tbuckley/cabot-search huggingface dataset:
Abstract 4094: The TLR4 agonist G100 enhances rituximab-mediated ADCC <i>in vitro</i> and has synergistic anti-tumor effects with anti-CD20 mAb <i>in vivo</i>
Authors: Hailing Lu, Alec Betancur, Jan ter Meulen
Journal: Cancer Research (2019)

Abstract Background: G100, which contains the synthetic TLR4 agonist Glucopyranosyl lipid A (GLA) formulated in a stable oil-in-water emulsion (SE) for intratumoral therapy, is currently in clinical development in combination with pembrolizumab for the treatment of B-cell follicular lymphoma (FL). The current study was undertaken to investigate the interaction of G100 with rituximab, the anti-CD20 mAb that is standard-of-care treatment for FL. Methods: In vitro studies were performed using peripheral blood mononuclear cells (PBMC) from healthy human donors to investigate the effect of GLA-AF (an aqueous formulation of GLA) on natural killer (NK) cell activation. IFNγ production in NK cells after activation with plate-bound anti-CD16 or target K562 leukemia cells was measured by intracellular cytokine staining (ICS). Rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) was measured using pretreated or untreated PBMC and rituximab-coated Raji Burkitt’s lymphoma cells as target cells. In vivo studies were carried out in Balb/c mice with bilateral A20 lymphoma. Mice received G100 alone (10μg, intratumoral, 3 injections/week), anti-CD20 alone (clone 5D2, provided by Genentech, 200μg, intraperitoneal, 1 injection/week), or G100+anti-CD20 for a total of 3 weeks. Results: Incubation of PBMC from 3 different donors with GLA-AF (1 μg/mL) resulted in NK cell activation as demonstrated by increased IFNγ production, as well as enhanced response to the K562 target cells and anti-CD16. When PBMC from 5 normal donors were used in rituximab-mediated ADCC assay, pretreated PBMCs had significantly enhanced lysis of target Raji cells compared to untreated PBMC (p&amp;lt;0.05). In mice with bilateral A20 tumors, the combination of G100 with anti-CD20 resulted in significantly better tumor control and prolonged survival (n=5 per group, p&amp;lt;0.05). Conclusions: G100 enhances NK cell activity and rituximab-mediated ADCC in human PBMC. Combination of G100 and anti-CD20 mAb has synergistic anti-tumor effects in a mouse lymphoma model. These data support clinical testing of G100 with rituximab in patients with FL. Citation Format: Hailing Lu, Alec Betancur, Jan ter Meulen. The TLR4 agonist G100 enhances rituximab-mediated ADCC in vitro and has synergistic anti-tumor effects with anti-CD20 mAb in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4094.
Expiratory muscle dysfunction in critically ill patients: towards improved understanding
Authors: Zhong-Hua Shi, Annemijn Jonkman, Heder de Vries, Diana Jansen, Coen Ottenheijm, Armand Girbes, Angelique Spoelstra-de Man, Jian-Xin Zhou, Laurent Brochard, Leo Heunks
Journal: Intensive Care Medicine (2019)

This narrative review summarizes current knowledge on the physiology and pathophysiology of expiratory muscle function in ICU patients, as shared by academic professionals from multidisciplinary, multinational backgrounds, who include clinicians, clinical physiologists and basic physiologists.
Cost-effectiveness of bivalent versus monovalent vaccines against hand, foot and mouth disease
Authors: D. Liu, K. Leung, M. Jit, H. Yu, J. Yang, Q. Liao, F. Liu, Y. Zheng, J.T. Wu
Journal: Clinical Microbiology and Infection (2019)

ObjectivesEnterovirus 71 (EV71) and coxsackievirus A16 (CA16) were responsible for 43.3% (235 123/543 243) and 24.8% (134 607/543 243) of all laboratory-confirmed hand, foot and mouth disease (HFMD) cases during 2010–2015 in China. Three monovalent EV71 vaccines have been licensed in China while bivalent EV71/CA16 vaccines are under development. A comparative cost-effectiveness analysis of bivalent EV71/CA16 versus monovalent EV71 vaccination would be useful for informing the additional value of bivalent HFMD vaccines in China.MethodsWe used a static model parameterized with the national HFMD surveillance data during 2010–2013, virological HFMD surveillance records from all 31 provinces in mainland China during 2010–2013 and caregiver survey data of costs and health quality of life during 2012–2013. We estimated the threshold vaccine cost (TVC), defined as the maximum additional cost that could be paid for a cost-effective bivalent EV71/CA16 vaccine over a monovalent EV71 vaccine, as the outcome. The base case analysis was performed from a societal perspective. Several sensitivity analyses were conducted by varying assumptions governing HFMD risk, costs, discounting and vaccine efficacy.ResultsIn the base case, choosing the bivalent EV71/CA16 over monovalent EV71 vaccination would be cost-effective only if the additional cost of the bivalent EV71/CA16 compared with the monovalent EV71 vaccine is less than €4.7 (95% CI 4.2–5.2). Compared with the TVC in the base case, TVC increased by up to €8.9 if all the test-negative cases were CA16-HFMD; decreased by €1.1 with an annual discount rate of 6% and exclusion of the productivity loss; and increased by €0.14 and €0.3 with every 1% increase in bivalent vaccine efficacy against CA16-HFMD and differential vaccine efficacy against EV71-HFMD, respectively.ConclusionsBivalent EV71/CA16 vaccines can be cost-effective compared with monovalent EV71 vaccines, if suitably priced. Our study provides further evidence for determining the optimal use of HFMD vaccines in routine paediatric vaccination programme in China.
Abstract 3518: SPARC related signaling genes in non-small cell lung cancer by RNA-sequencing transcriptome analysis
Authors: Sajani S. Lakka, Bhavesh K. Ahir
Journal: Cancer Research (2019)

Abstract Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 80 % cases of lung cancer and is the leading cause of cancer-related death in the United States and worldwide. SPARC (secreted protein acidic and rich in cysteine), a multicellular non-structural glycoprotein is known to be involved in the regulation of cell adhesion, cell proliferation as well as in tumorigenesis and metastasis in various cancers including NSCLC. SPARC contributes to matrix remodeling and turnover and is involved in modulating the tumor microenvironment. Previous studies have suggested that SPARC can be used as a prognostic factor for NSCLC and represents a highly promising therapeutic modality. In this study we used high-throughput RNA-sequencing transcriptome profiling analysis to delineate pathways involved in SPARC signaling. We assessed differentially expressed genes, novel genes, biological processes and biological signaling pathways in SPARC expressed NSCLC cell line. We identified a total of 3,280 upregulated and 1,608 downregulated differentially expressed genes with known functions in SPARC expressed NSCLC cells. KEGG enrichment analysis indicated that the differentially expressed genes were involved in cellular metabolic processes, regulation of biological processes or biological signaling pathways like cell cycle, spliceosome, apoptosis and WNT signaling pathway. The RNA-seq analysis further revealed that genes involved in apoptosis were significantly altered after SPARC modulation to NSCLC cells. Co-transfection experiments using SPARC shRNA indicated that SPARC modulation induced apoptosis via regulating PI3K/AKT signaling pathway. In summary, this study uncovers SPARC dependent regulatory mechanisms in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Sajani S. Lakka, Bhavesh K. Ahir. SPARC related signaling genes in non-small cell lung cancer by RNA-sequencing transcriptome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3518.
Mass Drug Administration for Scabies — 2 Years of Follow-up
Authors: Lucia Romani, Margot J Whitfeld, Josefa Koroivueta, Mike Kama, Handan Wand, Lisi Tikoduadua, Meciusela Tuicakau, Aminiasi Koroi, Ross M Andrews, John M Kaldor, Andrew C Steer
Journal: New England Journal of Medicine (2019)

Ivermectin for Scabies In this 2-year follow-up report in Fiji, the single mass administration of oral ivermectin was more effective in reducing the prevalence of both scabies and impetigo than eit...
Impact on survival of local complications in Pancreatic Cancer: experience at the Ramón y Cajal University Hospital (HURyC)
Authors: J. Serrano Domingo, R. Martín Huertas, E. Corral de la Fuente, A. Barquín García, C. Saavedra Serrano, V. Albarrán Artahona, P. Reguera Puertas, R. Fuentes, R. Ferreiro Monteagudo, V. Pachón Olmos, M. Vaz, M. Villamayor Delgado, M. Rodriguez Garrote, A. Carrato, F. Longo Muñoz
Journal: Annals of Oncology (2019)
Abstract 31: Organoid derived from human operative sample of NET shows NET characteristics
Authors: Yasushi Ichikawa, Yukihiko Hiroshima, Noritoshi Kobayashi, Yusaku Masuda, Ayumu Goto, Motohiko Tokuhisa, Yuma Takeda, Takashi Ishikawa, Itaru Endo
Journal: Cancer Research (2019)

Abstract Background: Neuroendocrine tumor is a rare neoplasm, then, it was difficult to examine using in vitro or animal models. Recently, patient-derived tumor organoid (PDTO) is considered as a promising method to analyze natural characteristics of human tumor, because PDTO is cultured in near-natural circumstances compared with cell lines. We established PDTO of neuroendocrine tumor (NET) utilizing operative samples from a pancreatic NET patient. Aim: Aim of this study is to establish organoid derived from an operative sample of pancreatic NET patient and to compare its characteristics with original tumor using immuno-histochemistry. Material and Method: A pancreatic NET tissue derived from operative sample was cut into small pieces and was treated by collagenase. Prepared tissues were 3-dimensionally cultured on the Matrigel in a serum-free medium (Advanced MEM/F12) with 4 growth factors (Respondin, EGF, Rock inhibitor, Noggin), then PDTO was established. To evaluate growth rate of PDTO, Major axis of the organoid was measured on the day 1, 2, 3, and 6. One week after primary culture of the organoid, subculture was performed. Then major axis of the 2nd, 6th and 7th filial organoid was also measured and compared with each filial. To evaluate characteristics of PDTO as neuroendocrine tumor, immunohistochemistry was performed for the 1st, 2nd and 3rd filial PDTO using anti-chromogranin-A antibody (Dako, mouse IgG), anti-synaptophysin antibody (Abcam, rabbit IgG), anti-NCAM antibody (Abcam mouse IgG) and Neuro-specific enolase (Dako, rabbit IgG). Results: Growth rate of the 2nd and 3rd filial on the day 6 did not show significant difference compared with that of the 1st filial. On the other hand, Growth rate of the 2nd and 3rd filial was significantly lower than that of the 1st filial. Expression of the 4 factors in the 1st, 2nd and 3rd filial PDTO was kept as much as the primary tumor. Conclusion: PDTO derived from neuroendocrine tumor showed the same characteristics as the primary tumor. The 6th and 7th filial PDTO might show cellular aging. Citation Format: Yasushi Ichikawa, Yukihiko Hiroshima, Noritoshi Kobayashi, Yusaku Masuda, Ayumu Goto, Motohiko Tokuhisa, Yuma Takeda, Takashi Ishikawa, Itaru Endo. Organoid derived from human operative sample of NET shows NET characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 31.
Abstract 2485: Somatic analysis services with best practice workflows in a cloud-based platform
Authors: Junko Tsuji, Andrew Hollinger, Alyssa MacBeth, Brian R. Grander, Micah Rickles-Young, Tera Bowers, Carrie Cibulskis, Niall Lennon
Journal: Cancer Research (2019)

Abstract With advances in high-throughput sequencing technologies and analytical tools, genomic analysis of tumors has led to the identification of various important somatic mutations that shed light on diagnosis, prevention, and treatment for cancer. However, detecting somatic variants is not a trivial task in terms of the technical aspects (e.g. filtering germline events and removing a variety of noises in tumor samples) and computational resources to handle large-scale cohort analysis. There is also a demand for maintaining stable software versions and the workflows for studies over extended periods of time, that need consistency and traceability, such as clinical trials. We introduce here, the Translational Analysis Group (TAG), a team which deploys, validates, and conducts scalable analytical workflows in a secure, cloud-based environment. We maintain 29 well-tested workflows with best practice methods and ample resources for both somatic and germline analysis. Our cloud platform, FireCloud, enables us to run workflows at any scale. Since May 2017, our team has performed nearly 10,000 analyses for mutation detection (SNV, InDel, CNV, and SV) and cohort analysis on tumor samples and cell-free DNA samples. TAG offers a range of options for somatic and germline variant detection, from legacy pipelines through recently validated contemporary pipelines to allow for continuity across long running projects. Citation Format: Junko Tsuji, Andrew Hollinger, Alyssa MacBeth, Brian R. Grander, Micah Rickles-Young, Tera Bowers, Carrie Cibulskis, Niall Lennon. Somatic analysis services with best practice workflows in a cloud-based platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2485.
Abstract 19893: Accuracy of Implantable Loop Recorder for Detecting Atrial Fibrillation Early Recurrence After Catheter Ablation
Authors: Hyun Jun Cho, Yoon Nyun Kim, Seongwook Han, Hyoung-Seob Park, Seung-Woon Jun, Sang-Woong Choi, Han-Jun Bae, In-Cheol Kim, Yun-Kyeong Cho, Hyuck-Jun Yoon, Hyungseop Kim, Chang-Wook Nam, Seung-Ho Hur, Na Young Kang
Journal: Circulation (2017)

Background: The implantable loop recorder (ILR) could provide the highest possibility to detect AF than any other modality, but it is invasive and costly. The purpose of this study is determined th...
Circulating T cell subsets differ in PDAC patients at initial diagnosis and after two months of treatment: a single institution prospective study
Authors: S. Tulyte, A. Sileikis, I. Tamulyte, A. Ranceva, D. Characiejus, R. Matuzeviciene, A. Janiulionienė, T. Zvirblis
Journal: Annals of Oncology (2019)
Rapid Aldosterone-Mediated Signaling in the DCT Increases Activity of the Thiazide-Sensitive NaCl Cotransporter
Authors: Lei Cheng, Søren Brandt Poulsen, Qi Wu, Cristina Esteva-Font, Emma T. B. Olesen, Li Peng, Björn Olde, L. M. Fredrik Leeb-Lundberg, Trairak Pisitkun, Timo Rieg, Henrik Dimke, Robert A. Fenton
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The NaCl cotransporter NCC in the kidney distal convoluted tubule (DCT) regulates urinary NaCl excretion and BP. The long-term effects of the mineralocorticoid aldosterone on modulating NaCl reabsorption via NCC are well established, and their importance illustrated by the effects of NCC-targeting diuretics and the salt-wasting observed in Gitelman syndrome. In this study the authors demonstrate that aldosterone also has rapid effects on the DCT, partly via the membrane receptors EGFR and GPR30. Signaling from these receptors affect NCC activity so that when aldosterone is released in response to hypovolemia, aldosterone rapidly increases NaCl reabsorption to help restore blood volume. Background The NaCl cotransporter NCC in the kidney distal convoluted tubule (DCT) regulates urinary NaCl excretion and BP. Aldosterone increases NaCl reabsorption via NCC over the long-term by altering gene expression. But the acute effects of aldosterone in the DCT are less well understood. Methods Proteomics, bioinformatics, and cell biology approaches were combined with animal models and gene-targeted mice. Results Aldosterone significantly increases NCC activity within minutes in vivo or ex vivo . These effects were independent of transcription and translation, but were absent in the presence of high potassium. In vitro , aldosterone rapidly increased intracellular cAMP and inositol phosphate accumulation, and altered phosphorylation of various kinases/kinase substrates within the MAPK/ERK, PI3K/AKT, and cAMP/PKA pathways. Inhibiting GPR30, a membrane-associated receptor, limited aldosterone’s effects on NCC activity ex vivo , and NCC phosphorylation was reduced in GPR30 knockout mice. Phosphoproteomics, network analysis, and in vitro studies determined that aldosterone activates EGFR-dependent signaling. The EGFR immunolocalized to the DCT and EGFR tyrosine kinase inhibition decreased NCC activity ex vivo and in vivo . Conclusions Aldosterone acutely activates NCC to modulate renal NaCl excretion.
Abstract SY19-02: Metabolic tumor suppressors and disease progression
Authors: M Celeste Simon
Journal: Cancer Research (2019)

Abstract Altered tumor cell metabolism is now firmly established as a hallmark of human cancer. Downstream of oncogenic events, metabolism is re-wired to support cellular energetics and supply the building blocks for biomass expansion and cell motility. Rapid, uncontrolled proliferation results in tumor growth beyond the reach of existing vasculature and triggers cellular adaptations to overcome limiting nutrient and oxygen delivery. However, oncogenic activation and metabolic re-programming also elicit cell intrinsic stresses, independent of the tumor microenvironment. To ensure metabolic robustness and stress resistance, pro-growth signals downstream of oncogene activation or tumor suppressor loss simultaneously activate homeostatic processes. Here, I will summarize adaptive mechanisms based on loss of fructose-1,6-bisphosphatases FBP1 and FBP2 in the settings of renal carcinoma, liver cancer, and soft tissue sarcoma. Both FBPs function in the cytoplasm and the nucleus to carry out enzymatic activity-dependent and -independent processes that suppress tumor growth. FBP1 and FBP2 impact both malignant and stromal cells in the tumor microenvironment, including inflammayory cells. Ultimately, an understanding of the adaptations required downstream of specific metabolic tumor suppressors could reveal targetable metabolic vulnerabilities. Citation Format: M Celeste Simon. Metabolic tumor suppressors and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY19-02.
Abstract SY19-01: Metabolic consequences and liabilities of TCA cycle truncation in cancer
Authors: Eyal Gottlieb
Journal: Cancer Research (2019)

Abstract Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes while SDH is also part of the respiratory chain. Despite their key housekeeping activities, the genetic loss of FH or of any of the SDH subunits is associated with susceptibility to cancers. SDH or FH inactivation leads to the accumulation of metabolites which cause the activation of hypoxia-inducible factors and the inhibition of histone and DNA demethylases, establishing pseudohypoxic and hypermethylator phenotype. However, surviving the loss of these essential metabolic enzymes requires a significant metabolic adaptation as backup mechanisms for the dysfunctional TCA cycle and oxidative phosphorylation in these tumors. Identifying these adaptations would reveal effective and specific metabolic vulnerabilities which can serve as potential molecular targets for therapeutic intervention. We have identified in the past a few metabolic essentialities in cells deficient in FH and SDH and now performed a pharmacologic phenotypic synthetic lethal screen to identified effective drugs that specifically kill SDH- and FH-deficient cells. Utilizing metabolomics, we have delineated the molecular target of the effective compounds. Citation Format: Eyal Gottlieb. Metabolic consequences and liabilities of TCA cycle truncation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY19-01.
A phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab in patients with metastatic renal cell carcinoma (mRCC)
Authors: J. A. Garcia, B. I. Rini, T. Mekhail, P. Triozzi, P. Elson, C. Nemec, R. M. Bukowski
Journal: Journal of Clinical Oncology (2007)

5103 Background: Interleukin-2 and bevacizumab, a VEGF ligand-binding antibody, have each demonstrated antitumor activity in mRCC. Increased VEGF levels can lead to immunosuppression and resistance to immunotherapy through inhibition of dendritic cell (DC) differentiation and increase in immunosuppressive regulatory T cells (Tregs). To further evaluate the clinical and immunomodulatory effect of low-dose IL-2 and bevacizumab in mRCC, a phase II trial was conducted. Methods: Previously untreated good and intermediate risk mRCC pts received 8-week cycles of IL-2 (250,000 U/kg/d SC D1–5 during week 1 and 125,000 U/kg/d SC D1–5 during weeks 2–6, followed by a 2 week break). Bevacizumab 10mg/kg was administered IV every 2 weeks starting on day -14. Eligibility included RECIST-defined measurable disease, clear cell histology, normal organ function, and prior nephrectomy. A Simon 2 stage phase II design was employed to test the hypothesis of a 40% improvement in the 3-month PFS vs. historical IL-2-treated controls. Overall response rate (ORR) and toxicity were recorded. Exploratory endpoints included activation of circulating DC’s, Tregs and VEGF levels. Results: To date 16 of a planned 35 pts are enrolled. Median age is 59 years (range, 44–67); Eight patients have &gt;1 site of metastasis; median treatment duration is 8 weeks (8–32+). Among 11 pts evaluable for response, 1 PR and 3 SD lasting &gt;3 months have been observed. All pts with SD have demonstrated some degree of tumor shrinkage. Seven pts have discontinued therapy (5 PD, 2 withdrew consent). Most common treatment-related toxicity included fatigue, nausea, diarrhea, and fever. When comparing immune correlates at day 56 of therapy vs. baseline, all pts had an increase in the number of Tregs (median increase 1.65, range; 0.76–10.4; p= 0.008). Similarly, all pts had a decline in VEGF levels (median decline 164.38 pg/ml, range; 2.20–393.04 pg/ml; p= 0.008). No differences in DC activation have been observed. Conclusions: The combination of LD IL-2 and bevacizumab produces antitumor activity and moderate toxicity. Preliminary correlative data demonstrates inhibition of VEGF and increase in Tregs without effect on DC activation. No significant financial relationships to disclose.