tbuckley/cabot-search huggingface dataset:
Abstract IA23: Single cell-resolution lineage tracing of tumors in a mouse xenograft model reveals rapid and multidirectional metastasis
Authors: Jonathan S. Weissman
Journal: Cancer Research (2020)

Abstract The pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale, single-cell lineage tracing exploration of the phylogenetic principles that govern important biologic processes at unprecedented resolution and scale. We recently described a flexible, high-information, multichannel molecular recorder with a single-cell readout and applied it as an evolving lineage tracer to define a mouse cell fate map from fertilization through gastrulation. In the present study, we now apply our Cas9-based lineage tracer to investigate metastatic progression in a lung cancer xenograft model in mouse. We describe &amp;gt;100 single cell-resolution phylogenies for tens of thousands of cancer cells from multiple tumors, and we observe a wide range of clade-specific behaviors. From these family trees, we infer the number of ancestral metastatic events and thus calculate the metastatic potential for every population, the frequency of metastasis, and the tissue routes through which metastases transit. We overlay single-cell transcriptomic signatures on the phylogenies and find distinct clone- or clade-specific expression signatures that correlate with metastatic potential, highlighting the diversity of cancer phenotypes even within this single xenograft model. We illustrate numerous examples of complex, multidirectional metastatic architectures, including self-seeding, monoclonal seeding, and seeding cascades. More generally, our approach provides an unprecedented ability to monitor tumor formation, evolution, growth, and spread in an in vivo setting. Citation Format: Jonathan S. Weissman. Single cell-resolution lineage tracing of tumors in a mouse xenograft model reveals rapid and multidirectional metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA23.
The Correlation of Salivary Gland Uptake Between 18F-FP-CIT PET/CT and Salivary Scan
Authors: Seo Young Kang, Ji Young Yun, Hye Ok Kim, Byung Seok Moon, Hai-Jeon Yoon, Bom Sahn Kim
Journal: Clinical Nuclear Medicine (2020)

Abstract An 85-year-old woman visited our hospital with repetitive diarrhea, nausea, and anorexia, as well as aggressive behavior. The neurologist decided to perform dopamine transporter imaging ( 18 F-FP-CIT PET/CT) for accurate diagnosis, taking into account the potential adverse effects of l -dopa that the patient had been taking for a long time. The uptake of dopamine transporter in the bilateral basal ganglia was well preserved, but reduced uptake in the left parotid gland was incidentally detected. A subsequent salivary scan showed reduced uptake in the left parotid gland with the same pattern as that on 18 F-FP-CIT PET/CT.
Abstract 13385: Impact of Respiratory Exchange Ratio on Prognostic Power of Peak Oxygen Consumption in Adults With Fontan Circulation
Authors: Jianli Niu, Aliana Godoy, Bibhuti B Das
Journal: Circulation (2019)

Objectives: Peak oxygen consumption (pVO2) is a powerful predictor of prognosis in patients with acquired heart failure, but the implication in patients with Fontan circulation remains uncertain. W...
Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome
Authors: Wei-Yuan Hsieh, Quan D. Zhou, Autumn G. York, Kevin J. Williams, Philip O. Scumpia, Eliza B. Kronenberger, Xen Ping Hoi, Baolong Su, Xun Chi, Viet L. Bui, Elvira Khialeeva, Amber Kaplan, Young Min Son, Ajit S. Divakaruni, Jie Sun, Stephen T. Smale, Richard A. Flavell, Steven J. Bensinger
Journal: Cell Metabolism (2020)
Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice
Authors: Ying Tan, Fu Hang, Zhong-Wu Liu, Milan Stoiljkovic, Mingxing Wu, Yue Tu, Wenfei Han, Angela M. Lee, Craig Kelley, Mihály Hajós, Lingeng Lu, Luis de Lecea, Ivan De Araujo, Marina R. Picciotto, Tamas L. Horvath, Xiao-Bing Gao
Journal: Journal of Clinical Investigation (2020)

The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking, and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress-coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seeking, and altered stress response) in obese animals.
Man, 34, who didn’t want to live with stoma should be allowed to die, says judge
Authors: Clare Dyer
Journal: BMJ (2020)

A 34 year old man should have artificial feeding and hydration withdrawn because he would not have wanted to live with an irreversible stoma, a High Court judge has ruled.1

The man, referred to as MSP, drew up an advance decision stating that he would not want to be kept alive with a stoma that had less than a 50% chance of reversibility, but the document was not binding because he had failed to get two witnesses to his signature.

As a result the Court of Protection had to decide whether it was in MSP’s best interests for Barnsley Hospital NHS Foundation Trust to withdraw artificial feeding and allow him to die with palliative care.

At a virtual hearing, which the clinical lead for …
Abstract PHA05: Strategies to improve engineering cancer-associated SNVs with base editing
Authors: Alyna Katti, Miguel Foronda, Jill Zimmerman, Bianca Diaz, Maria Paz Zafra, Sukanya Goswami, Elena Piskounova, Lukas E. Dow
Journal: Cancer Research (2020)

Abstract Base editing (BE) is a powerful tool for engineering single-nucleotide variants (SNVs) and has been used to create targeted mutations in cell lines, organoids, and animal models. Recent development of new BE enzymes has provided an extensive toolkit for genome modification; however, unlike Cas9, which shows remarkable efficacy in creating homozygous disruptive mutations following DNA double-strand breaks (DSBs), BE is relatively inefficient and identifying and isolating edited cells for analysis has proved challenging. To enable simple identification and enrichment of base editing events, we developed a “Gene On” (GO) reporter system that indicates precise cytosine or adenine base editing in situ with high sensitivity and specificity. We validate GO using an activatable GFP and use it to measure the kinetics, efficiency, PAM specificity, and fidelity of a range of new BE variants. Further, GO is flexible and can be easily adapted to induce expression of numerous genetically encoded markers, antibiotic resistance genes, or enzymes such as Cre recombinase. With these tools, GO can be exploited to functionally link BE events at endogenous genomic loci to cellular enzymatic activities in human and mouse cell lines and organoids. We further demonstrate the application of GO in detecting in vivo BE activity using a newly generated mouse model with inducible and reversible base editor expression that will enable generation of novel cancer models in vivo. GO provides a powerful approach to increase the practicality and feasibility of implementing CRISPR BE in biomedical research. This abstract is also being presented as Poster A45. Citation Format: Alyna Katti, Miguel Foronda, Jill Zimmerman, Bianca Diaz, Maria Paz Zafra, Sukanya Goswami, Elena Piskounova, Lukas E. Dow. Strategies to improve engineering cancer-associated SNVs with base editing [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA05.
Abstract B28: Development and validation of a novel organotypic in vitro model of the tumor-lymph-immune interface for predicting immunotherapy resistance
Authors: Ruolan Zhou, Rachel Weathered, Trevin Kurtanich, Renata Mezyk-Kopec, Aslan Mansurov, Jeffrey Hubbell, Melody A. Swartz
Journal: Cancer Research (2020)

Abstract Tumor-associated lymphatics and their connection to the tumor-draining lymph node (TdLN) play important roles in cancer metastasis as well as in modulating the tumor immune microenvironment. They bathe the TdLN in cytokines, exosomes, antigens, and suppressive factors from the tumor microenvironment (TME) to alter the antitumor immune response. Such interactions are complex and difficult to study in vivo, yet currently they cannot be readily explored in vitro either. To address this need, we developed a novel in vitro model system of the tumor-lympho-immune (TLI) circuit. These in vitro ”avatars,” dubbed TLI-Ivatars, can sustain ex vivo cocultures of tumors and their TdLNs in a parallelized format, within perfused 3D matrices and communicating channels in a flexible manner. The TLI-Ivatar platform has been shown to sustain long-term cultures (&amp;gt; 3 weeks) of a number of tumor cell lines, which form complex architectures reminiscent of actual tumors, as well as of ex vivo tumor tissue. It also supports the function and viability of immune cells (such as T lymphocytes and dendritic cells) and stromal cells (such as lymphatic endothelial cells and fibroblasts). To validate the modeling of the crosstalk between the tumor and TdLN, we demonstrate that TLI-Ivatar can faithfully recapitulate major in vivo immunotherapy responses with the B16 melanoma model, including (i) dampened cytotoxic T-cell function in tumor-conditioned tdLNs, (ii) enhanced tumor invasion to TdLN of lymphangiogenic (and more metastatic) tumors (compared to the TdLN of non-lymphangiogenic tumors), and (iii) immunotherapy potentiation by factors known to enhance immunotherapy efficacy in vivo, such as lymphangiogenic growth factors and matrix-binding immunomodulatory cytokines. Together, these data highlight the potential of TLI-Ivatar for long-term study of the complex tumor-host cell interplay in TME to gain mechanistic insight and pave the way for patient-specific screening of cancer immunotherapy. Citation Format: Ruolan Zhou, Rachel Weathered, Trevin Kurtanich, Renata Mezyk-Kopec, Aslan Mansurov, Jeffrey Hubbell, Melody A. Swartz. Development and validation of a novel organotypic in vitro model of the tumor-lymph-immune interface for predicting immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B28.
Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1
Authors: Rodrigo Romero, Francisco J. Sánchez-Rivera, Peter M. K. Westcott, Kim L. Mercer, Arjun Bhutkar, Alexander Muir, Tania J. González Robles, Swanny Lamboy Rodríguez, Laura Z. Liao, Sheng Rong Ng, Leanne Li, Caterina I. Colón, Santiago Naranjo, Mary Clare Beytagh, Caroline A. Lewis, Peggy P. Hsu, Roderick T. Bronson, Matthew G. Vander Heiden, Tyler Jacks
Journal: Nature Cancer (2020)
High and Highly Variable Spontaneous Mutation Rates in <i>Daphnia</i>
Authors: Eddie K H Ho, Fenner Macrae, Leigh C Latta, Peter McIlroy, Dieter Ebert, Peter D Fields, Maia J Benner, Sarah Schaack
Journal: Molecular Biology and Evolution (2020)

The rate and spectrum of spontaneous mutations are critical parameters in basic and applied biology because they dictate the pace and character of genetic variation introduced into populations, which is a prerequisite for evolution. We use a mutation-accumulation approach to estimate mutation parameters from whole-genome sequence data from multiple genotypes from multiple populations of Daphnia magna, an ecological and evolutionary model system. We report extremely high base substitution mutation rates (µ-n,bs = 8.96 × 10-9/bp/generation [95% CI: 6.66-11.97 × 10-9/bp/generation] in the nuclear genome and µ-m,bs = 8.7 × 10-7/bp/generation [95% CI: 4.40-15.12 × 10-7/bp/generation] in the mtDNA), the highest of any eukaryote examined using this approach. Levels of intraspecific variation based on the range of estimates from the nine genotypes collected from three populations (Finland, Germany, and Israel) span 1 and 3 orders of magnitude, respectively, resulting in up to a ∼300-fold difference in rates among genomic partitions within the same lineage. In contrast, mutation spectra exhibit very consistent patterns across genotypes and populations, suggesting the mechanisms underlying the mutational process may be similar, even when the rates at which they occur differ. We discuss the implications of high levels of intraspecific variation in rates, the importance of estimating gene conversion rates using a mutation-accumulation approach, and the interacting factors influencing the evolution of mutation parameters. Our findings deepen our knowledge about mutation and provide both challenges to and support for current theories aimed at explaining the evolution of the mutation rate, as a trait, across taxa.
First antibody against COVID-19 spike protein enters phase I
Authors: Asher Mullard
Journal: Nature Reviews Drug Discovery (2020)

Vaccine developers have advanced ten COVID-19 candidates into the clinic, less than 6 months since the SARS-CoV-2 virus was first sequenced.Leading candidates include an adenovirus-based candidate that is in a phase IIb/III trial and an mRNA vaccine that is in a phase II trial.The University of Oxford and AstraZeneca's AZD1222, currently the most advanced COVID-19 vaccine candidate, consists of a chimpanzee adenovirus vector that has been engineered to carry the SARS-CoV-2 spike protein.Investigators hope that this vaccine will train the immune system to generate neutralizing antibodies against the spike protein, which the virus uses to bind and enter human cells.The immunogenic properties of the adenovirus vector could boost the potency of this approach.A 10,000-volunteer phase IIb/III trial is already underway in the UK, and a
FRI0432 INTEREST OF IMAGING IN THE DIAGNOSIS OF INFECTIOUS SPONDYLODISCITIS (ABOUT 113 CASES)
Authors: L. Ben Ammar, A. Ben Tekaya, M. Ben Hammamia, O. Saidane, S. Bouden, R. Tekaya, I. Mahmoud, L. Abdelmoula
Journal: Annals of the Rheumatic Diseases (2020)

Background: Infectious spondylodiscitis is a diagnosis and therapeutic emergency. Its clinical presentation can be insidious and standard radiographs can be falsely reassuring. This explains the interest of cross-sectional imaging and more particularly magnetic resonance imaging (MRI). Objectives: To analyse the contribution of imaging in the diagnosis of infectious spondylodiscitis. Methods: These are 113 cases of spondylodiscitis collected in a rheumatology department over a period of 20 years [1998-2018]. The diagnosis is made on the basis of clinical, biological, radiological and bacteriological data. Results: Our population was divided into 62 men (54.9%) and 51 women (45.1%) (p = 0.8) with an average age of 55 years [16–86]. Predisposing factors were found in 52.2% of cases: diabetes (23%), neoplasia (2.7%), hepathopathy (5.3%), long-term corticosteroid therapy (1.8), recent surgery (3.5%), history of tuberculosis (2.7%) and consumption of unpasteurized dairy products (28.3%). The approximate time between onset of symptoms and diagnosis ranged from 0.23 to 24 months (median 3 months). Impaired general condition was observed in 81% of the cases and fever in 34.5% of the cases. Radiculalgia was found in 46% of the cases and a neurological deficit was noted in 16% of the cases. Biological inflammatory syndrome was found in 91.2% of the cases. Standard radiographs of the spine were abnormal in 85% of cases, showing disc space narrowing (72%), irregularity of the vertebral plates (35.5%), erosions (13.1%) and para-vertebral spindle (4.7%). CT and spinal MRI were performed respectively in 57.5% and 70.8% of cases and revealed: erosions (46.2%), mirrored geodes (16.9%), para-vertebral abscess (57.5%), epiduritis (71.3%) and spinal compression (26.3%). The lumbar spine was the most affected (55.8%), followed by the dorsal spine (30.1%) and the cervical spine (8.8%). The Infectious spondylodiscitis was multifocal in 24.8% and multi-stage in 12.4% of cases. A disco-vertebral biopsy was performed in 70% of cases and was contributory in 44.3% of cases. The causative organism was tuberculosis in 55.8% of cases, brucellosis in 21.2% of cases and pyogenic germs in 23% of cases. Conclusion: Imaging plays an important role in the diagnosis of spondylodiscitis. MRI is considered the key examination, capable of mapping injuries and detecting potentially serious neurological complications. The importance of imaging the entire spine to detect multifocal forms should also be emphasized. Disclosure of Interests: None declared
Clinical impact of multi-parameter continuous non-invasive monitoring in hospital wards: a systematic review and meta-analysis
Authors: Lin Sun, Meera Joshi, Sadia N Khan, Hutan Ashrafian, Ara Darzi
Journal: Journal of the Royal Society of Medicine (2020)

Objective Delayed response to clinical deterioration as a result of intermittent vital sign monitoring is a cause of preventable morbidity and mortality. This review focuses on the clinical impact of multi-parameter continuous non-invasive monitoring of vital signs (CoNiM) in non-intensive care unit patients. Design Systematic review and meta-analysis of primary studies. Embase, MEDLINE, HMIC, PsycINFO and Cochrane were searched from April 1964 to 18 June 2019 with no language restriction. Setting The search was limited to hospitalised, non-intensive care unit adult patients who had two or more vital signs continuously monitored. Participants All primary studies that evaluated the clinical impact of using multi-parameter CoNiM in adult hospital wards outside of the intensive care unit. Main outcome measures Clinical impact of multi-parameter CoNiM. Results This systematic review identified 14 relevant studies from 3846 search results. Five studies were classified as Group A – associations found between measured vital signs and clinical parameters. Nine studies were classified as Group B – comparison between clinical outcomes of patients with and without multi-parameter CoNiM. Vital signs data from CoNiM were found to associate with type of presenting complaint, level of renal function and incidence of major clinical events. CoNiM also assisted in diagnosis by differentiating between patients with acute heart failure, stroke and sepsis (with sub-clustering of septic patients). In the meta-analysis, patients on multi-parameter CoNiM had a 39% decrease in risk of mortality (risk ratio [RR] 0.61; 95% confidence interval [95% CI] 0.39, 0.95) when compared to patients with regular intermittent monitoring. There was a trend of reduced intensive care unit transfer (RR 0.86; 95% CI 0.67, 1.11) and reduced rapid response team activation (RR 0.61; 95% CI 0.26–1.43). A trend towards reduced hospital length of stay was also found using weighted mean difference (WMD –3.32 days; 95% CI -8.82–2.19 days). Conclusion There is evidence of clinical benefit in implementing CoNiM in non-intensive care unit patients. This review supports the use of multi-parameter CoNiM outside of intensive care unit with further large-scale RCTs required to further affirm clinical impact.
FRI0560 INCREASED RISK OF RHEUMATOID ARTHRITIS DIAGNOSIS IN STATIN USERS IN A LARGE NATIONWIDE US STUDY
Authors: M. Peterson, H. J. Dykhoff, C. S. Crowson, J. M. Davis III, L. Sangaralingham, E. Myasoedova
Journal: Annals of the Rheumatic Diseases (2020)

Background: Studies evaluating the effect of statin use on the risk of rheumatoid arthritis (RA) onset have shown conflicting results. Most of these studies evaluated European populations while data from the US are scarce. Objectives: We aimed to assess the association between statin use (and intensity) and RA occurrence using claims data from the US population. Methods: For this case-control study, we used the OptumLabs Data Warehouse, a large administrative database of commercially insured and Medicare Advantage beneficiaries, to identify cases of RA and matched controls. Cases were defined as patients with 2 or more diagnoses of RA in January 1, 2010 - June 30, 2019 who were ≥18 years old, filled ≥1 prescription for a conventional or biologic disease modifying anti-rheumatic drug, and had no diagnoses of RA during the prior year. Controls were persons without RA matched 1:1 to RA cases on age, sex, census region, calendar year of index date (corresponding to the date of second diagnosis code for RA), and length of prior medical/pharmacy coverage. Statin use was defined as any filled prescription for a statin medication during prior coverage (excluding any new statin prescriptions filled up to 90 days before first RA diagnosis or index date). Logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (CI) adjusted for age, sex, race, census region, calendar year and Charlson comorbidity index (excluding RA component). Results: The study included 32,465 cases with RA (mean age 57.0, 72.2% female) and 32,465 matched controls (mean age 57.0, 72.2% female). There were 10,759 (33.1%) statin users among RA patients and 4,016 (12.4%) statin users among the matched controls. Statin use was associated with increased risk of RA (adjusted OR 3.34, 95%CI 3.19-3.49). All levels of statin intensity were associated with increased risk of RA (high OR: 3.60, 95% CI 3.28-3.94; medium OR: 3.20, 95% CI 3.04-3.37; low OR: 3.72, 95% CI 3.34-4.15) compared to non-users. Both former and current statin users showed an increased risk of RA (current OR: 3.04, 95% CI 2.80-3.30 and former OR: 3.37, 95% CI 3.20-3.54) compared to non-users. Conclusion: This large nationwide study showed increased risk of RA in statin-users vs non-users. The lack of dose dependence may suggest confounding by indication or a common genetic predisposition for cardiovascular disease and RA. The underlying mechanisms for these associations require further investigation. Disclosure of Interests: Madeline Peterson: None declared, Hayley J. Dykhoff: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, John M Davis III Grant/research support from: Research grants from Pfizer, Consultant of: Served on advisory boards for Abbvie and Sanofi-Genzyme, Lindsey Sangaralingham: None declared, Elena Myasoedova: None declared