Digital Commons Network^™

Prolonged Cardiac Nr4a2 Activation Causes Dilated Cardiomyopathy In Mice, Sadia Ashraf, Heinrich Taegtmeyer, Romain Harmancey

Faculty, Staff and Student Publications

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, …

Lfa-1 Activation Enriches Tumor-Specific T Cells In A Cold Tumor Model And Synergizes With Ctla-4 Blockade, Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, Leilei Shi, Simone Punt, Leila Williams, Cara Haymaker, Charles B Chesson, Faisal Fa'ak, Ana L Dominguez, Richard Jones, Isere Kuiatse, Amy R Caivano, Sayadeth Khounlo, Navin D Warier, Upendra Marathi, Robert V Market, Ronald J Biediger, John W Craft, Patrick Hwu, Michael A Davies, Darren G Woodside, Peter Vanderslice, Adi Diab, Willem W Overwijk, Yared Hailemichael

Faculty, Staff and Student Publications

The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic …

Frailty Repels The Knife: The Impact Of Frailty Index On Surgical Intervention And Outcomes, Katelyn F Handley, Anil K Sood, Graziela Zibetti Dal Molin, Shannon N Westin, Larissa A Meyer, Bryan Fellman, Pamela T Soliman, Robert L Coleman, Nicole D Fleming

Faculty, Staff and Student Publications

Objective: To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes.

Methods: A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated.

Results: 592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less …

Prospecting Cellular Gold Nanoparticle Biomineralization As A Viable Alternative To Prefabricated Gold Nanoparticles, Aaron S Schwartz-Duval, Konstantin V Sokolov

Faculty, Staff and Student Publications

Gold nanoparticles (GNPs) have shown considerable potential in a vast number of biomedical applications. However, currently there are no clinically approved injectable GNP formulations. Conversely, gold salts have been used in the clinic for nearly a century. Further, there is evidence of GNP formation in patients treated with gold salts (i.e., chrysiasis). Recent reports evaluating this phenomenon in human cells and in murine models indicate that the use of gold ions for in situ formation of theranostic GNPs could greatly improve the delivery within dense biological tissues, increase efficiency of intracellular gold uptake, and specificity of GNP formation within cancer …

Cardiovascular Events In Patients Treated With Chimeric Antigen Receptor T-Cell Therapy For Aggressive B-Cell Lymphoma, Raphael E Steiner, Jose Banchs, Efstratios Koutroumpakis, Melody Becnel, Cristina Gutierrez, Paolo Strati, Chelsea C Pinnix, Lei Feng, Gabriela Rondon, Catherine Claussen, Nicolas Palaskas, Kaveh Karimzad, Sairah Ahmed, Sattva S Neelapu, Elizabeth Shpall, Michael Wang, Francisco Vega, Jason Westin, Loretta J Nastoupil, Anita Deswal

Faculty, Staff and Student Publications

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large …

A Win Consortium Phase I Study Exploring Avelumab, Palbociclib, And Axitinib In Advanced Non-Small Cell Lung Cancer, Benjamin Solomon, Ana Callejo, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Fanny Wunder, Jacques Raynaud, Nicolas Girard, J Jack Lee, Raed Sulaiman, Bruce Prouse, Catherine Bresson, Hila Ventura, Shai Magidi, Eitan Rubin, Brandon Young, Amir Onn, Brian Leyland-Jones, Richard L Schilsky, Vladimir Lazar, Enriqueta Felip, Razelle Kurzrock

Faculty, Staff and Student Publications

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Lymphoid Neoplasms, Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto De Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne De Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao

Faculty, Staff and Student Publications

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as …

Functional Genomic Analysis Of Epithelioid Sarcoma Reveals Distinct Proximal And Distal Subtype Biology, Samuel V Rasmussen, Jia Xiang Jin, Lissett R Bickford, Andrew D Woods, Felix Sahm, Kenneth A Crawford, Kiyo Nagamori, Hiroaki Goto, Keila E Torres, Angelo Sidoni, Erin R Rudzinski, Khin Thway, Robin L Jones, Alessio Ciulli, Hollis Wright, Melvin Lathara, Ganapati Srinivasa, Kavya Kannan, Paul H Huang, Thomas G P Grünewald, Noah E Berlow, Charles Keller

Faculty, Staff and Student Publications

Background: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat.

Methods: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance.

Results: Other biologically inspired functional …

Leveraging Single-Cell Sequencing To Unravel Intratumour Heterogeneity And Tumour Evolution In Human Cancers, Amy L Bowes, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) and tumour evolution are well-documented phenomena in human cancers. While the advent of next-generation sequencing technologies has facilitated the large-scale capture of genomic data, the field of single-cell genomics is nascent but rapidly advancing and generating many new insights into the complex molecular mechanisms of tumour biology. In this review, we provide an overview of current single-cell DNA sequencing technologies, exploring how recent methodological advancements have enumerated new insights into ITH and tumour evolution. Areas highlighted include the potential power of single-cell genome sequencing studies to explore evolutionary dynamics contributing to tumourigenesis through to progression, metastasis, and …

Kalium Channelrhodopsins Are Natural Light-Gated Potassium Channels That Mediate Optogenetic Inhibition, Elena G Govorunova, Yueyang Gou, Oleg A Sineshchekov, Hai Li, Xiaoyu Lu, Yumei Wang, Leonid S Brown, François St-Pierre, Mingshan Xue, John L Spudich

Faculty, Staff and Student Publications

Channelrhodopsins are used widely for optical control of neurons, in which they generate photoinduced proton, sodium or chloride influx. Potassium (K+) is central to neuron electrophysiology, yet no natural K+-selective light-gated channel has been identified. Here, we report kalium channelrhodopsins (KCRs) from Hyphochytrium catenoides. Previously known gated potassium channels are mainly ligand- or voltage-gated and share a conserved K+-selectivity filter. KCRs differ in that they are light-gated and have independently evolved an alternative K+ selectivity mechanism. The KCRs are potent, highly selective of K+ over Na+, and open in less than 1 ms following photoactivation. The permeability ratio PK/PNa of …

Gene-Mapping Study Of Extremes Of Cerebral Small Vessel Disease Reveals Trim47 As A Strong Candidate, Aniket Mishra, Cécile Duplaà, Dina Vojinovic, Hideaki Suzuki, Muralidharan Sargurupremraj, Nuno R Zilhão, Shuo Li, Traci M Bartz, Xueqiu Jian, Wei Zhao, Edith Hofer, Katharina Wittfeld, Sarah E Harris, Sandra Van Der Auwera-Palitschka, Michelle Luciano, Joshua C Bis, Hieab H H Adams, Claudia L Satizabal, Rebecca F Gottesman, Piyush G Gampawar, Robin Bülow, Stefan Weiss, Miao Yu, Mark E Bastin, Oscar L Lopez, Meike W Vernooij, Alexa S Beiser, Uwe Völker, Tim Kacprowski, Aicha Soumare, Jennifer A Smith, David S Knopman, Zoe Morris, Yicheng Zhu, Jerome I Rotter, Carole Dufouil, Maria Valdés Hernández, Susana Muñoz Maniega, Mark Lathrop, Erik Boerwinkle, Reinhold Schmidt, Masafumi Ihara, Bernard Mazoyer, Qiong Yang, Anne Joutel, Elizabeth Tournier-Lasserve, Lenore J Launer, Ian J Deary, Thomas H Mosley, Philippe Amouyel, Charles S Decarli, Bruce M Psaty, Christophe Tzourio, Sharon L R Kardia, Hans J Grabe, Alexander Teumer, Cornelia M Van Duijn, Helena Schmidt, Joanna M Wardlaw, M Arfan Ikram, Myriam Fornage, Vilmundur Gudnason, Sudha Seshadri, Paul M Matthews, William T Longstreth, Thierry Couffinhal, Stephanie Debette

Faculty, Staff and Student Publications

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 …

Genotype-To-Phenotype Associations In The Aggressive Variant Prostate Cancer Molecular Profile (Avpc-M) Components, Rama Soundararajan, Paul Viscuse, Patrick Pilie, Jingjing Liu, Souzana Logotheti, Caddie Laberiano Fernández, Daniele Lorenzini, Anh Hoang, Wei Lu, Luisa Maren Solis Soto, Ignacio I Wistuba, Mingchu Xu, Xingzhi Song, Peter D A Shepherd, Nora M Navone, Rebecca S S Tidwell, Guillermina Lozano, Christopher Logothetis, Jianhua Zhang, James P Long, Marcos R Estecio, Vasiliki Tzelepi, Ana M Aparicio

Faculty, Staff and Student Publications

The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen indifference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high …

Ewi2 Prevents Egfr From Clustering And Endocytosis To Reduce Tumor Cell Movement And Proliferation, Chenying Fu, Jie Wang, Sandeep Pallikkuth, Yingjun Ding, Junxiong Chen, Jonathan D Wren, Yuchao Yang, Kwong-Kwok Wong, Hiroyasu Kameyama, Muralidharan Jayaraman, Anupama Munshi, Takemi Tanaka, Keith A Lidke, Xin A Zhang

Faculty, Staff and Student Publications

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate …

Worsening Glycemia Increases The Odds Of Intermittent But Not Persistent Staphylococcus Aureus Nasal Carriage In Two Cohorts Of Mexican American Adults, Heather T Essigmann, Craig L Hanis, Stacia M Desantis, William B Perkison, David A Aguilar, Goo Jun, D Ashley Robinson, Eric L Brown

Faculty, Staff and Student Publications

Numerous host and environmental factors contribute to persistent and intermittent nasal Staphylococcus aureus carriage in humans. The effects of worsening glycemia on the odds of S. aureus intermittent and persistent nasal carriage was established in two cohorts from an adult Mexican American population living in Starr County, Texas. The anterior nares were sampled at two time points and the presence of S. aureus determined by laboratory culture and

Validation Of A High Flow Rate Puff Topography System Designed For Measurement Of Sub-Ohm, Third Generation Electronic Nicotine Delivery Systems, Evan Floyd, Toluwanimi Oni, Changjie Cai, Bilal Rehman, Jooyeon Hwang, Tyler Watson

Faculty, Staff and Student Publications

There are few known puff topography devices designed solely for gathering electronic cigarette puff topography information, and none made for high-powered sub-ohm devices. Ten replicate Bernoulli flow cells were designed and 3D printed. The relationship between square root of pressure difference and flow rate was determined across 0−70 L/min. One representative flow cell was used to estimate puff volume and flow rate under six simulated puffing regimes (0.710 L, 2.000 L and 3.000 L, at low and high flow rates) to determine the system’s accuracy and utility of using dual pressure sensors for flow measurement. The relationship between flow rate …

Regulation Of Age-Associated Insulin Resistance By Mt1-Mmp-Mediated Cleavage Of Insulin Receptor, Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin …

An Epidemic Model With Time-Distributed Recovery And Death Rates, Samiran Ghosh, Vitaly Volpert, Malay Banerjee

Faculty, Staff and Student Publications

A compartmental epidemiological model with distributed recovery and death rates is proposed. In some particular cases, the model can be reduced to the conventional SIR model. However, in general, the dynamics of epidemic progression in this model is different. Distributed recovery and death rates are evaluated from COVID-19 data. The model is validated by the epidemiological data for different countries, and it shows better agreement with the data than the SIR model. The time-dependent disease transmission rate is estimated.

Divergent Outer Retinal Circuits Drive Image And Non-Image Visual Behaviors, Corinne Beier, Ulisse Bocchero, Lior Levy, Zhijing Zhang, Nange Jin, Stephen C Massey, Christophe P Ribelayga, Kirill Martemyanov, Samer Hattar, Johan Pahlberg

Faculty, Staff and Student Publications

Image- and non-image-forming vision are essential for animal behavior. Here we use genetically modified mouse lines to examine retinal circuits driving image- and non-image-functions. We describe the outer retinal circuits underlying the pupillary light response (PLR) and circadian photoentrainment, two non-image-forming behaviors. Rods and cones signal light increments and decrements through the ON and OFF pathways, respectively. We find that the OFF pathway drives image-forming vision but cannot drive circadian photoentrainment or the PLR. Cone light responses drive image formation but fail to drive the PLR. At photopic levels, rods use the primary and secondary rod pathways to drive the …

Aberrant Dna Hydroxymethylation Reshapes Transcription Factor Binding In Myeloid Neoplasms, Jia Li, Tingting Hong, Yue Wei, Lei Guo, Minjung Lee, Hui Yang, Caleb Class, Yaling Yang, Xiaoqiong Wang, Hua He, Stefan Siwko, M James You, Yubin Zhou, Guillermo Garcia-Manero, Yun Huang

Faculty, Staff and Student Publications

Epigenetic abnormalities in DNA hydroxymethylation (5hmC) have been detected in patients with myeloid neoplasms, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the disease status of myeloid neoplasms. Here, we report systematic genome-wide mapping of the DNA hydroxymethylomes in over 70 patients with myeloid neoplasms. Our integrative analysis leads to the identification of distinct 5hmC signatures that can sensitively discriminate patients from healthy individuals. At the molecular level, we unveiled dynamic 5hmC changes within key transcription factor (e.g., the CEBP family) binding motifs that are essential for hematopoiesis and myeloid lineage specification. 5hmC redistribution was found …

Gut Microbiome Alterations Associated With Diabetes In Mexican Americans In South Texas, Suet-Ying Kwan, Caroline M Sabotta, Aron Joon, Peng Wei, Lauren E Petty, Jennifer E Below, Xiaogang Wu, Jianhua Zhang, Robert R Jenq, Ernest T Hawk, Joseph B Mccormick, Susan P Fisher-Hoch, Laura Beretta

Faculty, Staff and Student Publications

Mexican Americans have a high prevalence of diabetes and burden of diabetes-related complications, highlighting the need for novel preventive strategies and noninvasive predictors of diabetes risk tailored to this population. Changes in the gut microbiome have the potential to predict diabetes. Here, we aimed to identify alterations in the gut microbiome associated with diabetes in the high-risk population of Mexican Americans in South Texas. Stool samples were collected from 216 subjects from the population-based Cameron County Hispanic Cohort. Among them, 75 had type 2 diabetes. Taxonomic and functional profiling of the stool samples were assessed by 16S and shotgun metagenomic …

Reflections On Beam Configuration Optimization For Intensity-Modulated Proton Therapy, Wenhua Cao, Humberto Rocha, Radhe Mohan, Gino Lim, Hadis M Goudarzi, Brígida C Ferreira, Joana M Dias

Faculty, Staff and Student Publications

Presumably, intensity-modulated proton radiotherapy (IMPT) is the most powerful form of proton radiotherapy. In the current state of the art, IMPT beam configurations (i.e. the number of beams and their directions) are, in general, chosen subjectively based on prior experience and practicality. Beam configuration optimization (BCO) for IMPT could, in theory, significantly enhance IMPT's therapeutic potential. However, BCO is complex and highly computer resource-intensive. Some algorithms for BCO have been developed for intensity-modulated photon therapy (IMRT). They are rarely used clinically mainly because the large number of beams typically employed in IMRT renders BCO essentially unnecessary. Moreover, in the newer …

Transmission, Strain Diversity, And Zoonotic Potential Of Chronic Wasting Disease, Sandra Pritzkow

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting several species of captive and free-ranging cervids. In the past few decades, CWD has been spreading uncontrollably, mostly in North America, resulting in a high increase of CWD incidence but also a substantially higher number of geographical regions affected. The massive increase in CWD poses risks at several levels, including contamination of the environment, transmission to animals cohabiting with cervids, and more importantly, a putative transmission to humans. In this review, I will describe the mechanisms and routes responsible for the efficient transmission of CWD, the strain diversity of natural CWD, …

Occult Polyclonality Of Preclinical Pancreatic Cancer Models Drives In Vitro Evolution, Maria E Monberg, Heather Geiger, Jaewon J Lee, Roshan Sharma, Alexander Semaan, Vincent Bernard, Justin Wong, Fang Wang, Shaoheng Liang, Daniel B Swartzlander, Bret M Stephens, Matthew H G Katz, Ken Chen, Nicolas Robine, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Heterogeneity is a hallmark of cancer. The advent of single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts. Here we apply single-cell sequencing technologies to reveal inherent heterogeneity in assumptively monoclonal pancreatic cancer (PDAC) cell lines and patient-derived organoids (PDOs). Our findings reveal a high degree of both genomic and transcriptomic polyclonality in monolayer PDAC cell lines, custodial variation induced by growing apparently identical cell lines in different laboratories, and transcriptomic shifts in transitioning from 2D to 3D spheroid growth models. Our findings also call into question the validity of widely available immortalized, …

Phosphatidylserine And Phosphatidylethanolamine Asymmetry Have A Negligible Effect On The Global Structure, Dynamics, And Interactions Of The Kras Lipid Anchor, Mussie K Araya, Alemayehu A Gorfe

Faculty, Staff and Student Publications

The intrinsically disordered C-terminus of the prominent oncogenic protein KRAS-4B (KRAS) selectively interacts and clusters with phosphatidylserine (PS) lipids in the plasma membrane (PM). This 11-residue segment, called tK, contains a polybasic domain (PBD) of six contiguous lysine residues and a farnesylated cysteine. Previous molecular dynamics (MD) simulation studies of tK in phosphatidylcholine (PC)/PS bilayers have suggested that backbone conformational dynamics modulate tK-PS interactions. These simulations have been conducted in symmetric membranes whereas the PM is compositionally asymmetric, with the inner leaflet, where KRAS is localized, being enriched with PS and phosphatidylethanolamine (PE) lipids. To examine if bilayer asymmetry affects …

The Three Two-Pore Channel Subtypes From Rabbit Exhibit Distinct Sensitivity To Phosphoinositides, Voltage, And Extracytosolic Ph, Xinghua Feng, Jian Xiong, Weijie Cai, Jin-Bin Tian, Michael X Zhu

Faculty, Staff and Student Publications

Two pore channels (TPCs) are implicated in vesicle trafficking, virus infection, and autophagy regulation. As Na+- or Ca2+-permeable channels, TPCs have been reported to be activated by NAADP, PI(3,5)P2, and/or high voltage. However, a comparative study on the function and regulation of the three mammalian TPC subtypes is currently lacking. Here, we used the electrophysiological recording of enlarged endolysosome vacuoles, inside-out and outside-out membrane patches to examine the three TPCs of rabbit (Oryctolagus cuniculus, or Oc) heterologously expressed in HEK293 cells. While PI(3,5)P2 evoked Na+ currents with a potency order of OcTPC1 > OcTPC3 > OcTPC2, only OcTPC2 displayed a strict dependence …

Hematologic Complications Of Immune Checkpoint Inhibitors, Michael H Kroll, Cristhiam Rojas-Hernandez, Cassian Yee

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. There are currently 7 medications that have been approved by the US Food and Drug Administration for the treatment of 14 solid tumors and 2 hematologic malignancies. These medications commonly cause immune-related adverse effects as a result of overactive T lymphocytes, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses, such as autoimmune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia. Management is …

Biochemical, Biophysical, And Immunological Characterization Of Respiratory Secretions In Severe Sars-Cov-2 Infections, Michael J Kratochvil, Gernot Kaber, Sally Demirdjian, Pamela C Cai, Elizabeth B Burgener, Nadine Nagy, Graham L Barlow, Medeea Popescu, Mark R Nicolls, Michael G Ozawa, Donald P Regula, Ana E Pacheco-Navarro, Samuel Yang, Vinicio A De Jesus Perez, Harry Karmouty-Quintana, Andrew M Peters, Bihong Zhao, Maximilian L Buja, Pamela Y Johnson, Robert B Vernon, Thomas N Wight, Carlos E Milla, Angela J Rogers, Andrew J Spakowitz, Sarah C Heilshorn, Paul L Bollyky

Faculty, Staff and Student Publications

Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these …

Effect Of Neoadjuvant Chemotherapy On Intraoperative Core Temperature In Patients With Breast Cancer: A Retrospective Cohort Study, Daniel B Zamler, Takashi Shingu, Laura M Kahn, Kristin Huntoon, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Rocio Zorilla-Veloz, Cassian Yee, Kunal Rai, Betty Ys Kim, Stephanie S Watowich, Amy B Heimberger, Giulio F Draetta, Jian Hu

Faculty, Staff and Student Publications

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that …

Immune Landscape Of A Genetically Engineered Murine Model Of Glioma Compared With Human Glioma, Daniel B Zamler, Takashi Shingu, Laura M Kahn, Kristin Huntoon, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Rocio Zorilla-Veloz, Cassian Yee, Kunal Rai, Betty Ys Kim, Stephanie S Watowich, Amy B Heimberger, Giulio F Draetta, Jian Hu

Faculty, Staff and Student Publications

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that …

A Multi-Ethnic Polygenic Risk Score Is Associated With Hypertension Prevalence And Progression Throughout Adulthood, Nuzulul Kurniansyah, Matthew O Goodman, Tanika N Kelly, Tali Elfassy, Kerri L Wiggins, Joshua C Bis, Xiuqing Guo, Walter Palmas, Kent D Taylor, Henry J Lin, Jeffrey Haessler, Yan Gao, Daichi Shimbo, Jennifer A Smith, Bing Yu, Elena V Feofanova, Roelof A J Smit, Zhe Wang, Shih-Jen Hwang, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Donald M Lloyd-Jones, Stephen S Rich, Ruth J F Loos, Susan Redline, Adolfo Correa, Charles Kooperberg, Myriam Fornage, Robert C Kaplan, Bruce M Psaty, Jerome I Rotter, Donna K Arnett, Alanna C Morrison, Nora Franceschini, Daniel Levy, Tamar Sofer, Nhlbi Trans-Omics In Precision Medicine (Topmed) Consortium

Faculty, Staff and Student Publications

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 …