tbuckley/cabot-search huggingface dataset:
Abstract 1371: Overexpression Of Mitochondrial Transcription Factor A Protects Failing Myocardium From Oxidative Stress
Authors: Masayoshi Yoshida, Tomomi Ide, Mayumi Yamato, Masaki Ikeuchi, Takaki Tsutsumi, Takahiro Inoue, Makoto Ando, Koji Todaka, Dongchon Kang, Hideo Utsumi, HIroyuki Tsutsui, Kenji Sunagawa
Journal: Circulation (2008)

Background: Reactive oxygen species (ROS) from mitochondria play a pivotal role in the pathogenesis and progression of heart failure. Mitochondrial transcription factor A (TFAM), a nucleus-encoded protein, in mitochondria promotes transcription of mitochondrial DNA (mtDNA), maintains mtDNA, and increases mtDNA copy number. We previously reported that overexpression of human TFAM ameliorated cardiac remodeling and improved survival by maintaining mitochondrial function. We investigated whether those beneficial effects result from the increase of antioxidative properties both in vivo and in vitro. Methods and Results: [in vivo study] We created myocardial infarction (MI) in wild type (WT) mice and human TFAM transgenic (TG) mice as a model of heart failure. We evaluated free radical generation by in vivo ESR on 28th day after the operation. MI size did not different between WT and MI. Overexpression of TFAM ameliorated MI-induced cardiac hypertrophy (histology) and LV dysfunction (2D echo and cath). Furthermore, the rate of signal decay in in vivo ESR, indicative of oxidative stress, was accelerated in WT-MI (0.10 ± 0.01 vs 0.19 ± 0.02/min, n=4–5, P&lt;0.01) whereas decelerated in TG-MI (0.12 ± 0.02/min; n=4, P&lt;0.01). DNA microarrays analysis of myocardium (8 weeks old, male) indicated that TG overexpressed (double or more) antioxidant relevant genes mostly encoded in nuclear DNA, such as Mthfd2 and Adh1 without affecting mitochondrial respiratory enzyme activities. [in vitro study] We measured superoxide in Hela cells using Dihydroethidium in the presence of rotenone, a complex I inhibitor. Overexpression of TFAM in Hela cells significantly reduced superoxide production (72.8 %). Conclusion: Overexpression of TFAM suppresses ROS. Such an antioxidative property of TFAM may contribute to its powerful anti-remodeling effect in failing heart.
Abstract 5867: The Beneficial Effect of Raloxifene in Aortic Valve Calcification is Associated with Up-Regulation of Gas6-Axl Pathway
Authors: Mony Shuvy, Suzan Abedat, Sameh Daher, Michael Valitsky, Ronen Beeri, Chaim Lotan
Journal: Circulation (2008)

Aortic valve calcification (AVC) is an inflammatory regulated process. Growth arrest-specific 6 (Gas6) is involved in atherosclerosis and inflammation; in addition the Gla domain of Gas6 directly inhibits mineralization. We sought to assess the role of Gas6 in AVC using our unique animal model of reversible AVC based on a uremia-inducing diet. We also evaluated the possible role of raloxifene (a selective estrogen modulator), which has demonstrated anti inflammatory effects on blood vessels, in the pathogenesis of AVC. Aortic valves were obtained from four groups of rats (n=10 each): calcified valves- from rats fed with the uremia-inducing diet for 7 weeks (group A), valves after calcification resolution following diet cessation (group B), valves from rats fed with the same diet who also received subcutaneous raloxifen (1 mg/kg/day) (group C), and control valves. Valves were examined using multislice computed tomography (MSCT), histology, RT-PCR and western blot. Histological evaluation of calcified valves (group A) revealed positive staining for calcium deposits and osteoblast’s markers (osteopontin, Runx-2). Gene expression analyses of these valves revealed 2.5 times decrease in Gas6 level compared to control valves (p&lt;0.01). Western blot confirmed these results, and further showed a significant decrease of 33 % in Axl (Gas6 receptor) level along with down-regulation of the AKT survival pathway. Resolution of AVC (group B) was demonstrated using MSCT and histology; it was associated with down-regulation of osteoblast features, and up-regulation of both Gas6-Axl and AKT pathways. MSCT of raloxifene treated rats (group C) showed only minimal valve calcification compared with group A (Agatston score 23 ± 7 vs. 105± 15; p&lt; 0.05). The beneficial effect of raloxifene was also confirmed by histology and was associated with up-regulation of Gas6 and Axl (30% and 40% increase respectively compared with group A; p&lt;0.05) and of the AKT pathway. Down-regulation of the Gas6-Axl pathway is a critical step in inducing AVC. The reversibility of AVC was associated with up-regulation of the Gas6-Axl and AKT pathways. These pathways were significantly restored by raloxifene, which may be a promising treatment for AVC.
Abstract 18543: Whole Exome Sequencing in Sudden Infant Death Syndrome Identifies a High Proportion of Putative Pathogenic and Functionally Significant Rare Variants Related to Inherited Cardiac Conditions
Authors: Leonie C Wong, Michael A Simpson, David J Tester, David R FitzPatrick, Jacob Tfelt-Hansen, Steve Bevan, James S Ware, Margaret J Evans, Peter J Fleming, Craig C Platt, Iona J Jeffrey, Marta C Cohen, Michael J Ackerman, Elijah R Behr
Journal: Circulation (2014)

Introduction: Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant which remains unexplained after comprehensive clinical and pathological assessment. Prior studies have implicated inherited cardiac conditions (ICC). Hypothesis: Whole exome sequencing will identify a significant burden of putative pathogenic (PP) and rare functionally significant (RFS) cardiac genetic variants in SIDS. Methods: 96 SIDS cases with complete phenotypic data were selected from 434 cases. Prone sleeping position was excluded to enrich for genetic risk. Genomic DNA underwent target enrichment using Agilent SureSelect Human All Exon v5 kit and sequencing on Illumina HiSeq. Reads were aligned to GRCh37 reference genome with Novoalign and variants called with SAMtools. Principal component analysis identified 82 cases of North European (NE) ancestry. Variants were annotated with Annovar and compared to control data from a local exome database, 1000 Genomes and ESP. Analysis focused on 83 known ICC susceptibility genes (27 channelopathy-associated [CH]; 56 cardiomyopathy-associated [CM]). PP was defined as ultra rare nonsense or frameshift mutations or other variants previously reported as disease-associated and absent in controls. RFS was defined as variants with abnormal functional characterization and &lt;0.5% prevalence in controls. Results: 20/82 cases (24%) carried at least 1 PP/RFS variant: 12 CH variants in 9 genes (AKAP9, ANK2, CACNB2, CAV3, KCNE2, RYR2, SCN5A, SNTA1, TRDN) in 13 cases; 7 CM variants in 5 genes (ABCC9, ACTN2, CSRP3, TCAP, TTN) in 8 cases. Variants were most commonly identified in the 3-6 months age group (p=0.009). There were no other significant phenotypic differences between variant-positive and negative cases (Table 1). Conclusions: There was an 11% yield of PP variants in non-prone sleeping SIDS cases of NE ancestry, with an additional 13% hosting RFS variants. These may provide a potential substrate in the pathophysiology of SIDS.
Clinical trial accrual patterns and barriers among newly diagnosed adult patients at a community cancer center: A prospective study
Authors: K. A. Frisby, J. A. Lee, M. A. Mathiason, C. M. Meyer, J. L. Ostern, S. M. Walther, J. E. Schroeder, L. A. Meyer, K. E. Umberger, R. S. Go
Journal: Journal of Clinical Oncology (2005)

6017 Background: While most cancer patients are initially diagnosed and treated in the community setting, few prospective data are available on clinical trial accrual patterns and barriers encountered among newly diagnosed patients seen at community-based cancer centers. Methods: We prospectively collected clinical data from patients age ≥18 years seen at our institution who have new cancers diagnosed between Nov. 1, 2003 and Oct. 31, 2004. Factors that may potentially affect accrual into trials were identified. Results: At the time of this report, data were complete for 1000 patients. There was an equal number of women (51.8%) and men. The median age at diagnosis was 67 years (range, 20–99). In 706 (70.6%) patients, clinical trials appropriate for the diagnosis and stage of disease were not available. Among those patients with available trials, 15.7% (40/294) were enrolled. While more women were eligible for trials than men (68% vs 32%, p<0.01), the accrual rates were equal (13.5% vs 13.8%, p=0.94). Elderly (age ≥65 years) patients comprise about 55.1% of those with available trials, but they are less likely to be enrolled (8.1% vs 20.5%, p<0.01). Major barriers for non-participation can be grouped into physician and patient decisions and are summarized in the Table. The overall accrual rate when patients of all diagnostic stages were included was 4% (40/1000). When cancers highly curable by surgery alone (5 year DFS ≥90%) were excluded in the analysis, the accrual rate was 5.8% (35/607). Conclusions: At our institution, participation in clinical trials is low. Unavailability of appropriate trials represents the single most important barrier. Elderly patients are underrepresented. Several physician and patient related barriers are also identified. If found to be applicable to other community-based cancer centers, these findings may be useful to guide development of clinical trials by our national cancer cooperative groups. No significant financial relationships to disclose.
Differences between anhedonic and normally hedonic depressive states
Authors: J Fawcett, D C Clark, W A Scheftner, D Hedeker
Journal: American Journal of Psychiatry (1983)

In this study of 101 patients who met DSM-III criteria for major depression, those with extreme anhedonia (N = 23) were younger, more depressed, and less neurotic than the patients with a normal-range capacity for pleasurable experiences (N = 78). The anhedonic depressed patients recovered more rapidly; at discharge they consequently had levels of symptom severity equal to those of the hedonic patients, yet they remained significantly more anhedonic. The anhedonic patients exhibited loss of pleasure in appetite, sex, social contacts, and work, which suggests a global dulling of the capacity for pleasure.
Inhibition and Stimulation of Tumor Homoiotransplants by Prior Injections of Lyophilized Tumor Tissue&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: By George D. Snell, Arthur M. Cloudman, Elizabeth Failor, Patricia Douglass
Journal: JNCI Journal of the National Cancer Institute (1946)

Journal Article Inhibition and Stimulation of Tumor Homoiotransplants by Prior Injections of Lyophilized Tumor Tissue Get access By George D. Snell, By George D. Snell research associate Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Arthur M. Cloudman, Arthur M. Cloudman research associate Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Elizabeth Failor, Elizabeth Failor research assistant Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Patricia Douglass Patricia Douglass research assistant Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 6, Issue 6, June 1946, Pages 303–316, https://doi.org/10.1093/jnci/6.6.303 Published: 01 June 1946
Abstract #671: Anti-tumor activity of a tumor-targeting peptide that binds eukaryotic translation initiation factor 4E
Authors: Song Yi Ko, Huifang Guo, Nicolas Barengo, Honami Naora
Journal: Cancer Research (2009)

The process of protein synthesis, on which cell growth depends, is tightly regulated at the level of translation initiation. A critical step of translation initiation involves the liberation of the mRNA cap-binding eukaryotic translation initiation factor 4E (eIF4E) from the 4EBP inhibitory binding proteins, and its engagement to the scaffolding protein eIF4G. eIF4E is a candidate cancer therapeutic target because it is overexpressed or activated in many types of tumors. In this study, we designed and evaluated 4EBP-based peptides that bind eIF4E and prevent eIF4E from binding eIF4G. These peptides inhibited cap-dependent translation. The lead candidate peptide was fused to an analog of gonadotropin-releasing hormone (GnRH) to target its receptor that is widely overexpressed in ovarian and other endocrine cancers. GnRH agonist-4EBP fusion peptide was taken up by, and inhibited growth of, GnRH receptor-expressing tumor cells, but not receptor-negative cells. Moreover, the fusion peptide inhibited growth of i.p. ovarian tumors and ascites in mice without significant cytotoxic effects to host tissues. Because ovarian cancer is rarely cured by conventional texane-platinum combination therapy, the fusion peptide may be of therapeutic potential for treatment of this disease.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 671.
Abstract 1961: Multi-Modality Comparison of Volumetric Quantification of Right Ventricular Volumes Using a Novel Semi-Automated Border Detection Software
Authors: Lissa Sugeng, Lynn Weinert, Johannes Niel, Regina Steringer-Mascherbauer, Martin Hyca, Rolf Bartolles, Georg Schummers, Victor Mor-Avi, Roberto M Lang, Hans-Joachim Nesser
Journal: Circulation (2007)

Background. Right ventricular volumes (RVV) and ejection fraction (RVEF) measurements are challenging due to the complex shape of the right ventricle (RV). Current methods are tedious and have limited ability to take into account the base of the RV and right ventricular outflow tract. Novel semi-automated border detection software, RV analysis (RVA) was recently developed (TomTec) to overcome these limitations. Our goal was to determine whether there are inter-modality differences between real-time 3D echocardiographic (RT3DE), cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) data using the same RVA. Methods. We acquired transthoracic RT3DE images of the RV (Philips iE33 w/X4 probe) from the apical window using a full-volume mode in 12 patients referred for CMR imaging (1.5T Siemens scanner) and CCT (Toshiba) on the same day. CMR and CCT images were obtained in a stack of short-axis slices from RV base to apex, four-chamber and coronal views, and reformatted to obtain Cartesian volume data. All three types of images were analyzed to obtain end-systolic and end-diastolic volumes (ESV, EDV) and EF using RV analysis software (RVA). RT3DE and CCT were compared to CMR values as the reference standard, using linear regression and Bland-Altman analyses. Results. Analysis of RT3DE, CCT and CMR data were feasible in all patients. RT3DE and CCT RVV and RVEF correlated well with CMR (Table). CCT overestimated RVV whereas RT3DE underestimated RVV. Both CCT and RT3DE slightly underestimated RVEF compared to CMR. Conclusion. This new technique for volumetric RV surface detection applied to RT3DE and CCT data provides accurate RVV and RVEF measurements in agreement with CMR.
Abstract 2062: Predictors Of Outcome In Low Flow, Low Gradient Aortic Stenosis. Result Of The Multicenter Topas Study
Authors: Marie-Annick Clavel, Christina Fuchs, Ian G Burwash, Gerald Mundigler, Jean G Dumesnil, Helmut Baumgartner, Jutta Bergler-Klein, Rob S Beanlands, Philippe Pibarot
Journal: Circulation (2007)

Background: Patients with low flow aortic stenosis (AS) have a poor prognosis and a high operative mortality. Dobutamine stress echocardiography (DSE) has been used to assess LV contractile reserve and determine the “actual” severity of the stenosis. Recently, we proposed the projected aortic valve area at a normal flow rate (AVA proj ) to better differentiate true-severe from pseudo-severe AS. The objective of this study was to identify the independent predictors of survival in low flow, low gradient AS. Methods and results: 101 patients with low flow, low gradient AS (AVA≤1.2cm 2 , LV Ejection Fraction (LVEF) ≤40% and mean gradient (MG) ≤40 mmHg) underwent DSE and an assessment of functional capacity using the Duke Activity Status Index (DASI). A subgroup of 74 patients underwent a 6-minute walk test (6MWT). Overall survival was 70±5% at 1 year and 61±5% at 2 years. On univariate analysis, predictors of mortality were 6MWT ≤320m (p&lt;0.0001), DASI ≤20 (p=0.0001), rest AVA ≤1cm 2 p=(0.006), peak DSE LVEF (LVEF peak ) ≤35% (p=0.02), AVA proj ≤1.2cm 2 (p=0.04). After adjusting for age, gender, and the type of treatment (surgical vs. medical), significant predictors of mortality were DASI ≤20 (HR: 1.79, 95%CI: 1.28 –2.53 p=0.0006) and AVA proj ≤1.2cm 2 (HR:1.64, 95%CI: 1.04 –2.87 p=0.03). In the subgroup of patients undergoing a 6MWT (n=74), independent predictors of mortality were: 6MWT ≤320m (HR: 2.49, 95%CI: 1.55– 4.30 p&lt;0.0001), AVA proj ≤1.2cm 2 (HR: 2.07, 95%CI: 1.18 – 4.08 p=0.01), and LVEF peak ≤35% (HR: 1.64, 95%CI: 1.10 –2.51 p=0.016). In the subset of patients undergoing valve replacement (n=44), unvariate predictors of operative mortality (18%) were: 6MWT ≤180m (OR: 9.8, 95%CI: 3.7–35, p=0.0002), DASI ≤15 (OR: 3.21, 95%CI: 1.67– 6.48, p=0.011) and LVEF peak ≤20% (HR:5.83, 95%CI: 2.6 –16.7 p=0.001). Conclusion: In low flow, low gradient AS, the most significant risk factors for poor outcome were: Impaired functional capacity documented by a reduced DASI or 6MWT, More severe valve stenosis as documented by a smaller AVA proj , and Reduced peak stress LVEF, a composite accounting for resting LV function and contractile reserve. This new knowledge may assist in predicting the prognosis of patients with low flow AS and improve operative risk stratification.
Identification of three novel splice-variants of a tumor suppressor candidate, ING4
Authors: Motoko Unoki, Jiang Cheng Shen, Zheng Zhi-Ming, Curtis C. Harris
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

2485 

The inhibitor of growth family member 4 (ING4) was identified in our laboratory as a candidate tumor suppressor gene that has growth suppressive effect. It has been also reported from other laboratories that the gene is down regulated in glioblastoma cells and head and neck squamous cell carcinoma. Here we identified three novel splice variants of ING4, ING4\_v2 (3 bp skip type), ING4\_v3 (9 bp skip type), and ING4\_v4 (12 bp skip type), that are produced from a combination of two splice donor sites at the end of exon 4 and two splice acceptor sites at the start of exon 5 of the ING4 gene. The longest splice variant (ING4\_v1) that was originally enrolled as ING4 encodes an intact NLS that is important for p53 binding besides nuclear localization, while the other three splice variants partially lack NLS, resulting in an increase of cytoplasmic localization. Recently, although it is known that ING4 has a variety of functions in cells, the entire role of ING4 has not been elucidated. We found one of the three NLS lacking ING4 variants, ING4\_v2, was expressed in cells at almost the same level of the original longest type, suggesting ING4 also has an important role in cytoplasm. Growth suppressive effect of the variants that have the partial NLS (ING4\_v2 and ING4\_v4) was attenuated by weaker effect of the variants on p21 promoter activation. We also found that the ING4\_v4 acts as a dominant negative on induction of p21 by ING4_v1. The functional roles of the proteins generated by alternate spliced forms of ING4 may provide new insight into human carcinogenesis.
Improving the management of soft tissue sarcoma
Authors: A. Rydholm
Journal: BMJ (1998)

Musculoskeletal sarcomas comprise 1% of all malignancies and have traditionally been associated with a poor prognosis. However, the past two decades have shown a dramatic improvement in prognosis for osteosarcoma and Ewing's sarcoma when treated by teams of pathologists, radiologists, oncologists, and surgeons who can provide the necessary combination of chemotherapy, surgery, and radiotherapy. A similar evolution has also occurred in some places in the treatment of soft tissue sarcoma. However, whereas no one questions that patients with bone sarcomas should be treated at specialist tumour centres, many patients with soft tissue sarcoma (which is at least twice as common) are treated outside such centres, often with a poor outcome.

Last December Clasby et al reported recent treatment outcomes for soft tissue sarcoma in the South East Thames region of England.1 The first surgical procedure was a marginal excision (shelling out) in two thirds of cases. Less than half of these patients were given radiotherapy or had a re-excision with wider margins. This means that almost half of the patients had …
Abstract 3631: Validation of Two Non-invasive Imaging Methods, High-resolution Echocardiography (ECHO) and Magnetic Resonance Imaging (MRI) for Assessment of Pulmonary Hemodynamics in Rats With Pulmonary Arterial Hypertension
Authors: Dalia Urboniene, Idith Haber, Yong-Hu Fang, Stephen L Archer
Journal: Circulation (2009)
Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer
Authors: Nicholas C. Turner, Jungsil Ro, Fabrice André, Sherene Loi, Sunil Verma, Hiroji Iwata, Nadia Harbeck, Sibylle Loibl, Cynthia Huang Bartlett, Ke Zhang, Carla Giorgetti, Sophia Randolph, Maria Koehler, Massimo Cristofanilli
Journal: New England Journal of Medicine (2015)

Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer.This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred.The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo.Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. (Funded by Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.).
Abstract 15982: Are Cardiac Mechanics Useful to Identify Subclinical Ventricular Impairment and to Predict Long-Term Performance in Patients With Mitral Regurgitation and Ejection Fraction >65%?
Authors: Diego Bellavia, Patricia A Pellikka, Traci Jurrens, Jae K Oh, Maurice Sarano, Sarah Mangiafico, Fletcher A Miller, Charles Bruce
Journal: Circulation (2011)

Background and Aims: Patients with chronic mitral regurgitation (MR) may have sub-clinical left ventricular (LV) dysfunction despite having a normal ejection fraction. The aim of this study was two...