Medicine and Health Sciences Commons^™

S6k1 Modulates Stat3 Activation To Promote Resistance To Radiotherapy In Lung Cancer, Ali Calderon-Aparicio, Noelle Francois, Tyler Grenda, Shan Xu, Olugbenga Okusanya, Jun He, Nicole L Simone

Department of Radiation Oncology Faculty Papers

Radiotherapy is a mainstay in the management of locally advanced lung cancer; however, intrinsic and acquired radioresistance contribute to poor prognosis. S6K1, a serine/threonine kinase, regulates cell growth, protein synthesis, and survival, and is increased in tumors, which is linked to enhanced survival under therapeutic stress, including radiation. The mechanisms, however, are not fully understood. This study investigates the role of S6K1 in lung cancer radioresistance and the mechanisms involved. Intrinsic radioresistance in lung cancer cells was associated with increased S6K1 activation. Pharmacologic inhibition or genetic deletion of S6K1 enhanced radiosensitivity both in vitro and in vivo, highlighting the therapeutic …

Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis And Elicits Antitumor Immunity In Pancreatic Cancer, Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Yue Zeng, Xiaofei Wang, Jun Yao, Jennifer Li, Prapassorn Thirasastr, Jangho Park, Yangxi Zheng, Long T Vien, Khalida M Wani, Huamin Wang, Sisi Gao, Tim Heffernan, Lawrence Kwong, Ignacio I Wistuba, Laura Bover, Giulio F Draetta, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, …

Variable And Conserved Features Of Copy-Back Viral Genome Populations Generated De Novo During Sendai Virus Infection, Yanling Yang, Yuchen Wang, Carolina B López

2020-Current year OA Pubs

Copy-back viral genomes (cbVGs) are generated during the replication of negative-sense RNA viruses when the polymerase drops off from the genome and reattaches to the nascent strand. cbVGs have strong immunostimulatory properties and impact infection outcomes. Despite their importance, the composition and mechanisms of

Engineering Chimeric Antigen Receptor Cd4 T Cells For Alzheimer's Disease, Pavle Boskovic, Rotem Shalita, Wenqing Gao, Hailey Vernon, Yu Lin Deng, Marco Colonna, Robbie G Majzner, Ido Amit, Jonathan Kipnis

2020-Current year OA Pubs

Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8

Larval Zebrafish Minimize Energy Consumption During Hunting Via Adaptive Movement Selection, Thomas Darveniza, Robert Wong, Shuyu I Zhu, Zac Pujic, Biao Sun, Matthew Levendosky, Ramesh Agarwal, Michael H Mccullough, Geoffrey J Goodhill

2020-Current year OA Pubs

Animals must balance behavioral goals with the energetic costs of movement. How such trade-offs are implemented algorithmically during natural behavior, and how they adapt to changing energetic constraints, remains poorly understood. Here we show that larval zebrafish adjust their motor strategies during prey hunting to minimize energy expenditure. Using high-speed video tracking and 3D computational fluid dynamics simulations, we quantified the energy costs (in Joules) of different movement types across three developmental stages. While the structure of discrete movement types ("bouts") remained stable with age, their selection probabilities changed depending on their energetic cost, such that more expensive bouts were …

Accurate Interpretation Of Within-Host Dissemination Using Barcoded Bacteria, Rachel T Giorgio, My T Le, Ting Zhang, Caitlyn L Holmes, Karthik Hullahalli

2020-Current year OA Pubs

Bacterial dissemination across tissues is a critically important process influencing infection outcomes. Monitoring within-host dissemination is challenging because conventional measures of bulk bacterial burden cannot distinguish between lineages that are shared between tissues and those that replicate locally. This limitation can be overcome using barcoded bacteria, where deep sequencing of the barcode locus and comparisons of barcodes between tissues define which lineages spread within the host. Numerous studies have used barcoded bacteria to generate high-resolution maps of dissemination. However, since multiple cells in the infectious inoculum can contain identical barcodes, inferences about dissemination can be confounded when distinct lineages from …

Sting-Induced Blood-Brain Barrier Opening Combined With Radiotherapy Potentiates Antitumor Response In A High-Grade Glioma Model, Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen Mccortney, Karl J Habashy, Peng Zhang, Craig M Horbinski, Lara Leoni, Ryan J Avery, Rimas V Lukas, Timothy L Sita, David R Raleigh, Sean Sachdev, Roger Stupp, Maciej S Lesniak, David M Ashley, Daniele Procissi, Michael A Curran, Irina Balyasnikova, Amy B Heimberger

Faculty, Staff and Student Publications

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect …

Non-Canonical Role Of Dna Mismatch Repair On Sensory Processing In Mice, Sadia N Rahman, Demetrios Neophytou, Siboney Oviedo-Gray, Bao Q Vuong, Hysell V Oviedo

2020-Current year OA Pubs

DNA repair mechanisms are essential for cellular development and function. In post-mitotic neurons, deficiencies in DNA damage response proteins can lead to severe neurodegenerative and neurodevelopmental disorders. One highly conserved factor involved in DNA repair is MutS Homolog 2 (Msh2), which is responsible for correcting base-base mismatches and insertion/deletion loops during cell proliferation. However, its role in mature neurons remains poorly understood. This study investigates the impact of Msh2 loss on sensory processing in mice. Using electrophysiological and molecular assays, we identifiedsignificant deficits in cortical and thalamic sound processing in Msh2

Targeting Oxalate Production By Combining Enzyme Inhibition And Proteolysis Activation: A Novel Therapeutic Approach For Primary Hyperoxaluria Type 1, Fabio Arias, Sumati Rohilla, Yudibeth Sixto-López, Koral S E Richard, Sandeep Das, Sumit K Anand, Pilar Maria Luque-Navarro, Guillermo Bañuelos-Sanchez, Juan Luis Pacheco-García, Reethika Gade, M Peyton Mckinney, Dhananjay Kumar, Jemiah Maxie, W Rylan Corr, Nilesh Pandey, Harpreet Kaur, Jibin Ding, Lin Tan, Elisha Scott, Hyung Nam, Eyal Gottlieb, A Wayne Orr, Nirav Dhanesha, Arif Yurdagul, Angel L Pey, Francisco Franco-Montalbán, José A Gómez Vidal, Oren Rom, Mónica Díaz-Gavilán

Faculty, Staff and Student Publications

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (K i = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt –/– mice, both in primary …

Targeting The Lung Innate Pathways During Tuberculosis Can Improve Vaccine-Induced Protection Via Th17 Responses In Diversity Outbred Mice, Mushtaq Ahmed, Shibali Das, Bruce A Rosa, Javier Rangel Moreno, Deepak Kaushal, Makedonka Mitreva, Shabaana A Khader

2020-Current year OA Pubs

UNLABELLED: Tuberculosis (TB), caused by the bacterium

IMPORTANCE: Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against

Bioactive Lipid-Mediated Structural And Functional Regulation Of The Essential Human Potassium Channel Kir7.1, Qingwei Niu, Simon Vu, Yuanjian Xu, Mingxing Qian, Anastasiia Rudenko, Jin Ye, Jianwei Zeng, Wei Huang, Douglas F Covey, Rui Zhang, Ziao Fu, Polina V Lishko

2020-Current year OA Pubs

The inwardly rectifying potassium channel Kir7.1 is essential for the physiological function of diverse tissues, including the retinal pigment epithelium and the gestational myometrium. Loss-of-function mutations in KCNJ13, which encodes Kir7.1, or conditional ablation of Kir7.1 in the retinal pigment epithelium, lead to early-onset vision loss. Despite strong genetic evidence supporting Kir7.1 as a therapeutic target, its regulation by endogenous ligands-beyond phosphoinositides-remains poorly understood. Here, we report cryo-electron microscopy structures of human Kir7.1 in multiple functional states at resolutions ranging from 2.8 Å to 4.0 Å. These structures uncover the molecular basis of Kir7.1 modulation by PI

Molecular Determinant Of Low-Voltage Dependence Of Human Nav1.7 Inactivation Revealed By Efficacy-Based Nav1.7 Selective Inhibitor, Fang Zhao, Chuchu Xi, Jie Li, Kerui Ren, Qinglian Tang, Huaduan Liang, Shilong Yang, Michael X Zhu, Zhengyu Cao

Faculty, Staff and Student Publications

Nav1.7 is a voltage-gated sodium channel (VGSC) subtype predominantly expressed in sensory neurons, amplifying threshold currents. Here, we identify that Uvarigranol D (UGD) suppresses human (h) Nav1.7 with a much greater maximal inhibition than other VGSC subtypes, despite having similar apparent affinities. We demonstrate that Thr1398 determines the greater inhibitory efficacy of UGD, the leftward shift in voltage-dependence and faster inactivation kinetics of hNav1.7. UGD binds to the inactivated state, with Gln360, Ile394, Lys1395, Phe1737, and Tyr1744 being critically involved. Moreover, while UGD suppresses action potentials in both rat dorsal root ganglion neurons and human induced pluripotent stem cell-derived cardiomyocytes, …

Myokine Sirpα Exacerbates Kidney Disease In Diabetes, Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas

Faculty, Staff and Students Publications

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced …

Consensus Paper: Models Of Cerebellar Functions, Shinji Kakei, Andreea C Bostan, Timothy J Ebner, Mohammad Amin Fakharian, Hiroaki Gomi, Xavier Guell, Marie Hemelt, Huu Hoang, Court Hull, Masato Inoue, Takahiro Ishikawa, Masashi Kameda, Mitsuo Kawato, Shigeru Kitazawa, Mario Manto, Javier F Medina, Hiroshi Mitoma, Keiko Ohmae, Shogo Ohmae, Ken-Ichi Okada, Laurentiu S Popa, Jeremy D Schmahmann, Reza Shadmehr, Peter L Strick, Hirokazu Tanaka, Masaki Tanaka, Tadashi Yamazaki

Faculty, Staff and Students Publications

For a long time, from the nineteenth century to most of the twentieth century, the cerebellum was thought to be an organ that regulates movement. Towards the end of the twentieth century, the brain functions associated with the cerebellum began to extend beyond motor control. Now, there is a consensus that the cerebellum is involved not only in motor functions but also in the most basic autonomic functions and the most complex cognitive and emotional functions, with a focus on predictions and internal models. A new functional model of the cerebellum is needed to explain all layers of brain functions …

Ubiquitination-Directed Cytosolic Dna Degradation Governs Cgas-Sting-Mediated Immune Response To Dna Damage, Lei Li, Qi Ye, Jinlu Ma, Zixi Wang, Tianjie Liu, Yuzeshi Lei, Mingming Lu, Jialu Kang, Haohan Xiang, Buyun Li, Shan Xu, Ke Wang, Yule Chen, Jiaqi Chen, Bohan Ma, Wenyue Huang, Mengjiao Cai, Nan Wu, Yanqiang Li, Jiale An, Chongming Jiang, Rui Ye, Jing Liu, Steven H Lin, Yang Gao, Jian Ma, Lei Li

Faculty, Staff and Student Publications

Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, …

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Therapeutic Reprogramming Of Tumour-Associated Macrophages In Pancreatic Cancer Using A Cytotoxic Ccr2-Targeted Nanotheranostic, Vikas Kumar Somani, Xiaohui Zhang, Timothy Hung-Po Chen, Ashenafi Bulle, Sapana Bansod, Lin Li, Yutong Geng, Liang-I Kang, Gyu Seong Heo, Hannah Luehmann, Yuena Zhang, Muhammad A Saeed, Kory J Lavine, David G Denardo, Russell K Pachynski, Yongjian Liu, Kian-Huat Lim

2020-Current year OA Pubs

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict adaptive immunity and drive resistance to immune checkpoint blockade (ICB). Recruitment of CCR2⁺ IMs by tumour-derived CCL2 is a central mechanism underlying TAM accumulation. Conventional gemcitabine (GEM) and small-molecule CCR2 inhibitors provide limited benefit due to poor intratumoural delivery, transient target engagement, and compensatory myeloid recruitment. METHODS: We engineered a CCR2-targeted nanotheranostic by conjugating a CCR2-binding peptide (ECL1i) and GEM onto ultrasmall copper nanoclusters (CuNCs-ECL1i-GEM; C-E-G). Therapeutic efficacy and immune remodelling were evaluated using orthotopic subcutaneous and …

Extracellular Matrix Mediates Circulating Tumor Cell Clustering In Triple-Negative Breast Cancer Metastasis, Georg Om Bobkov, Khushali J Patel, Bree M Lege, Rong Zheng, Gad Shaulsky, Matthew J Ellis, Chonghui Cheng

Faculty, Staff and Students Publications

Metastatic tumor cell dissemination is the leading cause of cancer-related deaths. Clustered circulating tumor cells (CTCs) possess higher metastatic potential than single CTCs. Epithelial adherens junction (AJ) proteins typically mediate stable cell-cell interactions; however, these proteins are frequently lost in highly aggressive triple-negative breast cancers (TNBCs), raising the question of how CTCs from such tumors cluster. Here we show that the extracellular matrix (ECM) component hyaluronan (HA) mediates AJ-independent CTC clustering in TNBCs. HA is necessary and sufficient to drive clustering of tumor cells expressing its receptor CD44. Mechanistically, HA initiates contact between neighboring cells through actin-based membrane protrusions. As …

Tracking Focal Adhesion Turnover: A Novel Reporter For Fa-Phagy Flux, Kuizhi Qu, Mengjun Dai, Ying Jiang, Sophie Liu, John P Hagan, Louise D Mccullough, Zhen Xu, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces a novel tandem fluorescence reporter capable of tracking the entire FA-phagy flux, from autophagosome formation to lysosomal degradation. The reporter, based on a red–green fluorescence system with a lysosome-specific cleavage site, integrates seamlessly into endogenous focal adhesion complexes, demonstrating sensitivity and specificity to autophagy stimuli. Validated in multiple cell lines, the tool revealed dynamic FA-phagy responses to …

Bi-Allelic Variants In Neuronal Adhesion Molecule Astrotactin 1 Gene Astn1 Cause Diverse Neurodevelopmental Disorders, Jesse M Levine, Daniel G Calame, Riccardo Sangermano, Haowei Du, Ahmed Saad, Jasmin Lisfeld, Tatjana Bierhals, Jonas Denecke, Eyyup Uctepe, Merve Yoldas Celik, Ahmet Yesilyurt, Hilal Yildiz Er, Elif Yilmaz Gulec, Aziza Mushiba, Naif Almontashiri, Pawel Gawlinski, Wojciech Wiszniewski, Ender Karaca, Lama Alabdi, Davut Pehlivan, Dana Marafi, Maha S Zaki, Fowzan S Alkuraya, Joseph G Gleeson, Shalini N Jhangiani, Richard A Gibbs, Jennifer E Posey, Kinga M Bujakowska, James R Lupski

Faculty, Staff and Students Publications

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs …

Sclerostin Deficiency Sensitizes White Adipocytes To Thermogenic Signals That Induce Beiging In Mice, Gillian M Choquette, Soohyun P Kim, Kevin J Wilkinson, Belen C Avelar, Sushrut Pathy, Zhu Li, Jasmine Wu, Susan Aja, Daniel L J Thorek, Michael J Wolfgang, Ryan C Riddle

2020-Current year OA Pubs

Maintenance of bone mass is coordinated with adipose tissue function through the secretion of hormones and endocrine factors that act on the opposing tissue. Sclerostin, a small glycoprotein produced by osteocytes embedded within the bone matrix, potently suppresses bone formation by antagonizing Wnt/β-catenin signaling while stimulating adipose tissue accumulation via the same mechanism of action. Since sclerostin-deficient mice develop pockets of multilocular adipocytes in subcutaneous adipose, we investigate the influence of sclerostin on thermogenic and β3-adrenergic stimuli-induced white adipose tissue beiging. Here, we report that Sost gene expression in bone and serum sclerostin levels are induced by β3-adrenergic agonists via …

Targeting Tau In Alzheimer's Disease: Rationale, Approach And Challenges, Aram Aslanyan, Martha S Foiani, Tatiana A Giovannucci, Eric Mcdade, Karen E Duff, Catherine J Mummery, Michael Schöll, Kristin R Wildsmith, Ross W Paterson

2020-Current year OA Pubs

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia characterised by the accumulation of beta amyloid (Aβ) plaques and neurofibrillary tangles (NFT). Several monoclonal antibodies against amyloid in early AD have shown the utility of reducing brain amyloid in large phase 3 studies, resulting in modest clinical benefit. To further slow, or even halt disease progression, targeting additional pathobiological pathways is likely to be necessary. In this review, we aim to appraise the scientific rationale for targeting tau in AD. The burden of tau pathology is correlated with disease severity and its role in …

Multiparent Recombinant Inbred Lines Crossed To A Tester Provide Novel Insights Into Sources Of Cis And Trans Regulation Of Gene Expression, Fabio Marroni, Alison M Morse, Adalena V Nanni, Nadja Nolte, Patricka Williams-Simon, Luis G León-Novelo, Rita M Graze, Paul Schmidt, Elizabeth King, Lauren M Mcintyre

Faculty, Staff and Student Publications

To understand the relative importance of cis and trans effects on regulation, we crossed multi-parent recombinant-inbred lines (RILs) to a common tester and measured allele-specific gene expression in the offspring. Testing the difference of allelic imbalance between two RIL × Tester crosses is a test of cis or trans, depending on the RIL alleles compared. The study design also enables to separation of two sources of trans variation, genetic and environmental, detected via interactions with cis effects. We demonstrate the effectiveness of this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster. …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

Repurposing Of The Macrolide Antibiotic Clarithromycin For The Prevention Of Lung Cancer, Shanshan Deng, Tabish Hussain, Thais F Bartelli, Manu M Sebastian, Melody Zarghooni, Walter V Velasco, Brandon Somerville, Linda Phan, Michelle I Savage, Yurong Song, John L Clifford, Humam Kadara, Florencia Mcallister, Powel H Brown, Seyed Javad Moghaddam, C Marcelo Aldaz

Faculty, Staff and Student Publications

Drug repurposing is the process of reusing existing pharmaceuticals for novel clinical purposes, which offers advantages such as streamlined clinical trial access and reduced drug development costs. Clarithromycin (CAM), a member of the macrolide antibiotics family, is a promising candidate for repurposing in cancer therapy due to its known preclinical and clinical immunomodulatory and anticancer properties. In the current study, we investigated whether CAM could be repurposed as a preventive treatment for KRAS-mutant lung cancer, a subtype of lung adenocarcinoma that is strongly associated with heavy smoking. CCSPCre; LSL-KrasG12D mice at an early stage of tumor development were treated with …

Rev-Erb-Alpha And -Beta Coordinately Regulate Astrocyte Reactivity And Proteostatic Function, Collin J Nadarajah, Michelle Y Li, Elsa I Quillin, Kevin Boyer, Julie M Dimitry, Yining Chen, Melvin W King, Ibrahim O Saliu, Jiyeon Lee, Patrick W Sheehan, Albert A Davis, Mitchell A Lazar, Guoyan Zhao, Erik S Musiek

2020-Current year OA Pubs

The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (

Osimertinib Activates A Tgf-Β2-Dependent Secretory Program That Drives Lung Adenocarcinoma Progression, Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique Nilsson, John V Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate Grimley, William K Russell, Chad J Creighton, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist osimertinib (Osi) eventually relapse, owing in part to the emergence of drug-tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intratumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell …

Slc7a8 Is Essential For Metabolic Fitness And Function Of Th2 Cells, Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Shitong Wu, Patrick Fernandes Rodrigues, Raki Sudan, Yizhou Liu, Haerin Jung, Intelly Lee, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna

2020-Current year OA Pubs

Amino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 …

Amyloidosis Of Bridging Veins Is A Pathologic Feature Of Alzheimer's Disease, Leon C D Smyth, Daan Verhaege, Elio Standen-Bloom, Yue Wu, Steffen E Storck, Pavle Boskovic, Benjamin A Plog, Tornike Mamuladze, Jose A Mazzitelli, Zhuoying Wang, Daniel D Lee, Gwendalyn J Randolph, Katherine E Schwetye, Song Hu, Jonathan Kipnis, Et Al.

2020-Current year OA Pubs

Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance …