tbuckley/cabot-search huggingface dataset:
Effect of exacerbation history on clinical response to dupilumab in moderate-to-severe uncontrolled asthma
Authors: Jonathan Corren, Constance H. Katelaris, Mario Castro, Jorge F. Maspero, Linda B. Ford, David M.G. Halpin, Megan S. Rice, Amr Radwan, Yamo Deniz, Paul J. Rowe, Ariel Teper, Michel Djandji
Journal: European Respiratory Journal (2021)

Background The phase 3 LIBERTY ASTHMA QUEST study ( ClinicalTrials.gov : NCT02414854 ) in patients with uncontrolled, moderate-to-severe asthma has demonstrated the efficacy and safety of dupilumab 200 and 300 mg every 2 weeks versus placebo. This post hoc analysis assessed the effect of dupilumab on efficacy outcomes and asthma control across a range of historical exacerbation rates in patients with type 2-high asthma. Methods Annualised severe exacerbation rates over the 52-week treatment period, pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) at weeks 12 and 52, and the five-item Asthma Control Questionnaire (ACQ-5) score at weeks 24 and 52 were assessed in patients with ≥1, ≥2 or ≥3 exacerbations in the previous year. Subgroups were stratified by baseline blood eosinophils ≥150 or ≥300 cells·μL −1 or baseline exhaled nitric oxide fraction ≥25 ppb and baseline inhaled corticosteroid (ICS) dose. Results Across all type 2-high subgroups, dupilumab versus placebo significantly reduced severe exacerbations by 54–90%, with greater improvements in patients with more exacerbations prior to study initiation. Similarly, improvements in FEV 1 (least squares (LS) mean difference versus placebo: ≥1 exacerbations, 0.15–0.25 L; ≥2 exacerbations, 0.12–0.32 L; ≥3 exacerbations, 0.09–0.38 L; majority p&lt;0.05) and ACQ-5 score (LS mean difference range: ≥1 exacerbations, −0.30 to −0.57; ≥2 exacerbations, −0.29 to −0.56; ≥3 exacerbations, −0.43 to −0.61; all p&lt;0.05) were observed, irrespective of prior exacerbation history, across all subgroups. Conclusions Dupilumab significantly reduced severe exacerbations and improved FEV 1 and asthma control in patients with elevated type 2 biomarkers irrespective of exacerbation history and baseline ICS dose.
Abstract 2898: Rac1 as a driver and therapeutic target in ovarian cancer
Authors: Melanie Rivera, Martha M. Grimes, Laurie G. Hudson, Angela Wandinger-Ness
Journal: Cancer Research (2021)

Abstract Aberrant Rac1 signaling contributes to cancer growth and metastasis, therefore, we investigated the effect of altering Rac1 expression and activity to pinpoint which metastatic processes and tumor microenvironment immune factors are influenced by Rac1 signaling. We have identified that the R- enantiomer of ketorolac, a drug given for pain management, is a Rac1 and Cdc42 selective inhibitor. In a retrospective study, we found that treatment with racemic ketorolac significantly increased the survival probability of ovarian cancer patients. RNA seq analyses of ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief, showed significant downregulation of genes involved in endocytosis, regulation of actin cytoskeleton, ER protein processing, TNF and NOD signaling. To further distinguish the activities most directly regulated by Rac1 and important in ovarian cancer, we tested the impact of manipulating the expression of Rac1 in ovarian cancer cells on adhesive and invasive cell behaviors, as well as the impacts of gene expression relative to ketorolac treatment. Using electric cell-substrate impedance sensing (ECIS), Rac1 overexpression resulted in increased cell-cell barrier formation and cell adhesion. Whereas, CRISPR-CAS9 mediated knockdown of Rac1 resulted in decreased cell adhesion. Using Matrigel invasion chambers and mesothelial clearance assays, Rac1 overexpression led to increased ovarian cancer cell invasion when compared to parental and Rac1 knockdown cell lines. Furthermore, intraperitoneal growth of ovarian cancer cells overexpression Rac1 relative to parental control lines increased tumor burden in vivo. Conversely, with knockdown of Rac1, tumor burden and omental adhesion was decreased, as quantified using IVIS bioluminescence imaging. RNA seq analyses of tumors manipulated for Rac1 as compared to R-ketorolac will be presented. The composite data indicate that targeting Rac1 in ovarian cancer with R-ketorolac or otherwise has therapeutic benefit in decreasing tumor cell dissemination and metastasis. Citation Format: Melanie Rivera, Martha M. Grimes, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 as a driver and therapeutic target in ovarian 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 2898.
Human osteoclast formation and resorptive function on biomineralized collagen
Authors: Daniel de Melo Pereira, Noel Davison, Pamela Habibović
Journal: Bioactive Materials (2021)

Biomineralized collagen composite materials pose an intriguing alternative to current synthetic bone graft substitutes by offering a biomimetic composition that closely resembles native bone. We hypothesize that this composite can undergo cellular resorption and remodeling similar to natural bone. We investigate the formation and activity of human osteoclasts cultured on biomineralized collagen and pure collagen membranes in comparison to cortical bone slices. Human monocytes/macrophages from peripheral blood differentiate into multinucleated, tartrate-resistant alkaline phosphatase (TRAP)-positive osteoclast-like cells on all substrates. These cells form clear actin rings on cortical bone, but not on biomineralized collagen or pure collagen membranes. Osteoclasts form resorption pits in cortical bone, resulting in higher calcium ion concentration in cell culture medium; however, osteoclast resorption of biomineralized collagen and collagen membranes does not measurably occur. Activity of osteoclast enzymes – TRAP, carbonic anhydrase II (CA-II), and cathepsin-K (CTS-K) – is similar on all substrates, despite phenotypic differences in actin ring formation and resorption. The mesh-like structure, relatively low stiffness, and lack of RGD-containing binding domains are likely the factors responsible for preventing formation of stable actin rings on and resorption of (biomineralized) collagen membranes. This insight helps to guide further research toward the optimized design of biomineralized collagen composites as a more biomimetic bone-graft substitute.
Abstract 1940: Autophagy mediates leptin induced migration and erk activation in breast cancer cells
Authors: Alin García Miranda, Karen A. Solano Alcalá, José B. Montes Alvarado, Julio Reyes Leyva, Paola Maycotte, Eduardo Castañeda Saucedo
Journal: Cancer Research (2021)

Abstract Autophagy is an intracellular recycling process active in eukaryotic cells which involves the formation of an autophagosome that delivers cytoplasmic components to the lysosome for degradation. This process occurs at low rates under basal conditions, but it can be induced by diverse stress conditions such as starvation, hypoxia or metabolic disorders. Autophagic flux can also be enhanced in response to hormones, including leptin. Leptin is considered a pro-tumorigenic protein whose circulating levels have been related to a bad prognosis in obese breast cancer patients. It has been recently demonstrated that leptin can induce autophagy in cancer cell lines from different tissues, suggesting that autophagy could modulate the pro-tumorigenic effects associated with leptin. In this study, the role of autophagy in leptin-induced proliferation, migration, apoptosis and ERK phosphorylation in breast cancer cell lines was evaluated. Methods: MCF7 estrogen receptor positive and MDA-MB-231 triple negative breast cancer cell lines were used. MCF7 and MDA-MB-231 cell lines were stimulated with 400 and 50 ng/ml of leptin, respectively. Autophagy was assessed by LC3-II and p62 protein levels by western blot, and autophagosome formation by fluorescence microscopy. Proliferation and migration were assessed by real-time microscopy in an IncuCyte analyzer; and cell death was evaluated by fluorescence analysis of caspase activity. Changes in ERK phosphorylation were measure by western blot. Results: Leptin increased autophagy in MCF7 cells but not in triple negative MDA-MB-231 cells. In MCF7 cells, autophagy inhibition reduced leptin-induced cell proliferation, changes associated to a mesenchymal morphology, cell migration, and ERK activation. In MDA-MB-231 cells, autophagy inhibition reduced proliferation and increased apoptosis independently of leptin treatment. In both cell lines, leptin-induced migration and ERK phosphorylation were reduced by the inhibition of autophagy. Conclusion: Autophagy was important for increased cancer cell migration induced by leptin and for the maintenance of ERK phosphorylation. Our data suggest a potential use for the inhibition of autophagy in breast cancer associated with obesity. Citation Format: Alin García Miranda, Karen A. Solano Alcalá, José B. Montes Alvarado, Julio Reyes Leyva, Paola Maycotte, Eduardo Castañeda Saucedo. Autophagy mediates leptin induced migration and erk activation in breast cancer 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 1940.
Abstract 771: Cytokine expression and levels in plasma-derived exosomes are underestimated as contributors to cytokine profiles in cancer patients and healthy donors
Authors: Chang- Sook Hong, Brenda Diergaarde, Theresa L. Whiteside
Journal: Cancer Research (2021)

Abstract Exosomes play a key role in cell-to-cell signaling. Emerging evidence suggests that biologically active cytokines may be present on the surface or in the lumen of exosomes. We evaluated cytokines in exosomes isolated by size-exclusion chromatography from pre-cleared plasma of 13 patients with head and neck cancer and three healthy donors (HDs). Paired untreated plasma and detergent-treated exosomes were studied by Luminex and cytokine microarrays. On-bead flow cytometry was used to assess relative levels of cytokines on the surface or in the vesicle lumen. Measured by Luminex, for the majority of cytokines (10 of 12), the level observed in plasma was concordant with the level in exosomes. MCP-1 and MIF were the exceptions. They were highly elevated in untreated plasma. Cytokine levels in exosomes determined in parallel by Luminex and the microarray were concordant, except for IL-1β and GM-CSF, which were elevated in Luminex assays. Our data show that only a fraction of most cytokines in untreated plasma is soluble and detectable by Luminex, while the rest is associated with exosomes and can only be detected after exosome permeabilization. Exosome cytokine profiles and levels measured by either method discriminated cancer patients from healthy donors as did levels of soluble cytokines in plasma. By on bead flow cytometry, the relative levels of cytokines in the lumen and on the exosome surface were confirmed for IFN-γ, IL-17, TNF-α and TGF-β, while IL-8 was only detected in the exosome lumen. Thus, cytokines are packaged into exosomes, which carry cytokines on the surface and in the vesicle lumen and contribute to inaccurate, largely underestimated, levels of plasma cytokines reported by laboratories. Citation Format: Chang- Sook Hong, Brenda Diergaarde, Theresa L. Whiteside. Cytokine expression and levels in plasma-derived exosomes are underestimated as contributors to cytokine profiles in cancer patients and healthy donors [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 771.
TOB1はEGF依存性HER2およびEGFRシグナリングにより調節され,高度にリン酸化され,リンパ節陰性乳房腫瘍において予後不良である
Authors: W Helms Mike, Kemming Dirk, H Contag Christopher, Pospisil Heike, Bartkowiak Kai, Wang Alice, Chang Sheng-Yung, Buerger Horst, H Brandt Burkhard
Journal: Cancer Research (2009)
Abstract 17526: The Role of Endothelial Function on Paroxysmal and Chronic Atrial Fibrillation
Authors: Savvas Mazaris, Dimitris Tousoulis, Gerasimos Siasos, Konstantinos Zisimos, Evangelos Oikonomou, Eleni Kokkou, Theodosia Konsola, George Lazaros, Christine Chrysohoou, Christodoulos Stefanadis
Journal: Circulation (2014)

Introduction: Atrial fibrillation (AF) is associated with various cardiovascular diseases. Endothelial dysfunction is well validated as a strong predictor of adverse cardiovascular outcomes. Hypothesis: We hypothesized that endothelial dysfunction affects the development and progression of AF. Methods: We enrolled 152 consecutive subjects with AF. Thirty five subjects had paroxysmal AF and 117 chronic (long standing persistent or permanent) AF. Endothelial function was evaluated by flow mediated dilation (FMD). All subjects underwent two-dimensional echocardiographic assessment. Left ventricle ejection fraction (LVEF) was calculated based on biplane method of discs, left ventricle mass index to body surface area (LVmass/BSA) was calculated with the method of Devereux, left atrial diameter index to body surface area (LAdiam/BSA) was measured from the parasternal window and left atrial volume index to body surface area (LAvol/BSA) was measured based on biplane Simpson’s rule. Results: Subjects with chronic AF compared to subjects with paroxysmal AF were older (73±10 years vs. 66±15 years, p=0.002), had impaired LVEF (44±14% vs. 53±9%, p=0.001) increased LAdiam/BSA (26±4mm/m2 vs. 20±3mm/m2, p&lt;0.001), increased LAvol/BSA (41±9.6ml/m2 vs. 29±7.7ml/m2, p&lt;0.001), increased LVmass/BSA (116±35 gr/m2 vs. 99±29 gr/m2, p=0.06) and impaired creatinine clearance (64±18 ml/min/1.73m2 vs. 83±20 ml/min/1.73m2, p=0.001). Importantly, subjects with chronic AF had impaired FMD compared to subjects with paroxysmal AF (4.09±1.67% vs. 6.83±1.38% p&lt;0.001). In addition, there was an inverse correlation between FMD and LAdiam/BSA (r=-0.53, p&lt;0.001), LAvol/BSA (r=-48, p&lt;0.001), LVmass/BSA (r=-0.364, p=0.007) and a positive correlation between FMD and LVEF (rho=0.30, p=0.003). Interestingly, a linear regression model revealed that subjects with chronic AF had impaired FMD [b=-1.61 95%CI(-2.33 to -0.89), p&lt;0.001] even after adjustment for confounders such as age, sex, LVEF, LVmass/BSA, LAvol/BSA, creatinine clearance, arterial hypertension and the presence of diabetes mellitus. Conclusions: Endothelial dysfunction is associated with atrial remodeling in patients with AF and is implicated in the progression from paroxysmal to chronic AF.
Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma
Authors: Clément Meiller, François Montagne, Theo Z. Hirsch, Stefano Caruso, Julien de Wolf, Quentin Bayard, Jean-Baptiste Assié, Léa Meunier, Yuna Blum, Lisa Quetel, Laure Gibault, Ecaterina Pintilie, Cécile Badoual, Sarah Humez, Françoise Galateau-Sallé, Marie-Christine Copin, Eric Letouzé, Arnaud Scherpereel, Jessica Zucman-Rossi, Françoise Le Pimpec-Barthes, Marie-Claude Jaurand, Didier Jean
Journal: Genome Medicine (2021)

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2 , a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.
Abstract 3024: Targeting the RNA binding protein LIN28B in Group 3 medulloblastoma decreases proliferation and promotes apoptosis
Authors: Shubin W. Shahab, Jo Lynne Rokita, Kyle Juraschka, Sachin Kumar, Michael Taylor, Robert W. Schnepp, Tobey J. MacDonald, Anna M. Kenney
Journal: Cancer Research (2021)

Abstract Medulloblastoma (MB) is the most common pediatric malignant brain tumor and is currently divided into WNT, SHH, Group 3 and Group 4 subtypes. Even with multimodal chemotherapy, radiotherapy and surgery, many children with Group 3 MBs do not survive. While the molecular aberrations underlying WNT- and SHH-driven MBs are relatively well understood, the oncogenic drivers that lead to Group 3/4 MBs are poorly defined, limiting therapeutic progress. In addition to genetic mutations and alterations, cancers display dysregulated transcription and translation. RNA-binding proteins (RBPs) play key roles in both transcription and translation, and a subset of RBPs are differentially expressed in many different cancers. Indeed, we have previously demonstrated an oncogenic role for the RBP LIN28B in neuroblastoma and it is known to be upregulated in Wilms tumor, hepatoblastoma, germ cell tumors, leukemia among others. LIN28B is a key regulator of let-7 family miRNAs, which in turn inhibit LIN28B and other oncogenes. We hypothesize that LIN28B plays an important role in Group 3 MB and that a better understanding of LIN28B and LIN28B-driven networks will reveal novel therapeutic vulnerabilities. In support of our hypothesis we find that among the four subtypes, LIN28B levels are highest in Group 3 MB, and that overexpression is associated with significantly worse survival. Down-regulation of LIN28B results in significant reduction in cell proliferation by CellTiter-Glo and increased apoptosis by Caspase-Glo (as well as induction of cleaved PARP on immunoblots). In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. In addition we find that PDZ-binding kinase (PBK) a downstream target of LIN28B is downregulated when LIN28B is depleted. PBK knock down also leads to decreased proliferation of Group 3 MB cells. Finally, in order to robustly define the signaling networks downstream from LIN28B that are involved in Group 3 MB metastasis, we have performed who transcriptome RNA-seq profiling of two group 3 cell lines following LIN28B depletion and plan to interrogate a subset of these based on expression change and functional relevance to LIN28B-mediated Group 3 MB metastasis. This work will help define the role for LIN28B in Group 3 MB aggressiveness and pave the way for similar studies in other cancers. Citation Format: Shubin W. Shahab, Jo Lynne Rokita, Kyle Juraschka, Sachin Kumar, Michael Taylor, Robert W. Schnepp, Tobey J. MacDonald, Anna M. Kenney. Targeting the RNA binding protein LIN28B in Group 3 medulloblastoma decreases proliferation and promotes apoptosis [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 3024.
Abstract 987: Ovarian carcinoma cells are susceptible to ferroptosis
Authors: Jing Li, Oscar Gee Wong, Annie Nga Cheung
Journal: Cancer Research (2021)

Abstract Ovarian carcinoma (OC) is a malignancy with grave prognosis owing to its high recurrence rate and broad resistance to a variety of apoptosis-inducing chemotherapeutic agents. Induction of alternative, non-apoptotic cell death represents a novel strategy for anti-cancer therapies worldwide. Ferroptosis is a recently defined type of non-apoptotic cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS), resulting in membrane damage and cell rupture. Lines of evidence suggested that OC may be susceptible to ferroptosis. However, the exact effects mediated by ferroptosis and the underlying regulatory mechanisms in OC are not fully characterized. Herein, we sought to explore the susceptibility of a number of OC cell line models towards ferroptosis and investigate the possibility of enhancing conventional platinum-based chemotherapy with ferroptosis inducers. Ferroptosis inducers Erastin and RSL3 dose-dependently induced ferroptotic cell death in ovarian cancer cell lines OVCAR3 and TUOC1, hallmarked by a significant decrease of GSH level and increase of ROS and lipid peroxidation levels after treatment. Treatment by a lipid ROS scavenger ferrostatin-1 (Fer-1), but not by the apoptosis inhibitor Z-VAD-FMK, significantly rescued OVCAR3 and TUOC1 cells from Erastin- and RSL3- induced cell death. Additionally, Erastin and RSL3 could significantly promote cytotoxicity of cisplatin in a cisplatin-resistant ovarian cancer cells OVCA420. Collectively, our results indicate a crucial role of ferroptosis in susceptibility of ovarian carcinomas, suggesting a potential anticancer strategy. Citation Format: Jing Li, Oscar Gee Wong, Annie Nga Cheung. Ovarian carcinoma cells are susceptible to ferroptosis [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 987.