tbuckley/cabot-search huggingface dataset:
Abstract 2278: CTLA-4 targeted engineered toxin bodies designed to deplete regulatory T cells (Tregs)
Authors: Aimee Iberg, Edith Acquaye-Seedah, Lilia A. Rabia, Garrett L. Robinson, Hilario J. Ramos, Joseph D. Dekker, Jay Zhao, Erin K. Willert
Journal: Cancer Research (2020)

Abstract Tumor resident regulatory T cells (Tregs) are important mediators of an immunosuppressive tumor microenvironment (TME) promoting tumor immune evasion. The presence of Tregs, and a higher ratio of Tregs to effector T cells in the TME, are associated with poor prognosis. The depletion of Tregs in the TME is expected to re-expose the tumor to the immune system to allow for tumor control. CLTA-4 is expressed on the cell surface of Tregs and is a clinically validated target. Better responses to CTLA-4 monoclonal antibody (mAb) treatment are correlated with stronger ADCC-mediated Treg depletion in preclinical models, and patient FcγR polymorphism has been reported to correlate with response to CTLA-4 mAb therapy. Towards improving on current therapies, many efforts to increase effective depletion of Tregs (such as by Fc effector modification) are being pursued. Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Targeted ETBs are being developed to specifically target and destroy CTLA-4 expressing cells. In vitro, cells expressing CTLA-4 are effectively and specifically killed by targeted ETBs. This direct cell kill activity of the ETB has the potential to deplete Tregs in the TME without a requirement for ADCC mechanisms. ETBs have been designed to bind various CTLA-4 epitopes, and to comprise of different targeting domains formats, including monomeric and diabody single chain variable fragments (scFvs) as well as single domain and biparatopic antibody fragments. The development of a CTLA-4 targeted ETB is ongoing. The entry of a protein with direct cell kill properties into the therapeutic space represents a differentiated mechanism of action to deplete Tregs for ultimate re-invigoration of the anti-tumor immune response, and has the potential to provide benefit to patients, including in the relapsed or refractory setting. Citation Format: Aimee Iberg, Edith Acquaye-Seedah, Lilia A. Rabia, Garrett L. Robinson, Hilario J. Ramos, Joseph D. Dekker, Jay Zhao, Erin K. Willert. CTLA-4 targeted engineered toxin bodies designed to deplete regulatory T cells (Tregs) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2278.
RNA Aptamers Deliver Chemotherapy Directly to Tumors
Authors: Tracy Hampton
Journal: JAMA (2020)

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Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.<i>Fas</i><sup>lpr</sup> mice
Authors: Hong Kyung Lee, Hyung Sook Kim, Minji Pyo, Eun Jae Park, Sundong Jang, Hye Won Jun, Tae Yong Lee, Kyung Suk Kim, Sang-Cheol Bae, Youngsoo Kim, Jin Tae Hong, Jaesuk Yun, Sang-Bae Han
Journal: Theranostics (2020)

Rationale: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) ameliorate lupus symptoms by inhibiting T cells, whether they inhibit B cells has been controversial. Here we address this issue and reveal how to prime MSCs to inhibit B cells and improve the efficacy of MSCs in SLE. Methods: We examined the effect of MSCs on purified B cells in vitro and the therapeutic efficacy of MSCs in lupus-prone MRL.Faslpr mice. We screened chemicals for their ability to activate MSCs to inhibit B cells. Results: Mouse bone marrow-derived MSCs inhibited mouse B cells in a CXCL12-dependent manner, whereas human bone marrow-derived MSCs (hMSCs) did not inhibit human B (hB) cells. We used a chemical approach to overcome this hurdle and found that phorbol myristate acetate (PMA), phorbol 12,13-dibutyrate, and ingenol-3-angelate rendered hMSCs capable of inhibiting IgM production by hB cells. As to the mechanism, PMA-primed hMSCs attracted hB cells in a CXCL10-dependent manner and induced hB cell apoptosis in a PD-L1-dependent manner. Finally, we showed that PMA-primed hMSCs were better than naïve hMSCs at ameliorating SLE progression in MRL.Faslpr mice. Conclusion: Taken together, our data demonstrate that phorbol esters might be good tool compounds to activate MSCs to inhibit B cells and suggest that our chemical approach might allow for improvements in the therapeutic efficacy of hMSCs in SLE.
NO INCREASE IN INTRAHEPATIC MONONUCLEAR CELL OR STELLATE CELL ACTIVATION IN HIV-HBV CO-INFECTED INDIVIDUALS WITH ADVANCED HIV AND MILD LIVER DISEASE
Authors: David M Iser, Alison J Boyd, Anchalee Avihingsanon, Alex L Thompson, Tin Nguyen, Gail Matthews, Scott Bowden, Stephen Locarnini, John Slavin, Paul V Desmond, Gregory J Dore, Kiat Ruxrungtham, Sharon R Lewin
Journal: Hepatology (2009)
シナプス伝達のセロトニン抑制:Gα 0 によるリリース・サイトにおけるUNC-13の存在量の減少 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Nurrish S, Segalat L, Kaplan J M
Journal: Neuron (1999)
Correction: Common variant burden contributes to the familial aggregation of migraine in 1,589 families
Authors: Padhraig Gormley, Mitja Kurki, Marjo Eveliina Hiekkala, Kumar Veerapen, Paavo Häppölä, Adele A. Mitchell, Dennis Lal, Priit Palta, Ida Surakka, Eija Hamalainen, Salli Vepsäläinen, Hannele Havanka, Hanna Harno, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja Liisa Sumelahti, Jarmo Liukkonen, Matti Sillanpää, Liisa Metsähonkala, Seppo Koskinen, Terho Lehtimäki, Olli Raitakari, Minna Männikkö, Caroline Ran, Pekka Jousilahti, Verneri Anttila, Veikko Salomaa, Ville Artto, Markus Färkkilä, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nick Furlotte, Karen E. Huber, Aaron Kleinman, Nadia Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson, Andrea Carmine Belin, Dorret I. Boomsma, Sigrid Børte, Daniel I. Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann Louise Esserlind, Michel D. Ferrari, Rune R. Frants, Tobias Freilinger, Lyn Griffiths, Thomas Folkmann Hansen, M. Arfan Ikram, Andres Ingason, Marjo Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Tobias Kurth, Lenore Launer, Davor Lessel, Lannie Ligthart, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M. Neale, Carrie Northover, Dale R. Nyholt, Jes Olesen, Aarno Palotie, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S. Winsvold, William Wrenthal, Huiying Zhao, John Anker Zwart, Heiko Runz, Mark J. Daly, Samuli Ripatti
Journal: Neuron (2018)
Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of <i>CTNNB1</i> Mutational Status
Authors: Olivier Mir, Charles Honoré, Ali N. Chamseddine, Julien Dômont, Sarah N. Dumont, Andrea Cavalcanti, Matthieu Faron, Françoise Rimareix, Leila Haddag-Miliani, Cécile Le Péchoux, Antonin Levy, Charles Court, Sylvain Briand, Elie Fadel, Olaf Mercier, Arnaud Bayle, Anaïs Brunet, Carine Ngo, Etienne Rouleau, Julien Adam, Axel Le Cesne
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments. Experimental Design: We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included. Results: From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06–4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23–6.27; P = 0.04). Toxicity profile was favorable, without grade 3–4 toxicity, except for one grade 3 neutropenia. Conclusions: Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.
COVID-19 and Children With Diabetes—Updates, Unknowns, and Next Steps: First, Do No Extrapolation
Authors: Linda A. DiMeglio, Anastasia Albanese-O’Neill, Cynthia E. Muñoz, David M. Maahs
Journal: Diabetes Care (2020)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide pandemic has been devastating particularly for older adults and those from vulnerable groups, including racial and ethnic minority populations. Additionally, people with certain underlying medical conditions, including diabetes, are also at increased risk of severe illness from coronavirus disease 2019 (COVID-19) (1,2). Some children experience significant disease (3), and pediatric deaths have been reported (4). Because “diabetes” (generally grouping together type 1 diabetes and type 2 diabetes) and chronically elevated hyperglycemia have been associated with worse outcomes in adults with COVID-19 (5), the pediatric community has voiced great concerns about risk and outcomes for children with diabetes.

A foundation of pediatrics is caution about the extrapolation of adult practice to children. Many publications report poor outcomes from COVID-19 and diabetes without emphasizing that data reported are from adults, frequently older adults with additional comorbidities. Moreover, there have been warnings related to COVID-19 and immunosuppression leading to confusion, predominately outside the medical community, about the difference between immunocompromised and autoimmune. In sum, these worries have led to increases in frequency and severity of diabetic ketoacidosis (DKA), due in part to families being reluctant to enter health care settings, especially in areas where COVID-19 cases cluster (6,7).

Data scarcity regarding many aspects of how COVID-19 is affecting children with both new-onset and established diabetes has magnified these concerns. In this issue of Diabetes Care , Rabbone et al. (8) describe cross-sectional data from Italy, an early pandemic epicenter. This team examined diabetes diagnoses as well as reports of DKA and SARS-CoV-2 infection in children with new-onset and established type 1 diabetes from 20 February to 14 April 2020. They compare data on new presentations and DKA rates to data from the same period in 2019. They report …
Abstract B62: Integrating highly-multiplexed imaging with multi-omics data to uncover immunologic vulnerabilities in high-grade serous ovarian cancer
Authors: Miikka K. Kilkkila, Julia Casado, Connor Jacobson, Antti Hakkinen, Erdogan Erkai, Jun Dai, Kaiyang Zhan, Zoltan Maliga, Olli Carpen, Rainer Lehtonen, Sampsa Hautaniemi, Peter Sorger, Anna Vaharautio, Anniina Farkkila
Journal: Clinical Cancer Research (2020)

Abstract A key event in cancer progression is the establishment of an immunosuppressive environment that prevents the immune system from effectively attacking the cancer cells. In this study we aim to characterize the cellular determinants and the spatial features of immune suppressive mechanisms in high-grade serous ovarian cancer (HGSOC) via integrating tissue Cyclic Immunofluorescence (tCycIF), a novel highly multiplexed single-cell spatial proteomics platform with multi-omics data, including state-of-the-art single-cell RNA sequencing. We have conducted a comprehensive analysis of a unique dataset consisting of 23 HGSOC samples, including 7 pairs of treatment-naïve and post-chemotherapy samples, using tCycIF, single-cell, and bulk RNA sequencing coupled with novel deconvolution algorithms and whole-genome sequencing. All samples were prospectively collected from patients treated at Turku University Hospital, Finland, as a part of the HERCULES consortium. Our preliminary findings suggest that tCycIF can reliably capture tumor microenvironment composition in HGSOC. Overall, there was a good correlation with tumor purity between all the methods used. In tCycIF, scRNAseq and bulk deconvolution macrophages were the most common immune cell type in the HGSOC microenvironment. However, specific immune subpopulations, such as CD8+T-cells, had a larger proportion in tCycIF compared to single-cell RNA sequencing and bulk-deconvoluted RNAseq data. Further, the immune profiling based on RNAseq deconvolution algorithm showed highly variable results based on the algorithm used. We are in the process of using our complete dataset to compare state-of-the-art methods and improve algorithms for HGSOC immunophenotyping. tCycIF’s spatial proteomic data in single-cell resolution allows us to gain new insights into the tumor microenvironment and discover the previously latent cell-to-cell interactions that make up the immunosuppressive milieus in HGSOC tumors. The improvement of novel reliable single-cell immunophenotyping methods is critical to develop more effective immunotherapies to improve the outcomes and survival of patients with HGSOC. Citation Format: Miikka K. Kilkkila, Julia Casado, Connor Jacobson, Antti Hakkinen, Erdogan Erkai, Jun Dai, Kaiyang Zhan, Zoltan Maliga, Olli Carpen, Rainer Lehtonen, Sampsa Hautaniemi, Peter Sorger, Anna Vaharautio, Anniina Farkkila. Integrating highly-multiplexed imaging with multi-omics data to uncover immunologic vulnerabilities in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B62.
Association of Minimum Age Laws for Handgun Purchase and Possession With Homicides Perpetrated by Young Adults Aged 18 to 20 Years
Authors: Caitlin A. Moe, Miriam J. Haviland, Andrew G. Bowen, Ali Rowhani-Rahbar, Frederick P. Rivara
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Laws mandating a minimum age to purchase or possess firearms are viewed as a potentially effective policy tool to reduce homicide by decreasing young adults' access to firearms. <h3>Objective</h3> To evaluate whether state laws that raised the minimum age to purchase and/or possess a handgun to 21 years were associated with lower rates of firearm homicide perpetrated by young adults aged 18 to 20 years. <h3>Design, Setting, and Participants</h3> In this difference-in-differences analysis of a national cohort, young adult–perpetrated homicide rates were compared between states that did and did not implement stricter minimum age laws than the 1994 federal statute, adjusting for state-level factors. Under 1994 US federal law, the minimum age to purchase a handgun from a licensed dealer is 21 years; to purchase a handgun from an unlicensed dealer, 18 years; and to possess a handgun, 18 years. The 12 states that raised the minimum ages to purchase and/or possess a handgun beyond those set by federal law before 1994 were excluded from the stricter implementation group. Data were collected from January 1, 1995, to December 31, 2017, and analyzed from November 7, 2019, to June 23, 2020. <h3>Exposures</h3> Implementation of state law to raise the minimum age to purchase and/or possess a handgun beyond federal minimum age laws. During the study period, Massachusetts, Maryland, New Jersey, New York, and Wyoming raised the minimum age from 18 to 21 years to purchase a handgun from all dealers. With the exception of Wyoming, these states also increased the minimum age from 18 to 21 years to possess a handgun. <h3>Main Outcomes and Measures</h3> Firearm homicides perpetrated by young adults aged 18 to 20 years. Homicide data were obtained from the Supplementary Homicide Reports. <h3>Results</h3> During the study period, 35 960 firearm homicides were perpetrated by young adults aged 18 to 20 years. There was no statistically significant change in the rates of homicide perpetrated by this age group in the 5 states that imposed stricter age limits compared with the 32 that did not (crude incidence rate ratio, 1.10; 95% CI, 0.86-1.40). The adjusted incidence rate ratio was 1.14 (95% CI, 0.89-1.45) in states that implemented stricter minimum age laws compared with those that did not. <h3>Conclusions and Relevance</h3> This study found that stricter state minimum age laws were not associated with significantly lower rates of young adult–perpetrated homicide in states that adopted them compared with states that did not, and policy makers should reassess their use.
NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics
Authors: Weijun Wang, Nagore I Marín-Ramos, Haiping He, Shan Zeng, Hee-Yeon Cho, Stephen D Swenson, Long Zheng, Alan L Epstein, Axel H Schönthal, Florence M Hofman, Ligang Chen, Thomas C Chen
Journal: Neuro-Oncology (2020)

Abstract Background Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood–brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol. Methods In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan’s blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells. Results NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells. Conclusion We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.
Author Correction: Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment
Authors: Xuexian O. Yang, Pornpimon Angkasekwinai, Jinfang Zhu, Juan Peng, Zhiduo Liu, Roza Nurieva, Xikui Liu, Yeonseok Chung, Seon Hee Chang, Bing Sun, Chen Dong
Journal: Nature Immunology (2020)
Abstract 933: Pre-clinical characterization of TIM-3 antibody NB002
Authors: Xin Dong, Jannie Dong, Jun Ma, Lianqi Zhao, Haojie Wang, Binbin Wang, Qian Gao, Hui Pan, Dong Wang, Liegang Shao
Journal: Cancer Research (2020)

Abstract Targeting immune checkpoint molecules PD1 and CTLA-4 by activating the immune system have improved the lives of many cancer patients. However, this type of immunotherapy is not effective for all patients, suggesting that there are additional mechanisms of immune evasion. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) has been reported to be expressed on exhausted T and NK cells within the tumor microenvironment. The data in many preclinical models suggest that targeting TIM-3 pathway might provide an additional immune modulation of this anti-tumor axis in cancer patients. We have developed a novel monoclonal antibody NB002 against TIM-3,which forms a high-affinity interaction with a unique epitope. NB002 can enhance IFN-gamma secretion and proliferation of these exhausted T cells that has increased TIM-3 expression. Moreover, TIM-3 is constitutively expressed on NK cells. TIM-3 blockade could enhance in vitro cytotoxic activity of NK cells. Altogether, our data shows that NB002 is capable of targeting exhausted T cells and NK cells resulting activation of antitumor immunity. Further preclinical assessment in vivo and in vitro for solid tumors will support clinical development of NB002. Citation Format: Xin Dong, Jannie Dong, Jun Ma, Lianqi Zhao, Haojie Wang, Binbin Wang, Qian Gao, Hui Pan, Dong Wang, Liegang Shao. Pre-clinical characterization of TIM-3 antibody NB002 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 933.