tbuckley/cabot-search huggingface dataset:
Abstract 19567: Severe Pulmonary Insufficiency is Common > 10 Years Following Balloon Pulmonary Valvuloplasty for Isolated Pulmonary Valve Stenosis
Authors: Rajiv Devanagondi, Dan Peck, Janaki Sagi, Janet Donohue, Sunkyung Yu, Sara K Pasquali, Aimee Armstrong
Journal: Circulation (2014)

Introduction: While balloon pulmonary valvuloplasty (BPV) for isolated pulmonary stenosis successfully relieves obstruction acutely, long term outcomes remain unclear, with only one study to date exclusively reporting >10 year outcomes (n=48 subjects). We evaluated the long-term incidence of ≥moderate pulmonary insufficiency (PI) and reintervention.

Methods: Patients undergoing BPV at our institution from 1982-2002 for isolated pulmonary valve stenosis (n=211) were eligible for inclusion. Long-term follow-up data were available for 103 patients (primarily those followed at our center). Incidence of ≥moderate PI and reintervention were reported and risk factors for ≥moderate PI assessed in univariate and multivariable analysis.

Results: Of 103 included patients, age at initial BPV was 0.7 yrs (range 1d-42.2 years), BSA 0.38 m2 (range 0.14-1.99 m2), peak cath gradient 65 mmHg (range 31-169 mmHg) and 23% had critical pulmonary stenosis. In the first 10 years after BPV, 16% had surgical pulmonary valvotomy, transannular patch, or BT shunt and 2% died. Of the remaining patients with >10-year follow up data (median follow-up 15.1 years, range 10.1-26.3 years), 62 had a recent echocardiogram. Of these patients, 37% had moderate and 23% had severe PI; RV dilatation was mild in 32% and moderate in 10%, while 5% had mild RV systolic dysfunction. Three patients had pulmonary valve replacement 16.8-22.2 yrs following BPV due to severe PI. In univariate analysis, critical pulmonary stenosis, younger age, smaller BSA, and smaller pulmonary annulus at the time of BPV, as well as greater pre-BPV cath gradient were associated with ≥moderate PI (all p<0.05). There was no significant association between balloon:annulus ratio and ≥moderate PI. In multivariable analysis, BSA <0.3 m2 remained significantly associated with ≥moderate PI (OR 6.4, 95% CI 1.2-33.6; p=0.03).

Conclusions: In the largest study to date of > 10 year outcomes following BPV nearly ¼ of patients developed severe PI. Although few patients have required pulmonary valve replacement to date, close follow up is necessary. Patients with younger age, lower BSA, and/or more severe pulmonary stenosis at the time of BPV have a greater risk of significant PI and should be counseled regarding the long term risks.
C-Type Natriuretic Peptide-Mediated Coronary Vasodilation: Role of the Coronary Nitric Oxide and Particulate Guanylate Cyclase Systems11This study was supported in part by grants from the American Heart Association, Minnesota Affiliate, Minneapolis, Minnesota; the National Heart, Lung, and Blood Institute (Grant HL-033643), National Institutes of Health, Bethesda, Maryland; and the Mayo Foundation, Rochester, Minnesota.
Authors: R. SCOTT WRIGHT, CHI-MING WEI, CHEOL H. KIM, MASAHIKO KINOSHITA, YUZURU MATSUDA, LAWRENCE L. AARHUS, JOHN C. BURNETT, WAYNE L. MILLER
Journal: Journal of the American College of Cardiology (1996)
Abstract 16499: Initial Prothrombin Time Response After Warfarin Loading as a Major Determinant Influencing Maintenance Dose
Authors: Young Dae Kim, Yong Rak Cho, Kyung Il Park, Jong Sung Park, Tae Ho Park, Ji Hye Ahn, Eu Gene Jeong
Journal: Circulation (2014)

Introduction:  Warfarin is still the most commonly used oral anticoagulant, but the standardization of its dosing is difficult due to wide variability in dose-response relation among the patients.   Hypothesis:  Initial prothrombin time response to warfarin loading has the potential to predict the maintenance dose because it incorporate both genetic trait and acquired factors related to dose requirement.   Methods:  In retrospective cohort design, 65 patients were studied in whom anticoagulation was started with 3 day loading of warfarin 5 mg/day and stable maintenance dose was achieved during follow-up. International normalization ratio (INR) was measured, and demographic and clinical parameters were collected for the analysis.   Results:  In study subjects, the INR values after loading and at maintenance were1.65+/-0.29, 2.42+/-0.54, respectively. Warfarin maintenance dose was 2.69+/-1.10 mg/d. There was significant negative relation between the initial INR after loading and maintenance dose of wafarin (Figure, r=0.523, P   Conclusions:  Among the factors influencing warfarin dose requirement, INR value after loading exhibited strong negative correlation with maintenace dose during follow-up. Accordingly, an equation for predicting maintenance dose could be formulated. Further study enrolling large population is needed to validate this correlation.
Consideraciones generales sobre las pruebas de función pulmonar
Authors: Miller, R Crapo, J Hankinson, Brusasco, F Burgos, R Casaburi, A Coates, P Enright, Cpm van der Grinten, P Gustafsson, R Jensen, DC Johnson, N Maclntyre, R McKay, D Navajas, OF Pedersen, R Pellegrino, G Viegi, J Wanger
Journal: European Respiratory Journal (2005)
The Distal Zinc Finger Domain of AML1/MDS1/EVI1 Is an Oligomerization Domain Involved in Induction of Hematopoietic Differentiation Defects in Primary Cells <i>In vitro</i>
Authors: Vitalyi Senyuk, Donglan Li, Alexander Zakharov, Fady M. Mikhail, Giuseppina Nucifora
Journal: Cancer Research (2005)

Abstract AML1/MDS1/EVI1 (AME) is a chimeric transcription factor produced by the (3;21)(q26;q22) translocation. This chromosomal translocation is associated with de novo and therapy-related acute myeloid leukemia and with the blast crisis of chronic myelogenous leukemia. AME is obtained by in-frame fusion of the AML1 and MDS1/EVI1 (ME) genes. The mechanisms by which AME induces a neoplastic transformation in bone marrow cells are unknown. AME interacts with the corepressors CtBP and HDAC1, and it was shown that AME is a repressor in contrast to the parent transcription factors AML1 and ME, which are transcription activators. Studies with murine bone marrow progenitors indicated that the introduction of a point mutation that destroys the CtBP-binding consensus impairs but does not abolish the disruption of cell differentiation and replication associated with AME expression, suggesting that additional events are required. Several chimeric proteins, such as AML1/ETO, BCR/ABL, and PML/RARa, are characterized by the presence of a self-interaction domain critical for transformation. We report that AME is also able to oligomerize and displays a complex pattern of self-interaction that involves at least three oligomerization regions, one of which is the distal zinc finger domain. Although the deletion of this short domain does not preclude the self-interaction of AME, it significantly reduces the differentiation defects caused in vitro by AME in primary murine bone marrow progenitors. The addition of a point mutation that inhibits CtBP binding completely abrogates the effects of AME on differentiation, suggesting that AME induces hematopoietic differentiation defects through at least two separate but cooperating pathways.
Effects of Bleomycin on Mouse Bone-Marrow Stem Cells2
Authors: G. Briganti, L. Galloni, G. Levi, V. Spalletta, F. Mauro
Journal: JNCI Journal of the National Cancer Institute (1975)

The mouse hematopoietic stem-cell population was tested by the spleen colony technique for effects of the antineoplastic agent bleomycin (BLM). The time response of normal bone marrow was investigated by a single dose of BLM (400 mg/kg) between 0 and 72 hours. The dose response was studied over a wide range of doses (from 40 to 1,600 mg/kg) at a 4-hour exposure. Additional experiments concerned 1) the fraction of colony-forming units in the S phase after BLM administration (by means of pulse hydroxyurea treatment), 2) the response of bone marrow stimulated by endotoxin, and 3) the effects of split-dose treatments. The relatively low toxicity of BLM on both the differentiated and stem-cell populations of unstimulated bone marrow was confirmed and detailed. This drug exhibited peculiar, proliferation-dependent cell inactivation kinetics. Furthermore, BLM induced parasynchronous behavior in the unstimulated stem-cell population. The various aspects of BLM action are discussed with regard to its use in cancer chemotherapy.
Characterization of endogenous BRMS1, and splice variants, in the MCF10 breast cancer progression model
Authors: Douglas Hurst, Blake Moore, Mick Edmonds, Alka Mehta, Kevin Nash, Danny Welch
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

484 

Breast cancer metastasis suppressor 1 ( BRMS1 ) suppresses metastasis without blocking tumorigenesis in multiple human and murine cancer cells of diverse origins. The molecular mechanisms of BRMS1 are not well understood and thus far, mechanistic studies of BRMS1 have been limited to systems in which BRMS1 was re-expressed in metastatic cell lines that normally have no detectable levels of BRMS1 protein. The purpose of this study was to determine the functional role of endogenous BRMS1 in the progression of breast cancer using the isogenic MCF10 cell lines. These genetically related cell lines represent normal breast epithelial cells (MCF10A), pre-malignant breast disease (MCF10AT and MCF10DCIS.com), and metastatic carcinoma (MCF10CA a.1 and MCF10CA d.1α). Real-time RT-PCR showed higher levels of BRMS1 mRNA in the metastatic cell lines, although BRMS1 protein expression and nuclear localization were not significantly different. Alternatively spliced variants were detected by RT-PCR and found to be differentially expressed; specifically, BRMS1.v2 and BRMS1.v4 were only detected in the pre-malignant MCF10A and AT cell lines, while BRMS1 and BRMS1.v3 were detected in all lines. However, translated protein for these splice variants was not detected. Since BRMS1 protein, but not splice variants, was expressed in both the metastatic and non-metastatic cell lines, BRMS1 exons were sequenced and scanned for possible mutations. All sequences were found to be wild-type with the exception of a synonymous T/C transition in exon 7. Together, these results demonstrate that BRMS1 expression alone is not sufficient to prevent metastasis and further suggests that the expression and/or activation of BRMS1 protein interactors are necessary for metastasis suppression.

Support: CA87728, F32CA113037, and National Foundation for Cancer Research
Clinical Trial Registration and the ICMJE
Authors: Rebecca Dresser
Journal: JAMA (2005)

To the Editor: Calls to establish a comprehensive clinical trial registry are welcome. As registry supporters point out, the failure to publicize full trial data denies physicians and patients valuable information and unjustifiably diminishes the contributions of researchers and trial participants. The lack of a comprehensive trial registry has another negative consequence: it fosters the general perception that investigational interventions are better than existing alternatives. When this perception guides patients, they enroll in trials assuming that they will receive cutting-edge therapy. If negative and inconclusive trial results were widely reported, the public would receive an accurate picture of medicine’s slow and incremental advances. Such reporting could also raise awareness that research is done to advance knowledge, not to provide individual trial participants with the best treatment. In 1997, Congress directed health officials to establish www.clinicaltrials.gov as a national registry so that patients could locate trials relevant to their conditions. Unfortunately, the registry contains information that could encourage patients to equate trial participation with optimal patient care. For example, in its “Introduction to Clinical Trials,” the ClinicalTrials.gov Web site calls investigational interventions “new treatments” or “new therapies,” which is inappropriate in a discussion that covers placebocontrolled and phase 1 trials.
Abstract 1701: A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells
Authors: Amrita Datta, Barbara J. Rider, Zakaria Y. Abd Elmageed, Hogyoung Kim, Debasis Mondal, Asim B. Abdel Mageed
Journal: Cancer Research (2014)

Abstract Chemotherapy is a mainstay in the treatment of breast cancer. FDA approved, Doxorubicin (Dox) is considered to be the most effective chemotherapeutic agent for the treatment of solid tumors like breast cancer. However, resistance to Dox impairs successful treatment. The increased expression of multidrug-resistance P-glycoprotein (P-gp) pump that constantly efflux drugs, such as Dox, is a well documented mechanism of resistance. Flavonoids as a class have been implicated in the inhibition of ABC transporters such as BCRP, P-gp and MRP-1, have potent anxiolytic activity, protect against anthracycline induced cardiotoxicity, and improve general health. Our current study proposes to examine the efficacy of a synthetic flavonoid, SF as a chemotherapeutic agent alone and in combination with Dox in a xenograft nude mouse model and to delineate the specific molecular targets involved. Treatment with a combination of Dox and SF lead to significant cell death in the Dox resistant, MCF-7/Dox cells as compared to treatment with Dox alone. In vivo studies using a xenograft nude mouse model corroborated these findings. Also, mice treated with SF alone and in combination with Dox showed improved overall health. SF also inhibited P-gp pump activity and increased Dox sequestration in cancer cells, leading to chemosensitization. Moreover, SF alone or in combination with Dox caused remarkable de-phosphorylation of constitutively active FAK(Focal Adhesion Kinase) in MCF-7/Dox cells. In conclusion, our study beings forth an excellent prototype candidate, SF- as an anti-tumor agent with little to no toxicity and provides new insights into previously uncharacterized mechanisms for the anti-cancer activity of SF alone and in combination with Dox in resistant breast cancer cells. The desirable traits of endowed pleiotropic activities, safety, synergistic action with therapeutic agents make SF attractive for clinical use. Citation Format: Amrita Datta, Barbara J. Rider, Zakaria Y. Abd Elmageed, Hogyoung Kim, Debasis Mondal, Asim B. Abdel Mageed. A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells. [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 1701. doi:10.1158/1538-7445.AM2014-1701
Indigestion: What It Is and How to Prevent It.
Authors: Arthur L. Holland
Journal: JAMA (1926)

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Abstract 17556: The Symptom Limited Up-titration of VNS May Result in Neural Damage, Thus Too Strong to Benefit Chronic Heart Failure
Authors: Akiko Nishizaki, Keita Saku, Kazuo Sakamoto, Takuya Kishi, Takuya Akashi, Takako Takehara, Yasuhiro Oga, Kana Fujii, Tomomi Ide, Kenji Sunagawa
Journal: Circulation (2014)

Background: Vagal nerve stimulation (VNS) improves chronic heart failure (CHF) in animals and in human. Although the stimulus intensity was up-titrated to the symptomatic threshold such as twitching and cough, whether such symptom-limited threshold exerts maximum benefits for CHF remains unknown. In this study we investigated the dose response of VNS for CHF after large myocardial infarction (MI) in rats. Methods: In 8 weeks Sprague-Dawley rats, we created large MI. We implanted a device for VNS and started stimulation from 2 weeks after MI (Sham: n=21, C-VNS: n=15, H-VNS: n=16). In the conventional stimulation group (C-VNS), we up-titrated VNS until it reached the symptom limits. In the second group, we halved VNS intensity (H-VNS). To evaluate the early impact of VNS on inflammatory responses, we compared the macrophage invasion and plasma inflammatory cytokines at 3 days after VNS. 4 weeks after VNS, we evaluated its chronic effects on hemodynamics and CHF parameters. Results: At 3 days after VNS, both...
Abstract 12456: Mitochondrial Protein ES1 Deficiency Leads to Cardiac Hypertrophy Due to Disturbances in Mitochondrial Energy Metabolism
Authors: Qinqiang Long, Huan Yang, Aibing Wang, Yuquan Li, Yiqun Zhou, Lan He, Yishu Ding, Teayoun Kim, Kevin Yang, Lufang Zhou, Qinglin Yang
Journal: Circulation (2014)

Defects in myocardial energy metabolism have been linked to pathological cardiac hypertrophy and congestive heart failure; however, the regulation of myocardial energy metabolism remains obscure. ATP synthase is an enzyme complex in the mitochondria and plays a central role in energy metabolism. In the present study, we identified ES1, a mitochondrial protein with unknown function, as a key determinant of myocardial energy metabolism via controlling ATP synthase activities. We uncovered that ES1 interacts with both α and β subunit of ATP synthase, and its expression levels in cultured H9c2 cardiomyocytes were directly correlated to ATP synthesis and inversely to ATP hydrolysis. Cellular energetic analysis revealed that ES1 levels in H9c2 cardiomyocytes were directly correlated with mitochondrial oxidative metabolism. We have generated an ES1 knockout mouse (ES1-/-) line. Echocardiography revealed substantially cardiac dysfunction with decreased ejection fraction (EF%) (55.3 ± 2.4 vs 46.1 ± 1.7) and fractional shortening (FS%) (28.6 ± 1.6 vs 22.8 ± 1.0) in 3-month-old ES1-/- mice compared with controlled littermates (ES1f/f) under a basal condition. As a result, ES1-/- mice showed increased left ventricular mass compared. Morphometric assessment confirmed that heart weight to body weight ratio was increased by 23% in ES1-/- vs controlled mice. Masson’s Trichrome blue and Sirius red staining on heart sections of ES1-/- mice showed markedly increased interstitial fibrosis. Transmission electron microscope (TEM) examination revealed substantial loss of mitochondrial cristae structure on ES1-/- knockout hearts. ATP synthase activity assays on isolated mitochondria revealed that ATP synthesis activities decreased and hydrolysis activities increased in cardiac mitochondria from ES1-/- mice compared with those of ES1f/f control mice. These results indicate that ES1 is a novel and important ATP synthase regulator and its deficiency causes mitochondrial energy metabolism dysfunction in the heart followed by cardiac pathology. Therefore, ES1 is a important determinant of cardiac pathophysiology and a potential therapeutic target in treating cardiac hypertrophy and heart failure.
Roles of microsomal prostaglandin E synthase-1 in lung metastasis formation in prostate cancer cells in mice
Authors: Ryo Takahashi, Hideki Amano, Masataka Majima
Journal: European Respiratory Journal (2014)

We have previously reported that host stromal microsomal prostaglandin E synthase-1 (mPGES-1) signaling appeared critical for tumor-associated angiogenesis and tumor growth. Here, we estimated whether mPGES-1 has a critical role in prostate cancer in lung metastasis formation or not.

 

Murine prostate cancer cells (RM9) were intravenously injected to Wild type mice (WT) and mPGES-1 knockout mice (mPGES-1KO). Lung metastasis was estimated by number of colonies in the lung and the lung weight. Angiogenesis was estimated by measuring plasma level and mRNA expression of VEGF-A and SDF-1, and microvessel density and microvessel area in the lung.

 

Lung metastasis formation was significantly suppressed in mPGES-1 KO mice compared with WT mice . The plasma levels of VEGF-A in mPGES-1 KO mice on day 21 after injection of the prostate cancer cells were found to be lower than that in WT (WT:4.83±0.51pg/ml, mPGES-1 KO:3.29±0.21pg/ml, P<0.05). In addition, the plasma levels of SDF-1 in mPGES-1KO mice were decreased compared with WT (WT:1.51±0.43ng/ml, mPGES-1 KO:0.45±0.13ng/ml, P<0.05).

The expressions of VEGF-A and SDF-1 in the lung tissue were significantly suppressed in mPGES-1KO mice.

Furthermore, the expressions matrix metalloproteinases (MMP)-9, metalloproteinases (MMP)-2 were down-regulated in metastatic lungs of mPGES-1 KO mice.

 

These results suggested that mPGES-1 signaling in stroma was essential for MMP-2 and MMP-9 up-regulation that enhances angiogenesis and tumor metastasis. The selective mPGES-1 inhibitors under development will be a promising therapeutic tool for the inhibition of tumor hematogenous metastasis.
Prospective, Randomized, Multicenter Comparison of Laser-Facilitated Balloon Angioplasty Versus Stand-Alone Balloon Angioplasty in Patients With Obstructive Coronary Artery Disease
Authors: Gregg W. Stone, Eduardo de Marchena, David Dageforde, Alberto Foschi, Joseph B. Muhlestein, Michael McIvor, David Rizik, Ronald Vanderlaan, JoAnn McDonnell
Journal: Journal of the American College of Cardiology (1997)

The goal of this study was to examine the relative safety and efficacy of laser-facilitated percutaneous transluminal coronary angioplasty (PTCA) versus "stand-alone" PTCA.Plaque debulking with lasing before PTCA may result in improved lumen dimensions and decreased rates of periprocedural ischemic complications, thus improving short- and long-term outcomes after percutaneous intervention. The mid-infrared holmium:yttrium-aluminum-garnet (YAG) laser has been shown to be effective in a variety of plaque subtypes and may be particularly useful in high risk acute ischemic syndromes.A total of 215 patients (mean [+/-SD] age 61 +/- 12 years) with 244 lesions were prospectively randomized at 14 clinical centers to laser versus stand-alone PTCA. After laser treatment, all patients underwent PTCA; 148 patients (69%) had unstable angina.The procedural success rate without major catheterization laboratory complications was similar in patients assigned to laser treatment or PTCA alone (96.6% vs. 96.9%, p = 0.88), as was the in-hospital clinical success rate (89.7% vs. 93.9%, p = 0.27). There was no difference in postprocedural diameter stenosis after laser treatment compared with PTCA (18.3% +/- 13.6% vs. 19.5% +/- 15.1%, p = 0.50). However, use of the laser, versus PTCA alone, did result in significantly more major and minor procedural complications (18.0% vs. 3.1%, p = 0.0004), myocardial infarctions (4.3% vs. 0%, p = 0.04) and total in-hospital major adverse events (103% vs. 4.1%, p = 0.08). At a mean follow-up time of 11.2 +/- 7.7 months, there were no differences in late or event-free survival in patients assigned to laser treatment versus PTCA alone.Compared with stand-alone PTCA, laser-facilitated PTCA results in a more complicated hospital course, without immediate or long-term benefits.