Digital Commons Network^™

Heartworm Adulticide Treatment: A Tropical Perspective, Filipe Dantas-Torres, Jennifer Ketzis, Gabriela Pérez Tort, Andrei Daniel Mihalca, Gad Baneth, Domenico Otranto, Malaika Watanabe, Bui Khanh Linh, Tawin Inpankaew, Pablo Borrás, Sangaran Arumugam, Barend Louis Penzhorn, Adrian Patalinghug Ybañez, Peter Irwin, Rebecca J Traub

Faculty, Staff and Student Publications

Dirofilaria immitis (the canine heartworm) is widespread in the tropics, with prevalence surpassing 30% in high-risk areas. In addition to the suitable climatic conditions that favour mosquito abundance and filarial larva development, there is low compliance with the recommended year-round use of preventives in these transmission hotspots. This represents a major concern, considering that melarsomine (first-line heartworm adulticide) is unavailable in several tropical countries, resulting in the so-called slow-kill protocol being the only available adulticide treatment option. In this article, the members of TroCCAP (Tropical Council for Companion Animal Parasites) review the current distribution of heartworm in the tropics and …

Alternative Splicing Of Gsdmb Modulates Killer Lymphocyte-Triggered Pyroptosis, Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Xiaoqiang Tang, Nidhi Sahni, S Stephen Yi, Xing Liu, Hao Wu, Michael B Elowitz, Judy Lieberman, Zhibin Zhang

Faculty, Staff and Student Publications

Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic …

Cvam: Cna Profile Inference Of The Spatial Transcriptome Based On The Vgae And Hmm, Jian Ma, Jingjing Guo, Zhiwei Fan, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

Tumors are often polyclonal due to copy number alteration (CNA) events. Through the CNA profile, we can understand the tumor heterogeneity and consistency. CNA information is usually obtained through DNA sequencing. However, many existing studies have shown a positive correlation between the gene expression and gene copy number identified from DNA sequencing. With the development of spatial transcriptome technologies, it is urgent to develop new tools to identify genomic variation from the spatial transcriptome. Therefore, in this study, we developed CVAM, a tool to infer the CNA profile from spatial transcriptome data. Compared with existing tools, CVAM integrates the spatial …

Enhancing Cancer Diagnosis With Real-Time Feedback: Tumor Metabolism Through Hyperpolarized 1-13c Pyruvate Mrsi, Gaurav Sharma, José S Enriquez, Ryan Armijo, Muxin Wang, Pratip Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

This review article discusses the potential of hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) as a noninvasive technique for identifying altered metabolism in various cancer types. Hyperpolarization significantly improves the signal-to-noise ratio for the identification of 13C-labeled metabolites, enabling dynamic and real-time imaging of the conversion of [1-13C] pyruvate to [1-13C] lactate and/or [1-13C] alanine. The technique has shown promise in identifying upregulated glycolysis in most cancers, as compared to normal cells, and detecting successful treatment responses at an earlier stage than multiparametric MRI in breast and prostate cancer patients. The review provides a concise overview of the applications …

The Genomic Landscape Of Familial Glioma, Dong-Joo Choi, Georgina Armstrong, Brittney Lozzi, Prashanth Vijayaraghavan, Sharon E Plon, Terence C Wong, Eric Boerwinkle, Donna M Muzny, Hsiao-Chi Chen, Richard A Gibbs, Quinn T Ostrom, Beatrice Melin, Benjamin Deneen, Melissa L Bondy, Gliogene Consortium, Genomics England Research Consortium, Matthew N Bainbridge, Christopher I Amos, Jill S Barnholtz-Sloan, Jonine L Bernstein, Elizabeth B Claus, Richard S Houlston, Dora Il'yasova, Robert B Jenkins, Christoffer Johansen, Daniel Lachance, Rose Lai, Beatrice S Melin, Ryan T Merrell, Sara H Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, J C Ambrose, P Arumugam, R Bevers, M Bleda, F Boardman-Pretty, C R Boustred, H Brittain, M A Brown, M J Caulfield, G C Chan, A Giess, J N Griffin, A Hamblin, S Henderson, T J P Hubbard, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, A Kousathanas, L Lahnstein, A Lakey, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, M Mcentagart, F Minneci, J Mitchell, L Moutsianas, M Mueller, N Murugaesu, A C Need, P O'Donovan, C A Odhams, C Patch, D Perez-Gil, M B Pereira, J Pullinger, T Rahim, A Rendon, T Rogers, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, S C Smith, A Sosinsky, A Stuckey, M Tanguy, A L Taylor Tavares, E R A Thomas, S R Thompson, A Tucci, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Faculty, Staff and Student Publications

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to …

The Genetic Determinants Of Recurrent Somatic Mutations In 43,693 Blood Genomes, Joshua S Weinstock, Cecelia A Laurie, Jai G Broome, Kent D Taylor, Xiuqing Guo, Alan R Shuldiner, Jeffrey R O'Connell, Joshua P Lewis, Eric Boerwinkle, Kathleen C Barnes, Nathalie Chami, Eimear E Kenny, Ruth J F Loos, Myriam Fornage, Susan Redline, Brian E Cade, Frank D Gilliland, Zhanghua Chen, W James Gauderman, Rajesh Kumar, Leslie Grammer, Robert P Schleimer, Bruce M Psaty, Joshua C Bis, Jennifer A Brody, Edwin K Silverman, Jeong H Yun, Dandi Qiao, Scott T Weiss, Jessica Lasky-Su, Dawn L Demeo, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Michael H Cho, Ramachandran S Vasan, Andrew D Johnson, Lisa R Yanek, Lewis C Becker, Sharon Kardia, Jiang He, Robert Kaplan, Susan R Heckbert, Nicholas L Smith, Kerri L Wiggins, Donna K Arnett, Marguerite R Irvin, Hemant Tiwari, Adolfo Correa, Laura M Raffield, Yan Gao, Mariza De Andrade, Jerome I Rotter, Stephen S Rich, Ani W Manichaikul, Barbara A Konkle, Jill M Johnsen, Marsha M Wheeler, Brian S Custer, Ravindranath Duggirala, Joanne E Curran, John Blangero, Hongsheng Gui, Shujie Xiao, L Keoki Williams, Deborah A Meyers, Xingnan Li, Victor Ortega, Stephen Mcgarvey, C Charles Gu, Yii-Der Ida Chen, Wen-Jane Lee, M Benjamin Shoemaker, Dawood Darbar, Dan Roden, Christine Albert, Charles Kooperberg, Pinkal Desai, Thomas W Blackwell, Goncalo R Abecasis, Albert V Smith, Hyun M Kang, Rasika Mathias, Pradeep Natarajan, Siddhartha Jaiswal, Alexander P Reiner, Alexander G Bick, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium

Faculty, Staff and Student Publications

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Mice, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Consensus Proposal For Revised International Working Group 2023 Response Criteria For Higher-Risk Myelodysplastic Syndromes, Amer M Zeidan, Uwe Platzbecker, Jan Philipp Bewersdorf, Maximilian Stahl, Lionel Adès, Uma Borate, David Bowen, Rena Buckstein, Andrew Brunner, Hetty E Carraway, Naval Daver, Maria Díez-Campelo, Theo De Witte, Amy E Dezern, Fabio Efficace, Guillermo Garcia-Manero, Jacqueline S Garcia, Ulrich Germing, Aristoteles Giagounidis, Elizabeth A Griffiths, Robert P Hasserjian, Eva Hellström-Lindberg, Marcelo Iastrebner, Rami Komrokji, Austin G Kulasekararaj, Luca Malcovati, Yasushi Miyazaki, Olatoyosi Odenike, Valeria Santini, Guillermo Sanz, Phillip Scheinberg, Reinhard Stauder, Arjan A Van De Loosdrecht, Andrew H Wei, Mikkael A Sekeres, Pierre Fenaux

Faculty, Staff and Student Publications

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria …

Experiencing Moral Distress Within The Intimate Partner Violence & Sexual Assault Workforce, Rachel J Voth Schrag, Sophia Fantus, Sarah Leat, Saltanat Childress, Leila Wood

Faculty, Staff and Student Publications

PURPOSE: Moral distress (MD) refers to the psychological disequilibrium that emerges when institutional policies and/or practices conflict with an individual's professional values and ethics. MD has been interrogated frequently in health care and ancillary medical settings, and has been identified as a critical barrier to enhanced organizational climate and patient care. However, little work has investigated experiences of MD among members of the intimate partner violence (IPV) and sexual violence (SV) workforce.

METHODS: This study investigates MD in a sample of IPV and SV service providers via secondary analysis of 33 qualitative interviews conducted with service providers in the summer …

Positive Selection Of Somatically Mutated Clones Identifies Adaptive Pathways In Metabolic Liver Disease, Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes …

Mapping The Functional Interactions At The Tumor-Immune Checkpoint Interface, Behnaz Bozorgui, Elisabeth K Kong, Augustin Luna, Anil Korkut

Faculty, Staff and Student Publications

The interactions between tumor intrinsic processes and immune checkpoints can mediate immune evasion by cancer cells and responses to immunotherapy. It is, however, challenging to identify functional interactions due to the prohibitively complex molecular landscape of the tumor-immune interfaces. We address this challenge with a statistical analysis framework, immuno-oncology gene interaction maps (ImogiMap). ImogiMap quantifies and statistically validates tumor-immune checkpoint interactions based on their co-associations with immune-associated phenotypes. The outcome is a catalog of tumor-immune checkpoint interaction maps for diverse immune-associated phenotypes. Applications of ImogiMap recapitulate the interaction of SERPINB9 and immune checkpoints with interferon gamma (IFNγ) expression. Our analyses …

The Current State Of Prenatal Detection Of Genetic Conditions In Congenital Heart Defects, Areebah S Ahmad, Kathleen M Mulligan, David X Zheng, Katie A O'Connell, Benjamin Gallo Marin, Misha V Koshelev

Faculty, Staff and Student Publications

Interest in subspecialty training remains high for dermatology residency graduates. Fellowship program directors (FPDs) are largely responsible for fellowship organization and development. Here, we study the dermatology fellowship leadership landscape and identify notable differences in the characteristics of current dermatopathology, paediatric dermatology, and Mohs micrographic surgery and dermatologic oncology FPDs.

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Miceb, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Increased Risk Of Dementia In Patients With Atopic Dermatitis: A Nationwide Population-Based Cohort Study, Yu Ri Woo, Minah Cho, Kyung Do Han, Sang Hyun Cho, Ji Hyun Lee

Faculty, Staff and Student Publications

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with bimodal incidence peaks in early childhood and middle-aged and older adults. Few studies have focused on the risk of dementia in AD. The aims of this study were to analyse the incidence, and risk factors for dementia in patients with AD. This nationwide population-based retrospective cohort study enrolled 38,391 adults ≥ 40 years of age with AD and 2,643,602 controls without AD from the Korean National Health Insurance System (NHIS) database from 2009 to 2016. The cumulative incidence probability of all-cause dementia, Alzheimer's disease, or vascular dementia at 8 years …

Hica Toxin-Based Counterselection Marker For Allelic Exchange Mutations In Fusobacterium Nucleatum, Bibek Gc, Peng Zhou, Chenggang Wu

Faculty, Staff and Student Publications

The study of fusobacterial virulence factors has dramatically benefited from the creation of various genetic tools for DNA manipulation, including galK-based counterselection for in-frame deletion mutagenesis in Fusobacterium nucleatum, which was recently developed. However, this method requires a host lacking the galK gene, which is an inherent limitation. To circumvent this limitation, we explored the possibility of using the hicA gene that encodes a toxin consisting of a HicAB toxin-antitoxin module in Fusobacterium periodonticum as a new counterselective marker. Interestingly, the full-length hicA gene is not toxic in F. nucleatum, but a truncated hicA gene version lacking the first …

Effectors And Effects Of Arginine Methylation, Yalong Wang, Mark T Bedford

Faculty, Staff and Student Publications

Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Methylarginine marks are catalyzed by members of the protein arginine methyltransferases (PRMTs) family of enzymes. Substrates for arginine methylation are found in most cellular compartments, with RNA-binding proteins forming the majority of PRMT targets. Arginine methylation often occurs in intrinsically disordered regions of proteins, which impacts biological processes like protein-protein interactions and phase separation, to modulate gene transcription, mRNA splicing and signal transduction. With regards to protein-protein interactions, the major 'readers' of methylarginine marks are …

Covid-19 Severity Scale For Claims Data Research, Trudy Millard Krause, Raymond Greenberg, Lopita Ghosh, Joseph S Wozny, Regina M Hansen, Caroline Schaefer

Faculty, Staff and Student Publications

OBJECTIVE: to create and validate a methodology to assign a severity level to an episode of COVID-19 for retrospective analysis in claims data.

DATA SOURCE: Secondary data obtained by license agreement from Optum provided claims records nationally for 19,761,754 persons, of which, 692,094 persons had COVID-19 in 2020.

STUDY DESIGN: The World Health Organization (WHO) COVID-19 Progression Scale was used as a model to identify endpoints as measures of episode severity within claims data. Endpoints used included symptoms, respiratory status, progression to levels of treatment and mortality.

DATA COLLECTION/EXTRACTION METHODS: The strategy for identification of cases relied upon the February …

Overcoming Adaptive Resistance To Anti-Vegf Therapy By Targeting Cd5l, Christopher J Lafargue, Paola Amero, Kyunghee Noh, Lingegowda S Mangala, Yunfei Wen, Emine Bayraktar, Sujanitha Umamaheswaran, Elaine Stur, Santosh K Dasari, Cristina Ivan, Sunila Pradeep, Wonbeak Yoo, Chunhua Lu, Nicholas B Jennings, Vinod Vathipadiekal, Wei Hu, Anca Chelariu-Raicu, Zhiqiang Ku, Hui Deng, Wei Xiong, Hyun-Jin Choi, Min Hu, Takae Kiyama, Chai-An Mao, Rouba Ali-Fehmi, Michael J Birrer, Jinsong Liu, Ningyan Zhang, Gabriel Lopez-Berestein, Vittorio De Franciscis, Zhiqiang An, Anil K Sood

Faculty, Staff and Student Publications

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. …

Bridging Clinic And Wildlife Care With Ai-Powered Pan-Species Computational Pathology, Khalid Abduljabbar, Simon P Castillo, Katherine Hughes, Hannah Davidson, Amy M Boddy, Lisa M Abegglen, Lucia Minoli, Selina Iussich, Elizabeth P Murchison, Trevor A Graham, Simon Spiro, Carlo C Maley, Luca Aresu, Chiara Palmieri, Yinyin Yuan

Faculty, Staff and Student Publications

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves …

Cloning A Profibrotic Stem Cell Variant In Idiopathic Pulmonary Fibrosis, Shan Wang, Wei Rao, Ashley Hoffman, Jennifer Lin, Justin Li, Tao Lin, Audrey-Ann Liew, Matthew Vincent, Tinne C J Mertens, Harry Karmouty-Quintana, Christopher P Crum, Mark L Metersky, David A Schwartz, Peter J A Davies, Clifford Stephan, Soma S K Jyothula, Ajay Sheshadri, Erik Eddie Suarez, Howard J Huang, John F Engelhardt, Burton F Dickey, Kalpaj R Parekh, Frank D Mckeon, Wa Xian

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell …

Modelling Radiation Cancer Treatment With A Death-Rate Term In Ordinary And Fractional Differential Equations, Nicole Wilson, Corina S Drapaca, Heiko Enderling, Jimmy J Caudell, Kathleen P Wilkie

Faculty, Staff and Student Publications

Fractional calculus has recently been applied to the mathematical modelling of tumour growth, but its use introduces complexities that may not be warranted. Mathematical modelling with differential equations is a standard approach to study and predict treatment outcomes for population-level and patient-specific responses. Here, we use patient data of radiation-treated tumours to discuss the benefits and limitations of introducing fractional derivatives into three standard models of tumour growth. The fractional derivative introduces a history-dependence into the growth function, which requires a continuous death-rate term for radiation treatment. This newly proposed radiation-induced death-rate term improves computational efficiency in both ordinary and …

Cdk5-Prmt1-Wdr24 Signaling Cascade Promotes Mtorc1 Signaling And Tumor Growth, Shasha Yin, Liu Liu, Lauren E Ball, Yalong Wang, Mark T Bedford, Stephen A Duncan, Haizhen Wang, Wenjian Gan

Faculty, Staff and Student Publications

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation …

Immune Cellular Patterns Of Distribution Affect Outcomes Of Patients With Non-Small Cell Lung Cancer, Edwin Roger Parra, Jiexin Zhang, Mei Jiang, Auriole Tamegnon, Renganayaki Krishna Pandurengan, Carmen Behrens, Luisa Solis, Cara Haymaker, John Victor Heymach, Cesar Moran, Jack J Lee, Don Gibbons, Ignacio Ivan Wistuba

Faculty, Staff and Student Publications

Studying the cellular geographic distribution in non-small cell lung cancer is essential to understand the roles of cell populations in this type of tumor. In this study, we characterize the spatial cellular distribution of immune cell populations using 23 makers placed in five multiplex immunofluorescence panels and their associations with clinicopathologic variables and outcomes. Our results demonstrate two cellular distribution patterns-an unmixed pattern mostly related to immunoprotective cells and a mixed pattern mostly related to immunosuppressive cells. Distance analysis shows that T-cells expressing immune checkpoints are closer to malignant cells than other cells. Combining the cellular distribution patterns with cellular …

Bone Marrow Endosteal Stem Cells Dictate Active Osteogenesis And Aggressive Tumorigenesis, Yuki Matsushita, Jialin Liu, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Mizuki Nagata, Yuki Arai, Wanida Ono, Kouhei Yamamoto, Thomas L Saunders, Joshua D Welch, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal …

Tumor Suppressor Candidate 2 (Tusc2): Discovery, Functions, And Cancer Therapy, Austin Arrigo, Angelina T Regua, Mariana K Najjar, Hui-Wen Lo

Faculty, Staff and Student Publications

Tumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2's normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that …

Spatiotemporally Distributed Frontotemporal Networks For Sentence Reading, Oscar Woolnough, Cristian Donos, Elliot Murphy, Patrick S Rollo, Zachary J Roccaforte, Stanislas Dehaene, Nitin Tandon

Faculty, Staff and Student Publications

Reading a sentence entails integrating the meanings of individual words to infer more complex, higher-order meaning. This highly rapid and complex human behavior is known to engage the inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) in the language-dominant hemisphere, yet whether there are distinct contributions of these regions to sentence reading is still unclear. To probe these neural spatiotemporal dynamics, we used direct intracranial recordings to measure neural activity while reading sentences, meaning-deficient Jabberwocky sentences, and lists of words or pseudowords. We isolated two functionally and spatiotemporally distinct frontotemporal networks, each sensitive to distinct aspects of word and …

Rapid Escape Of New Sars-Cov-2 Omicron Variants From Ba2-Directed Antibody Responses, Aiste Dijokaite-Guraliuc, Raksha Das, Daming Zhou, Helen M Ginn, Chang Liu, Helen M E Duyvesteyn, Jiandong Huo, Rungtiwa Nutalai, Piyada Supasa, Muneeswaran Selvaraj, Thushan I De Silva, Megan Plowright, Thomas A H Newman, Hailey Hornsby, Alexander J Mentzer, Donal Skelly, Thomas G Ritter, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J Dunachie, Optic Consortium, Cornelius Roemer, Thomas P Peacock, Neil G Paterson, Mark A Williams, David R Hall, Elizabeth E Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I Stuart, Gavin R Screaton

Faculty, Staff and Student Publications

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent …

Saturated Fatty Acids Dampen The Immunogenicity Of Cancer By Suppressing Sting, Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show …

Bone Marrow Endosteal Stem Cells Dictate Active Osteogenesis And Aggressive Tumorigenesis, Yuki Matsushita, Jialin Liu, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Mizuki Nagata, Yuki Arai, Wanida Ono, Kouhei Yamamoto, Thomas L Saunders, Joshua D Welch, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to …

Nothing About Us Without Us: The Roles Of Diverse Stakeholders In Scientific Publishing, Diana M Proctor

Faculty, Staff and Student Publications

No abstract provided.