tbuckley/cabot-search huggingface dataset:
The Human Microcirculation
Authors: David D. Gutterman, Dawid S. Chabowski, Andrew O. Kadlec, Matthew J. Durand, Julie K. Freed, Karima Ait-Aissa, Andreas M. Beyer
Journal: Circulation Research (2016)

The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.
Simultaneous Multi-plane Imaging of Neural Circuits
Authors: Weijian Yang, Jae-eun Kang Miller, Luis Carrillo-Reid, Eftychios Pnevmatikakis, Liam Paninski, Rafael Yuste, Darcy S. Peterka
Journal: Neuron (2016)

Recording the activity of large populations of neurons is an important step toward understanding the emergent function of neural circuits. Here we present a simple holographic method to simultaneously perform two-photon calcium imaging of neuronal populations across multiple areas and layers of mouse cortex in vivo. We use prior knowledge of neuronal locations, activity sparsity, and a constrained nonnegative matrix factorization algorithm to extract signals from neurons imaged simultaneously and located in different focal planes or fields of view. Our laser multiplexing approach is simple and fast, and could be used as a general method to image the activity of neural circuits in three dimensions across multiple areas in the brain.
METABOLIC PRODUCTS OF ADRENALINE AND NORADRENALINE IN HUMAN URINE1
Authors: McC. Goodall
Journal: Pharmacological Reviews (1959)

1. dl -Adrenaline-2-C14 and dl -noradrenaline-2-C14 were infused in 12 healthy males and the urine collected hourly thereafter for 24 hours.

2. The urinary catabolites of adrenaline and of noradrenaline were separated by means of a combination of ion exchange and paper chromatography. Radioactivity of each catabolite was measured with a thin window Geiger tube and corrected to infinite thinness.

3. After an infusion of labeled adrenaline, 73 ± 2% of the radioactivity was recovered in 24 hours, and after an infusion of labeled noradrenaline, 67 ± 4% of the radioactivity was recovered in 24 hours.

4. Distribution of radioactivity in the 24-hour urine following an infusion of labeled adrenaline was: adrenaline, 4 ± 0%; metadrenaline, 5 ± 0%; unidentified compound, 1 ± 0%; metadrenaline conjugate fraction, 42 ± 3%; 3-methoxy-4-hydroxymandelic acid, 27 ± 2%; 3,4-dihydroxymandelic acid plus unidentified compound, 12 ± 2%.

5. Distribution of radioactivity in the 24-hour urine following an infusion of labeled noradrenaline was: noradrenaline, 4 ± 1%; normetadrenaline, 3 ± 1%; unidentified compound, 2 ± 1%; normetadrenaline conjugate, 19 ± 2%; unidentified compound, 10 ± 2%; 3-methoxy-4-hydroxymandelic acid, 32 ± 2%; 3,4-dihydroxymandelic acid plus two unidentified compounds, 11 ± 2% and 13 ± 2%.

6. The role of the metabolic products of noradrenaline as a possible barometer of the physiological functioning of the sympathetic nervous system is discussed.
Abstract 11743: Association of Waist Circumference with Atherosclerosis among US South Asians: Results from the MASALA Study
Authors: Alka M Kanaya, Michael Schembri, Shweta Srivastava, Swapna Dave, Ritu Gupta, Yasin Patel, Kiang Liu, Matthew J Budoff, David Herrington, Namratha Kandula
Journal: Circulation (2012)
Subcellular localization of PTEN is regulated by LKB1 with or without the AMPK/TSC2/mTOR signaling intermediates
Authors: Juinn-Lin Liu, Zhenyu Mao, Jeannine Garnett, Oliver Bogler, W. K. Yung
Journal: Cancer Research (2008)

2774   The tumor suppressor PTEN plays distinct growth-regulatory roles in the cytoplasm and nucleus. It has been shown to be preferentially localized to the nucleus in differentiated or resting cells, but to the cytoplasm in advanced tumor cells. Thus the regulation of PTEN’s subcellular localization appears to be critical to its tumor suppressing functions. Our group has been focused on elucidating the molecular mechanisms involved in PTEN’s nuclear export. We found that activation of the PI3K cascade triggers PTEN’s Crm1-dependent nuclear export during the G1/S transition. This scenario indicates the existence of a reciprocal regulation between PI3K and PTEN during cell cycle progression. It has been well documented that mTOR can be alternatively downregulated by AMPK-mediated TSC2 activation. We reasoned that the activation of AMPK would also block PTEN’s nuclear export during the G1/S transition the same way as inhibitors of PI3K, mTOR and S6K do. AMPK is mainly activated by LKB1, or by CaMKK. To test our hypothesis, we analyzed the effects of a panel of AMPK activators on several cell lines with different genetic backgrounds. In LKB1-null A549 cells, AICAR and metformin failed to block the nuclear export of PTEN, since AMPK was not activated in the absence of LKB1. In contrast, PTEN’s nuclear export was inhibited in cells treated with the CaMKK activator 2-DG, and this inhibition was reversed by the addition of inhibitors for AMPK (compound C) or CaMKK (STO-609). Further, the reintroduction of functional LKB1 into A549 cells restored the AICAR- or metformin-mediated inhibition of PTEN’s nuclear export. In contrast, although PTEN’s nuclear export is blocked by AICAR and metformin in MDA-MB-468 or MCF-7 cells carrying wild-type LKB1, this inhibition could not be reversed by an AMPK inhibitor, suggesting that LKB1 regulates PTEN’s nuclear export, thereby bypassing AMPK. Compared to AMPK +/+  or TSC2 +/+  MEFs, however, the CaMKK activator could not block PTEN’s nuclear export in AMPK -/-  or TSC2 -/-  MEFs because of the absence of AMPK or TSC2 in these cells. However, AICAR and metformin were still able to induce an LKB1-mediated inhibition of PTEN’s nuclear export in these cells. Taken together, these findings strongly suggest that while CaMKK mainly mediates PTEN’s nuclear retention through activation of AMPK; LKB1 can regulate PTEN’s nuclear-cytoplasmic trafficking with or without the AMPK/TSC2/mTOR-signaling intermediatesr. Further identification of LKB1’s novel substrates involved in blocking PTEN’s nuclear export will lead to drug discovery of pharmaceutical agents that facilitate PTEN’s nuclear retention as a novel therapeutic strategy for glioblastoma multiforme (GBM) and other advanced tumors expressing PTEN in the cytoplasm.
Abstract 195: TIP30 Interferes With Protein Synthesis And Inhibits Cardiac Hypertrophy
Authors: Andrea Grund, Natali Froese, Mortimer Korf-Klingebiel, Thomas Thum, Kai C Wollert, Oliver Müller, Manuel Mayr, Johann Bauersachs, Jörg Heineke
Journal: Circulation Research (2013)

Background: Pathological cardiac hypertrophy is a crucial risk factor for the development of heart failure. It is characterized by a massive increase of contractile and structural proteins within cardiomyocytes, mainly as a result of enhanced protein synthesis. The regulatory mechanisms of increased RNA translation during hypertrophy, however, remain largely unknown. Here, we examined the cardiac function of TIP30, which has previously emerged as a tumor suppressor gene with reduced expression in malignant tumours. Results: We identified myocardial TIP30 mRNA as dramatically downregulated (&gt;80%) in a mouse model of dilative cardiomyopathy (MLP knock-out mice) as well as in human failing hearts. A protein pull-down screen with a GST-TIP30 fusion protein and proteomic candidate identification revealed the eukaryotic translation elongation factor 1A1 (eEF1A1) as binding partner of TIP30, which was independently verified by GST-pulldown and co-immunoprecipitation (IP). Interestingly, this interaction between TIP30 and eEF1A1 was not detectable during pro-hypertrophic (phenylephrine, PE) stimulation in neonatal rat cardiac myocytes (NRCM). Adenoviral (Ad-) TIP30 overexpression in NRCM during PE stimulation led to a reduced hypertrophic response compared to Ad-control infected cells (cell size in % of control: Ad-TIP30 135 ± 4 vs. Ad-control 200 ± 3 p&lt;0.05). At the same time, a dramatic decrease in protein:DNA ratio was observed. siRNA downregulation of eEF1A1 ablated the anti-hypertrophic effects of TIP30. Measurement of translational activity by determination of the polysome/monosome ratio revealed a blunted translation rate after TIP30 overexpression. In line with our in vitro data, myocardial overexpression of TIP30 by an adeno-associated virus (AAV9-TIP30) significantly reduced cardiac hypertrophy during two weeks of Angiotensin (Ang)/PE infusion in vivo. In turn, Ang/PE infusion as well as aortic constriction (TAC) led to an increased hypertrophic response in TIP30 knock-out versus wild-type mice. Conclusion: TIP30 inhibits hypertrophy and translational activity most likely through inhibition of eEF1A1 in cardiomyocytes. TIP30 is downregulated in human failing hearts and could thereby contribute to aggravated hypertrophy.
P-254 A multicentre, non-interventional, post-authorization study to observe in daily clinical practice the treatment duration of patients treated with bevacizumab in 1st line mCRC in Belgium
Authors: J.-C. Goeminne, J.-M. Vandenbulcke, A. Bols, L. Marcelis, J. Arts, B. Naessens, M. De Man, D. Frijns, J. Decaestecker
Journal: Annals of Oncology (2015)
Abstract 17841: Study Type Determines Outcomes After Multivessel or Culprit-Vessel Intervention for ST-Elevation Myocardial Infarction in Patients with Multivessel Coronary Artery Disease
Authors: John A Bittl, Christopher D Lang
Journal: Circulation (2014)

Introduction: The optimal way to use percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD) remains uncertain. Randomized controlled trials (RCTs), which are restrictive and rigorous, support the use of multivessel PCI; but cohort studies, which are reflective of actual practice and susceptible to bias, support the use of culprit-vessel PCI. Hypothesis: A cross-design meta-analysis may allow inferences to be made about the parameter θ, which is conditional on both study design and observed mortality differences within and between trials and reflects the underlying hypothesis that the multivessel PCI strategy is superior to culprit-vessel strategy in patients with STEMI and multvessel CAD. Methods: We used Bayesian hierarchical and cross-design methodologies for statistical inference of 15 clinical trials (4 RCTs, 4 matched cohort studies and 7 other cohort studies) that compared multivessel and culprit-vessel strat...
Abstract P041: Relations of Three Types of Low Carbohydrate Diet to Cardiometabolic Risk Factors and C-Reactive Protein: The INTERLIPID Study
Authors: Yasuyuki Nakamura, Hirotsugu Ueshima, Nagako Okuda, Katsuyuki Miura, Yoshikuni Kita, Naoko Miyagawa, Katsushi Yoshita, Hideaki Nakagawa, Kiyomi Sakata, Shigeyuki Saitoh, Tomonori Okamura, Akira Okayama, Sohel R Choudhry, Beatriz Rodriguez, Kamal H Masaki, Queenie Chan, Jeremiah Stamler
Journal: Circulation (2015)

Introduction: Sizable numbers of people have tried low carbohydrate diets (LCD) of varied types; data are sparse on effects on cardiometabolic risk factors with different types of LCD. Hypothesis: We assessed the hypothesis that relationships of LCD score to cardiometabolic risk factors and an inflammatory marker, high-sensitivity C-reactive protein (CRP), are different among usual, animal-based, and plant-based LCD. Methods: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high sensitivity C-reactive protein (CRP), and nutrient intakes by standardized methods in men and women ages 40 to 59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton, et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) +polyunsaturated fatty acids (PUFA). Multiple linear regression analyses were used to examine relations of LCD scores to log-CRP and cardiometabolic risk factors. Results: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, years of education, and Keys dietary lipid score, all three LCD scores were significantly directly related to HDLc (all Ps&lt;0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log-CRP (coefficient=-0.011, P=0.017). Conclusions: All three LCD scores were significantly directly related to HDLc, but not to LDLc. The plant-based LCD score, associated with higher PUFA and lower SFA and dietary cholesterol in comparison with the other two LCD scores, was significantly inversely related to log-CRP.
Fatness, Fitness, Stiffness, and Age
Authors: Barry A. Borlaug
Journal: JACC Heart Failure (2014)

There is no proven effective treatment for heart failure with preserved ejection fraction (HFpEF) [(1)][1], making prevention even more important. To design preventive trials, we must first understand which people are at the highest risk for HFpEF, and why they are so vulnerable. HFpEF is associated
Abstract 19144: Fish Oil and Cyclooxygenase Inhibitors: a Novel Strategy to Manage Obesity-linked Dyslipidemia
Authors: Viswanathan Saraswathi, Curtis Perriotte-Olson, Robert D Heineman, Cyrus V Desouza
Journal: Circulation (2014)

Introduction: Dyslipidemia is a prevalent condition in obesity and type 2 diabetes. Although fish oil rich in omega-3 fatty acids (ω-3) is a widely used hypolipidemic agent, it is often required at high doses. At high doses, these fatty acids can induce oxidative stress or endothelial activation and therefore, strategies to improve their beneficial effects are needed. We previously reported that fish oil in combination with cyclooxygenase (COX) inhibitors exerts enhanced hypolipidemic and anti-inflammatory effects in low density lipoprotein receptor knock-out mice. Here, we sought to determine the effects of ω-3 fatty acids in combination with naproxen (NX), a COX inhibitor, on dyslipidemia and gene expression in subcutaneous adipose tissue (scAT) in humans. Methods: Obese dyslipidemic patients were randomly assigned to receive one of these interventions (n=8/group) for 12 wk: 1) Standard nutrition counseling (control), 2) ω-3 (2 g twice daily), 3) NX (220 mg twice daily), and 4) ω-3 (2 g twice daily) + NX (220 mg twice daily). Results: The body mass index, HOMA-IR, and plasma total, LDL, and HDL cholesterol levels were not altered significantly in any of the groups. The percent change in plasma triglycerides (TG) from baseline was 75% ( P &lt;0.1) and 68% ( P &lt;0.05) in ω-3 and ω3 + NX-treated subjects, respectively. Notably, 25% of subjects who received ω-3s alone did not show a reduction in TG whereas all the patients that received ω-3 + NX showed a reduction in TG. Realtime PCR analysis of scAT showed that the expression of glucose transporter 4 (GLUT-4), a marker of glucose uptake and a key regulator of glucose homeostasis was significantly reduced in ω-3 compared to control group ( P &lt;0.01). However, combining NX with ω-3 abolished this effect. Moreover, the expression of MCP-1 and VCAM-1, markers of inflammatory response or endothelial activation, was significantly increased in ω-3 but not in ω-3 + NX group. The plasma levels of MCP-1 and E-selectin did not vary significantly in any of the groups. Conclusions: Our data reveal previously unrecognized effects of fish oil in scAT. Our data suggest that combining NX with ω-3 fatty acids will increase their effectiveness in reducing plasma TG and improve the benefits of ω-3 supplements by favorably altering gene expression in scAT.
In vitro and in vivo anti-leukemia activity of CHR-2845, a cell-targeted HDAC inhibitor for use in monocytic leukemia
Authors: W. Tong, W. Stevenson, J. Cortes, L. Needham, D. Brotherton, A. Davidson, A. Drummond, G. Garcia-Manero
Journal: Journal of Clinical Oncology (2009)

e14579 Background: Histone deacetylase inhibitors alter gene expression and induce apoptosis in a wide range of cancer cells including those derived from human leukemias. CHR-2845 is a novel hydroxamic acid derivative histone deacetylase inhibitor (HDACi) which is a selective substrate for the intracellular carboxylesterase hCE-1, whose expression is restricted to cells of the monocyte- macrophage lineage. Methods: We studied the in vitro and in vivo anti-leukemia activity of CHR-2845 using cell proliferation assay, annexin V binding assay, cell cycle analysis, western blot and in vitro primary leukemia cell culture. Results: Both U937 and THP1 cells express high levels of hCE-1 whereas the myeloid cell line, HL60, does not. In comparison to vorinostat, CHR-2845 showed increased anti-proliferative potency (IC 50 ) against monocytic cell lines (THP1, 30 nM vs 700 nM and U937, 30 nM vs 475 nM), compared to a myeloid cell line (HL60, 700nM vs 470 nM). In a broad panel of leukemic cell lines, the potency of CHR-2845 over vorinostat correlated completely with hCE-1 expression. In monocytic cell lines, CHR-2845 induced more apoptosis than vorinostat (THP1: 45±5% vs 11±1% and U937: 23±14% vs 6±1%), as measured by flow cytometry using Annexin V. Biochemical assessment of histone H3 and H4 protein acetylation by Western blot also indicateed that CHR-2845 is at least 10 times more potent than vorinostat in monocytic cell lines but not in HL-60 cells. This increase in histone acetylation was associated with increased phosphohistone H2AX, indicating formation of double-strand DNA breaks induced by this compound. These data for CHR-2845 and vorinostat on apoptosis and histone acetylation in THP1 and U937 versus HL60 cells, confirmed the selectivity of this novel compound for cells of the monocytic lineage. We also studied the anti-leukemia activity of CHR-2845 in primary leukemia cells from 8 patients with acute or chronic myelomonocytic leukemia. CHR-2845 decreased proliferation and induced apoptosis more than an equivalent dose of vorinostat in some of the patients we studied. Conclusions: These results indicated that CHR-2845 has potential to be efficacious in the treatment of patients with monocytic leukemia. [Table: see text]
Does Vascular Calcification Accelerate Inflammation?
Authors: Francis R. Joshi, Nikil K. Rajani, Markus Abt, Mark Woodward, Jan Bucerius, Venkatesh Mani, Ahmed Tawakol, David Kallend, Zahi A. Fayad, James H.F. Rudd
Journal: Journal of the American College of Cardiology (2016)
Abstract #LB-144: Ectopic lymphoid tissue in colonic adenocarcinoma
Authors: Domenico Coppola, Farah Khalil, Larry Tjoelker, Matthew Moyle, James Mulé
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Infiltrative colorectal carcinoma (CRC) may elicit a host immune response, which is histologically evident as lymphocytic infiltration. The pathogenesis and significance of this response are not fully elucidated. Here we analyze a subset of CRC with prominent lymphocytic infiltrate (LI) with respect to organizational structure and cell type composition. Design: Twenty cases of human CRC were selected from the Moffitt Cancer Center (MCC) pathology file; 10 of these cases were found to have prominent LI upon further examination. The formalin-fixed, paraffin embedded sections were immunostained using the avidin-biotin-peroxidase method to detect expression of CD3, CD20, CD21, CD79a and Ki-67. The stained tissue sections were evaluated by two independent observers. Results: In the CRC with prominent LI, the Ki-67+ proliferating cell population was found to contain both B and T lymphocytes. CD3+ cells were present in parafollicular regions, at the tumor edge, and also scattered within the tumor parenchyma. In contrast, CD20+ cells were localized exclusively within well-defined, lymphoid aggregates in all 10 cases examined; the presence of B cell precursors was identified by CD79a. CD21+ dendritic cells were present within germinal centers of these structures in nine of the ten cases, establishing the true follicular nature of the lymphoid aggregates. Five of the ten CRC showed the expression of Ki-67 expressing cells within the germinal centers. Collectively, these findings may represent stages in a process of ectopic lymph node formation and activation. Conclusions: These findings show that in some colorectal adenocarcinoma cases, the lymphocytic host response can be organized as ectopic lymph node-like structures within the solid tumor mass.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-144.
Quality of life in 269 poor-risk diffuse large B-cell lymphoma patients treated with rituximab versus observation after front-line auto transplantation: The GELA LNH98-3 randomized trial.
Authors: N. Mounier, N. Heutte, C. Haioun, P. Feugier, B. Coiffier, H. Tilly, C. Ferme, J. Gabarre, F. Morchhauser, C. Gisselbrecht
Journal: Journal of Clinical Oncology (2010)

8082 Background: Little is known about the longitudinal course of health-related quality of life (QoL) in DLBCL patients during their post-treatment follow-up. We report on the QoL of patients treated in the randomised LNH98-3 trial of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess QoL and fatigue following front-line autotransplantation (ASCT) and to analyse relations with rituximab maintenance. Methods: This study is registered with www.ClinicalTrials.gov number NCT00169169 (C Haioun, Annals of Oncology, 2009). High-dose CHOP induction therapy was received by 476 patients, and 330 responder-patients received ASCT. Following response to ASCT, 269 patients were randomized to rituximab treatment (4 cycles) or observation. They received the EORTC QLQ-C30 questionnaires at day 45 after ASCT and during follow-up (100 days, 1yr, 2yr, and 3 yr). Changes of mean QoL scores over time were analysed with mixed models. Analyses were done on an intention-to- treat basis. Results: From the 555 assessments initially obtained, 64 were excluded (29 before the randomization, 5 after relapse, 30 as doublets) and 491 assessments in 200 patients remained for analysis. There were 136 male and 64 female. Median age was 45 yr [18;59]. 191 were in CR/CRU. 107 receive Rituximab maintenance. The median follow-up was 52 months. 4 yrs EFS was 81%. Significant improvements with time were observed in all scales except for nausea. Frequencies of patients with clinically significant improvement (change score > 10) varied from 6% (constipation) to 56% (fatigue). Improvement with time showed similar patterns with marked increase until D100 and then a plateau after one year. Age, gender and previous treatment toxicities were not predictive. There was a significant influence of treatment arm upon pain and financial impact; the lower level of symptoms was observed on the rituximab arm. Conclusions: QoL data showed that patients experience rapid recovery after ASCT in all subdomains. Differences in QoL improvement with time were not linked to rituximab maintenance. No significant financial relationships to disclose.