tbuckley/cabot-search huggingface dataset:
Direct effects of cholinergic stimulation on ventricular automaticity in guinea pig myocardium.
Authors: D P Rardon, J C Bailey
Journal: Circulation Research (1983)

The purpose of these experiments was to determine whether muscarinic cholinergic agonists exerted a negative chronotropic effect in the absence of endogenous norepinephrine in isolated guinea pig ventricular myocardial strips. The chronotropic response to physostigmine (10(-6) M) in control, reserpine-pretreated animals, and in the presence of increased norepinephrine release induced by superfusion of tyramine (10(-5) M), was studied. The control rates in the control, reserpine-pretreated, and tyramine-treated groups were 106 +/- 40, 93 +/- 31, 109 +/- 28/min, respectively. Propranolol (10(-6) M) produced a 23% slowing in rate in control animals and an 8% slowing in reserpine pretreated animals (P less than 0.01), suggesting basal secretion of norepinephrine. Tyramine (10(-5) M) produced a 28% increase in rate in control animals (P less than 0.05) and tyramine (10(-4) M) produced no increase in reserpine-pretreated animals. Physostigmine produced similar negative chronotropic response in control, reserpine-pretreated, and tyramine-treated groups of 45, 49, and 28%, respectively. Physostigmine produced no change in measured Purkinje fiber action potential characteristics, except for a decreased rate of spontaneous diastolic depolarization. Our results demonstrate that physostigmine slows the spontaneous rate in control, reserpine-pretreated and tyramine-treated groups, indicating that muscarinic cholinergic agonists exert a direct negative chronotropic effect at postjunctional cell surface receptors, independent of the presence or level of adrenergic tone.
Bispectral fluorescence imaging of aggressive basal cell carcinoma combined with histopathological mapping: a preliminary study indicating a possible adjunct to Mohs micrographic surgery
Authors: B. Stenquist, M.B. Ericson, C. Strandeberg, L. Mölne, A. Rosén, O. Larkö, A.M. Wennberg
Journal: British Journal of Dermatology (2005)

Fluorescence imaging is an attractive diagnostic technique for skin tumour demarcation with potential to move to clinical use. Bispectral fluorescence imaging combines skin autofluorescence with delta-aminolaevulinic acid-induced fluorescence. To evaluate the technique, fluorescence data must be compared with the histopathological extent of the tumour, which is the purpose of the current study.To investigate the agreement between bispectral fluorescence images and the histopathological tumour boundary of ill-defined basal cell carcinomas (BCCs). After fluorescence imaging the tumours were removed using Mohs micrographic surgery (MMS) to obtain histopathological maps of the tumour boundaries.Twelve patients with aggressive BCC of mean diameter 16 mm (range 5-32) in the face were included in the study. The patients were subjected to bispectral fluorescence imaging within the 2 months prior to MMS. The fluorescence images and histopathological maps were aligned using image warping.Five patients (42%) showed good agreement with the histopathological mapping and the remaining seven patients (58%) showed partial agreement. Bispectral investigation combining autofluorescence with protoporphyrin IX (PpIX) fluorescence generally yielded better agreement with the histopathological boundaries of the tumours compared with using only the PpIX fluorescence.In this preliminary study the fluorescence has been compared with the histopathological tumour boundaries. The result implies that the technique can be applied as a useful tool for indicating tumour boundary of aggressive BCCs. Further refinement is needed to be able to indicate the exact tumour border.
Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression <i>In vivo</i>
Authors: Shinji Takeuchi, Akiko Takahashi, Noriko Motoi, Shin Yoshimoto, Tomoko Tajima, Kimi Yamakoshi, Atsushi Hirao, Shigeru Yanagi, Kiyoko Fukami, Yuichi Ishikawa, Saburo Sone, Eiji Hara, Naoko Ohtani
Journal: Cancer Research (2010)

Abstract Although the p16INK4a and p21Waf1/Cip1 cyclin-dependent kinase (CDK) inhibitors are known to play key roles in cellular senescence in vitro, their roles in senescence remain rather poorly understood in vivo. This situation is partly due to the possibility of compensatory effect(s) between p16INK4a and p21Waf1/Cip1 or to the upregulation of functionally related CDK inhibitors. To directly address the cooperative roles of p16INK4a and p21Waf1/Cip1 in senescence in vivo, we generated a mouse line simply lacking both p16INK4a and p21Waf1/Cip1 genes [double-knockout (DKO)]. Mouse embryonic fibroblasts (MEF) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro. Moreover, DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture. This was not the case in MEFs lacking either p16INK4a or p21Waf1/Cip1, indicating that p16INK4a and p21Waf1/Cip1 play cooperative roles in cellular senescence and contact inhibition in vitro. Notably, we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate–induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene. Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21Waf1/Cip1 loss, with increased malignant conversion of benign skin tumors caused by p16INK4a loss. Our findings establish an intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo. Cancer Res; 70(22); 9381–90. ©2010 AACR.
Emerging Paradigms in Cancer Genetics: Some Important Findings from High-Density Single Nucleotide Polymorphism Array Studies
Authors: Manny D. Bacolod, Gunter S. Schemmann, Sarah F. Giardina, Philip Paty, Daniel A. Notterman, Francis Barany
Journal: Cancer Research (2009)

Abstract High-density single nucleotide polymorphism (SNP) mapping arrays have identified chromosomal features whose importance to cancer predisposition and progression is not yet clearly defined. Of interest is that the genomes of normal somatic cells (reflecting the combined parental germ-line contributions) often contain long homozygous stretches. These chromosomal segments may be explained by the common ancestry of the individual's parents and thus may also be called autozygous. Several studies link consanguinity to higher rates of cancer, suggesting that autozygosity (a genomic consequence of consanguinity) may be a factor in cancer predisposition. SNP array analysis has also identified chromosomal regions of somatic uniparental disomy (UPD) in cancer genomes. These are chromosomal segments characterized by loss of heterozygosity (LOH) and a normal copy number (two) but which are not autozygous in the germ-line or normal somatic cell genome. In this review, we will also discuss a model [cancer gene activity model (CGAM)] that may explain how autozygosity influences cancer predisposition. CGAM can also explain how the occurrence of certain chromosomal aberrations (copy number gain, LOH, and somatic UPDs) during carcinogenesis may be dependent on the germ-line genotypes of important cancer-related genes (oncogenes and tumor suppressors) found in those chromosomal regions. [Cancer Res 2009;69(3):723–7]
Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate
Authors: P. Chiusolo, G. Reddiconto, I. Casorelli, L. Laurenti, F. Sorà, L. Mele, L. Annino, G. Leone, S. Sica
Journal: Annals of Oncology (2002)
Fever and pancytopenia in a patient with Crohn's disease
Authors: Robert Weinkove, Michelle Dickson, Elena Eliadou, Nigel Henry Stace, Louise Goossens, Peter Ferguson
Journal: Gut (2012)

A 21-year-old male with ileal Crohn's disease on maintenance with azathioprine presented with fevers and pancytopenia. Erythrocyte 6-thioguanine nucleotide level was therapeutic. CT excluded an abscess and showed thickening of the rectum, sigmoid and terminal ileum. His condition failed to respond to azathioprine withdrawal, intravenous piperacillin/tazobactam and granulocyte colony-stimulating factor. Blood tests showed hyperbilirubinemia, transaminitis, marked hyperferritinemia (>7000 μg/l), hypofibrinogenemia and hypertriglyceridaemia. Bone marrow aspirate microscopy is shown in figure 1.



Figure 1 
Bone marrow aspirate showing a macrophage.



The patient developed rectal bleeding, refractory to blood product support and …
Hair darkening in porphyria cutanea tarda
Authors: F.C.G. Shaffrali, A.J.G. Mcdonagh, A.G. Messenger
Journal: British Journal of Dermatology (2002)

Journal Article Hair darkening in porphyria cutanea tarda Get access F.C.G. Shaffrali, F.C.G. Shaffrali Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K Search for other works by this author on: Oxford Academic Google Scholar A.J.G. Mcdonagh, A.J.G. Mcdonagh Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K Search for other works by this author on: Oxford Academic Google Scholar A.G. Messenger A.G. Messenger Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 146, Issue 2, 1 February 2002, Pages 325–329, https://doi.org/10.1046/j.1365-2133.2002.04591.x Published: 01 February 2002 Article history Accepted: 01 October 2001 Published: 01 February 2002
Obliterative bronchiolitis caused by multiple tumourlets and microcarcinoids successfully treated by single lung transplantation.
Authors: N Sheerin, N K Harrison, M N Sheppard, D M Hansell, M Yacoub, T J Clark
Journal: Thorax (1995)

Histological examination of a lung removed at transplantation revealed multiple peripheral tumourlets and microcarcinoids in close association with bronchioles causing an obliterative bronchiolitis. This was an unexpected finding but explained the progressive airflow limitation which characterised the patient9s clinical course.
Control of muscle tone in the human colon.
Authors: C J Steadman, S F Phillips, M Camilleri, N J Talley, A Haddad, R Hanson
Journal: Gut (1992)

Human colonic muscle tone varies diurnally and postprandially in predictable ways. Increased tone reduces the capacity of the colon to store contents after a meal, whereas increased distensibility (lesser tone) during sleep enlarges the storage capabilities and may slow transit. We tested the hypothesis that antidiarrhoeal drugs would also alter tone which, in turn, might reduce diarrhoea by facilitating the storage and salvage of fluids. Using a colonic barostat to create low pressure, isobaric colonic distension in healthy volunteers, we found that intravenous atropine (0.01 mg/kg) relaxed the colon during fasting, reduced the postprandial increase in tone, and enhanced relaxation in the late (1-2 hour) postprandial period. Intravenous morphine (0.1 mg/kg) caused variable effects soon after injection but, in fasting subjects, the descending colon relaxed 70-90 minutes after morphine. These changes in colonic motility were not always obvious by conventional manometric recording. Colonic distensibility is increased by antidiarrhoeal drugs and this effect may contribute to their efficacy in slowing colonic transit and augmenting absorption.
The Evolution of Biased Codon and Amino Acid Usage in Nematode Genomes
Authors: Asher D. Cutter, James D. Wasmuth, Mark L. Blaxter
Journal: Molecular Biology and Evolution (2006)

Despite the degeneracy of the genetic code, whereby different codons encode the same amino acid, alternative codons and amino acids are utilized nonrandomly within and between genomes. Such biases in codon and amino acid usage have been demonstrated extensively in prokaryote genomes and likely reflect a balance between the action of mutation, selection, and genetic drift. Here, we quantify the effects of selection and mutation drift as causes of codon and amino acid-usage bias in a large collection of nematode partial genomes from 37 species spanning approximately 700 Myr of evolution, as inferred from expressed sequence tag (EST) measures of gene expression and from base composition variation. Average G + C content at silent sites among these taxa ranges from 10% to 63%, and EST counts range more than 100-fold, underlying marked differences between the identities of major codons and optimal codons for a given species as well as influencing patterns of amino acid abundance among taxa. Few species in our sample demonstrate a dominant role of selection in shaping intragenomic codon-usage biases, and these are principally free living rather than parasitic nematodes. This suggests that deviations in effective population size among species, with small effective sizes among parasites, are partly responsible for species differences in the extent to which selection shapes patterns of codon usage. Nevertheless, a consensus set of optimal codons emerges that is common to most taxa, indicating that, with some notable exceptions, selection for translational efficiency and accuracy favors similar sets of codons regardless of the major codon-usage trends defined by base compositional properties of individual nematode genomes.
Role of angiotensin II in the altered renal function of congestive heart failure.
Authors: I Ichikawa, J M Pfeffer, M A Pfeffer, T H Hostetter, B M Brenner
Journal: Circulation Research (1984)

Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial
Authors: Edward S Kim, Vera Hirsh, Tony Mok, Mark A Socinski, Radj Gervais, Yi-Long Wu, Long-Yun Li, Claire L Watkins, Mark V Sellers, Elizabeth S Lowe, Yan Sun, Mei-Lin Liao, Kell Østerlind, Martin Reck, Alison A Armour, Frances A Shepherd, Scott M Lippman, Jean-Yves Douillard
Journal: The Lancet (2008)
Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34
Authors: D. Miao
Journal: Journal of Clinical Investigation (2005)

Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1–34 amino-terminal fragment of parathyroid hormone (PTH 1–34) to Pthrp+/– mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1–34.
Kruppel-Associated Box Domain-Associated Protein-1 as a Latency Regulator for Kaposi's Sarcoma-Associated Herpesvirus and Its Modulation by the Viral Protein Kinase
Authors: Pei-Ching Chang, Latricia D. Fitzgerald, Albert Van Geelen, Yoshihiro Izumiya, Thomas J. Ellison, Don-Hong Wang, David K. Ann, Paul A. Luciw, Hsing-Jien Kung
Journal: Cancer Research (2009)

Abstract Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies, including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can affect the development of intervention strategies. Here, we report that Kruppel-associated box domain-associated protein-1 (KAP-1)/transcriptional intermediary factor 1β, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by small interfering RNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phoshorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser824. Several lines of evidence directly linked the viral protein kinase to this post-translational modification. Additional studies showed that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and viral protein kinase modulates the chromatin remodeling function of this repressor. [Cancer Res 2009;69(14):5681–9]
Precordial Vibrations Clinical Clues from Palpation
Authors: E. GREY DIMOND
Journal: Circulation (1964)

The low-frequency precordial vibrations originating at the point of the apex beat, and especially those in the subaudible range, seem to offer considerable clinical usefulness. In this paper I have briefly outlined some of the physiologic, pathologic, and pharmacologic evidence to support this impression. The instrumentation we have used is crude and undoubtedly we have been misled on occasion by artifacts. However, there is sufficient validity in the technic, reproducibility of result, and correlation with intracardiac events to warrant intensive study.
Effects of Metabolic Acidosis on Ventricular Isometric Systolic Tension and the Response to Epinephrine and Levarterenol
Authors: THOMAS D. DARBY, EARL E. ALDINGER, RICHARD H. GADSDEN, WENDELL B. THROWER, Sidney H. Westbroo, James M. Tenneii
Journal: Circulation Research (1960)

Hyperglycemia and hypoxia acidosis are known to occur during periods of shock. The plasma levels of catechol amines have been reported to be elevated during periods of shock. Injection of epinephrine or levarterenol can produce increments in blood glucose and have been shown to elicit a metabolic acidosis. In the present studies the effects of reducing circulating blood volume or infusion of lactic acid and of forced CO 2 inhalation on ventricular isometric systolic tension (VCF) and the cardiovascular response to test injections of levarterenol were studied. The experiments with a reduction in circulating blood volume and with lactic acid infusions resulted in a decrease in arterial pH. whole blood total CO 2 and whole blood CO 2 combining power. Concomitant with these changes there was a marked depression of VCF and the response to test injections of levarterenol. Correction of the acid-base changes with 2-amino-2-hydroxymethyl, 1, 3-propane diol resulted in an immediate improvement in VCF and in the response to levarterenol. This change occurred despite a greater increase in blood lactate levels. Anaerobic metabolism with lactate production leads to a decrease in total blood CO 2 and an increase in dissolved CO 2 . This decrease in the CO 2 -carrying capacity would lead to an increase in tissue CO 2 . Since the heart is markedly depressed by CO 2 , this increment could be largely responsible for the myocardial depression. The oxygen debt which the heart can incur is thought to be limited. Therefore, the build-up of CO 2 one of the end-products of aerobic metabolism, would depress oxidative metabolism according to the law of mass action. This hypothesis was further tested by forced CO 2 ventilation which resulted in a marked depression of VCF and the response to levarterenol. Correction of the respiratory acidosis by the administration of THAM which increased the CO 2 -carrying capacity of the blood resulted in an immediate improvement in VCF and the levarterenol response.
Metastamir: The Field of Metastasis-Regulatory microRNA Is Spreading
Authors: Douglas R. Hurst, Mick D. Edmonds, Danny R. Welch
Journal: Cancer Research (2009)

Despite advancements in knowledge from more than a century of metastasis research, the genetic programs and molecular mechanisms required for cancer metastasis are still incompletely understood. Genes that specifically regulate the process of metastasis are useful tools to elucidate molecular mechanisms and may become markers and/or targets for antimetastatic therapy. Recently, several noncoding regulatory RNA genes, microRNA (miRNA), were identified, which play roles in various steps of metastasis, some without obvious roles in tumorigenesis. Understanding how these metastasis-associated miRNA, which we term metastamir, are involved in metastasis will help identify possible biomarkers or targets for the most lethal attribute of cancer: metastasis.