paclitaxel causes sensory loss and functional impairment, with limited treatment options. To better model patient-relevant outcomes, we used open field video tracking in rodents to assess gait, anxiety, and exploratory behavior. This approach provides a more comprehensive assessment of CIPN-related deficits beyond pain responses.

Methods and materials: Adult male and female Sprague Dawley rats were given paclitaxel (Taxol; 24 mg/kg cumulative dose) or a vehicle over 8 days. Their distance traveled, time spent in the center and outer zones of the OF test, and rearing behaviors were recorded using a PhenoTyper 4500 …

Lessons Learned From An Epic Transformation Of A Radiation Oncology Department In Guatemala: Keys To Success, Edgar Ruiz, Hiram A Gay, Milton Ixquiac, Angel Velarde, Baozhou Sun, Jose García-Ramirez, Eric Laugeman, Benjamin Li, Jeff Michalski, Vicky De Falla, Geoff Hugo, Jacaranda Van Rheenen

Faculty, Staff and Students Publications

Purpose: We describe the radical modernization of a radiation oncology department in a developing country, Guatemala, from 2015 to the beginning of 2024. The Instituto de Cancerología y Hospital Dr. Bernardo del Valle S (INCAN) is the only public radiotherapy clinic serving patient referrals from the Ministry of Public Health and Social Assistance program.

Methods and materials: We describe the state of the radiation oncology department in 2015 versus 2024 while chronicling its gradual transformation. This multifaceted collaboration involved academic centers, government agencies, International Atomic Energy Agency (IAEA), industry, and nonprofits and continues to this day. We analyze the infrastructure, …

Gallbladder Decompression And Hydrodissection As Adjuncts For Ablation Of Pericholecystic Hepatocellular Carcinomas, Taylor Hoffman, Arta Kasaeian, Johnathon Chung, Ashkan Berenji, David Wynne, Mohammad Ghasemi-Rad, David Léon

Faculty, Staff and Students Publications

Microwave ablation is an effective treatment for hepatocellular carcinoma, but tumors adjacent to extrahepatic organs carry a higher risk for thermal injury. Thermoprotective techniques such as hydrodissection and gallbladder decompression can reduce this risk and expand the range of lesions amenable to percutaneous treatment. We present a case of a 68-year-old woman with hepatocellular carcinoma in hepatic segment V, with partial treatment response from prior transarterial chemoembolization. Due to the lesion's proximity to the gallbladder and transverse colon, microwave ablation was performed with concurrent ultrasound- and CT-guided gallbladder decompression and hydrodissection. The ablation was technically successful without post-procedural complications. At …

Facilitators To The Implementation Of Exercise Into Cancer Care: A Systematic Review, Georgia L. White, Mary A. Kennedy, Brent J. Cunningham, Riley Dunn, Jason Martin, Meegan Walker, Craig T. Wallington-Gates, Hattie Wright, Bryan Chan, Grace L. Rose

Research outputs 2022 to 2026

Purpose: Although governing bodies urge the importance of integrating exercise into routine cancer care, facilitators to implementation have not been systematically identified and collated. This review aimed to summarise facilitators to implement exercise services within real-world settings. Methods: A systematic review of qualitative, quantitative, and mixed-method studies was conducted (three databases, 13th September 2024). Reports were included if they documented the implementation of co-located exercise services (delivered onsite within cancer centres) or referral pathways to external exercise services from cancer centres. The updated Consolidated Framework for Implementation Research (CFIR 2.0) was used to code and synthesise facilitators. Results: Of 8544 …

Measuring Cancer Equity Globally: Harmonising International Rural-Urban Classifications For Exploring Cancer Outcomes, Charlene Wright, Sharina Riva, Megan Crichton, Helena Rodi, Hannah Jongebloed, Lucy Leigh, Elizabeth A. Johnston, Rebecca J. Bergin, Anna Chapman, Laura Alston, Fiona Crawford–Williams, Nicolas H. Hart, Joel Rhee, Lan Gao, Kate Gunn, Harry Gasper, Anna Ugalde, Skye Marshall

Research outputs 2022 to 2026

Geographic disparities in cancer outcomes represent a critical health equity challenge, with rural populations consistently experiencing poorer outcomes than urban populations. The lack of harmonised rurality measures creates substantial barriers to evidence synthesis and has precluded meta-analyses. This perspectives paper discusses concepts of rurality, identifies rurality classification systems used by cancer researchers in OECD countries that can be harmonised with the OECD Extended Typology, and develops recommendations for consistent rural-urban coding. Targeted searches of grey and published literature on cancer policy and rurality classification systems were conducted. The secondary analysis examined studies identified through systematic database searching of OVID Medline, …

Circulating Tumor Cells In Uveal Melanoma: Multi-Marker Detection And Association With Disease State, Daniel P. De Bruyn, Fabiana Lucia Bassil, Mike Wu, Aaron B. Beasley, Jolanda Vaarwater, Mai N. Van, Jaco Kraan, Robert M. Verdijk, Dion Paridaens, Caroline M. Van Rij, Nicole C. Naus, Annelies De Klein, Elin S. Gray, Erwin Brosens, Emine Kiliç

Research outputs 2022 to 2026

Purpose. Uveal melanoma (UM) is primarily treated with eye-sparing radiotherapy, leaving limited tumor tissue for molecular analysis. Circulating tumor cells (CTCs) may offer a minimally invasive alternative for genomic tumor profiling. This pilot study evaluated the feasibility of a multi-marker CTC capture approach in UM patients at diagnosis, during fractionated stereotactic radiotherapy (fSRT), and at metastatic progression. Methods. Patients with localized or metastatic UM were prospectively enrolled. Peripheral blood samples were collected at baseline, during fSRT, and on detection of metastases. CTCs were captured and enumerated using a multi-marker approach and fluorescence microscopy. Results. A total of 76 patients were …

Rapid Decentralized Prostate Cancer Risk Stratification By Portable Liquid Biopsy Analysis Within A Clinical Biosensor Validation Framework, Kevin M. Koo, Grant Phillips, Sriganesh Srihari, Áine Farrell, Binny Jaradi, Kira J. Fitzpatrick, John W. Yaxley, Hemamali Samaratunga, Paul N. Mainwaring, Ke-Lin Ru, Darren J. Korbie, Scott A. Tomlins, Matthew J. Roberts, Robert A. Gardiner, Matt Trau

Research outputs 2022 to 2026

Clinical liquid biopsy (e.g., blood or urine) specimens, as a minimally invasive source of crucial molecular information, continue to grow in importance for efficacious targeted cancer treatment. Yet, current molecular profiling technologies are still confined to centralized laboratory testing, which escalates testing costs, result turnaround time, and patient anxiety. Crucially, there is also a scarcity of purposeful clinical validation studies to rigorously evaluate emerging liquid biopsy technologies from research settings to facilitate clinical translation. Here, we report liquid biopsy biosensor advancements in achieving rapid, accurate, and decentralized molecular profiling of a clinically accredited prostate cancer (PCa) urinary circulating RNA biomarker …

Adjuvant Pembrolizumab For Stage Iib Or Iic Melanoma: A Secondary Analysis Of A Randomized Clinical Trial, Sancy A. Leachman, Jason J. Luke, Paolo A. Ascierto, Georgina V. Long, Muhammad Khattak, Piotr Rutkowski, Zhi Jin Xu, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M.M. Eggermont, Dirk Schadendorf

Research outputs 2022 to 2026

Importance Patients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown. Objective To analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo. Design, Setting, and Participants The multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol. Interventions Participants were randomly assigned to receive …

Effects Of Resistance Vs High Intensity Interval Training On Myokines And Cancer Cell Suppression In Breast Cancer Survivors: A Randomized Trial, Francesco Bettariga, Dennis R. Taaffe, Cristina Crespo-Garcia, Timothy D. Clay, Mauro De Santi, Giulia Baldelli, Sanjeev Adhikari, Elin S. Gray, Daniel A. Galvão, Robert U. Newton

Research outputs 2022 to 2026

Purpose: Reducing recurrence and mortality is crucial for breast cancer survivors. We investigated the effects of a 12-week resistance training (RT) vs high-intensity interval training (HIIT) program on myokines, cytokines secreted by skeletal muscle cells at rest in response to muscle contraction, and cancer cell inhibition. Methods: Twenty-eight survivors of breast cancer (age 55.5 ± 8.8 yr, body mass index 27.9 ± 5.1 kg/m², time since diagnosis 31 ± 12.3 months) were randomly allocated to a 12-week supervised moderate to high intensity RT (n = 14) or HIIT (n = 14) program 3 days per week. Resting blood …

Cancer Survivor Preferences For Breast Cancer Follow-Up Care: A Discrete Choice Experiment, Sameera Senanayake, Sanjeewa Kularatna, Fiona Crawford-Williams, David Brain, Michelle Allen, Ruvini M. Hettiarachchi, Nicolas H. Hart, Bogda Koczwara, Carolyn Ee, Raymond J. Chan

Research outputs 2022 to 2026

Purpose: To identify the key attributes of breast cancer follow-up care models preferred by cancer survivors in Australia. Methods: A discrete choice experiment (DCE) was conducted to elicit preferences for attributes of breast cancer follow-up care. Respondents were presented with two hypothetical scenarios, known as choice sets, and asked to select a preference. Respondents were individuals living in Australia who were diagnosed with breast cancer within the past five years prior to survey completion and were recruited through the Breast Cancer Network of Australia and other community or consumer networks. Latent class modelling (LCM) approach under a random utility framework …

Feasibility And Preliminary Efficacy Of Integrative Neuromuscular Training For Childhood Cancer Survivors: A Pilot Study, Anna Maria Markarian, U. Newton, Dennis Taaffe, Nicholas G. Gottardo, Santosh Valvi, Carolyn J. Peddle-Mcintyre, Jodie Cochrane Wilkie, Daniel A. Galvão

Research outputs 2022 to 2026

Background: Survivors of childhood acute lymphoblastic leukemia (ALL) often exhibit early deficits in muscle and movement competence, which can compromise long-term health. Integrative neuromuscular training (INT), a multifaceted approach combining fundamental movement activities with strength exercises, may help address these deficits during critical developmental periods. Methods: Eight children treated for ALL (aged 6–12 years) completed a supervised INT intervention (2 sessions/week for 8 weeks). Primary outcomes were feasibility (recruitment, retention, adherence, compliance, and tolerance) and program acceptability. Secondary outcomes included muscle function (isometric midthigh pull [IMTP], countermovement jump, and handgrip strength), dual-energy x-ray absorptiometry (DXA)-derived body composition, peripheral quantitative computed …

Multidimensional Sleep Health And Sleep Environment Factors In Individuals With Cancer Undergoing Outpatient Chemotherapy: An Exploratory Cross-Sectional Analysis, Sam Adams, D. Clay, Arman Hasani, Mitchell Turner, Travis Cruickshank

Research outputs 2022 to 2026

Purpose: Sleep problems are common amongst individuals with cancer receiving chemotherapy and are associated with poorer health outcomes. Considerable research to date has investigated specific sleep domains or symptomology, with little attention given to overall sleep health, which is more closely associated with overall health. This exploratory cross-sectional study aimed to characterize multidimensional sleep health in individuals with cancer reporting sleep complaints whilst undergoing chemotherapy, with exploratory examination of environmental associations. Patients and Methods: Twenty-three participants were included in this exploratory cross-sectional analysis. Participants were diagnosed with cancer within the last 6 months, undergoing outpatient chemotherapy at time of study …

It Was Part Of The Plan, So I Showed Up: An Exploration Of Patient Experiences With An Embedded Exercise Referral Process During Cancer Treatment, Mary A. Kennedy, Jack Dalla Via, Kim Edmunds, Pam Eldridge, Yvonne Zissiadis, Lauren Fortington

Research outputs 2022 to 2026

Introduction: Exercise is a key part of cancer care, yet its integration into routine practice remains limited. This study explored the experiences of people living with and beyond cancer, with an updated, opt-out referral model embedded within a supportive oncology setting, focusing on initial engagement with exercise physiology appointments. Through this model, patients were automatically scheduled for a consultation with an in-house exercise professional during their cancer treatment. Methods: A qualitative descriptive design comprised of two focus groups with 13 participants was employed to explore views across pre-defined elements of the model: referral to exercise, appointments, counselling, and tailoring. Results: …

Development Of A Clinical Prediction Model To Guide The Selective Use Of Spect/Ct In Papillary Thyroid Cancer, Liya Zhu, Junik Son, Lu Wang, Haifeng Hou, Byeong Cheol Ahn

Research outputs 2022 to 2026

Background: Radioiodine whole-body scan (WBS) is routinely performed after radioiodine therapy in papillary thyroid cancer (PTC), but its two-dimensional nature limits anatomical localization. The addition of single-photon emission computed tomography/computed tomography (SPECT/CT) improves diagnostic accuracy; however, routine use exposes patients to additional radiation, longer imaging time, and higher costs. This study aimed to establish a predictive model to identify which patients with PTC are more likely to benefit by adding SPECT/CT imaging after WBS, enabling selective rather than routine use. Methods: This retrospective study included 265 patients with pathologically confirmed PTC who underwent postoperative radioiodine therapy followed by WBS and …

Emerging Blood-Based Biomarkers For The Detection Of Parenchymal Brain Metastasis: Current Progress And Future Perspectives, Désirée Sexauer, Elin S. Gray, Helen Rizos, Pauline Zaenker, Aaron B. Beasley

Research outputs 2022 to 2026

Parenchymal brain metastases of solid malignancies remain a significant clinical challenge, as they are often detected at later symptomatic stages, which are typically associated with worse prognosis. Delayed detection limits treatment options and contributes to poor outcomes, while early detection is critical for improving patient outcomes and quality of life. In this comprehensive review, we investigated the potential use and challenges of blood-based biomarkers, including circulating tumor cells, cell-free DNA, noncoding RNAs, extracellular vesicles, proteins, and other immune-related biomarkers, for the early detection of parenchymal brain metastasis. The use of blood-based liquid biopsies offers a promising avenue for early detection …

Gwas Meta-Analysis Provides New Insights Into Uveal Melanoma Risk, Matthew D’Mellow, Huanwei Wang, Jane M. Palmer, Kari Hemminki, Colleen M. Cebulla, Aaron B. Beasley, Nikolaos E. Bechrakis, Antonia L. Pritchard, Karin W. Wadt, Peter A. Johansson, Lenha Mobuchon, Samantha Barlow, Kelly Brooks, Timothy Beckman, Catherine M. Olsen, Sunil K. Warrier, Lindsey Byrne, Helen Kalirai, Colette Mustard, Nathan Ingold, Asta Försti, Timothy Isaacs

Research outputs 2022 to 2026

Objective: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. Methods: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM’s genetic architecture. …

Analysis And Numerical Investigation Of A Breast Cancer Treatment Model Incorporating Ketogenic Diet And Immune Boosters Via Optimal Control Theory, Kunnisai Muniroh, Ummu Habibah, Wuryansari Muharini Kusumawinahyu, Nur’Izzati Hamdan

Mathematical Modelling and Numerical Simulation with Applications

This paper develops a mathematical model to investigate breast cancer dynamics by incorporating tumor–immune interactions, ketogenic diet effects, and medical treatment. The model is formulated as a system of nonlinear ordinary differential equations and analyzed within an optimal control framework. Time-dependent control variables are introduced to represent treatment strategies aimed at minimizing tumor progression while reducing therapeutic costs. The model’s well-posedness is established through positivity and boundedness analysis. The necessary conditions for optimality are derived using Pontryagin’s Minimum Principle, resulting in a coupled system of state and adjoint equations. Numerical solutions are obtained using the fourth-order Runge–Kutta method combined with …

Inflammatory Co-Regulation Of Voltage-Gated Sodium Channels And Na,K-Atpase In Metastatic Breast Cancer, Steven D. Scahill, Kelly Jean Sherman, Dennis Paul

School of Graduate Studies Faculty Publications

Sodium regulation is a potentially major driver of cancer metastasis. Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters that are upregulated in many advanced carcinomas and are implicated as metastatic drivers. However, little is known about what drives this overexpression, how these proteins influence metastatic behavior, or whether these complementary sodium transporters are co-regulated in cancer. Using sodium transporter regulation in healthy neurons as a model, the present study demonstrated that the inflammatory mediator tumor necrosis factor alpha (TNFα) affects the expression of VGSCs and Na,K-ATPase in an in vitro model of metastatic breast cancer. Acute TNFα challenge increased …

Netrin-1 Promotes Pancreatic Tumorigenesis And Innervation Through Neo1, Hiroki Kobayashi, Yosuke Ochiai, Junya Arai, Masahiro Hata, Feijing Wu, Masaki Sunagawa, Tadashi Iida, Taisuke Baba, Ermanno Malagola, Takayuki Tanaka, Zhengyu Jiang, Ruth A White, Xiaofei Zhi, Jin Qian, Quin T Waterbury, Ruhong Tu, Biyun Zheng, Yi Zeng, Hualong Zheng, Puran Zhang, Shuang Li, Leah B Zamechek, Jonathan S Labella, Takahiro Sugie, Atsushi Enomoto, Holger K Eltzschig, Carmine F Palermo, Iok In Christine Chio, Kenneth P Olive, Timothy C Wang

Faculty, Staff and Student Publications

Nerves can regulate tumorigenesis and cancer progression. However, clarification of the role of axon guidance molecules in tumorigenesis, innervation, and metastasis is required to better understand the tumor-promoting functions of nerves. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules and identified netrin-1 upregulation. Netrin-1 was also upregulated in vivo during pancreatic tumorigenesis in humans and mice. Mutant KRAS and β-adrenergic signaling upregulated netrin-1 and its receptor NEO1 in epithelial cells in part through the MAPK pathway. Ex vivo culture of celiac ganglia showed that netrin-1 promoted the axonogenesis of sympathetic neurons through nerve NEO1. In the Pdx1-Cre;LSL-KrasG12D/+ model, …

Speeding Up Interval Estimation For R2-Based Mediation Effect Of High-Dimensional Mediators Via Cross-Fitting, Zhichao Xu, Chunlin Li, Sunyi Chi, Tianzhong Yang, Peng Wei

Faculty, Staff and Student Publications

Mediation analysis is a useful tool in investigating how molecular phenotypes such as gene expression mediate the effect of exposure on health outcomes. However, commonly used mean-based total mediation effect measures may suffer from cancellation of component-wise mediation effects in opposite directions in the presence of high-dimensional omics mediators. To overcome this limitation, we recently proposed a variance-based R-squared total mediation effect measure that relies on the computationally intensive nonparametric bootstrap for confidence interval estimation. In the work described herein, we formulated a more efficient two-stage, cross-fitted estimation procedure for the R2 measure. To avoid potential bias, we performed …