tbuckley/cabot-search huggingface dataset:
Abstract 116: Targeting EZH2 catalytic independent functions in breast cancer
Authors: Keng Gat Lim
Journal: Cancer Research (2015)

Abstract Advances in drug discovery have enabled the development of catalytic inhibitors or inhibitors that disrupt protein-protein interactions. One validated drug target is the polycomb repressive complex 2 (PRC2), which promotes cancer development and reduces patient survival in multiple cancers. The core of PRC2 consists of Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED). Currently, inhibitors targeting the catalytic site of EZH2 were efficacious in inhibiting a subset of blood cancers. In addition, a recently developed peptidomimetic inhibitor that disrupts the EED-EZH2 interaction also inhibits PRC2 activity and decreases proliferation of solid tumors. In this study, we investigated the effects of EZH2 protein depletion versus EZH2 catalytic inhibition with two small molecule inhibitors, GSK126 (an EZH2 catalytic inhibitor) and DZNep (a histone methylation inhibitor that depletes EZH2). We found that catalytic inhibition of EZH2 was insufficient to block cancer cell proliferation whereas depletion of EZH2 was effective at killing cancer cells. This study suggests that depleting EZH2 to inhibit both catalytic dependent and independent functions could be useful in the treatment of solid tumors such as breast cancer. Citation Format: Keng Gat Lim. Targeting EZH2 catalytic independent functions in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 116. doi:10.1158/1538-7445.AM2015-116
The cytotoxic effects of FK228, histone deacetylase inhibitor, in combination with other anticancer agents.
Authors: Yoshinori Naoe, Takeshi Inoue, Masahiko Matsuo, Seitaro Mutoh, Yasuhiko Kano
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

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FK228 is a novel antitumor agent that inhibits histone deacetylase. It has broad antitumor activity in preclinical studies and is currently under phase I/II evaluations. As histone deacetylase inhibitor is new category antitumor agent, effects of combination chemotherapy of histone deacetylase inhibitor with antitumor agents are poorly understood. To investigate its potential for inclusion in combination chemotherapy, we studied the optimal schedule of FK228 and various anticancer agents (cisplatin, taxol, adriamycin, etoposide and 5fluorouracil) in combination at various schedules in vitro using human prostate cancer DU-145 cells. Cells were simultaneously exposed to FK228 and antitumor agent for 24 h or sequentially exposed to FK228 for 24 h followed antitumor agent for 24 h or vice versa. Cell growth inhibition after 5 days was determined by MTT assay. The effects of drug combinations at the concentration of drug that produced 80% cell growth inhibition (the IC80 level) were analyzed by the isobologram method. The simultaneous exposure to FK228 and cisplatin, taxol, adriamycin, etoposide or 5fluorouracil produced additive to synergistic effects in DU-145 cells. The sequential exposure to anticancer agents followed by FK228 produced additive to synergistic effects in the cells. The sequential exposure to FK228 followed by taxol showed antagonistic effect in the cells. These findings suggest that a sequential administration the anticancer agents followed by FK228 may be the appropriate schedule for this combination. On the basis of the observed in vitro synergism, further in vivo and clinical studies are necessary to clarify the toxicity and proposed antitumor effects of this schedule.
Abstract 16411: Abo Blood Group and Risk of Myocardial Infarction in Hispanics
Authors: Tao Huang, Yanping Li, Min Xu, Ana Baylin, Hannia Campos, Lu Qi
Journal: Circulation (2014)

Hypothesis: ABO blood group has been associated with myocardial infarction (MI) in Caucasians. This study evaluated whether genotype-derived ABO blood group associated with MI in Hispanics, and whether lifestyle risk factors modified the associations. Methods: Cases (n=2273) with a first acute nonfatal MI and population-based controls (n=2274) living in Costa Rica were studied. Five ABO single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS: Three SNPs (rs687289, rs507666, and rs579459) at ABO locus showed significant associations with MI risk, with odds ratios (ORs, 95% confidence interval) of 1.17(1.05-1.30), 1.18(1.05-1.32), and 1.14(1.02-1.28), respectively. Compared to subjects with blood group O, the ORs for blood group A, AB and B were 1.24 (95% CI, 1.08-1.43), 1.15 (95% CI, 0.95-1.39), and 1.10 (95% CI, 0.77-1.57), respectively. Subjects with non-O blood group had an adjusted OR for MI of 1.20 (95% CI, 1.05-1.37) when compared to subjects with O blood group after adjustment for age, sex, area of residence, smoking, alcohol consumption, physical activity, total calories, and family history of MI. CONCLUSIONS: Our results indicate both the consistency and disparity of ABO genetic effects on MI risk between Hispanics and Caucasians.
Abstract 15514: Same Day Discharge vs Overnight Stay After Transradial PCI Results in Equivalent Safety with Significant Cost Savings/Increased Margin for the Hospital
Authors: Quinn Capers, Ernest L Mazzaferri, Charles A Bush, Randy Allen
Journal: Circulation (2012)

Traditionally, PCI patients are kept in the hospital overnight to monitor for possible complications. As the process of PCI has improved and cardiac complications have dropped significantly, the ju...
Randomized study testing as adjuvant chemotherapy the same primary (neoadjuvant) epirubicin/vinorelbine (EN) regimen versus docetaxel (TXT) in inflammatory breast cancer (IBC)
Authors: M. Brandi, S. Petroni, B. Stea, C. D'Amico, R. Necchia, R. Altieri, F. Schittulli
Journal: Journal of Clinical Oncology (2008)

590 Background: The multimodal approach of IBC resulted in improved survival but the IBC still remains the most aggressive form of breast cancer. The endpoints of the study were to a) evaluate the efficacy and safety of primary chemotherapy (EN), b) evaluate a better chemotherapy sequence (primary and adjuvant), and c) analyze the predictive value and changes of some biomarkers (ER, PR, Ki67 and HER2 status) in IBC. Methods: From 4/2002 to 10/2007, 56 patients with IBC entered the study. The molecular markers were obtained from tumor specimens before chemotherapy by biopsy and surgery after. After diagnosis the pts were randomized to the following sequence: EN (E 120 mg/m2 d 1 plus N 25 mg/m2 d 1 & 8) x 4 cycles -> surgery or radiotherapy -> adjuvant TXT (100 mg/m2) x 4 cycles (Group A) or EN x 4 cycles (Group B), all regimens q 3 wks. After adjuvant therapy all pts received RT and endocrine therapy in ER/PgR+ tumors. From 6/2006 the pts with HER2+ status also received trastuzumab adjuvant x 1 yr. The characteristics of the evaluable pts (28 group A and 26 group B) were well balanced between the groups (A/B): median age (53/53.5 yrs), premenopausal (12/10 pts), ER- (15/15 pts), PgR- (15/17), and HER2+ (20/21). Results: Also the overall clinical objective responses to induction chemotherapy were well balanced between group A vs. B: 89% vs. 85%. One patient in group A and 3 pts in group B underwent local-regional radiotherapy instead of surgery. The pathologic objective responses between group A vs. B were: cCR (7 vs. 11%) and cPR (82 vs. 73%). At median 36 months of follow-up, we observed 10 vs. 16 relapses and 3 vs. 9 deaths. Both sequential chemotherapies were manageable, feasible and well tolerated. One patient showed an anaphylactic reaction to TXT after the first cycle. Better results in group A with 5yrs DFS odds ratio rates 0.50 (95%CI 1.1–0.3, p 0.8), and OS odds ratio 0.30 (95% CI 1.0–01, p.06). Conclusions: The data suggest that the sequential use of two non- cross resistance chemotherapy schedules is well tolerated, active and feasible. This monocentric study demonstrates for the first time an improvement of the principal survival endpoints by means of an adjuvant regimen different from the primary one. No significant financial relationships to disclose.
An outbreak of Salmonella Typhimurium infections in Denmark, Norway and Sweden, 2008
Authors: T Bruun, G Sørensen, L P Forshell, T Jensen, K Nygård, G Kapperud, B A Lindstedt, T Berglund, A Wingstrand, R F Petersen, L Muller, C Kjelsø, S Ivarsson, M Hjertqvist, S Löfdahl, S Ethelberg
Journal: Eurosurveillance (2009)

In November-December 2008, Norway and Denmark independently identified outbreaks of Salmonella Typhimurium infections characterised in the multiple-locus variable number of tandem repeats analysis (MLVA) by a distinct profile. Outbreak investigations were initiated independently in the two countries. In Denmark, a total of 37 cases were identified, and multiple findings of the outbreak strain in pork and pigs within the same supply chain led to the identification of pork in various forms as the source. In Norway, ten cases were identified, and the outbreak investigation quickly indicated meat bought in Sweden as the probable source and the Swedish authorities were alerted. Investigations in Sweden identified four human cases and two isolates from minced meat with the distinct profile. Subsequent trace-back of the meat showed that it most likely originated from Denmark. Through international alert from Norway on 19 December, it became clear that the Danish and Norwegian outbreak strains were identical and, later on, that the source of the outbreaks in all three countries could be traced back to Danish pork. MLVA was instrumental in linking the outbreaks in the different countries and tracing the source. This outbreak illustrates that good international communication channels, early alerting mechanisms, inter-sectoral collaboration between public health and food safety authorities and harmonised molecular typing tools are important for effective identification and management of cross-border outbreaks. Differences in legal requirements for food safety in neighbouring countries may be a challenge in terms of communication with consumers in areas where cross-border shopping is common.
P0192 : Assessment of liver function by the exhaled breath-print during chronic liver disease
Authors: A. De Vincentis, U. Vespasiani-Gentilucci, G. Galati, P. Gallo, G. Colarusso, G. Pennazza, M. Santonico, C. Vernile, R. Antonelli-Incalzi, A. Picardi
Journal: Journal of Hepatology (2015)
Abstract 1451: Hyperpolarization Induces Differentiation Of Human Cardiomyocyte Progenitor Cells
Authors: Piet van Vliet, Teun P de Boer, Marcel A van der Heyden, Joost P Sluijter, Pieter A Doevendans, Marie-Jose Goumans
Journal: Circulation (2008)

Background: Recently, we have isolated cardiomyocyte progenitor cells (hCMPCs) from human fetal and adult hearts. These cells differentiate into spontaneously beating cardiomyocytes when stimulated with 5-azacytidine. Subsequent stimulation by TGFβ enhances differentiation efficiency to nearly 100%. The underlying molecular mechanisms mediating this cardiomyogenic differentiation are not understood. In skeletal myoblasts, hyperpolarization-mediated activation of calcineurin signaling is crucial for myogenic differentiation. In hCMPCs, whole-cell patch clamp recordings showed a hyperpolarized membrane potential after stimulation with TGFβ or BMP. We hypothesized that hyperpolarization and calcineurin signaling regulate cardiomyogenic differentiation of hCMPCs after TGFβ stimulation. Methods &amp; Results: To test whether hyperpolarization initiates cardiomyogenic differentiation, hyperpolarization was induced by 1) co-culture of hCMPCs with HEK 293 cells overexpressing a Kir2.1GFP fusion protein (KWGF cells) or 2) culture of hCMPCs overnight in medium containing low potassium concentrations. During co-culture, Lucifer Yellow dye injection in KWGF cells spread to neighboring hCMPCs, indicating cellular coupling. This resulted in stable hyperpolarization in hCMPCs, which could be blocked by addition of the gap junction inhibitor halothane. After two weeks, qPCR analysis revealed increased expression of cardiac sarcomeric genes in the hCMPCs in a dose-dependent manner. Induction of hyperpolarization by culturing hCMPCs with low potassium concentrations also resulted in increased expression of cardiac genes and the formation of spontaneously beating cells. Immunofluorescence staining revealed striated patterns of troponin I and α-actinin. Interestingly, hyperpolarization also increased intracellular calcium levels in hCMPCs, as measured by ratiometric imaging of indo-1 fluorescence, and, subsequently, a time-dependent increase in NFAT-Luciferase reporter activity, indicating activation of the calcineurin pathway. Conclusion: TGFβ and/or BMP-mediated hyperpolarization of hCMPCs induces calcineurin-mediated cardiomyogenic differentiation.
What Is Value in Health Care?
Authors: Jon C Tilburt, Victor Manuel Montori, Nilay D Shah
Journal: New England Journal of Medicine (2011)

To the Editor: In his Perspective article, Porter (Dec. 23 issue)1 defines “value” as “outcomes relative to cost.” His views represent a payer-centered perspective rather than a patient-centered one and reduce caring to “services” in a (mythical) health care marketplace. His “value” could reward mediocre outcomes delivered cheaply — a bargain for payers, not patients. Moreover, paying for value on the basis of long-term outcomes in patients with chronic disease will remain an important challenge for the foreseeable future. Value from patients’ perspective — if we were to ask them — should reward high-quality, affordable care, no doubt. But it would also reward practitioners whose care centers around the patient, not solely “value” based on cost, measurable outcomes, and efficiency metrics. Judged by Porter’s metric, “amenities” such as chaplain services, fine art, and an unhurried examination would quickly become extinct.2 More than a decade ago, Cleary et al. identified a patient-centered definition of quality that has gone largely unnoticed in the research and policy communities.3 Unless we start defining value from a patient-centered, not payer-centered, perspective, we will further silence the patient’s voice in U.S. health care.
Abstract 747: A Novel Cardiac Myosin Light Chain Kinase Regulates Sarcomere Assembly in the Vertebrate Heart
Authors: Osamu Seguchi, Seiji Takashima, Satoru Yamazaki, Masanori Asakura, Yoshihiro Asano, Yasunori Shintani, Masakatsu Wakeno, Tetsuo Minamino, Soichiro Kitamura, Hitonobu Tomoike, Naoki Mochizuki, Masafumi Kitakaze
Journal: Circulation (2007)

Background Cardiomyocytes mainly consist of sarcomere structure and marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing myocardium. Among several constituents of sarcomeres, myosin regulatory light chain 2 (MLC2v) affects physiological cardiac sarcomere formation and heart development through its phosphorylation. Exact upstream kinase of MLC2v in cardiomyocytes however, have not been elucidated so far. Mathods and Results We identified a novel cardiac-specific gene whose expression was upregulated in failing myocardium and was also correlated with the values of pulmonary arterial pressure of each patient. This gene has kinase domain and MLC2v was identified as a putative substrate by in vitro kinase reaction using mouse heart extracts and recombinant protein of this gene. Therefore, we termed this novel gene as a cardiac-specific myosin light chain kinase (cardiac-MLCK, gene symbol: MYLK3 ). To further investigate the function of cardiac-MLCK, we targeted cardiac-MLCK using specific siRNAs in cultured neonatal rat cardiomyocytes. Reduced expression of cardiac-MLCK caused the impairment of sarcomere reassembly on epinephrine treatment. Also knockdown of cardiac-MLCK expression in zebrafish embryos using specific morpholino antisense oligonucleotides led to dilation of the cardiac ventricle with incomplete sarcomere formation. We also analyzed the nature of cardiac-MLCK and MLC2v in mouse models of heart failure. Expression levels of cardiac-MLCK proteins and phosphorylation levels of MLC2v were severely reduced in the failing heart of trans-aortic constriction mice. Conclusions We identified a novel cardiac-MLCK which contributed mainly to cardiac MLC2v phosphorylation. Attenuation of cardiac-MLCK expression caused severe sarcomere disorganization both in vitro and in vivo implies its important roles in cardiac functions. Our results suggest that cardiac-MLCK mRNA expression may be upregulated to compensate for the lower expression and reduced phosphorylation of MLC2v in failing myocardium. As a possible therapeutic modality in patients with CHF, upregulation of cardiac-MLCK may promote sarcomere assembly and enhanced contractility of the failing heart
Abstract 2621: C-type Natriuretic Peptide Attenuates Vascular Remodeling In Severe Pulmonary Hypertension
Authors: Jeffrey M Mazer, Brian Casserly, Sharon Rounds, Gaurav Choudhary
Journal: Circulation (2008)

Pulmonary vascular remodeling and endothelial proliferation are important pathophysiological processes contributing to increased vascular resistance seen with pulmonary hypertension (PH). C-type natriuretic peptide (CNP) is an endothelium derived natriuretic peptide that has been shown to have anti-inflammatory, anti-mitogenic and anti-proliferative actions. However, its role in modulating severe PH is not known. We hypothesized that CNP will attenuate severe PH through its effect on pulmonary vascular remodeling. In order to test our hypothesis we chose to study the effect of continuous infusion of CNP, delivered by an osmotic pump, in a rat model of severe PH. This model combines the use of a VEGF receptor blocker, SU5416 (SU), and hypoxia to induce severe PH and plexiform lesions. Adult male Sprague Dawley rats were implanted with osmotic pumps to deliver CNP or vehicle for three weeks. Subsequently they received a single dose of SU or diluant and were placed in either normoxic or hypoxic (10% FiO 2 ) environment for 3 wks. the animals then underwent echocardiogram, right heart catheterization, and carotid catheterization to evaluate right ventricle (RV) function, RV mass, and RV pressure (RVP). The lungs were fixed and evaluated for vascular remodeling using H&amp;E staining and immunohistochemistry. Rats exposed to hypoxia alone developed moderate PH, while animals given SU and exposed to hypoxia developed severe PH (RVP (mmHg)- Normoxia: 27±1; Hypoxia: 79±6; Hypoxia+SU: 92±3). RV hypertrophic response mirrored the RVP in each group. Animals with severe PH receiving low dose CNP (0.75μg/hr) had increased RV mass and RVP, similar to vehicle treated animals, but demonstrated a 19% reduction in the microvascular wall thickness (p&lt;0.05 compared to vehicle). Upon treatment with a higher dose of CNP (2.25μg/hr), animals demonstrated a significant reduction in RVP in the severe PH group (76±5 mmHg), as compared to vehicle treated animals (95±6 mmHg, p&lt;0.05). CNP attenuates severe pulmonary hypertension likely via its effects on microvascular remodeling.
Abstract 1829: Circadian Changes in ST-RR and QT-RR Relationships During Daily Life of Patients with Brugada Syndrome
Authors: Koichi Mizumaki, Akira Fujiki, Kunihiro Nishida, Takayuki Tsuneda, Tamotsu Sakamoto, Jotaro Iwamoto, Hiroshi Inoue
Journal: Circulation (2007)

In patients with Brugada syndrome, abnormal rate-dependent repolarization dynamics has been proposed as a modulating factor of arrhythmogenesis. In the present study, we assessed the hypothesis that circadian changes in both ST-RR and QT-RR relationship could relate to occurrence of ventricular fibrillation (VF) in daily life of patients with Brugada syndrome. Methods: Thirty-five male patients with Brugada syndrome who had the type I ST elevation were categorized into 14 symptomatic (with documented VF or syncope) and 21 asymptomatic groups. Unipolar V 2 and V 5 leads digital Holter ECG was recorded, and ST level in V 2 and QT interval in V 5 were automatically measured. Both ST-RR and QT-RR relationships were evaluated by means of ST-RR and QT-RR linear regression lines according to four 6-hour periods. In all 14 symptomatic patients, the time of spontaneous episodes of VF were investigated from the implantable cardioverter defibrillator stored data. Results: In symptomatic patients, ST-RR slope was highest during 18:00–24:00 and was lowest during 0:00 – 6:00; however, these circadian changes were blunted in asymptomatic patients. ST-RR intercept was not different between the 2 groups and didn’t show distinct circadian changes in both groups. The QT-RR slope was always lower, except during 6:00–12:00, in symptomatic patients than in asymptomatic patients. Circadian changes in QT-RR relationship were not evident in both groups. QT-RR intercept was not different between the 2 groups and didn’t show distinct circadian changes in both groups. Nineteen (59%) of total 32 episodes of spontaneous VF of 14 symptomatic patients occurred between 18:00 and 24:00, and 9 episodes (28%), between 0:00 and 6:00. VF seldom occurred during the daytime. Conclusions: In symptomatic patients with Brugada syndrome, a combination of augmentation of ST elevation with inhibited prolongation of QT interval during bradycardia could relate to an occurrence of VF in the late evening. Circadian Changes in ST-RR and QT-RR Slopes
Erratum to: Prevention of acute kidney injury and protection of renal function in the intensive care unit
Authors: Michael Joannidis, Wilfred Druml, Lui G. Forni, A. B. Johan Groeneveld, Patrick Honore, Heleen M. Oudemans-van Straaten, Claudio Ronco, Marie R. C. Schetz, Arend Jan Woittiez
Journal: Intensive Care Medicine (2010)
Inhibition Of Histone Deacetylases With Panobinostat As a Treatment For Relapsed Or Refractory Diffuse Large B-Cell Lymphoma: A Phase II Study By The Fondazione Italiana Linfomi
Authors: Francesco Zaja, Flavia Salvi, Silvia Franceschetti, Gianluca Gaidano, Marco Ladetto, Manuela Zanni, Gian Matteo Pica, Angelo Michele Carella, Annalisa Chiappella, Stefano Volpetti, Pier Luigi Zinzani, Alfonso Maria D'Arco, Andrea Evangelista, Alessandra Tucci, Pier Paolo Piccaluga, Stefano A. Pileri, Renato Fanin, Alessandro Levis
Journal: Blood (2013)