tbuckley/cabot-search huggingface dataset:
Abstract 276: Cyclin D2 Is a Critical Mediator of Exercise-Induced Cardiac Hypertrophy
Authors: Stephen W Luckey, Christopher D Haines, John P Konhilas, Elizabeth D Luczak, Leslie A Leinwand
Journal: Circulation Research (2012)

Exercise training activates a number of hypertrophic signaling pathways that can be distinct from those activated by pathologic stimuli. However, there must be some overlap in those pathways underlying myocyte cell growth. Using a number of mouse genetic models, we investigated the role of several molecules implicated in pathologic cardiac hypertrophy for their cardiac responses to exercise. We used three-month-old female transgenic mice expressing the anti-hypertrophic molecules, cardiac-specific constitutively active glycogen synthase kinase-3β (caGSK-3β), an inhibitor of Ca 2+ -calmodulin-dependent protein kinase (CaMKII Inh), and doubly transgenic mice expressing both caGSK-3β and CaMKII inhibition (caGSK-3β/CaMKII Inh). We also studied the exercise responsiveness of mice expressing the pro-hypertrophic cardiac-specific activated (myr)Akt. MAPK/ERK kinase kinase-1 (MEKK1) has been shown to be essential for pathologic cardiac hypertrophy and we therefore studied the requirement of MEKK1 for exercise-induced cardiac growth. Cell cycle regulators such as cyclin D2 have been shown to be required for pathologic cardiac hypertrophy; therefore we studied cyclin D2 null mice. Mice were divided into sedentary and 21 days of voluntary exercise on a cage wheel. Across the seven different mouse models, exercise capacity was similar with regards to running duration, distance, and speed. Importantly, we analyzed the impact of exercise on cardiac hypertrophy by measuring heart weight-to-body weight (HW/BW) ratios of sedentary and exercised mice. While exercise had no impact on body weight, heart weight increased significantly in all mouse models except the cyclin D2 -/- mice. Overall there was a 3.5-fold range of percent increase in HW/BW ratios from the highest (caGSK-3β) to the lowest (cyclin D2 -/- ). In conclusion, genetic manipulation of these hypertrophic signaling pathways has little impact on exercise performance and only the loss of cyclin D2 attenuates exercise-induced cardiac growth. These data establish cyclin D2 as an important regulator of physiological hypertrophy and underscore the differences in pathologic and physiologic cardiac hypertrophy.
Centrifugal Lithography: Self‐Shaping of Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer Drops
Authors: Huisuk Yang, Suyong Kim, Geonwoo Kang, Shayan F. Lahiji, Mingyu Jang, Young Mi Kim, Jae‐Myung Kim, Sang‐Nae Cho, Hyungil Jung
Journal: Advanced Healthcare Materials (2017)

Polymeric microstructures encapsulating biopharmaceutics must be fabricated in a controlled environment to preserve the biological activity. There is increasing demand for simple methods designed to preserve the biological activity by utilizing the natural properties of polymers. Here, the paper shows that centrifugal lithography (CL) can be used for the fabrication of such microstructures in a single centrifugation, by engineering the self-shaping properties of hyaluronic acid (HA). In this method, HA drops are self-shaped into hourglass-microstructures to produce two dissolving microneedles (DMN), which facilitate transdermal delivery via implantation on the skin. In addition, tuberculin purified protein derivatives are encapsulated into HA DMNs under refrigerated conditions (4 °C) during CL. Therefore, the tuberculin skin test (TST) with the DMNs indicates minimal damage, as opposed to the case of TST with traditional hypodermic needles. These findings on the fabrication of polymeric microstructures with biopharmaceutics may trigger the development of various biomedical devices and therapies.
Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
Authors: Giovanni B Frisoni, Marina Boccardi, Frederik Barkhof, Kaj Blennow, Stefano Cappa, Konstantinos Chiotis, Jean-Francois Démonet, Valentina Garibotto, Panteleimon Giannakopoulos, Anton Gietl, Oskar Hansson, Karl Herholz, Clifford R Jack, Flavio Nobili, Agneta Nordberg, Heather M Snyder, Mara Ten Kate, Andrea Varrone, Emiliano Albanese, Stefanie Becker, Patrick Bossuyt, Maria C Carrillo, Chiara Cerami, Bruno Dubois, Valentina Gallo, Ezio Giacobini, Gabriel Gold, Samia Hurst, Anders Lönneborg, Karl-Olof Lovblad, Niklas Mattsson, José-Luis Molinuevo, Andreas U Monsch, Urs Mosimann, Alessandro Padovani, Agnese Picco, Corinna Porteri, Osman Ratib, Laure Saint-Aubert, Charles Scerri, Philip Scheltens, Jonathan M Schott, Ida Sonni, Stefan Teipel, Paolo Vineis, Pieter Jelle Visser, Yutaka Yasui, Bengt Winblad
Journal: The Lancet Neurology (2017)
In patients receiving DAPT after coronary stents, the PRECISE-DAPT score predicted bleeding moderately well
Authors: Ana Carolina Alba, Gordon Guyatt
Journal: Annals of Internal Medicine (2017)

Source Citation Costa F, van Klaveren D, James S, et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet. 2017;389:1025-34 28290994
Abstract 130: Il-10 Regulates the Immunoregulatory Response in the Regression of Atherosclerosis
Authors: Cathal McCarthy, Michelle Duffy, Declan Mooney, William James, Desmond J Fitzgerald, Matthew D Griffin, Orina Belton
Journal: Circulation Research (2012)

We have previously shown that dietary administration of conjugated linoleic acid (CLA) induces regression of pre-established atherosclerosis in the apoE -/- mouse, via modification of inflammatory cell function. However, the exact mechanism through which this occurs has not been elucidated. Here we describe a functional role for signaling of the anti-inflammatory cytokine, IL-10, in atherosclerosis regression and investigate the consequence of enhanced IL-10 generation on the immune cell population in vivo . Our initial aim was todelineate the atheroprotective mechanisms modulated by CLA. Transcriptomic analysis of aortic tissue in the CLA-induced regression model identified an enrichment of the IL-10 signaling pathway. Further analysis of the network identified increased IL-10 receptor expression (localized to the macrophage cells) and STAT3 phosphorylation; and increased expression of downstream target genes such as the anti-inflammatory cytokine IL-1Ra (by 3.45 ± 0.83 p&lt;0.05 fold) and suppressor of cytokine signaling (SOCS3) (by 2.24± 0.44 p&lt;0.01 fold). Moreover, there was increased circulating IL-10 serum levels in apoE -/- mice fed a CLA supplemented 1% cholesterol diet compared with apoE -/- mice fed a 1% cholesterol diet alone (41.9 ± 8.9 vs 79.8 pg/ml ± 22.4 p&lt;0.01). Interestingly, both IL-10 production and STAT3 phosphorylation was significantly increased in bone marrow derived macrophages from CLA fed mice. We next employed flow cytometry to delineate the phenotype of single cell suspensions of aortae. CLA supplementation regulated immune cell infiltration of the aorta with increased number of the anti-inflammatory Ly6C lo monocytes evident during regression (29±8 vs 77±14cells/mg aorta p&lt;0.05). In addition, CLA-induced regression was associated with increased polarization towards an anti-inflammatory M2 phenotype, confirmed by an enrichment of M2 genes in the aorta, which occurred as a consequence of increased aortic IL-10 production. In summary CLA mediated induction of IL-10 signaling alters the immunoinflammatory response to atherosclerosis, with increased volume of Ly6C lo monocytes infiltrating the regressing lesions and directed polarization of macrophages towards an M2 phenotype in the plaque microenvironment.
Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD
Authors: Nicholas J. Gloude, Pooja Khandelwal, Nathan Luebbering, Dana T. Lounder, Sonata Jodele, Matthew N. Alder, Adam Lane, Alyss Wilkey, Kelly E. Lake, Bridget Litts, Stella M. Davies
Journal: Blood (2017)
Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation
Authors: Akiko Seki, Taisuke Ishikawa, Xavier Daumy, Hiroyuki Mishima, Julien Barc, Ryo Sasaki, Kiyomasa Nishii, Kayoko Saito, Mari Urano, Seiko Ohno, Saki Otsuki, Hiroki Kimoto, Alban-Elouen Baruteau, Aurelie Thollet, Swanny Fouchard, Stéphanie Bonnaud, Philippe Parent, Yosaburo Shibata, Jean-Philippe Perrin, Hervé Le Marec, Nobuhisa Hagiwara, Sandra Mercier, Minoru Horie, Vincent Probst, Koh-Ichiro Yoshiura, Richard Redon, Jean-Jacques Schott, Naomasa Makita
Journal: Journal of the American College of Cardiology (2017)
Abstract B08: Keap1–Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein
Authors: Kuo-Tai Hua, Min-Liang Kuo
Journal: Cancer Research (2016)

Abstract Purpose: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2–related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1–Nrf2 axis in the progression of non-small cell lung cancer (NSCLC). Experimental Design: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1–Nrf2 axis in lung cancer mobility and progression. Results: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival ofNSCLC patients. Moreover,manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100Pwas downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells. Conclusions: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression. Citation Format: Kuo-Tai Hua, Min-Liang Kuo. Keap1–Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B08.
Spark Advances Gene Therapy for Inherited Vision Loss
Authors: Jennifer Abbasi
Journal: JAMA (2017)

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Pancreatic Neuroendocrine Tumor Producing Insulin and Vasopressin
Authors: Omalkhaire M. Alshaikh, Ju-Yoon Yoon, Bryan A. Chan, Monika K. Krzyzanowska, Jagdish Butany, Sylvia L. Asa, Shereen Ezzat
Journal: Endocrine Pathology (2017)
The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall
Authors: Guanghong Jia, Annayya R. Aroor, James R. Sowers
Journal: Cardiovascular Research (2017)

Vascular dysfunction and impaired endothelial mediated relaxation are powerful underlying abnormalities in the pathogenesis of hypertension, coronary heart disease, and stroke. Obesity, type 2 diabetes mellitus, and other metabolic abnormalities are associated with activation of mineralocorticoid receptor (MRs) in the vasculature and adipose tissue. While MR signaling is involved in the normal physiological differentiation and maturation of adipocyte, enhanced activation of MRs also contributes to increase oxidative stress, release of pro-inflammatory adipokines, and dysregulation of adipocyte autophagy. This, in turn, increases the maladaptive expansion of subcutaneous, visceral and perivascular adipose tissue, resulting in systemic and cardiovascular (CV) insulin resistance and increased CV stiffness and impaired vascular and cardiac relaxation. This review summarizes the normal role of MR activation in adipose tissues and explores the mechanisms by which excessive MR activation mediates adipose tissue inflammation and vascular dysfunction. Potential preventative and therapeutic strategies directed in the prevention of MR activation and CV disease are also discussed.
Lifestyle in progression from hypertensive disorders of pregnancy to chronic hypertension in Nurses’ Health Study II: observational cohort study
Authors: Simon Timpka, Jennifer J Stuart, Lauren J Tanz, Eric B Rimm, Paul W Franks, Janet W Rich-Edwards
Journal: BMJ (2017)

Objectives To study the association between lifestyle risk factors and chronic hypertension by history of hypertensive disorders of pregnancy (HDP: gestational hypertension and pre-eclampsia) and investigate the extent to which these risk factors modify the association between HDP and chronic hypertension.Design Prospective cohort study.Setting Nurses' Health Study II (1991-2013).Participants 54 588 parous women aged 32 to 59 years with data on reproductive history and without previous chronic hypertension, stroke, or myocardial infarction.Main outcome measure Chronic hypertension diagnosed by a physician and indicated through nurse participant self report. Multivariable Cox proportional hazards models were used to investigate the development of chronic hypertension contingent on history of HDP and four lifestyle risk factors: post-pregnancy body mass index, physical activity, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, and dietary sodium/potassium intake. Potential effect modification (interaction) between each lifestyle factor and previous HDP was evaluated with the relative excess risk due to interaction.Results 10% (n=5520) of women had a history of HDP at baseline. 13 971 cases of chronic hypertension occurred during 689 988 person years of follow-up. Being overweight or obese was the only lifestyle factor consistently associated with higher risk of chronic hypertension. Higher body mass index, in particular, also increased the risk of chronic hypertension associated with history of HDP (relative excess risk due to interaction P<0.01 for all age strata). For example, in women aged 40-49 years with previous HDP and obesity class I (body mass index 30.0-34.9), 25% (95% confidence interval 12% to 37%) of the risk of chronic hypertension was attributable to a potential effect of obesity that was specific to women with previous HDP. There was no clear evidence of effect modification by physical activity, DASH diet, or sodium/potassium intake on the association between HDP and chronic hypertension.Conclusion This study suggests that the risk of chronic hypertension after HDP might be markedly reduced by adherence to a beneficial lifestyle. Compared with women without a history of HDP, keeping a healthy weight seems to be especially important with such a history.
American Heart Association’s Call to Action for Payment and Delivery System Reform
Authors: Vincent J. Bufalino, Scott A. Berkowitz, Timothy J. Gardner, Ileana L. Piña, Madeleine Konig, Mary Anne Bauman, Michael Barbouche, Mark Creager, Gregg Fonarow, Ray Gibbons, David Meltzer, Neil Meltzer, Lee Schwamm, John Warner
Journal: Circulation (2017)

The healthcare system is undergoing a transition from paying for volume to paying for value. Clinicians, as well as public and private payers, are beginning to implement alternative delivery and payment models, such as the patient-centered medical home, accountable care organizations, and bundled payment arrangements. Implementation of these new models will necessitate delivery system transformation and will actively involve all fields of medical care, in particular medicine and surgery. This call to action, on behalf of the American Heart Association’s Expert Panel on Payment and Delivery System Reform, serves to offer support and direction for further involvement by the American Heart Association. In doing so, it (1) provides baseline review and definition of the present models and some of the early results of these delivery models, including outcomes; (2) initiates a conversation within the American Heart Association on the impact of payment and delivery system reform, as well as how the American Heart Association should engage in the interest of patients; (3) issues a call to action to our organization and to cardiovascular and stroke health professionals across the country to become educated about these models so to as to understand their impact on patient care; and (4) asks the government and other funding agencies, including the American Heart Association, to begin supporting and prioritizing meaningful research endeavors to further evaluate these models.
FDA panel recommends approval of first gene therapy in US
Authors: Owen Dyer
Journal: BMJ (2017)

A 10 member expert panel convened by the US Food and Drug Administration has voted unanimously to recommend approval of a cancer treatment that could transform the survival prospects of young people with refractory leukemia, though at a steep price.

The Novartis treatment, called CTL019, or tisagenlecleucel, is a chimeric antigen receptor T cell (CAR-T) treatment, a class whose career in development has already earned them a name for astronomical cost, alarming side effects, and spectacular results.

In treatment with CTL019 T cells are extracted from a patient’s blood, frozen, and sent to a Novartis plant in New Jersey. There they are genetically modified to hunt and destroy cancer causing B cells, multiplied, refrozen, and shipped …
Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group
Authors: O Al-Sawaf, S Robrecht, J Bahlo, A M Fink, P Cramer, J von Tresckow, C Maurer, M Bergmann, T Seiler, E Lange, M Kneba, S Stilgenbauer, H Döhner, M G Kiehl, U Jäger, C M Wendtner, K Fischer, V Goede, M Hallek, B Eichhorst, G Hopfinger
Journal: Leukemia (2017)
The expression level of HER3 ligand heregulin mRNA as a predictive biomarker for anti-HER3 antibody patritumab combined with erlotinib in non-small cell lung cancer.
Authors: Kimio Yonesaka, Hisato Kawakami, Hiroyasu Kaneda, Isamu Okamoto, Kenji Hirotani, Kazuto Nishio, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2014)

e19082 Background: Human epidermal growth factor receptor 3 (HER3) is activated after it binds with its ligand heregulin (HRG). Patritumab (Pmab), a fully human anti-HER3 antibody, can inhibit the binding of HER3 with HRG. Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a treatment option in patients with non-small cell lung cancer (NSCLC). The biomarker analysis of the randomized phase II HERALD study comparing Pmab + erlotinib vs. erlotinib + placebo showed a significantly longer PFS with Pmab therapy in the higher HRG mRNA group (von Pawel et al, submitted to ASCO2014). We evaluated HRG and HER3 mRNA expression in NSCLC cell lines to further elucidate this potential predictive biomarker for Pmab in NSCLC. Methods: HRG and HER3 mRNA expression were quantified in 50 NSCLC cell lines using RT-PCR. Cell lines were divided into Higher or Lower HRG groups by the median. The sensitivity to each drug was analyzed with the colony formation assay and xenograft study. The efficacy of Pmab, erlotinib and combination was evaluated in PC9Mock with EGFR exon 19 deletion or PC9HRG stably transfected with HRG. Cell signal was analyzed with immune-blotting. Results: HRG and HER3 mRNA expression levels were variable and uncorrelated with each other in the 50 cell lines. Higher HRG cell lines were significantly more sensitive to 100 ug/ml Pmab than lower HRG cell lines in vitro (p=0.002) and in vivo. In contrast HER3 expression level had no correlation with Pmab sensitivity. Specific HRG knockdown with siRNA reduced sensitivity to Pmab in higher HRG cell lines. Further, higher HRG cell lines possessed activated HER3 and Akt, which were reduced with Pmab. Secondary HRG induced erlotinib resistance accompanied with persistent HER3 and Akt activation in PC9HRG (IC50 value for PC9Mock vs PC9HRG; 0.04 vs 10 uM). However Pmab combination could overcome resistance to erlotinib in PC9HRG. Conclusions: HRG mRNA expression correlated with Pmab efficacy and also erlotinib resistance pre-clinically. Combined with the result of the HERALD study, HRG mRNA in tumors was a primarily relevant predictive biomarker for the Pmab combination with erlotinib in NSCLC.