Medicine and Health Sciences Commons^™

Mitochondria-Mediated Epigenetic Transfer Between Chondrosarcoma And Wild-Type Cells, Caleb C. J. Wyckoff

Biomedical Sciences Theses & Dissertations

Glioblastoma (GB), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), cholangiocarcinoma, and chondrosarcoma (CS) cancers all contain mutations in the gene isocitrate dehydrogenase 2 (IDH2). The mutant IDH2 enzyme exhibits transformation of alpha-ketoglutarate (αKG) into the oncometabolite D-2-hydroxyglutarate (D2HG) in the mitochondria of these cancers. Mitochondrial-mediated transfer between cancer cells and recipient cells is a significant event that impacts the physiology of the receiving cell, specifically the epigenetic landscape. Previous experiments indicating increased DNA methylation in mesenchymal stem cells exposed to IDH1 or IDH2 conditioned medium underscore the potential role of D2HG to alter methylation states. Additionally, the presence of …

The Microstructure Of Metastatic Bone Lesions Suggests Tumor Mediated Alterations In Bone Mineralization, Hanwen Fan, Zhan Xu, Carla Berrospe Rodriguez, Noah Dover, Andrei Demkov, Morgan Lilly, Guillermo Aguilar, Larry J Suva, Xiang H-F Zhang, Yuxiao Zhou

Faculty, Staff and Students Publications

Breast, prostate and lung cancer cells frequently metastasize to bone, leading to disruption of the bone microstructure. This study utilized mechanical testing coupled with micro-CT imaging, digital volume correlation (DVC), and atomic force microscopy (AFM) nanomechanical testing to examine the mechanical property variations in mouse long bones (tibia) with metastatic lung cancer cell involvement, spanning from the whole-bone scale to the microstructural level. In addition, we also investigated how metastatic invasion alters the morphology of hydroxyapatite nanocrystals in bone at the nanometer scale. The biochemical composition within metastatic lesions was assessed using Raman spectroscopy and correlated with AFM mechanical testing …

Lilrb4 Regulates Circadian Disruption-Induced Mammary Tumorigenesis Via Non-Canonical Wnt Signaling Pathway, Olajumoke Ogunlusi, Mrinmoy Sarkar, Kayla Carter, Arhit Chakrabarti, Devon J Boland, Tristan Nguyen, James Sampson, Christian Nguyen, Danielle Fails, Yava Jones-Hall, Loning Fu, Gus Wright, Da Mi Kim, James J Cai, Bani Mallick, Alex C Keene, Jeff R Jones, Tapasree Roy Sarkar

Faculty, Staff and Students Publications

Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanism underlying CRD-induced carcinogenesis remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model of aggressive breast cancer was used. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA-seq, flow cytometry, multiplexing immunostaining, and realtime PCR. The effect of LILRB4-immunotherapy on CRD-induced tumorigenesis was also investigated. Here we investigated …

Differential Microrna Profiling Of Blood L1cam And Bulk Extracellular Vesicles In Bipolar Disorder, Gabriel R Fries, Salahudeen Mirza, Jun Wang, Camila N C Lima, Wei Zhang, Marcela Carbajal Tamez, Giselli Scaini, Jair C Soares, Joao Quevedo

Faculty, Staff and Student Publications

Objective: This preliminary study aimed to identify microRNA (miRNA) signatures associated with bipolar disorder (BD) by profiling blood-derived extracellular vesicles (EVs) of both putative neuronal origin and from all sources.

Method: In two parallel studies of individuals with BD and controls (CON), we characterized miRNA expression profiles of blood EVs selected for L1CAM, a putative marker of neuronal origin (n = 20 BD/20 CON), as well as bulk EVs (n = 21 BD/20 CON). For each study, analyses identified miRNAs differentially expressed between groups, followed by functional interrogation and testing for associations with clinical features.

Results: Results of …

Decomposition Processes And Insect Indicators In Forensic Investigations, Eli Taylor

University Honors Theses

Insects play an essential biological and ecological role in human life, and their predictable relationship with decomposing remains has positioned them as a cornerstone of modern forensic science. Since the early 20th century, forensic entomology has provided critical evidence for estimating the postmortem interval (PMI), relying on patterns of colonization, species succession, and insect developmental timelines. Accurate PMI estimations are vital to medicolegal investigations, influencing the interpretation of biological evidence, guiding resource allocation, and informing determinations of cause and manner of death. However, insect activity is profoundly shaped by environmental and ecological variables, including temperature, humidity, seasonal shifts, and geographic …

Genetic Variations In Extracellular Matrix Degradation Pathways Linking To Major Depressive Disorder: Evidence From A Large-Scale Genetic Association Study, Halliru Zailani, Daniel Tzu-Li Chen, Sheng-Che Lin, Jia-Hau Lee, Mei-Ling Li, Jane Pei-Chen Chang, Kuan-Pin Su

BioMedicine

Dysregulation of extracellular matrix (ECM) degradation pathways has been increasingly implicated in major depressive disorder (MDD), yet its genetic basis remains unclear. This study investigated the relationship between ECM-related genetic polymorphisms and MDD susceptibility. In a case-control study, we analyzed 317 MDD patients and 1,268 sexmatched controls from the Taiwan Biobank (TWB). Genomic DNA was analyzed using the Affymetrix TWB array, targeting single nucleotide polymorphisms (SNPs) in 140 ECM degradation genes (Reactome database). Full-model association tests identified significant SNPs, validated with 5,000 max(T) permutations and adjusted via logistic regression for age, body mass index, education level, and marital status. We …

Neuroprotection Of Paeoniflorin As Antidepressant Candidate, Yuh-Fung Chen, Yi-Jui Chen, Jai-Sing Yang, Min-Min Lee, Huei-Yann Tsai

BioMedicine

Background: Depression is one of the common mental disorders worldwide, and currently used antidepressants have undesirable effects; therefore, the development of new antidepressants without side effects is urgently needed. Paeoniflorin (PF) exhibits various pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective effects. NMDA receptors in the hippocampus play a vital role in the pathophysiology of depression. Due to the scarcity of reports on the neuroprotection of PF on NMDA-induced excitotoxicity in the hippocampus, the present study aims to investigate the effects of PF on NMDA-mediated EPSP and calcium influx in the hippocampus to evaluate the potential of PF as an antidepressant. …

Prophylactic Effect Of Omega-3 Polyunsaturated Fatty Acids Monotherapy In Preventing Recurrent Major Depressive Disorder: A Randomized Controlled Trial, Ikbal Andrian Malau, Cheng-Ho Chang, Wei-Jen Chen, Wen-Chun Liu, Halliru Zailani, Hsien-Feng Liao, Jane Pei-Chen Chang, Wei-Che Chiu, Kuan-Pin Su

BioMedicine

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have demonstrated efficacy as adjunctive treatment for MDD. In fact, fewer studies assessed the prophylactic properties of n-3 PUFAs as monotherapy on the recurrence of MDD.

Aims: This study aimed to assess the prophylactic effect of n-3 PUFAs monotherapy against recurrent MDD.

Methods: We conducted a 6-month randomized controlled trial to assess the prophylactic effect of n-3 in preventing recurrent MDD. We assigned 60 remitted MDD patients to the n-3 group (n = 30) and placebo (n = 30). Furthermore, we assessed the difference in depression severity and MDD recurrence based on the …

Tai Chi For Cardiovascular Wellness: Integrating An Ancient Practice Into Modern Therapeutic Approaches, Chun-Han Cheng, Wen-Rui Hao, Huan-Yuan Chen, Po-Yuan Chen, Ju-Chi Liu, Tzu-Hurng Cheng

BioMedicine

Tai Chi, a traditional Chinese martial art characterized by gentle, fluid movements and deep breathing, has gained increasing recognition for its cardiovascular health benefits. This study investigated the integration of Tai Chi into contemporary cardiovascular health practices, focusing on its physiological and psychological effects. The slow, controlled movements characteristic of Tai Chi contribute to enhanced cardiovascular fitness, decreased blood pressure, and improved vascular function, while simultaneously alleviating stress and fostering emotional well-being. Through a review of clinical studies and trials, this study underscores the efficacy of Tai Chi in cardiovascular rehabilitation programs and its accessibility as a community-based intervention. Additionally, …

Circadian Rhythms And Neuroendocrine Dysregulation In Adhd: Therapeutic Insights From Omega-3 Fatty Acids, Ayesha Zafar Iqbal, Patricia Marest Suwindi, Sunny Yin-Shan Chen, Lindsay Liang-Tien Cho, Kuan-Pin Su, Jane Pei-Chen Chang

BioMedicine

Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition often accompanied by circadian rhythm disturbances, particularly delayed sleep phase. These involve superchiasmatic nucleus (SCN) dysregulation, altered melatonin secretion, and hypothalamic–pituitary–adrenal (HPA) axis activity, which may be exacerbated by artificial light exposure. Genetic studies further implicate circadian mechanisms, linking ADHD with polymorphisms in clock genes such as PER and CLOCK.

Nutraceuticals, particularly omega-3 polyunsaturated fatty acids (n-3 PUFAs), have been proposed as modulators of circadian rhythms. N-3 PUFAs are essential for brain health and may influence melatonin synthesis and sleep–wake regulation. Preclinical and clinical findings suggest that supplementation can improve cognitive …

The Integrative Role Of Melatonin In Psychiatric Disorders: A Systematic Review Of Evidence From Circadian Biology, Lifestyle Medicine, And Psychoneuroimmunology, Ho Bao Chau Le, Kollawat Somsri, Thansita Bhunyakarnjanarat, Nattiya Hirankarn, Asada Leelahavanichkul

BioMedicine

Melatonin, a hormone produced by the pineal gland, is known for regulating circadian rhythms and has emerging therapeutic potential in psychiatric disorders. This systematic review examines evidence from clinical and preclinical studies to assess melatonin’s efficacy in the following conditions: depression, anxiety, bipolar disorder, and schizophrenia. Beyond its role in circadian regulation, melatonin exhibits antioxidative, anti-inflammatory, and immunomodulatory properties, which intersect with nutrition, lifestyle medicine, and psychoneuroimmunology (PNI).

The review finds that melatonin improves sleep quality, restores circadian balance, and modulates stress-related neuroimmune pathways. It also supports neuroplasticity and reduces oxidative stress, contributing to resilience against psychosocial and environmental stressors. …

From Rhythm To Resilience: The Interplay Of Circadian Rhythm, Melatonin, Lifestyle, Nutrition In Psychoneuroimmunology (Pni), Jane Pei-Chen Chang, Kuan-Pin Su

BioMedicine

Emerging evidence reveals that circadian rhythm, melatonin signaling, nutrition, and inflammation are intricately intertwined in shaping both mental and physical health. Circadian disruptions and lifestyle imbalances contribute to neuroinflammation, mood dysregulation, and cardiometabolic dysfunction, as seen in attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), metabolic syndrome,and cardiovascular diseases. This special issue highlights interdisciplinary research that integrates circadian biology, nutrition, and psychoneuroimmunology (PNI) toward personalized and preventive psychiatry. Featured studies explore circadian and melatonin mechanisms in ADHD and MDD, the therapeutic and prophylactic potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs), the neuroprotective potentical of paeoniflorin, and the role of extracellular …

Stage- And Smoking-Associated Microrna Expression In Lung Adenocarcinoma, Min Huang, Yimin Ge, Huiqin Chen, Caimiao Wei, David Cogdell, Cristina Ivan, Meng Chen, Wei Zhang, George A Calin, Ming Guo

Faculty, Staff and Student Publications

Background: Altered expression of microRNAs (miRNAs) is implicated in lung carcinogenesis, but little research has investigated the association of miRNA alterations with lung cancer stage or smoking status. To identify such alterations in lung adenocarcinoma, we conducted miRNA profiling.

Methods: Lung adenocarcinoma specimens and paired nonneoplastic lung tissues from 58 patients who had received no preoperative therapy and underwent tumor resection from 1991 to 2006 were collected from tumor tissue banks. Thirty (52%) of the tumors were stage I and 28 (48%) stage II or higher. Twenty-five (43%) patients were nonsmokers and 33 (57%) were smokers. To identify miRNAs of …

Workplace Policy And Associated Factors Of Minimum Acceptable Diet Practices: An Online Survey Among Working Mothers In Indonesia, Fadhila Iswi Deandra, Judhiastuty Februhartanty, Muchtaruddin Mansyur

Kesmas

Working mothers in Indonesia may influence complementary feeding practices, particularly their ability to ensure that their infants properly meet the minimum acceptable diet (MAD). In this cross-sectional study, an online survey was distributed through various online platforms where participants were recruited using convenience sampling. The questionnaire covered sociodemographic factors, workplace policies, and infant and young child feeding (IYCF) practices. Descriptive and logistic regression analyses were conducted. A total of 394 working mothers participated, of which over 90% of the respondents reported meeting minimum dietary diversity, minimum milk frequency, minimum milk feeding frequency, and MAD indicators as assessed with a standardized …

Emission Characterization And Health Risk Assessment Of Volatile Organic Compounds From Automotive Painting In Thailand, Vanitchaya Kultan, Sarawut Thepanondh, Jutarat Keawboonchu, Nattaporn Pinthong, Wissawa Malakan

Kesmas

The automotive industry is a significant source of volatile organic compound (VOC) emissions, particularly from solvent-based painting processes. This study evaluated VOC characteristics and distribution to assess associated health risks for workers and communities at varying distances from automotive painting facilities in Thailand, focusing on stacks and wastewater treatment plants that handle solvent-containing wastewater. The findings revealed aromatic compounds were predominant (66% of the total emissions), followed by oxygenated VOCs (26%). The stacks mainly emitted aromatics such as toluene and ethylbenzene, whereas the wastewater released oxygenated VOCs, particularly methyl isobutyl ketone and methyl ethyl ketone. The exposure concentrations in each …

Benchmarking Dna Foundation Models For Genomic And Genetic Tasks, Haonan Feng, Lang Wu, Bingxin Zhao, Chad Huff, Jianjun Zhang, Jia Wu, Lifeng Lin, Peng Wei, Chong Wu

School of Medicine Faculty Publications

The rapid evolution of DNA foundation models promises to revolutionize genomics, yet comprehensive evaluations are lacking. Here, we present a comprehensive, unbiased benchmark of five models (DNABERT-2, Nucleotide Transformer V2, HyenaDNA, Caduceus-Ph, and GROVER) across diverse genomic and genetic tasks including sequence classification, gene expression prediction, variant effect quantification, and topologically associating domain (TAD) region recognition, using zero-shot embeddings. Our analysis reveals that mean token embedding consistently and significantly improves sequence classification performance, outperforming other pooling strategies. Model performance varies among tasks and datasets; while general purpose DNA foundation models showed competitive performance in pathogenic variant identification, they were less …

Developmental Stage-Dependent Transcriptomic Responses To Neonatal Intraventricular Hemorrhage, Elizabeth Wallace-Anthony, Miriam Zamorano, Hemendra J Vekaria, Braden B Oldham, Kiara P Umpornpun, Scott D Olson, Stefano Berto, Brandon A Miller

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a major complication of preterm birth, yet how developmental stage influences the brain's response to injury remains unclear. We performed single-nucleus RNA sequencing on rat brains 24 h after IVH at postnatal day 2 (PND2) or day 5 (PND5) to define transcriptional responses across cell types. We identified 42 distinct cell populations and found that PND5 brains exhibited a markedly stronger immune and inflammatory response to IVH, with a threefold increase in differentially expressed genes compared to PND2. Microglia were the most perturbed cell type at both stages, showing increased oxidative stress and polarization toward …

Benchmarking Dna Foundation Models For Genomic And Genetic Tasks, Haonan Feng, Lang Wu, Bingxin Zhao, Chad Huff, Jianjun Zhang, Jia Wu, Lifeng Lin, Peng Wei, Chong Wu

Faculty, Staff and Student Publications

The rapid evolution of DNA foundation models promises to revolutionize genomics, yet comprehensive evaluations are lacking. Here, we present a comprehensive, unbiased benchmark of five models (DNABERT-2, Nucleotide Transformer V2, HyenaDNA, Caduceus-Ph, and GROVER) across diverse genomic and genetic tasks including sequence classification, gene expression prediction, variant effect quantification, and topologically associating domain (TAD) region recognition, using zero-shot embeddings. Our analysis reveals that mean token embedding consistently and significantly improves sequence classification performance, outperforming other pooling strategies. Model performance varies among tasks and datasets; while general purpose DNA foundation models showed competitive performance in pathogenic variant identification, they were less …

Radiologist-Validated Automatic Lumbar T1-Weighted Spinal Mri Segmentation Tool Via An Attention U-Net Algorithm, Aryan Kalluvila, Ethan Wang, Michael C Hurley, Colbey Freeman, Jason M Johnson

Faculty, Staff and Student Publications

Background/Objectives: Spinal MRI segmentation has become increasingly important with the prevalence of disc herniation and vertebral injuries. Artificial intelligence can help orthopedic surgeons and radiologists automate the process of segmentation. Currently, there are few tools for T1-weighted spinal MRI segmentation, with most focusing on T2-weighted imaging. This paper focuses on creating an automatic lumbar spinal MRI segmentation tool for T1-weighted images using deep learning.

Methods: An Attention U-Net was employed as the main algorithm because the architecture has shown success in other segmentation applications. Segmentation loss functions were compared, focusing on the difference between BCE and MSE loss. Two board-certified …

Transdisciplinary Perspectives On Ai: The Fourth Annual Conference Of The European Culture And Technology Laboratory, Connell Vaughan, Ioana Madalina Moldovan, Silivan Moldovan, Noel Fitzpatrick

Books/Book Chapters

The fourth annual conference of the ECT Lab+ was hosted by Technical University of Cluj-Napoca over two days in October 2024 at the Cluj Innovation Park. The conference brought together experts from the Arts, Humanities, Social Sciences, Technology, and other fields to discuss and reflect on the advent of Artificial Intelligence and how the associated technologies are transforming how we live, work and study. Under the title Transdisciplinary perspectives on AI: Alternative Histories, Current Practices and Possible Futures the conference moved beyond simplistic technophila and technophobia to consider whether we can co-evolve with these new technologies which combine machine learning …

Met Overexpression Is Associated With Superior Immunotherapy Benefit In Advanced Non-Small Cell Lung Cancer, Hui Li, Lingzhi Hong, Pedro Rocha, Rafael Bach, Luisa M Solis Soto, Waree Rinsurongkawong, Bingnan Zhang, Haniel A Araujo, Yasir Y Elamin, Mehmet Altan, Claudio A Arrechedera, Jianling Zhou, Khaja B Khan, Wei Lu, Elliana Young, Carl M Gay, Tina Cascone, Lauren A Byers, Ferdinandos Skoulidis, George Blumenschein, Frank V Fossella, Anne Tsao, Marcelo V Negrao, Natalie Vokes, Jia Wu, Hai T Tran, Ignacio I Wistuba, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Xiuning Le, Jianjun Zhang

Faculty, Staff and Student Publications

Background/objectives: MET overexpression is common in non-small cell lung cancer (NSCLC). The correlation between MET overexpression and immune checkpoint inhibitor (ICI) efficacy in NSCLC is underexplored.

Methods: In this retrospective observational cohort study, we curated a dataset of 279 stage IV NSCLC patients who received ICI treatment and had MET expression assessed by CLIA-certified immunohistochemistry (IHC) assay. MET expression was graded on a scale from 0 to 3+, with overexpression defined as 2+ or 3+. Clinicopathological features associated with MET expression were assessed using logistic regression. Overall survival (OS) and progression-free survival (PFS) were evaluated via Kaplan-Meier analysis and the …

Improving Diagnostic Accuracy In Preoperative Glioma Classification: Performance Of Knowledge-Enhanced Large Language Models Compared With Radiologists, Shuang Li, Xin Fang, Yuqi Jin, Yujiao Deng, Wei Hu, Bing Wu, Xiaobo Zhou, Guotai Wang, Kang Li, Qiang Yue

Faculty, Staff and Student Publications

Accurate preoperative MRI classification of gliomas is essential but challenging due to complex radiological features and inter-observer variability. This study evaluated three large language models (LLMs) for VASARI-based glioma classification compared to radiologist interpretations. We retrospectively analyzed 150 histopathologically confirmed gliomas (43 circumscribed astrocytic, 53 high-grade diffuse, 54 low-grade diffuse gliomas) using standardized MRI protocols. Three radiologists extracted VASARI features, while three LLMs (GPT-4, Claude3.5-Sonnet, Claude3.0-Opus) analyzed these features using standard input-output or knowledge-enhanced prompting incorporating diagnostic guidelines. Knowledge-enhanced prompting consistently outperformed standard prompting, improving diagnostic consistency (intra-model agreement: Sonnet κ = 0.91, Opus κ = 0.92, GPT-4 κ = …

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Soluble Immune Factor Profiles In Blood And Csf Associated With Lrrk2 Mutations And Parkinson's Disease, Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed, Jackson G Schumacher, Jae Ahn, Leilei Shi, Yujia Wang, Yukun Tan, Jiayin Zhang, Ken Chen, Hussein Tawbi, Jian Wang, Michael A Schwarzschild, Weiyi Peng, Xiqun Chen

Faculty, Staff and Student Publications

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of …

Dna Extrusion Size Determines Pathway Choice During Cag Repeat Expansion, Mayuri Bhatia, Ashutosh S. Phadte, Anna Lakhina, Anthony R. Monte Carloi Iii, Sarah Barndt, Anna Pluciennik

Department of Biochemistry and Molecular Biology Faculty Papers

DNA triplet repeat expansion causes several primarly neurological disorders like Huntington's disease, myotonic dystrophy type 1, and fragile-X related disorders. There is general consensus that recognition of extrahelical extrusions or hairpin-loop structures (formed by strand slippage) by the DNA mismatch repair protein MutSβ leads to repeat expansion by a mutagenic process. By contrast, the FAN1 nuclease attenuates triplet repeat expansion, the molecular basis of which was explained by our recent finding that FAN1 nuclease cleaves and initiates removal of extrahelical extrusions. Here we show that extrusions containing two or more triplet repeats are subject to recognition and processing by either …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

Loss Of Idh1 And Idh2 Mutations During The Evolution Of Metastatic Chondrosarcoma, William Cross, Iben Lyskjær, Christopher Davies, Abigail Bunkum, Ana Maia Rocha, Tom Lesluyes, Fernanda Amary, Roberto Tirabosco, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Charles Swanton, Nischalan Pillay, Simone Zaccaria, Adrienne M Flanagan, Peter Van Loo

Faculty, Staff and Student Publications

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Optimizing Lower Intensity Triplet Therapy In Acute Myeloid Leukemia: A Practical Guide, Wei-Ying Jen, Curtis A Lachowiez, Jennifer Marvin-Peek, Jessica K Altman, Musa Yilmaz, Jacqueline S Garcia, Yasmin Abaza, Nicholas J Short, Joshua F Zeidner, Naval G Daver, Andrew H Wei, Ghayas C Issa, Courtney D Dinardo

Faculty, Staff and Student Publications

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and …

Targeting The Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma, Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase …

Patient-Reported Outcomes After Ipsilateral Radiation Therapy For N2b Tonsillar Squamous Cell Carcinoma, Chike O Abana, Adam S Garden, G Brandon Gunn, Gregory M Chronowski, Abdallah S R Mohamed, Andrew J Frankart, Natalie Geier, Houda Bahig, Carly E A Barbon, Kate Hutcheson, Vinita Takiar, Clifton D Fuller, Steven J Frank, David I Rosenthal, Jack Phan

Faculty, Staff and Student Publications

Background: Previous studies have reported excellent disease control and survival in patients with well-lateralized, American Joint Committee on Cancer (AJCC)-7 T1-2N2b tonsillar squamous cell carcinoma (SCC). The reduced treatment volume is associated with lower rates of physician-assessed toxicity. Patient-reported outcomes (PROs) have been proposed as a similarly reliable measure, but the body of literature is limited for unilaterally treated patients. Our goal was to review PROs of such patients who had reduced treatment volumes.

Methods: We reviewed PROs of patients with AJCC-7 T1-2N2b disease treated with ipsilateral radiation therapy (RT), with or without surgery or chemotherapy before RT. PROs were …