tbuckley/cabot-search huggingface dataset:
Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy
Authors: Alain Hendlisz, Marc Van den Eynde, Marc Peeters, Geert Maleux, Bieke Lambert, Jaarke Vannoote, Katrien De Keukeleire, Chris Verslype, Luc Defreyne, Eric Van Cutsem, Philippe Delatte, Thierry Delaunoit, Nicola Personeni, Marianne Paesmans, Jean-Luc Van Laethem, Patrick Flamen
Journal: Journal of Clinical Oncology (2010)

Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the beta-emitting isotope yttrium-90 ((90)Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues.We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A.Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80).Radioembolization with (90)Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.
[550] A NON-INVASIVE 13C METHACETIN BREATH TEST ACCURATELY DETECTS LIVER FIBROSIS IN PATIENTS WITH CHRONIC HCV INFECTION OR NON ALCOHOLIC FATTY LIVER DISEASE
Authors: G. Lalazar, M. Braun, Z. Ben-Ari, B. Mullhaupt, O. Goetze, O. Pappo, M. Margalit
Journal: Journal of Hepatology (2007)
Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1
Authors: K. Satoh, Y. Fukumoto, M. Nakano, K. Sugimura, J. Nawata, J. Demachi, A. Karibe, Y. Kagaya, N. Ishii, K. Sugamura, H. Shimokawa
Journal: Cardiovascular Research (2008)

Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved.Chronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin.These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.
Comparison of cattle and sheep colonic permeabilities to horseradish peroxidase and hamster scrapie prion protein in vitro
Authors: A T McKie, P S Zammit, R J Naftalin
Journal: Gut (1999)

<h3>BACKGROUND</h3> Paracellular permeability to solutes across the descending colon is much higher in cattle than sheep. This is a possible route for transmission of infective materials, such as scrapie prion. <h3>AIMS</h3> To compare the permeabilities of labelled scrapie prion protein and other macromolecules in bovine and ovine descending colons in vitro. <h3>METHODS</h3> Using fresh slaughterhouse material, transepithelial fluxes of macromolecules across colonic mucosae mounted in Ussing chambers were measured by monitoring transport of either enzyme activity or radioactivity. <h3>RESULTS</h3> The comparative bovine to ovine permeability ratio of the probes increased with molecular weight: from 3.1 (0.13) for PEG400 to 10.67 (0.20) (p&lt;0.001) for PEG4000; and from 1.64 (0.17) for microperoxidase to 7.03 (0.20) (p&lt;0.001) for horseradish peroxidase (HRP). The permeability of<sup>125</sup>I-labelled inactivated Syrian hamster scrapie prion protein (ShaPrP<sup>sc</sup>) was 7.02 (0.33)-fold higher in bovine than ovine colon (p&lt;0.0025). In each species, the probe permeabilities decreased according to the formula: P = P<sub>o</sub>.exp(−K.ra). The "ideal" permeabilities, P<sub>o</sub> are similar, however, K<sub>(ovine)</sub> = 2.46 (0.20) cm/h/nm exceeds K<sub>(bovine)</sub> = 0.85 (0.15) cm/h/nm (p&lt;0.001) indicating that bovine colon has a higher proportion of wide pores than ovine. Image analysis confirmed that HRP permeated through the bovine mucosal layer via a pericryptal paracellular route much more rapidly than in sheep. <h3>CONCLUSIONS</h3> These data may imply that scrapie prion is transmitted in vivo more easily across the low resistance bovine colonic barrier than in other species.
Re: Granulocyte-Macrophage Colony-Stimulating Factor Gene-Modified Autologous Tumor Vaccines in Non-Small-Cell Lung Cancer
Authors: K. Altundag, O. Altundag, M. Cengiz, M. Gunduz, Y. Ozisik
Journal: JNCI Journal of the National Cancer Institute (2004)

Nemunaitis et al. (1) in their phase I/II study evaluated the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector to secrete human granulocyte–macrophage colony-stimulating factor (GMCSF) in patients with early and advanced stage non–small-cell lung cancer. They found that three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and 22 months). This exciting result may be related to activity of GM-CSF on recently defined cells termed “cancer stem cells.” There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. The unclear point is which clonogenic cells within the tumor clone possess tumorinitiating cell function and are capable of maintaining tumor growth (2). Stem cells have the ability to divide almost indefinitely. The division can give rise to a new stem cell as well as to differentiated cells of the tumor. These cancer stem cells, which have not been characterized totally, may carry almost the same as antigens hematopoietic stem cells. GM-CSF may activate and repopulate these stem cells in addition to stimulating blood stem cells. Thus, differentiated cancer cells may become more antigenic for host as in the patients with a diagnosis of bronchoalveoalar carcinoma. Activated cancer stem cells also become chemosensitive to various cellcycle-specific chemotherapeutic agents. Therefore, use of GM-CSF with chemotherapy in practice may result in better outcome in epithelial cancers.
The Pharmacology of ATP-Sensitive Potassium Channels
Authors: G Edwards, A H Weston
Journal: The Annual Review of Pharmacology and Toxicology (1993)

A potassium (K) channel that was inhibited by physiological (f1M) concen­ trations of intracellular ATP ([ATP]i) and that opened as [ATP]i decreased was first described in the heart ( l). Subsequently, similar K -channels all with unitary conductances in the range of 40-80 pS (measured under symmetrical high K+ conditions) were also found to exist in insulin-secreting cells and in skeletal muscle (2_5).1 Such channels constitute what are classically described as ATP-sensitive K-channels and were termed Type 1 by Ashcroft & Ashcroft (6). In this review they are designated KATP and the current flowing through them is defined as IK(ATP) . Type 1 KATP channels are essentially calciumand voltage-independent, K+ -selective, and are half-maximally inhibited by [ATP]i in the range 10-100 fJ.M. They exhibit inward rectification and a key pharmacological feature is their inhibition by agents like tolbutamide and glyburide . Other ATP-sensitive K-channels exist and these were designated Types 2, 3, 4, and 5 (6). Such channels vary not only in their sensitivity to calcium and to the inhibitory effects of [ATP]i, but also in their selectivity for potassium and their susceptibility to pharmacological modulation.
Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial
Authors: Bryan H Burmeister, B Mark Smithers, Val Gebski, Lara Fitzgerald, R John Simes, Peter Devitt, Stephen Ackland, David C Gotley, David Joseph, Jeremy Millar, John North, Euan T Walpole, James W Denham
Journal: The Lancet Oncology (2005)
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
Authors: Benjamin J. Thompson, Silvia Buonamici, Maria Luisa Sulis, Teresa Palomero, Tomas Vilimas, Giuseppe Basso, Adolfo Ferrando, Iannis Aifantis
Journal: The Journal of Experimental Medicine (2007)

Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1–FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to γ-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.
Myofibroblasts Induce Ectopic Activity in Cardiac Tissue
Authors: Michele Miragoli, Nicolò Salvarani, Stephan Rohr
Journal: Circulation Research (2007)

Focal ectopic activity in cardiac tissue is a key factor in the initiation and perpetuation of tachyarrhythmias. Because myofibroblasts as present in fibrotic remodeled myocardia and infarct scars depolarize cardiomyocytes by heterocellular electrotonic interactions via gap junctions in vitro, we investigated using strands of cultured ventricular cardiomyocytes coated with myofibroblasts, whether this interaction might give rise to depolarization-induced abnormal automaticity. Whereas uncoated cardiomyocyte strands were invariably quiescent, myofibroblasts induced synchronized spontaneous activity in a density dependent manner. Activations appeared at spatial myofibroblast densities >15.7% and involved more than 80% of the preparations at myofibroblast densities of 50%. Spontaneous activity was based on depolarization-induced automaticity as evidenced by: (1) suppression of activity by the sarcolemmal K(ATP) channel opener P-1075; (2) induction of activity in current-clamped single cardiomyocytes undergoing depolarization to potentials similar to those induced by myofibroblasts in cardiomyocyte strands; and (3) induction of spontaneous activity in cardiomyocyte strands coated with connexin 43 transfected Hela cells but not with communication deficient HeLa wild-type cells. Apart from unveiling the mechanism underlying the hallmark of monolayer cultures of cardiomyocytes, ie, spontaneous electromechanical activity, these findings open the perspective that myofibroblasts present in structurally remodeled myocardia following pressure overload and infarction might contribute to arrhythmogenesis by induction of ectopic activity.
The Pathogenesis of Sepsis
Authors: Deborah J. Stearns-Kurosawa, Marcin F. Osuchowski, Catherine Valentine, Shinichiro Kurosawa, Daniel G. Remick
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Sepsis is a serious clinical condition that represents a patient's response to a severe infection and has a very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions. In an ideal scenario, the first pathogen contact with the inflammatory system should eliminate the microbe and quickly return the host to homeostasis. The septic response may accelerate due to continued activation of neutrophils and macrophages/monocytes. Upregulation of lymphocyte costimulatory molecules and rapid lymphocyte apoptosis, delayed apoptosis of neutrophils, and enhanced necrosis of cells/tissues also contribute to the pathogenesis of sepsis. The coagulation system is closely tied to the inflammatory response, with cross talk between the two systems driving the dysregulated response. Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.
Developing a System to Assess the Quality of Cancer Care: ASCO's National Initiative on Cancer Care Quality
Authors: Eric C. Schneider, Arnold M. Epstein, Jennifer L. Malin, Katherine L. Kahn, Ezekiel J. Emanuel
Journal: Journal of Clinical Oncology (2004)

2][3][4][5][6][7] In a 1999 report, the Institute of Medicine (IOM) concluded that many patients with cancer did not receive state-of-the-art care. 8The IOM committee recommended a number of steps including the creation of a quality monitoring system capable of regularly reporting on the quality of care for patients with cancer.Oncologists might find the IOM recommendation surprising.Efforts to monitor the care and outcomes of oncology patients date back at least to 1922, when the American College of Surgeons (ACS) founded its Commission on Cancer-a group specifically tasked with standardizing and improving the quality of cancer care. 9The Commission's National Cancer Data Base (NCDB) has provided useful data about the epidemiology of cancer and treatment patterns. 10Furthermore, oncology trials have led the way in assessment of patient outcomes such as health status and quality of life; the results from these trials have improved treatments, survival, and the quality of life for many patients with cancer.2][13][14][15][16] Accumulating evidence suggests that "underuse" and "overuse" of care may occur for patients with cancer. 17-19Also, compared with the outcomes of patients in clinical trials, the outcomes of treatment for the general population of patients with cancer may be less favorable.
Enhancing the efficacy of the 20 m multistage shuttle run test
Authors: A D Flouris, G S Metsios, Y Koutedakis
Journal: British Journal of Sports Medicine (2005)

Objective: Maximal oxygen uptake (Vo 2max ) of 44 ml kg −1 min −1 is an accepted criterion (Vo 2CR ) below which health and fitness for young male adults may be compromised. New algorithms validated for Vo 2CR screening using the 20 m multistage shuttle run test (20mMST) were developed. Methods: Vo 2max was assessed in 110 males using a stationary gas analyser in a treadmill test (TT) and in 40 of these subjects using a portable gas analyser in the 20mMST. Vo 2max predicted from the 20mMST in 70 subjects was used for cross validation. Two equations predicting Vo 2max during 20mMST (EQ MST ) and TT (EQ TT ) were developed. Results: Significant energy cost variance (EC V ) was detected between TT and 20mMST (p&lt;0.001), correlated significantly with subject height, and was a significant predictor of Vo 2max differences between TT and 20mMST. The r 2 of EQ MST was 0.92 (p&lt;0.001). Predicted Vo 2max values from EQ MST correlated with directly measured 20mMST Vo 2max at r = 0.96 (p&lt;0.001). ANOVA detected no mean difference (p&gt;0.05) between predicted and measured values. Prevalence of low fitness based on Vo 2CR was 0.37. McNemar χ 2 indicated significant differences in sensitivity (p&lt;0.001) and specificity (p&lt;0.05) between the original 20mMST equation (EQ LÉG ) and EQ TT , regarding Vo 2CR screening. Cohen’s κ demonstrated higher agreement with TT Vo 2max for EQ TT (p&lt;0.001) than EQ LÉG (p&lt;0.05). TT Vo 2max correlated with the end result of both EQ LÉG and EQ TT at r = 0.75 (p&lt;0.001). Unlike EQ TT (p&gt;0.05), mean predicted Vo 2max from EQ LÉG was significantly higher compared to TT Vo 2max (p&lt;0.001). Conclusion: These algorithms increase the efficacy of 20mMST to accurately evaluate aspects of health and fitness.
Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure
Authors: Y Shi
Journal: Cardiovascular Research (2002)

Atrial remodeling contributes to the maintenance of atrial fibrillation (AF) in several cardiac disorders. There is evidence that angiotensin-converting enzyme (ACE) inhibitors reduce the prevalence of AF in patients with congestive heart failure (CHF). There have been no studies performed to assess the effects of ACE inhibitors on atrial dimensions and emptying function in relationship to vulnerability to AF in the setting of experimental CHF.CHF was produced in 20 dogs by rapid right ventricular pacing during 5 weeks. The dogs were randomized to enalapril (EN) therapy (2 mg/kg/day, n=10) or to a control group (n=10). Echocardiography was performed at baseline and weekly thereafter. At the 5-week electrophysiological study, AF was induced by burst pacing and AF duration was measured.Atrial areas increased significantly with CHF. Left atrial (LA) fractional area shortening (FAS) decreased by 42% (P=0.0001) in controls but by 9% (P=NS) in the EN group (P=0.01, EN vs. controls). Similar findings were observed for right atrial (RA) changes (P=0.02). Atrial fibrosis was highly correlated with the decrease in LA FAS (r=0.85, P<0.01) and was reduced by EN (from 11.2+/-1.6 to 8.3+/-0.7%, P=0.008). AF duration was 720+/-461 s for controls and 138+/-83 s for EN (P=0.001). LA and RA areas and FAS at 5 weeks correlated with AF duration (P< or =0.001 for all). FAS decrease in both atria also correlated with AF duration at follow-up (r=0.78 and 0.77 for LA and RA, P< or =0.001 for both).Experimental CHF causes structural and functional abnormalities in both atria, which are correlated with AF duration. ACE inhibition attenuates CHF-induced atrial fibrosis and remodeling and reduces associated AF promotion. These results indicate a role for the renin-angiotensin system in arrhythmogenic atrial structural remodeling in CHF.
Effect of Eotaxin and Platelet-activating Factor on Airway Inflammation and Hyperresponsiveness in Guinea Pigs<i>in Vivo</i>
Authors: SATORU FUKUYAMA, HIROMASA INOUE, HISAMICHI AIZAWA, MASAHIRO OIKE, MOTOJI KITAURA, OSAMU YOSHIE, NOBUYUKI HARA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Although eotaxin causes selective infiltration of eosinophils into the lung, its role in airway hyperresponsiveness remains unclear. We studied the effects of local administration of eotaxin on airway inflammation and hyperresponsiveness in guinea pigs in vivo. Airway responsiveness to inhaled histamine and differential cell counts in bronchoalveolar lavage fluid (BALF) were evaluated 12 h, 24 h, 3 d, and 7 d after intratracheal instillation of eotaxin. Significant eosinophilia in BALF was observed between 6 h and 7 d after eotaxin administration. Histologically, eosinophil accumulation was observed in the airways but not in the alveoli. In contrast, eotaxin did not affect airway responsiveness between 12 h and 7 d after its administration. We then studied the effects on airway responsiveness of subthreshold doses of interleukin 5, leukotriene D4 (LTD4), and platelet-activating factor (PAF) combined with eotaxin. Neither interleukin 5 nor LTD4 affected airway responsiveness. After eotaxin treatment, PAF significantly enhanced airway responsiveness without further increases in eosinophil counts. Eotaxin plus PAF significantly increased in eosinophil peroxidase activity in BALF compared with control and with eotaxin alone. These data indicate that eotaxin alone causes eosinophil accumulation in the airways but not hyperresponsiveness, and that additional factors such as PAF are needed to activate eosinophils for the development of airway hyperresponsiveness.
Cigarette smoking, smoking cessation and acute pancreatitis: a prospective population-based study
Authors: O Sadr-Azodi, Å Andrén-Sandberg, N Orsini, A Wolk
Journal: Gut (2011)

<h3>Background</h3> Several studies have shown that smoking increases the risk of chronic pancreatitis. However, the impact of smoking on the development of acute pancreatitis has not been fully studied. <h3>Objective</h3> To clarify the association between cigarette smoking, smoking cessation and the risk of acute pancreatitis. <h3>Design</h3> A follow-up study was conducted of 84 667 Swedish women and men, aged 46–84, during 12 years to study the association between smoking status, smoking intensity and duration, duration of smoking cessation and the risk of acute pancreatitis. Only those with the first event of the disease and no previous history of acute pancreatitis were included. Cox proportional hazards models were used to estimate rate ratios (RRs) with 95% CI for different smoking-related variables, adjusted for age, gender, body mass index, diabetes, educational level and alcohol consumption. <h3>Results</h3> In total, 307 cases with non-gallstone-related and 234 cases with gallstone-related acute pancreatitis were identified. The risk of non-gallstone-related acute pancreatitis was more than double (RR=2.29; 95% CI 1.63 to 3.22, p&lt;0.01) among current smokers with ≥20 pack-years of smoking as compared with never-smokers. The corresponding risk among individuals with ≥400 g monthly consumption of alcohol was increased more than fourfold (RR=4.12; 95% CI 1.98 to 8.60, p&lt;0.01). The duration of smoking rather than smoking intensity increased the risk of non-gallstone-related acute pancreatitis. After two decades of smoking cessation the risk of non-gallstone-related acute pancreatitis was reduced to a level comparable to that of non-smokers. There was no association between smoking and gallstone-related acute pancreatitis. <h3>Conclusion</h3> Smoking is an important risk factor for non-gallstone-related acute pancreatitis. Early smoking cessation should be recommended as a part of the clinical management of patients with acute pancreatitis.