tbuckley/cabot-search huggingface dataset:
Effect of Ouabain on the ATPase of Cardiac Myosin B at High Ionic Strength
Authors: ADA L. JACOBSON
Journal: Circulation Research (1968)

The effect of ouabain (10 -8 to 10 -3 m ) on the hydrolysis of ATP by beef cardiac myosin B was measured at various KC1 concentrations and at various interaction times at 25°C. Using an ionic strength of 0.24 m KC1 and a 10-minute contact time, 10 -7 and 10 -5 m ouabain approximately doubled the ATPase activity of freshly prepared natural actomyosin. After storage of the myosin B sample in 0.6 m KC1 at 2°C, ouabain had a small inhibitory effect in 0.24 m KC1 on the ATPase activity. At an ionic strength of 0.36 m KC1, only the inhibitory effect was observed. This effect was dependent on contact time and on calcium ion concentration. Previous treatment of the myosin B with EDTA removed the activating effect observed in 0.24 m KC1 at short contact times. Addition of 0.1 mM MgCl 2 restored the activating effect of ouabain. In the EDTA-treated myosin B in 0.6 m KC1 at high ouabain concentrations in the presence of 1 m m CaCl 2 , a small activation was observed. Addition of 0.1 m m MgCl 2 under the same experimental conditions produced a small deactivation. The effect of ouabain on the ATPase of myosin B in solution appears to be dependent on protein preparation, age of the protein preparation (which may affect aggregation), ionic strength, ouabain concentration, contact time, and divalent ions present. All effects induced by ouabain on the ATPase activity of myosin B may be related to the conformation of the myosin B in solution. However, no simple relationship was observed with any individual variable such as preparation, age, contact time, or ouabain concentration.
Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
Authors: Felipe Cardenal, M. Paz López-Cabrerizo, Antonio Antón, Vicente Alberola, Bartomeu Massuti, Alfredo Carrato, Isidoro Barneto, María Lomas, Margarita García, Pilar Lianes, Joaquín Montalar, Catalina Vadell, José Luis González-Larriba, Binh Nguyen, Angel Artal, Rafael Rosell
Journal: Journal of Clinical Oncology (1999)

PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m 2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m 2 IV days 1 to 3 along with cisplatin 100 mg/m 2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.
High prevalence of occult left heart disease in scleroderma-pulmonary hypertension
Authors: Benjamin D. Fox, Avi Shimony, David Langleben, Andrew Hirsch, Lawrence Rudski, Robert Schlesinger, Mark J. Eisenberg, Dominique Joyal, Marie Hudson, Kim Boutet, Alexandrina Serban, Ariel Masetto, Murray Baron
Journal: European Respiratory Journal (2012)

Our study aimed to determine the prevalence of occult left-heart disease in patients with scleroderma and pulmonary hypertension. In patients with pulmonary hypertension (mean pulmonary artery pressure (mean PAP) ≥25 mmHg), differentiation between pre- and post-capillary pulmonary hypertension has been made according to pulmonary artery wedge pressure (PAWP) less than or more than 15 mmHg, respectively. We performed a retrospective chart review of 107 scleroderma patients. All patients with suspected pulmonary hypertension had routine right or left heart catheterisation with left ventricular end-diastolic pressure (LVEDP) measurement pre-/post-fluid challenge. We extracted demographic, haemodynamic and echocardiographic data. Patients were classified into one of four groups: haemodynamically normal (mean PAP&lt;25 mmHg); pulmonary venous hypertension (PVH) (mean PAP≥25 mmHg, PAWP&gt;15 mmHg); occult PVH (mean PAP≥25 mmHg, PAWP≤15 mmHg, LVEDP&gt;15 mmHg before or after fluid challenge); and pulmonary arterial hypertension (PAH) (mean PAP≥25 mmHg, PAWP≤15 mmHg and LVEDP≤15 mmHg before or after fluid challenge). 53 out of 107 patients had pulmonary hypertension. Based on the PAWP-based definition, 29 out of 53 had PAH and 24 out of 53 had PVH. After considering the resting and post-fluid-challenge LVEDP, 11 PAH patients were reclassified as occult PVH. The occult PVH group was haemodynamically, echocardiographically and demographically closer to the PVH group than the PAH group. PVH had high prevalence in our scleroderma-pulmonary hypertension population. Distinguishing PAH from PVH with only PAWP may result in some PVH patients being misclassified as having PAH.
Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma
Authors: Shinji Kohsaka, Kunihiko Hinohara, Lei Wang, Tatsunori Nishimura, Masana Urushido, Kazuhiro Yachi, Masumi Tsuda, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Noriko Gotoh, Shinya Tanaka
Journal: Neuro-Oncology (2014)

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target. Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples. Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG. These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients.
Unsymbolized thinking, sensory awareness, and mindreading
Authors: Russell T. Hurlburt
Journal: Behavioral and Brain Sciences (2009)

Abstract Carruthers views unsymbolized thinking as “purely propositional” and, therefore, as a potential threat to his mindreading-is-prior position. I argue that unsymbolized thinking may involve (non-symbolic) sensory aspects; it is therefore not purely propositional, and therefore poses no threat to mindreading-is-prior. Furthermore, Descriptive Experience Sampling lends empirical support to the view that access to our own propositional attitudes is interpretative, not introspective.
Web-Based Tailored Education Program for Disease-Free Cancer Survivors With Cancer-Related Fatigue: A Randomized Controlled Trial
Authors: Young Ho Yun, Keun Seok Lee, Young-Woo Kim, Sang Yoon Park, Eun Sook Lee, Dong-Young Noh, Sung Kim, Jae Hwan Oh, So Youn Jung, Ki-Wook Chung, You Jin Lee, Seung-Yong Jeong, Kyu Joo Park, Young Mog Shim, Jae Ill Zo, Ji Won Park, Young Ae Kim, En Jung Shon, Sohee Park
Journal: Journal of Clinical Oncology (2012)

To determine whether an Internet-based tailored education program is effective for disease-free cancer survivors with cancer-related fatigue (CRF).We randomly assigned patients who had completed primary cancer treatment within the past 24 months in any of four Korean hospitals and had reported moderate to severe fatigue for at least 1 week to participate in a 12-week, Internet-based, individually tailored CRF education program or to receive routine care. We based the program on the CRF guidelines of the National Comprehensive Cancer Network (NCCN) and incorporated the transtheoretic model (TTM). At baseline and 12 weeks, we used the Brief Fatigue Inventory (BFI) and Fatigue Severity Scale (FSS) as primary outcomes and the Hospital Anxiety and Depression Scale (HADS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) for secondary outcomes.We recruited 273 participants and randomly assigned 136 to the intervention group. Compared with the control group, the intervention group had an improvement in fatigue as shown by a significantly greater decrease in BFI global score (-0.66 points; 95% CI -1.04 to -0.27) and FSS total score (-0.49; 95% CI, -0.78 to -0.21). In secondary outcomes, the intervention group experienced a significantly greater decrease in HADS anxiety score (-0.90; 95% CI, -1.51 to -0.29) as well as global quality of life (5.22; 95% CI, 0.93 to 9.50) and several functioning scores of the EORTC QLQ-C30.An Internet-based education program based on NCCN guidelines and TTM may help patients manage CRF.
The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells
Authors: Michele Cioffi, Sara M Trabulo, Yolanda Sanchez-Ripoll, Irene Miranda-Lorenzo, Enza Lonardo, Jorge Dorado, Catarina Reis Vieira, Juan Carlos Ramirez, Manuel Hidalgo, Alexandra Aicher, Stephan Hahn, Bruno Sainz, Christopher Heeschen
Journal: Gut (2015)

<h3>Objective</h3> Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. <h3>Design</h3> Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. <h3>Results</h3> We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. <h3>Conclusions</h3> Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.
A Novel Inhibitor of STAT3 Homodimerization Selectively Suppresses STAT3 Activity and Malignant Transformation
Authors: Xiaolei Zhang, Ying Sun, Roberta Pireddu, Hua Yang, Murali K. Urlam, Harshani R. Lawrence, Wayne C. Guida, Nicholas J. Lawrence, Saïd M. Sebti
Journal: Cancer Research (2013)

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding, and transcriptional regulation of downstream target genes. Here, we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation, and malignant transforming activity. Fluorescence polarization assay and molecular modeling suggest that S3I-1757 interacts with the phospho-Y-705-binding site in the SH2 domain and displaces fluorescein-labeled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated hemagglutinin (HA)-tagged STAT3 and FLAG-tagged STAT3 and showed using coimmunoprecipitation and colocalization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor (EGFR) binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analog, S3I-1756, which does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding, and transcriptional activation and suppresses the expression levels of STAT3 target genes, such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1), and matrix metalloproteinase (MMP)-9. Furthermore, S3I-1757, but not S3I-1756, inhibits anchorage-dependent and -independent growth, migration, and invasion of human cancer cells, which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyperactivated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3.
Artificial systems as models in biological cybernetics
Authors: Titus R. Neumann, Susanne Huber, Heinrich H. Bülthoff
Journal: Behavioral and Brain Sciences (2001)

From the perspective of biological cybernetics, “real world” robots have no fundamental advantage over computer simulations when used as models for biological behavior. They can even weaken biological relevance. From an engineering point of view, however, robots can benefit from solutions found in biological systems. We emphasize the importance of this distinction and give examples for artificial systems based on insect biology.
Effect of Nuclear Hydroxy Substituents on Aqueous Solubility and Acidic Strength of Bile Acids
Authors: Aldo Roda, Adamo Fini
Journal: Hepatology (1984)

The aqueous solubility and thermodynamic dissociation constants of a representative series of bile acids with varying numbers and configuration of nuclear hydroxyl substituents were determined. The pKa values were calculated by extrapolating pKa’ values determined in solutions of aqueous methanol of different mole fractions at 25 o C. All bile acids had the same acidic strength in water, indicating that the pattern of hydroxyl nuclear substituents does not affect the acidic strength probably because of the distance between the hydroxyl and ionizing groups. In contrast, aqueous solubility was dependent on the number, position and orientation of the hydroxyl groups. The solubility values ranged from 5 x 10 −8 M (0.05 μM) for 3αr-hydroxy-5β-cholanoic acid (lithocholic acid) to 1.67 x 10 −3 M (1,670 μM) for 3α,7β,12α-trihydroxy-5β-cholanoic acid (urso-cholic acid). The hydroxy groups notably affect solubility by forming hydrogen bonds with water but also by reducing, according to their orientation, hydrophobicity of the steroid nucleus.
Hepatitis C Virus Infection in Patients with Nonalcoholic Chronic Liver Disease
Authors: José M. Sánchez-Tapias
Journal: Annals of Internal Medicine (1990)

To determine the prevalence and meaning of antibodies to the hepatitis C virus (HCV) in patients with nonalcoholic chronic liver diseases.Cross-sectional study.The liver unit of a referral-based university hospital.Three hundred and forty-six consecutive patients, including 137 with cryptogenic chronic liver disease, 156 with chronic hepatitis B, 47 with primary biliary cirrhosis, and 8 with persistently abnormal aminotransferase serum levels and normal liver histology. Among patients with cryptogenic liver disease, 41 received blood transfusions before discovery of liver disease and 18 had circulating nonorgan-specific autoantibodies. For comparison, 1495 apparently healthy volunteer blood donors were included in the study. LABORATORY INVESTIGATIONS: The presence of anti-HCV antibodies (anti-HCV) was determined by a recently developed enzyme-linked immunoassay.In patients with cryptogenic liver disease, the prevalence of anti-HCV was 82% (95% CI, 76% to 89%), being higher (P = 0.02) in patients with histories of blood transfusion than in those with unknown sources of exposure. Antibodies to HCV were not detected in patients with antinuclear antibodies at high titer. Among patients with chronic hepatitis B, anti-HCV were found in 11% (CI, 5% to 18%) of those with hepatitis B virus (HBV)-associated DNA in serum and in 29% (CI, 17% to 43%) of those with undetectable HBV replication (P less than 0.05). The prevalence of anti-HCV in blood donors was 1.2% (CI, 1.1% to 1.3%).Our results indicate that HCV infection probably plays an important etiologic role in cryptogenic liver disease and, in some patients, in chronic hepatitis B. Determining whether anti-HCV are present appears to be useful for differentiating viral from autoimmune chronic liver diseases.
TNF-alpha increases albumin permeability of isolated rat glomeruli through the generation of superoxide.
Authors: E T McCarthy, R Sharma, M Sharma, J Z Li, X L Ge, K N Dileepan, V J Savin
Journal: Journal of the American Society of Nephrology (1998)

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that plays a central role in inflammation. Glomerular levels of TNF-alpha are elevated in human and experimental glomerulonephritis. Glomerular cells produce and respond to TNF-alpha. One of the mechanisms by which these cells respond to TNF-alpha is through generation of reactive oxygen species. In this study, the effect of TNF-alpha on albumin permeability (P(albumin)) of isolated rat glomeruli and the possible mechanism of this effect were examined. Isolated rat glomeruli were incubated with TNF-alpha (0.4 ng/ml), TNF-alpha with anti-TNF-alpha antibodies, and TNF-alpha with the reactive oxygen species scavengers superoxide dismutase, catalase, DMSO, or dimethylthiourea for 12 min at 37 degrees C, and P(albumin) was calculated. TNF-alpha increased P(albumin) of isolated glomeruli compared with control (0.70 +/- 0.02, n = 25 versus 0.00 +/- 0.05, n = 26), and this effect was abrogated by anti-TNF-alpha antibodies (-0.18 +/- 0.05, n = 23). Superoxide dismutase abolished the increase in P(albumin) (-0.04 +/- 0.11, n = 23), whereas catalase (0.73 +/- 0.08, n = 30), DMSO (0.64 +/- 0.03, n = 10), or dimethylthiourea (0.51 +/- 0.08, n = 10) did not alter the effect of TNF-alpha. These results indicate that TNF-alpha increased P(albumin+)++ of isolated glomeruli and that the mediator of the increased P(albumin) is superoxide. It is concluded that TNF-alpha derived from glomerular or extraglomerular sources can increase glomerular P(albumin) through generation of superoxide and may lead to proteinuria.
Heterogeneity of clonogenic cells in acute myeloblastic leukemia.
Authors: K D Sabbath, E D Ball, P Larcom, R B Davis, J D Griffin
Journal: Journal of Clinical Investigation (1985)

The expression of differentiation-associated surface antigens by the clonogenic leukemic cells from 20 patients with acute myeloblastic leukemia (AML) was studied with a panel of seven cytotoxic monoclonal antibodies (anti-Ia, -MY9, -PM-81, -AML-2-23, -Mol, -Mo2, and -MY3). The surface antigen phenotypes of the clonogenic cells were compared with the phenotypes of the whole leukemic cell population, and with the phenotypes of normal hematopoietic progenitor cells. In each case the clonogenic leukemic cells were found within a distinct subpopulation that was less "differentiated" than the total cell population. Clonogenic leukemic cells from different patients could be divided into three phenotype groups. In the first group (7 of 20 cases), the clonogenic cells expressed surface antigens characteristic of the normal multipotent colony-forming cell (Ia, MY9). These cases tended to have "undifferentiated" (FAB M1) morphology, and the total cell population generally lacked expression of "late" monocyte antigens such as MY3 and Mo2. A second group (seven cases) of clonogenic cells expressed surface antigens characteristic of an "early" (day 14) colony-forming unit granulocyte-monocyte (CFU-GM), and a third group (six cases) was characteristic of a "late" (day 7) CFU-GM. The cases in these latter two groups tended to have myelomonocytic (FAB M4) morphology and to express monocyte surface antigens. These results suggest that the clonogenic cells are a distinct subpopulation in all cases of AML, and may be derived from normal hematopoietic progenitor cells at multiple points in the differentiation pathway. The results further support the possibility that selected monoclonal antibodies have the potential to purge leukemic clonogenic cells from bone marrow in some AML patients without eliminating critical normal progenitor cells.
Association of the polymorphism of the CAG repeat in the mitochondrial DNA polymerase gamma gene (POLG) with testicular germ-cell cancer
Authors: M. Blomberg Jensen, H. Leffers, J.H. Petersen, G. Daugaard, N.E. Skakkebaek, E. Rajpert-De Meyts
Journal: Annals of Oncology (2008)