Medical Genetics Commons^™

Evaluation Of Major Pathologic Response And Pathologic Complete Response As Surrogate End Points For Survival In Randomized Controlled Trials Of Neoadjuvant Immune Checkpoint Blockade In Resectable In Nsclc, Jacobi B Hines, Robert B Cameron, Alessandra Esposito, Leeseul Kim, Luca Porcu, Antonio Nuccio, Giuseppe Viscardi, Roberto Ferrara, Giulia Veronesi, Patrick M Forde, Janis Taube, Everett Vokes, Christine M Bestvina, James M Dolezal, Matteo Sacco, Marta Monteforte, Tina Cascone, Marina C Garassino, Valter Torri

Faculty, Staff and Student Publications

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC.

Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were …

Mycophenolate Mofetil Is Associated With Inferior Overall Survival In Cytomegalovirus-Seropositive Patients With Acute Myeloid Leukemia Undergoing Hematopoietic Cell Transplantation, Rima M Saliba, Stephanie J Lee, Paul A Carpenter, Geoffrey R Hill, Catherine J Lee, Amin Alousi, May Daher, George Chen, Richard E Champlin, Katayoun Rezvani, Elizabeth J Shpall, Rohtesh S Mehta

Faculty, Staff and Student Publications

No abstract provided.

Apoptosis Pathway-Associated Proteins Are Frequently Expressed In Melanoma: A Study Of 32 Cases With Focus On Acral Lentiginous Melanoma, Debora A Ledesma, Mario L Marques-Piubelli, Elsa Li-Ning-Tapia, Courtney Hudgens, Jun Gu, Rossana Lazcano, Sandro Casavilca-Zambrano, Miluska Castillo, Michael A Davies, Wen-Jen Hwu, Phyu P Aung, Alessio Giubellino, Jonathan L Curry, Carlos Torres-Cabala

Faculty, Staff and Student Publications

Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and …

Evaluating The Relationship Between Magnetic Resonance Image Quality Metrics And Deep Learning-Based Segmentation Accuracy Of Brain Tumors, Rajarajeswari Muthusivarajan, Adrian Celaya, Joshua P Yung, James P Long, Satish E Viswanath, Daniel S Marcus, Caroline Chung, David Fuentes

Faculty, Staff and Student Publications

Background: Magnetic resonance imaging (MRI) scans are known to suffer from a variety of acquisition artifacts as well as equipment-based variations that impact image appearance and segmentation performance. It is still unclear whether a direct relationship exists between magnetic resonance (MR) image quality metrics (IQMs) (e.g., signal-to-noise, contrast-to-noise) and segmentation accuracy.

Purpose: Deep learning (DL) approaches have shown significant promise for automated segmentation of brain tumors on MRI but depend on the quality of input training images. We sought to evaluate the relationship between IQMs of input training images and DL-based brain tumor segmentation accuracy toward developing more generalizable models …

Technical Note: Radiological Clinical Equivalence For Phantom Materials In Carbon Ion Therapy, Paige A Taylor, Alfredo Mirandola, Mario Ciocca, Shannon Hartzell, Alessandro Vai, Paola Alvarez, Rebecca M Howell, Eugene J Koay, Christopher R Peeler, Christine B Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: As carbon ion radiotherapy increases in use, there are limited phantom materials for heterogeneous or anthropomorphic phantom measurements. This work characterized the radiological clinical equivalence of several phantom materials in a therapeutic carbon ion beam.

Methods: Eight materials were tested for radiological material-equivalence in a carbon ion beam. The materials were computed tomography (CT)-scanned to obtain Hounsfield unit (HU) values, then irradiated in a monoenergetic carbon ion beam to determine relative linear stopping power (RLSP). The corresponding HU and RLSP for each phantom material were compared to clinical carbon ion calibration curves. For absorbed dose comparison, ion chamber measurements …

The Dynamic Trpv2 Ion Channel Proximity Proteome Reveals Functional Links Of Calcium Flux With Cellular Adhesion Factors Ncam And L1cam In Neurite Outgrowth, Pamela N Gallo, Elaine Mihelc, Robyn Eisert, Gary A Bradshaw, Florian Dimek, Andreas Leffler, Marian Kalocsay, Vera Moiseenkova-Bell

Faculty, Staff and Student Publications

TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2's physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation. Quantitative TRPV2 proximity proteomics further revealed activation-induced enrichment of protein clusters with biological functions in neural and cellular projection. We demonstrate a functional connection between TRPV2 and the neural immunoglobulin cell adhesion molecules NCAM and L1CAM. …

Navigating The Critical Translational Questions For Implementing Flash In The Clinic, Billy W Loo, Ioannis I Verginadis, Brita Singers Sørensen, Anthony E Mascia, John P Perentesis, Albert C Koong, Emil Schüler, Erinn B Rankin, Peter G Maxim, Charles L Limoli, Marie-Catherine Vozenin

Faculty, Staff and Student Publications

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of …

Post-Trial Responsibilities In Pragmatic Clinical Trials: Fulfilling The Promise Of Research To Drive Real-World Change, Stephanie R Morain, P Pearl O'Rourke, Joseph Ali, Vasiliki Rahimzadeh, Devon K Check, Hayden B Bosworth, Jeremy Sugarman

Center for Medical Ethics and Health Policy Staff Publications

While considerable scholarship has explored responsibilities owed to research participants at the conclusion of explanatory clinical trials, no guidance exists regarding responsibilities owed at the conclusion of a pragmatic clinical trial (PCT). Yet post-trial responsibilities in PCTs present distinct considerations from those emphasized in existing guidance and prior scholarship. Among these considerations include the responsibilities of the healthcare delivery systems in which PCTs are embedded, and decisions about implementation for interventions that demonstrate meaningful benefit following their integration into usual care settings-or deimplementation for those that fail to do so. In this article, we present an overview of prior scholarship …

Genetic Deletion Of Galectin-3 Inhibits Pancreatic Cancer Progression And Enhances The Efficacy Of Immunotherapy, Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.

Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated …

Type I Conventional Dendritic Cells Facilitate Immunotherapy In Pancreatic Cancer, Krishnan K Mahadevan, Allison M Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari M Sockwell, Kathleen M Mcandrews, Lakshmi Kavitha Sthanam, Huamin Wang, Shabnam Shalapour, Stephanie S Watowich, Raghu Kalluri

Faculty, Staff and Student Publications

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study …

Author Correction: Plasmonic Nano-Aperture Label-Free Imaging Of Single Small Extracellular Vesicles For Cancer Detection, Nareg Ohannesian, Mohammad Sadman Mallick, Jianzhong He, Yawei Qiao, Nan Li, Simona F Shaitelman, Chad Tang, Eileen H Shinn, Wayne L Hofstetter, Alexei Goltsov, Manal M Hassan, Kelly K Hunt, Steven H Lin, Wei-Chuan Shih

Faculty, Staff and Student Publications

No abstract provided.

The Significant Associations Between Epigenetic Clocks And Bladder Cancer Risks, Yang Deng, Chia-Wen Tsai, Wen-Shin Chang, Yifan Xu, Maosheng Huang, Da-Tian Bau, Jian Gu

Faculty, Staff and Student Publications

Bladder cancer is an age-related disease, with over three-quarters of cases occurring in individuals aged 65 years and older. Accelerated biological aging has been linked to elevated cancer risks. Epigenetic clocks serve as excellent predictors of biological age, yet it remains unclear whether they are associated with bladder cancer risk. In this large case-control study, we assessed the associations between four well-established epigenetic clocks-HannumAge, HorvathAge, GrimAge, and PhenoAge-and bladder cancer risk. Utilizing single nucleotide polymorphisms (SNPs), which were identified in a genome-wide association study (GWAS), linked to these clocks as instruments, we constructed a weighted genetic risk score (GRS) for …

Developing A Fit-For-Purpose Composite Symptom Score As A Symptom Burden Endpoint For Clinical Trials In Patients With Malignant Pleural Mesothelioma, Charles S Cleeland, Karen N Keating, Brian Cuffel, Cem Elbi, Jonathan M Siegel, Christoph Gerlinger, Tara Symonds, Jeff A Sloan, Amylou C Dueck, Andrew Bottomley, Xin Shelley Wang, Loretta A Williams, Tito R Mendoza

Faculty, Staff and Student Publications

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma …

Contribution Of Matrix Metalloproteinase-2 And Matrix Metalloproteinase-9 To Upper Tract Urothelial Cancer Risk In Taiwan, Bo-Ren Wang, Hung-Huan Ma, Chao-Hsiang Chang, Cheng-Hsi Liao, Wen-Shin Chang, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau, Chia-Wen Tsai

Faculty, Staff and Student Publications

Matrix metalloproteinase (MMP)-2 and -9, which degrade type IV collagen, are linked to cancer invasion and metastasis. Gene polymorphisms in MMP-2 and MMP-9 can influence their function, impacting cancer development and progression. This study analyzed the association between polymorphisms MMP-2 rs243865 (C-1306T), rs2285053 (C-735T), and MMP-9 rs3918242 (C-1562T) with serum concentrations of these enzymes in upper tract urothelial cancer (UTUC) patients. We conducted a case-control study with 218 UTUC patients and 580 healthy individuals in Taiwan. Genotyping was performed using PCR/RFLP on DNA from blood samples, and MMP-2 and MMP-9 serum levels and mRNA expressions in 30 UTUC patients were …

Mettl3-Mediated Chromatin Contacts Promote Stress Granule Phase Separation Through Metabolic Reprogramming During Senescence, Chen Wang, Hideki Tanizawa, Connor Hill, Aaron Havas, Qiang Zhang, Liping Liao, Xue Hao, Xue Lei, Lu Wang, Hao Nie, Yuan Qi, Bin Tian, Alessandro Gardini, Andrew V Kossenkov, Aaron Goldman, Shelley L Berger, Ken-Ichi Noma, Peter D Adams, Rugang Zhang

Faculty, Staff and Student Publications

METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase …

Hypoxia Inducible Factor 2Α Promotes Tolerogenic Macrophage Development During Cardiac Transplantation Through Transcriptional Regulation Of Colony Stimulating Factor 1 Receptor, Matthew Deberge, Samantha Schroth, Fanfan Du, Xin Yi Yeap, Jiao-Jing Wang, Zheng Jenny Zhang, Mohammed Javeed Ansari, Evan A Scott, Edward B Thorp

Faculty, Staff and Student Publications

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice …

Car T-Cell Expansion: Harmful Or Helpful?, Anath C Lionel, Sattva S Neelapu

Faculty, Staff and Student Publications

No abstract provided.

Clinical And Genomic Profile Of Primary Cranial Neurolymphomatosis, Emily B Wolf, Robin Imperial, Liuyan Jiang, Amit K Agarwal, Han W Tun

Faculty, Staff and Student Publications

Primary cranial neurolymphomatosis (PCNL) is a rare subtype of primary CNS lymphoma (PCNSL) in which infiltrative lymphomatous involvement is confined to cranial nerves. Here, we report a case of PCNL with successful genomic profiling. A 57-year-old male had a lengthy prediagnostic phase spanning approximately 30 months, characterized by multiple episodes of cranial neuropathies managed by steroids. At the time of diagnosis, the patient had right-sided cranial neuropathies involving cranial nerves (CN) V, VI, and VII. Pathological findings of the right cavernous lesion biopsy were consistent with large B-cell lymphoma-infiltrating nerve fibers. The clinical course was aggressive and refractory, characterized by …

Discovery Of Runs-Of-Homozygosity Diplotype Clusters And Their Associations With Diseases In Uk Biobank, Ardalan Naseri, Degui Zhi, Shaojie Zhang

Faculty, Staff and Student Publications

Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number …

Study Of Prognostic Splicing Factors In Cancer Using Machine Learning Approaches, Mengyuan Yang, Jiajia Liu, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Splicing factors (SFs) are the major RNA-binding proteins (RBPs) and key molecules that regulate the splicing of mRNA molecules through binding to mRNAs. The expression of splicing factors is frequently deregulated in different cancer types, causing the generation of oncogenic proteins involved in cancer hallmarks. In this study, we investigated the genes that encode RNA-binding proteins and identified potential splicing factors that contribute to the aberrant splicing applying a random forest classification model. The result suggested 56 splicing factors were related to the prognosis of 13 cancers, two SF complexes in liver hepatocellular carcinoma, and one SF complex in esophageal …

Multiple Omics Levels Of Chronic Lymphocytic Leukemia, Aleksander Turk, Eva Čeh, George A Calin, Tanja Kunej

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by the proliferation of functionally mature but incompetent B cells. It is the most prevalent type of leukemia in Western populations, accounting for approximately 25% of new leukemia cases. While recent advances, such as ibrutinib and venetoclax treatment have improved patient outlook, aggressive forms of CLL such as Richter transformation still pose a significant challenge. This discrepancy may be due to the heterogeneity of factors contributing to CLL development at multiple -omics levels. However, information on the omics of CLL is fragmented, hindering multi-omics-based research into potential treatment options. To address …

Electronic Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: Long-Term Results Of A Multicenter, Randomized, Controlled Trial, Wei Dai, Yaqin Wang, Jia Liao, Xing Wei, Zhen Dai, Wei Xu, Yangjun Liu, Xin Shelley Wang, Cecilia Pompili, Hongfan Yu, Yang Pu, Yuqian Zhao, Bangrong Cao, Qifeng Wang, Wenhong Feng, Yuanqiang Zhang, Fang Liu, Yuanle Deng, Jin Zhou, Juan Li, Shaohua Xie, Run Xiang, Xiang Wang, Bo Tian, Xiaozun Yang, Bin Hu, Xiaoqin Liu, Tianpeng Xie, Xiaojun Yang, Xiang Zhuang, Guibin Qiao, Qiang Li, Qiuling Shi

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported superior symptom control of electronic patient-reported outcome (ePRO)-based symptom management after lung cancer surgery for up to 1 month postdischarge. Here, we present the long-term results (1-12 months) of this multicenter, randomized trial, where …

Keep Fingers On The Cpg Islands, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

The post-genomic era has ushered in the extensive application of epigenetic editing tools, allowing for precise alterations of gene expression. The use of reprogrammable editors that carry transcriptional corepressors has significant potential for long-term epigenetic silencing for the treatment of human diseases. The ideal scenario involves precise targeting of a specific genomic location by a DNA-binding domain, ensuring there are no off-target effects and that the process yields no genetic remnants aside from specific epigenetic modifications (i.e., DNA methylation). A notable example is a recent study on the mouse

Microglial P2y6 Calcium Signaling Promotes Phagocytosis And Shapes Neuroimmune Responses In Epileptogenesis, Anthony D Umpierre, Bohan Li, Katayoun Ayasoufi, Whitney L Simon, Shunyi Zhao, Manling Xie, Grace Thyen, Benjamin Hur, Jiaying Zheng, Yue Liang, Dale B Bosco, Mark A Maynes, Zhaofa Wu, Xinzhu Yu, Jaeyun Sung, Aaron J Johnson, Yulong Li, Long-Jun Wu

Faculty, Staff and Student Publications

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium …

The Cdk9 Inhibitor Enitociclib Overcomes Resistance To Btk Inhibition And Car-T Therapy In Mantle Cell Lymphoma, Vivian Jiang, William Lee, Tianci Zhang, Alexa Jordan, Fangfang Yan, Qingsong Cai, Joseph Mcintosh, Jovanny Vargas, Yang Liu, Michael Wang

Faculty, Staff and Student Publications

Inhibitors of Bruton's tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes …

Neurogranin Modulates The Rate Of Association Between Calmodulin And Target Peptides, John A Putkey, Laurel Hoffman, Vladimir Berka, Xu Wang

Faculty, Staff and Student Publications

The best-known mode of action of calmodulin (CaM) is binding of Ca2+ to its N- and C-domains, followed by binding to target proteins. An underappreciated facet of this process is that CaM is typically bound to proteins at basal levels of free Ca2+, including the small, intrinsically disordered, neuronal IQ-motif proteins called PEP-19 and neurogranin (Ng). PEP-19 and Ng would not be effective competitive inhibitors of high-affinity Ca2+-dependent CaM targets at equilibrium because they bind to CaM with relatively low affinity, but they could influence the time course of CaM signaling by affecting the rate of association of CaM with …

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

Deepcg: A Cell Graph Model For Predicting Prognosis In Lung Adenocarcinoma, Baoyi Zhang, Chenyang Li, Jia Wu, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung cancer is the first leading cause of cancer-related death in the United States, with lung adenocarcinoma as the major subtype accounting for 40% of all cases. To improve patient survival, image-based prognostic models were developed due to the ready availability of pathological images at diagnosis. However, the application of these models is hampered by two main challenges: the lack of publicly available image datasets with high-quality survival information and the poor interpretability of conventional convolutional neural network models. Here, we integrated matched transcriptomic and H&E staining data from TCGA (The Cancer Genome Atlas) to develop an image-based prognostic model, …

Variance-Components Tests For Genetic Association With Multiple Interval-Censored Outcomes, Jaihee Choi, Zhichao Xu, Ryan Sun

Faculty, Staff and Student Publications

Massive genetic compendiums such as the UK Biobank have become an invaluable resource for identifying genetic variants that are associated with complex diseases. Due to the difficulties of massive data collection, a common practice of these compendiums is to collect interval-censored data. One challenge in analyzing such data is the lack of methodology available for genetic association studies with interval-censored data. Genetic effects are difficult to detect because of their rare and weak nature, and often the time-to-event outcomes are transformed to binary phenotypes for access to more powerful signal detection approaches. However transforming the data to binary outcomes can …

Exploring The Genetics Of Myotonic Dystrophy Type 1 And Its Ethical Implications, Caleb Smith

NEXUS: The Liberty Journal of Interdisciplinary Studies

No abstract provided.