Digital Commons Network^™

Androgen Deprivation Induces Neuroendocrine Phenotypes In Prostate Cancer Cells Through Creb1/Ezh2-Mediated Downregulation Of Rest, Dayong Zheng, Yan Zhang, Sukjin Yang, Ning Su, Michael Bakhoum, Guoliang Zhang, Samira Naderinezhad, Zhengmei Mao, Zheng Wang, Ting Zhou, Wenliang Li

Faculty, Staff and Student Publications

Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor …

Nanobodies In The Fight Against Infectious Diseases: Repurposing Nature's Tiny Weapons, Dina Mohamed Moustafa, Soha S. Rizk, Shahira A. Elbanna, Hanzada Tawfik Nour El-Din, Ahmed Sherif Attia

Dentistry

Nanobodies are the smallest known antigen-binding molecules to date. Their small size, good tissue penetration, high stability and solubility, ease of expression, refolding ability, and negligible immunogenicity in the human body have granted them excellence over conventional antibodies. Those exceptional attributes of nanobodies make them promising candidates for various applications in biotechnology, medicine, protein engineering, structural biology, food, and agriculture. This review presents an overview of their structure, development methods, advantages, possible challenges, and applications with special emphasis on infectious diseases-related ones. A showcase of how nanobodies can be harnessed for applications including neutralization of viruses and combating antibiotic-resistant bacteria …

Age-Specific Induction Of Mutant P53 Drives Clonal Hematopoiesis And Acute Myeloid Leukemia In Adult Mice, Rasoul Pourebrahim, Rafael Heinz Montoya, Hiroki Akiyama, Lauren Ostermann, Shayuan Khazaei, Muharrem Muftuoglu, Natalia Baran, Ran Zhao, Tom Lesluyes, Bin Liu, Joseph D Khoury, Mihai Gagea, Peter Van Loo, Michael Andreeff

Faculty, Staff and Student Publications

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem …

Selective Refueling Of Car T Cells Using Ada1 And Cd26 Boosts Antitumor Immunity, Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor …

Targeting The Substrate For Atrial Fibrillation: Jacc Review Topic Of The Week, Mark D Mccauley, Gianluca Iacobellis, Na Li, Stanley Nattel, Jeffrey J Goldberger

Faculty, Staff and Students Publications

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy-the underlying anatomic, electrical, and/or autonomic disease affecting the …

Ciliary Tip Actin Dynamics Regulate Photoreceptor Outer Segment Integrity, Roly Megaw, Abigail Moye, Zhixian Zhang, Fay Newton, Fraser Mcphie, Laura C Murphy, Lisa Mckie, Feng He, Melissa K Jungnickel, Alex Von Kriegsheim, Peter A Tennant, Chloe Brotherton, Christine Gurniak, Alecia K Gross, Laura M Machesky, Theodore G Wensel, Pleasantine Mill

Faculty, Staff and Students Publications

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a …

An Unexpected Path For Malat1 In Neurons: Trafficking Out Of The Nucleus For Translation, Bradley W Wright, Jeremy E Wilusz

Faculty, Staff and Students Publications

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene …

Comprehensive In Vitro And In Vivo Evaluation Of Therapeutic Potential Of Bacopa-Derived Asiatic Acid Against A Human Oral Pathogen Streptococcus Mutans, Rajendran Jeyasri, Pandiyan Muthuramalingam, Arumugam Priya, Rajaiah Alexpandi, N. R. Siva Shanmugam, Saminathan Nivetha, Hyunsuk Shin, Shunmugiah Karutha Pandian, Arumugam Veera Ravi, Manikandan Ramesh

Food for Health: Publications

Dental caries is a common human oral disease worldwide, caused by an acid-producing bacteria Streptococcus mutans. The use of synthetic drugs and antibiotics to prevent dental caries has been increasing, but this can lead to severe side effects. To solve this issue, developing and developed countries have resorted to herbal medicines as an alternative to synthetic drugs for the treatment and prevention of dental caries. Therefore, there is an urgent need for plant-derived products to treat such diseases. Bacopa monnieri, a well-documented medicinal plant, contains 52 phytocompounds, including the pentacyclic triterpenoid metabolite known as asiatic acid (ASTA). Hence, …

Systemic Inflammatory Markers Of Persistent Cerebral Edema After Aneurysmal Subarachnoid Hemorrhage, Nadia Khan, Magdalena Kurnik-Łucka, Gniewomir Latacz, Krzysztof Gil

Faculty, Staff and Student Publications

In the first part of this article, the role of intestinal epithelial tight junctions (TJs), together with gastrointestinal dopaminergic and renin-angiotensin systems, are narratively reviewed to provide sufficient background. In the second part, the current experimental data on the interplay between gastrointestinal (GI) dopaminergic and renin-angiotensin systems in the regulation of intestinal epithelial permeability are reviewed in a systematic manner using the PRISMA methodology. Experimental data confirmed the copresence of DOPA decarboxylase (DDC) and angiotensin converting enzyme 2 (ACE2) in human and rodent enterocytes. The intestinal barrier structure and integrity can be altered by angiotensin (1-7) and dopamine (DA). Both …

Il-2-Free Tumor-Infiltrating Lymphocyte Therapy With Pd-1 Blockade Demonstrates Potent Efficacy In Advanced Gynecologic Cancer, Jing Guo, Chunyan Wang, Ning Luo, Yuliang Wu, Wei Huang, Jihui Zhu, Weihui Shi, Jinye Ding, Yao Ge, Chunhong Liu, Zhen Lu, Robert C Bast, Guihai Ai, Weihong Yang, Rui Wang, Caixia Li, Rong Chen, Shupeng Liu, Huajun Jin, Binghui Zhao, Zhongping Cheng

Faculty, Staff and Student Publications

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer.

METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, …

Developing A Membrane-Proximal Cd33-Targeting Car T Cell, Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin Mcavoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan

Faculty, Staff and Student Publications

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both …

A Novel Positive-Contrast Magnetic Resonance Imaging Line Marker For High-Dose-Rate (Hdr) Mri-Assisted Radiosurgery (Mars), Li Wang, Yao Ding, Teresa L Bruno, R Jason Stafford, Eric Lin, Tharakeswara K Bathala, Jeremiah W Sanders, Matthew S Ning, Jingfei Ma, Ann H Klopp, Aradhana Venkatesan, Jihong Wang, Karen S Martirosyan, Steven J Frank

Faculty, Staff and Student Publications

Magnetic resonance imaging (MRI) can facilitate accurate organ delineation and optimal dose distributions in high-dose-rate (HDR) MRI-Assisted Radiosurgery (MARS). Its use for this purpose has been limited by the lack of positive-contrast MRI markers that can clearly delineate the lumen of the HDR applicator and precisely show the path of the HDR source on T1- and T2-weighted MRI sequences. We investigated a novel MRI positive-contrast HDR brachytherapy or interventional radiotherapy line marker, C4:S, consisting of C4 (visible on T1-weighted images) complexed with saline. Longitudinal relaxation time (T1) and transverse relaxation time (T2) for C4:S were measured on a 1.5 T …

A Model Of Oocyte Population Dynamics For Fish Oogenesis, Louis Fostier, Frédérique Clément, Romain Yvinec, Violette Thermes

Biology and Medicine Through Mathematics Conference

No abstract provided.

Dynamic Visual Acuity, Vestibulo-Ocular Reflex, And Visual Field In National Football League (Nfl) Officiating: Physiology And Visualization Engineering For 3d Virtual On-Field Training, Joshua Ong, Nicole V Carrabba, Ethan Waisberg, Nasif Zaman, Hamza Memon, Nicholas Panzo, Virginia A Lee, Prithul Sarker, Ashtyn Z Vogt, Noor Laylani, Alireza Tavakkoli, Andrew G Lee

Faculty, Staff and Student Publications

The ability to make on-field, split-second decisions is critical for National Football League (NFL) game officials. Multiple principles in visual function are critical for accuracy and precision of these play calls, including foveation time and unobstructed line of sight, static visual acuity, dynamic visual acuity, vestibulo-ocular reflex, and sufficient visual field. Prior research has shown that a standardized curriculum in these neuro-ophthalmic principles have demonstrated validity and self-rated improvements in understanding, confidence, and likelihood of future utilization by NFL game officials to maximize visual performance during officiating. Virtual reality technology may also be able to help optimize understandings of specific …

Unraveling Etc Complex I Function In Ferroptosis Reveals A Potential Ferroptosis-Inducing Therapeutic Strategy For Lkb1-Deficient Cancers, Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes …

Enhancer Switching In Cell Lineage Priming Is Linked To Erna, Brg1’S At-Hook, And Swi/Snf Recruitment, Dhurjhoti Saha, Srinivas Animireddy, Junwoo Lee, Anna Thommen, Mckenzie M Murvin, Yue Lu, J Mauro Calabrese, Blaine Bartholomew

Faculty, Staff and Student Publications

RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the …

Localization Of Rnas To The Mitochondria-Mechanisms And Functions, Surbhi Sharma, Furqan M Fazal

Faculty, Staff and Students Publications

The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to the outer mitochondrial membrane (OMM) in a pre- or cotranslational state. Upon reaching the mitochondrial surface, these mRNAs are locally translated to produce proteins that are cotranslationally imported into mitochondria. Here, we summarize various mechanisms cells use to localize RNAs, including transfer RNAs (tRNAs), to the OMM and recent technological advancements in the field to study these processes. While most early studies in the field were carried out in yeast, recent studies reveal …

Brg1/Brm Inhibitor Targets Aml Stem Cells And Exerts Superior Preclinical Efficacy Combined With Bet Or Menin Inhibitor, Warren Fiskus, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christopher P Mill, Christine E Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Jian Wang, Sanam Loghavi, Rwik Sen, Xinjia Ruan, Xiaoping Su, Lauren B Flores, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with …

Ataxia-Telangiectasia Mutated Loss-Of-Function Displays Variant And Tissue-Specific Differences Across Tumor Types, Patrick G Pilié, Virginia Giuliani, Wei-Lien Wang, Daniel J Mcgrail, Christopher A Bristow, Natalie Y L Ngoi, Keith Kyewalabye, Khalida M Wani, Hung Le, Erick Campbell, Nora S Sanchez, Dong Yang, Jinesh S Gheeya, Rohit Vivek Goswamy, Vijaykumar Holla, Kenna Rael Shaw, Funda Meric-Bernstam, Chiu-Yi Liu, Xiaoyan Ma, Ningping Feng, Annette A Machado, Jennifer P Bardenhagen, Christopher P Vellano, Joseph R Marszalek, Eeson Rajendra, Desiree Piscitello, Timothy I Johnson, Maria Likhatcheva, Elias Elinati, Jayesh Majithiya, Joana Neves, Vera Grinkevich, Marco Ranzani, Marina Roy Luzarraga, Marie Boursier, Lucy Armstrong, Lerin Geo, Giorgia Lillo, Wai Yiu Tse, Alexander J Lazar, Scott E Kopetz, Mary K Geck Do, Sarah Lively, Michael G Johnson, Helen M R Robinson, Graeme C M Smith, Christopher L Carroll, M Emilia Di Francesco, Philip Jones, Timothy P Heffernan, Timothy A Yap

Faculty, Staff and Student Publications

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF …

Targeting Ccl2/Ccr2 Signaling Overcomes Mek Inhibitor Resistance In Acute Myeloid Leukemia, Rucha V Modak, Katia G De Oliveira Rebola, John Mcclatchy, Mona Mohammadhosseini, Alisa Damnernsawad, Stephen E Kurtz, Christopher A Eide, Guanming Wu, Ted Laderas, Tamilla Nechiporuk, Marina A Gritsenko, Joshua R Hansen, Chelsea Hutchinson, Sara J C Gosline, Paul Piehowski, Daniel Bottomly, Nicholas Short, Karin Rodland, Shannon K Mcweeney, Jeffrey W Tyner, Anupriya Agarwal

Faculty, Staff and Student Publications

Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML.

Experimental design: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 …

Integrative Molecular Analyses Of The Md Anderson Prostate Cancer Patient-Derived Xenograft (Mda Pca Pdx) Series, Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone

Faculty, Staff and Student Publications

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived …

The Calcineurin-Nfatc Pathway Modulates The Lipid Mediators In Bal Fluid Extracellular Vesicles, Thereby Regulating Microvascular Endothelial Cell Barrier Function, Manjula Karpurapu, Yunjuan Nie, Sangwoon Chung, Jiasheng Yan, Patrick Dougherty, Sonal Pannu, Jon Wisler, Ryan Harkless, Narasimham Parinandi, Evgeny Berdyshev, Dehua Pei, John W Christman

Faculty, Staff and Student Publications

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse …

Ire1Α Determines Ferroptosis Sensitivity Through Regulation Of Glutathione Synthesis, Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong

Faculty, Staff and Student Publications

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is …

Heterogeneous Profile Of Ror1 Protein Expression Across Tumor Types, Maria Gabriela Raso, Elizve Barrientos Toro, Kurt Evans, Yasmeen Rizvi, Rossana Lazcano, Argun Akcakanat, Patrizia Sini, Francesca Trapani, Eva Johanna Madlener, Lorenz Waldmeier, Alexander Lazar, Funda Meric-Bernstam

Faculty, Staff and Student Publications

The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 …

Optical Coherence Tomography-Guided Brillouin Microscopy Highlights Regional Tissue Stiffness Differences During Anterior Neural Tube Closure In The Mthfd1l Murine Mutant, Yogeshwari S Ambekar, Carlo Donato Caiaffa, Bogdan J Wlodarczyk, Manmohan Singh, Alexander W Schill, John W Steele, Jitao Zhang, Salavat R Aglyamov, Giuliano Scarcelli, Richard H Finnell, Kirill V Larin

Faculty, Staff and Students Publications

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos …

Jag1/2 Maintain Esophageal Homeostasis And Suppress Foregut Tumorigenesis By Restricting The Basal Progenitor Cell Pool, Haidi Huang, Yu Jiang, Jiangying Liu, Dan Luo, Jianghong Yuan, Rongzi Mu, Xiang Yu, Donglei Sun, Jihong Lin, Qiyue Chen, Xinjing Li, Ming Jiang, Jianming Xu, Bo Chu, Chengqian Yin, Lei Zhang, Youqiong Ye, Bo Cao, Qiong Wang, Yongchun Zhang

Faculty, Staff and Students Publications

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and …

Optical Coherence Tomography-Guided Brillouin Microscopy Highlights Regional Tissue Stiffness Differences During Anterior Neural Tube Closure In The Mthfd1l Murine Mutant, Yogeshwari S Ambekar, Carlo Donato Caiaffa, Bogdan J Wlodarczyk, Manmohan Singh, Alexander W Schill, John W Steele, Jitao Zhang, Salavat R Aglyamov, Giuliano Scarcelli, Richard H Finnell, Kirill V Larin

Faculty, Staff and Students Publications

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos …

Abnormal Morphology And Synaptogenic Signaling In Astrocytes Following Prenatal Opioid Exposure, Ethan B. Niebergall, Daron Weekley, Anna Mazur, Nathan A. Olszewski, Kayla M. Deschepper, N. Radant, Aishwarya S. Vijay

Biomedical Sciences

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and …

Astrocytes Remember Inflammation, Michael R Williamson, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes respond to all forms of central nervous system maladies. In a recent issue of Nature, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.

Mv140 Mucosal Vaccine Induces Targeted Immune Response For Enhanced Clearance Of Uropathogenic E Coli In Experimental Urinary Tract Infection, Paula Saz-Leal, Marianne Morris Ligon, Carmen María Diez-Rivero, Diego García-Ayuso, Soumitra Mohanty, Marcos Viñuela, Irene Real-Arévalo, Laura Conejero, Annelie Brauner, José Luis Subiza, Indira Uppugunduri Mysorekar

Faculty, Staff and Students Publications

MV140 is an inactivated whole-cell bacterial mucosal vaccine with proven clinical efficacy against recurrent urinary tract infections (UTIs). These infections are primarily caused by uropathogenic E. coli (UPEC) strains, which are unique in their virulence factors and remarkably diverse. MV140 contains a non-UPEC strain, suggesting that it may induce an immune response against different UPEC-induced UTIs in patients. To verify this, we experimentally evaluated the cellular and humoral responses to UTI89, a prototypical UPEC strain, in mice vaccinated with MV140, as well as the degree of protection achieved in a UPEC UTI89 model of acute cystitis. The results show that …