tbuckley/cabot-search huggingface dataset:
Multicycle Dose-Intensive Chemotherapy for Women With High-Risk Primary Breast Cancer: Results of International Breast Cancer Study Group Trial 15-95
Authors: Russell L Basser, Anne O'Neill, Giovanni Martinelli, Michael D Green, Fedro Peccatori, Saverio Cinieri, Alan S Coates, Richard D Gelber, Stefan Aebi, Monica Castiglione-Gertsch, Guiseppe Viale, Karen N Price, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2006)

To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes.Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS).After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC.There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.
Rapid increase in gonorrhoea and syphilis diagnoses in England in 2011
Authors: E  J Savage, K Marsh, S Duffell, C A Ison, A Zaman, G Hughes
Journal: Eurosurveillance (2012)

There has been a rapid rise in the number of gonorrhoea and syphilis diagnoses in England during 2011, an increase of 25% and 10% respectively. Large increases of both gonorrhoea (61%) and syphilis (28%) were observed among men who have sex with men. Although these rises can partly be attributed to increased testing, ongoing high-levels of unsafe sexual behaviour probably contributed to the rise. The rise in gonorrhoea rates is worrying in an era of decreased susceptibility to treatments.
Abstract 17052: Cardiac Specific mRFP-GFP-LC3 Transgenic Mice Are a Useful Tool to Evaluate Autophagic Flux in vivo
Authors: Nirmala Hariharan, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation (2010)

Autophagy mediates bulk protein degradation by the formation of autophagosomes (APs) followed by lysosomal degradation. Transgenic mice (Tg) expressing GFP-LC3 are useful for evaluating AP formatio...
Abstract 2961: CCN2/CTGF - Connective Tissue Growth Factor - Reduces {beta}-Adrenergic Receptor Responsiveness and Catecholamine-Induced Cardiotoxicity by Upregulation of Cardiac Myocyte G Protein-Coupled Receptor Kinase-5
Authors: Jorgen A Gravning, Mohammed S Ahmed, Eirik Qvigstad, Julia F Sagave, Kurt A Krobert, Thor Edvardsen, Guro Valen, Tor Skomedal, Jan-Bjorn Osnes, Havard Attramadal
Journal: Circulation (2009)

Background: Myocardial CTGF is dramatically induced in CHF, a condition associated with diminution of β-adrenergic receptor (βAR) responsiveness. Accordingly, we aimed to investigate if CTGF is mec...
Abstract 177: Regional Cerebral Oxygen Saturation as a Novel Termination of Resuscitation Rule in Cases of Refractory Out-of-Hospital Cardiac Arrest
Authors: Noritoshi Ito, Shinsuke Nanto, Ken Nagao, Tetsuo Hatanaka, Kei Nishiyama, Yasuji Doi, Yuma Kurozumi, Tomoaki Natsukawa, Masaya Morita, Atsushi Kawata, Ayumu Tsuruoka, Hirotaka Sawano, Hiroyuki Shibata, Noriaki Yamada, Ken-ichiro Okada, Yasuyuki Hayashi, Tatsuro Kai, Toru Hayashi
Journal: Circulation (2011)

Background: To better utilize medical resources, basic life support (BLS) and advanced life support (ALS) pre-hospital termination-of-resuscitation (TOR) rules have been developed, validated, and implemented in North America. Recently, “regional cerebral oxygen saturation (rSO2) ≤15%”, as no detectable cortical oxygen value (N-value), has been considered to be a strong predictor of poor neurological outcome in patients with out-of-hospital cardiac arrest (OHCA). Objective: To assess the impact of the N-value as a novel TOR rule. Method: This study was a prospective cohort study. Of 418 OHCA patients, 186 consecutive non-traumatic, cardiac arrest on arrival (CAOA) patients were prospectively registered. The rSO2 were measured with sensors placed on either side of their forehead using a near-infrared spectroscopy (NIRS) device (INVOS, Covidien, US) immediately on hospital arrival. We monitored rSO2 values at least for more than one minute and used the lower of the 2 measured rSO2 values for analysis. Clinical staff performed ordinary post-cardiac-arrest interventions (PCAIs) regardless of rSO2 values. Primary outcome measure was good neurological outcome (CPC =&lt;2) at hospital discharge according to the “Utstein-style”. We calculated the specificity and positive predictive value (PPV) of N-value TOR rule and BLS/ALS TOR rules for identifying CAOA patients without good neurological outcome. Results: Among 186 CAOA patients in the PCAIs era, 18 patients (9.7%) had good neurological outcome at hospital discharge, and the specificity and PPV of N-value, BLS and ALS TOR rules were high. However, N-value TOR rule had relatively high specificity and PPV compared with BLS TOR rule and relatively high sensitivity compared with ALS TOR rule. In addition, NIRS provides non-invasive and objective rSO2 values immediately. Conclusion: The N-value TOR rule may be of considerable help to make decisions to cease futile resuscitative efforts in CAOA patients after OHCA.
Abstract 17: Preconditioning With Whole Body Periodic Acceleration (pGz) is Neuroprotective in Model of Asphyxial Cardiac Arrest in Rats.
Authors: Jose A Adams, Arkady Uryash, Anna Pastuszko, Jorge Bassuk, David F Wilson, Robert A Berg, Paul Kurlansky, Vinay Nadkarni
Journal: Circulation (2010)
Abstract 5946: Ntprobnp Guided Treatment for Chronic Heart Failure: Results from the Battlescarred Trial
Authors: A Mark Richards, John G Lainchbury, Richard W Troughton, Kim Strangman, Christopher M Frampton, Anna Pilbrow, Tim G Yandle, Amjad Hamid, M Gary Nicholls
Journal: Circulation (2008)

Three hundred and sixty four (364) patients satisfying Framingham and ESC criteria for symptomatic heart failure were randomized 1:1:1 (with prospective sub-stratification according to age ≤ or &gt; 75 years) to Usual Care (UC), Intensive Clinical Management (CC) or Hormone Guided Care (HGC) incorporating serial measurement of NTproBNP levels into the treatment algorithm. The 3 treatment strategies were applied for 2 years. Minimum follow-up was 12 months with median follow-up 2.8 years. The primary end-points were all-cause mortality and death+/− admission with decompensated Heart Failure (HF). Groups were matched for age (median 76–77years); LVEF (37%) and baseline NTproBNP (medians 235–239 pmol/L ie 1997–2021 pg/ml). All-cause mortality at 12 months was halved by both intensive strategies (18.9, 9.1 and 9.1% respectively for UC, CC and HGC respectively; (P=0.028 overall and P=0.029 for pairwise (UC vs CC and UC vs HGC) intergroup comparisons). At 2 and 3 years follow-up mortality rates did not differ overall but significant treatment effects were observed in those aged ≤75years (P&lt;0.025 for interaction between age and management strategy at all time points). At 1, 2 and 3 years, in those ≤ 75 years, cumulative all-cause mortality was 1.7, 7.3 and 15.5% in HGC; 7.3, 20.0, and 30.9% in CC and 20.3, 23.4 and 31.3% in UC. HGC significantly reduced cumulative mortality below that in UC throughout follow-up (P=0.001 and P=0.021 at 1 and 3 years respectively) and also below that in CC by 3 years follow-up (P=0.048) whereas CC conferred no advantage over UC after one year of follow-up (P=0.04 and ns at 1 and 3 years respectively). The composite end-point of death+/− admission with HF was reduced only in younger patients receiving HGC (P&lt;0.05 at 1, 2 and 3 years follow-up compared with UC). Total days “alive and not in hospital with HF” over 3 years of follow-up, averaged 206 days more in this subgroup than in their peers within the UC group (P&lt;0.05). No benefits were observed in those aged &gt; 75 years. Intensive management of chronic HF reduces one-year mortality compared to usual care. Over long-term follow-up hormone guided therapy may offer an additional mortality advantage over otherwise similarly intensive specialist clinic-based care particularly in those aged ≤ 75 years.
Abstract 1452: Mutation of a SWI/SNF-associated Protein Leads to Massive Cardiac Hyperplasia in the Zebrafish Mutant <i>heart of stone</i>
Authors: Tillman Dahme, Steffen Just, David Hassel, Benjamin Meder, Hugo A Katus, Wolfgang Rottbauer
Journal: Circulation (2008)

Mature cardiac myocytes are considered postmitotic. The process, how cardiac precursors lose the ability to proliferate is unknown. The identification of factors that control the proliferative potential of cardiac myocytes would be an important step towards unraveling the process and ultimately to overcome it for therapeutic purposes. The zebrafish is an intriguing model organism for this objective, because zebrafish cardiac myocytes retain the ability to proliferate and therefore to regenerate cardiac injuries. In a forward genetics screen in zebrafisch, we have isolated the recessive, embryonically lethal mutant heart of stone ( hst HJ163 ). Hearts of hst -mutant zebrafish are characterized by wall-thickening of the cardiac ventricles up to almost complete obliteration of the ventricular lumen. Histology revealed massive hyperplasia of ventricular cardiac myocytes. Hyperplasia is caused by an increase in cardiomyocyte proliferation. By positional cloning we narrowed down the heart of stone locus to one gene, which encodes an evolutionary highly conserved SWI/SNF-associated protein, known to be involved in transcriptional regulation. Sequencing of cDNA and genomic DNA identified a splice donor-site mutation leading to intron-integration with premature termination of protein translation in hst -mutant zebrafish. Injection of wildtype mRNA into hst -mutant embryos fully rescues the mutant phenotype, while injection of morpholino-modified antisense oligonucleotides directed against hst -transcripts copies the hst phenotype, demonstrating the causality of the identified mutation. In order to define how the mutation of a SWI/SNF-associated protein causes hyperplasia of cardiac myocytes we conducted yeast-two-hybrid screens with a cardiac cDNA-library and the human homologue of hst as a bait. Surprisingly, we identified several sarcomeric proteins such as troponin T and α-actinin as robust interactors. By immunofluorescence staining we indeed found distinct nuclear and sarcomeric pools of the hst homologue in rat heart sections. It appears, that this SWI/SNF-associated protein shuttles between the sarcomere and the nucleus in order to transmit proliferative signals from the contractile apparatus to the transcriptional machinery.
Reply
Authors: James E. Everhart, Constance E. Ruhl
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN276201200161U). We thank Zhao et al. for their interest in our article.1 They make two points. The first is that patients with hepatic decompensation or cirrhosis are at increased risk of diabetes. This relationship is well known and bears no relevance to our findings and conclusions in the general healthy U.S. population. The second point is that factors that we did not consider might have affected the outcomes of our analyses. They offer no hypotheses in this regard, but do point to a published report that found an association of hepatitis C virus (HCV) infection and diabetes that was revealed in multivariate analysis only when controlling for blood cholesterol and triglyceride concentrations.2 No biological reason was suggested for this finding. Nevertheless, we have now considered serum triglyceride and cholesterol concentrations in the main analysis of our article that demonstrated strong relationships of elevated alanine aminotransferase (ALT) and gamma‐glutamyl transferase (GGT) activities with diabetes that were independent of HCV infection (Fig. 2 of the article). Table 1 shows the multivariate odds ratios (ORs) for ALT and anti‐HCV with diabetes when controlling for fasting serum triglyceride and cholesterol concentrations as well as the other cofactors originally considered (age, sex, race/ethnicity, education, body mass index, elevated C‐reactive protein, smoking, alcohol use, and blood transfusion before 1992). As in the published article, an association of elevated ALT was found with diabetes regardless of anti‐HCV status. For study participants with normal ALT activity, there was no association of anti‐HCV and diabetes. Results were similar for ALT with prediabetes, GGT with diabetes and prediabetes, and when HCV RNA status was considered. Table 1 - Multivariate‐Adjusted ORs for Diabetes by HCV and ALT Status Normal ALT Elevated ALT OR 95% CI P Value OR 95% CI P Value HCV negative 1.0 — — 1.84 1.41‐2.40 <0.001 Anti‐HCV positive 0.70 0.30‐1.63 0.41 2.62 1.15‐5.97 <0.001 Abbreviation: CI, confidence interval.
Stimulation of the HER-kinase axis promotes resistance to the Raf-kinase activity of sorafenib, which can be reversed by the addition of MEK inhibitor U0126
Authors: Anjali Jain, Michael Hedvat, Schmidt Joanna, David Agus
Journal: Cancer Research (2007)

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

5412 

The multi-kinase inhibitor, BAY 43-9006 (sorafenib), was originally discovered in a high throughput kinase screen as a potent inhibitor of the Raf-MEK-MAPK pathway (IC50 for B-Raf: 22±6 nM; Raf-1: 6±3 nM). Despite its high affinity for the Raf-kinases, sorafenib does not efficiently block the Raf-kinases in in vivo model systems. Fortuitously, sorafenib also inhibits the VEGF receptors, which increased its clinical utility and subsequent FDA approval for renal carcinoma. However, the question still remains with respect to the efficient in vivo targeting of Raf-kinases, which lie at a critical junction of several interacting kinase networks in cancer cells.

Utilizing sorafenib’s effect on Raf-kinase activity as a molecular readout in in vitro kinase assays, we demonstrate that a ligand-stimulated HER-kinase axis compromises inhibition of the Raf-kinase activity by sorafenib in several cancer cell lines. An active HER-kinase axis works via the Raf-MEK-MAPK pathway and is commonly recognized as an initiator of cellular proliferation in several solid tumors. In contrast, sorafenib blocked the Raf-kinases more efficiently in the absence of HER-kinase specific stimulation. These differences are also observed when evaluating the downstream effectors, i.e., phospho-MEK and phospho-MAPK in western blots. However, combination with a MEK1/2-specific inhibitor, U0126, boosts HER-kinase stimulated, sorafenib-specific inhibition on phospho-MAPK. These results indicate that in vivo Raf-inhibition by sorafenib may exclude MEK1/2 inhibition, thus allowing the cells to continue to proliferate. To conclusively address if active MEK-kinases are the reason for inefficient sorafenib activity, experiments combining MEK1/2-specific siRNA knockdown followed by sorafenib treatment are being performed. Further studies are warranted for delineating the components of the Raf pathway targeted by sorafenib. Nonetheless, results from our study provide justification for efficient combination of Raf and MEK inhibitors and a molecular framework for the efficient design of future Raf-kinase inhibitors.
Abstract 59: Miniaturized Mechanical Chest Compressor for Cardiopulmonary Resuscitation
Authors: Shijie Sun, Wei Chen, Yinlun Weng, Xiaobo Wu, Sen Ye, Max H Weil, Wanchun Tang
Journal: Circulation (2011)

After cardiac arrest, effective and uninterrupted chest compression provides blood flow to the vital organs and improves the success of CPR. In this study, we investigated the hemodynamic efficacy of a newly developed pneumatically driven miniaturized mechanical chest compressor (MCC) in a porcine model of cardiopulmonary resuscitation (CPR). Our hypothesis was that because of the design of the MCC, it should produce better hemodynamic efficacy with lesser compression depth. Ventricular fibrillation (VF) was induced in domestic pigs weighing between 35 and 36 kg. CPR was initiated after 7 minutes of untreated VF. Animals were randomized to receive mechanical chest compression with either the MCC or the conventional device (Thumper). Both devices provided the same compression rate of 100/min. The initial compression depth was adjusted to achieve a coronary perfusion pressure (CPP) above 12 mm Hg. After 5 minutes of CPR, a single 150J defibrillation (DF) was delivered. If resuscitation was not successful, CPR was continued for 2 minutes before the next DF. The protocol was continued until successful resuscitation or for a total of 15 minutes. All animals were resuscitated except 1 from the Thumper group. During CPR, significantly greater CPP with lesser compression depth was observed in the MCC group (Table). Significantly greater intrathoracic positive (31±6 vs 10±7 mm Hg, p&lt;0.01) and negative pressures (-10±3 vs -3±2 mm Hg, p&lt;0.01) were observed in MCC treated animals. Significantly shorter durations of CPR (5±0 vs 11±4 min, p&lt;0.05) and lesser numbers of DF (1±0 vs 9.8±11, p&lt;0.05) that were required for achieving successful resuscitation were observed in animals treated with MCC. None of the MCC treated animals had rib fracture compared with the Thumper group with an average of 2.75±1.9 rib fractures (p&lt;0.05). MCC substantially improved hemodynamic efficacy and successful of CPR with significantly less injury.
Abstract 809: Greater Fluid Retention is Associated with Increased Cardiovascular Mortality in Different Groups of CKD Patients on Hemodialysis
Authors: Kamyar Kalantar-Zadeh, Deborah L Regidor, Csaba P Kovesdy, Suphamai Bunnapradist, David Van Wyck, Tamara B Horwich, Gregg C Fonarow
Journal: Circulation (2008)

Patients with chronic kidney disease (CKD) who undergo hemodialysis (HD) treatment have striking similarities to heart failure (HF) patients, in that both populations retain fluid frequently, have excessively high mortality, and exhibit an obesity paradox. We hypothesized that in HD patients greater interdialytic fluid retention is associated with poor cardiovascular (CV) survival. We examined the 2-year (7/01– 6/03) mortality in 34,003 MHD patients across the United States, who had an average weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent HD treatment started. The 3-month average interdialytic weight gain was dichotomized into two categories of 0.5 to 2.0 kg (reference) and &gt;=2.0 kg. After multivariate adjustment for demographics (case-mix) and laboratory surrogates of malnutrition and inflammation, higher weight gain &gt;=2.0 kg was significantly associated with increased death risk in most subgroups of patients particularly among Blacks (death hazard ratio [HD] and 95% confidence interval [CI]: 1.10 [1.01–1.20]), non-diabetics (1.07 [1.01–1.14]), those with 3 to 6 months on dialysis (1.23 [1.14–1.33]) and between 6 months and 2 years on dialysis (1.20 [1.09–1.33]), and those with albumin &gt;3.8 g/dL (1.08 [1.01–1.18]) (see Figure ): In MHD patients greater fluid retention of 2 kg or higher between two consecutive HD treatment sessions appears associated with higher death risk particularly among Blacks, non-diabetics, those with less than 2 years of HD treatment, and those with better nutritional status. The mechanisms by which fluid retention influences survival in HD may be similar to HF patients and warrants further research. This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada &amp; Utah).
Abstract 15088: Multiple Biomarker Panels for Risk Assessment of Cardiocerebrovascular Events and Mortality after Elective Percutaneous Coronary Intervention with Drug-Eluting Stents
Authors: Eiryu Sai, Kazunori Shimada, Katsumi Miyauchi, Yoshiyuki Masaki, Takahiko Kojima, Ken Yokoyama, Akihisa Nishino, Tadashi Miyazaki, Takeshi Kurata, Manabu Ogita, Shuta Tsuboi, Yoshifumi Fukushima, Maeng-Kyu Kim, Hiromichi Ohsaka, Kosuke Fukao, Kuniaki Hirose, Tetsuro Miyazaki, Hirotoshi Ohmura, Akimichi Ohsaka, Hiroyuki Daida
Journal: Circulation (2011)

Background: Numerous biomarkers have been introduced to improve risk stratification for cardiovascular diseases. The purpose of this study is to assess the hypothesis that multiple biomarker panels...
Abstract 2495: Sinus Rhythm R-wave Amplitude Does Not Predict Undersensing of Ventricular Fibrillation by Implantable Cardioverter-Defibrillators
Authors: Linda L Ruetz, Jodi L Koehler, Troy E Jackson, Paul Belk
Journal: Circulation (2009)

Background: Ventricular fibrillation (VF) is induced at implantable cardioverter-defibrillator (ICD) implants to test VF sensing and defibrillation. Based on limited data from several publications,...
Are brief interventions to increase physical activity cost-effective? A systematic review
Authors: Vijay GC, Edward CF Wilson, Marc Suhrcke, Wendy Hardeman, Stephen Sutton
Journal: British Journal of Sports Medicine (2015)

To determine whether brief interventions promoting physical activity are cost-effective in primary care or community settings.Systematic review of economic evaluations.We searched MEDLINE, EMBASE, PsycINFO, CINAHL, EconLit, SPORTDiscus, PEDro, the Cochrane library, National Health Service Economic Evaluation Database and the Cost-Effectiveness Analysis Registry up to 20 August 2014. Web of Knowledge was used for cross-reference search. We included studies investigating the cost-effectiveness of brief interventions, as defined by National Institute for Health and Care Excellence, promoting physical activity in primary care or the community. Methodological quality was assessed using Drummond's checklist for economic evaluations. Data were extracted from individual studies fulfilling selection criteria using a standardised pro forma. Comparisons of cost-effectiveness and cost-utility ratios were made between studies.Of 1840 identified publications, 13 studies fulfilled the inclusion criteria describing 14 brief interventions. Studies varied widely in the methods used, such as the perspective of economic analysis, intervention effects and outcome measures. The incremental cost of moving an inactive person to an active state, estimated for eight studies, ranged from £96 to £986. The cost-utility was estimated in nine studies compared with usual care and varied from £57 to £14 002 per quality-adjusted life year; dominant to £6500 per disability-adjusted life year; and £15 873 per life years gained.Brief interventions promoting physical activity in primary care and the community are likely to be inexpensive compared with usual care. Given the commonly accepted thresholds, they appear to be cost-effective on the whole, although there is notable variation between studies.