tbuckley/cabot-search huggingface dataset:
Abstract 3786: ILC-k: Human innate lymphoid cells displaying unique metabolic features and KIR-independent cytotoxicity, impaired in acute myeloid leukemia
Authors: Bérengère Salomé, Alejandra Gomez-Cadena, Romain Loyon-Bonato, Madeleine Suffiotti, Valentina Salvestrini, Antonio Curti, Paolo Tentorio, Domenico Mavilio, Carsten Riether, Adrian Ochsenbein, Emanuela Marcenaro, David Gfeller, Pedro Romero, Sara Trabanelli, Camilla Jandus
Journal: Cancer Research (2018)

Abstract Innate Lymphoid Cells (ILCs) are a recently identified family of lymphocytes, divided into 3 different groups that mirror the functional specialization of helper CD4 T cells. However, it is now clear that the spectrum of ILC diversity is much broader than originally appreciated. ILCs have been shown to play important roles in inflammatory and autoimmune diseases, and their involvement in anti-tumor responses has also recently been evidenced by us and others. Here, we report on the identification of a previously undescribed human ILC subset, named hereafter “ILC-killer” (ILC-k), characterized by a Lineage negative, CD127+ cKIT- CRTh2- CD56+ phenotype, thus being distinct from conventional helper ILCs, e.g ILC1 (CD56-), ILC2 (CRTh2) and ILC3 (cKIT+). Transcriptomic profiling of ex-vivo highly pure ILC-k, conventional ILC subsets and conventional Natural Killer (NK) cell subsets showed closeness between ILC-k, ILC3 and CD56bright NK cells. However, ILC-k display a specific metabolism (low glucose uptake, high mitochondrial activity) and cytotoxic gene signature, also confirmed at protein level. By their functional evaluation, ILC-k showed specific ability to kill tumor cell lines in a KIR-independent, but NKp30- and Trail-dependent manner. Their relative frequency is decreased and both their metabolic fitness and cytotoxic potential are impaired in Acute Myeloid Leukemia (AML) patients at diagnosis (N=51). Upon remission, ILC frequencies and functions are restored to normal levels. Overall, we identified cytotoxic ILCs, distinct from conventional NK cells, that are functionally impaired in AML. Given their KIR-independence, ILC-k might represent promising therapeutic candidates to improve NK-cell based immunotherapy, that currently necessitates KIR-HLA mismatch between donor and recipient for full efficiency. Citation Format: Bérengère Salomé, Alejandra Gomez-Cadena, Romain Loyon-Bonato, Madeleine Suffiotti, Valentina Salvestrini, Antonio Curti, Paolo Tentorio, Domenico Mavilio, Carsten Riether, Adrian Ochsenbein, Emanuela Marcenaro, David Gfeller, Pedro Romero, Sara Trabanelli, Camilla Jandus. ILC-k: Human innate lymphoid cells displaying unique metabolic features and KIR-independent cytotoxicity, impaired in acute myeloid leukemia [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 3786.
Relation Between Endothelial Cell Apoptosis and Blood Flow Direction in Human Atherosclerotic Plaques
Authors: OlivierTricot, ZiadMallat, ChristopheHeymes, JoëlBelmin, GuyLesèche, AlainTedgui
Journal: Circulation (2000)

Background—Blood flow characteristics influence endothelial cell apoptosis. However, little is known about the occurrence of endothelial cell apoptosis in human atherosclerosis and its relation to blood flow. Methods and Results—A total of 42 human carotid atherosclerotic plaques were retrieved by endarterectomy; they were examined in the longitudinal axial direction. Plaques were included in this study when upstream and downstream parts were clearly visible, occlusion was absent, and immunostaining for luminal endothelium was present all along the plaque. Using these criteria, 13 plaques were processed for further immunohistochemical studies (using anti-CD31, anti-Ki-67, and anti-splicing factor antibodies) and in situ detection of apoptosis (terminal dUTP nick end-labeling and ligase assay). Eight plaques showed ≥1 apoptotic endothelial cell at the luminal surface. Quantitative analysis of endothelial cell apoptosis in these plaques showed a systematic preferential occurrence of apoptosis in the downstr...
Abstract 2009: Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer
Authors: Jae-Sung Kim
Journal: Cancer Research (2018)

Abstract Although it has been proposed that the benefits of HER2-targeted therapy in HER2-negative breast cancer are associated with molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Herein, we showed that breast cancer stem cells (BCSCs) mediate HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44+/CD24-/low BCSCs from HER2-negative breast cancer cells overexpressed HER2/EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44+/CD24-/low cells with decreased levels of HER2/EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer may be effective by targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in recurrent HER2-negative breast cancer patients. Therefore, our data provide in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer. Citation Format: Jae-Sung Kim. Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer [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 2009.
Physical Training Alters the Pathogenesis of Pacing-Induced Heart Failure Through Endothelium-Mediated Mechanisms in Awake Dogs
Authors: JieWang, Geng-HuaYi, MathiasKnecht, Bo-linCai, SulliPoposkis, MiltonPacker, DanielBurkhoff
Journal: Circulation (1997)

Background Beneficial effects of exercise training on cardiovascular function in chronic heart failure (CHF) have been suggested previously, but the underlying mechanisms are unknown. We tested whether daily exercise training improves systemic hemodynamics and preserves endothelium-mediated vasodilator function during development of heart failure. Methods and Results Fifteen dogs were surgically instrumented for hemodynamic measurements. One group of dogs underwent 4 weeks of cardiac pacing (210 bpm for 3 weeks and 240 bpm during week 4), and another group underwent pacing plus daily exercise training (4.4±0.3 km/h, 2 h/d). Pacing-alone dogs developed CHF characterized by typical hemodynamic abnormalities, blunted endothelium-mediated vasodilator function in coronary and femoral circulations, and decreased gene expression of endothelial constitutive nitric oxide synthase (ECNOS, normalized to GAPDH expression; normal, 1.15±0.31 versus CHF, 0.29±0.08, P<.05). Exercise training preserved normal hemodynamics...
Contribution of Head-Up Tilt Testing and ATP Testing in Assessing the Mechanisms of Vasovagal Syndrome
Authors: DanielFlammang, MarkErickson, SallyMcCarville, TimothyChurch, DjamelHamani, ErwanDonal
Journal: Circulation (1999)

Background—In patients with vasovagal syndrome, head-up tilt testing may reproduce symptoms generally associated with vasodepression. Recent research suggests ATP testing identifies patients with abnormal vagal cardiac inhibition. This preliminary study examined the joint contribution of both tests in identifying underlying mechanisms in the general population with vasovagal syndrome. Methods and Results—Both tests were performed in random order during 1 session and outside of predominant sympathetic periods in 72 patients hospitalized for syncope (n=56) or presyncope (n=16) for whom no cardiac or extracardiac cause was found. For passive and isoproterenol-provocative tilt testing by standard protocol, reproduction of symptoms defined a positive test. The ATP test consisted of injecting ATP 20 mg IV at bedside, continuously monitoring ECG and blood pressure; a vagal cardiac pause >10 seconds defined a positive test. For most patients (64%), ≥1 test was positive. Of the 41 patients (57%) with a positive ti...
Circulating Endothelial Cell Count as a Diagnostic Marker for Non–ST-Elevation Acute Coronary Syndromes
Authors: JacquesQuilici, NathalieBanzet, PhilippePaule, Jean-BaptisteMeynard, MurielleMutin, Jean-LouisBonnet, PierreAmbrosi, JoséSampol, FrançoiseDignat-George
Journal: Circulation (2004)

Background— Shedding of endothelial cells from damaged endothelium into the blood occurs in a variety of vascular disorders. The purpose of this study was to evaluate the utility of circulating endothelial cell (CEC) count as a diagnostic marker of non–ST-elevation acute coronary syndromes (ACSs). Methods and Results— CEC counts were determined immediately (H0), 4 hours (H4), and 8 hours (H8) after admission in 60 patients with documented non–ST-elevation ACS and 40 control patients with no evidence of coronary artery disease. A total of 32 patients in the ACS group had elevated CEC counts (>3 cells/mL) in relation to early admission and single-episode chest pain. Patients from the control group had normal CEC counts. The interval between the chest pain episode and elevation was significantly shorter for CEC than troponin I. No correlation was found between the 2 markers. Interestingly, a subgroup of ACS patients with initially normal troponin I levels had high CEC counts, thus allowing early diagnosis in...
Abstract 17275: Sex Differences in Biomarkers Predicting Severity of Coronary Artery Disease in Patients With Suspected Coronary Heart Disease: Baseline Data From the ANOX Study
Authors: Hiromichi Wada, Masahiro Suzuki, Morihiro Matsuda, Yoichi Ajiro, Tsuyoshi Shinozaki, Satoru Sakagami, Kazuya Yonezawa, Masatoshi Shimizu, Junichi Funada, Takeaki Kaneko, Yukiko Morita, Takashi Unoki, Daisuke Takagi, Shuichi Ura, Masataka Murakami, Moritake Iguchi, Nobutoyo Masunaga, Mitsuru Ishii, Kazuhiko Kotani, Noriko Satoh-Asahara, Mitsuru Abe, Masaharu Akao, Koji Hasegawa
Journal: Circulation (2016)

Background: Sex differences in biomarkers predicting the presence and severity of coronary artery disease (CAD) are unclear. Methods: The ANOX study is a multicenter, prospective cohort study to determine the predictive value of possible novel biomarkers related to angiogenesis or oxidative stress for major adverse cardiovascular events among patients undergoing elective angiography. Between January 2010 and November 2013, a total of 2,513 patients were enrolled. After excluding 93 patients who were subsequently found ineligible or withdrew consent, the baseline data of 1,625 male patients (63% with CAD, 38% with multi-vessel disease [MVD]) and 795 female patients (46% with CAD, 23% with MVD) were analyzed, respectively. Blood samples were collected from the arterial catheter sheath at the beginning of coronary angiography. The presence of angiographic CAD (≥50% stenosis in ≥ 1 coronary artery) and its severity were assessed using the Gensini score. Serum levels of vascular endothelial growth factor (VEGF...
Staphylococcal Infections of the Heart
Authors: Sidneycohen
Journal: Circulation (1959)

The basic problems of staphylococcal infections do not seem near to solution. Possibly an effective and safe antibiotic will be found to which resistant, pathogenic staphylococcal mutants will not appeal. This may, not be an overly sanguine hope. Had it not been for the ability of the staphylococcus to synthesize penicillinase, this goal would have been achieved already, for staphylococcal mutants pathogenic to man and intrinsically resistant to penicillin (i.e., without the production of penicillinase) have not been reported. Even with better antibiotics grave problems would remain, however, for the staphylococcus often inflicts severe or even irremediable damage, especially in the heart, before the disease can be diagnosed. Prevention is the crucial problem. Refinements in isolation technics and hospital sanitation may improve the protection of the patient in the operating room and the newborn infant in the nursery. Nevertheless, the hard core of infections in debilitated or otherwise susceptible medica...
Abstract 728: Optimization of peptide vaccines to induce robust antitumor CD4 T-cell responses
Authors: Takumi Kumai, Hussein Sultan, Hiroya Kobayashi, Yasuaki Harabuchi, Esteban Celis
Journal: Cancer Research (2018)

Abstract Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor- associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL-2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Citation Format: Takumi Kumai, Hussein Sultan, Hiroya Kobayashi, Yasuaki Harabuchi, Esteban Celis. Optimization of peptide vaccines to induce robust antitumor CD4 T-cell responses [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 728.
Diabetes, related factors, and breast cancer risk.
Authors: Peter Boyle, Mathieu Boniol, Alice Koechlin, Chris Robertson, Julio Rosenstock, Geremia Bolli, Philippe Autier
Journal: Journal of Clinical Oncology (2012)

1509 Background: Diabetes and breast cancer are both common conditions in women and may share common risk factors. Methods: To shed clarification on the potential association between diabetes, related factors and breast cancer risk, a comprehensive literature review and formal meta-analysis was carried out, planned, conducted and reported following PRISMA guidelines regarding meta-analysis of observational studies. Variables studies in relation to breast cancer risk were adiposity, physical activity, glycaemic load, glycaemic index, diabetes, IGF-1, fasting glucose, fasting insulin and C-peptide, adiponectin, metformin and glargine use. The Summary Relative Risk (SRR) and the corresponding 95% Confidence Interval (CI) was calculated. Results: For breast cancer at all ages, the calculated risks were as follows: diabetes (SRR=1.23 95% CI (1.12, 1.34); physical activity (SRR=0.88, 95% CI (0.85, 0.92)); glycaemic load (SRR=1.05, 95% CI (1.00, 1.10)); glycaemic index (SRR=1.05, 95% CI (1.00, 1.09)); fasting glucose (SRR=1.14, 95% CI (0.94, 1.37)); serum insulin (SRR=1.26, 95% CI (0.86, 1.84)); c-peptide (SRR=1.29, 95% CI (0.91, 1.82)); adiponectin (SRR=1.16, 95% CI (0.93, 1.46)); metformin (SRR=0.97, 95% CI (0.82, 1.16)); and glargine (SRR=1.10, 95% CI (0.94, 1.30)). An increase of 5 units in Body Mass Index (a weight increase if 14.5 kg in a person 1.70 metres tall) was associated in post-menopausal breast cancer (SRR=1.12, 95% CI (1.08, 1.16)) but not at pre-menopausal ages (SRR=0.83, 95% CI (0.72, 0.95)). Serum insulin was associated with breast cancer at post-menopausal ages but not at pre-menopausal ages whereas with c-peptide there was a significant association at pre-menopausal ages but not post-menopausal. For IGF-1, Hodge’s Standardised Mean Difference (HSMD) was calculated and there was no significant association with breast cancer at all ages (HSMD=-0.026, 95% CI (-0.031, 0.084)), at post-menopausal ages (HSMD=0.007, 95% CI (-0.068, 0.082)) or at pre-menopausal ages (HSMD=-0.065, 95% CI (-0.009, 0.140)). Conclusions: Key risk factors for breast cancer appear to be adiposity and physical activity which are both related to the risk of developing diabetes.
Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes
Authors: TetsuroAgo, JunyaKuroda, JayashreePain, CexiongFu, HongLi, JunichiSadoshima
Journal: Circulation Research (2010)

Rationale: NADPH oxidases are a major source of superoxide (O2−) in the cardiovascular system. The function of Nox4, a member of the Nox family of NADPH oxidases, in the heart is poorly understood. Objective: The goal of this study was to elucidate the role of Nox4 in mediating oxidative stress and growth/death in the heart. Methods and Results: Expression of Nox4 in the heart was increased in response to hypertrophic stimuli and aging. Neither transgenic mice with cardiac specific overexpression of Nox4 (Tg-Nox4) nor those with catalytically inactive Nox4 (Tg-Nox4-P437H) showed an obvious baseline cardiac phenotype at young ages. Tg-Nox4 gradually displayed decreased left ventricular (LV) function with enhanced O2− production in the heart, which was accompanied by increased apoptosis and fibrosis at 13 to 14 months of age. On the other hand, the level of oxidative stress was attenuated in Tg-Nox4-P437H. Although the size of cardiac myocytes was significantly greater in Tg-Nox4 than in nontransgenic, the ...
Abstract LB-118: A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation
Authors: Zachary T. Freeman, Daniel H. Hovleson, Alexander T. Pearson, Jingyi Zhai, Ali Ghasemzadeh, Thomas R. Nirschl, Hui Jiang, Scott A. Tomlins, Charles G. Drake
Journal: Cancer Research (2018)

Abstract Regulatory T (Treg) cells play an important role in modulating the tumor microenvironment, leading to the suppression of anti-tumor immune responses. Tumor Tregs could be targeted by taking advantage of the differential expression of immune checkpoints on these cells as compared to other T cell subsets. While the elevated expression of checkpoints such as CTLA-4 on Tregs compared to conventional T cells is well-characterized, less is known about the collective landscape of Treg specific checkpoint expression specific in the tumor microenvironment. We identified a network of Treg-associated checkpoint markers including those previously associated with Treg function (CTLA4, ICOS) as well as several additional checkpoints (BTLA, LAG3, TIGIT, TNFRSF9) by characterizing the expression of 28 checkpoint molecules across 7,608 bulk tumor samples (31 tumor types) from TCGA. We then utilized whole transcriptome RNA sequencing of purified peripheral and tumor Treg cell populations across 4 different tumor types (glioblastoma multiforme, prostatic adenocarcinoma, urothelial transitional cell carcinoma, renal clear cell carcinoma) to characterize the Treg specific expression of checkpoint molecules. Peripheral and tumor Tregs demonstrate differential checkpoint expression landscapes, with tumor Tregs uniquely discriminated by collective expression of TNFRSF9 (4-1BB), HAVCR-2 (TIM-3), and LAG-3. This discriminatory signature was conserved across the 4 profiled tumor types, was associated with changes in Treg biology, and was confirmed in published data from three additional cancer cohorts (breast, colorectal, and non-small-cell-lung cancers). Furthermore, normalized TNFRSF9 expression in TCGA was also associated with a worse survival outcome, suggesting that elevated Treg TNFRSF9 expression may be a poor prognostic factor across a wide range of tumors. Taken together, these data highlight the potential of targeting TNFRSF9 expressing Tregs in the tumor as a novel immunotherapeutic approach for several types of cancer. Citation Format: Zachary T. Freeman, Daniel H. Hovleson, Alexander T. Pearson, Jingyi Zhai, Ali Ghasemzadeh, Thomas R. Nirschl, Hui Jiang, Scott A. Tomlins, Charles G. Drake. A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation [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 LB-118.
Abstract 5566: LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies
Authors: Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter
Journal: Cancer Research (2018)

Abstract The retinoic acid-related orphan receptor γt (RORγt) is a nuclear receptor transcription factor that acts as an immune cell master control switch driving the generation and function of Th17 (helper) and Tc17 (cytotoxic) T cells. Preclinical data show that synthetic RORγ agonists modulate immune cell gene expression to both increase immune activity and decrease immunosuppressive mechanisms in the tumor microenvironment. Because RORγ agonists impact multiple antitumor mechanisms, these compounds have the potential to combine with other agents to enhance tumor immunity. In addition to preclinical data supporting a biologic rationale, bioinformatic and machine learning approaches based on the RORγ pathway were undertaken to prioritize possible clinical combinations. This work highlighted other immuno-oncology agents as well as targeted therapies and more conventional treatments. Preclinical, syngeneic mouse cancer models were used to test some of the hypotheses. Based on the finding that RORγ agonists decrease PD-1 expression and that anti-CTLA4 induces ICOS, which stabilizes RORγ expression, anti-PD1 or anti-CTLA4 agents were combined with the RORγ agonist LYC-54143 in 12 syngeneic murine models. Compared with individual agents, combination treatments elicited superior tumor growth inhibition in 6 of the models (Table). RORγ agonist treatment was also able to augment antitumor activity of doxorubicin. In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule RORγ agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer. Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine modelAnti-PD1 aloneAnti-CTLA4 aloneRORγ agonist aloneRORγ agonist + anti-PD1RORγ agonist + anti-CTLA4H22 (Liver)30-50%&amp;gt;50%*10-30%&amp;gt;50%*&amp;gt;50%*Pan02 (Pancreas)&amp;lt;10%10-30%&amp;lt;10%10-30%*10-30%*CT26 (Colon)10-30%&amp;lt;10%&amp;lt;10%&amp;lt;10%30-50%B16F10 (Melanoma)10-30%10%10-30%10-30%30-50%A230 (Lymphoma)&amp;lt;10%&amp;lt;10%10-30%30-50%10%Renca (Renal)&amp;lt;10%10-30%30-50%*30-50%*30-50%*P&amp;lt;.05 vs vehicle. Citation Format: Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter. LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies [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 5566.