Digital Commons Network^™

Genome-Wide Association Studies And Fine-Mapping Identify Genomic Loci For N-3 And N-6 Polyunsaturated Fatty Acids In Hispanic American And African American Cohorts, Chaojie Yang, Jenna Veenstra, Traci M Bartz, Matthew C Pahl, Brian Hallmark, Yii-Der Ida Chen, Jason Westra, Lyn M Steffen, Christopher D Brown, David Siscovick, Michael Y Tsai, Alexis C Wood, Stephen S Rich, Caren E Smith, Timothy D O'Connor, Dariush Mozaffarian, Struan F A Grant, Floyd H Chilton, Nathan L Tintle, Rozenn N Lemaitre, Ani Manichaikul

Faculty, Staff and Students Publications

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10

Targeting Bcl2 Overcomes Resistance And Augments Response To Aurora Kinase B Inhibition By Azd2811 In Small Cell Lung Cancer, Kavya Ramkumar, Azusa Tanimoto, Carminia M Della Corte, C Allison Stewart, Qi Wang, Li Shen, Robert J Cardnell, Jing Wang, Urszula M Polanska, Courtney Andersen, Jamal Saeh, J Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M Gay, Jelena Urosevic, Lauren A Byers

Faculty, Staff and Student Publications

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.

EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. …

Prolonged Cytopenia Following Cd19 Car T Cell Therapy Is Linked With Bone Marrow Infiltration Of Clonally Expanded Ifnγ-Expressing Cd8 T Cells, Paolo Strati, Xubin Li, Qing Deng, Mario L Marques-Piubelli, Jared Henderson, Grace Watson, Laurel Deaton, Taylor Cain, Haopeng Yang, Vida Ravanmehr, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Frederick B Hagemeister, Edwin R Parra, Neeraj Saini, Koichi Takahashi, Nathan H Fowler, Jason R Westin, Raphael E Steiner, Ranjit Nair, Christopher R Flowers, Linghua Wang, Sairah Ahmed, Gheath Al-Atrash, Francisco Vega, Sattva S Neelapu, Michael R Green

Faculty, Staff and Student Publications

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine …

Indoor Airborne Microbiome And Endotoxin: Meteorological Events And Occupant Characteristics Are Important Determinants, Hesham Amin, Tina Šantl-Temkiv, Christine Cramer, Kai Finster, Francisco Gomez Real, Thorarinn Gislason, Mathias Holm, Christer Janson, Nils Oskar Jögi, Rain Jogi, Andrei Malinovschi, Ian P G Marshall, Lars Modig, Dan Norbäck, Rajesh Shigdel, Torben Sigsgaard, Cecilie Svanes, Hulda Thorarinsdottir, Inge M Wouters, Vivi Schlünssen, Randi J Bertelsen

Faculty, Staff and Student Publications

Airborne bacteria and endotoxin may affect asthma and allergies. However, there is limited understanding of the environmental determinants that influence them. This study investigated the airborne microbiomes in the homes of 1038 participants from five cities in Northern Europe: Aarhus, Bergen, Reykjavik, Tartu, and Uppsala. Airborne dust particles were sampled with electrostatic dust fall collectors (EDCs) from the participants’ bedrooms. The dust washed from the EDCs’ clothes was used to extract DNA and endotoxin. The DNA extracts were used for quantitative polymerase chain (qPCR) measurement and 16S rRNA gene sequencing, while endotoxin was measured using the kinetic chromogenic limulus amoebocyte …

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis And Muscle Recovery In Preclinical Model Of Pad, Danesh H Sopariwala, Andrea S Rios, Addison Saley, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9)

Spatial Immunoprofiling Of Adenoid Cystic Carcinoma Reveals B7-H4 Is A Therapeutic Target For Aggressive Tumors, Luana Guimaraes Sousa, Daniel J Mcgrail, Felippe Lazar Neto, Kaiyi Li, Mario L Marques-Piubelli, Sammy Ferri-Borgogno, Hui Dai, Yoshitsugu Mitani, Nicole Spardy Burr, Zachary A Cooper, Krista Kinneer, Maria Angelica Cortez, Shiaw-Yih Lin, Diana Bell, Adel El Naggar, Jared Burks, Renata Ferrarotto

Faculty, Staff and Student Publications

PURPOSE: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets.

EXPERIMENTAL DESIGN: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm …

Impact Of Geroscience On Therapeutic Strategies For Older Adults With Cardiovascular Disease: Jacc Scientific Statement, Daniel E Forman, George A Kuchel, John C Newman, James L Kirkland, Elena Volpi, George E Taffet, Nir Barzilai, Ambarish Pandey, Dalane W Kitzman, Peter Libby, Luigi Ferrucci

Faculty, Staff and Students Publications

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel …

Insight Into The Mechanism Of H+-Coupled Nucleobase Transport, Jun Weng, Xiaoming Zhou, Pattama Wiriyasermkul, Zhenning Ren, Kehan Chen, Eva Gil-Iturbe, Ming Zhou, Matthias Quick

Faculty, Staff and Students Publications

The nucleobase/ascorbic acid transporter (NAT) family comprises proteins in all kingdoms of life. Their substrates, nucleobases and their analogs, have special attention in therapeutic applications, such as the treatment of solid tumors, lymphoproliferative diseases, viral infections, and inflammatory diseases. Here, we present the crystal structure of a bacterial NAT member, PurT of Colwellia psychrerythraea (PurTCp) at 2.80 Å resolution that, together with functional data, provide insight into the transport mechanism of NAT family members.

Oleoylethanolamide Facilitates Pparα And Tfeb Signaling And Attenuates Aβ Pathology In A Mouse Model Of Alzheimer’S Disease, Michele M Comerota, Manasee Gedam, Wen Xiong, Feng Jin, Lisheng Deng, Meng C Wang, Jin Wang, Hui Zheng

Faculty, Staff and Students Publications

BACKGROUND: Age is the strongest risk factor for the development of Alzheimer's disease (AD). Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles, emerging evidence demonstrates a critical role of microglia and neuroinflammation in AD pathogenesis. Oleoylethanolamide (OEA) is an endogenous lipid amide that has been shown to promote lifespan and healthspan in C. elegans through regulation of lysosome-to-nucleus signaling and cellular metabolism. The goal of our study was to determine the role of OEA in the mediation of microglial activity and AD pathology using its stable analog, KDS-5104.

METHODS: We used primary microglial cultures and genetic and …

Spatial Organization Of The Mouse Retina At Single Cell Resolution By Merfish, Jongsu Choi, Jin Li, Salma Ferdous, Qingnan Liang, Jeffrey R Moffitt, Rui Chen

Faculty, Staff and Students Publications

The visual signal processing in the retina requires the precise organization of diverse neuronal types working in concert. While single-cell omics studies have identified more than 120 different neuronal subtypes in the mouse retina, little is known about their spatial organization. Here, we generated the single-cell spatial atlas of the mouse retina using multiplexed error-robust fluorescence in situ hybridization (MERFISH). We profiled over 390,000 cells and identified all major cell types and nearly all subtypes through the integration with reference single-cell RNA sequencing (scRNA-seq) data. Our spatial atlas allowed simultaneous examination of nearly all cell subtypes in the retina, revealing …

Loss Of Syncrip Unleashes Apobec-Driven Mutagenesis, Tumor Heterogeneity, And Ar-Targeted Therapy Resistance In Prostate Cancer, Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T Mendell, Bo Li, Tao Wang, Ping Mu

Faculty, Staff and Student Publications

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, …

Bacteroides Uniformis-Induced Perturbations In Colonic Microbiota And Bile Acid Levels Inhibit Th17 Differentiation And Ameliorate Colitis Developments, Yiting Yan, Yu Lei, Ying Qu, Zhen Fan, Ting Zhang, Yangbin Xu, Qian Du, Daniel Brugger, Yulin Chen, Ke Zhang, Enping Zhang

Faculty, Staff and Student Publications

Inflammatory bowel disease (IBD) is associated with gut dysbiosis and can lead to colitis-associated malignancies. Bacteroides uniformis (Bu) regulates animal intestinal homeostasis; however, the mechanism by which it alleviates colitis in mice remains unknown. We investigated the effects of B. uniformis JCM5828 and its metabolites on female C57BL/6J mice with dextran sulfate sodium salt (DSS) induced colitis. Treatment with Bu considerably alleviated colitis progression and restored the mechanical and immune barrier protein expression. Additionally, Bu increased the abundance of the symbiotic bacteria Bifidobacterium and Lactobacillus vaginalis while decreasing that of pathogenic Escherichia-Shigella, and modulated intestinal bile acid metabolism. Bu largely …

Hepatitis A Virus And Hepatitis E Virus As Food- And Waterborne Pathogens—Transmission Routes And Methods For Detection In Food, Katalin Nemes, Sofia Persson, Magnus Simonsson

Faculty, Staff and Student Publications

Foodborne viruses are an important threat to food safety and public health. Globally, there are approximately 5 million cases of acute viral hepatitis due to hepatitis A virus (HAV) and hepatitis E virus (HEV) every year. HAV is responsible for numerous food-related viral outbreaks worldwide, while HEV is an emerging pathogen with a global health burden. The reported HEV cases in Europe have increased tenfold in the last 20 years due to its zoonotic transmission through the consumption of infected meat or meat products. HEV is considered the most common cause of acute viral hepatitis worldwide currently. This review focuses …

Characterization Of Vascular Morphology Of Neovascular Age-Related Macular Degeneration By Indocyanine Green Angiography, Anish Attarde, Thomas S Riad, Zhao Zhang, Manisha Ahir, Yingbin Fu

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a leading cause of blindness among older individuals, and its prevalence is rapidly increasing due to the aging population. Choroidal neovascularization (CNV) or wet AMD, which accounts for 10%-20% of all AMD cases, is responsible for an alarming 80%-90% of AMD-related blindness. Current anti-VEGF therapies show suboptimal responses in approximately 50% of patients. Resistance to anti-VEGF treatment in CNV patients is often associated with arteriolar CNV, while responders tend to have capillary CNV. While fluorescein angiography (FA) is commonly used to assess leakage patterns in wet AMD patients and animal models, it does not provide …

Multifocal And Multicentric Glioblastoma: Imaging Signature, Molecular Characterization, Patterns Of Spread, And Treatment, Maguy Farhat, Gregory N Fuller, Max Wintermark, Caroline Chung, Vinodh A Kumar, Melissa Chen

Faculty, Staff and Student Publications

Multifocal and multicentric glioblastoma (GBM) or collectively, m-GBM, is an imaging diagnosis present in up to 34% of patients with GBM. Compared to unifocal disease, patients with m-GBM have worse outcomes owing to the enhanced aggressive nature of the disease and its resistance to currently available treatments. To improve the understanding of its complex behavior, many associations have been established between the radiologic findings of m-GBM and its gross histology, genetic composition, and patterns of spread. Additionally, the holistic knowledge of the exact mechanisms of m-GBM genesis and progression is crucial for identifying potential targets permitting enhanced diagnosis and treatment. …

Strategies For The Genomic Analysis Of Admixed Populations, Taotao Tan, Elizabeth G Atkinson

Faculty, Staff and Students Publications

Admixed populations constitute a large portion of global human genetic diversity, yet they are often left out of genomics analyses. This exclusion is problematic, as it leads to disparities in the understanding of the genetic structure and history of diverse cohorts and the performance of genomic medicine across populations. Admixed populations have particular statistical challenges, as they inherit genomic segments from multiple source populations-the primary reason they have historically been excluded from genetic studies. In recent years, however, an increasing number of statistical methods and software tools have been developed to account for and leverage admixture in the context of …

Generation Of A Novel Stra8-Driven Cre Recombinase Strain For Use In Pre-Meiotic Germ Cells In Mice†, Avery A Ahmed, Ernesto Salas, Denise G Lanza, Jason D Heaney, Stephanie A Pangas

Faculty, Staff and Students Publications

The development of oocytes occurs over a broad time frame, starting at the earliest stages of embryogenesis and continuing into adulthood. Conditional knockout technologies such as the Cre/loxP recombination system are useful for analyzing oocyte development at specific stages, but not every time frame has appropriate Cre drivers, for instance, during oocyte meiotic initiation through early prophase I in the embryo. Here, we generated a novel knockin mouse line that produces a bicistronic transcript from the endogenous Stra8 locus that includes a "self-cleaving" 2A peptide upstream of cre. This allows for high efficiency cleavage and production of both proteins individually …

Dimethyl Sulfoxide Inhibits Bile Acid Synthesis In Healthy Mice But Does Not Protect Mice From Bile-Acid-Induced Liver Damage, Xi Chen, Huiqiao Li, Yu'e Liu, Jing Qi, Bingning Dong, Shixia Huang, Shangang Zhao, Yi Zhu

Faculty, Staff and Students Publications

Bile acids serve a vital function in lipid digestion and absorption; however, their accumulation can precipitate liver damage. In our study, we probed the effects of dimethyl sulfoxide (DMSO) on bile acid synthesis and the ensuing liver damage in mice induced by bile acids. Our findings indicate that DMSO efficaciously curbs bile acid synthesis by inhibiting key enzymes involved in the biosynthetic pathway, both in cultured primary hepatocytes and in vivo. Contrarily, we observed that DMSO treatment did not confer protection against bile-acid-induced liver damage in two distinct mouse models: one induced by a 0.1% DDC diet, leading to bile …

A De Novo Missense Variant In Ezh1 Associated With Developmental Delay Exhibits Functional Deficits In Drosophila Melanogaster, Sharayu V Jangam, Lauren C Briere, Kristy L Jay, Jonathan C Andrews, Melissa A Walker, Lance H Rodan, Frances A High, Undiagnosed Diseases Network, Shinya Yamamoto, David A Sweetser, Michael F Wangler

Faculty, Staff and Students Publications

EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have …

Loss Of Microrna-30a And Sex-Specific Effects On The Neonatal Hyperoxic Lung Injury, Sandra L Grimm, Samuel Reddick, Xiaoyu Dong, Connor Leek, Amy Xiao Wang, Manuel Cantu Gutierrez, Sean M Hartig, Bhagavatula Moorthy, Cristian Coarfa, Krithika Lingappan

Faculty, Staff and Students Publications

BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.

METHODS: Wild-type and miR-30a−/− neonatal mice were exposed …

Molecular Mechanisms Of Snorna-Ll-15 Crosstalk In Adipocyte Lipolysis And Nk Cell Rejuvenation, Yaohua Zhang, Zilong Zhao, Lisa A Huang, Yuan Liu, Jun Yao, Chengcao Sun, Yajuan Li, Zhao Zhang, Youqiong Ye, Fei Yuan, Tina K Nguyen, Nikhil Reddy Garlapati, Andrew Wu, Sergey D Egranov, Abigail S Caudle, Aysegul A Sahin, Bora Lim, Laura Beretta, George A Calin, Dihua Yu, Mien-Chie Hung, Michael A Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced …

Traf3-Ewsr1 Signaling Axis Acts As A Checkpoint On Germinal Center Responses, Yanchuan Li, Lele Zhu, Chun-Jung Ko, Jin-Young Yang, Hongjiao Wang, Ganiraju Manyam, Jing Wang, Xuhong Cheng, Shuli Zhao, Zuliang Jie

Faculty, Staff and Student Publications

The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer's patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

The At-Hook Is An Evolutionarily Conserved Auto-Regulatory Domain Of Swi/Snf Required For Cell Lineage Priming, Dhurjhoti Saha, Solomon Hailu, Arjan Hada, Junwoo Lee, Jie Luo, Jeff A Ranish, Yuan-Chi Lin, Kyle Feola, Jim Persinger, Abhinav Jain, Bin Liu, Yue Lu, Payel Sen, Blaine Bartholomew

Faculty, Staff and Student Publications

The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome, controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe however that the AT-hook regulates the intrinsic DNA-stimulated ATPase activity aside from promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (K

Shp2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors To Re-Treatment With Targeted Therapy, Alexander Drilon, Manish R Sharma, Melissa L Johnson, Timothy A Yap, Shirish Gadgeel, Dale Nepert, Gang Feng, Micaela B Reddy, Allison S Harney, Mohamed Elsayed, Adam W Cook, Christina E Wong, Ronald J Hinklin, Yutong Jiang, Eric N Brown, Nickolas A Neitzel, Ellen R Laird, Wen-I Wu, Anurag Singh, Ping Wei, Keith A Ching, John J Gaudino, Patrice A Lee, Dylan P Hartley, S Michael Rothenberg

Faculty, Staff and Student Publications

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion–positive lung cancer, BRAF^V600E-mutant colorectal cancer, KRAS^G12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition …

Csf1r Regulates Schizophrenia-Related Stress Response And Vascular Association Of Microglia/Macrophages, Ling Yan, Yanli Li, Fengmei Fan, Mengzhuang Gou, Fangling Xuan, Wei Feng, Keerthana Chithanathan, Wei Li, Junchao Huang, Hongna Li, Wenjin Chen, Baopeng Tian, Zhiren Wang, Shuping Tan, Alexander Zharkovsky, L Elliot Hong, Yunlong Tan, Li Tian

Faculty, Staff and Student Publications

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility.

METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating …

Spatial Transcriptomics Of Intraductal Papillary Mucinous Neoplasms Of The Pancreas Identifies Nkx6-2 As A Driver Of Gastric Differentiation And Indolent Biological Potential, Marta Sans, Yuki Makino, Jimin Min, Kimal I Rajapakshe, Michele Yip-Schneider, C Max Schmidt, Mark W Hurd, Jared K Burks, Javier A Gomez, Fredrik I Thege, Johannes F Fahrmann, Robert A Wolff, Michael P Kim, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric …

The Co-Delivery Of Adenovirus-Based Immune Checkpoint Vaccine Elicits A Potent Anti-Tumor Effect In Renal Carcinoma, Nan Jiang, Yanyan Zheng, Jiage Ding, Jiawei Wang, Fei Zhu, Meng Wang, Navid Sobhani, Praveen Neeli, Gang Wang, Hailong Li, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Immune-based checkpoint therapy has made significant progress in cancer treatment, but its therapeutic effect is limited. A replication-defective adenovirus (Ad) vaccine encoding tumor antigen carbonic anhydrase IX (CAIX) combined with Ad-encoding immune checkpoint PD-L1 was developed to treat renal carcinoma. Three tumor models, subcutaneous, lung metastasis and orthotopic tumor were established, and Ad vaccines were used to immunize them and evaluate the vaccine's therapeutic effect. Compared to the single Ad vaccine group, the subcutaneous tumor growth was significantly reduced in Ad-CAIX/Ad-PD-L1 combination group. Co-immunization of Ad-CAIX/Ad-PD-L1 enhanced the induction and maturation of CD11c

Combined Crispri And Proteomics Screening Reveal A Cohesin-Ctcf-Bound Allele Contributing To Increased Expression Of Ruvbl1 And Prostate Cancer Progression, Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y Park, Gong-Hong Wei, Liang Wang

Faculty, Staff and Student Publications

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10