tbuckley/cabot-search huggingface dataset:
Activity of pm02734 against human breast and prostate tumors
Authors: Mariano Elices, Doreen J. Lepage, Wendy Grant, Enrique Alvarez, M. Jose Guillen, Carmen Cuevas, Pablo Aviles, Glynn Faircloth
Journal: Cancer Research (2006)

4712   The novel investigational agent PM02734 is a member of the Kahalalide F family of compounds that display marked anttumor activity properties and is currently undergoing multicenter phase I clinical trials in Europe and the U.S. In this limited study, we implanted human tumors subcutaneously into athymic nude mice (N = 10) and allowed them to grow  in situ  until they reached a size of approximately 100 ± 15 mm 3  at which time animals were randomized and drug treatment commenced. We evaluated the effect of PM02734 individually against human breast (MX-1) and prostate (DU-145) tumors grown as xenografts in either female or male cohorts, respectively, when PM02734 was administered as a five-consecutive-day (QDx5) intravenous injection regimen. Interestingly, PM02734 QDx5 at a dose of 320-325 μg/kg/day abrogated, on average, growth of established tumors in both xenografts, and this effect was concurrent with treatment. In particular, the ratio of tumor sizes applicable to animals treated with drug relative to the vehicle control cohort on a percentage basis on Day 3 of dosing was 49% and 46% in breast and prostate xenografts, respectively. This tumor growth exhibited a high degree of statistical significance when compared to corresponding vehicle control groups in breast and prostate xenografts and remained statistically significant beyond the treatment schedule. In fact, tumor growth delay of drug- compared to vehicle-treated cohorts was approximately five and four days for breast and prostate tumor xenografts, respectively. Based on body weight measurements, treatment with PM02734 QDx5 appeared to be well-tolerated. In summary, PM02734 QDx5 demonstrates a rapid onset of tumor inhibition activity and a strong cytostatic effect judging from breast and prostate xenografts reported herein. Additional studies are ongoing.
Abstract 108: Inhibition of demethylase, JMJD3 sensitizes diffuse large B-cell lymphoma (DLBCL) to chemotherapy
Authors: Rohit Mathur, Lalit Sehgal, Zuzana Berkova, Sattva S. Neelapu, Felipe Samaniego
Journal: Cancer Research (2015)

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL) representing more than 30% of new cases diagnosed in the United States. DLBCL comprises multiple biologically and clinically distinct subtypes including germinal center B-cell-like (GCB) and activated B-cell like (ABC) DLBCL. Despite improvement in current therapies, nearly 40% of patients die from the disease. Recent studies of the epigenome and the methylome in particular, have revealed widespread epigenetic changes in DLBCL. Aberrant methylation of core histone tails occur with deregulation of methylase enzymes such as Ezh2 in DLBCL. In contrast, the role of JMJD3 and UTX, H3K27(me)3 demethylases in DLBCL remains unknown. In this study, we have evaluated the activity of the selective JMJD3 inhibitor GSK-J4 in DLBCL and investigated the mechanism of its action. Methods Panel of DLBCL cell lines: DB, KARPAS 422, Pfeiffer, Toledo, Sudhl2, Sudhl6, Sudhl8, TMD8, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly8, OCI-Ly4, OCI-Ly10, and primary DLBCL cells were analyzed for the expression of lysine demethylases (KDMs) using RT-PCR and Western blot analysis. Sub-G1 analysis was performed to analyze drug-induced apoptosis. Chemical inhibitor GSK-J4 and siRNAs were used for specific inhibition of the JMJD3. Results JMJD3 inhibitor, GSK-J4 induced the killing of DLBCL cell lines of both GC and ABC subtypes. Cell sensitivity to GSK-J4 could not be predicted from the expression of prognostic markers in DLBCL such as Bcl6, IRF4 and Ezh2. For further studies, we selected a cell line Sudhl6 (Bcl6 dependent), sensitive to the killing effect of GSK-J4. Treatment with GSK-J4 reduced the Bcl6 levels along with concomitant increase in IRF4 and FBXO11, negative regulators of Bcl6. Knockdown of JMJD3 by siRNAs also reduced the levels of Bcl6, implicating Bcl6 in the mechanism of action of GSK-J4. Additionally, GSK-J4 synergized in killing with vincristine, doxorubicin as well as proteasome inhibitors bortezomib and carfilzomib. Conclusion We demonstrate the potent effects of inhibition of H3K27(me)3 demethylase JMJD3 by GSK-J4 on proliferation and apoptosis of DLBCL cells. Our results clearly show synergistic effects of inhibition of demethylase with standard drugs in elimination of DLBCL cells. Note: This abstract was not presented at the meeting. Citation Format: Rohit Mathur, Lalit Sehgal, Zuzana Berkova, Sattva S. Neelapu, Felipe Samaniego. Inhibition of demethylase, JMJD3 sensitizes diffuse large B-cell lymphoma (DLBCL) to chemotherapy. [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 108. doi:10.1158/1538-7445.AM2015-108
Bioavailability of the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), in mice: Dose-dependence and improvement via peracetylation
Authors: Joshua D. Lambert, Shengmin Sang, Jungil Hong, Mao-Jung Lee, Lauren Diamond, Jihyeung Ju, Mousumi Bose, Seok-Joo Kwon, Chung S. Yang
Journal: Cancer Research (2006)

3101   Epigallocatechin-3-gallate (EGCG) has been shown to undergo extensive biotransformation to yield methylated and glucuronidated metabolites in mice, rats, and humans. In the present study, we determined the concentration-dependent uptake of EGCG (20 - 600 μM) by HT-29 human colon cancer cells and the dose-dependence of EGCG plasma and tissue levels following a single dose of EGCG (50 - 2000 mg/kg,  i.g. ) to male CF-1 mice. The cytosolic levels of EGCG were linear with respect to extracellular concentration of EGCG following treatment of HT-29 cells for 2 h (915.3 - 6851.6 μg/g).  In vivo  EGCG exhibited a linear dose-relationship in the plasma (0.03 - 4.17 μg/mL), prostate (0.01 - 0.91 μg/g), and liver (0.09 - 18.3 μg/g). In the small intestine and colon, however, the levels of EGCG plateaued between 500 and 2000 mg/kg,  i.g.  The levels of 4“- O -methylEGCG and 4’,4”-di- O -methylEGCG parallel those of EGCG with respect to dose. As a means of improving the stability and bioavailability of EGCG, we have also prepared a peracetylated EGCG (AcEGCG) derivative. AcEGCG exhibited enhanced growth inhibitory activity relative to EGCG in both KYSE150 human esophageal squamous cell carcinoma (IC 50  = 10 vs. 20 μM) and HCT116 human colon adenocarcinoma cells (IC 50  = 32 vs. 45 μM). AcEGCG was rapidly converted to EGCG by HCT116 cells, and treatment of cells with AcEGCG resulted in a 2.8 - 30-fold greater intracellular concentration of EGCG as compared to treatment with EGCG. AcEGCG was also more potent than EGCG at inhibiting nitric oxide-production (4.4-fold) and arachidonic acid-release (2.0-fold) from lipopolysaccharide-stimulated RAW264.7 murine macrophages. Intragastric administration of AcEGCG to CF-1 mice resulted in improved bioavailability compared to administration of equimolar doses of EGCG. The plasma AUC 0→∞  of total EGCG was 3.29x10 5  and 1.26x10 5  ((ng/mL) . min) for AcEGCG and EGCG, respectively. The t 1/2  of EGCG was also increased following administration of AcEGCG compared to EGCG (310.4 vs. 135.2 min). The AUC 0→∞  and t 1/2  were also increased in the small intestine (18.5- and 3.3-fold, respectively) and the colon (4.0 and 4.4-fold, respectively). The present study provides information with respect to what concentrations of EGCG are achieveable in mice. Our results suggest that absorption of EGCG from the small intestine is largely via passive diffusion, however, at high concentrations, the small intestinal and colonic tissues become saturated. Acetylation represents a means of increasing the biological potency  in vitro , increasing the bioavailability of EGCG  in vivo , and may result in improved cancer preventive activity  (Supported by NIH grant CA88961) .
Abstract 9672: Pressure Volume Relationship is Related to Coronary Flow Reserve in Non-Ischemic Dilated Cardiomyopathy
Authors: Quirino Ciampi, Lorenza Pratali, Fausto Rigo, Sonia Gerardi, Bruno Villari, Eugenio Picano, Rosa Sicari
Journal: Circulation (2011)

Background. Coronary flow reserve (CFR) on left anterior descending (LAD) can be reduced in non-ischemic dilated cardiomyopathy (DCM). Pressure-volume relationship (PVR) is a useful method for evaluating LV myocardial contractility during stress echocardiography (SE). Aim of the study was to assess the relationship between CFR on LAD and PVR in DCM patients. Methods. Sixty DCM patients (36 men; 63±13 years, mean value of ejection fraction: 36±7%) underwent dipyridamole stress echo (dypSE, 0.84 mg/kg in 6′). CFR was defined as the ratio between maximal vasodilation and rest peak diastolic flow velocity in LAD. PVR was defined as systolic cuff pressure/end-systolic volume index difference between rest-peak dypSE. Results. PVR was inversely related to wall motion score index at rest (r=-.424, p=.001) and at peak dypSE (r=-.528, p&lt;.001), and directly related to E wave deceleration time (r=.365, p=.014). PVR was not related to ejection fraction at rest, and directly related to ejection fraction at peak dypSE (r=.482, p&lt;.001). CFR on LAD was abnormal (&lt;2) in 25/60 (42%) patients. PVR was directly related to CFR on LAD (r=.412, p=.001, Figure). Conclusions. In DCM patients, the presence of myocardial contractile reserve is directly related to CFR on LAD.
A Study of the National Health Service of Great Britain.
Authors: O. L. Peterson
Journal: JAMA (1952)

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Lesson of the Week: The risks of delay in diagnosis of breathlessness in pregnancy
Authors: C A Morley, B A Lim
Journal: BMJ (1995)

Heart disease is an important cause of dyspnoea in pregnancy.The diagnosis can easily be missed by the unwary unless it is specifically looked for.Owing to the physiological change and hyperdynamic circulation of pregnancy, patients often deteriorate suddenly and unexpectedly, catching both them and their doctors by surprise.If the diagnosis is not made early this may prove fatal.We describe five cases (over two years) of cardiac disease presenting for the first time during pregnancy.Case reports
Abstract 2455: Short Sleep Duration is an Independent Predictor of Cardiovascular Events in Hypertensive Patients
Authors: Kazuo Eguchi, Thomas G Pickering, Joseph E Schwartz, Satoshi Hoshide, Joji Ishikawa, Kazuyuki Shimada, Kazuomi Kario
Journal: Circulation (2008)

We aimed this study to test the hypothesis that short duration of sleep is independently associated with incident cardiovascular diseases (CVD) in hypertensive patients. We performed ambulatory BP monitoring (ABPM) in 1255 subjects with hypertension (mean age: 70.4 ± 9.9 years) and they were followed for an average of 50 ± 23 months. Short sleep duration was defined as &lt;7.5 hrs (20 th percentile). Multivariable Cox hazard models predicting CVD events were used to estimate the adjusted hazard ratio (HR) and 95% CI for short sleep duration. A riser pattern was defined when average nighttime SBP exceeded daytime SBP. The end point was cardiovascular events: stroke, fatal or non-fatal myocardial infarction (MI), and sudden cardiac death. In multivariable analyses, short duration of sleep (&lt;7.5 hrs) was associated with incident CVD (HR=1.68; 1.06 –2.66, P=.03). A synergistic interaction was observed between short sleep duration and the riser pattern (P=.089). When subjects were categorized on the basis of their sleep time and riser/non-riser patterns, the shorter sleep+riser group had a highest incidence of CVD among the 4 groups ( Figure ), and substantially and significantly higher incidence of CVD than the predominant normal sleep+non-riser group (HR=4.43; 2.09 –9.39, P&lt;0.001), independent of covariates. Short duration of sleep is associated with incident CVD risk, and the combination of riser pattern and short duration of sleep that is most strongly predictive of future CVD, independent of ambulatory BP levels. Physicians should inquire about sleep duration in the risk assessment of hypertensive patients.
Hypersensitivity Cases Associated With Drug-Eluting Coronary Stents
Authors: Jonathan R. Nebeker, Renu Virmani, Charles L. Bennett, Jennifer M. Hoffman, Matthew H. Samore, Jorge Alvarez, Charles J. Davidson, June M. McKoy, Dennis W. Raisch, Brian K. Whisenant, Paul R. Yarnold, Steven M. Belknap, Dennis P. West, Jonathan E. Gage, Richard E. Morse, Gordana Gligoric, Laura Davidson, Marc D. Feldman
Journal: Journal of the American College of Cardiology (2005)
Abstract 908: Impact of microbial metabolites and resveratrol in prostate cancer progression and clearance
Authors: James Stokes, Manoj K. Mishra
Journal: Cancer Research (2015)

Abstract Short-chain fatty acids (SCFAs) are the chemical by-products of microbial fermentation. Resistant carbohydrates, some starches, and foods generally rich in fiber are used as substrates for this process. SCFAs are known to activate key cellular receptors such as GPR43/FFA2, which mediate programmed cell death in different cancer cells. Resveratrol (RES) is a polyphenolic compound found in select vegetables and fruits and has been known for its versatility in preventing and reversing a number of diseases including some cancers. Much like SCFAs, RES has the ability to induce programmed cell death in many clinical cancer models. To find out if the SCFAs and RES modulates the different pathways that controls the cancer progression, we utilized prostate cancer (PCa) cell lines to establish a) if, there is any homology between SCFAs produced by normal host epithelial cells and SCFAs produced by host intestinal microflora, and b) assess the in vitro/vivo effectiveness of derived SCFAs utilizing transgenic adenocarcinoma mouse prostate (TRAMP C1, C2, and C3) cell line(s), human prostate cancer cell line (PC-3) and live murine specimens, respectively. Preliminary data indicates that SCFAs and RES together regulate cell death pathways of PCa cells. Additionally, the SCFAs have the capability to manipulate different molecular signatures that directly govern the progression of PCa cells. Therefore, our data suggests that these two compounds (SCFAs and RES) share related biological pathways facilitated by intestinal microflora that can be used to regulate prostate cancer progression and clearance. Citation Format: James Stokes, Manoj K. Mishra. Impact of microbial metabolites and resveratrol in prostate cancer progression and clearance. [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 908. doi:10.1158/1538-7445.AM2015-908
Homogeneous generation of iDA neurons with high similarity to bona fide DA neurons using a drug inducible system
Authors: Hanseul Park, Hongwon Kim, Junsang Yoo, Jaekwang Lee, Hwan Choi, Soonbong Baek, C. Justin Lee, Janghwan Kim, Christopher J. Lengner, Jung-Suk Sung, Jongpil Kim
Journal: Biomaterials (2015)
Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance
Authors: Laurent Bonello, Laurence Camoin-Jau, Stéphane Arques, Christian Boyer, Dimitri Panagides, Olivier Wittenberg, Marie-Claude Simeoni, Paul Barragan, Françoise Dignat-George, Franck Paganelli
Journal: Journal of the American College of Cardiology (2008)
Inhibition Of RNA Polymerase I Transcription By CX-5461 As a Therapeutic Strategy For The Cancer-Specific Activation Of p53 In Highly Refractory Haematological Malignancies
Authors: Nadine Hein, Sean O'Brien, Denis Drygin, Simon J. Harrison, Amit Khot, Carleen Cullinane, Matthews Geoff, Marta Chesi, Peter Leif Bergsagel, Johannes Zuber, Scott W. Lowe, Ricky W Johnstone, Rick Pearson, Grant A. McArthur, Ross D Hannan
Journal: Blood (2013)
ImmunoVEX ex vivo: A herpes simplex virus-based, dendritic cell-mediated anti-cancer vaccine platform
Authors: P. A. Reay, M. Yi-Sun, B. Liu, Y. McGrath, M. Wakeling, J. John, E. Turnbull, S. Thomas, R. Coffin
Journal: Journal of Clinical Oncology (2004)

2602 Background: Dendritic cell (DC)-based vaccines are promising for cancer treatment. However, there are significant problems of efficient antigen loading and practicality of current approaches. Herpes simplex virus (HSV), unlike most viruses, infects DC very efficiently suggesting its use for antigen delivery to DC. The large size of HSV allows delivery of multiple antigens (up to 30Kb), as may be beneficial for anti-cancer vaccination. However, DC infected with HSV loose the ability to become activated as is necessary for the induction of an effective immune response, probably to minimize immune responses to HSV. Methods: We have iteratively tested an extensive range of HSV mutants with individual and combinations of genes deleted to identify the HSV DC blocking genes. This has allowed us to develop an optimal HSV backbone which activates DC similarly to LPS, rather than blocking activation as with wild type HSV. These viruses are deleted for the HSV virion host shutoff protein (vhs), which we found to be a key mediator of DC inactivation, ICP47, which blocks antigen presentation, UL43, deletion of which improves DC function, and ICP4, deletion of which blocks HSV replication. Results: This virus significantly up-regulates levels of CD80, CD83, CD86 and MHC class I on infected cells, gives very high level transduction of DC at a low virus dose (MOI<1), and gives potent immune stimulation. These vectors therefore provide a platform for ex vivo transduction of DC for anti-cancer vaccination. Here automated magnetic bead technology is used for the preparation of human DC precursors from peripheral blood. Conclusions: Using DC prepared in this manner, which are transduced and frozen in aliquots for subsequent vaccination, a clinical trial is in preparation in melanoma where a vector has been constructed expressing the three full length melanoma-associated antigens MART-1, gp100 and tyrosinase. Pre-clinical data relating to this program will be presented. However, other vectors encoding other combinations of tumour antigens relevant to other tumour types are also at earlier stages of construction and development. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BioVex Ltd.
Abstract 14257: Cell Type-Specific Decrease of Gene Body DNA Methylation Levels in Cardiomyocyte-Specific Genes Contribute to the Transcriptional Efficiency at Postnatal Development of Mouse Cardiomyocytes
Authors: Mayumi Oda, Shinji Makino, Hirokazu Enomoto, Kojiro Yae, Ruri Kaneda, Shinsuke Yuasa, Keiichi Fukuda
Journal: Circulation (2011)

[INTRODUCTION] Efficient and coordinated transcription of cardiomyocyte-specific genes is important throughout life for the maintenance of cardiomyocyte performance in response to diverse physiolog...
Abstract 16568: Bmp Receptor II Reduction Causes Endothelial Inflammation in vitro and Increases Atherosclerosis in Apoe Knockout Mice
Authors: Chanwoo Kim, Hannah Song, Dongju Son, Sandeep Kumar, Hanjoong Jo
Journal: Circulation (2011)

Atherosclerosis is an inflammatory disease, occurring preferentially in arterial regions exposed to disturbed flow. We have shown that in the endothelial cells (ECs), bone morphogenic protein-4 (BM...
Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926
Authors: Tara Lin, Qiuju Wang, Patrick Brown, Craig Peacock, Sarah Brennan, Akil Merchant, Evan Jones, Karen McGovern, D. Watkins, Kathleen Sakamoto, William Matsui
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4999 

During embryonic development, conserved signaling pathways such as Hedgehog (Hh), Wingless and Notch precisely regulate critical cellular processes such as self-renewal and differentiation. These pathways are normally silenced in most adult tissues, but may be reactivated in a wide range of human malignancies, such as Notch in T-cell acute lymphocytic leukemia (ALL). The cellular processes regulating self-renewal in B-cell ALL are poorly understood, but we hypothesized that these conserved signaling pathways may play a role. We studied expression of the Hh signaling components PATCHED-1 (PTCH), SMOOTHENED (SMO) and Gli-1 in human B-precursor ALL cell lines (HB1119, Nalm-6, REH, RS4;11, SEM-K2 and TOM-1) and 41 primary B-precursor ALL specimens. The Hh signaling pathway was common in B-precursor ALL as expression of PTCH, SMO and Gli-1 was detected in all 6 cell lines and 39/41 clinical specimens. Furthermore, functional pathway activity was detected in REH and RS4;11 cells using a Gli-responsive luciferase reporter that could be augmented by Sonic Hedgehog (SHh) ligand or inhibited by the SMO antagonist cyclopamine or the novel semi-synthetic cyclopamine derivative IPI-926. To examine the functional role of Hh in ALL self-renewal, we examined clonogenic growth in methylcellulose and found that colony-formation was significantly inhibited by cyclopamine and IPI-926. Cancer stem cells can be identified by relatively high activity of the intracellular enzyme retinaldehyde dehydrogenase (ALDH) similar to normal hematopoietic and neural stem cells. We found that high ALDH activity could also identify rare cell populations in the REH and RS4;11 cell lines and treatment with cyclopamine or IPI-926 significantly reduced the relative proportion of ALDHhigh cells. These results suggest that the inhibition of Hh signaling impairs ALL self-renewal by targeting a rare cell population which may be responsible for disease propagation. Therefore, novel inhibitors of the Hh signaling pathway such as IPI-926 may offer promising approaches for development of therapies in this disease.
Abstract 3041: Biventricular Pacing in Patients with Severely Reduced LV-function After CABG - The BIVAC-Trial
Authors: Thorsten Hanke, Martin Misfeld, Matthias Heringlake, Maximilian Massalme, Anika Dyllus, Uwe Wiegand, Hans-H. Sievers, Frank Eberhardt
Journal: Circulation (2007)