tbuckley/cabot-search huggingface dataset:
Abstract 5763: Large-scale use of knockout validation to confirm antibody specificity to key oncology targets
Authors: Sam Heaton, Monica Sassi, Alejandra Solache, Bruce Hamilton, Sambhav Dave
Journal: Cancer Research (2018)

Abstract Antibodies are the most common tools in basic science and clinical research. Over the past several years there has been an ongoing discussion around antibody validation in light of poor experimental reproducibility between laboratories. This is in part due to the cross-reactivity between antibodies and off-target proteins and the variability between different antibody batches. As a result, experimental irreproducibility leads to wasted resources and compromises the advancement of science. In response to this, Abcam has introduced knockout (KO) validation to help produce target-specific antibodies. This initiative uses KO cells lines made possible through a partnership with Horizon Discovery. Target genes are mutated via CRISPR-Cas9 within a haploid cell line. This results in a frameshift and a complete loss of gene expression. These KO cell lines provide a true negative control for antibody validation as a lack of signal confirms that the antibody binds to its intended target. As a result, both antibody specificity and reproducibility on a large scale can be addressed. We have KO-validated over a thousand antibodies, including several that are relevant to immuno-oncology research. Examples of such targets are the ERK1/2 pathway, which regulates cell survival, proliferation and cell death. Inhibition of this pathway is an attractive target for the treatment of malignant tumors with increased ERK1/2 activity. Similarly, Ki67 expression is strongly associated with tumor cell proliferation and can be used as a marker for tumor aggressiveness. Finally, overexpression of vimentin in tumors correlates with increased growth and invasion, leading to poor prognosis. It is imperative that reproducible data can be produced on these targets to further our understanding of tumor biology and patient prognosis. Here we present the data for antibodies to these key targets that have been validated in both flow cytometry and immunocytochemistry. The antibodies have been tested in KO and wild-type cells to confirm their specificity. The antibodies shown gave signal in wild-type cells but showed complete loss of signal when tested in knockout cell lines. By providing researchers with reliable and specific antibodies that work first time we hope to minimize wasted resources and improve reproducibility. Citation Format: Sam Heaton, Monica Sassi, Alejandra Solache, Bruce Hamilton, Sambhav Dave. Large-scale use of knockout validation to confirm antibody specificity to key oncology targets [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 5763.
Instant Power Spectrum Analysis of Heart Rate Variability During Orthostatic Tilt Using a Time-/Frequency-Domain Method
Authors: SylvainJasson, ClaireMédigue, PierreMaison-Blanche, NicolaMontano, LaurentMeyer, ChristopheVermeiren, PascaleMansier, PhilippeCoumel, AlbertoMalliani, BernardSwynghedauw
Journal: Circulation (1997)

Background Spectral analysis of heart rate (HR) variability (HRV) requires, as a rule, some level of stationarity and, as a result, is inadequate to quantify biological transients. A time-/frequency-domain method (TF) was developed to obtain an instant spectral power (SP) of HRV during tilt. Methods and Results HR was recorded by Holter monitoring in volunteers and analyzed with a TF, the smoothed pseudo–Wigner-Ville transformation (SPWVT), with the table inclination randomly set or continuously increased while the table rotated in head-up position. (1) The SPWVT assesses, beat by beat, the instant center frequency (ICF) of the SP. ICF correlates better with instant HR than the ratio of low- (LF) to high-frequency (HF) oscillations. The transient effect of tilt is better characterized as a shift of SP toward lower frequencies than by changes in amplitudes. (2) The method evidences variations of HR from one second to another. During the passage to head-up position, the vagal withdrawal and the sympathetic ...
G Protein β3 Subunit 825T Allele and Enhanced Coronary Vasoconstriction on α2-Adrenoceptor Activation
Authors: DietrichBaumgart, ChristophNaber, MichaelHaude, OlafOldenburg, RaimundErbel, GerdHeusch, WinfriedSiffert
Journal: Circulation Research (1999)

Abstract—Recently, α2-adrenoceptor activation was shown to play an important role in the vasoconstriction of normal coronary arteries, whereas in the presence of atherosclerosis, the activation of both α1- and α2-adrenoceptors reduces coronary blood flow in humans. α2-Adrenoceptors activate pertussis toxin (PTX)-sensitive G proteins, whereas α1-adrenoceptors couple to PTX-insensitive G proteins. Thus, the 825T allele of the β3 subunit of heterotrimeric G proteins, associated with enhanced PTX-sensitive G protein signaling, was expected to determine the α2-adrenoceptor–, but not the α1-adrenoceptor–, mediated reduction in coronary blood flow (CBF). Genotyping was performed on 48 individuals. Twelve of the 48 received the α1-adrenoceptor agonist methoxamine (MTX; 5 mg IC), and 12 received the α2-adrenoceptor agonist BHT 933 (BHT; 5 mg IC). Twenty-four additional individuals received both MTX and BHT during the same investigational procedure. CBF was calculated on the basis of coronary angiography and intrac...
Abstract 12754: The Association Between Surgical Indications, Operative Risk and Outcome in Infective Endocarditis
Authors: AndrewWang
Journal: Circulation (2014)

Introduction: The use of surgery in IE relative to indications and operative risk has not been well defined. Objectives: 1) To evaluate the use of surgery in IE as related to indications and operative risk; 2) to analyze the association between surgical indications, operative risk, and 6-month survival. Methods: The International Collaboration on Endocarditis-PLUS is a prospective registry involving 29 centers in 16 countries with 1296 patients with definite left-sided IE. Factors related to surgical decision making and Society of Thoracic Surgery (STS-IE) risk score were evaluated for relationship to surgical treatment and 6-month mortality. Results: Patients had a median age of 62 years (25th, 75th %tile: 47, 72) and a substantial rate of medical comorbidities. A surgical indication was present in 74% of all patients; surgery was performed in 57% of the cohort and 76% of patients with an indication. The most common reason for lack of surgery among patients with a surgical indication was having a poor pr...
A large-scale genetic analysis reveals an autoimmune origin of idiopathic retroperitoneal fibrosis
Authors: Davide Martorana, Ana Márquez, F. David Carmona, Francesco Bonatti, Alessia Adorni, Maria L. Urban, Federica Maritati, Eugenia Accorsi Buttini, Chiara Marvisi, Alessandra Palmisano, Giovanni M. Rossi, Giorgio Trivioli, Paride Fenaroli, Lucio Manenti, Maria Nicastro, Monia Incerti, Davide Gianfreda, Stefano Bani, Stefania Ferretti, Domenico Corradi, Federico Alberici, Giacomo Emmi, Gerardo Di Scala, Gabriella Moroni, Antonio Percesepe, Paul J. Scheel, Eric Vermeer, Eric F. van Bommel, Javier Martín, Augusto Vaglio
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 3784: Intraoperative changes of low density granulocyte (LDG) in gastrointestinal cancer surgery
Authors: Yuko Kumagai
Journal: Cancer Research (2018)

Abstract Background: Low density granulocytes (LDG) have been shown to be increased in peripheral blood of autoimmune disease, severe sepsis and cancer. In this study, we examined the frequency and function of the LDG in patients who received abdominal surgery for gastrointestinal malignancy. Method: In 57 patients who received laparotomy due to the gastrointestinal cancer ( 5 esophageal, 25 gastric , 27 colorectal cancer), peripheral blood was collected before and after operative procedure in operation room. After Ficoll-Hypaque centrifugation, intermediate layer which consists mainly of mononuclear cells was collected and immunestained with mAbs to CD66b, CD45 as well as 7AAD and their expressions were examined with flow cytometer. CD66b(+) CD45(+) cells were defined as LDG and the ratios of LDG in total CD45(+) leukocytes were calculated in 7AAD(-) live cell fraction. Next, CD66b(+) LDG and CD66b(-) mononuclear cells were separated with MACS method, and LDG were cultured and examined for extracellular traps (NETs) formation in vitro. Finally, CD66b(-) mononuclear cells were cultured on anti-CD3 mAb coated plate with or without autologous LDG, and proliferation of T lymphocytes was examined with CFSE dilution method. Results: The ratio of the LDG is low (median= 1.14%, 0.62 ~1.66%, n=57) at a beginning of surgery. In contrast, the ratio was markedly increased (median= 8.10%, 5.91~10.3%, n=57, p&amp;lt;0.001) at the end of surgery. The ratio of postoperative LDG showed significant correlation with operation time and positive trend with intraoperative bleeding. The LDG showed relatively week expression of CD11b and CD66b, but highly expressed in IL8 receptor and CD62L, suggesting immature LDG. The short-term culture of the LDG produced massive SYTOX-positive web like stricture which was characteristic for NETs. The mixture of tumor cells on the LDG culture demonstrated that many tumor cells were trapped in the NETs within 5 min incubation and vigorously grew thereafter. Finally, addition of the LDG on mononuclear cell culture strongly suppressed the anti-CD3 stimulated T cell division. Conclusion: LDG with immature phenotype increase in circulating blood of the patients who underwent gastrointestinal cancer surgery, probably due to the surgical stress. The LDG produce NETs which may efficiently trap circulating tumor cells, and can inhibit T lymphocyte mediated-immune reaction. Thus, the LDG provide tumor permissive microenvironment in target organ and have supportive roles on the development of postoperative hematogenous metastasis in gastrointestinal cancer. Citation Format: Yuko Kumagai. Intraoperative changes of low density granulocyte (LDG) in gastrointestinal cancer surgery [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 3784.
Abstract 1932: Discovery of ENPP1 inhibitors as agonists of STING pathway
Authors: Sunil Sharma, Alexis Weston, Trason Thode, Eric Gomez, Mohan Kaadige, Hariprasad Vankayalapti
Journal: Cancer Research (2018)

Abstract The discovery of STING (Stimulator of interferon genes) pathway and the second messenger 2′3′-cGAMP that activate it opened up several new possibilities for the development of anti-cancer and anti-pathogen therapeutics. STING is a pattern-recognition receptor anchored on endoplasmic reticulum and has pivotal roles in surveillance and innate immune response. Binding of 2′3′-cGAMP with STING induces conformational changes, which subsequently leads to perinuclear migration of STING and recruitment of TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3). TBK1 phosphorylates IRF3, which then translocates to the nucleus and drives the transcription of innate immune genes, including IFN-β. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a dominant hydrolyzing enzyme of 2′3′-cGAMP. In ENPP-/- cells, 2′3′-cGAMP is more active in stimulating STING activation, and this is predicted to be due to increased half-life. Similarly, hydrolysis resistant 2′3′-cGAMP analogs are reported to be potent STING agonists. We hypothesized that inhibition of ENPP1 activity with an orally available small molecule would be a novel approach to activate STING pathway when compared with the cyclic dinucleotides (CDNs) due to their parenteral route of administration. We have utilized computational methods successfully discovered small molecule candidates that showed a strong binding affinity towards ENPP1. With the help of in vitro enzymatic inhibition and direct binding assays we have identified few lead candidates with an IC50 of &amp;lt;100 nM. Cellular assays further showed target specific inhibition of ENPP1 activity and subsequent activation of STING pathway. Additionally, our lead series of compounds showed no effect on other members of the ENPP family, a kinome panel, and several epigenetic regulators, suggesting the specificity towards ENPP1. In summary, we have developed small molecule inhibitors of ENPP1 and one of our lead candidate's is currently under investigation for ADME-Tox, PK and efficacy. The results from these studies will be presented. Citation Format: Sunil Sharma, Alexis Weston, Trason Thode, Eric Gomez, Mohan Kaadige, Hariprasad Vankayalapti. Discovery of ENPP1 inhibitors as agonists of STING pathway [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 1932.
Abstract 2321: Molecular crosstalk between ferroptosis and apoptosis: Emerging role of ER stress-induced p53-independent PUMA expression
Authors: Young-Sun Lee, Se Hoon Hong, Dae-Hee Lee, Min J. Jo, Yoo A. Jeong, William T. Kwon, Haroon A. Choudry, David L. Bartlett, Yong J. Lee
Journal: Cancer Research (2018)

Abstract Ferroptosis is a type of programmed cell death that depends on iron and is characterized by the accumulation of lipid peroxides. In the present study, we investigated the nature of the interplay between ferroptosis and other forms of cell death such as apoptosis. Human pancreatic cancer PANC-1 and BxPC-3 and human colorectal cancer HCT116 cells were treated with ferroptotic agents such as erastin and artesunate (ART) in combination with the apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We observed synergistic interaction of erastin or ART with TRAIL as determined by cell death assay, caspase activation, poly [ADP-ribose] polymerase 1 (PARP-1) cleavage, flow cytometry analysis, and lipid peroxidation assay. Moreover, erastin and ART induced endoplasmic reticulum (ER) stress and promoted p53 upregulated modulator of apoptosis (PUMA) expression via C/EBP-homologous protein (CHOP). Synergy of erastin/ART and TRAIL was abolished in PUMA-deficient HCT116 cells and CHOP-deficient mouse embryonic fibroblasts, but not in p53-deficient HCT116 cells. The results suggest the involvement of the p53-independent CHOP/PUMA axis in response to ferroptosis inducers, which may play a key role in ferroptotic agent-mediated sensitization to TRAIL-induced apoptosis. Citation Format: Young-Sun Lee, Se Hoon Hong, Dae-Hee Lee, Min J. Jo, Yoo A. Jeong, William T. Kwon, Haroon A. Choudry, David L. Bartlett, Yong J. Lee. Molecular crosstalk between ferroptosis and apoptosis: Emerging role of ER stress-induced p53-independent PUMA expression [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 2321.
Modulation of Growth Factor Action
Authors: JohannesWaltenberger
Journal: Circulation (1997)

Abstract Peptide growth factors are involved in fundamental cellular processes relevant for cardiovascular physiology and pathology, namely, atherogenesis and angiogenesis. The modulation of growth factor–related signals represents a novel strategy for the treatment of cardiac and vascular disease. Experimental modulation of growth factor action has already provided a better understanding of cardiovascular biology and pathophysiology. In turn, the development of specific and powerful molecular tools is setting the stage for the exploration of their clinical potentials. Current strategies include the use of recombinant proteins, specific inhibitors of protein-protein interactions, tyrosine kinase inhibitors, the generation and application of dominant-negative molecules, the development of antisense strategies, and a variety of different gene transfer approaches. Parallel avenues of research are heading toward the same goal, the specific suppression of potent pathogenic stimuli that induce and promote ather...
Abstract 963: Screening of neoantigen-specific T cells in head and neck cancer and establishment of T-cell receptor-engineered T cells with cytotoxic reactivity
Authors: Lili Ren, Tatsuo Matsuda, Boya Deng, Kazuma Kiyotani, Taigo Kato, Jae-Hyun Park, Tanguy Seiwert, Everett Vokes, Nishant Agrawal, Yusuke Nakamura
Journal: Cancer Research (2018)

Abstract Neoantigen-reactive T cells are considered to be crucial mediators for anti-tumor activity in adoptive T cell transfer (ACT) immunotherapy although the efficacy of ACT using in vitro expanded tumor-infiltrating T lymphocytes (TILs) has been limited. Since characterization of T cell receptor (TCR) repertoires of TILs before and after in vitro expansion has not well investigated, we in present study performed whole exome sequencing (WES) and transcriptome analysis, and selected candidate neoantigen epitopes to induce cytotoxic T lymphocytes (CTLs) in 20 patients with head and neck cancer (10 frozen tissues and 10 freshly resected tumors). 36 potential neoantigen peptides including missense somatic mutations were examined for induction of neoantigen-reactive cytotoxic T cells in vitro using patients' derived dendritic cells. We have so far confirmed three neoantigen-reactive T cells and obtained the sequence information of a pair of TCR alpha and beta chains, which were identical to those identified in resident dominant TILs in the original tumors. We cloned the TCR genes into T lymphocytes and constructed the neoantigen-reactive T-cell receptor-engineered (TCR-engineered) T cells, which showed HLA-restricted neoantigen-reactive cytotoxic activity. In addition, we compared the TCR composition of TILs before/after in vitro expansion in 10 fresh head and neck cancers, and found that TCR clonotypes in original TILs and in vitro expanded TILs are drastically different except for those between expanded CD8 cells and resident TILs in three tumors, which had unusually high mutational burden due to mutations in the mismatch repair genes (MSH2, MSH6) or a DNA polymerase (POLE) gene. Our data also suggest that some expanded TILs are likely to be cancer-specific T cells and may be good cell sources for ACT immunotherapy and that the mutational load might be a good biomarker to screen effective TIL treatment. We demonstrate establishment of an effective and rapid protocol to generate neoantigen-specific T cells and to identify neoantigen-specific TCRs for individual patients, which makes TCR-engineered T cells applicable for the clinical use. Citation Format: Lili Ren, Tatsuo Matsuda, Boya Deng, Kazuma Kiyotani, Taigo Kato, Jae-Hyun Park, Tanguy Seiwert, Everett Vokes, Nishant Agrawal, Yusuke Nakamura. Screening of neoantigen-specific T cells in head and neck cancer and establishment of T-cell receptor-engineered T cells with cytotoxic reactivity [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 963.
Dilated Form of Endocardial Fibroelastosis as a Result of Deficiency in Respiratory-Chain Complexes I and IV
Authors: DomenicoCorradi, BertrandTchana, DylanMiller, LauraManotti, RobertaMaestri, DavideMartorana, SergioCallegari, ValentinaAllegri, NicolaCarano, AldoAgnetti, UmbertoSquarcia
Journal: Circulation (2009)
The T-Type Ca2+ Channel Blocker Mibefradil Prevents the Development of a Substrate for Atrial Fibrillation by Tachycardia-Induced Atrial Remodeling in Dogs
Authors: SamirFareh, AgnèsBénardeau, BernardThibault, StanleyNattel
Journal: Circulation (1999)

Background—Ca2+ overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca2+ channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca2+ channel blocker mibefradil on tachycardia-induced atrial remodeling. Methods and Results—Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76±5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7±2.4%), AF duration (414±232 seconds), and AF inducibility by single extrastimuli (41±10% of sites) compared with 10 unpaced control dogs (ERP 114±3 ms, ERP heterogeneity...
Abstract 3928: Sertraline in melanoma treatment: TCTP as a therapeutic target
Authors: Marianna Boia-Ferreira, Alana Basílio, Antonielle B. Baldissera, Fernando H. Matsubara, Marcia H. Appel, Cleber R. da Costa, Olga M. Chaim, Luiza H. Gremski, Silvio S. Veiga, Andrea Senff-Ribeiro
Journal: Cancer Research (2018)

Abstract Background: Sertraline (an SSRI antidepressant) binds directly to TCTP protein and decreases its intracellular levels. TCTP (Translationally Controlled Tumor Protein) is an antiapoptotic protein highly conserved through phylogeny. TCTP overexpression was detected in several tumor types. Silencing TCTP was shown to induce tumor reversion, a process overriding at the molecular level the malignant process. There is a reciprocal repression between TCTP and P53. Methods: We evaluated the role of TCTP in melanoma using sertraline and siRNA. Cell viability, migration and clonogenicity were assessed in human and murine melanoma cell in vitro. Sertraline was evaluated in vivo in a murine melanoma model and compared to dacarbazine, a major a chemotherapeutic agent used in melanoma treatment. Long-term effect of sertraline was evaluated keeping cells on regular culture for 5 days after a 72h-treatment and then assessing proliferation, clonogenicity and in vivo growth. Results: (i) In human melanoma cell lines, sertraline treatment and decrease of TCTP levels (by siRNA) are related to the inhibition of clonogenicity and migration; (ii) TCTP levels are related to melanoma malignancy and invasiveness (in B16F10/F1 murine model); (iii) knockdown of TCTP triggers decrease of proliferation and migration on murine melanoma cells; (iv) sertraline decreases TCTP mRNA levels in B16F10 cells and results in inhibition of clonogenicity; (v) sertraline presents remarkable in vivo antitumoral effects in B16F10/C57BL6 model, greater than dacarbazine, the main chemotherapeutic agent used for melanoma; (vi) sertraline treatment is capable of a long-term effect on melanoma cells, suggesting that the drug can trigger tumor reversion, a reprogram of tumor cells to a less malignant phenotype. Our data could pave the way for new approaches in the treatment of melanoma, a pathology whose prognostic is poor in late stages, and the efficiency of the current available chemotherapeutic treatment is very low. Conclusion: Altogether, these results indicate that sertraline could be effective against melanoma and TCTP can be a target for melanoma treatment, opening up new therapies for melanoma treatment. Citation Format: Marianna Boia-Ferreira, Alana Basílio, Antonielle B. Baldissera, Fernando H. Matsubara, Marcia H. Appel, Cleber R. da Costa, Olga M. Chaim, Luiza H. Gremski, Silvio S. Veiga, Andrea Senff-Ribeiro. Sertraline in melanoma treatment: TCTP as a therapeutic target [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 3928.