tbuckley/cabot-search huggingface dataset:
Abstract 691: Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1
Authors: Tony Rady, Stéphane Erb, Safia Deddouche-Grass, Renaud Morales, Hervé Bouchard, Guilhem Chaubet, Sarah Cianférani, Dmitri Wiederschain, Nicolas Basse, Alain Wagner
Journal: Cancer Research (2021)

Abstract Simultaneous access to several targets has become the subject of intense studies in immuno-oncology. In order to benefit from the synergies provided by the activation of different signaling pathways in immunology and the knockdown of proteins involved in cancer cell survival, we established a bispecific approach. The activation of the innate immune response by delivering agonists of pattern-recognition receptors (PRR) such as RIG-I (retinoic acid-inducible I) represents a promising strategy. RIG-I detects short double-stranded RNA molecules ended by a 5'-di/triphosphate moiety (5'ppp-dsRNA). RIG-I activation promotes type I IFN secretion and cancer-cell selective apoptosis. To obtain a bifunctional molecule, the 5'ppp-dsRNA sequence was designed to silence PLK1 (polo-like kinase 1). Suppressing PLK1 expression with small interfering RNAs (siRNA) leads to cell cycle arrest and retards cancer cell growth. This concept of bifunctional RNAs has been validated by using non-targeted systems.1 To enhance this synergy, we conjugated this 5'ppp-siPLK1 to an antibody for a specific delivery to cancerous cells that overexpress erythropoietin-producing hepatocellular receptor A2 (EphA2) at their surface. Upon binding to EphA2 receptor, the antibody is well internalized, thus making it a good vehicle to deliver the bispecific 5'ppp-siPLK1. After EphA2-positive cells treatment, we observed RIG-I specific activation as well as PLK1 depletion. Both effects were correlated with cellular apoptosis and the mode of action was further confirmed with mechanistic and kinetic studies. Finally, while non-modified unconjugated siRNA has a very short half-life in plasma, we observed an increase in stability for the antibody-5'ppp-siPLK1 conjugates. These data suggest that anti-EphA2 receptor antibody could be used to deliver a bispecific RNA molecule. References:1H. Poeck, R. Besch, C. Maihoefer, M. Renn, D. Tormo, S. S. Morskaya, S. Kirschnek, E. Gaffal, J. Landsberg, J. Hellmuth, A. Schmidt, D. Anz, M. Bscheider, T. Schwerd, C. Berking, C. Bourquin, U. Kalinke, E. Kremmer, H. Kato, S. Akira, R. Meyers, G. Häcker, M. Neuenhahn, D. Busch, J. Ruland, S. Rothenfusser, M. Prinz, V. Hornung, S. Endres, T. Tüting and G. Hartmann, 5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma, Nat. Med., 2008, 14, 1256-1263. Citation Format: Tony Rady, Stéphane Erb, Safia Deddouche-Grass, Renaud Morales, Hervé Bouchard, Guilhem Chaubet, Sarah Cianférani, Dmitri Wiederschain, Nicolas Basse, Alain Wagner. Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 691.
Abstract 2393: The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique
Authors: Roslyn M. Ray, Lu Lang, Sheela P. Pokharel, Denis O'Meally, Tristan A. Scott, Chun-Wei Chen, Kevin V. Morris
Journal: Cancer Research (2021)

Abstract Long non-coding RNAs (LncRNAs) have been found to play important roles in maintaining and promoting cellular proliferation in cancerous cells. One such lncRNA, LINC00963 has been found to promote cellular proliferation, migration and tumorigenesis in prostate, ovarian, breast and non-small cell lung (NSCLC) cancer. In this study, we aim to identify important functional regions of this lncRNA with a view to identify unique regions for targeted drug therapy. In order to achieve this, we sought to investigate this lncRNA in the A549 NSCLC cell line. We found that LINC00963 was highly expressed and when targeted with either siRNAs or antisense oligonucleotides, cells rapidly undergo apoptosis. Using cell death as a proxy for loss-of-function, we characterized LINC00963 at the genomic level using a CRIPSRScan approach. CRISPRScan is a novel way of determining lncRNA functional domains through the introduction of local mutations. These mutations could potentially disrupt lncRNA function, which for LINC00963 would lead to apoptosis of the cell. We created a unique lentivirus library comprised of 1784 single guide RNAs spanning the length of LINC00963 in order to precisely identify regions of functional importance. Upon transduction in a stably expressing Cas9-A549 cell line, we collected cellular fractions over time, and using high-throughput sequencing (NextSeq, Illumina), evaluated the depletion of these sgRNAs as a proxy for their importance in LINC00963 function. The identification of these key genomic regions that may render LINC00963 non-functional may offer new lncRNA target sites for anti-cancer therapies in the future. Additionally, the utilization of an in-depth CRISPR-Cas9 approach to determine important lncRNA domains provides a novel and precise way in which to evaluate lncRNA function. Citation Format: Roslyn M. Ray, Lu Lang, Sheela P. Pokharel, Denis O'Meally, Tristan A. Scott, Chun-Wei Chen, Kevin V. Morris. The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2393.
Abstract 329: Targeting an emerging oncogenic biomarker, heparanase
Authors: Lina Cui
Journal: Cancer Research (2021)

Abstract Heparan sulfate proteoglycans (HSPGs), major components in the extracellular matrix (ECM) of all tissue types, maintain ECM structural integrity and regulate cellular signaling via binding with ECM components and protein ligands such as growth factors and chemokines. Heparanase, the only known enzyme that can cleave the heparan sulfate (HS) side chains of HSPGs, regulates many cellular processes including ECM remodeling and homeostasis of cell-associated HS, and controls the bioavailability and activity of molecules attached to HS. The expression of heparanase is significantly elevated in almost all cancer types, and increased heparanase activity is mostly linked with increased angiogenesis, metastasis, and shortened post-surgery survival. Our research focuses on the development of molecular tools that can target and visualize the spatiotemporal activities of heparanase in both cells and living organisms. We have applied our molecular probes of heparanase towards cancer diagnostics and drug discovery. Citation Format: Lina Cui. Targeting an emerging oncogenic biomarker, heparanase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 329.
Efficacy of Portable Air Cleaners and Masking for Reducing Indoor Exposure to Simulated Exhaled SARS-CoV-2 Aerosols — United States, 2021
Authors: William G. Lindsley, Raymond C. Derk, Jayme P. Coyle, Stephen B. Martin, Kenneth R. Mead, Francoise M. Blachere, Donald H. Beezhold, John T. Brooks, Theresa Boots, John D. Noti
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

SARS-CoV-2, the virus that causes COVID-19, can be spread by exposure to droplets and aerosols of respiratory fluids that are released by infected persons when they cough, sing, talk, or exhale. To reduce indoor transmission of SARS-CoV-2 between persons, CDC recommends measures including physical distancing, universal masking (the use of face masks in public places by everyone who is not fully vaccinated), and increased room ventilation (1). Ventilation systems can be supplemented with portable high efficiency particulate air (HEPA) cleaners* to reduce the number of infectious particles in the air and provide enhanced protection from transmission between persons (2); two recent reports found that HEPA air cleaners in classrooms could reduce overall aerosol particle concentrations by ≥80% within 30 minutes (3,4). To investigate the effectiveness of portable HEPA air cleaners and universal masking at reducing exposure to exhaled aerosol particles, the investigation team used respiratory simulators to mimic a person with COVID-19 and other, uninfected persons in a conference room. The addition of two HEPA air cleaners that met the Environmental Protection Agency (EPA)-recommended clean air delivery rate (CADR) (5) reduced overall exposure to simulated exhaled aerosol particles by up to 65% without universal masking. Without the HEPA air cleaners, universal masking reduced the combined mean aerosol concentration by 72%. The combination of the two HEPA air cleaners and universal masking reduced overall exposure by up to 90%. The HEPA air cleaners were most effective when they were close to the aerosol source. These findings suggest that portable HEPA air cleaners can reduce exposure to SARS-CoV-2 aerosols in indoor environments, with greater reductions in exposure occurring when used in combination with universal masking.
Abstract 1036: Identification of Tofacitinib, Filgotinib and Ruxolitinib on experimental Sjögren's syndrome model in mice
Authors: Ruiqing Yan, Yanping Yuan, Chao Luo, Chuanzhi Yangmeng, Li Fang, Qing Lin
Journal: Cancer Research (2021)

Abstract Sjögren's syndrome, which is affected hundreds of millions of people worldwide, is a chronic autoimmune disorder characterized by leukocytic infiltration into the exocrine glands, such as the salivary and lacrimal glands. However, the pathological mechanism remains to be elucidated, and urgent need for the novel treatment should still meet. Over the past decades, an extensive progress has been made in establishment of Sjögren's syndrome model in mice, which offers us an invaluable tool to understand SjS pathogenesis and makes it possible to develop the novel drug and treatment. Here, we identified the potential effect of Tofacitinib, Filgotinib and Ruxolitinib on the experimental Sjögren's syndrome model in C57/B6L mice from both In-life study and ex-vivo study at the endpoint. Our data suggest that Tofacitinib, Filgotinib and Ruxolitinib, three JAK inhibtors exhibits the effect on reducing the severity of Sjögren's syndrome in mice, reduces autoantibodies producion and promotes the saliva secretion in mice, which also provides the direction of novel JAK inhibitor on treatment for Sjögren's syndrome. Citation Format: Ruiqing Yan, Yanping Yuan, Chao Luo, Chuanzhi Yangmeng, Li Fang, Qing Lin. Identification of Tofacitinib, Filgotinib and Ruxolitinib on experimental Sjögren's syndrome model in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1036.
A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma
Authors: Obada T Alhalabi, Michael N C Fletcher, Thomas Hielscher, Tobias Kessler, Tolga Lokumcu, Ulrich Baumgartner, Elena Wittmann, Silja Schlue, Mona Göttmann, Shaman Rahman, Ling Hai, Lea Hansen-Palmus, Laura Puccio, Ichiro Nakano, Christel Herold-Mende, Bryan W Day, Wolfgang Wick, Felix Sahm, Emma Phillips, Violaine Goidts
Journal: Neuro-Oncology (2021)

Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal, and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, have failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials.We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples.Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen-related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype.This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.
Abstract 3059: Heavy ion radiation exposure perturbs intestinal stem cell homeostasis and induces accelerated tumorigenesis in apc mutant mouse intestine
Authors: Santosh Kumar, Shubhankar Suman, Kamal Datta, Albert J. Fornace
Journal: Cancer Research (2021)

Abstract In a previous study, we demonstrated long-term decreased intestinal epithelial cell migration after low-dose heavy ion iron radiation, and this was associated with increased senescence-associated secretory phenotype (SASP) signaling. However, we know very little about the long-term effects of low dose space radiation on intestinal stem cell (ISC) senescence and SASP that have implications for intestinal homeostasis. Male Lgr5+ (Lgr5-EGFP-IRES-creERT) mice or Lgr5+/APC1638N/+ were exposed to 0.5 Gy of sham, γ-rays, or 28Si (69 keV/μm) radiation and were euthanized 60 or 150 days after irradiation. ISCs were FACS sorted for oxidative stress analysis and assessed for senescence and SASP signaling in tissue sections by immunostaining. Greater cellROX or mitoSOX staining was observed after 28Si indicating higher oxidative stress compared to γ-rays or control Lgr5 positive cells. β-gal co-staining with Lgr5, lysozyme, IL1R, or ILβ showed highest staining in 28Si irradiated compared to controls ISCs samples. γ-H2AX staining showed greater foci numbers in 28Si relative to γ-rays or control group. Higher expression of secretory cytokines IL8 and IL15 was observed in 28Si irradiated ISCs relative to γ-rays or control group at both time points. Elevated expression of DKK2 and activation of NF-κB and p38 MAPK were observed in senescent stem cells of 28Si irradiated relative to γ-rays or control group at these time points. A higher GI tumor count was observed in 28Si compared to γ-irradiated or control Lgr5+/APC1638N/+ mice. In summary, our results demonstrate low dose heavy ion exposure induces ongoing DNA damage, persistent oxidative stress, senescence and acquisition of the SASP in ISCs. Higher levels of oxidative stress, senescence and SASP were observed at 150 compared to the 60-day timepoint. Overall, space radiation-induced oxidative stress, senescence, SASP, and activated p38MAPK/NF-κB pathway may very well have implications in GI carcinogenesis, accelerated aging, and pathological conditions, such as intestinal dysfunction, in astronauts during deep space flights. Since similar effects have been seen in our studies with other particle beams including carbon ions, this has potential relevance to particle radiotherapy as well. This work was supported by NASA NNX15AI21G Citation Format: Santosh Kumar, Shubhankar Suman, Kamal Datta, Albert J. Fornace. Heavy ion radiation exposure perturbs intestinal stem cell homeostasis and induces accelerated tumorigenesis in apc mutant mouse intestine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3059.
Prognostic value of the systemic immune-inflammation index in non-muscle invasive bladder carcinoma
Authors: S. Katayama, K. Mori, E. Laukhtina, V.M. Schuettfort, B. Pradere, F. Quhal, R. Sari Motlagh, H. Mostafaei, N.C. Grossmann, S. Egawa, Y. Nasu, S.F. Shariat
Journal: European Urology (2021)
Mistranslation Reduces Mutation Load in Evolving Proteins through Negative Epistasis with DNA Mutations
Authors: Jia Zheng, Ning Guo, Andreas Wagner
Journal: Molecular Biology and Evolution (2021)

Abstract Translational errors during protein synthesis cause phenotypic mutations that are several orders of magnitude more frequent than DNA mutations. Such phenotypic mutations may affect adaptive evolution through their interactions with DNA mutations. To study how mistranslation may affect the adaptive evolution of evolving proteins, we evolved populations of green fluorescent protein (GFP) in either high-mistranslation or low-mistranslation Escherichia coli hosts. In both hosts, we first evolved GFP under purifying selection for the ancestral phenotype green fluorescence, and then under directional selection toward the new phenotype yellow fluorescence. High-mistranslation populations evolved modestly higher yellow fluorescence during each generation of evolution than low-mistranslation populations. We demonstrate by high-throughput sequencing that elevated mistranslation reduced the accumulation of deleterious DNA mutations under both purifying and directional selection. It did so by amplifying the fitness effects of deleterious DNA mutations through negative epistasis with phenotypic mutations. In contrast, mistranslation did not affect the incidence of beneficial mutations. Our findings show that phenotypic mutations interact epistatically with DNA mutations. By reducing a population’s mutation load, mistranslation can affect an important determinant of evolvability.
Parkinson's Disease Genetics and Pathophysiology
Authors: Gabriel E. Vázquez-Vélez, Huda Y. Zoghbi
Journal: Annual Review of Neuroscience (2021)

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.
Asymptomatic and Symptomatic COVID-19 Infections Among Health Care Personnel Before and After Vaccination
Authors: Shruti K. Gohil, Keith Olenslager, Kathleen A. Quan, Cyrus K. Dastur, Nasim Afsar, Wayne Chang, Susan S. Huang
Journal: JAMA Network Open (2021)

Any positive Positive, true asymptomaticMost health care personnel who tested positive using the asymptomatic testing pathway reported symptoms consistent with COVID-19 (81% [34 of 42]).Asymptomatic cases declined to 0 after vaccination.
Abstract 2818: In vivo imaging of mitochondrial bioenergetics in lung cancer
Authors: Mingqi Han, Milica Momcilovic, Eric Bushong, Linsey Stiles, Orian Shirihai, Carla Koehler, Saman Sadeghi, Mark Ellisman, David B. Shackelford
Journal: Cancer Research (2021)

Abstract Non-small cell lung cancer (NSCLC) is a histologically, genetically and metabolically heterogeneous disease. The mitochondria are essential regulators of cellular energy and metabolism and they play a critical role in sustaining growth and survival of lung tumor cells. However, our understanding of mitochondrial metabolism in cancer at an in vivo level has been limited thus leaving a large gap in our knowledge of how mitochondrial bioenergetics support tumor growth. To better study mitochondrial bioenergetics in lung tumors, we recently developed and validated a voltage sensitive, positron emission tomography (PET) tracer known as 4-[18F]fluorobenzyl triphenylphosphonium (18FBnTP) that we used to profile mitochondrial bioenergetics in autochthonous K-Ras driven mouse models of lung cancer (Momcilovic et al., (2019) Nature). The use of 18FBnTP PET imaging enabled us to functionally profile mitochondrial bioenergetics in live tumors and discover distinct functional mitochondrial heterogeneity conserved across different NSCLC tumor subtypes. In order to study mitochondria at the level of ultrastructure we coupled 18FBnTP PET with 3D serial block-face scanning electron microscopy (3D SBEM). By coupling these two techniques we are able to image and quantify mitochondria heterogeneity from whole tumors down to the ultrastructures of individual mitochondria within tumor cells. Our study reveals distinct organization of mitochondrial structure and function as lung tumors adapt during tumorigenesis. We anticipate that coupling 18FBnTP PET imaging with 3D SBEM will have dynamic applications beyond that of lung cancer and enrich our understanding how mitochondria impact human disease. Citation Format: Mingqi Han, Milica Momcilovic, Eric Bushong, Linsey Stiles, Orian Shirihai, Carla Koehler, Saman Sadeghi, Mark Ellisman, David B. Shackelford. In vivo imaging of mitochondrial bioenergetics in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2818.
Abstract 1622: Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression
Authors: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides
Journal: Cancer Research (2021)

Abstract Rituximab is a CD20-targeting antibody that is the standard-of-care for patients with Non-Hodgkin Lymphoma (NHL) cases. Rituximab's mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) - herein referred to as Humoral Immuno-Oncology (HIO) mechanism. Recent clinical evidence suggest that high serum levels of the tumor-produced MUC16/CA125 protein has a negative impact on the effectiveness of rituximab clinical activity on up to 40% of follicular lymphoma patients. In this study we demonstrate that CA125 binds to rituximab and reduces its tumor cell killing activity. Moreover, we describe the generation of a rituximab variant, named NAV-006, using a proprietary technology called Block-Removed Immunoglobulin Technology (BRITE) that employs randomized amino substitution and high-throughput screening to identify HIO-refractory rituximab variants. Here, we demonstrate that NAV-006 is more refractory to the immunosuppressive effects mediated by CA125 as shown by its reduced CA125 interaction and increased HIO activity. These data warrants further investigation of NAV-006 as a next generation anti-CD20 antibody that could improve upon the efficacy of the parent rituximab in NHL patients with high levels of CA125. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1622.