Life Sciences Commons^™

Genetic Inactivation Of Β-Catenin Is Salubrious, Whereas Its Activation Is Deleterious In Desmoplakin Cardiomyopathy, Melis Olcum, Siyang Fan, Leila Rouhi, Sirisha Cheedipudi, Benjamin Cathcart, Hyun-Hwan Jeong, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Student and Faculty Publications

AIMS: Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy.

METHODS AND RESULTS: The Dsp gene was conditionally deleted in …

Glp1 Receptor Agonists-Effects Beyond Obesity And Diabetes, Sydney S Wilbon, Mikhail G Kolonin

Student and Faculty Publications

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits …

Gpr84-Mediated Signal Transduction Affects Metabolic Function By Promoting Brown Adipocyte Activity, Xue-Nan Sun, Yu A An, Vivian A Paschoal, Camila O De Souza, May-Yun Wang, Lavanya Vishvanath, Lorena Ma Bueno, Ayanna S Cobb, Joseph A Nieto Carrion, Madison E Ibe, Chao Li, Harrison A Kidd, Shiuhwei Chen, Wenhong Li, Rana K Gupta, Da Young Oh

Student and Faculty Publications

The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes …

Oncogenic Kras Drives Lipofibrogenesis To Promote Angiogenesis And Colon Cancer Progression, Wen-Hao Hsu, Kyle A Labella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A Depinho

Student and Faculty Publications

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. …

Hnf4Α Isoforms Regulate The Circadian Balance Between Carbohydrate And Lipid Metabolism In The Liver, Jonathan R Deans, Poonamjot Deol, Nina Titova, Sarah H Radi, Linh M Vuong, Jane R Evans, Songqin Pan, Johannes Fahrmann, Jun Yang, Bruce D Hammock, Oliver Fiehn, Baharan Fekry, Kristin Eckel-Mahan, Frances M Sladek

Student and Faculty Publications

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different …

Crispr-Cas9-Based Functional Interrogation Of Unconventional Translatome Reveals Human Cancer Dependency On Cryptic Non-Canonical Open Reading Frames, Caishang Zheng, Yanjun Wei, Peng Zhang, Kangyu Lin, Dandan He, Hongqi Teng, Ganiraju Manyam, Zhao Zhang, Wen Liu, Hye Rin Lindsay Lee, Ximing Tang, Wei He, Nelufa Islam, Antrix Jain, Yulun Chiu, Shaolong Cao, Yarui Diao, Sherita Meyer-Gauen, Magnus Höök, Anna Malovannaya, Wenbo Li, Ming Hu, Wenyi Wang, Han Xu, Scott Kopetz, Yiwen Chen

Student and Faculty Publications

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a …

An Ace2 Decamer Viral Trap As A Durable Intervention Solution For Current And Future Sars-Cov, Hailong Guo, Bomsoo Cho, Paul R Hinton, Sijia He, Yongjun Yu, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Zhiqiang Ku, Kristen Campo, Sarah Holland, Sameer Sachdeva, Christopher Mensch, Mohamed Dawod, Annalis Whitaker, Philip Eisenhauer, Allison Falcone, Rebekah Honce, Jason W Botten, Stephen F Carroll, Bruce A Keyt, Andrew W Womack, William R Strohl, Kai Xu, Ningyan Zhang, Zhiqiang An, Sha Ha, John W Shiver, Tong-Ming Fu

Student and Faculty Publications

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by …

Loss Of The Methylarginine Reader Function Of Snd1 Confers Resistance To Hepatocellular Carcinoma, Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

Student and Faculty Publications

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can …

Loss Of The Methylarginine Reader Function Of Snd1 Confers Resistance To Hepatocellular Carcinoma, Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

Student and Faculty Publications

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can …

Galectin-3 Cooperates With Cd47 To Suppress Phagocytosis And T-Cell Immunity In Gastric Cancer Peritoneal Metastases, Yibo Fan, Shumei Song, Yuan Li, Shilpa S Dhar, Jiankang Jin, Katsuhiro Yoshimura, Xiaodan Yao, Ruiping Wang, Ailing W Scott, Melissa Pool Pizzi, Jingjing Wu, Lang Ma, George A Calin, Samir Hanash, Linghua Wang, Michael Curran, Jaffer A Ajani

Student and Faculty Publications

UNLABELLED: The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that …

Dhodh: A Promising Target In The Treatment Of T-Cell Acute Lymphoblastic Leukemia, Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David B Sykes

Student and Faculty Publications

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, …

Iron Overload Induces Cerebral Endothelial Senescence In Aged Mice And In Primary Culture In A Sex-Dependent Manner, Brian Noh, Maria Pilar Blasco-Conesa, Syed Mushfiqur Rahman, Sheelu Monga, Rodney Ritzel, Gary Guzman, Yun-Ju Lai, Bhanu Priya Ganesh, Akihiko Urayama, Louise D Mccullough, Jose Felix Moruno-Manchon

Student and Faculty Publications

Iron imbalance in the brain negatively affects brain function. With aging, iron levels increase in the brain and contribute to brain damage and neurological disorders. Changes in the cerebral vasculature with aging may enhance iron entry into the brain parenchyma, leading to iron overload and its deleterious consequences. Endothelial senescence has emerged as an important contributor to age-related changes in the cerebral vasculature. Evidence indicates that iron overload may induce senescence in cultured cell lines. Importantly, cells derived from female human and mice generally show enhanced senescence-associated phenotype, compared with males. Thus, we hypothesize that cerebral endothelial cells (CEC) derived …

Cardiac Muscle-Restricted Partial Loss Of Nos1ap Expression Has Limited But Significant Impact On Electrocardiographic Features, Alexa Smith, Dallas Auer, Morgan Johnson, Ernesto Sanchez, Holly Ross, Christopher Ward, Aravinda Chakravarti, Ashish Kapoor

Student and Faculty Publications

Genome-wide association studies have identified sequence polymorphisms in a functional enhancer of the NOS1AP gene as the most common genetic regulator of QT interval and human cardiac NOS1AP gene expression in the general population. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have also demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT …

Adavosertib Enhances Antitumor Activity Of Trastuzumab Deruxtecan In Her2-Expressing Cancers, Timothy P Diperi, Kurt W Evans, Maria Gabriela Raso, Ming Zhao, Yasmeen Q Rizvi, Xiaofeng Zheng, Bailiang Wang, Bryce P Kirby, Kathleen Kong, Michael Kahle, Timothy A Yap, Ecaterina E Dumbrava, Jaffer A Ajani, Siqing Fu, Khandan Keyomarsi, Funda Meric-Bernstam

Student and Faculty Publications

PURPOSE: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.

EXPERIMENTAL DESIGN: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to …

Early Skeletal Muscle Loss In Adolescent And Young Adult Cancer Patients Treated With Anthracycline Chemotherapy, Savannah V Wooten, Fei Wang, Michael E Roth, Guanshu Liu, J Andrew Livingston, Behrang Amini, Susan C Gilchrist, Michelle Hildebrandt, Eugenie S Kleinerman

Student and Faculty Publications

BACKGROUND: Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline-induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status.

METHODS: Computed tomography (CT) scans were used to investigate changes in skeletal muscle of 153 AYA sarcoma and Hodgkin lymphoma patients at thoracic vertebra 4 after anthracycline treatment. Images were examined at three time …

Anthocyanins: Molecular Aspects On Their Neuroprotective Activity, César A Zaa, Álvaro J Marcelo, Zhiqiang An, José L Medina-Franco, Marco A Velasco-Velázquez

Student and Faculty Publications

Anthocyanins are a type of flavonoids that give plants and fruits their vibrant colors. They are known for their potent antioxidant properties and have been linked to various health benefits. Upon consumption, anthocyanins are quickly absorbed and can penetrate the blood-brain barrier (BBB). Research based on population studies suggests that including anthocyanin-rich sources in the diet lower the risk of neurodegenerative diseases. Anthocyanins exhibit neuroprotective effects that could potentially alleviate symptoms associated with such diseases. In this review, we compiled and discussed a large body of evidence supporting the neuroprotective role of anthocyanins. Our examination encompasses human studies, animal models, …

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee

Student and Faculty Publications

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted …

Oncolytic Virus M1 Functions As A Bifunctional Checkpoint Inhibitor To Enhance The Antitumor Activity Of Dc Vaccine, Jia Dan, Jing Cai, Yingqian Zhong, Chaoqun Wang, Shanyu Huang, Ying Zeng, Zhen Fan, Cuiying Xu, Linyi Hu, Jiayu Zhang, Jun Hu, Ying Liu, Xingwen Su, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Yuan Lin

Student and Faculty Publications

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can …

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Student and Faculty Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Endogenous Renal Adiponectin Drives Gluconeogenesis Through Enhancing Pyruvate And Fatty Acid Utilization, Toshiharu Onodera, May-Yun Wang, Joseph M Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S Balzer, Dae-Seok Kim, Xuenan Sun, Yu A An, Bianca C Field, Charlotte Lee, Ei-Ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M Kusminski, Ruth Gordillo, Laurent Gautron, Denise K Marciano, Ming Chang Hu, Shawn C Burgess, Katalin Susztak, Orson W Moe, Philipp E Scherer

Student and Faculty Publications

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Student and Faculty Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …

Mathematical Modeling Of Radiotherapy: Impact Of Model Selection On Estimating Minimum Radiation Dose For Tumor Control, Achyudhan R Kutuva, Jimmy J Caudell, Kosj Yamoah, Heiko Enderling, Mohammad U Zahid

Student and Faculty Publications

INTRODUCTION: Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose.

METHODS: In this study, we evaluate the mathematical implications and biological effects of 2 …

High-Fat Diet, But Not Duration Of Lactation, Increases Mammary Gland Lymphatic Vessel Function And Subsequent Growth Of Inflammatory Breast Cancer Cells, Wintana Balema, Janelle Morton, Richard A Larson, Li Li, Fred Christian Velasquez, Natalie W Fowlkes, Savitri Krishnamurthy, Bisrat G Debeb, Eva Sevick-Muraca, Wendy A Woodward

Student and Faculty Publications

Inflammatory breast cancer (IBC) presents as rapid-onset swelling and breast skin changes caused by tumor emboli in the breast and breast skin lymphatics. IBC has been linked with obesity and duration of breastfeeding, but how these factors affect IBC tumor progression is not clear. We modeled the simultaneous effects of diet and weaning in mice on in vivo lymphatic function; on IBC tumor growth; and on aspects of the mammary gland microenvironment before and after IBC (SUM149) xenograft inoculation. We hypothesized that weaning status and diet would have synergistic effects on lymphatic function and the breast microenvironment to enhance IBC …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Student and Faculty Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

Intraperitoneal Paclitaxel Is A Safe And Effective Therapeutic Strategy For Treating Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Abdelrahman M G Yousef, Saikat Chowdhury, Princess N Dickson, Zahra A Naini, Michael G White, Karianne G Fleten, Kjersti Flatmark, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Student and Faculty Publications

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy …

Abemaciclib Is Effective In Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers, Juliana Navarro-Yepes, Nicole M Kettner, Xiayu Rao, Cassandra Santaella Bishop, Tuyen N Bui, Hannah F Wingate, Akshara Singareeka Raghavendra, Yan Wang, Jing Wang, Aysegul A Sahin, Funda Meric-Bernstam, Kelly K Hunt, Senthil Damodaran, Debu Tripathy, Khandan Keyomarsi

Student and Faculty Publications

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex …

Therapeutic Effects Of Combining Curcumin And Swimming In Osteoarthritis Using A Rat Model, Mona M Saber, Manal Moustafa Mahmoud, Hesham M Amin, Reham M Essam

Student and Faculty Publications

Osteoarthritis (OA) is a common debilitating degenerative disease of the elderly. We aimed to study the therapeutic effects of combining curcumin and swimming in monosodium iodoacetate (MIA)-induced OA in a rat model. The rats were divided into 5 groups (n = 9). Group 1 received saline and served as a control group. Groups 2-5 were injected intra-articularly in the right knee with 100 μL MIA. One week later, groups 3 and 5 were started on daily swimming sessions that gradually increased to 20-mins per session, and for groups 4 and 5, oral curcumin was administered at a dose of 200 …

Pd-1 Blockade In Combination With Dasatinib Potentiates Induction Of Anti-Acute Lymphocytic Leukemia Immunity, Paul Koller, Natalia Baran, Karine Harutyunyan, Antonio Cavazos, Saradhi Mallampati, Renee L Chin, Zhou Jiang, Xian Sun, Heng-Huan Lee, Jennifer L Hsu, Patrick Williams, Xuelin Huang, Michael A Curran, Mien-Chie Hung, Marina Konopleva

Student and Faculty Publications

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism …

Recent Insights Into The Pathogenesis And Therapeutic Targets Of Chronic Liver Diseases, Yankai Wen, Lichun Ma, Cynthia Ju

Student and Faculty Publications

Viral hepatitis, alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the three major causes of chronic liver diseases, which account for approximately 2 million deaths per year worldwide. The current direct-acting antiviral drugs and vaccinations have effectively reduced and ameliorated viral hepatitis infection, but there are still no effective drug treatments for ALD, NAFLD and liver cancer due to the poor understanding of their pathogenesis. To better understand the pathogenesis, the fifth Chinese American Liver Society/Society of Chinese Bioscientists in America Hepatology Division Annual Symposium, which was held virtually on 21-22 October 2022, focused on the topics …

New Jak3-Insl3 Fusion Transcript-An Oncogenic Event In Cutaneous T-Cell Lymphoma, Loka Reddy Velatooru, Cheng Hui Hu, Pedram Bijani, Xiaohong Wang, Pierr Bojaxhi, Hao Chen, Madeleine Duvic, Xiao Ni

Student and Faculty Publications

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays …