tbuckley/cabot-search huggingface dataset:
High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8
Authors: Ozlem Kucukoglu, Nurdan Guldiken, Yu Chen, Valentyn Usachov, Amin El-Heliebi, Johannes Haybaeck, Helmut Denk, Christian Trautwein, Pavel Strnad
Journal: Hepatology (2014)

Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated keratins 8/18 (K8/K18). MDBs are characteristic of alcoholic and nonalcoholic steatohepatitis (NASH) and discriminate between the relatively benign simple steatosis and the more aggressive NASH. Given the emerging evidence for a genetic predisposition to MDB formation and NASH development in general, we studied whether high-fat (HF) diet triggers MDB formation and liver injury in susceptible animals. Mice were fed a high-fat (HF) or low-fat (LF) diet plus a cofactor for MDB development, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Additionally, we fed nontransgenic and K8 overexpressing mice (K8tg) with the HF diet. The presence of MDB and extent of liver injury was evaluated using biochemical markers, histological staining, and immunofluorescence microscopy. In DDC-fed animals, an HF diet resulted in greater liver injury and up-regulation of inflammation-related genes. As a potential mechanism, K8/K18 accumulation and increased ecto-5'-nucleotidase (CD73) levels were noted. In the genetically susceptible K8tg mice, HF diet triggered hepatocellular injury, ballooning, apoptosis, inflammation, and MDB development by way of 1) decreased expression of the major stress-inducible chaperone Hsp72 with appearance of misfolded keratins; 2) elevated levels of the transglutaminase 2 (TG2); 3) increased K8 phosphorylation at S74 with subsequent TG2-mediated crosslinking of phosphorylated K8; and 4) higher production of the MDB-modifier gene CD73.Our data demonstrate that HF diet triggers aggregate formation and development of liver injury in susceptible individuals through misfolding and crosslinking of excess K8.
Impact of Platelet Reactivity on Clinical Outcomes After Percutaneous Coronary Intervention
Authors: Somjot S. Brar, Jurrien ten Berg, Rossella Marcucci, Matthew J. Price, Marco Valgimigli, Hyo-Soo Kim, Giuseppe Patti, Nicoline J. Breet, Germano DiSciascio, Thomas Cuisset, George Dangas
Journal: Journal of the American College of Cardiology (2011)
<scp>EAARN</scp> score, a predictive score for mortality in patients receiving cardiac resynchronization therapy based on pre‐implantation risk factors
Authors: Malek Khatib, José M. Tolosana, Emilce Trucco, Roger Borràs, Ángeles Castel, Antonio Berruezo, Adelina Doltra, Marta Sitges, Elena Arbelo, Maria Matas, Josep Brugada, Lluís Mont
Journal: European Journal of Heart Failure (2014)

Aims The beneficial effects of CRT in patients with advanced heart failure, wide QRS , and low LVEF have been clearly established. Nevertheless, mortality remains high in some patients. The aims of our study were to identify the predictors of mortality in patients treated with CRT and to design a risk score for mortality. Methods and results A cohort of 608 consecutive patients treated with CRT from 2000 to 2011 in our centre was prospectively analysed. Baseline clinical and echocardiography variables were analysed and mortality data were collected. During a mean follow‐up of 36.2 ± 29.2 months, 174 patients died: 123/174 (71%) due to cardiovascular causes, 25/174 (14%) non‐cardiac causes, and 26/174 (15%) unknown aetiology. In a multivariate analysis the predictors of mortality were NYHA class IV [hazard ratio ( HR ) 2.54, 95% confidence interval ( CI ) 1.7–3.7, P &lt; 0.001], glomerular filtration rate ( GFR ) &lt;60 mL /min/1.73 m 2 ( HR 1.61, 95% CI 1.14–2.30, P = 0.008), AF ( HR 1.67, 95% CI 1.19–2.3, P = 0.01), age ≥70 years ( HR 1.44, (95% CI 1.04–2.00, P = 0.02), and LVEF &lt;22% ( HR 1.83, 95% CI 1.33–2.52, P ≤ 0.001). The EAARN score ( EF , Age, AF , Renal dysfunction, NYHA class IV ) summarizes the predictors. Each additional predictor increased the mortality: one predictor, HR 3.28 (95% CI 1.37–7.8, P = 0.008); two, HR 5.23 (95% CI 2.24–12.10, P &lt; 0.001); three, HR 9.63 (95% CI 4.1–22.60, P &lt; 0.001); and four or more, HR 14.38 (95% CI 5.8–35.65, P &lt; 0.001). Conclusion The predictors of mortality have a significant add‐on predictive effect on mortality. The EAARN score could be useful to stratify the prognosis of CRT patients.
Abstract 13892: Fragmented QRS Activity Representing Inhomogeneous Left Ventricular Conduction on Magnetocardiography Predicts Adverse Outcomes in Patients With LBBB and Left Ventricular Dysfunction
Authors: Yasutaka Oguchi, Hiroshi Takaki, Shuji Hashimoto, Mitsuru Wada, Ikutaro Nakajima, Kohei Ishibashi, Koji Miyamoto, Hideo Okamura, Takashi Noda, Takeshi Aiba, Kengo Kusano, Satoshi Yasuda, Shiro Kamakura, Masaru Sugimachi
Journal: Circulation (2014)

Background: Left bundle branch block (LBBB) is known to be a risk factor in patients with heart failure or structural heart diseases. We have already reported that the fragmented QRS (fQRS) activity on QRS vector magnitude waveform (VMW) derived from high-resolution multi-channel magnetocardiography (MCG) represents heterogeneous left ventricular (LV) activation sequences due to myocardial scar and can predict adverse outcomes in patients with dilated and hypertrophic cardiomyopathy. Therefore, we investigated whether MCG also can predict the outcome of patients with LBBB noninvasively using fQRS. Methods: 64-ch MCG was recorded in 58 patients with LV dysfunction (LVEF&lt;45%) and LBBB (QRS interval ≥120ms). Clinical characteristics, electrocardiographic parameters, and clinical outcomes were compared between patients with and without fQRS on the QRS VMW, which was constructed from 64 superimposed signals during sinus rhythm. The fQRS on MCG was defined as the presence of ≥1 discrete component larger than 20% of the maximum amplitude within QRS complex. Results: The fQRS was identified on MCG in 29 patients (Group-A), but not in the rest of 29 patients (Group-B). Age, Sex, presence of structural heart disease, QRS or QTc interval, fQRS (≥8 spikes in leads I, aVL, V5 and V6) on 12-lead ECG, history of arrhythmias, LVEF, and medications were not different between 2 groups. During the follow-up of 30 ± 23 months, cardiac events (sudden cardiac death, heart failure, hospitalization, and life-threatening arrhythmia) occurred more frequently in the Group-A (17/29, 58.6%) than in the Group-B (3/29, 10.3%; p &lt; 0.0002), although patients with fQRS on ECG showed the similar event rate to those without. Multivariate analysis revealed that the presence of fQRS on MCG was only an independent predictor of poor outcome (p=0.0137). Conclusions: The prognosis of LBBB patients with fQRS on MCG was poor. The fQRS on MCG, which indicates the presence of inhomogeneous LV conduction, can be a reliable marker for predicting adverse outcomes in patients not only with cardiomyopathy but also with LBBB.
Prevalence of heart disease in patients hospitalized for an acute exacerbation of COPD: Impact on clinical outcome. A 6 month follow-up study
Authors: Silvia Fernandez Serrano, Dan Sanchez Berenguer, Jaume Oriol, Ludmila San Vicente, Nuria Galofre, Gemma Beltran, Montse Altimira, Lidia Ortega
Journal: European Respiratory Journal (2011)

Aim: In order to analyze the prevalence of heart disease “HD” (known or not) in patients hospitalized due to an acute exacerbation of COPD, we carried out a prospective study.

Material and methods: A total of 103 patients were prospectively included. Clinical course and outcome were analyzed during a 6-month follow-up.

Assessment of mean length of stay, mortality and hospital readmission was made. ECG, Echocardiography and NTproBNP value were used for the cardiac evaluation.

Results: 103 patients (71.83±9.3 years) were recruited, 81% of them with GOLD stage ≥ 3.

Thirty-seven patients had a HD (a “newly” disease in 14): group FI. The COPD was alone in 63: group FII.

The mean length of stay was 5.74±3.4 days and the in-hospital mortality rate was 2.9%. At 6-month follow-up: the mortality rate was 4.9% and the readmission rate 46.6% (35.5% of early readmission). Between readmitted cases, 56% were in GOLD stage 4.

With regard to the cardiac evaluation, the phisical examination (yugular venous distention: 21.1% vs 4.6%, p=0.017; peripheral edema:31.6% vs 12.3%, p=0.022, pulmonary rales: 18.4% vs 2%, p=0.04), the ECG (28.9% vs 10.8%, p=0.030), the ecocardiography (LVEF   1200 pg/ml: 44.4% vs 13.3%, p=0.003) were more frequent abnormal in the group FI than in the group FII.

Conclusions: 1. The global prevalence of HD in our cohort of patients with an acute exacerbation of COPD was 37%.

2. In this setting, physical examination, an abnormal ECG, an EF  1200pg/mL, could help to identify patients with a probable HD.

3. Fifty-six% of readmissions were patients in GOLD stage IV.
Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile
Authors: M. A. Calderón, F. E. R. Simons, H.‐J. Malling, R. F. Lockey, P. Moingeon, P. Demoly
Journal: Allergy (2011)

Allergen immunotherapy reorients inappropriate immune responses in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical tolerance. Although 40-75% of patients receiving SLIT experience mild, transient local reactions in the oral mucosa, these primary reactions rarely necessitate dose reduction or treatment interruption. We discuss 11 published case reports of anaphylaxis (all nonfatal) diagnosed according to the World Allergy Organization criteria and relate this figure to the approximately 1 billion SLIT doses administered worldwide since 2000. Anaphylaxis risk factors associated with SCIT and/or SLIT should be characterized further.
Hormone therapy and the risk of stroke after acute myocardial infarction in postmenopausal women11A complete listing of registry hospitals is available from STATProbe, Inc., Lexington, Kentucky.
Authors: Brad G. Angeja, Michael G. Shlipak, Alan S. Go, S.Claiborne Johnston, Paul D. Frederick, John G. Canto, Hal V. Barron, Deborah Grady
Journal: Journal of the American College of Cardiology (2001)
CD43 Interacts With Moesin and Ezrin and Regulates Its Redistribution to the Uropods of T Lymphocytes at the Cell-Cell Contacts
Authors: Juan M. Serrador, Marta Nieto, José L. Alonso-Lebrero, Miguel A. del Pozo, Javier Calvo, Heinz Furthmayr, Reinhard Schwartz-Albiez, Francisco Lozano, Roberto González-Amaro, Paloma Sánchez-Mateos, Francisco Sánchez-Madrid
Journal: Blood (1998)
Estimated Glomerular Filtration Rate Calculated By The CKD-EPI Formula Has Improved Prognostic Ability Over MDRD Formula In Patients With Newly Diagnosed, Symptomatic, Multiple Myeloma: Analysis In 1937 Patients
Authors: Meletios A. Dimopoulos, Evangelos Terpos, Argiris S. Symeonidis, Eirini Katodritou, Anastasia Pouli, Sosana Delimpasi, Kostas Konstantopoulos, Michalis Michael, Eleftheria Hatzimichael, Maria Kotsopoulou, Dimitra Gika, Maria Roussou, Stavroula Giannouli, Costas Tsatalas, Efstathios Kastritis
Journal: Blood (2013)
Induction of apoptosis by TLK199 in human leukemia cells
Authors: Mary Stofega, Shu Chi Hsu, Jason Chew, Gail Brown, James Keck, Azra Raza, Danying Cai
Journal: Cancer Research (2008)

2270   TLK199 (ezatiostat hydrochloride) is a novel glutathione analog inhibitor of the enzyme glutathione S-transferase P1-1 (GST P1-1) that is currently under investigation for the treatment of cytopenias due to myelodysplastic syndrome or chemotherapy. GST P1-1 has been shown to negatively regulate JNK activity and decrease cellular reactive oxygen species (ROS) levels. Since both JNK activity and ROS levels have a role in cell proliferation, differentiation and apoptosis, a GST P1-1 inhibitor may modulate these cellular processes. Previously we have reported that TLK199 stimulates colony formation from normal peripheral blood and bone marrow cells at non-cytotoxic doses. In this study, we investigated additional effects of TLK199 on the growth of TF-1 erythroleukemia and HL-60 promyelocytic cells. Treatment with TLK199 in these leukemia cell lines resulted in apoptosis and increase in ROS levels. JNK activation was observed in TF-1 but not HL-60 cells. Consistent with the induction of apoptosis, treatment with TLK199 resulted in cleavage of PARP protein in a dose- and time-dependent manner, indicating the activation of caspase 3. In HL-60 cells, caspase 3 was maximally induced by 40 μM TLK199 in 5.5 hours, and its activation resulted in degradation of anti-apoptotic Mcl-1 protein. Treatment with TLK199 led to a loss of mitochondrial membrane potential and activation of caspase 9, but not caspase 8, suggesting that TLK199 induced the intrinsic apoptotic pathway. In support of the caspase cascade leading to loss of cell viability by TLK199, the pan-caspase inhibitor z-VAD-FMK protected HL-60 cells from undergoing apoptosis in the presence of TLK199 and increased the cytotoxic concentration of TLK199 by 2.5-fold. Microarray analysis of gene expression in TF-1 and HL-60 cells was performed. In both cell lines, TLK199 treatment resulted in the upregulation of several genes involved in the cellular response to ER stress. Consistent with the activation of JNK in TF-1 cells, TLK199 treatment upregulated genes for AP-1 transcription factors such as c- jun . These data indicate that TLK199 induces apoptosis in human leukemia cell lines TF-1 and HL-60 by activation of the caspase cascade and that caspase activation mediates the cytotoxic effects of TLK199.
Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
Authors: Frédérique Bard, Catherine Cannon, Robin Barbour, Rae-Lyn Burke, Dora Games, Henry Grajeda, Teresa Guido, Kang Hu, Jiping Huang, Kelly Johnson-Wood, Karen Khan, Dora Kholodenko, Mike Lee, Ivan Lieberburg, Ruth Motter, Minh Nguyen, Ferdie Soriano, Nicki Vasquez, Kim Weiss, Brent Welch, Peter Seubert, Dale Schenk, Ted Yednock
Journal: Nature Medicine (2000)
Abstract 4210: CPAP contributes to HBx-mediated NF-κB activation in hepatocellular carcinoma
Authors: Liang-Yi Hung
Journal: Cancer Research (2014)

Abstract Hepatocellular carcinoma (HCC) is a type of tumor that results from chronic inflammation triggered by hepatotropic viruses or other toxic chemicals. Constitutive activation of nuclear factor (NF)-κB is an important event involved in chronic inflammation of the liver. The HBV X protein (HBx) is shown to activate NF-κB by inducing phosphorylation of IκBα and decreasing IκBα stability. Centrosomal protein P4.1-associated protein (CPAP), which plays important roles in centrosomal functions, is previously identified as the transcriptional co-activator of NF-κB. Herein, we demonstrate that CPAP can directly interact with HBx to enhance HBx-mediated NF-κB activation. Knockdown expression of CPAP abolishes this effect, indicating that CPAP is required for HBx-mediated NF-κB activation. In addition, HBx cooperates with cyclic adenosine monophosphate response element-binding protein (CREB) to increase the expression of CPAP by up-regulating its promoter activity. Furthermore, overexpression of CPAP enhances the protein stability of HBx. These results suggest that a positive feedback regulation exists between CPAP and HBx. The stable expression of CPAP in HCC cell lines increases cell proliferation. In addition, the co-expression of CPAP and HBx more greatly enhances the cell proliferation ability than either CPAP or HBx alone. Taken together, our study indicates that CPAP can cooperate with HBx and is important for HBx-induced NF-κB activation. Citation Format: Liang-Yi Hung. CPAP contributes to HBx-mediated NF-κB activation in hepatocellular carcinoma. [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 4210. doi:10.1158/1538-7445.AM2014-4210
Abstract MP89: Epidemiology of Ischemic Stroke Subtypes within the Mashhad Stroke Incidence Study (MSIS): A Population-Based Study of Stroke in the Middle East
Authors: Hamidreza Saber, Ashkan Shoamanesh, Mahmoud Reza Azarpazhooh
Journal: Circulation (2015)

BACKGROUND: Incidence and case fatality rates of ischemic stroke subtypes are unknown in the Middle-East due to the lack of community-based incidence stroke studies in this region. AIM: To characterize ischemic stroke subtypes in a Middle Eastern population. Methods: MSIS is a community-based study, that prospectively ascertained all cases of stroke among the 450 229 inhabitants of Mashhad, Iran between 2006-2007. Within this population, we identified 560 cases of first-ever ischemic stroke. Ischemic stroke subtypes were classified according to the modified-TOAST criteria. Incidence rates were age standardized to the European population. The primary outcome of interest was all cause mortality at 1-year follow-up. Results: The proportion of stroke subtypes were distributed as follows: 53% large-artery disease (LAD), 14% cardioembolic, 23% small vessel disease (SVD), 6% undetermined and 5% other. The incidence rates (per 100 000) were 157 for LAD, 34 for cardioembolism, 66 for SVD, 16 for undetermined and 7...
Bone-targeted rapamycin analogs inhibit osteolysis and tumor growth in a PC-3-GFP intratibial bone cancer model in nude mice
Authors: Chester Metcalf, Brendan Boyce, Yan Lu, Lianping Xing, Dong Zou, Mathew Thomas, Brian Lawrence, Raji Sundaramoorthi, Ingrid Chen, Lisi Cai, Victor Rivera, Jeffrey Keats, Narayana Narasimhan, Joseph Snodgrass, Karin Russian, Noel Reid, Frank Wang, Manfred Weigele, Camille Bedrosian, John Iuliucci, Tomi Sawyer, Tim Clackson
Journal: Cancer Research (2006)

1116   mTOR is a PI3K-like kinase that links mitogenic stimuli and nutrient status to cell growth, division and metabolism, and is an important target for anti-tumor therapy. Rapamycin is a natural product mTOR inhibitor that functions by inducing an inhibitory complex between mTOR and FKBP. Rapamycin and its derivatives also have inhibitory effects on osteoclasts and osteoclast cell precursors  in vitro  and in animal models of bone disease. These observations have prompted us to design bone-targeted analogs of rapamycin with the aim of enhancing the anti-tumor and anti-osteoclast effects at bone, for potential use in treating primary bone cancers and bone metastases. Previously we reported on several novel bone-targeted mTOR inhibitors, including AP23841, which demonstrated potent and sustained inhibition of PTH-induced hypercalcemia in mice. In this study, we synthesized a series of optimized analogs of AP23841 and tested them in a mouse model of bone-localized disease. Compounds were synthesized from common, activated rapamycin intermediates and various functionalized bone-targeted groups in good yield and high purity (>98%). Bone-targeted compounds varied according to  in vitro  hydroxyapatite (HA) affinity and linker functionality (e.g., cleavable or non-cleavable). Compounds were also tested for FKBP binding affinity using a fluorescence polarization assay. For  in vivo  testing, PC-3-GFP prostate cancer cells were injected intratibially into nude mice, and anti-tumor and anti-osteolytic effects assessed by GFP imaging, radiology and histology. One compound in particular, AP24170, demonstrated potent inhibitory effects on tumor growth (38% T/C) following 2-3 wks dosing (14 mg/kg iv, QDx5 and weekly) that were similar to rapamycin dosed equivalently (45% T/C). AP24170 also potently inhibited osteolysis in the mice, as scored semi-quantitatively by whole animal radiography with a statistically significant greater reduction in the osteolysis score vs. rapamycin (p
A book that changed me: Our NHS: A celebration of 50 years
Authors: N. Bosanquet
Journal: BMJ (1999)

Ed Gordon Macpherson 

BMJ Books, £25, pp 227

ISBN 0 7279 1279 8

Reviewed BMJ 25 July 1998

For me, this book turned a vague intuition into a focus for action in the future: rarely before can the gulf in the NHS between “top down” aspirations and local experience have been charted with such directness and honesty.

There is a deep contrast in this volume, with its 30 contributions, between the repeated powerful endorsement of the NHS as a national institution and the troubling personal experience of some contributors. The NHS appears as an organisation that has been kept in place by negatives—the blind, even pathetic, loyalty of patients and the desire of politicians to avoid trouble about funding. Much of the personal experience has been highly disquieting, and the BMA itself appears as …