tbuckley/cabot-search huggingface dataset:
Coronary and Myocardial Actions of Angiotensin
Authors: NOBLE O. FOWLER, JOHN C. HOLMES
Journal: Circulation Research (1964)

In the dog heart-lung preparation, single injections of 40 µg angiotensin II produced consistently a biphasic response. Initial impairment of cardiac function was observed with decrease of cardiac output and of ventricular force, and with increase of atrial pressures. After 10 to 20 seconds, there was a positive inotropic effect, with an increase of cardiac output and of ventricular force, and a decrease in atrial pressures. Responses were comparable in reserpinized and nonreserpinized preparations. Tachyphylaxis to angiotensin was found consistently in the heart-lung preparation, with a regular decrease in response following second and third injections. A positive inotropic action of angiotensin II was demonstrated in the cat papillary muscle preparation. These studies demonstrated that angiotensin has a direct cardiac action, namely a positive inotropic effect. This action probably does not depend upon myocardial stores of catecholamines. When the left anterior descending coronary artery of the dog was perfused with blood at a constant flow, single intracoronary injections of angiotensin (1.0 µg) consistently increased coronary resistance (6% to 92%). Continuous intracoronary infusion of angiotensin increased coronary vascular resistance when blood concentrations were as low as 0.42 µg/ liter. No evidence of initial cardiac depression or of increased coronary vascular resistance was found after norepinephrine. It is concluded that the initial impairment of cardiac performance following angiotensin is caused at least in part by decreased coronary blood flow. Caution is suggested in the use of angiotensin in the treatment of human shock because of its action upon the coronary circulation.
Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease
Authors: J C Bestall, E A Paul, R Garrod, R Garnham, P W Jones, J A Wedzicha
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Methods of classifying chronic obstructive pulmonary disease (COPD) depend largely upon spirometric measurements but disability is only weakly related to measurements of lung function. With the increased use of pulmonary rehabilitation, a need has been identified for a simple and standardised method of categorising disability in COPD. This study examined the validity of the Medical Research Council (MRC) dyspnoea scale for this purpose. <h3>METHODS</h3> One hundred patients with COPD were recruited from an outpatient pulmonary rehabilitation programme. Assessments included the MRC dyspnoea scale, spirometric tests, blood gas tensions, a shuttle walking test, and Borg scores for perceived breathlessness before and after exercise. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ). The Nottingham Extended Activities of Daily Living (EADL) score and Hospital Anxiety and Depression (HAD) score were also measured. <h3>RESULTS</h3> Of the patients studied, 32 were classified as having MRC grade 3 dyspnoea, 34 MRC grade 4 dyspnoea, and 34 MRC grade 5 dyspnoea. Patients with MRC grades 1 and 2 dyspnoea were not included in the study. There was a significant association between MRC grade and shuttle distance, SGRQ and CRQ scores, mood state and EADL. Forced expiratory volume in one second (FEV<sub>1</sub>) was not associated with MRC grade. Multiple logistic regression showed that the determinants of disability appeared to vary with the level of disability. Between MRC grades 3 and 4 the significant covariates were exercise performance, SGRQ and depression score, whilst between grades 4 and 5 exercise performance and age were the major determinants. <h3>CONCLUSIONS</h3> The MRC dyspnoea scale is a simple and valid method of categorising patients with COPD in terms of their disability that could be used to complement FEV<sub>1</sub> in the classification of COPD severity.
HIGH-THROUGHPUT DRUG SCREENING IDENTIFIES HDAC INHIBITORS AS CANDIDATE THERAPEUTICS FOR MYC-DRIVEN MEDULLOBLASTOMA
Authors: R. J. Wechsler-Reya, Y. Pei, K.-W. Liu, J. Wang, L. A. Esparza, D. L. Maier, X.-N. Li, Y.-J. Cho
Journal: Neuro-Oncology (2014)

BACKGROUND: Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MBs with high levels of the MYC oncogene have a particularly poor prognosis, and would benefit from novel therapies. METHODS: To identify such therapies, we used an animal model of MYC-driven MB for high-throughput drug screening (HTS). RESULTS: Among the most effective compounds identified by HTS were histone deacetylase inhibitors (HDACI). In vitro, HDACI potently inhibited growth of murine and human MYC-driven MB cells, with minimal toxicity to normal cells. In vivo, HDACI significantly slowed growth of MYC-driven tumors, and synergized with PI3-Kinase inhibitors to cause tumor regression. CONCLUSIONS: These studies highlight the value of HTS for identification of effective therapies, and point to HDACI and PI3K inhibitors as promising agents for treatment of aggressive MB. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
OLIGOMERIC IGA: THE MAJOR COMPONENT OF THE IN VITRO PRIMARY RESPONSE OF MOUSE SPLEEN FRAGMENTS
Authors: Ichiro Nakamura, Alex Ray, O. Mäkelä
Journal: The Journal of Experimental Medicine (1973)

The primary antibody response elicited from mouse spleen explants by conjugates of the 3-nitro-5-iodo-4-hydroxyphenylacetic acid (NIP) hapten consisted mostly of the IgA class. Poly-L-lysine, pneumococcal polysaccharide Type SIII, keyhole limpet hemocyanin, and sheep erythrocytes were effective carriers in this system, whereas chicken globulin was not. The anti-NIP response against all of the immunogenic conjugates was detectable in culture media 4 days after explantation and immunization, and reached peak titers by 8-10 days. IgA was identified by sucrose gradient velocity centrifugation in conjunction with the use of a class-specific antiserum. The media collected at 4 days contained low titers of IgM antibody, whereas the peak response at 8 days consisted almost entirely of IgA. The primary response IgA secreted by the spleen fragments was characterized as polymeric by its sedimentation rate through a sucrose gradient, and as polyvalent by its drastically greater avidity for NIP(14)BSA than for free NIP-aminocaproic acid. Its haptenated phage-inactivating activity was abolished by treatment with 0.1 M 2-mercaptoethanol. These experiments indicate that precursor cells existing in the spleen before primary immunization can give rise to production of polymeric IgA.
PET/MRI of Inflammation in Myocardial Infarction
Authors: Won Woo Lee, Brett Marinelli, Anja M. van der Laan, Brena F. Sena, Rostic Gorbatov, Florian Leuschner, Partha Dutta, Yoshiko Iwamoto, Takuya Ueno, Mark P.V. Begieneman, Hans W.M. Niessen, Jan J. Piek, Claudio Vinegoni, Mikael J. Pittet, Filip K. Swirski, Ahmed Tawakol, Marcelo Di Carli, Ralph Weissleder, Matthias Nahrendorf
Journal: Journal of the American College of Cardiology (2012)
Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen α1(I) gene expression in cardiac fibroblasts
Authors: J Papakrivopoulou
Journal: Cardiovascular Research (2004)

We have previously demonstrated that mechanical loading of cardiac fibroblasts leads to increased synthesis and gene expression of the extracellular matrix protein collagen. We hypothesised that the upregulation of procollagen gene expression in cardiac fibroblasts, in response to cyclic mechanical load, is mediated by one or more members of the MAP kinase family. To test this hypothesis, the effect of mechanical load on the activation of extracellular signal-regulated kinase (ERK) 1/2, p46/54JNK, and p38MAPK was examined in rat cardiac fibroblasts.Peak phosphorylation of ERK 1/2, p38MAPK kinases, and p46/54JNK was observed following 10-20 min of continuous cyclic mechanical load. Mechanical load significantly increased procollagen alpha1(I) mRNA levels up to twofold above static controls after 24 h. This increase was completely abolished by the MEK 1/2 inhibitor U0126, with no effect on basal levels. In contrast, SB203580, a specific inhibitor of p38MAPK, enhanced both basal and stretch-stimulated levels of procollagen mRNA. Consistent with this finding, selective activation of the p38MAPK signalling pathway by expression of MKK6(Glu), a constitutive activator of p38MAPK, significantly reduced procollagen alpha1(I) promoter activity. SB203580-dependent increase in procollagen alpha1(I) was accompanied by ERK 1/2 activation, and inhibition of this pathway completely prevented SB203580-induced procollagen alpha1(I) expression.These results suggest that mechanical load-induced procollagen alpha1(I) gene expression requires ERK 1/2 activation and that the p38MAPK pathway negatively regulates gene expression in cardiac fibroblasts. These pathways are likely to be key in events leading to matrix deposition during heart growth and remodelling induced by mechanical load.
Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis
Authors: Santhi D. Konduri, Jonathan Ticku, George C. Bobustuc, Robert M. Sutphin, Jimmie Colon, Beth Isley, Kishor K. Bhakat, Srivenugopal S. Kalkunte, Cheryl H. Baker
Journal: Clinical Cancer Research (2009)

We sought to determine whether administration of a MGMT blocker, O(6)-benzyl guanine (O(6)BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth.Human pancreatic cancer L3.6pl and PANC1 cells were treated with O(6)BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated.O(6)BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O(6)BG. In sharp contrast, protein expression and mRNA message of p21(cip1) were significantly increased. Interestingly, O(6)BG increases p53-mediated p21(cip1) transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21(cip1) and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O(6)BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O(6)BG inhibited expression of MGMT and cyclins, and increased expression of p21(cip1). Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis.Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O(6)BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer.
Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines
Authors: Ana I. Robles, Mollie H. Wright, Bheru Gandhi, Steven S. Feis, Christin L. Hanigan, Adrian Wiestner, Lyuba Varticovski
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Loss of p53 function impairs apoptosis induced by DNA-damaging agents used for cancer therapy. Here, we examined the effect of the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) on doxorubicin-induced apoptosis in lymphoma. We aimed to establish the optimal schedule for administration of both drugs in combination and the molecular basis for their interaction. Experimental Design: Isogenic lymphoblastoid and nonisogenic lymphoma cell lines differing in p53 status were exposed to each drug or combination. Drug effects were examined using Annexin V, active caspase-3, cell cycle, and cytotoxicity assays. Synergy was evaluated by median effect/combination index. Protein expression and kinase inhibition provided insight into the molecular mechanisms of drug interaction. Results: Presence of mutant p53 conferred increased survival to single agents. Nevertheless, DMAG showed synergistic toxicity with doxorubicin independently of p53 status. Synergy required exposure to doxorubicin before DMAG. DMAG-mediated down-regulation of CHK1, a known HSP90 client, forced doxorubicin-treated cells into premature mitosis followed by apoptosis. A CHK1 inhibitor, SB-218078, reproduced the effect of DMAG. Administration of DMAG before doxorubicin resulted in G1-S arrest and protection from apoptosis, leading to additive or antagonistic interactions that were exacerbated by p53 mutation. Conclusions: Administration of DMAG to doxorubicin-primed cells induced premature mitosis and had a synergistic effect on apoptosis regardless of p53 status. These observations provide a rationale for prospective clinical trials and stress the need to consider schedule of exposure as a critical determinant of the overall response when DMAG is combined with chemotherapeutic agents for the treatment of patients with relapsed/refractory disease.
THE CAPSULAR POLYSACCHARIDE OF PNEUMOCOCCUS TYPE IX
Authors: C. V. N. Rao, Michael Heidelberger
Journal: The Journal of Experimental Medicine (1966)

The capsular polysaccharide of Type IX pneumococcus contains D-glucose, N-acetyl-D-glucosamine, and D-glucuronic acid. Complete hydrolysis is difficult. All of the N-acetylglucosamine is resistant to oxidation by periodate, but the other two sugars are degraded in part. Chemical and quantitative serological data are consistent with the linkage of two D-glucose residues 1 → 4, as in maltose; others may be linked 1 → 3. Part, at least, of the glucuronic acid and N-acetylglucosamine is linked to glucose.
Effect of Fish Oil Versus Corn Oil Supplementation on LDL and HDL Subclasses in Type 2 Diabetic Patients
Authors: Martin Petersen, Helle Pedersen, Atheline Major-Pedersen, Tonny Jensen, Peter Marckmann
Journal: Diabetes Care (2002)

OBJECTIVE—The increased risk of coronary heart disease associated with type 2 diabetes may be partially explained by dyslipidemia characterized by high plasma triacylglycerol (TAG), low HDL cholesterol, and a predominance of atherogenic small dense LDLs. Fish oil reduces plasma TAG and has previously been shown to improve the distribution of LDL subclasses in healthy subjects and might, therefore, be a good nonpharmacological treatment for type 2 diabetic patients. In the present study, we investigate the effect of fish oil supplementation on the fasting lipid profile, including LDL and HDL subclasses. RESEARCH DESIGN AND METHODS—A total of 42 type 2 diabetic patients were randomized to supplementation (capsules) with 4 g daily of either fish oil (n = 20) or corn oil (n = 22) for 8 weeks preceded by a 4-week run-in period of corn oil supplementation. Blood was drawn before and after the 8-week intervention period. Plasma lipoproteins, including LDL and HDL subclasses, were separated by ultracentrifugation. RESULTS—Fish oil lowered TAG (group difference: P = 0.025) and raised HDL-2b cholesterol (P = 0.012) and HDL-2a cholesterol (P = 0.007) concentrations as compared with corn oil. We observed no significant effects of fish oil on LDL cholesterol, HDL cholesterol, or the concentration of small dense LDL particles. CONCLUSIONS—Fish oil supplementation may partially correct the dyslipidemia of type 2 diabetic patients. However, the putative very important aspect of diabetic dyslipidemia—the predominance of small dense LDL particles—was unaffected by fish oil.
Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model
Authors: Yitang Li, Amit Prasad, Yonghui Jia, Saurabh Ghosh Roy, Fabien Loison, Subhanjan Mondal, Paulina Kocjan, Leslie E. Silberstein, Sheng Ding, Hongbo R. Luo
Journal: Blood (2011)
Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant Breast Cancer
Authors: Sarat Chandarlapaty, Rita A. Sakr, Dilip Giri, Sujata Patil, Adriana Heguy, Monica Morrow, Shanu Modi, Larry Norton, Neal Rosen, Clifford Hudis, Tari A. King
Journal: Clinical Cancer Research (2012)

Abstract Purpose: HER2-amplified breast cancer is sometimes clinically insensitive to HER2-targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy. Experimental Design: From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or World Health Organization–defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom and analyzed for HER2 and PTEN status by immunohistochemistry. Results: In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pretreatment tumor failed to confirm HER2 overexpression in five cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared with 44% (P = 0.007) in an unexposed cohort of 73 HER2-amplified tumors. Conclusions: In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare, whereas activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed. Clin Cancer Res; 18(24); 6784–91. ©2012 AACR.
Molecular population genetics of Escherichia coli: DNA sequence diversity at the celC, crr, and gutB loci of natural isolates.
Authors: B G Hall, P M Sharp
Journal: Molecular Biology and Evolution (1992)

The DNA sequences of three genes--celC, crr, and gutB--have been determined for each of 11 or 12 natural isolates of Escherichia coli from the ECOR collection. These genes encode the phosphoenolpyruvate-dependent phosphotransferase-system enzyme III proteins specific for beta-glucoside sugars (celC), glucose (crr), and glucitol (gutB), respectively. There is little evidence of recombination at or among these loci; among these strains, relationships inferred from each gene are largely consistent with each other and with the relationship inferred from multilocus enzyme electrophoresis. DNA sequence diversity is similar for all three genes, particularly when silent (synonymous) sites only are considered. This is surprising because there is much stronger codon usage bias at crr than at celC or gutB. The extent of divergence in the protein sequences encoded by these three genes varies considerably. The constitutively expressed glucose-specific enzyme is completely conserved. It is surprising that the inducible glucitol-specific enzyme, which is functional, is more variable than the cellobiose-specific enzyme, which is cryptic; the latter might be expected to be under less (if any) purifying selection.
Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea
Authors: S Kordasti
Journal: Gut (2004)

<b>Background and aims:</b> The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT<sub>3</sub>) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea. <b>Methods:</b> Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus. <b>Results:</b> While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04–3.56), the 5-HT<sub>3</sub> receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe<sup>6</sup>,Leu<sup>17</sup>)-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31–2.9) (p&lt;0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days; p&lt;0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice. <b>Conclusions:</b> Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea; observations that could imply new principles for treatment of this disease with significant global impact.
Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization
Authors: Hidenori Mizugaki, Noboru Yamamoto, Yutaka Fujiwara, Hiroshi Nokihara, Yasuhide Yamada, Tomohide Tamura
Journal: Journal of Clinical Oncology (2015)

In Japan, phase I trials, except first-in-human trials, are usually initiated from approximately 50% of the maximum-tolerated dose (MTD) or maximum administered dose (MAD) determined during the initial phase I trials in North America and Europe (the West). However, the key findings of phase I trials in Japan and the West, such as dose-limiting toxicity (DLT) profiles and MTD or MAD levels, have not been compared.We retrospectively analyzed data for patients enrolled onto single-agent phase I trials at the National Cancer Center Hospital between 1995 and 2012. DLT profiles, MTDs, and MADs of single-agent phase I trials in Japan were compared with those from trials in the West that were obtained from the literature.A total of 777 patients were enrolled onto 54 single-agent phase I trials, including five first-in-human trials. DLTs were observed in 11.1% of the patients. Importantly, 66.4% of the DLTs were observed within a dose range (80% to 120%) similar to those reported for the trials in the West. The majority of MTDs or MADs could be considered similar between patients, and 80.3% of the drugs had similar MTDs or MADs in the West.The toxicity profiles of single-agent phase I agents determined from trials conducted in Japan were comparable to those obtained from trials in the West. We believe that phase I trials in Japan could be conducted over timelines similar to those in the West, allowing for global or parallel phase I clinical trials.
Outer Retinal Tubulation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)
Authors: Joo Yong Lee, Francisco A. Folgar, Maureen G. Maguire, Gui-shuang Ying, Cynthia A. Toth, Daniel F. Martin, Glenn J. Jaffe
Journal: Ophthalmology (2014)