Diseases Commons^™

Soy Isoflavone Reduces Lps-Induced Acute Lung Injury Via Increasing Aquaporin 1 And Aquaporin 5 In Rats, Yuan-Hao Lee, W Wade Kothmann, Ya-Ping Lin, Alice Z Chuang, Jeffrey S Diamond, John O'Brien

Faculty, Staff and Student Publications

Synaptic plasticity is a fundamental feature of the CNS that controls the magnitude of signal transmission between communicating cells. Many electrical synapses exhibit substantial plasticity that modulates the degree of coupling within groups of neurons, alters the fidelity of signal transmission, or even reconfigures functional circuits. In several known examples, such plasticity depends on calcium and is associated with neuronal activity. Calcium-driven signaling is known to promote potentiation of electrical synapses in fish Mauthner cells, mammalian retinal AII amacrine cells, and inferior olive neurons, and to promote depression in thalamic reticular neurons. To measure local calcium dynamics

Heterozygous Midnolin Knockout Attenuates Severity Of Nonalcoholic Fatty Liver Disease In Mice Fed A Western-Style Diet High In Fat, Cholesterol, And Fructose, Soo-Mi Kweon, Jose Irimia-Dominguez, Gayeoun Kim, Patrick T Fueger, Kinji Asahina, Keith K Lai, Daniela S Allende, Quincy R Lai, Chih-Hong Lou, Walter M Tsark, Ju Dong Yang, Dominic S Ng, Ju-Seog Lee, Patrick Tso, Wendong Huang, Keane K Y Lai

Faculty, Staff and Student Publications

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first …

Ifit2 Restricts Murine Coronavirus Spread To The Spinal Cord White Matter And Its Associated Myelin Pathology, Madhav Sharma, Debanjana Chakravarty, Afaq Hussain, Ajay Zalavadia, Amy Burrows, Patricia Rayman, Nikhil Sharma, Lawrence C. Kenyon, Cornelia Bergmann, Ganes C. Sen, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection. To understand this, RSA59 infected Ifit2-/- and Ifit2+/+ (WT) were observed for neuropathological outcomes at day 5 (acute phase) and 30 …

Recombinant Adamts-13 Improves Survival Of Mice Subjected To Endotoxemia, Daniel Gao, Zhou Zhou, Ruidong Ma, Huaizhu Wu, Trung Nguyen, Li Liu, Jingfei Dong

Faculty, Staff and Students Publications

When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a …

Anoctamin 4 Channel Currents Activate Glucose-Inhibited Neurons In The Mouse Ventromedial Hypothalamus During Hypoglycemia, Longlong Tu, Jonathan C Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Kristine M Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Student Publications

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Faculty, Staff and Student Publications

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Myc Regulates Csf1 Expression Via Microrna 17/20a To Modulate Tumor-Associated Macrophages In Osteosarcoma, Bikesh K Nirala, Tajhal D Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T Yustein

Faculty, Staff and Students Publications

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that …

Vitamin B2 Enables Regulation Of Fasting Glucose Availability, Peter M Masschelin, Pradip Saha, Scott A Ochsner, Aaron R Cox, Kang Ho Kim, Jessica B Felix, Robert Sharp, Xin Li, Lin Tan, Jun Hyoung Park, Liping Wang, Vasanta Putluri, Philip L Lorenzi, Alli M Nuotio-Antar, Zheng Sun, Benny Abraham Kaipparettu, Nagireddy Putluri, David D Moore, Scott A Summers, Neil J Mckenna, Sean M Hartig

Faculty, Staff and Students Publications

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found …

The Swi/Snf Chromatin-Remodeling Subunit Dpf2 Facilitates Nrf2-Dependent Antiinflammatory And Antioxidant Gene Expression, Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K Mookhtiar, Kranthi Kunkalla, Alfredo M Valencia, Clayton K Collings, Cigall Kadoch, Francisco Vega, Scott C Kogan, Ramin Shiekhattar, Lluis Morey, Daniel Bilbao, Stephen D Nimer

Faculty, Staff and Student Publications

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a …

A Serological Assay To Detect And Differentiate Rodent Exposure To Soft Tick And Hard Tick Relapsing Fever Infections In The United States, Christina M Parise, Ying Bai, Kevin S Brandt, Shelby L Ford, Sarah Maes, Adam J Replogle, Alexander R Kneubehl, Job E Lopez, Rebecca J Eisen, Andrias Hojgaard

Faculty, Staff and Students Publications

Human cases of relapsing fever (RF) in North America are caused primarily by Borrelia hermsii and Borrelia turicatae, which are spread by argasid (soft) ticks, and by Borrelia miyamotoi, which is transmitted by ixodid (hard) ticks. In some regions of the United States, the ranges of the hard and soft tick RF species are known to overlap; in many areas, recorded ranges of RF spirochetes overlap with Lyme disease (LD) group Borrelia spirochetes. Identification of RF clusters or cases detected in unusual geographic localities might prompt public health agencies to investigate environmental exposures, enabling prevention of additional cases through locally …

Evaluation Of The Orally Bioavailable 4-Phenylbutyrate-Tethered Trichostatin A Analogue Ar42 In Models Of Spinal Muscular Atrophy, Casey J. Lumpkin, Ashlee W. Harris, Andrew J. Connell, Ryan W. Kirk, Joshua A. Whiting, Luciano Saieva, Livio Pellizzoni, Arthur H.M. Burghes, Matthew E.R. Butchbach

Department of Pediatrics Faculty Papers

Proximal spinal muscular atrophy (SMA) is a leading genetic cause for infant death in the world and results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of SMN protein and small molecules that can increase SMN expression are of considerable interest as potential therapeutics. Previous studies have shown that both 4-phenylbutyrate (4PBA) and trichostatin A (TSA) increase SMN expression in dermal fibroblasts derived from SMA patients. AR42 is a 4PBA-tethered TSA derivative that is a very potent histone deacetylase inhibitor. SMA patient fibroblasts were treated with either AR42, AR19 (a …

Secretogranin Iii Selectively Promotes Vascular Leakage In The Deep Vascular Plexus Of Diabetic Retinopathy, Liyang Ji, Prabuddha Waduge, Yan Wu, Chengchi Huang, Avinash Kaur, Paola Oliveira, Hong Tian, Jinsong Zhang, J Timothy Stout, Christina Y Weng, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, induces mosaic patterns of vasculopathy that may be associated with spatial heterogeneity of intraretinal endothelial cells. We recently reported that secretogranin III (Scg3), a neuron-derived angiogenic and vascular leakage factor, selectively binds retinal vessels of diabetic but not healthy mice. Here, we investigated endothelial heterogeneity of three retinal vascular plexuses in DR pathogenesis and the therapeutic implications. Our unique in vivo ligand binding assay detected a 22.7-fold increase in Scg3 binding to retinal vessels of diabetic mice relative to healthy mice. Functional immunohistochemistry revealed that Scg3 predominantly binds …

An Improved Reporter Identifies Ruxolitinib As A Potent And Cardioprotective Camkii Inhibitor, Oscar E Reyes Gaido, Nikoleta Pavlaki, Jonathan M Granger, Olurotimi O Mesubi, Bian Liu, Brian L Lin, Alan Long, David Walker, Joshua Mayourian, Kate L Schole, Chantelle E Terrillion, Lubika J Nkashama, Mohit M Hulsurkar, Lauren E Dorn, Kimberly M Ferrero, Richard L Huganir, Frank U Müller, Xander H T Wehrens, Jun O Liu, Elizabeth D Luczak, Vassilios J Bezzerides, Mark E Anderson

Faculty, Staff and Students Publications

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and …

Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling By Regulating Myocardial Tissue Angiotensin Ii, Binh Y Nguyen, Fangchao Zhou, Pablo Binder, Wei Liu, Susanne S Hille, Xiaojing Luo, Min Zi, Hongyuan Zhang, Antony Adamson, Fozia Z Ahmed, Sam Butterworth, Elizabeth J Cartwright, Oliver J Müller, Kaomei Guan, Elizabeth M Fitzgerald, Xin Wang

Faculty, Staff and Student Publications

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg …

Sox7 Deficiency Causes Ventricular Septal Defects Through Its Effects On Endocardial-To-Mesenchymal Transition And The Expression Of Wnt4 And Bmp2, Andrés Hernández-García, Katherine E Pendleton, Sangbae Kim, Yumei Li, Bum J Kim, Hitisha P Zaveri, Valerie K Jordan, Aliska M Berry, M Cecilia Ljungberg, Rui Chen, Rainer B Lanz, Daryl A Scott

Faculty, Staff and Students Publications

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq …

Scutellaria Baicalensis Enhances 5-Fluorouracil-Based Chemotherapy Via Inhibition Of Proliferative Signaling Pathways, Haizhou Liu, Hui Liu, Zhiyi Zhou, Jessica Chung, Guojing Zhang, Jin Chang, Robert A Parise, Edward Chu, John C Schmitz

Abington Jefferson Health Papers

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and …

Hematopoietic Progenitor Kinase 1 Inhibits The Development And Progression Of Pancreatic Intraepithelial Neoplasia, Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of …

Microbiome Alterations Driven By Trypanosoma Cruzi Infection In Two Disjunctive Murine Models, Sergio Castañeda, Marina Muñoz, Peter J Hotez, Maria Elena Bottazzi, Alberto E Paniz-Mondolfi, Kathryn M Jones, Rojelio Mejia, Cristina Poveda, Juan David Ramírez

Faculty, Staff and Students Publications

Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune responses against infection. Thus, a better understanding of this parasite-host-microbiome interaction may yield relevant information in the comprehension of the pathophysiology of the disease and the development of new prophylactic and therapeutic alternatives. Therefore, we implemented a murine model with two mice strains (BALB/c and C57BL/6) to evaluate the impact of Trypanosoma cruzi (Tulahuen strain) infection on the gut microbiome utilizing cytokine profiling and shotgun metagenomics. Higher parasite burdens were observed in cardiac and intestinal …

Antitumor Efficacy Of Dual Blockade With Encorafenib + Cetuximab In Combination With Chemotherapy In Human Brafv600e-Mutant Colorectal Cancer, Stefania Napolitano, Melanie Woods, Hey Min Lee, Vincenzo De Falco, Giulia Martini, Carminia Maria Della Corte, Erika Martinelli, Vincenzo Famiglietti, Davide Ciardiello, Amanda Anderson, Natalie Wall Fowlkes, Oscar Eduardo Villareal, Alexey Sorokin, Preeti Kanikarla, Olu Coker, Van Morris, Lucia Altucci, Josep Tabernero, Teresa Troiani, Fortunato Ciardiello, Scott Kopetz

Faculty, Staff and Student Publications

PURPOSE: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.

EXPERIMENTAL DESIGN: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were …

Whole Genome Analysis For 163 Grnas In Cas9-Edited Mice Reveals Minimal Off-Target Activity, Kevin A Peterson, Sam Khalouei, Nour Hanafi, Joshua A Wood, Denise G Lanza, Lauri G Lintott, Brandon J Willis, John R Seavitt, Robert E Braun, Mary E Dickinson, Jacqueline K White, K C Kent Lloyd, Jason D Heaney, Stephen A Murray, Arun Ramani, Lauryl M J Nutter

Faculty, Staff and Students Publications

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 …

Preparation And Immunofluorescence Staining Of Bundles And Single Fiber Cells From The Cortex And Nucleus Of The Eye Lens, Michael P Vu, Catherine Cheng

Faculty, Staff and Student Publications

The lens is a transparent and ellipsoid organ in the anterior chamber of the eye that changes shape to finely focus light onto the retina to form a clear image. The bulk of this tissue comprises specialized, differentiated fiber cells that have a hexagonal cross section and extend from the anterior to the posterior poles of the lens. These long and skinny cells are tightly opposed to neighboring cells and have complex interdigitations along the length of the cell. The specialized interlocking structures are required for normal biomechanical properties of the lens and have been extensively described using electron microscopy …

Steroid Receptor Coactivator 3 Is A Key Modulator Of Regulatory T Cell-Mediated Tumor Evasion, Sang Jun Han, Prashi Jain, Yosef Gilad, Yan Xia, Nuri Sung, Mi Jin Park, Adam M Dean, Rainer B Lanz, Jianming Xu, Clifford C Dacso, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were "permanently eradicated" in a genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor …

Concomitant Targeting Of Flt3 And Btk Overcomes Flt3 Inhibitor Resistance In Acute Myeloid Leukemia Through The Inhibition Of Autophagy, Weiguo Zhang, Guopan Yu, Hongying Zhang, Mahesh Basyal, Charlie Ly, Bin Yuan, Vivian Ruvolo, Sujan Piya, Seemana Bhattacharya, Qi Zhang, Gautam Borthakur, Venkata Battula, Marina Konopleva, William G Rice, Michael Andreeff

Faculty, Staff and Student Publications

Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia …

The Role Of Extracellular Heat Shock Proteins In Cardiovascular Diseases, Soumya Patnaik, Sriram Nathan, Biswajit Kar, Igor D Gregoric, Yi-Ping Li

Faculty, Staff and Student Publications

In the early 1960s, heat shock proteins (HSPs) were first identified as vital intracellular proteinaceous components that help in stress physiology and reprogram the cellular responses to enable the organism's survival. By the early 1990s, HSPs were detected in extracellular spaces and found to activate gamma-delta T-lymphocytes. Subsequent investigations identified their association with varied disease conditions, including autoimmune disorders, diabetes, cancer, hepatic, pancreatic, and renal disorders, and cachexia. In cardiology, extracellular HSPs play a definite, but still unclear, role in atherosclerosis, acute coronary syndromes, and heart failure. The possibility of HSP-targeted novel molecular therapeutics has generated much interest and hope …

An Ocular Th1 Immune Response Promotes Corneal Nerve Damage Independently Of The Development Of Corneal Epitheliopathy, Alexia Vereertbrugghen, Manuela Pizzano, Florencia Sabbione, Irene Angelica Keitelman, Carolina Maiumi Shiromizu, Douglas Vera Aguilar, Federico Fuentes, Cintia S De Paiva, Mirta Giordano, Analía Trevani, Jeremías G Galletti

Faculty, Staff and Students Publications

Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured …

Toll-Like Receptors 2, 4, And 9 Modulate Promoting Effect Of Copd-Like Airway Inflammation On K-Ras-Driven Lung Cancer Through Activation Of The Myd88/Nf-ĸb Pathway In The Airway Epithelium, Walter V Velasco, Nasim Khosravi, Susana Castro-Pando, Nelly Torres-Garza, Maria T Grimaldo, Avantika Krishna, Michael J Clowers, Misha Umer, Sabah Tariq Amir, Diana Del Bosque, Soudabeh Daliri, Maria Miguelina De La Garza, Marco Ramos-Castaneda, Scott E Evans, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

INTRODUCTION: Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable

METHODS: In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on …

Cardiac Pericytes Mediate The Remodeling Response To Myocardial Infarction, Pearl Quijada, Shuin Park, Peng Zhao, Kamal Ss Kolluri, David Wong, Kevin D Shih, Kai Fang, Arash Pezhouman, Lingjun Wang, Ali Daraei, Matthew D Tran, Elle M Rathbun, Kimberly N Burgos Villar, Maria L Garcia-Hernandez, Thanh Td Pham, Charles J Lowenstein, M Luisa Iruela-Arispe, S Thomas Carmichael, Eric M Small, Reza Ardehali

Faculty, Staff and Students Publications

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac …

3-Phosphoinositide-Dependent Kinase 1 Drives Acquired Resistance To Osimertinib, Ismail M Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, Ruping Shao, Renduo Song, Feng Li, Yonathan Lissanu, Huiqin Chen, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan Wesley Riess, Victor Olivas, Trever G Bivona, Jack A Roth

Faculty, Staff and Students Publications

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of …

Maackia Amurensis Seed Lectin (Masl) Increases Movement Velocity Of Mice With Tnfα Induced Rheumatoid Arthritis, Amanda A. Greenspan, Kelly L. Hamilton, Alan J. Shienbaum, Bradford Fischer, Andrea Bottaro, Gary S. Goldberg

Rowan-Virtua Research Day

Up to 70 million people around the world suffer from rheumatoid arthritis. Current treatment options have varied efficacy and can cause unwanted side effects. New approaches are needed to treat this condition. Sialic acid modifications on chondrocyte receptors have been associated with arthritic inflammation and joint destruction. The transmembrane mucin receptor protein podoplanin (PDPN) has been identified as a functionally relevant receptor that presents extracellular sialic acid motifs. PDPN signaling promotes inflammation and invasion associated with arthritis and, therefore, has emerged as a target that can be used to inhibit arthritic inflammation. Maackia amurensis seed lectin (MASL) can target PDPN …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …