Digital Commons Network^™

Description Of A New Pavlovskyella Species (Acari: Argasidae) From Chile, Sebastián Muñoz-Leal, José M Venzal, Alexander R Kneubehl, Job E Lopez, Thiago F Martins, Marcelo B Labruna

Faculty, Staff and Students Publications

Soft ticks (Argasidae) of the Pavlovskyella Pospelova-Shtrom subgenus are important vectors of relapsing fever spirochetes, which are agents of disease globally. South American representatives of the Pavlovskyella subgenus include 3 species: Ornithodoros (Pavlovskyella) brasiliensis Aragão, Ornithodoros (Pavlovskyella) furcosus Neumann, and Ornithodoros (Pavlovskyella) rostratus Aragão. Here, we describe a fourth species based on morphological and mitogenomic evidence of ticks collected in burrows of unknown hosts in central Chile. The larva of the new species separates from other South American soft ticks by the following combination of characters: 13 pairs of dorsolateral setae, dorsal plate hexagonal, hypostome blunt with denticles from apex …

Disease Modeling And Gene Correction Of Lgmdr21 Ipscs Elucidates The Role Of Poglut1 In Skeletal Muscle Maintenance, Regeneration, And The Satellite Cell Niche, Jose L Ortiz-Vitali, Jianbo Wu, Nasa Xu, Annie W Shieh, Nima Niknejad, Megumi Takeuchi, Carmen Paradas, Chunru Lin, Hamed Jafar-Nejad, Robert S Haltiwanger, Sidney H Wang, Radbod Darabi

Faculty, Staff and Student Publications

Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro …

The Endosomal Escape Vehicle Platform Enhances Delivery Of Oligonucleotides In Preclinical Models Of Neuromuscular Disorders, Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian

Faculty, Staff and Student Publications

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of …

Interaction Between Myelodysplasia-Related Gene Mutations And Ontogeny In Acute Myeloid Leukemia, Joseph G W Mccarter, David Nemirovsky, Christopher A Famulare, Noushin Farnoud, Abhinita S Mohanty, Zoe S Stone-Molloy, Jordan Chervin, Brian J Ball, Zachary D Epstein-Peterson, Maria E Arcila, Aaron J Stonestrom, Andrew Dunbar, Sheng F Cai, Jacob L Glass, Mark B Geyer, Raajit K Rampal, Ellin Berman, Omar I Abdel-Wahab, Eytan M Stein, Martin S Tallman, Ross L Levine, Aaron D Goldberg, Elli Papaemmanuil, Yanming Zhang, Mikhail Roshal, Andriy Derkach, Wenbin Xiao

Faculty, Staff and Student Publications

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort …

Chronic Gvhd Nih Consensus Project Biology Task Force: Evolving Path To Personalized Treatment Of Chronic Gvhd, Nataliya P Buxbaum, Gerard Socié, Geoffrey R Hill, Kelli P A Macdonald, Victor Tkachev, Takanori Teshima, Stephanie J Lee, Jerome Ritz, Stefanie Sarantopoulos, Leo Luznik, Defu Zeng, Sophie Paczesny, Paul J Martin, Steven Z Pavletic, Kirk R Schultz, Bruce R Blazar

Faculty, Staff and Students Publications

Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused …

Reduced Maternal Immunity And Vertical Transfer Of Immunity Against Sars-Cov-2 Variants Of Concern With Covid-19 Exposure Or Initial Vaccination In Pregnancy., Rupsa Boelig, Sidhartha Chaudhury, Gregory D Gromowski, Sandra Mayer, Jocelyn King, Zubair H Aghai, Elke Bergmann-Leitner

Department of Obstetrics and Gynecology Faculty Papers

INTRODUCTION: As the SARS-CoV-2 pandemic continues to evolve, we face new variants of concern with a concurrent decline in vaccine booster uptake. We aimed to evaluate the difference in immunity gained from the original SARS-CoV-2 mRNA vaccine series in pregnancy versus SARS-CoV-2 exposure during pregnancy against recent variants of concern.

STUDY DESIGN: This is a retrospective analysis of previously collected samples from 192 patients who delivered between February 2021 and August 2021. Participants were categorized as 1) COVID vaccine: mRNA vaccine in pregnancy, 2) COVID-exposed, and 3) controls. The primary outcome was neutralizing capacity against wild-type, Delta, and Omicron-B1 between …

Preface: Causes Of Obesity, Theories, Conjectures And Evidence, David B Allison, Thorkild I A Sørensen, Kevin D Hall, John R Speakman

Children’s Nutrition Research Center Staff Publications

No abstract provided.

The Spatiotemporal Dynamics Of Semantic Integration In The Human Brain, Evan S Schaffer, Neeli Mishra, Matthew R Whiteway, Wenze Li, Michelle B Vancura, Jason Freedman, Kripa B Patel, Venkatakaushik Voleti, Liam Paninski, Elizabeth M C Hillman, L F Abbott, Richard Axel

Faculty, Staff and Student Publications

What are the spatial and temporal scales of brainwide neuronal activity? We used swept, confocally-aligned planar excitation (SCAPE) microscopy to image all cells in a large volume of the brain of adult Drosophila with high spatiotemporal resolution while flies engaged in a variety of spontaneous behaviors. This revealed neural representations of behavior on multiple spatial and temporal scales. The activity of most neurons correlated (or anticorrelated) with running and flailing over timescales that ranged from seconds to a minute. Grooming elicited a weaker global response. Significant residual activity not directly correlated with behavior was high dimensional and reflected the activity …

Sex Hormone-Binding Globulin (Shbg) Mitigates Er Stress And Improves Viability And Insulin Sensitivity In Adipose-Derived Mesenchymal Stem Cells (Asc) Of Equine Metabolic Syndrome (Ems)-Affected Horses, Nabila Bourebaba, Mateusz Sikora, Badr Qasem, Lynda Bourebaba, Krzysztof Marycz

Faculty, Staff and Student Publications

BACKGROUND: Equine metabolic syndrome (EMS), which encompasses insulin resistance, low-grade inflammation and predisposition to laminitis is a critical endocrine disorder among the most prevalent conditions affecting horses from different breeds. According to the most recent research, low human sex hormone-binding globulin (SHBG) serum levels correlate with an increased risk of obesity, insulin resistance and diabetes, and may contribute to overall metabolic dysregulations. This study aimed to test whether exogenous SHBG could protect EMS affected adipose-derived stromal stem cells (EqASC

METHODS: EqASC

RESULTS: Obtained data demonstrated that exogenous SHBG treatment significantly promoted ASCs cells proliferation, cell cycle and survival with reduced …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen presenting cells. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show …

Proteogenomic Insights Suggest Druggable Pathways In Endometrial Carcinoma, Yongchao Dou, Lizabeth Katsnelson, Marina A Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kolodziejczak, Rita Jui-Hsien Lu, Chia-Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C Arend, Jasmin Bavarva, Lijun Chen, Rosalie K Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G Demicco, Deborah Delair, Kelly Devereaux, Saravana M Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L Fillmore, Mckenzie Foxall, Catherine E Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D Jewell, Isabelle Johnson, Andrea G Kahn, Amy T Ku, Chandan Kumar-Sinha, Paweł Kurzawa, Alexander J Lazar, Rossana Lazcano, Jonathan T Lei, Yi Li, Yuxing Liao, Tung-Shing M Lih, Tai-Tu Lin, John A Martignetti, Ramya P Masand, Rafał Matkowski, Wilson Mckerrow, Mehdi Mesri, Matthew E Monroe, Jamie Moon, Ronald J Moore, Michael D Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S Omenn, Samuel H Payne, Vladislav A Petyuk, Ana I Robles, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Athena A Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason Taylor, Mathangi Thiagarajan, Joshua M Wang, Karl K Weitz, Bo Wen, C M Williams, Yige Wu, Matthew A Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David Mutch, Arul M Chinnaiyan, Richard D Smith, Alexey I Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D R Mani, Hui Zhang, Matthew L Anderson, Karin D Rodland, Bing Zhang, Tao Liu, David Fenyö

Faculty, Staff and Students Publications

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render …

A Split And Inducible Adenine Base Editor For Precise In Vivo Base Editing, Hongzhi Zeng, Qichen Yuan, Fei Peng, Dacheng Ma, Ananya Lingineni, Kelly Chee, Peretz Gilberd, Emmanuel C Osikpa, Zheng Sun, Xue Gao

Faculty, Staff and Students Publications

DNA base editors use deaminases fused to a programmable DNA-binding protein for targeted nucleotide conversion. However, the most widely used TadA deaminases lack post-translational control in living cells. Here, we present a split adenine base editor (sABE) that utilizes chemically induced dimerization (CID) to control the catalytic activity of the deoxyadenosine deaminase TadA-8e. sABE shows high on-target editing activity comparable to the original ABE with TadA-8e (ABE8e) upon rapamycin induction while maintaining low background activity without induction. Importantly, sABE exhibits a narrower activity window on DNA and higher precision than ABE8e, with an improved single-to-double ratio of adenine editing and …

Phasedancer: A Novel Targeted Assembler Of Segmental Duplications Unravels The Complexity Of The Human Chromosome 2 Fusion Going From 48 To 46 Chromosomes In Hominin Evolution, Barbara Poszewiecka, Krzysztof Gogolewski, Justyna A Karolak, Paweł Stankiewicz, Anna Gambin

Faculty, Staff and Students Publications

Resolving complex genomic regions rich in segmental duplications (SDs) is challenging due to the high error rate of long-read sequencing. Here, we describe a targeted approach with a novel genome assembler PhaseDancer that extends SD-rich regions of interest iteratively. We validate its robustness and efficiency using a golden-standard set of human BAC clones and in silico-generated SDs with predefined evolutionary scenarios. PhaseDancer enables extension of the incomplete complex SD-rich subtelomeric regions of Great Ape chromosomes orthologous to the human chromosome 2 (HSA2) fusion site, informing a model of HSA2 formation and unravelling the evolution of human and Great Ape genomes.

Integrative Multi-Omic Cancer Profiling Reveals Dna Methylation Patterns Associated With Therapeutic Vulnerability And Cell-Of-Origin, Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G Jayasinghe, Steven M Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H Payne, David Fenyö, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D R Mani, Karin D Rodland, Alexander J Lazar, Ana I Robles, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A …

Treatment Of Older Adults With Flt3-Mutated Aml: Emerging Paradigms And The Role Of Frontline Flt3 Inhibitors, Nicholas J Short, Daniel Nguyen, Farhad Ravandi

Faculty, Staff and Student Publications

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable …

Krasg12d Inhibition Reprograms The Tumor Microenvironment Of Early And Advanced Pancreatic Cancer To Promote Fas-Mediated Killing By Cd8+ T Cells, Krishnan K Mahadevan, Kathleen M Mcandrews, Valerie S Lebleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri

Faculty, Staff and Student Publications

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 …

Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows …

Unfolding The Secrets Of Small Cell Lung Cancer Progression: Novel Approaches And Insights Through Rapid Autopsies, Zsolt Megyesfalvi, Simon Heeke, Benjamin J Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M Gay, Lauren A Byers, Benjamin B Morris, John V Heymach, Peter Van Loo, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Early Onset Horizontal Gaze Palsy And Progressive Scoliosis Due To A Noncanonical Splicing-Site Variant And A Missense Variant In The Robo3 Gene, Sheng Yi, Zailong Qin, Xunzhao Zhou, Junjie Chen, Shang Yi, Qiuli Chen, Limei Huang, Qinle Zhang, Biyan Chen, Jingsi Luo

Faculty, Staff and Student Publications

BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.

METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.

RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention …

Sex Differences In Paternal Arsenic-Induced Intergenerational Metabolic Effects Are Mediated By Estrogen, Yanfeng Xue, Yingyun Gong, Xin Li, Fei Peng, Guolian Ding, Zhao Zhang, Junchao Shi, Ilma Saleh Savul, Yong Xu, Qi Chen, Leng Han, Shengyong Mao, Zheng Sun

Faculty, Staff and Students Publications

BACKGROUND: Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences.

METHODS: After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 …

The Classification Of Obesity Based On Metabolic Status Redefines The Readmission Of Non-Hodgkin’S Lymphoma—An Observational Study, Eunju Kim, Kazuaki Mawatari, Seung-Hee Yoo, Zheng Chen

Faculty, Staff and Student Publications

Obesity is a known risk factor for metabolic diseases and is often associated with chronic inflammation in adipose tissue. We previously identified the polyethoxylated flavonoid Nobiletin (NOB) as a circadian clock modulator that directly binds to and activates the ROR receptors in the core oscillator, markedly improving metabolic fitness in obese mice. Here, we show that NOB enhanced the oscillation of core clock genes in differentiated 3T3-L1 adipocytes, including ROR target genes such as Bmal1, Cry1, Dec1, and Dec2. NOB inhibited lipid accumulation in 3T3-L1 and SVF cells, concomitant with the dysregulated circadian expression of adipogenic …

Stereotactic Ablative Radiotherapy With Or Without Immunotherapy For Early-Stage Or Isolated Lung Parenchymal Recurrent Node-Negative Non-Small-Cell Lung Cancer: An Open-Label, Randomised, Phase 2 Trial, Joe Y Chang, Steven H Lin, Wenli Dong, Zhongxing Liao, Saumil J Gandhi, Carl M Gay, Jianjun Zhang, Stephen G Chun, Yasir Y Elamin, Frank V Fossella, George Blumenschein, Tina Cascone, Xiuning Le, Jenny V Pozadzides, Anne Tsao, Vivek Verma, James W Welsh, Aileen B Chen, Mehmet Altan, Reza J Mehran, Ara A Vaporciyan, Stephen G Swisher, Peter A Balter, Junya Fujimoto, Ignacio I Wistuba, Lei Feng, J Jack Lee, John V Heymach

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC.

METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older …

Comparative Retrospective Study Of Proton Arc Planning With Elsa Algorithm And Impt With Monte Carlo Algorithm With Raystation Treatment Planning System, Matthew L. Carpenter Ms, Msha, Bsrt(R)(T)

Masters Projects

Proton arc therapy (PAT) will become widely available soon. It is crucial to determine if this technique and the associated calculation algorithms provided by treatment planning system vendors compete favorably with established proton therapy techniques like intensity modulated proton therapy (IMPT) and the Monte Carlo dose calculation algorithm used to compute IMPT doses in today’s clinic. RaySearch Laboratories have produced a modified Monte Carlo algorithm called ELSA.

ELSA stands for early layer spot assignment and is RaySearch Laboratories proposed solution to reduce optimization time during treatment planning for PAT. This research study will look at proton plan robustness to determine …

Single-Cell Profiling Reveals Inflammatory Polarization Of Human Carotid Versus Femoral Plaque Leukocytes, Joshua Slysz, Arjun Sinha, Matthew Deberge, Shalini Singh, Harris Avgousti, Inhyeok Lee, Kristofor Glinton, Reina Nagasaka, Prarthana Dalal, Shaina Alexandria, Ching Man Wai, Ricardo Tellez, Mariavittoria Vescovo, Ashwin Sunderraj, Xinkun Wang, Matthew Schipma, Ryan Sisk, Rishab Gulati, Jenifer Vallejo, Ryosuke Saigusa, Donald M Lloyd-Jones, Jon Lomasney, Samuel Weinberg, Karen Ho, Klaus Ley, Chiara Giannarelli, Edward B Thorp, Matthew J Feinstein

Faculty, Staff and Student Publications

Femoral atherosclerotic plaques are less inflammatory than carotid plaques histologically, but limited cell-level data exist regarding comparative immune landscapes and polarization at these sites. We investigated intraplaque leukocyte phenotypes and transcriptional polarization in 49 patients undergoing femoral (n = 23) or carotid (n = 26) endarterectomy using single-cell RNA-Seq (scRNA-Seq; n = 13), flow cytometry (n = 24), and IHC (n = 12). Comparative scRNA-Seq of CD45+-selected leukocytes from femoral (n = 9; 35,265 cells) and carotid (n = 4; 30,655 cells) plaque revealed distinct transcriptional profiles. Inflammatory foam cell-like macrophages and monocytes comprised higher proportions of myeloid cells in …

Sars-Cov-2 Niches In Human Placenta Revealed By Spatial Transcriptomics, Enrico R Barrozo, Maxim D Seferovic, Eumenia C C Castro, Angela M Major, David N Moorshead, Michael D Jochum, Ricardo Ferral Rojas, Cynthia D Shope, Kjersti M Aagaard

Faculty, Staff and Students Publications

BACKGROUND: Functional placental niches are presumed to spatially separate maternal-fetal antigens and restrict the vertical transmission of pathogens. We hypothesized a high-resolution map of placental transcription could provide direct evidence for niche microenvironments with unique functions and transcription profiles.

METHODS: We utilized Visium Spatial Transcriptomics paired with H&E staining to generate 17,927 spatial transcriptomes. By integrating these spatial transcriptomes with 273,944 placental single-cell and single-nuclei transcriptomes, we generated an atlas composed of at least 22 subpopulations in the maternal decidua, fetal chorionic villi, and chorioamniotic membranes.

FINDINGS: Comparisons of placentae from uninfected healthy controls (n = 4) with COVID-19 asymptomatic …

Acculturation And Subjective Norms Impact Non-Prescription Antibiotic Use Among Hispanic Patients In The United States, Lindsey A Laytner, Kiara Olmeda, Juanita Salinas, Osvaldo Alquicira, Susan Nash, Roger Zoorob, Michael K Paasche-Orlow, Barbara W Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Using antibiotics without medical guidance (non-prescription antibiotic use) may contribute to antimicrobial resistance. Hispanic individuals are a growing demographic group in the United States (US) with a high prevalence of non-prescription antibiotic use. We investigated the effects of acculturation and subjective norms on Hispanic individuals’ intentions to use antibiotics without a prescription from the following sources: (1) markets in the United States (not legal), (2) other countries (abroad), (3) leftovers from previous prescriptions, and (4) friends/relatives. We surveyed self-identified Hispanic outpatients in eight clinics from January 2020 to June 2021 using the previously validated Short Acculturation Scale for Hispanics (SASH). …

Modulation Of The Proteostasis Network Promotes Tumor Resistance To Oncogenic Kras Inhibitors, Xiangdong Lv, Xuan Lu, Jin Cao, Qin Luo, Yao Ding, Fanglue Peng, Apar Pataer, Dong Lu, Dong Han, Eric Malmberg, Doug W Chan, Xiaoran Wang, Sara R Savage, Sufeng Mao, Jingjing Yu, Fei Peng, Liang Yan, Huan Meng, Laure Maneix, Yumin Han, Yiwen Chen, Wantong Yao, Eric C Chang, Andre Catic, Xia Lin, George Miles, Pengxiang Huang, Zheng Sun, Bryan Burt, Huamin Wang, Jin Wang, Qizhi Cathy Yao, Bing Zhang, Jack A Roth, Bert W O'Malley, Matthew J Ellis, Mothaffar F Rimawi, Haoqiang Ying, Xi Chen

Faculty, Staff and Student Publications

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In …

Beyond The Symptom: The Biology Of Fatigue, David M Raizen, Janet Mullington, Christelle Anaclet, Gerard Clarke, Hugo Critchley, Robert Dantzer, Ronald Davis, Kelly L Drew, Josh Fessel, Patrick M Fuller, Erin M Gibson, Mary Harrington, W Ian Lipkin, Elizabeth B Klerman, Nancy Klimas, Anthony L Komaroff, Walter Koroshetz, Lauren Krupp, Anna Kuppuswamy, Julie Lasselin, Laura D Lewis, Pierre J Magistretti, Heidi Y Matos, Christine Miaskowski, Andrew H Miller, Avindra Nath, Maiken Nedergaard, Mark R Opp, Marylyn D Ritchie, Dragana Rogulja, Asya Rolls, John D Salamone, Clifford Saper, Vicky Whittemore, Glenn Wylie, Jarred Younger, Phyllis C Zee, H Craig Heller

Faculty, Staff and Student Publications

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a …

Click Display: A Rapid And Efficient In Vitro Protein Display Method For Directed Evolution, Yu Zeng, Michael Woolley, Karuppiah Chockalingam, Benjamin Thomas, Srishtee Arora, Magnus Hook, Zhilei Chen

Faculty, Staff and Student Publications

We describe a novel method for in vitro protein display-click display-that does not depend on maintaining RNA integrity during biopanning and yields covalently linked protein-cDNA complexes from double-stranded input DNA within 2 h. The display is achieved in a one-pot format encompassing transcription, translation and reverse transcription reactions in series. Stable linkage between proteins and the encoding cDNA is mediated by a modified DNA linker-ML-generated via a click chemistry reaction between a puromycin-containing oligo and a cDNA synthesis primer. Biopanning of a click-displayed mock library coupled with next-generation sequencing analysis revealed >600-fold enrichment of target binders within a single round …