tbuckley/cabot-search huggingface dataset:
Abstract 5127: Eradication of the gut microbiota reduces cancer burden in multiple models by modulating the immune system
Authors: Vrishketan Sethi, Saba Kurtom, Mohd Tarique, Bhuwan Giri, Bharti Garg, Shweta Lavania, Anthony Ferrantella, Zoe Malchiodi, Leonor Hellmund, Harrys Charles Jacob, Rajinder Dawra, Sulagna Banerjee, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja
Journal: Cancer Research (2018)

Abstract Introduction: Bacteria residing in the human body outnumber ‘human' cells and most of these bacteria exist in the gut. This gut microbiome forms a unique and dynamic metagenome which changes with nutrition and even disease state. A growing body of evidence has implicated the role of the gut microbiome in modulating our immune system. We aimed to investigate this association in murine models of cancer. Methods: C57BL/6 mice were either orally given saline or a gut sterilizing cocktail of poorly absorbable broad-spectrum antibiotics. These mice were used to model multiple cancers, viz. subcutaneous injection of melanoma cells derived from Tyr::CreER; Braf V600E/+;Ptenlox5/lox5 mice, subcutaneous injection of pancreatic cancer cells derived from KPC (Kras LSL.G12D/+; p53 R172H/+ ;Pdx::Cre) mice, intrasplenic injection of KPC pancreatic cancer cells and intrasplenic injection of B16-F10 melanoma cells. The tumors were immunophenotyped through flow cytometry and immunostained for multiple antigens. Mice plasma was used for chemokine analysis. To confirm the role of immunity, subcutaneous experiments were repeated in mice carrying a Rag1tm1Mom mutation (RAG1 knockout), thereby having an immature adaptive immune system. Results: Gut microbiome depletion reduced tumor burden across all four subcutaneous and hepatic metastases models. This effect disappeared when experiments were repeated in immunosuppressed RAG1 knockout mice. Antibiotic-treated tumors had increased TNF-secreting macrophages and NKT cells as well a higher number of iNOS staining cells in the microenvironment. Plasma from antibiotic-treated tumor-bearing mice had decreased levels of CXCL12, a chemokine known to cause tumor immunosuppression. Conclusion: Eradication of the gut microbiota decreases tumor burden by activating the anti-cancer immune system Citation Format: Vrishketan Sethi, Saba Kurtom, Mohd Tarique, Bhuwan Giri, Bharti Garg, Shweta Lavania, Anthony Ferrantella, Zoe Malchiodi, Leonor Hellmund, Harrys Charles Jacob, Rajinder Dawra, Sulagna Banerjee, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja. Eradication of the gut microbiota reduces cancer burden in multiple models by modulating the immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5127.
Grade 3 Neuroendocrine Tumor (G3 NET) in a Background of Multiple Serotonin Cell Neoplasms of the Ileum Associated with Carcinoid Syndrome and Aggressive Behavior
Authors: Francesca Capuano, Oneda Grami, Luigi Pugliese, Marco Paulli, Andrea Pietrabissa, Enrico Solcia, Alessandro Vanoli
Journal: Endocrine Pathology (2018)
Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure
Authors: ShinichiOkuda, MasafumiYano, MasahiroDoi, TetsuroOda, TakahiroTokuhisa, MasateruKohno, ShigekiKobayashi, TakeshiYamamoto, TomokoOhkusa, MasunoriMatsuzaki
Journal: Circulation (2004)

Background— Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure. Methods and Results— SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of β-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A–hyperphosphorylated, showed an abnormal Ca2+ leak, and had a decreased amount ...
Atrial Mapping and Radiofrequency Catheter Ablation in Patients With Idiopathic Atrial Fibrillation
Authors: FiorenzoGaita, RiccardoRiccardi, LeonardoCalò, MarcoScaglione, LuciaGarberoglio, RenzoAntolini, MicheleKirchner, FilippoLamberti, ElenaRichiardi
Journal: Circulation (1998)

Background—Knowledge of the electrophysiological substrates and the cure of atrial fibrillation (AF) is still unsatisfactory. The goal of this study was to evaluate the electrophysiological features of idiopathic AF and their relationship to the results of radiofrequency (RF) catheter ablation of AF and the safety and effectiveness of this procedure. Methods and Results—Sixteen patients with idiopathic AF underwent atrial mapping during AF and then RF ablation in the right atrium. The atrial activation was simultaneously recorded in four regions in the right atrium: high lateral wall (HL), low lateral wall (LL), high septum (HS), and low septum (LS) and in the left atrium through the coronary sinus (CS). In these regions, we evaluated the atrial fibrillation intervals (FF) and the morphological features of AF recordings by Wells’ classification. No complications occurred during RF ablation. Of the 16 patients, 9 (56%) without AF recurrences during the follow-up (11±4 months) were considered successfully a...
Abstract 1842: Novel KIF5B-RET+ NSCLC cell lines demonstrate differential responses to RET inhibitors
Authors: Laura Schubert, Anh T. Le, Andrea E. Doak, Robert C. Doebele
Journal: Cancer Research (2018)

Abstract Chromosomal rearrangements involving the rearranged during transfection (RET) tyrosine kinase occur in 1-2% of NSCLCs. This results in the expression of a constitutively active fusion kinase that promotes cancer cell growth, proliferation and survival. In lung cancer, RET is most commonly fused to KIF5B, but can have many other 5' partners such as CCDC6, NCOA, TRIM33 and TRIM24. Clinical trials with several multi-kinase inhibitors, which potently inhibit RET, have had low response rates between 18-53%. Novel, more highly specific RET inhibitors are now in clinical development. Collectively, the clinical trial data suggest that patients with KIF5B-RET rearrangements have exceptionally low responses to RET inhibitors in relation to non-KIF5B-RET fusions. In order to understand the role of RET 5' partners in regulating response to RET inhibitors we have generated two novel KIF5B-RET+ patient-derived cell lines, CUTO22 (K23;R12) and CUTO32 (K15;R12). We have confirmed that each of these cell lines contain the KIF5B-RET fusion and express the RET fusion protein. MTS proliferation assays have revealed that the CUTO22 cell line is very sensitive to the highly specific RET inhibitor, CEP-32496/RXDX-105, and the multi-kinase inhibitor ponatinib. Conversely, the CUTO32 cell line is dramatically resistant to both RXDX-105 and ponatinib. Phospho-RET (pRET) is inhibited by RXDX-105 and ponatinib in a dose-dependent manner in both the CUTO22 and CUTO32 cell line. Interestingly, despite successful RET inhibition, downstream signaling in pERK and pAKT remains active. In a time-course experiment, pRET is inhibited for up to 24 hours while pERK and pAKT is sustained. Additionally, knockdown of RET with siRNA did not reduce downstream signaling activation in CUTO22 or CUTO32 cells. Combined inhibition of possible bypass pathways, EGFR or mTOR, did not significantly enhance sensitivity to RET inhibitors in CUTO22 and CUTO32 cell lines. To isolate the role of the 5' partners in response to RET inhibitors we have utilized CRISPR/Cas9 technology to generate Kif5b-Ret and Trim24-Ret rearrangements in Ba/F3 cells. We have confirmed with PCR or RT-PCR that these cell lines harbor the intended Ret fusions and express the RET protein. Both the Kif5b-Ret+ and Trim24-Ret+ Ba/F3 cell lines are highly sensitive to multiple RET inhibitors. In conclusion, these data suggest that RET inhibitors successfully inhibit the target protein, but not downstream signaling, suggesting that KIF5B-RET may have unique co-alterations or reliance on alternative pathways to promote growth and proliferation. Citation Format: Laura Schubert, Anh T. Le, Andrea E. Doak, Robert C. Doebele. Novel KIF5B-RET+ NSCLC cell lines demonstrate differential responses to RET inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1842.
Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension
Authors: SaadiaEddahibi, ChristopheGuignabert, Anne-MarieBarlier-Mur, LaurenceDewachter, ElieFadel, PhilippeDartevelle, MarcHumbert, GeraldSimonneau, NaïmaHanoun, FrançoiseSaurini, MichelHamon, SergeAdnot
Journal: Circulation (2006)

Background— The mechanism of pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary artery hypertension (iPH) may involve both an inherent characteristic of PA-SMCs and abnormal control by external stimuli. We investigated the role of pulmonary microvascular endothelial cells (P-ECs) in controlling PA-SMC growth. Methods and Results— Serum-free medium of quiescent P-ECs elicited marked PA-SMC proliferation, and this effect was greater with P-ECs from patients with iPH than from control subjects and greater with PA-SMCs from these patients than from control subjects. Fluoxetine, which inhibits serotonin-induced mitogenesis by blocking the serotonin transporter, and p-chlorophenylalanine, which inhibits serotonin synthesis by blocking tryptophan hydroxylase (TPH), caused a similar 60% reduction in the growth-promoting effect of P-EC media, whereas endothelin receptor blockers had no effect. Assays of TPH activity in P-EC medium based on p-chlorophenylalanine–sensitive 5-hydroxytryp...
The Long Noncoding RNA CHRF Regulates Cardiac Hypertrophy by Targeting miR-489
Authors: KunWang, FangLiu, Lu-YuZhou, BoLong, Shu-MinYuan, YinWang, Cui-YunLiu, TengSun, Xiao-JieZhang, Pei-FengLi
Journal: Circulation Research (2014)

Rationale:Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years. Objective:We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro. Methods and Results:A microarray was performed to analyze miRNAs in response to angiotensin II treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response on angiotensin II treatment. We identified myeloid differentiation primary response gene...
Abstract 1911: Uncovering novel targets of recurrent glioblastoma using transcriptomic profiling in a patient-derived xenograft model
Authors: Nicolas Yelle, Chirayu Chokshi, Parvez Vora, Kevin R. Brown, Maleeha A. Qazi, Mohini Singh, Jarrett J. Adams, Chitra Venugopal, Sachdev Sidhu, Jason Moffat, Sheila K. Singh
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most common and aggressive adult primary brain tumor feared for its near uniformly fatal prognosis despite advances in multimodal therapy including surgical resection, chemotherapy and radiation. Poor patient survival due to tumor relapse is thought to be linked to intratumoral heterogeneity (ITH), driven by various environmental cues including chemotherapy and radiation treatment. ITH can be explained at the cellular level by the existence of multiple populations of cancer cells, including cancer stem cells (CSCs), which have acquired stemness properties like self-renewal, proliferation, and multilineage differentiation. In brain tumors, CSCs or brain tumor initiating cells (BTICs), have been shown to be resistant to both chemotherapy and radiation treatment, allowing them to escape therapy and allowing for tumor recurrence. To profile ITH as it evolves through therapy delivery, we have developed a novel and dynamic BTIC patient-derived xenograft (PDX) model of treatment-refractory human GBM, allowing for multimodal profiling of GBM BTICs through tumor engraftment, remission, and recurrence. In this study, we present the transcriptomic profiling at each stage, and novel target selection and validation through CRISPR/Cas9 knockouts, well-established in vitro stem cell assays, and in vivo characterization of their tumor initiation, development, and maintenance properties. Despite the fact that the BTIC population is responsible for GBM recurrence and thus patient demise, it remains a largely unknown landscape. Consequently, therapies that focus on targeting the BTIC compartment within the bulk tumor would provide better treatment and prognosis for patients with brain tumors. The study we present provides a unique therapeutic window into the recurrence of GBM, which drives patient mortality, yet is profiled far less than primary treatment-naïve GBM. Citation Format: Nicolas Yelle, Chirayu Chokshi, Parvez Vora, Kevin R. Brown, Maleeha A. Qazi, Mohini Singh, Jarrett J. Adams, Chitra Venugopal, Sachdev Sidhu, Jason Moffat, Sheila K. Singh. Uncovering novel targets of recurrent glioblastoma using transcriptomic profiling in a patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1911.
Abstract 4385: p53 activation induces a targetable dependence on FLIPL
Authors: Alexander McIntyre, Andrea Lees, Fiammetta Falcone, Gemma Gregg, Sessler Tamas, Gerard Quinn, Nyree Crawford, Darragh McArt, Phillip Dunne, Mark Lawler, Longley B. Daniel, Simon S. McDade
Journal: Cancer Research (2018)

Abstract Background The tumor suppressive functions of the p53 transcription factor are inactivated via mutations or suppressed through non-mutational mechanisms in almost all cancer cells. A better understanding of the mechanisms through which p53 differentially regulates cell cycle arrest and cell death is important to maximize benefits from wild-type p53-dependent therapeutic strategies Methods A panel of matched p53 wild-type and deficient colorectal cancer cell line models were studied, using Nutlin-3A and Oxaliplatin as direct and indirect p53 activating agents respectively. A number of molecular (Western blot, RT-PCR), phenotypic (cell death) and genomic analyses were used to investigate the importance of p53 and its downstream transcriptional programs. Results Here, we report that activation of pro-apoptotic p53 targets in colorectal cancer cells imposes a critical targetable dependence on the long splice form of the caspase-8 regulator FLIP (FLIPL) for survival. p53 binds the promoter of the FLIP gene (CFLAR) and upregulates FLIPL expression in response to the p53 agonist Nutlin-3A in a manner dependent on HDAC1/2/3 activity. As such, preventing FLIPL upregulation with the clinically relevant HDAC1/2/3-selective inhibitor Entinostat promotes apoptosis induction in response to Nutlin-3A (or p53-activating chemotherapy), which otherwise predominantly induces growth arrest despite upregulating a range of pro-apoptotic target genes. Cell death in response to Nutlin-3A in FLIPL-depleted cells is primarily mediated via caspase-8. However, in the absence of caspase-8, apoptosis is delayed, but not prevented and is mediated via caspase-10. Of note, the cell death induced in both caspase-8-proficient and -deficient cells is mediated via TRAIL-R2 in a ligand-independent manner. Conclusion In summary, this work has uncovered novel, clinically-relevant biology, in which p53-mediated upregulation of FLIPL primes cells for TRAIL-R2-mediated apoptosis and identifies FLIPL as a key target for overcoming resistance to p53-stabilising agents in p53 wild-type cancers. Moreover, we show the potential of combining Nutlin-3A (or other p53 activating chemotherapies) with the clinically relevant Class I HDAC inhibitor Entinostat for the treatment of p53 wild-type CRC, and identify FLIPL as a critical p53-induced signaling node, the inhibition of which is necessary to promote Nutlin-3A-induced apoptosis. Citation Format: Alexander McIntyre, Andrea Lees, Fiammetta Falcone, Gemma Gregg, Sessler Tamas, Gerard Quinn, Nyree Crawford, Darragh McArt, Phillip Dunne, Mark Lawler, Longley B. Daniel, Simon S. McDade. p53 activation induces a targetable dependence on FLIPL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4385.
Abstract 13412: Differential Insulin-dependent Signaling Pathways Modulated by Hydrogen Peroxide in Cardiac Myocytes
Authors: Benjamin Steinhorn, Juliano Sartoretto, Hermann Kalwa, Natalia Romero, E. D Abel, Thomas Michel
Journal: Circulation (2016)

Hydrogen peroxide (H 2 O 2 ) has long been implicated in insulin signal transduction, yet the mechanisms whereby insulin regulates intracellular H 2 O 2 to modulate physiological responses remain obscure. Here we explore the roles of H 2 O 2 in regulation of insulin pathways in cardiac myocytes. We found that insulin inhibits cardiac myocyte beta adrenergic physiological and biochemical responses. We found that catalase (which degrades H 2 O 2 ) completely blocks the ability of insulin to activate the insulin-responsive kinases Akt/mTOR and also to attenuate beta adrenergic receptor-mediated increases in myocyte contractility. These insulin responses are abrogated in a mouse model of type 2 diabetes, establishing a key role for H 2 O 2 -dependent pathways in the diabetic heart. To directly probe intracellular H 2 O 2 responses to insulin in cardiac myocytes, we constructed a novel recombinant AAV9 vector expressing the fluorescent H 2 O 2 biosensor HyPer, which we used to infect mice in vivo . We isolated cardiac myocytes from mice infected with this biosensor and performed quantitative imaging studies. This approach revealed robust insulin-dependent increases in cardiac myocyte H 2 O 2 in response to insulin in wild-type mice. Attenuated H 2 O 2 responses were observed in myocytes isolated from mouse lines deficient in the NADPH oxidase isoforms Nox2 or Nox4 that had been infected with HyPer-AAV9. In Nox2 knockout myocytes, we found that insulin-promoted phosphorylation of kinases Akt and mTor is markedly attenuated, while insulin-dependent inhibition of beta adrenergic contractility is unaffected. In contrast, in cardiac myocytes isolated from the Nox4 knockout mouse, insulin-dependent Akt/mTor phosphorylation responses are unaffected, while the ability of insulin to attenuate the beta adrenergic increase in myocyte contractility was lost. These studies represent an important advance in our understanding of insulin action in the heart by identifying a proximal point of bifurcation in insulin signaling via the differential activation of two NADPH oxidase isoforms. The work also provides insight into mechanisms of diabetic cardiomyopathy, and suggest that insulin resistance in the diabetic heart may unmask potentially deleterious beta adrenergic responses.
Computed Tomographic Analysis of the Anatomy of the Left Atrium and the Esophagus
Authors: KristinaLemola, MichaelSneider, BenoitDesjardins, IanCase, JihnHan, EricGood, KamalaTamirisa, ArianeTsemo, AmanChugh, FrankBogun, FrankPelosi, EllaKazerooni, FredMorady, HakanOral
Journal: Circulation (2004)

Background— During left atrial (LA) catheter ablation, an atrioesophageal fistula can develop as a result of thermal injury of the esophagus during ablation along the posterior LA. No in vivo studies have examined the relationship of the esophagus to the LA. The purpose of this study was to describe the topographic anatomy of the esophagus and the posterior LA by use of CT. Methods and Results— A helical CT scan of the chest with 3D reconstruction was performed in 50 patients (mean age, 54±11 years) with atrial fibrillation before an ablation procedure. Consecutive axial and sagittal sections of the CT scan were examined to determine the relationship, size, and thickness of the tissue layers between the LA and the esophagus. The mean length and width of the esophagus in contact with the posterior LA were 58±14 and 13±6 mm, respectively. The esophagus had a variable course along the posterior LA. The esophagus was close (10±6 mm from the ostia) and parallel to the left-sided pulmonary veins (PVs) in 56% of...
Early Expression of Myocardial HIF-1α in Response to Mechanical Stresses
Authors: Chan-HyungKim, Young-SukCho, Yang-SookChun, Jong-WanPark, Myung-SukKim
Journal: Circulation Research (2002)

Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1α subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts. In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1α accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)–dependent Akt phosphorylation was found to be activate...