Digital Commons Network^™

A Subcortical Model For Auditory Forward Masking With Efferent Control Of Cochlear Gain., Braden N. Maxwell, Afagh Farhadi, Marc A Brennan, Adam Svec, Laurel H. Carney

All Faculty Scholarship

Previous physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may contribute to GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior …

Mvar: A Mouse Variation Registry., Baha El Kassaby, Francisco Castellanos, Matthew Gerring, Govindarajan Kunde-Ramamoorthy, Carol J Bult

Faculty Research 2024

The Mouse Variation Registry (MVAR) resource is a scalable registry of mouse single nucleotide variants and small indels and variant annotation. The resource accepts data in standard Variant Call Format (VCF) and assesses the uniqueness of the submitted variants via a canonicalization process. Novel variants are assigned a unique, persistent MVAR identifier; variants that are equivalent to an existing variant in the resource are associated with the existing identifier. Annotations for variant type, molecular consequence, impact, and genomic region in the context of specific transcripts and protein sequences are generated using Ensembl's Variant Effect Predictor (VEP) and Jannovar. Access to …

Altered Rna Export By Sf3b1 Mutants Confers Sensitivity To Nuclear Export Inhibition., Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M Totiger, Maurizio Affer, Abimbola Eunice Lawal, Skye Montoya, Francesco Tamiro, Olivia Tonini, Alexandra Chirino, Andrew Adams, Anya K Sondhi, Stephen Noudali, Alyssa Mauri Cornista, Miah Nicholls, Jumana Afaghani, Paola Robayo, Daniel Bilbao, Stephen D Nimer, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor

Faculty Research 2024

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic …

Targeting Undruggable Phosphatase Overcomes Trastuzumab Resistance By Inhibiting Multi-Oncogenic Kinases., Lu Wang, Yusheng Lin, Zhimeng Yao, Nipun Babu, Wan Lin, Chaoying Chen, Liang Du, Songwang Cai, Yunlong Pan, Xiao Xiong, Qiantao Ye, Hongzheng Ren, Dianzheng Zhang, Yexi Chen, Sai-Ching Jim Yeung, Edwin Bremer, Hao Zhang

PCOM Scholarly Works

AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2

METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2

RESULTS: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting …

Advancements In Apoe And Dementia Research: Highlights From The 2023 Aaic Advancements: Apoe Conference., Courtney M Kloske, Michael E Belloy, Elizabeth E Blue, Gregory R Bowman, Maria C Carrillo, Xiaoying Chen, Ornit Chiba-Falek, Albert A Davis, Gilbert Di Paolo, Francesca Garretti, David Gate, Lesley R. Golden, Jay W Heinecke, Joachim Herz, Yadong Huang, Costantino Iadecola, Lance A Johnson, Takahisa Kanekiyo, Celeste M Karch, Anastasia Khvorova, Sascha J Koppes-Den Hertog, Bruce T Lamb, Paige E Lawler, Yann Le Guen, Alexandra Litvinchuk, Chia-Chen Liu, Simin Mahinrad, Edoardo Marcora, Claudia Marino, Danny M Michaelson, Justin J Miller, Josh M. Morganti, Priyanka S Narayan, Michel S Naslavsky, Marlies Oosthoek, Kapil V Ramachandran, Abhirami Ramakrishnan, Ana-Caroline Raulin, Aiko Robert, Rasha N M Saleh, Claire Sexton, Nilomi Shah, Francis Shue, Isabel J Sible, Andrea Soranno, Michael R Strickland, Julia Tcw, Manon Thierry, Li-Huei Tsai, Ryan A Tuckey, Jason D Ulrich, Rik Van Der Kant, Na Wang, Cheryl L Wellington, Stacie C Weninger, Hussein N Yassine, Na Zhao, Guojun Bu, Alison M Goate, David M Holtzman

Physiology Faculty Publications

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.

METHODS: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates …

Identification Of Hypoxia-Alcamhigh Macrophage- Exhausted T Cell Axis In Tumor Microenvironment Remodeling For Immunotherapy Resistance, Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Faculty, Staff and Student Publications

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM

Target Engagement And Immunogenicity Of An Active Immunotherapeutic Targeting Pathological Α-Synuclein: A Phase 1 Placebo-Controlled Trial, Pepijn Eijsvogel, Pinaki Misra, Luis Concha-Marambio, Justin D Boyd, Shuang Ding, Lauren Fedor, Yueh-Ting Hsieh, Yu Shuang Sun, Madeline M Vroom, Carly M Farris, Yihua Ma, Marieke L De Kam, Igor Radanovic, Maurits F J M Vissers, Dario Mirski, Ghazal Shareghi, Mohammad Shahnawaz, Wolfgang Singer, Philip Kremer, Geert Jan Groeneveld, Hui Jing Yu, Jean-Cosme Dodart

Faculty, Staff and Student Publications

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks …

Automatic Vessel Attenuation Measurement For Quality Control Of Contrast-Enhanced Ct: Validation On The Portal Vein, Kevin Mccoy, Sujay Marisetty, Dominique Tan, Corey T Jensen, Jeffrey H Siewerdsen, Christine B Peterson, Moiz Ahmad

Faculty, Staff and Student Publications

Background: Adequate image enhancement of organs and blood vessels of interest is an important aspect of image quality in contrast-enhanced computed tomography (CT). There is a need for an objective method for evaluation of vessel contrast that can be automatically and systematically applied to large sets of CT exams.

Purpose: The purpose of this work was to develop a method to automatically segment and measure attenuation Hounsfield Unit (HU) in the portal vein (PV) in contrast-enhanced abdomen CT examinations.

Methods: Input CT images were processed by a vessel enhancing filter to determine candidate PV segmentations. Multiple machine learning (ML) classifiers …

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …

Meta-Analysis Identifies Key Genes And Pathways Implicated In Benzo[A]Pyrene Exposure Response, Mingze Zhu, Jooyeon Hwang, Chao Xu

Faculty, Staff and Student Publications

Introduction: Benzo[a]pyrene (B[a]P) is a carcinogenic polycyclic aromatic hydrocarbon that poses significant risks to human health. B[a]P influences cellular processes via intricate interactions; however, a comprehensive understanding of B[a]P's effects on the transcriptome remains elusive. This study aimed to conduct a comprehensive analysis focused on identifying relevant genes and signaling pathways affected by B[a]P exposure and their impact on human gene expression.

Methods: We searched the Gene Expression Omnibus database and identified four studies involving B[a]P exposure in human cells (T lymphocytes, hepatocellular carcinoma cells, and C3A cells). We utilized two approaches for differential expression analysis: the LIMMA package and …

Metabolic Cell Death In Cancer: Ferroptosis, Cuproptosis, Disulfidptosis, And Beyond, Chao Mao, Min Wang, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

Strategies For The Development Of Metalloimmunotherapies, Xiaoqi Sun, Xingwu Zhou, Xiaoyue Shi, Omar A Abed, Xinran An, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host-microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases.

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

Rewiring Cancer Cell Death: Lpcat1 Shapes Lipid Composition And Ferroptosis Resistance, Hyemin Lee, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

No abstract provided.

Early And Enduring: Targeting The Endothelium For Blood-Brain Barrier Protection, Silin Wu, Xuefang Sophie Ren, Yejie Shi

Faculty, Staff and Student Publications

The disruption of the blood-brain barrier marks a pivotal early pathological event in ischemic stroke that significantly contributes to subsequent permanent damage. Here we delve into the ramifications of a study conducted by Xu and colleagues, which underscores the essential role of the protein peroxiredoxin-4 in cerebrovascular endothelial cells. Peroxiredoxin-4 was shown to preserve blood-brain barrier integrity during the early stages after cerebral ischemia and reperfusion, ultimately leading to improved long-term outcomes.

Immunoprevention Strategies For Colorectal Cancer In Lynch Syndrome Carriers, Charles M Bowen, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce …

Inferring Super-Resolution Tissue Architecture By Integrating Spatial Transcriptomics With Histology, Daiwei Zhang, Amelia Schroeder, Hanying Yan, Haochen Yang, Jian Hu, Michelle Y Y Lee, Kyung S Cho, Katalin Susztak, George X Xu, Michael D Feldman, Edward B Lee, Emma E Furth, Linghua Wang, Mingyao Li

Faculty, Staff and Student Publications

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.

Small Molecules Targeting Micrornas: New Opportunities And Challenges In Precision Cancer Therapy, Ancuta Jurj, Beatrice Fontana, Gabriele Varani, George A Calin

Faculty, Staff and Student Publications

Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential …

Proteomic Analysis Of Ferroptosis Pathways Reveals A Role Of Cept1 In Suppressing Ferroptosis, Xiaoguang Liu, Zhen Chen, Yuelong Yan, Fereshteh Zandkarimi, Litong Nie, Qidong Li, Amber Horbath, Kellen Olszewski, Lavanya Kondiparthi, Chao Mao, Hyemin Lee, Li Zhuang, Masha Poyurovsky, Brent R Stockwell, Junjie Chen, Boyi Gan

Faculty, Staff and Student Publications

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

Vascular Heterogeneity Of Tight Junction Claudins Guides Organotropic Metastasis, Xunian Zhou, Valerie S Lebleu, Eliot Fletcher-Sananikone, Jiha Kim, Jianli Dai, Bingrui Li, Chia-Chin Wu, Hikaru Sugimoto, Toru Miyake, Lisa M Becker, Olga V Volpert, Erica Lawson, Cristina Espinosa Da Silva, Sarah I Patel, Akane Kizu, Ehsan A Ehsanipour, Di Sha, Jose Antonio Karam, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking …

Oric-101, A Glucocorticoid Receptor Antagonist, In Combination With Nab-Paclitaxel In Patients With Advanced Solid Tumors, Christopher T Chen, Vishesh Khanna, Shivaani Kummar, Raghad M Abdul-Karim, David Sommerhalder, Anthony W Tolcher, Naoto T Ueno, Sarah Lindsey Davis, Douglas W Orr, Erika Hamilton, Manish R Patel, Alexander I Spira, Shekeab Jauhari, Vaia Florou, Maureen Duff, Rongda Xu, Jian Wang, Shravani R Barkund, Haiying Zhou, Aleksandr Pankov, Wayne Kong, Nadine S Jahchan, Erica L Jackson, Jessica D Sun, Melissa R Junttila, Pratik S Multani, Anneleen Daemen, Edna Chow Maneval, Pamela N Munster

Faculty, Staff and Student Publications

Purpose: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial.

Patients and methods: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel.

Results: ORIC-101 reversed …

The Fibro-Adipogenic Progenitor Apod+Dcn+Llum+ Cell Population In Aggressive Carcinomas, Lingyi Cai, Mikhail G Kolonin, Dimitris Anastassiou

Faculty, Staff and Student Publications

We identified a progenitor cell population highly enriched in samples from invasive and chemo-resistant carcinomas, characterized by a well-defined multigene signature including APOD, DCN, and LUM. This cell population has previously been labeled as consisting of inflammatory cancer-associated fibroblasts (iCAFs). The same signature characterizes naturally occurring fibro-adipogenic progenitors (FAPs) as well as stromal cells abundant in normal adipose tissue. Our analysis of human gene expression databases provides evidence that adipose stromal cells (ASCs) are recruited by tumors and undergo differentiation into CAFs during cancer progression to invasive and chemotherapy-resistant stages.

A Guideline On The Molecular Ecosystem Regulating Ferroptosis, Enyong Dai, Xin Chen, Andreas Linkermann, Xuejun Jiang, Rui Kang, Valerian E Kagan, Hülya Bayir, Wan Seok Yang, Ana J Garcia-Saez, Maria S Ioannou, Tobias Janowitz, Qitao Ran, Wei Gu, Boyi Gan, Dmitri V Krysko, Xiaofeng Zhu, Jiayi Wang, Stefan Krautwald, Shinya Toyokuni, Yangchun Xie, Florian R Greten, Qing Yi, Joel Schick, Jiao Liu, Dmitry I Gabrilovich, Jinbao Liu, Herbert J Zeh, Donna D Zhang, Minghua Yang, Juan Iovanna, Manfred Kopf, Timon E Adolph, Jen-Tsan Chi, Changfeng Li, Hidenori Ichijo, Michael Karin, Vijay G Sankaran, Weiping Zou, Lorenzo Galluzzi, Ashley I Bush, Binghui Li, Gerry Melino, Eric H Baehrecke, Michael T Lotze, Daniel J Klionsky, Brent R Stockwell, Guido Kroemer, Daolin Tang

Faculty, Staff and Student Publications

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Mitochondrial Complex I Promotes Kidney Cancer Metastasis, Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, Mckenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis Mcdaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J Deberardinis

Faculty, Staff and Student Publications

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human …

A Potential Role For Magi-1 In The Bi-Directional Relationship Between Major Depressive Disorder And Cardiovascular Disease, Priyanka Banerjee, Khanh Chau, Sivareddy Kotla, Eleanor L Davis, Estefani Berrios Turcios, Shengyu Li, Zhang Pengzhi, Guangyu Wang, Gopi Krishna Kolluru, Abhishek Jain, John P Cooke, Junichi Abe, Nhat-Tu Le

Faculty, Staff and Student Publications

Purpose of review: Major Depressive Disorder (MDD) is characterized by persistent symptoms such as fatigue, loss of interest in activities, feelings of sadness and worthlessness. MDD often coexist with cardiovascular disease (CVD), yet the precise link between these conditions remains unclear. This review explores factors underlying the development of MDD and CVD, including genetic, epigenetic, platelet activation, inflammation, hypothalamic-pituitary-adrenal (HPA) axis activation, endothelial cell (EC) dysfunction, and blood-brain barrier (BBB) disruption.

Recent findings: Single nucleotide polymorphisms (SNPs) in the membrane-associated guanylate kinase WW and PDZ domain-containing protein 1 (MAGI-1) are associated with neuroticism and psychiatric disorders including MDD. SNPs in …

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRAS

Understanding, Diagnosing, And Treating Pancreatic Cancer From The Perspective Of Telomeres And Telomerase, Songting Shou, Yuanliang Li, Jiaqin Chen, Xing Zhang, Chuanlong Zhang, Xiaochen Jiang, Fudong Liu, Li Yi, Xiyuan Zhang, En Geer, Zhenqing Pu, Bo Pang

Faculty, Staff and Student Publications

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase …

Smyd5 Is A Ribosomal Methyltransferase That Catalyzes Rpl40 Lysine Methylation To Enhance Translation Output And Promote Hepatocellular Carcinoma, Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu, Xiang Li, Kun Chen, Jinkai Wan, Shenghui Xing, Lingnan Ren, Zhennan Shi, Shengnan Liu, Yajun Hu, Jiajia Chen, Yanyan Yu, Lijian Feng, Natasha M Flores, Zhihui Liang, Xinyi Xu, Ruoxin Wang, Jian Zhou, Jia Fan, Bin Xiang, En Li, Yuanhui Mao, Jingdong Cheng, Kehao Zhao, Pawel K Mazur, Jiabin Cai, Fei Lan

Faculty, Staff and Student Publications

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma …

Ketamine’S Mechanism Of Action With An Emphasis On Neuroimmune Regulation: Can The Complement System Complement Ketamine’S Antidepressant Effects?, Brandi Quintanilla, Carlos A Zarate, Anilkumar Pillai

Faculty, Staff and Student Publications

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital …

Emerging Treatment Landscape For Guillain-Barré Syndrome (Gbs): What’S New?, Alina Sprenger-Svačina, Martin K R Svačina, Tong Gao, Gang Zhang, Kazim A Sheikh

Faculty, Staff and Student Publications

Introduction: Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder characterized by acute paralysis. A significant portion of patients are left with residual deficits, which presents a considerable global healthcare challenge. The precise mechanisms underlying GBS pathogenesis are not fully elucidated. Recent studies have focused on postinfectious molecular mimicry and identified involvement of IgG autoantibodies and innate immune effectors in GBS. Intravenous immunoglobulins (IVIg) and plasma exchange (PE) are two established evidence-based immunomodulatory treatments for GBS, but a significant proportion of GBS patients fails to respond adequately to either therapy. This emphasizes an urgent need for novel and more potent …