tbuckley/cabot-search huggingface dataset:
Abstract 3163: Cell-based reporter bioassays for development of Fc-functional and Fc-silent SIRPa/CD47 checkpoint inhibitors
Authors: Jonathan Mitchell, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhijie Jey Cheng
Journal: Cancer Research (2020)

Abstract CD47, a membrane glycoprotein commonly overexpressed in human cancers, interacts with its cognate receptor SIRPα on myeloid cells to deliver a “don't eat me” signal that inhibits phagocytosis. This SIRPα/CD47 interaction has emerged as a critical and potentially druggable immune checkpoint. Blockade of SIRPα/CD47 interaction promotes phagocytosis of tumor cells in vitro, and SIRPα/CD47 inhibitors exhibit anti-tumor activity, including synergistic activity with other tumor-targeted mAbs (e.g. rituximab), in vivo. These encouraging pre-clinical data have sparked widespread development of SIRPα/CD47 inhibitors and driven a need for robust functional assays to measure the activity of these drug candidates. Biological activity of SIRPα/CD47 inhibitors is typically assessed via in vitro phagocytosis assays based on imaging or flow cytometry. These assays often use primary monocyte-derived macrophages and are inherently prone to donor variability, are low-throughput, and difficult to implement in drug development settings. Additionally, many SIRPα/CD47 inhibitors under development are designed to minimize Fc function to enhance safety and are thus incapable of driving phagocytosis directly. To overcome these limitations, we have developed a pair of reporter-based bioassays for measuring the biological activity of Fc-functional and Fc-silent SIRPα/CD47 inhibitors. These bioassays utilize a SIRPα-positive monocyte effector cell-line that expresses multiple Fc gamma receptors (FcγRs) and an FcγR-responsive NanoLuc luciferase reporter that is inhibited by SIRPα/CD47 interaction upon co-culture of SIRPα effector cells with CD47-positive target cells. Addition of CD47 inhibitors with Fc functional activity simultaneously disrupts the SIRPα/CD47 interaction and engages FcγRs on the SIRPα effector cells, resulting in NanoLuc reporter activation. To enable testing of Fc-silent inhibitors, we have engineered a second CD47 target cell-line which provides a constitutive activating stimulus to SIRPα effector cells that is restricted by SIRPα/CD47 interaction. Addition of Fc-silent SIRPα/CD47 blockers releases inhibition by SIRPα/CD47, resulting in NanoLuc reporter activation. These newly developed reporter bioassays provide a robust, high-throughput platform to facilitate discovery and development of diverse SIRPα/CD47 checkpoint inhibitors. Citation Format: Jonathan Mitchell, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhijie Jey Cheng. Cell-based reporter bioassays for development of Fc-functional and Fc-silent SIRPa/CD47 checkpoint inhibitors [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 3163.
Basophils prime group 2 innate lymphoid cells for neuropeptide-mediated inhibition
Authors: Juan M. Inclan-Rico, John J. Ponessa, Nuriban Valero-Pacheco, Christina M. Hernandez, Chandler B. Sy, Alexander D. Lemenze, Aimee M. Beaulieu, Mark C. Siracusa
Journal: Nature Immunology (2020)
Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation
Authors: Nefertiti El-Nikhely, Annika Karger, Poonam Sarode, Indrabahadur Singh, Andreas Weigert, Astrid Wietelmann, Thorsten Stiewe, Reinhard Dammann, Ludger Fink, Friedrich Grimminger, Guillermo Barreto, Werner Seeger, Soni S. Pullamsetti, Ulf R. Rapp, Rajkumar Savai
Journal: Cancer Research (2020)

Abstract Although NF-κB is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-κB in tumor context is largely unknown. Here we report that the IKK2/NF-κB signaling pathway modulates metastasis-associated protein 2 (MTA2), a component of the nucleosome remodeling and deacetylase complex (NuRD). In triple transgenic mice, downregulation of IKK2 (Sftpc-cRaf-IKK2DN) in cRaf-induced tumors in alveolar epithelial type II cells restricted tumor formation, whereas activation of IKK2 (Sftpc-cRaf-IKK2CA) supported tumor growth; both effects were accompanied by altered expression of MTA2. Further studies employing genetic inhibition of MTA2 suggested that in primary tumor growth, independent of IKK2, MTA2/NuRD corepressor complex negatively regulates NF-κB signaling and tumor growth, whereas later dissociation of MTA2/NuRD complex from the promoter of NF-κB target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-κB signaling, epithelial–mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-κB-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-κB would provide potential targets for intervention of tumor growth and metastasis. Significance: These findings strongly suggest a prominent role of MTA2 in primary tumor growth, lung metastasis, and NF-κB signaling modulatory functions.
SAT0554 CLINICAL FEATURES ANALYSIS OF 50 MESENTERIC PANNICULITIS CASES DIAGNOSED BY COMPUTERIZED TOMOGRAPHIC SCANNING
Authors: Yazhen Su, Qianyu Guo, Liyun Zhang, MA Dan, Gailian Zhang, Ke Xu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Mesenteric panniculitis (MP) is a chronic idiopathic inflammatory disease that occurs in mesenteric adipose tissue,which lacks of specific diagnostic methods. <h3>Objectives:</h3> To retrospectively summarize 50 cases of patients with mesenteric panniculitis(MP) diagnosed by CT to improve the clinicians' understanding of the disease. <h3>Methods:</h3> The patients with MP diagnosed by abdominal CT were collected from the hospital of Shanxi Medical University from January 2013 to May 2017. The demographic characteristics, clinical features, auxiliary examination, treatment and prognosis were analyzed and summarized. <h3>Results:</h3> The proportion of men and women was1:0.92, the age of onset was 25 ∼ 85 years old, the average age was (59.1±14.0) years old. Most of the patients presented with abdominal pain, fever, hematuria, and lymphadenopathy.22 cases with tumor, the most common type is lymphoma, 16 cases with abdominal surgery history. There were no special laboratory tests, no patients had mesenteric pathologic biopsy. 6 cases had abdominal CT review, 1 case of who used hormone treatment showed the lesion was significantly absorbed, the remaining 5 cases no significant changes. <h3>Conclusion:</h3> MP is common in the elderly, the clinical manifestations are diverse, easy to merge tumor, lymphoma more common, abdominal CT is its most important diagnostic means, when found MP, should pay attention to whether the merger with malignant tumors. <h3>References</h3> [1] Bashir MS, Abbott CR.Mesenteric lipodystrophy[J]. J Clin Pathol, 1993, 46(9):872-874. [2] Ehrenpreis ED, Roginsky G, Gore RM. Clinical significance of mesenteric panniculitis-like abnormalities on abdominal computerized tomography in patients with malignant neoplasms[J].World J Gastroenterol, 2016, 22(48):10601-10608. [3] Protin-Catteau L, Thiéfin G, Barbe C, et al. Mesenteric panniculitis: review of consecutive abdominal MDCT examinations with a matched-pair analysis[J]. Acta Radiol,2016, 57(12):1-7. [4] Scheer F, Spunar P, Wiggermann P, et al. Mesenteric Panniculitis (MP) in CT - A Predictor of Malignancy?[J]. Rofo, 2016, 188(10):926-932. [5] Mahmoud Rezk Abdelwahed, Hussein, Saad Rezk, Abdelwahed. Mesenteric panniculitis: an update[J]. Expert Rev Gastroenterol Hepatol, 2015, 9(1):67-78. [6] Emory TS, Monihan JM, Carr NJ, et al. Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?[J]. Am J Surg Pathol, 1997, 21(4):392-398. [7] Van PN, van Bommel EF, Elgersma OE, et al. Mesenteric panniculitis: prevalence, clinicoradiological presentation and 5-year follow-up[J]. Br J Radiol, 2014, 87(1044):20140451. <h3>Disclosure of Interests:</h3> None declared
Images of COVID-19 Infection Cases in Asymptomatic or Paucisymptomatic Patients With Neoplastic Diseases on 18F-FDG PET/CT
Authors: Jean-François Grellier, David Lussato, Mohamed Guernou, Mathieu Queneau, Gérald Bonardel
Journal: Clinical Nuclear Medicine (2020)

We describe the results of 18F-FDG PET/CT of 3 patients referred to our institution during the single day of Monday, March 23, 2020, for an initial assessment of cancer extension or for the therapeutic evaluation of chemotherapy of neoplastic pathology, with no obvious infectious or respiratory symptoms at the time of examination. A retrospective review of the recent clinical history of patients in association with the typical pulmonary images on CT scan suggested the diagnosis of COVID-19. The characteristic aspects of COVID-19 infection should be recognized on 18F-FDG PET/CT, even if patients are asymptomatic or minimally symptomatic.
Abstract 6666: Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist
Authors: Shakoora Sabree, Andrew Voigt, Laura Rogers, Sue Blackwell, Caitlin Lemke-Miltner, George J. Weiner
Journal: Cancer Research (2020)

Abstract CMP-001 is a virus-like particle containing a TLR9 agonist (class A CpG ODN) encapsulated by the Qβ capsid. Preclinical studies and early phase clinical trials of intralesional injection with CMP-001, combined with anti-PD1 antibody, demonstrate promising results. Prior work by our group has demonstrated that the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qβ antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNα. While a variety of cell types including monocytes and B cells can take up CMP-001, the immune response to CMP-001 is based in large part on rapid induction of IFNα production by pDCs. The current studies were designed to assess the downstream effects of CMP-001 and anti-Qβ antibody on various arms of the immune response using normal donor human peripheral blood mononuclear cells (PBMCs) as a model. Stimulation of PBMCs with CMP-001 and anti-Qβ antibody induced production of IFNα from pDCs as previously observed. This IFNα production occurred very rapidly (within 2 hours) and was short lived, but had long term secondary effects, including induction of CXCL10 production by monocytes. Single cell RNA sequencing done 24 hours after stimulation demonstrated additional downstream changes including the following: Upregulation of CXCL10, MIP1-α, IL1-RA and IDO by monocytes. Downregulation of CD14 by monocytes. Upregulation of a broad variety of interferon response genes in various cell types including NK cells and T cells. We conclude the primary effect of in situ immunization with CMP-001 is to induce rapid production of IFNα production by pDCs. This results in significant downstream effects on various cell populations that contribute to the anti-tumor immune response. Understanding these pathways could help identify the most promising combination immunotherapies involving CMP-001. Ongoing studies are exploring the kinetics of these responses and whether similar changes are observed in the tumor microenvironment. Citation Format: Shakoora Sabree, Andrew Voigt, Laura Rogers, Sue Blackwell, Caitlin Lemke-Miltner, George J. Weiner. Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist [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 6666.
Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective
Authors: Lee L. Marshall, Bryan A. Killinger, Elizabeth Ensink, Peipei Li, Katie X. Li, Wei Cui, Noah Lubben, Matthew Weiland, Xinhe Wang, Juozas Gordevicius, Gerhard A. Coetzee, Jiyan Ma, Stefan Jovinge, Viviane Labrie
Journal: Nature Neuroscience (2020)
Abstract 5999: The Warburg Effect suggests a palliative care approach to cancer therapy
Authors: Linda C. Meade-Tollin, Tom C. Tsang
Journal: Cancer Research (2020)

Abstract Introduction: Otto Warburg discovered in 1924 that cancer cells needed a lot more glucose than normal cells. Today, the “Warburg Effect” is not only recognized as a “hallmark of cancer” but also served as the scientific basis for cancer detection using fluorodeoxyglucose (FDG) Positron emission tomography (PET-scans). Warburg suggested in 1927 that treating cancer patients with insulin can deprive glucose to the cancer cells by lowering the blood glucose levels and may inhibit tumor growth. Although at least six peer-reviewed publications so far have provided support for the feasibility of this approach, no clinical trial has ever been done. We have previously presented an analysis of the data from hospitals in China suggesting that insulin can be safely administered for patients receiving a small dosage of standard chemotherapy drugs as palliative treatments for late-stage cancer patients. Here, we report additional data from more patients and medical facilities. Experimental procedures: Patients diagnosed with multiple types of late-stage solid tumors were treated with regular insulin (Humulin R) administered intravenously, and small doses of standard chemotherapy drugs (approximately 10% of the standard dosages). Blood glucose levels were monitored throughout the course of treatment. Hypoglycemia was reversed by ingestion of food and drink or injection of glucose solution. Depending on how well the patients tolerated the treatments, 5-30 units of insulin were used. No permanent side effects were observed or reported. Summary of data: Over 400 treatments have been performed on over 30 patients ranging from 30 to 76 years old, and diagnosed with 14 types of cancer. The average age of the patients was 56.2 years old. Symptoms of hypoglycemia were observed in all 30+ patients, and readily reversed by intravenous infusions of glucose or ingestion of food and drink. The insulin treatments were well tolerated and no longer -term side effects were observed. Conclusions: Our analysis supports the feasibility of using regular insulin as a reproducibly safe method to achieve glucose deprivation in patients with advanced stages of multiple types of cancer receiving palliative and hospice care. These and additional future studies could form the basis for eventually conducting a clinical trial testing whether regular insulin, which is inexpensive and available over the counter, can be an alternative therapeutic option for palliative and hospice care in some patients. Citation Format: Linda C. Meade-Tollin, Tom C. Tsang. The Warburg Effect suggests a palliative care approach to cancer therapy [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 5999.
Lubiprostone in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled, phase 2a trial
Authors: Takaomi Kessoku, Kento Imajo, Takashi Kobayashi, Anna Ozaki, Michihiro Iwaki, Yasushi Honda, Takayuki Kato, Yuji Ogawa, Wataru Tomeno, Shingo Kato, Takuma Higurashi, Masato Yoneda, Hiroyuki Kirikoshi, Kazumi Kubota, Masataka Taguri, Takeharu Yamanaka, Haruki Usuda, Koichiro Wada, Noritoshi Kobayashi, Satoru Saito, Atsushi Nakajima
Journal: The Lancet. Gastroenterology & hepatology (2020)
Automated and partly automated contact tracing: a systematic review to inform the control of COVID-19
Authors: Isobel Braithwaite, Thomas Callender, Miriam Bullock, Robert W Aldridge
Journal: The Lancet Digital Health (2020)

SummaryEvidence for the use of automated or partly automated contact-tracing tools to contain severe acute respiratory syndrome coronavirus 2 is scarce. We did a systematic review of automated or partly automated contact tracing. We searched PubMed, EMBASE, OVID Global Health, EBSCO Medical COVID Information Portal, Cochrane Library, medRxiv, bioRxiv, arXiv, and Google Advanced for articles relevant to COVID-19, severe acute respiratory syndrome, Middle East respiratory syndrome, influenza, or Ebola virus, published from Jan 1, 2000, to April 14, 2020. We also included studies identified through professional networks up to April 30, 2020. We reviewed all full-text manuscripts. Primary outcomes were the number or proportion of contacts (or subsequent cases) identified. Secondary outcomes were indicators of outbreak control, uptake, resource use, cost-effectiveness, and lessons learnt. This study is registered with PROSPERO (CRD42020179822). Of the 4036 studies identified, 110 full-text studies were reviewed and 15 studies were included in the final analysis and quality assessment. No empirical evidence of the effectiveness of automated contact tracing (regarding contacts identified or transmission reduction) was identified. Four of seven included modelling studies that suggested that controlling COVID-19 requires a high population uptake of automated contact-tracing apps (estimates from 56% to 95%), typically alongside other control measures. Studies of partly automated contact tracing generally reported more complete contact identification and follow-up compared with manual systems. Automated contact tracing could potentially reduce transmission with sufficient population uptake. However, concerns regarding privacy and equity should be considered. Well designed prospective studies are needed given gaps in evidence of effectiveness, and to investigate the integration and relative effects of manual and automated systems. Large-scale manual contact tracing is therefore still key in most contexts.
Atrial Fibrillation and Dementia
Authors: T. Jared Bunch
Journal: Circulation (2020)

Atrial fibrillation is associated with multiple adverse comorbidities, including the development of dementia in patients with and without a history of stroke. Mechanistic models have been proposed to explain the association of AF and dementia. Alterations of brain perfusion from embolic events, bleeding, and rhythm-related hypoperfusion underlie many of these models. Multiple mediators such as oxidative injury, inflammatory and autoimmune mechanisms, and genetic predisposition also interplay in the disease association. There are potential therapeutic opportunities to reduce dementia risk, including early and effective use of anticoagulation and strategies to improve brain perfusion through rhythm and rate control approaches. Prospective trials are needed to evaluate these therapeutic opportunities that carefully measure cognitive function and dementia incidence.
Challenges associated with the roll-out of HCC surveillance in sub-Saharan Africa - the case of Uganda
Authors: Stijn Van Hees, Winnie Muyindike, Geoffrey Erem, Ponsianoo Ocama, Emmanuel Seremba, Apiyo Paska, Peter Michielsen, Mark Okwir, Thomas Vanwolleghem
Journal: Journal of Hepatology (2020)
THU0242 Can social support and social network predict the evolution of quality of life over time in early rheumatoid arthritis? the euridiss cohort study
Authors: V Demange, F Guillemin, M Baumann, TP Suurmeijer, T Moum, D Doeglas, S Briançon, WJ Van den Heuvel
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> There is clear epidemiological evidence for a relationship between social support and health. Though, the mechanism remains unclear whether a poor social support precedes or follows a poor health status. Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting particularly quality of life. <h3>Objectives</h3> First, to investigate cross-sectional relationships between quality of life and social support (SS) and support network (SN) in patients with early RA. Then to look at how baseline SS or SN influence quality of life over time; and last, to explore how variations over time in SS or SN affect quality of life over time. <h3>Methods</h3> Subjects were members of the EURIDISS population-based cohort from France, the Netherlands and Norway, and had suffered from RA for less than 5 years. Yearly assessments were made of SS, SN, psychological well-being (GHQ), and functional disability (HAQ). Variance and covariance analyses with repeated measures were calculated and adjusted for potential confounding variables. <h3>Results</h3> A total of 542 subjects had yearly assessment for three years. On average, those receiving a greater amount of specific SS (daily emotional support or social companionship) (p = 0.05 to p = 0.0001) or surrounded by a stronger specific SN (those aspects providing emotional support) (p &lt; 0.001) experienced a better quality of life. No statistically significant relationship was observed between baseline level of SS or SN and changes in quality of life over time. Similarly, changes in SS or SN did not appear to be associated with improvements in quality of life over time. <h3>Conclusion</h3> Better specific SS and specific SN are cross-sectionally associated with better quality of life in early RA patients. Baseline or changes in SS or SN do not seem to predict changes in quality of life over time for these patients. It may be useful to measure SS in early RA patients in order to identify individuals who receive little specific SS. Further work is needed to devise simple ways to measure SS, to develop interventions that provide additional support, and to investigate whether provision of structured SS by relevant professionals would be more useful than increasing non-specific intervention.
<scp>C3</scp> inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab
Authors: Carlos de Castro, Federico Grossi, Ilene Ceil Weitz, Jaroslaw Maciejewski, Vivek Sharma, Eloy Roman, Robert A. Brodsky, Lisa Tan, Carl Di Casoli, Delphine El Mehdi, Pascal Deschatelets, Cedric Francois
Journal: American Journal of Hematology (2020)

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life‐threatening hematologic disease characterized by chronic complement‐mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL‐2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open‐label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment‐emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6‐8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well‐tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.