Medicine and Health Sciences Commons^™

Hippo Cooperates With P53 To Maintain Foregut Homeostasis And Suppress The Malignant Transformation Of Foregut Basal Progenitor Cells, Yu Jiang, Haidi Huang, Jiangying Liu, Dan Luo, Rongzi Mu, Jianghong Yuan, Jihong Lin, Qiyue Chen, Wufan Tao, Ling Yang, Man Zhang, Pingping Zhang, Fengqin Fang, Jianming Xu, Qingqiu Gong, Zhiping Xie, Yongchun Zhang

Faculty, Staff and Students Publications

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of

Microglia At Sites Of Atrophy Restrict The Progression Of Retinal Degeneration Via Galectin-3 And Trem2, Chen Yu, Yun Chen, Jinchao Hou, Marco Colonna, Et Al.

2020-Current year OA Pubs

Outer retinal degenerations, including age-related macular degeneration (AMD), are characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. In these blinding diseases, macrophages accumulate at atrophic sites, but their ontogeny and niche specialization remain poorly understood, especially in humans. We uncovered a unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and human AMD. In disease models, conditional deletion of galectin-3 in microglia led to phagocytosis defects and consequent augmented photoreceptor death, RPE damage, and vision loss, indicating protective roles. Mechanistically, Trem2 signaling orchestrated microglial migration to atrophic sites and induced galectin-3 …

Neuroinvasive West Nile Virus Infection In Immunosuppressed And Immunocompetent Adults., Amir A Mbonde, David Gritsch, Ehab Y Harahsheh, Sabirah N Kasule, Shemonti Hasan, Angela M Parsons, Nan Zhang, Richard Butterfield, Harn Shiue, Kathryn A Norville, Jenna L Reynolds, Holenarasipur R Vikram, Brian Chong, Marie F Grill

Neuroscience Articles

IMPORTANCE: West Nile virus (WNV) is the leading cause of human arboviral disease in the US, peaking during summer. The incidence of WNV, including its neuroinvasive form (NWNV), is increasing, largely due to the expanding distribution of its vector, the Culex mosquito, and climatic changes causing heavy monsoon rains. However, the distinct characteristics and outcomes of NWNV in individuals who are immunosuppressed (IS) and individuals who are not IS remain underexplored.

OBJECTIVE: To describe and compare clinical and radiographic features, treatment responses, and outcomes of NWNV infection in individuals who are IS and those who are not IS.

DESIGN, SETTING, …

Lilrb3 Supports Immunosuppressive Activity Of Myeloid Cells And Tumor Development, Ryan Huang, Xiaoye Liu, Jaehyup Kim, Hui Deng, Mi Deng, Xun Gui, Heyu Chen, Guojin Wu, Wei Xiong, Jingjing Xie, Cheryl Lewis, Jade Homsi, Xing Yang, Chengcheng Zhang, Yubo He, Qi Lou, Caroline Smith, Samuel John, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the …

A Genotyping Array For The Globally Invasive Vector Mosquito, Aedes Albopictus, Luciano Veiga Cosme, Margaret Corley, Thomas Johnson, Dave W Severson, Guiyun Yan, Xiaoming Wang, Nigel Beebe, Andrew Maynard, Mariangela Bonizzoni, Ayda Khorramnejad, Ademir Jesus Martins, José Bento Pereira Lima, Leonard E Munstermann, Sinnathamby N Surendran, Chun-Hong Chen, Kevin Maringer, Isra Wahid, Shomen Mukherjee, Jiannon Xu, Michael C Fontaine, Elizabet L Estallo, Marina Stein, Todd Livdahl, Patricia Y Scaraffia, Brendan H Carter, Motoyoshi Mogi, Nobuko Tuno, James W Mains, Kim A Medley, David E Bowles, Richard J Gill, Roger Eritja, Ranulfo González-Obando, Huynh T T Trang, Sébastien Boyer, Ann-Marie Abunyewa, Kayleigh Hackett, Tina Wu, Justin Nguyễn, Jiangnan Shen, Hongyu Zhao, Jacob E Crawford, Peter Armbruster, Adalgisa Caccone

Faculty, Staff and Student Publications

BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in …

Craniofacial Bone Anomalies Related To Cholesterol Synthesis Defects, Chihiro Iwaya, Akiko Suzuki, Junbo Shim, Aemin Kim, Junichi Iwata

Faculty, Staff and Student Publications

DHCR7 and SC5D are enzymes crucial for cholesterol biosynthesis, and mutations in their genes are associated with developmental disorders, which are characterized by craniofacial deformities. We have recently reported that a loss of either Dhcr7 or Sc5d results in a failure in osteoblast differentiation. However, it remains unclear to what extent a loss of function in either DHCR7 or SC5D affects craniofacial skeletal formation. Here, using micro computed tomography (μCT), we found that the bone phenotype differs in Dhcr7

The Identification Of A Distinct Astrocyte Subtype That Diminishes In Alzheimer's Disease, Haichao Wei, Joseph Withrow, Jyotirmoy Rakshit, Faiz Ul Amin, Joshua Nahm, Francesca E Mowry, Zhengmei Mao, Meenakshi B Bhattacharjee, Jay-Jiguang Zhu, Yongjie Yang, Jia Qian Wu

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is characterized by the presence of two hallmark pathologies: the accumulation of Amyloid beta (Aβ) and tau proteins in the brain. There is a growing body of evidence suggesting that astrocytes, a type of glial cell in the brain, play crucial roles in clearing Aβ and binding to tau proteins. However, due to the heterogeneity of astrocytes, the specific roles of different astrocyte subpopulations in response to Aβ and tau remain unclear. To enhance the understanding of astrocyte subpopulations in AD, we investigated astrocyte lineage cells based on single-nuclei transcriptomic data obtained from both human and mouse …

Adipose Triglyceride Lipase Is A Therapeutic Target In Advanced Prostate Cancer That Promotes Metabolic Plasticity, Dominik Awad, Pham Hong Anh Cao, Thomas L Pulliam, Meredith Spradlin, Elavarasan Subramani, Tristen V Tellman, Caroline F Ribeiro, Riccardo Muzzioli, Brittany E Jewell, Hubert Pakula, Jeffrey J Ackroyd, Mollianne M Murray, Jenny J Han, Mei Leng, Antrix Jain, Badrajee Piyarathna, Jingjing Liu, Xingzhi Song, Jianhua Zhang, Albert R Klekers, Justin M Drake, Michael M Ittmann, Cristian Coarfa, David Piwnica-Worms, Mary C Farach-Carson, Massimo Loda, Livia S Eberlin, Daniel E Frigo

Faculty, Staff and Students Publications

UNLABELLED: Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate …

A Greb1-Steroid Receptor Feedforward Mechanism Governs Differential Greb1 Action In Endometrial Function And Endometriosis, Sangappa B Chadchan, Eryk Andreas, Stephanie J Gunderson, Patricia T Jimenez, Emily S Jungheim, Kelle H Moley, Et Al.

2020-Current year OA Pubs

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback …

A Greb1-Steroid Receptor Feedforward Mechanism Governs Differential Greb1 Action In Endometrial Function And Endometriosis, Sangappa B Chadchan, Pooja Popli, Zian Liao, Eryk Andreas, Michelle Dias, Tianyuan Wang, Stephanie J Gunderson, Patricia T Jimenez, Denise G Lanza, Rainer B Lanz, Charles E Foulds, Diana Monsivais, Francesco J Demayo, Hari Krishna Yalamanchili, Emily S Jungheim, Jason D Heaney, John P Lydon, Kelle H Moley, Bert W O'Malley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback …

Cholinergic Basal Forebrain Connectivity To The Basolateral Amygdala Modulates Food Intake, Joshua Ortiz-Guzman, Jessica L Swanson, Evelyne K Tantry, Mikhail Kochukov, Kevin Ung, Angela P Addison, Snigdha Srivastava, Benjamin D Belfort, Emily Ji, Sean W Dooling, Sarah A Chen, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA …

Gene-Based Association Study Of Rare Variants In Children Of Diverse Ancestries Implicates Tnfrsf21 In The Development Of Allergic Asthma, Selene Clay, Katherine Rivera-Spoljaric, Et Al.

2020-Current year OA Pubs

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits.

OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes.

METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% …

Hypoimmune Induced Pluripotent Stem Cells Survive Long Term In Fully Immunocompetent, Allogeneic Rhesus Macaques, Xiaomeng Hu, Nathaniel J Hogrebe, Et Al.

2020-Current year OA Pubs

Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M

Distributed Feature Representations Of Natural Stimuli Across Parallel Retinal Pathways, Jen-Chun Hsiang, Ning Shen, Florentina Soto, Daniel Kerschensteiner

2020-Current year OA Pubs

How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, …

Estrogen-Induced Glial Il-1Β Mediates Extrinsic Retinal Ganglion Cell Vulnerability In Murine Nf1 Optic Glioma, Yunshuo Tang, Jit Chatterjee, Ngan Wagoner, Stephanie Bozeman, David H Gutmann

2020-Current year OA Pubs

Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1

Altered Larval Activation Response Associated With Multidrug Resistance In The Canine Hookworm Ancylostoma Caninum, Elise L Mckean, Emilia Grill, Young-Jun Choi, Makedonka Mitreva, Damien M O'Halloran, John M Hawdon

2020-Current year OA Pubs

Parasitic gastrointestinal nematodes pose significant health risks to humans, livestock, and companion animals, and their control relies heavily on the use of anthelmintic drugs. Overuse of these drugs has led to the emergence of resistant nematode populations. Herein, a naturally occurring isolate (referred to as BCR) of the dog hookworm,

Mfsd7c Functions As A Transporter Of Choline At The Blood-Brain Barrier, Xuan Thi Anh Nguyen, Angela Lee, Jorge L Granadillo, Catherine Gooch, Et Al.

2020-Current year OA Pubs

Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c

Mucosal Vaccine-Induced Cross-Reactive Cd8+ T Cells Protect Against Sars-Cov-2 Xbb.1.5 Respiratory Tract Infection, Baoling Ying, Tamarand L Darling, Pritesh Desai, Chieh-Yu Liang, Igor P Dmitriev, Nadia Soudani, Traci Bricker, Elena A Kashentseva, Houda Harastani, Saravanan Raju, Meizi Liu, Aaron G Schmidt, David T Curiel, Adrianus C M Boon, Michael S Diamond

2020-Current year OA Pubs

A nasally delivered chimpanzee adenoviral-vectored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (ChAd-SARS-CoV-2-S) is currently used in India (iNCOVACC). Here, we update this vaccine by creating ChAd-SARS-CoV-2-BA.5-S, which encodes a prefusion-stabilized BA.5 spike protein. Whereas serum neutralizing antibody responses induced by monovalent or bivalent adenoviral vaccines were poor against the antigenically distant XBB.1.5 strain and insufficient to protect in passive transfer experiments, mucosal antibody and cross-reactive memory T cell responses were robust, and protection was evident against WA1/2020 D614G and Omicron variants BQ.1.1 and XBB.1.5 in mice and hamsters. However, depletion of memory CD8

Extracellular Domain Mutations Of The Egf Receptor Differentially Modulate High-Affinity And Low-Affinity Responses To Egf Receptor Ligands, Jennifer L Macdonald-Obermann, Linda J Pike

2020-Current year OA Pubs

The EGF receptor is mutated in a number of cancers. In most cases, the mutations occur in the intracellular tyrosine kinase domain. However, in glioblastomas, many of the mutations are in the extracellular ligand binding domain. To determine what changes in receptor function are induced by such extracellular domain mutations, we analyzed the binding and biological response to the seven different EGF receptor ligands in three common glioblastoma mutants-R84K, A265V, and G574V. Our data indicate that all three mutations significantly increase the binding affinity of all seven ligands. In addition, the mutations increase the potency of all ligands for stimulating …

Decreased Sarcoplasmic Reticulum Phospholipids In Human Skeletal Muscle Are Associated With Metabolic Syndrome, Samantha E Adamson, Sangeeta Adak, Max C Petersen, Dustin Higgins, Larry D Spears, Rong Mei Zhang, Andrea Cedeno, Alexis Mckee, Aswathi Kumar, Sudhir Singh, Fong-Fu Hsu, Janet B Mcgill, Clay F Semenkovich

2020-Current year OA Pubs

Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca

The Hyphal-Specific Toxin Candidalysin Promotes Fungal Gut Commensalism, Shen-Huan Liang, Shabnam Sircaik, Joseph Dainis, Pallavi Kakade, Swathi Penumutchu, Liam D Mcdonough, Ying-Han Chen, Corey Frazer, Tim B Schille, Stefanie Allert, Osama Elshafee, Maria Hänel, Selene Mogavero, Shipra Vaishnava, Ken Cadwell, Peter Belenky, J Christian Perez, Bernhard Hube, Iuliana V Ene, Richard J Bennett

Faculty, Staff and Student Publications

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Targeted Inhibition Of Scfskp2 Confers Anti-Tumor Activities Resulting In A Survival Benefit In Osteosarcoma, Jichuan Wang, Alexander Ferrena, Ranxin Zhang, Swapnil Singh, Valentina Viscarret, Waleed Al-Harden, Osama Aldahamsheh, Hasibagan Borjihan, Amit Singla, Simon Yaguare, Janet Tingling, Xiaolin Zi, Yungtai Lo, Richard Gorlick, Edward L Schwartz, Hongling Zhao, Rui Yang, David S Geller, Deyou Zheng, Bang H Hoang

Faculty, Staff and Student Publications

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the …

The Efficacy-Associated Biomarkers For Immune Checkpoint Inhibitors In Gastrointestinal Cancer: A Literature Review, Jessie Lee, Yifei Shan, Angelique Wong, Elizabeth A Brown, Mitchell Callahan, Robert A Hernandez, Michael J Mienaltowski

Faculty, Staff and Student Publications

White striping (WS) is a common myopathy seen in fast-growing broilers. Studies have demonstrated that chitosan is effective as an antioxidant and has antiobesity and fat-absorption reduction properties. We hypothesized that the dietary supplementation of chitosan would have similar effects when fed to fast-growing broilers and would thus lower WS incidence and improve meat quality. One hundred twenty-six broilers were fed corn-soy diets. The grower and finisher diets contained either 0, 0.2, or 0.4% chitosan. After a 6 wk growth period, birds were euthanized, and then WS and gross pathology scores were assessed. Pectoralis major tissues were collected to evaluate …

Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain By Activation Of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 In The Dorsal Root Ganglia, Hee Kee Kim, Qi Wang, Seon-Hee Hwang, Patrick M Dougherty, Jing Wang, Salahadin Abdi

Faculty, Staff and Student Publications

Background: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP.

Methods: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, …

Peroxisome Proliferator-Activated Receptors As Therapeutic Target For Cancer, Yuqing Wang, Feifei Lei, Yiyun Lin, Yuru Han, Lei Yang, Huabing Tan

Faculty, Staff and Student Publications

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-β/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and …

Safety, Efficacy And Determinants Of Response Of Allogeneic Cd19-Specific Car-Nk Cells In Cd19+ B Cell Tumors: A Phase 1/2 Trial, David Marin, Ye Li, Rafet Basar, Hind Rafei, May Daher, Jinzhuang Dou, Vakul Mohanty, Merve Dede, Yago Nieto, Nadima Uprety, Sunil Acharya, Enli Liu, Jeffrey Wilson, Pinaki Banerjee, Homer A Macapinlac, Christina Ganesh, Peter F Thall, Roland Bassett, Mariam Ammari, Sheetal Rao, Kai Cao, Mayra Shanley, Mecit Kaplan, Chitra Hosing, Partow Kebriaei, Loretta J Nastoupil, Christopher R Flowers, Sadie Mae Moseley, Paul Lin, Sonny Ang, Uday R Popat, Muzaffar H Qazilbash, Richard E Champlin, Ken Chen, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were …

An Atlas Of Epithelial Cell States And Plasticity In Lung Adenocarcinoma, Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V Negrao, John V Heymach, Mingyao Li, Steven M Dubinett, Christopher S Stevenson, Avrum E Spira, Junya Fujimoto, Luisa M Solis, Ignacio I Wistuba, Jichao Chen, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver …

Preclinical Efficacy Of Targeting Epigenetic Mechanisms In Aml With 3q26 Lesions And Evi1 Overexpression, Christine E Birdwell, Warren Fiskus, Tapan M Kadia, Christopher P Mill, Koji Sasaki, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, Gautam Borthakur, John A Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D Khoury, Hagop Kantarjian, Kapil N Bhalla

Faculty, Staff and Student Publications

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, …

Visuo-Frontal Interactions During Social Learning In Freely Moving Macaques, Melissa Franch, Sudha Yellapantula, Arun Parajuli, Natasha Kharas, Anthony Wright, Behnaam Aazhang, Valentin Dragoi

Faculty, Staff and Student Publications

Social interactions represent a ubiquitous aspect of our everyday life that we acquire by interpreting and responding to visual cues from conspecifics1. However, despite the general acceptance of this view, how visual information is used to guide the decision to cooperate is unknown. Here, we wirelessly recorded the spiking activity of populations of neurons in the visual and prefrontal cortex in conjunction with wireless recordings of oculomotor events while freely moving macaques engaged in social cooperation. As animals learned to cooperate, visual and executive areas refined the representation of social variables, such as the conspecific or reward, by …