tbuckley/cabot-search huggingface dataset:
Abstract P135: Body Mass Index and Indicators of Adiposity Are Adversely Associated With Cardiovascular Biomarkers in Youth With Type 1 Diabetes Over 18 Months
Authors: Leah M Lipsky, Tonja R Nansel, Denise L Haynie, Lori M Laffel, Sanjeev N Mehta, Lisa K Volkening, Aiyi Liu
Journal: Circulation (2015)

Hypothesis: The association of excess weight with an adverse cardiometabolic profile in patients with type 1 diabetes (T1D) is unclear. The purpose of this study was to test the hypothesis that increasing BMI and adiposity indicators in youth with T1D are adversely associated with glycemic control and cardiovascular biomarkers. Methods: Subjects were youth participants of a family-based randomized controlled dietary intervention (N=136, age=12.3±2.5y, baseline A1c=8.1±1.1%). Glycemic control (A1c and 1,5-Anhydroglucitol, 1,5-Ag), body mass index (BMI, from measured height and weight), serum lipids (total cholesterol, TC; HDL-cholesterol, HDL-C; LDL-cholesterol, LDL-C; triglycerides, TG), inflammation (c-reactive protein, CRP), oxidative stress (8-iso-prostaglandin F2alpha, 8-iso-PGF2α), adiponectin and blood pressure (systolic, SBP; diastolic, DBP) were assessed at baseline and every 6 months for 18 months. Total and truncal lean, fat-free mass and percent fat (%fat) were measured by Dual X-ray Absorptiometry (DXA) scan at baseline, 12 months and 18 months. Multi-level linear mixed effects regression models (with a random intercept and a random slope for time) were used to estimate associations of time-varying BMI and body composition with time-varying indicators of glycemic control and cardiometabolic health. Covariates included time, sex, height, baseline age, treatment assignment, baseline diabetes duration, insulin regimen, insulin dose/kg and physical activity. Probability values &lt;0.05 were considered to indicate statistical significance. Results: Time-varying BMI and body composition indicators were differentially associated with time-varying glycemic control and cardiometabolic indicators. A1C was unrelated to BMI and body composition, although 1,5-Ag was inversely associated with total %fat; inverse associations of 1,5-Ag with BMI and trunk %fat approached statistical significance (p=0.07). LDL-C was positively associated with trunk fat and trunk %fat; TG and HDL-C were positively associated with BMI and trunk fat, and HDL-C was inversely associated with total lean and trunk lean mass. CRP was positively associated with BMI, and with total and truncal fat and %fat. SBP and DBP were positively associated with BMI, %fat, trunk fat and trunk %fat. TC, 8-iso-PGF2α and adiponectin were unrelated to BMI and body composition. Discussion: In a sample of youth with moderately well-controlled T1D, time-varying BMI and indicators of body fat were not universally associated with time-varying glycemic control and cardiometabolic indicators over 18 months. Significant associations of adiposity indicators, particularly BMI and trunk fat, with hyperglycemic excursions (1,5-Ag), several blood lipids (TG, HDL-C, and LDL-C), and inflammation (8-iso-PGF2α) suggest a role of excess body weight in the development of cardiovascular risk in this sample.
Osteoprotegerin is a significant prognostic factor for overall survival in patients with primary systemic amyloidosis independent of the Mayo staging
Authors: E Kastritis, M Gavriatopoulou, M A Dimopoulos, E Eleutherakis-Papaiakovou, N Kanellias, M Roussou, C Pamboucas, S T Toumanidis, E Terpos
Journal: Blood Cancer Journal (2015)

Bone metabolism has not been systematically studied in primary (AL) amyloidosis. Thus we prospectively evaluated bone remodeling indices in 102 patients with newly diagnosed AL amyloidosis, 35 healthy controls, 35 newly diagnosed myeloma and 40 monoclonal gammopathy of undetermined significance patients. Bone resorption markers (C-telopeptide of type-1 collagen, N-telopeptide of type-1 collagen) and osteoclast regulators (soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG)) were increased in AL patients compared with controls (P<0.01), but bone formation was unaffected. Myeloma patients had increased bone resorption and decreased bone formation compared with AL patients, while sRANKL/OPG ratio was markedly decreased in AL, due to elevated OPG in AL (P<0.001). OPG correlated with N-terminal pro-brain natriuretic peptide (P<0.001) and was higher in patients with cardiac involvement (P=0.028) and advanced Mayo stage (P=0.001). OPG levels above the upper value of healthy controls was associated with shorter survival (34 versus 91 months; P=0.026), while AL patients with OPG levels in the top quartile had very short survival (12 versus 58 months; P=0.024). In Mayo stage 1 disease, OPG identified patients with poor survival (12 versus >60 months; P=0.012). We conclude that increased OPG in AL is not only a compensation to osteoclast activation but may also reflect early cardiac damage and may identify patients at increased risk of death within those with earlier Mayo stage.
Reproducibility and learning effect of the 6-minute walk test in smokers
Authors: Andrea Akemi Morita, Diego Rodrigues Silva, Gianna Waldrich Bisca, Mahara Proença, Leandro Mantoani, Karina Couto Furlanetto, Juliana Zabatiero, Demetria Kovelis, Fabio Pitta
Journal: European Respiratory Journal (2014)

Background:  When performing the 6-minute walk test (6MWT) in patients with COPD, two walks are advised and the largest distance is used. However, there is no scientific evidence about the reproducibility and learning effect of the 6MWT in smokers.   Aims:  To investigate the reproducibility and the presence of learning effect of the 6MWT performed cross-sectionally and longitudinally.   Methods:  We included 167 smokers with normal spirometry (97men; 48±12years; BMI 26[23;28]kg.m - ²; 26[14;43]pack/years; FEV 1 /FVC 83±7 and FEV 1  89[80;97]%pred) who took part in a 5-month program aimed at increasing physical activity by using pedometers and booklets. Two 6MWT per assessment moment (AM) were performed throughout the program (AM1[n=167], AM2[n=81], AM3[n=59], and AM4[n=56]). Assessment moments had an interval of one month between AM1, AM2 and AM3, and three months between AM3 and AM4.   Results:  Mean distances for the first and second 6MWT were 542±74m and 563±75m (AM1) (p 0.05], but different from AM4 [p=0.002]). The two 6MWT showed very good reproducibility in all four AMs (ICC: AM1=0.92, AM2=0.94, AM3=0.95 and AM4=0.95).   Conclusion:  Despite the 6MWT presenting high reproducibility, the learning effect was present from the first to the third evaluation in smokers. This highlights the need to perform two 6MWT not only in the first assessment moment.
Ca2+/Calmodulin-dependent Protein Kinase (CaMK) Regulates Cell Cycle Progression in Osteosarcoma
Authors: Maggie A. McKenna, Hyeran Choo, Gene P. Siegal, Majd Zayzafoon
Journal: Cancer Research (2006)

4913   Osteosarcoma is the predominant primary malignant bone tumor in children and adolescents and is characterized by uncontrolled cell proliferation which when left untreated will progress to metastasis usually to the lungs or other bones. Overexpression of  c-fos  and subsequent alterations in the cell cycle have been suggested to be involved in the neoplastic transformation of osteoblasts. We have previously shown that CaMK is expressed in osteoblasts and regulates  c-fos  expression. The purpose of this work is to examine the role of CaMK in the growth of osteosarcoma. Here we show by immunofluorescence that α-CaMKII is expressed in all osteosarcoma cell lines and in primary human tumor tissue tested. Pharmacologic inhibition of CaMK by 10μM KN93 resulted in an 80% inhibition of the proliferation of osteosarcoma cells as determined by an MTT assay and cell counting. Furthermore, the inhibition of CaMK caused a 133% increase in the number of cells that are in the G1 phase of the cell cycle suggesting a role for CaMK in cell cycle progression. These results are confirmed by demonstrating a dramatic decrease in the number and size of colonies formed by osteosarcoma cells grown in growth factor reduced Matrigel supplemented with 10 μM KN93. In addition, KN93 dramatically decreased the size of tumor growth resulting from subcutaneous injection of osteosarcoma cells in a nude mice in vivo model. Mechanistically, we show that KN93 decreases protein levels of cyclin D2, c-Myc and the phosphorylation of retinoblastoma protein and increases p21. These results strongly suggest that inhibition of CaMK decreases the proliferation of osteosarcoma cells and promotes cell cycle arrest in the G1 phase.
Abstract 76: Does of Multiple Epinephrine Administration on OHCA Patients Associate with Good Cerebral Performance?
Authors: Ryo Sagisaka, Hiroshi Takyu, Hideharu Tanaka, Hiroyuki Akihama, Eiichi Hasegawa, Takahiro Hara, Yuta Sato, Shuji Shimazaki
Journal: Circulation (2014)

Background: Epinephrine, strong vasoconstrictor, is recommended that administered to OHCA patients every 3 to 5 minutes by the JRC 2010guideline. However, there are no scientific evidence of effectiveness multiple epinephrine administration on OHCA patients.

Purpose: The aim of this study is to determine the effectiveness of the number of epinephrine administration associated with good cerebral performance (CPC) outcome on OHCA patients.

Methods: A total of 925288 OHCA patients registered by the Japan Utstein registry between January 1, 2005 and December 31, 2012. Adult patients whose age from 15 to 89 years with presumed cardiac origin were included in this study. Non-cardiac origin and patients who regained return of spontaneous circulation before EMS arrival were excluded. Total 4679 OHCA patients received single or multiple administration of epinephrine.

Results: One thousand eight hundred forty three OHCA patients received single administration of epinephrine (as single epi group), 1367 OHCA patients did twice(as twice epi group), 739 patients did three times(as three times epi group), and 384 patients did four times(as four times epi-group), 346 patients did 5times and more (as 5times and more epi-group). All patient shows identical back ground (age, gender, bystander CPR ratio and response time), however, CPC-1.2 at one month after for patients with single epi-group was 5.9%, twice epi-group was 2.9%, three times epi-groups was 2.0%, and four times epi wad 2.1% , and 5 times and more epi-groups was 1.4% respectively. There were statistically significant between the groups single epi and other groups (P<.05).

Conclusions: One month of CPC-1/2 ratio fell down progressively with increasing times of administration in epinephrine. However, data suggest that multiple administration of epinephrine were might gave worsen condition than that of first administration.
Biomarkers and severity in community-acquired pneumonia (CAP)
Authors: Sergio Fandos, Elisa Minchole, Ana Lasierra, Ana Simon, Carolina Panadero, Guillermo Hernandez, Francisco De Pablo, Sandra Garcia, Carlos Lapresta, Salvador Bello
Journal: European Respiratory Journal (2012)

INTRODUCTION  To evaluate the prognostic value of biomarkers in community-acquired pneumonia (CAP), we studied the correlations between C-reactive protein (CRP), procalcitonin (PCT), leukocyte count (WBC) and proadrenomedulin (proADM) with the widely used PSI severity score.  MATERIAL AND METHODS  We prospectively studied 282 immunocompetent, adults patients hospitalized with CAP, calculated their PSI score and measured on admission the mentioned four blood biomarkers. Subsequently, we established the ROC curves to determine which of the biomarkers had a better discriminating power from mild CAP (PSI 1-3) to severe ones (PSI 4-5).  RESULTS  PCT and proADM significantly discriminated severe from mild CAP, although the area under curve was significantly higher for proADM (0.757 vs. 0.581). The other two biomarkers did not reach statistical significance.  CONCLUSIONS  ProADM is a good predictor of CAP severity at the time of admission, and can be useful, with the clinical scores to identify severe CAP. This may help us to make decisions of patients site of care and management in the early hours.
Low Yield of Myocardial Perfusion Imaging in Asymptomatic Patients With Atrial Fibrillation
Authors: Paul C. Cremer, Amgad Mentias, David Newton, Venu Menon, Oussama Wazni, Patrick J. Tchou, Wael A. Jaber
Journal: JAMA Internal Medicine (2015)

In this single-center study of asymptomatic patients with atrial fibrillation, the yield for detecting ischemia with myocardial perfusion imaging was low and did not significantly increase with increasing clinical risk.
Abstract 3441: Differential endothelialization of stent struts across side branches: A Scanning Electron Microscopy analysis.
Authors: Yi Zheng, Marlos R Fernandes, Guilherme V Silva, Cristiano O Cardoso, John F Canales, Fred Baimbridge, Edie M Oliveira, William Vaughn, Maria G Hansen, Emerson C Perin
Journal: Circulation (2007)

Background: The higher incidence of MACE events in paclitaxel eluting stents (PES) has been attributed to the presence of coronary artery side branches (SB) within stented segments. This study aimed to evaluate PES struts overlying SB in a porcine model of coronary restenosis. Methods: In a balloon overstretch model of coronary restenosis (balloon:artery ratio =1.2:1), 20 animals were randomized to either PES or bare metal stents (BMS). After 30 days, 22 stented segments were analyzed by Low Vacuum Scanning Electron Microscopy (SEM) and endothelialization was assessed using a score (0=100% endothelialization; 1=99 – 67%; 2=66 –34%; 3=33–1%; 4=0%). Comparison of the distribution of endothelialization scores for struts overlying and non-overlying SB was performed within each group by the Fisher exact test. Results: A total of 18 struts overlying SB (10 PES and 8 BMS) sized from 200 to 1800μ m, were identified by SEM. In the BMS group, complete endothelialization was observed in 62.5% of SB struts and 100% of non-overlying SB struts. In PES only 20% of SB struts, but almost 100% of the non-overlying SB struts were completely endothelialized. The endothelialization of struts overlying SB was significantly different in PES and BMS groups(Fig 1A and Fig 1B ), with a higher frequency of impaired endothelialization (scores 3 and 4) in PES struts crossing SB. Conclusions: PES struts overlying SB showed significantly impaired endothelialization compared with BMS in a pig model of coronary restenosis. This results might offer a new insight to explain the higher incidence of adverse events in PES stented segments. Further studies are needed to confirm the present study results.
Comparison of lung adenocarcinoma and squamous cell carcinoma genomes reveals distinct regions of amplification on chromosome 3q
Authors: William W. Lockwood, Cathie Garnis, Yong Ge, Adi F. Gazdar, John D. Minna, Stephen Lam, Calum Macaulay, Wan L. Lam
Journal: Cancer Research (2005)

879   Lung cancer is a leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) is the major disease type, with squamous cell carcinoma (SqCC) and adenocarcinoma (AC) as the two main sub-types. SqCC and AC are distinguished by differences in their histopathological and molecular characteristics: SqCC develops more rapidly and is located in the central airways, whereas AC is thought to originate from the epithelium of the lung periphery. Previous findings suggest that, although a similar degree of genetic imbalance exists for AC and SqCC, each type is characterized by a unique pattern of genomic imbalance. Objective: To comprehensively identify the underlying differences in genetic alteration patterns between SqCC and AC, we performed genome-wide tiling resolution array CGH analysis. Novel variations in copy number detected by this high resolution technology may reveal cancer-related loci and will provide potential targets for diagnosis and treatment. Design, Materials and Methods: DNA was isolated from 15 AC cell lines and 9 SqCC cell lines. Sample DNA and a pooled reference genomic DNA sample were differentially labeled and applied to the submegabase resolution tiling-set (SMRT) array for CGH analysis. This array consists of >32,000 overlapping human bacterial artificial chromosome clones that span the entire human genome, allowing true genome-wide assessment of copy number changes for a given sample. SMRT array data was assessed using multiple software applications (SeeGH, weighted frequency, aCGH smooth) and alterations in identified regions are presently be validated by fluorescent in situ hybridization using loci specific probes. Results: In total, 24 whole genome array CGH profiles of lung cancer cell lines were generated. Numerous novel, subtype-specific chromosomal alterations were observed. This included differences of alteration at chromosome arms 2q, 6q, 8q, 9q, 12q, 13q and 16p. Of specific interest were the different locations of chromosomal amplification at 3q in the sub-types. AC showed frequent gains between 3q13 and 3q22 while SqCC displayed a similar frequency at 3q23-3q26. These regions have previously been implicated in lung cancer but not mapped according to sub-type. Further analysis of genes within distinct altered regions will determine if these loci help drive the development of different lung cancer subtypes. Conclusions: Tiling resolution array CGH analysis of AC and SqCC lung cancers revealed both shared and subtype-specific regions of DNA copy aberration, suggesting that differences in tumor genomes help define distinct disease subtypes. Further characterization of the novel aberrations and minimal regions we have identified will implicate additional genes in the two tumorigenesis processes and help tailor disease diagnosis. Supported by NCI SPORE CA 70907, NCI Contract N01-85188 and Genome Canada
Abstract 479: Disruption of Myosin VI Expression Results in Altered Vasculature and VEGF Signaling
Authors: Anthony A Lanahan, Joanna S Kerley-Hamilton, Karen L Moodie, Zhen W Zhuang, Thomas W Chittenden, Michael Simons
Journal: Circulation (2007)

Background : Myosin VI is an actin-based molecular motor that is involved in endocytic trafficking of plasma membrane receptors. Myosin VI has multiple binding partners including the cytoplasmic PDZ protein synectin that has recently been shown to be involved in VEGF signaling and VEGF receptor endocytosis. Hypothesis : We assessed the hypothesis that disruption of the myosin VI gene results in altered VEGF signaling and receptor trafficking in endothelial cells (EC), leading to altered arterial morphogenesis. Methods : Myosin VI −/− mice were used for in vivo and in vitro studies. Primary myosin VI −/− (KO) and +/+ (WT) EC were isolated from mouse heart, lung, inferior vena cava and abdominal aorta by dissection followed by PECAM-1 cell sorting. Results: In response to VEGF-A, primary EC treated with an siRNA targeted against myosin VI showed decreased activation of Erk1/2 as determined by Western blotting. Further experiments using myosin VI −/− and +/+ EC confirmed a reduction in the activation of Erk1/2 in response to VEGF in cells lacking myosin VI. Activation of VEGFR-2 in myosin VI −/− endothelial cells is also decreased as assessed by diminished phosphorylation of tyrosine 1175 within the cytoplasmic domain of the receptor. To determine whether myosin VI is involved in vascular development and angiogenesis, micro CT analysis of myosin VI −/− and +/+ murine kidney vasculature was performed. Results suggest that myosin VI −/− animals have fewer large arterial vessels compared with the WT controls. Conclusions: VEGFR-2 activation and downstream signaling is decreased in myosin VI −/− endothelial cells in response to VEGF-A. Myosin VI −/− mice show altered vasculature structure as assessed by micro CT analysis. Similar perturbations in VEGF signaling and vasculature structure were seen in synectin −/− mice and endothelial cells. The decrease in VEGF signaling associated with reduced myosin VI and synectin levels points to a potential role of VEGF receptor trafficking resulting in these defects. Together these results suggest that the interaction of myosin VI and synectin is important in vascular development and angiogenesis.
Cardiotonic steroids: Revealed by cardiology, hoped for potential in oncology.
Authors: Tatjana Mijatovic, Eric Van Quaquebeke, Laurent Ingrassia, Francis Darro, Florence Lefranc, Robert Kiss
Journal: Cancer Research (2008)

624  Cardiotonic steroids (CSs: comprising cardenolides and bufadienolides) are characterised by their abundance in nature, diversity of structure, potential for chemical modification and wide use in cardiology for heart failure management. Epidemiological data have for some time also indicated lower mortality rates in cancer patients who were on digitalis at time of first diagnosis, compared to patients not on digitalis therapy. However, the inherent high toxicity and poor therapeutic margin of the commonly used CSs have prevented their development as anti-cancer agents. By binding to the sodium pump (Na+/K+-ATPase), CSs elicit several downstream signalling cascades affecting a number of different targets. The sodium pump could thus be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. There are currently more than 1000 papers investigating CSs in cancer, however it seems that the wider scientific community is still not sufficiently intrigued by the idea of CS use in oncology. In fact, there is a huge discrepancy between the number of reports dealing with the identification and isolation of new CSs with in vitro anti-tumour activity, and those concerned with the further investigation of these compounds. In this study, we present the in vitro and in vivo anti-cancer activity of different CSs and the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules. Indeed, the use of medicinal chemistry to target CSs towards specific sodium pump subunits over-expressed in certain cancers may improve both anti-tumour activity and reduce cardiotoxicity, the limiting toxicity for this class of compound. This strategy has in part been demonstrated with the hemi-synthetic analogue UNBS1450 derived from the naturally occurring CS: 2”-oxovoruscharin. Adverse effects have always been the companions of effective chemotherapeutics in oncology and the benefits contributed to patients have had to be counterbalanced by cumulative toxicity. In the absence of totally appropriate preclinical cardiotoxic models, the search for totally clean non-toxic anti-cancer CSs could prevent the development of some promising compounds with original mechanisms of action overcoming major chemoresistance pathways responsible for the failure of chemotherapy.
Antisense Inhibitor Lowers High Triglycerides
Authors: Anita Slomski
Journal: JAMA (2015)

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