tbuckley/cabot-search huggingface dataset:
Abstract 986: Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway
Authors: Mike Dorothea, Stephanie PT Yiu, Kwai Fung Hui, Alan K. S. Chiang
Journal: Cancer Research (2021)

Abstract The reactivation of lytic cycle of Epstein-Barr Virus (EBV) is an important component of the emerging lytic induction therapy to specifically target the virus in EBV-associated malignancies. The potency of the lytic induction is central to the effectiveness of the lytic induction therapy. It is hampered by cancer cells that are refractory to lytic induction. This study aims to elucidate novel pathways involved in inducing EBV lytic cycle in epithelial cancer cells using a small organic compound, E11 intermediate (E11.1), and develop new drug combinations to overcome the refractoriness of the cancer cells to lytic induction. E11.1 was found to be the active component in the original E11 compound which has a superior lytic induction capability in both gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Timepoint and dose dependent studies were performed to characterize E11.1's lytic reactivation kinetics of EBV in AGS-BDneo cells. Reactive oxygen species (ROS) scavengers and chemical pathway inhibitors were used to investigate the involvement of ROS and major cellular pathways in inducing lytic cycle of EBV by E11.1. Concomitant drug treatment of E11.1 and histone deacetylase (HDAC) inhibitor (suberoylanilide hydroxamic acid or romidepsin) was tested for synergistic action in lytic induction and cell death. E11.1 elicited a rapid kinetics of lytic induction through the activation of c-Jun N-terminal kinase (JNK) pathway in GC and NPC cells and induced the production of ROS and cell death at later timepoints. The combination of E11.1 and HDAC inhibitor reactivated the lytic cycle of EBV synergistically in both GC and NPC lines at 48 hours of treatment. In conclusion, we provided the evidence of activation of JNK pathway in the induction of EBV lytic cycle by E11.1 in EBV-positive epithelial malignancies. E11.1 and HDAC inhibitor induced the lytic cycle of EBV in EBV-positive epithelial cancer cells synergistically resulting in enhanced cell death. Citation Format: Mike Dorothea, Stephanie PT Yiu, Kwai Fung Hui, Alan K. S. Chiang. Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 986.
Abstract 15105: Comparative Analysis of Measured vs. Estimated VO2 in Sedated, Spontaneously Breathing Congenital Cardiac Catheterization Patients
Authors: Stephan Juergensen, Shalin Parekh, Amy Iams, Phillip Moore
Journal: Circulation (2019)

Background: Accurate estimation of VO2 is needed for reliable calculation of blood flow and resistance in patients with congenital heart disease. Commonly used estimates of VO2 are based on data fr...
Abstract 2682: STK11-loss-dependent YAP1-mediated transcriptional activation promotes immune evasion in KRAS-driven lung adenocarcinoma
Authors: David Joseph Seward
Journal: Cancer Research (2021)

Abstract Why Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD1 therapy resistance in the context of KRAS-driven lung adenocarcinomas remains unclear and represents a critical outstanding question in the field. To address this, we knocked out STK11 in KRAS-driven human lung adenocarcinoma cell lines and performed RNAseq to identify STK11-loss-dependent differentially expressed genes. Subsequent pathway enrichment analyses implied activation of the HIPPO/YAP1 signaling network occurs in the absence of STK11. Based on work linking YAP1 with transcriptional regulation of cytokine-mediated inflammation and immune-evasion in colorectal cancer and gastric cancer, we wondered whether YAP1 activation might impact anti-PD1 therapy response in KRAS-driven lung cancers lacking STK11. To evaluate this possibility, we applied a YAP1 transcriptional signature to the differentially expressed genes and performed gene set enrichment analysis (GSEA) revealing a strong positive correlation between STK11 LoF and upregulation of YAP1 target genes, most notably induction of IL-6, IL-8 and IL-32. To validate YAP1-mediated transcriptional activation is downstream of STK11 loss, we reasoned we could rescue STK11-loss-dependent YAP1-mediated cytokine induction by genetic disruption of YAP1, or pharmacologic inhibition of YAP1 with verteporfin. STK11/YAP1 double knock-out cell lines express significantly less IL-6, IL-8 and IL-32 compared with STK11 KO lines. Further, inhibition of YAP1 with verteporfin phenocopied YAP1 genetic disruption in these cell lines, changes mirrored at the level of secreted protein. Finally, we demonstrate YAP1 chromatin occupancy is STK11-dependent. Together these data link STK11 LoF with YAP1-mediated transcriptional activation, specifically the upregulation of immune-evasion promoting cytokines including IL-6, IL-8 and IL-32. We posit these STK11-loss-dependent YAP1-mediated tumor-intrinsic changes could result in anti-PD1 therapy resistance and immune-evasion by promoting recruitment of myeloid-derived suppressor cells, neutrophils and T-regulatory cells to the tumor microenvironment. Further, our results indicate that YAP1 antagonism may represent a valid therapeutic approach to circumvent STK11-loss-dependent transcriptional changes and potentially restore sensitivity to anti-PD1 therapy. Elucidating the mechanism(s) linking STK11 with YAP1 transcriptional activation and evaluating the potential for beneficial therapeutic intervention remains the focus of our continuing work. Citation Format: David Joseph Seward. STK11-loss-dependent YAP1-mediated transcriptional activation promotes immune evasion in KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2682.
Development of a classification system for reporting postoperative complications in prostate cancer patients treated with robot-assisted radical prostatectomy: A comprehensive analysis based on the EAU guidelines recommendations
Authors: G. Rosiello, G. Gandaglia, N. Fossati, S. Scuderi, A. Martini, F. Barletta, A. Stabile, V. Cucchiara, C.A. Bravi, D. Robesti, D. Cannoletta, A. Pellegrino, E. Camisassa, S. Comana, L. Sciacqua, E. Mazzone, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Historical HbA1c Values May Explain the Type 2 Diabetes Legacy Effect: UKPDS 88
Authors: Marcus Lind, Henrik Imberg, Ruth L. Coleman, Olle Nerman, Rury R. Holman
Journal: Diabetes Care (2021)

Type 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA
The multiple roles of RAB GTPases in female and male meiosis
Authors: Meng-Meng Shan, Shao-Chen Sun
Journal: Human Reproduction Update (2021)

Abstract BACKGROUND RAB GTPases constitute the largest family of small GTPases and are found in all eukaryotes. RAB GTPases regulate components of the endomembrane system, the nucleus and the plasma membrane, and are involved in intracellular actin/tubulin-dependent vesicle movement, membrane fusion and cell growth in mitosis. OBJECTIVE AND RATIONALE RAB GTPases play multiple critical roles during both female and male meiosis. This review summarizes the progress made in our understanding of the role of RAB GTPases in female and male meiosis in different species. We also discuss the potential relationship between RAB GTPases and oocyte/sperm quality, which may help in understanding the mechanisms underlying oogenesis and spermatogenesis and potential genetic causes of infertility. SEARCH METHODS The PubMed database was searched for articles published between 1991 and 2020 using the following terms: ‘RAB’, ‘RAB oocyte’, ‘RAB sperm’ and ‘RAB meiosis’. OUTCOMES An analysis of 126 relevant articles indicated that RAB GTPases are present in all eukaryotes, and ten subfamilies (almost 70 members) are expressed in human cells. The roles of 25 RAB proteins and orthologues in female meiosis and 12 in male meiosis have been reported. RAB proteins are essential for the accurate continuity of genetic material, successful fertilization and the normal growth of offspring. Distinct and crucial functions of RAB GTPases in meiosis have been reported. In oocytes, RAB GTPases are involved in spindle organization, kinetochore–microtubule attachment, chromosome alignment, actin filament-mediated spindle migration, cytokinesis, cell cycle and oocyte–embryo transition. RAB GTPases function in mitochondrial processes and Golgi-mediated vesicular transport during female meiosis, and are critical for cortical granule transport during fertilization and oocyte–embryo transition. In sperm, RAB GTPases are vital for cytoskeletal organization and successful cytokinesis, and are associated with Golgi-mediated acrosome formation, membrane trafficking and morphological changes of sperm cells, as well as the exocytosis-related acrosome reaction and zona reaction during fertilization. WIDER IMPLICATIONS Abnormal expression of RAB GTPases disrupts intracellular systems, which may induce diverse diseases. The roles of RAB proteins in female and male reproductive systems, thus, need to be considered. The mechanisms underlying the function of RAB GTPases and the binding specificity of their effectors during oogenesis, spermatogenesis and fertilization remain to be studied. This review should contribute to our understanding of the molecular mechanisms of oogenesis and spermatogenesis and potential genetic causes of infertility.
Abstract 1801: Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor
Authors: Christopher Brueckner, Ryan Faucette, Charles Caldwell, Sofia Reitsma, Stefan Wawersik, Ashish Kalra, Lu Gan, Si Tuen Lee-Hoeflich
Journal: Cancer Research (2021)

Abstract TGFβ signaling appears to be a key mediator of primary resistance to programmed cell death protein (PD-1) pathway blockade. SRK-181 is an investigational stage, high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. Preclinical data demonstrate that combining SRK-181 with a PD-1 inhibitor modulates tumor microenvironment (TME), including an influx of CD8 positive T cells that correlates with anti-tumor responses. The ongoing DRAGON trial is a multi-center, open-label, Phase 1, first in-human (FIH), dose-escalation, and dose-expansion study. The goal of the trial is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. To support this ongoing DRAGON clinical trial and further explore the mechanism of action of SRK-181, a comprehensive biomarker strategy is being developed to assess the alternation of immune profile in TME and potential predictors of therapeutic response to SRK-181. Here we describe the development and refinement of several biomarker assays. First, an image analysis-based algorithm for CD8 immunohistochemistry (IHC) is established utilizing human cancer tissue in a pre-clinical study. This novel digital pathology analysis enables identification of CD8 positive T cells in discrete compartments, including the tumor nests, stroma and tumor/stromal margins, to better capture the heterogeneity of the CD8 signal within tissues. Second, we describe methods to evaluate the TGFβ pathway including quantitative analysis of tumor tissue phospho-Smad2 and circulatory levels of TGFβ1 ligand. A companion assay to exclude blood samples with nonspecific background signals has been characterized and will be performed in parallel when evaluating circulatory TGFβ1 in clinic. In summary, we present several novel, tailored biomarker readouts that are part of a broader biomarker strategy aimed at maximizing detection of relevant clinical data to both support the ongoing clinical trial and provide further insight into the mechanism of action of SRK-181. Citation Format: Christopher Brueckner, Ryan Faucette, Charles Caldwell, Jr., Sofia Reitsma, Stefan Wawersik, Ashish Kalra, Lu Gan, Si Tuen Lee-Hoeflich. Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1801.
Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE
Authors: Jesus San-Miguel, Hervé Avet-Loiseau, Bruno Paiva, Shaji Kumar, Meletios A. Dimopoulos, Thierry Facon, María-Victoria Mateos, Cyrille Touzeau, Andrzej Jakubowiak, Saad Z. Usmani, Gordon Cook, Michele Cavo, Hang Quach, Jon Ukropec, Priya Ramaswami, Huiling Pei, Mia Qi, Steven Sun, Jianping Wang, Maria Krevvata, Nikki DeAngelis, Christoph Heuck, Rian Van Rampelbergh, Anupa Kudva, Rachel Kobos, Ming Qi, Nizar J. Bahlis
Journal: Blood (2021)
Abstract 2519: Targeting glucose metabolism in HER2+breast cancer
Authors: Simone Chang, Jason Chesney, John O. Trent, Sucheta Telang
Journal: Cancer Research (2021)

Abstract Primary and metastatic breast cancers are driven by oncogenic mutations to rely on glucose metabolism to support their rapid proliferation. Of these genetic changes, the increased activity of the human epidermal growth factor receptor 2 (HER2/ErbB2) is observed in a third of all breast tumors. HER2 has been shown to activate downstream effectors (e.g. Ras, HIF-1α) that stimulate glycolysis - in part by activation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which activates a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1). In preliminary studies, we found that the PFKFB4 family member was highly expressed in a series of patient-derived HER2+ breast tumors relative to normal breast with markedly higher expression in their matched metastatic lymph nodes. We next determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in HER2+ breast cancer cells and inhibited tumor growth in vivo. Through virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits PFKFB4 activity with a resultant decrease in F26BP, glycolysis and cancer cell growth. 5MPN also caused a significant decrease in the invasion and migration of HER2+ breast cancer cells in vitro, importantly at concentrations well below levels that affect cell viability and marked suppression in the growth of established tumors, without systemic toxicity. In additional studies, we have found that the related PFKFB3 isoform is also expressed in HER+ breast tumors. Our previous work found that the PFKFB4 enzyme localizes to the cytoplasm (where PFK1 and the glycolytic pathway function) indicating a possible dominant role for PFKFB4 in glycolytic regulation. PFKFB3 however largely localized to the nucleus where it serves an important function in proliferation via activation of cyclin-dependent kinases. Based on the different roles played by these enzymes in cancer cells, we next evaluated the effects of simultaneous administration of 5MPN ± a clinical candidate PFKFB3 inhibitor on survival and proliferation in HER2+ breast cancer and found that the combination synergistically and significantly decreased viability and growth in several examined HER2+ breast cancer cell lines. Our data indicate that targeting PFKFB4 may be a viable therapeutic option against breast cancer and strongly support the further exploration of co-targeting PFKFB4 and PFKFB3 as a potential therapeutic strategy for the successful treatment of HER2+ breast cancer. Citation Format: Simone Chang, Jason Chesney, John O. Trent, Sucheta Telang. Targeting glucose metabolism in HER2+breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2519.
Impact of In Vivo T-Cell Depletion in Patients with Myelodysplastic Syndromes Undergoing Allogeneic Hematopoietic Stem Cell Transplant: A Registry Study from the Chronic Malignancies Working Party of the EBMT
Authors: Edouard Forcade, Sylvie Chevret, Jürgen Finke, Gerhard Ehninger, Francis A Ayuk, Dietrich W Beelen, Linda Koster, Arnold Ganser, Gérard Socié, Liisa Volin, Henrik Sengeloev, Mauricette Michallet, Johanna Tischer, Pavel Jindra, Maria-Jesús Pascual, Yener Koc, Mutlu Arat, T. M. M de Witte, Nicolaus Kröger, Marie Robin
Journal: Blood (2017)
Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination
Authors: Johan Normark, Linnea Vikström, Yong-Dae Gwon, Ida-Lisa Persson, Alicia Edin, Tove Björsell, Andy Dernstedt, Wanda Christ, Staffan Tevell, Magnus Evander, Jonas Klingström, Clas Ahlm, Mattias Forsell
Journal: New England Journal of Medicine (2021)

Heterologous Vaccination with ChAdOx1 nCoV-19 and mRNA-1273 Health care workers who had received a dose of ChAdOx1 nCoV-19 were offered a choice of receiving either ChAdOx1 nCoV-19 or mRNA-1273 9 t...
Linguistic and clinical validation of the Spanish Acute Cystitis Symptoms Score (ACSS) questionnaire in females with acute cystitis
Authors: J. Medina-Polo, A. Arrébola-Pajares, J.F. Alidjanov, M.F. Lorenzo-Gómez, J.G. Corrales-Riveros, A.M. Tapia-Herrero, M.L. Martínez-Berganza, I.A. Ospina-Galeano, B.Y. Padilla-Fernández, A. Pilatz, K.G. Naber, F.M. Wagenlehner
Journal: European Urology (2021)
Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A Systematic Review and Meta-Analysis
Authors: Francesco Passiglia, Michela Cinquini, Luca Bertolaccini, Marzia Del Re, Francesco Facchinetti, Roberto Ferrara, Tindara Franchina, Anna R. Larici, Umberto Malapelle, Jessica Menis, Antonio Passaro, Sara Pilotto, Sara Ramella, Giulio Rossi, Rocco Trisolini, Silvia Novello
Journal: Journal of Clinical Oncology (2021)

This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS.Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach.Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer-related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer-related mortality by sex revealed nonsignificant differences between men and women (P = .21; I-squared = 33.6%).Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.
Fatigue, quality-of-life and metabolic changes in men treated with enzalutamide versus abiraterone plus prednisone for metastatic castration-resistant prostate cancer (HEAT): A randomised trial
Authors: K. Kvorning Ternov, J. Sønksen, M. Fode, H. Lindberg, C. Kistorp, R. Bisbjerg, J. Faber, T.W. Klausen, G. Palapattu, P.B. Østergren
Journal: European Urology (2021)
Abstract 1868: A long acting bi-specific T cell engager differentially targeting CD47 positive malignant cells but not CD47 expressing healthy cells
Authors: Shumin Liu, Weidong Lyu, Yang Lei, Shuangyu Tan, Zibin Wu, Shuqiang Yin, Liling Zheng, Qiudong Zhuo, Yu (Yvonne) Wen, David Wu
Journal: Cancer Research (2021)

Abstract Currently both bispecific T cell engagers (BiTE) and innate immune checkpoint blockades (eg. Anti-CD47/SIRPα) have been under development. In this study, we developed a novel compound pegylated anti-CD3 x anti-CD47 which could act with dual mechanisms of both a BiTE and an innate immune checkpoint blockade. The compound did not induce hemagglutination of RBC cells at the extremely high concentration of 2250 ug/ml, while the corresponding monoclonal antibody Hu5F9-G4 did at the concentration as low as 16.67 ug/ml. Meanwhile, in a T cell apoptosis assay, the apoptotic T cells were 16.13%, only 5.9% higher than that of the control T cell sample at the concentration of 100ug/ml of the compound and were about the same as the control sample (10.23%) at concentration of 10 ug/ml of the compound. For comparison, the reported T cell apoptosis induced by 10ug/ml Hu5F9-G4 was as high as 70%. Furthermore, the target affinity by flow cytometry demonstrated that at the concentration 10ug/ml of the compound, stained RBCs were 0.551%, while the compound bound BxPC3 cells were 22.1%, a 40-fold difference in binding. At the concentration 100ug/ml of the compound, only 7.24% RBCs were stained positively, but stained BxPC3 cells were as high as 89.3%. Although not completely understood yet, unique structure of the compound (PEGylated scFv antibody v.s. Fc-bearing antibodies) may have contributed to the differential effect of the compound to healthy cells and tumor cells, resulting in high safety performance of the compound. Furthermore, pharmacokinetics study demonstrated that in vivo elimination half-life of the compound in wild type C57BL/6 mice was 18.4 hours for the single dose of 1mg/kg. Further preclinical study about the compound is still ongoing. Citation Format: Shumin Liu, Weidong Lyu, Yang Lei, Shuangyu Tan, Zibin Wu, Shuqiang Yin, Liling Zheng, Qiudong Zhuo, Yu (Yvonne) Wen, David Wu. A long acting bi-specific T cell engager differentially targeting CD47 positive malignant cells but not CD47 expressing healthy cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1868.