tbuckley/cabot-search huggingface dataset:
Abstract 1689: Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma
Authors: Dhong Hyun Tony Lee, Jun Qi, James Bradner, Jonathan Said, Ngan Doan, Charles Forscher, H Phillip Koeffler
Journal: Cancer Research (2014)

Abstract Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facillitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity againts many hematological and solid cancers, mainly through inhibition of c-myc and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment, due to the frequent copy number gain and overexpression of c-myc in OS cells. JQ1 significantly inhibited the proliferation and survival of seven OS cells (U2OS, G292, MG-63, HT-161, MNNG/HOS, SAOS-2, SJSA), at a relatively higher dose than other cancers (median IC50 = 7.35 μM). JQ1 induced G1 cell cycle arrest and premature senescence of OS cells, but produced little apoptosis. Interestingly, c-myc protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable, as noted by Western blots. Although effective in vitro, JQ1 failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice in vivo. To overcome the resistance of OS cells to JQ1 treatment, we tested JQ1 in combination with rapamycin. Rapamycin inhibits the assembly of mTOR complexes which is one of the important growth signaling pathways in many cancers including OS. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro. The drug combination nearly abrogated expression of c-myc protein, enhanced levels of p21, and induced apoptosis in OS cells in vitro. After 24 days of treatment in vivo, JQ1 (50mg/kg body weight) or rapamycin (1.5 mg/kg body weight) alone showed little effect on the size of human OS xenografts in nude mice. However, combination of both drugs significantly inhibited tumor growth by 85% and 73% (p&amp;lt;0.05 for both) compared to either JQ1 or rapamycin alone, respectively. In conclusion, JQ1 inhibited proliferation and survival of OS cells in vitro but failed to reduce growth of OS xenografts in immunodeficient mice. When combined with rapamycin, JQ1 synergistically inhibited proliferation of OS cells both in vitro and in vivo. Citation Format: Dhong Hyun Tony Lee, Jun Qi, James Bradner, Jonathan Said, Ngan Doan, Charles Forscher, H Phillip Koeffler. Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1689. doi:10.1158/1538-7445.AM2014-1689
Improving the Intracellular Delivery and Molecular Efficacy of Antisense Oligonucleotides in Chronic Myeloid Leukemia Cells: A Comparison of Streptolysin-O Permeabilization, Electroporation, and Lipophilic Conjugation
Authors: David G. Spiller, Richard V. Giles, John Grzybowski, David M. Tidd, Richard E. Clark
Journal: Blood (1998)
Effect of Methotrexate Use and Erythrocyte Methotrexate Polyglutamate on Glycosylated Hemoglobin in Rheumatoid Arthritis
Authors: Maurits C. F. J. de Rotte, Pascal H. P. de Jong, Ethan den Boer, Saskia M. F. Pluijm, Behiye Özcan, Angelique E. A. M. Weel, Jan Lindemans, Johanna M. W. Hazes, Robert de Jonge
Journal: Arthritis & Rheumatology (2014)

Objective To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA 1c ) levels in rheumatoid arthritis (RA) patients. Methods The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease‐modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA 1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu 1–5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA 1c were compared by paired t ‐test. Associations of MTXGlu concentrations with changes in the level of HbA 1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort. Results In the derivation cohort, the mean change in HbA 1c level after 3 months of treatment was −1.9 mmoles/mole (−0.18%) ( P = 0.001). Levels of HbA 1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, −5.5 mmoles/mole (−0.50%) ( P &lt; 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, –3.7 mmoles/mole (−0.34%) ( P &lt; 0.001), for the MTX treatment arm, −0.8 mmoles/mole (−0.08%) ( P = 0.018), and for the HCQ treatment arm, −2.0 mmoles/mole (−0.19%) ( P = 0.175). Increased levels of MTXGlu 2 (β = −0.20, P = 0.005), MTXGlu 3 (β = −0.31, P &lt; 0.001), MTXGlu 4 (β = −0.33, P &lt; 0.001) after treatment, MTXGlu 5 (β = −0.39, P &lt; 0.001), and total MTXGlu (β = −0.29, P &lt; 0.001) were associated with decreased levels of HBA 1c . In the validation cohort, levels of HbA 1c were decreased by 2.6 mmoles/mole (0.23%) ( P &lt; 0.001) after treatment, and MTXGlu 3 was associated with decreased levels of HbA 1c (β = −0.26, P = 0.018). Conclusion MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA 1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA 1c levels, and glucocorticoid treatment resulted in increased levels of HbA 1c .
Abstract P084: Influence Of Amount And Rapidity Of Weight Loss On The Risk Of Subsequently Regaining Weight And Drop-out From Treatment Among Patients With Severe Obesity Dieting In Hospital Without Bariatric Surgery
Authors: Tomohide Yamada, Kazuo Hara, Takashi Kadowaki
Journal: Circulation (2014)

Although many obese patients with type 2 diabetes lose weight by dieting, most subsequently regain it. We performed a retrospective cohort analysis to assess the influence of the amount and rapidity of weight loss during hospitalization on the risk of subsequently regaining weight and stopping treatment in patients with severe obesity who dieted without bariatric surgery. A total of 131 severely obese patients (48±14 years old; BMI: 41.7±8.8; 75% with diabetes) received inpatient treatment that included diet, exercise, behavioral modification (charting weight four times daily), and educational seminars, and were followed after discharge. Regaining weight and drop-out were defined as returning to baseline body weight and failing to keep outpatient appointments, respectively. Patients lost an average of 5.3±3.0kg (4.9±2.4%) in hospital (mean: 19 days). Over the median 2-year follow-up period, unadjusted analysis showed that patients with &gt;3% weight loss in hospital had significantly less risk of regaining weight than patients losing≤3%. The risk decreased further with greater weight loss (&gt;7% loss; hazard ratio (HR):0.06; 95% confidence interval:0.007-0.47). Adjusted analysis revealed that &gt;5% weight loss was associated with significantly less risk of regaining weight after adjustment for age, sex, BMI, smoke, diabetes, insulin, sulfonylurea, antidepressant medication, and duration of hospitalization (&gt;7% loss; HR 0.04(0.004-0.36, p=0.004), 7%≥loss&gt;5%; HR 0.3(0.11-0.85, p=0.02)). No significant relation was observed between weight loss and drop-out. Among patients with &gt;3% weight loss during hospitalization, rapid weight loss (&gt;3% within 7 days) did not increase the risk of subsequently regaining weight compared with patients showing slower weight loss. In conclusion, achieving &gt;5% weight loss during comparatively brief hospitalization predicts subsequent maintenance of lower weight. Experiencing success in hospital might increase the motivation of obese patients.
Abstract 11125: Is the Rastelli Procedure Falsely Maligned?
Authors: Mohammed Al-Jughiman, Maryam Al-Omair, Osami Honjo, Erwin Oechslin, Christopher Caldarone, Glen Van Arsdell
Journal: Circulation (2014)

Background: Surgical options for transposition left ventricular outflow tract obstruction (TGA/LVOTO) are multiple. We and others have noted the Rastelli has high late mortality/morbidity for TGA/VSD/LVOTO. This led to a change in strategy in 2000.

Objective: We hypothesized that patients undergoing a Nikaidoh would have superior outcomes to the Rastelli procedure.

Methods: From ’82-‘13, 157 patients with TGA/LVOTO were operated. Of which 133 (84.7%) had associated VSD. Procedures were: Rastelli (n=41), Mustard ± LVOTO relief (n=41), ASO ± LVOTO relief (n=36), single V (n=26), REV (n=7), and Nikaidoh (n=6). Stratification by era was performed: era 1, ‘82-‘89 (n=70); era 2, ‘90-‘99 (n=50); era 3 ‘00-‘13 (n=37).

Results: Survival at 10 years was not different by strategy: Rastelli 77.9%, Mustard 82.3%, ASO 85.5%, single V 96.2%, REV 100%, and Nikaidoh 83.3% , P=0.24. Survival after the Rastelli improved over eras (at 9 years: era 1=45%, era 2=93%, and era 3=100%, P=0.01) (fig 1A). At 23 years, it was 45% for era 1 and 93% for era 2. Late mortality was independently associated with arrhythmia (OR 3.50; 95% CI 1.15-10.67, P=0.03) but not LVOT gradient (OR 0.95; 95% CI 0.89-1.01, P=0.13) though the first era had a positive time relationship (P=0.01) to increasing gradient (slope 0.49, SE=0.19, 95% CI 0.11-0.88) (LVOT reop fig 1B). The Rastelli and REV were independently associated with all reoperation (OR 10.58; 95% CI 4.23-26.46, P<0.001) and (OR 8.33; 95% CI 1.60-43.17, P=0.01) respectively. The Nikaidoh, Rastelli, and REV had similar RVOT reoperation.

Conclusion: The Rastelli since 1990, had a different outcome than a generation ago potentially suggesting a difference in starting physiologic substrate and or the operation. Greater sample size and follow up will be required to determine if long term outcome differs between the modern Rastelli and Nikaidoh. Given the significant improvement in survival over eras, the current Rastelli remains a viable strategy and is not inferior.

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Abstract 15899: Pro-Adrenomedullin (mr-proadm) Can Predict Short and Long Term Mortality in Stemi Patients
Authors: Johanne Silvain, Farzin Beygui, Maguy Bernard, Guillaume Cayla, Stephen O'Connor, Anne Bellemain-Appaix, Olivier Barthelemy, Delphine Brugier, Jean-Philippe Collet, Gilles Montalescot
Journal: Circulation (2011)

BACKGROUND: Midregional pro-Adrenomedulin (MR-proADM) appears to be a powerful predictor of adverse outcome after AMI when measured 3 to 5 days after symptoms onset. OBJECTIVES: We sought to assess...
Evaluation of current consensus panel guidelines for APBI: A pooled analysis of William Beaumont Hospital and American Society of Breast Surgeons MammoSite registry trial data.
Authors: John Ben Wilkinson, Peter D. Beitsch, Douglas W. Arthur, Chirag Shah, Bruce George Haffty, David E. Wazer, Martin Keisch, Simona Flora Shaitelman, Maureen Lyden, Frank Vicini
Journal: Journal of Clinical Oncology (2012)

145 Background: To determine whether the ASTRO Consensus Panel (CP) guidelines for accelerated partial breast irradiation (APBI) are associated with significantly different outcomes in a pooled analysis from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite Registry Trial. Methods: 2,127 cases of early-stage breast cancer were treated using APBI (WBH: n=678; ASBrS: n=1,449). Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3D-CRT, n=206) while all Registry Trial patients received balloon-based brachytherapy. Patients with complete coding necessary for ASTRO CP assignment (n=1,813) were divided into suitable (n=661, 36.5%), cautionary (n=850, 46.9%), and unsuitable (n=302, 16.7%) categories. Tumor characteristics and clinical outcomes were analyzed according to CP group. Results: Median age was 65 years (32-94 years) and median tumor size was 10.0mm (0-45mm). The WBH cohort had more node-positive disease (6.9% vs. 2.6%, p&lt;0.01) and cautionary patients (49.5% vs. 41.8%, p=0.06). Five-year rates of ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 2.8%, 0.6%, 1.6%, respectively. When analyzed by CP group, the rate of IBTR was not statistically higher for suitable (2.5%), cautionary (3.3%), or unsuitable (4.6%) patients (p=0.20). The non-significant increase in IBTR for grouped cautionary/unsuitable categories was due to increased elsewhere failures/new primaries (p=0.04), not true recurrences (1.1-1.2%, all groups, p=0.94). A higher rate of DM was observed within the cautionary and unsuitable groups (3.3-3.6% vs. 0.7% for suitable, p=0.01), although cause-specific survival was the same for all patient categories (98.0-98.6%, all groups, p=0.47). Conclusions: Excellent outcomes following breast conserving surgery and APBI were seen in our pooled analysis. The current ASTRO CP guidelines did not adequately differentiate patients at an increased risk of IBTR or tumor bed failure within the largest patient population of cases treated with APBI to date.
Abstract 18894: Standard Deviation of Segmental Left Atrial Strain is Impaired in Patients Treated by Pulmonary Vein Isolation With Late Failure
Authors: Michael Grafe, Charalampos Kriatselis, Hong Gerds-Li, Jan Kaufmann, Vesna Furundzija, Usan Thanabalasingam, Eckhart Fleck, Ernst Wellnhofer
Journal: Circulation (2014)

Introduction: Pulmonary vein isolation (PVI) has been established as effective interventional treatment in chronic atrial fibrillation (AF). Impairment of left atrial strain is considered a surrogate parameter of fibrosis. There is considerable variance of strain among different atrial wall segments. We hypothesized that early impairment of strain affects mobile segments and thus reduces inter-segmental variance of strain. Methods: We evaluated 89 consecutive PVI patients and 28 controls (mean age 60 ± 12 y, 33 female). The longitudinal strain of the left atrium in a 4-chamber apical window was determined by speckle tracking (Philips IE33 offline analysis by QLAB™). Success was defined as maintenance of sinus rhythm until last follow-up (minimum 3 months elapsed since PVI). Follow-up comprised repeated Holter-monitoring and echocardiography. Variance was evaluated as standard deviation of segmental strain before PVI (STD). Results: Atrial fibrillation recurred in 40 of 89 patients. STD was 16.5±7.9 in controls, 8.1±5.3 in PVI with persisting success and 4.6±2.2 in late PVI failure (see also box-plot). The group differences between controls, PVI success and PVI failure were all significant (p&lt;0.001 Kruskal-Wallis and median test) and improved prediction of PVI failure significantly in a binary logistic as well as linear discriminant model. Conclusions: Standard deviation of segmental left atrial strain is impaired in patients treated by pulmonary vein isolation with late failure and should be further evaluated as predictor for recurrence.
Poor Sanitation Practices Associated With Adverse Pregnancy Outcomes
Authors: M. J. Friedrich
Journal: JAMA (2015)

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Small molecule inhibitors of methionine aminopeptidase-2 (MetAP-2) fail to inhibit proliferation of human endothelial cells and formation of microvessel outgrowths from rat aortic rings in vitro
Authors: Thomas Garrabrant, Robert Tuman, Donald Ludovici, Rose Tominovich, Dana Johnson
Journal: Cancer Research (2004)

4580   Methionine aminopeptidase type 2 (MetAP-2) has been identified as a molecular target of the anti-angiogenic agents fumagillin and its derivative, TNP-470. Thus, MetAP-2 is considered to be an attractive target for the discovery of novel anti-angiogenic agents. Fumagillin and related compounds are irreversible inhibitors that block the aminopeptidase activity of MetAP-2 without affecting MetAP-1 at equivalent concentrations. We undertook a high-throughput screening program to identify selective, reversible inhibitors of MetAP-2 in order to discover structurally novel anti-angiogenic agents for potential therapeutic use in oncology. Screening was carried out versus rhMetAP-2 using a dipeptidyl peptidase IV-coupled homogeneous assay to produce a quantifiable fluorescent product. Potent inhibitors of MetAP-2 with varying molecular structures were identified from HTS, with IC 50  values as low as 8 nM. The most potent of these compounds contained a singly-substituted triazole moiety and were highly selective for MetAP-2 over MetAP-1 (greater than 60-fold difference in IC 50 ). Activity of the inhibitors was confirmed using an 8-amino acid substrate peptide to rule out possible artifacts resulting from use of an artificial 3-amino acid substrate for high-throughput screening. Unlike fumagillin, these potent MetAP-2 inhibitors failed to significantly inhibit the proliferation of primary human umbilical cord endothelial cells or to suppress microvessel outgrowth in an  in vitro  rat aortic ring explant assay of angiogenesis. Cellular penetration was confirmed for a potent representative of the triazole class of MetAP-2 inhibitors using the Caco-2 membrane permeability assay, suggesting that cellular permeability was not the direct cause for lack of cellular activity. Recently, the identity of the cations in the bimetallic active site of MetAP-2 has been questioned (Wang  et al ., Biochemistry 42, 5035-5042, 2003). Our inhibitors were identified using cobalt (II)-activated recombinant human MetAP-2. After substitution of manganese for cobalt, following EDTA treatment of the recombinant enzyme, the inhibitors we identified were less active (10 to 35-fold increase in IC 50 ) as MetAP-2 inhibitors. Inhibition of MetAP-2 by fumagillin was unchanged and was independent of the divalent cation present in the assay. This result supports the hypothesis that cobalt may not be the divalent metal ion cofactor for MetAP-2 found in cells and may explain the lack of cellular activity we observed for inhibitors of cobalt-activated MetAP-2. Alternatively, covalent inactivation of the target enzyme may be required to elicit a biological effect.
Biologically driven interpretation reveals molecular signatures predictive of oncogenic addiction to MEK signaling and cell line response to the MEK1/2 inhibitor AZD6244 (ARRY-142886)
Authors: Jonathan Dry, Chris Harbron, Mark Hickinson, Alex Graham, Tim French, Kai-Ming Chang, Andrew Cassidy, Garry Beran, Mark Cockeril, Christine Chresta, Nathalie Byrne, Rose McCormack, Paul Smith
Journal: Cancer Research (2008)

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

913 

The high incidence of BRAF/NRAS gene mutations in a number of tumor types has raised the prospect that pharmacological inhibition of the MEK/ERK pathway could be of clinical benefit. AZD6244 is an orally available, potent, ATP uncompetitive inhibitor of MEK1/2 and demonstrates a high degree of selectivity in inhibiting the RAF/MEK/ERK pathway in cells. AZD6244 has shown activity in preclinical models of numerous cancer types and is currently in Phase II clinical trials. In order to understand the determinants of response to AZD6244, we screened a cross-tumor panel of 58 cell lines, predominantly of lung and colorectal origin. Growth inhibitory effects (GI50) ranged from highly sensitive  10 μM using an assay of viable cell number. We determined protein expression and genetic lesions for selected genes relevant to MEK/ERK or related growth and survival signaling, including BRAF, KRAS, ERK, PTEN and AKT, and employed statistical methods to ascertain their relationship to AZD6244 sensitivity. We found BRAF and KRAS gene mutations to be highly significantly related to sensitivity. Since one of the consequences of MEK/ERK pathway activation is a change in gene expression, however, we also adopted a hypothesis-free approach and determined the baseline mRNA profile (Affymetrix HG_U133 Plus2) of all cell lines. We developed a workflow combining novel statistical and bioinformatic approaches to enable selection of genes strongly related to in vitro response through both biological rationale and matching expression pattern. We identified networks of genes showing inter-correlated expression and overlap to common signaling pathways, and filtered for consistency of such patterns in independent cell panels and associated tumor tissue samples, combining results with equivalent analysis in melanoma cell lines. The potential to use such signatures in combination to achieve highly significant prediction of in vitro response is shown. We suggest such incorporation of biological rationale in gene selection could enhance the predictive over prognostic potential and chance of translation of such pre-clinical models to the clinical setting. The importance of modeling target pathway ‘addiction’ as well as activity when predicting in vitro response is also highlighted. In addition, signaling mechanisms found to be associated with sensitivity and resistance of cell lines to MEK1/2 inhibition are shown. Molecular profiles are currently being determined for patients in AZD6244 clinical trials in melanoma to investigate the potential of such hypotheses for patient selection.