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1.  Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype 
Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy.
Experimental Design
Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production.
At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production.
Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
PMCID: PMC4537825  PMID: 25957288
Ependymoma; CNS; Myxopapillary; Cancer; Metabolism
2.  Epigenomic alterations define lethal CIMP-positive ependymomas of infancy 
Nature  2014;506(7489):445-450.
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
PMCID: PMC4174313  PMID: 24553142
4.  Finite Element Analysis of Stresses Developed in the Blood Sac of a Left Ventricular Assist Device 
Medical engineering & physics  2009;31(4):454-460.
The goal of this research is to develop a 3D finite element (FE) model of a left ventricular assist device (LVAD) to predict stresses in the blood sac. The hyperelastic stress-strain curves for the segmented poly(ether polyurethane urea) blood sac were determined in both tension and compression using a servo-hydraulic testing system at various strain rates. Over the range of strain rates studied, the sac was not strain rate sensitive, however the material response was different for tension versus compression. The experimental tension and compression properties were used in a FE model that consisted of the pusher plate, blood sac and pump case. A quasi-static analysis was used to allow for nonlinearities due to contact and material deformation. The 3D FE model showed that blood sac stresses are not adversely affected by the location of the inlet and outlet ports of the device and that over the systolic ejection phase of the simulation the prediction of blood sac stresses from the full 3D model and an axisymmetric model are the same. Minimizing stresses in the blood sac will increase the longevity of the blood sac in vivo.
PMCID: PMC2702508  PMID: 19131267
5.  No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis 
Journal of Clinical Pathology  2006;59(11):1186-1190.
That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence.
To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae.
Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H pylori and M pneumoniae. IgG antibody titres against H pylori and M pneumoniae and plasma levels of soluble E‐selectin, soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 were determined.
M pneumoniae‐specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M pneumoniae‐specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti‐M pneumoniae antibodies was not observed. H pylori‐specific DNA could not be detected in the specimens tested.
The absence of H pylori and the random distribution of M pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.
PMCID: PMC1860507  PMID: 16644879
6.  Asbestosis and lobar site of lung cancer 
OBJECTIVE—To assess the evidence for the hypothesis that lung cancer has a predilection for the lower lobes in workers with asbestosis.
METHOD—A review of the available literature with relevant information.
RESULTS—Six published reports were analysed. In four studies limited to series of cases with diagnoses of asbestosis, three showed lower lobe predominance of lung cancer whereas the fourth study included cases in which the radiographic readings did not meet the usual criterion of profusion for asbestosis. One cohort study showed lower lobe predominance; the other reported only 33% lower lobe cancers compared with 20% in unexposed controls.
CONCLUSION—There is some support for the hypothesis but more studies are needed.

Keywords: asbestos; asbestosis; lung cancer
PMCID: PMC1739953  PMID: 10769303
7.  Mannopeptimycins, New Cyclic Glycopeptide Antibiotics Produced by Streptomyces hygroscopicus LL-AC98: Antibacterial and Mechanistic Activities 
Mannopeptimycins α, β, γ, δ, and ɛ are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins γ, δ, and ɛ, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin ɛ was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 μg/ml for staphylococci and streptococci and 4 to 32 μg/ml for enterococci), while mannopeptimycins γ and δ were two- to fourfold less active. Mannopeptimycins α and β, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in Staphylococcus aureus mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins γ, δ, and ɛ were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient S. aureus and caused spheroplasting of Escherichia coli imp similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin δ rapidly inhibited [3H]N-acetylglucosamine incorporation into peptidoglycan in Bacillus subtilis and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin δ. The mannopeptimycins were inactive against Candida albicans, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from E. coli imp, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.
PMCID: PMC148986  PMID: 12499170
8.  Saccharomicins, Novel Heptadecaglycoside Antibiotics Produced by Saccharothrix espanaensis: Antibacterial and Mechanistic Activities 
Saccharomicins A and B, two new heptadecaglycoside antibiotics, were isolated from the fermentation broth of the rare actinomycete Saccharothrix espanaensis. They represent a novel class of bactericidal antibiotics that are active both in vitro and in vivo against bacteria and yeast (MICs: Staphylococcus aureus, <0.12 to 0.5; vancomycin-resistant enterococci, 0.25 to 16; gram-negative bacteria, 0.25 to >128; and yeast, >128 μg/ml), including multiply resistant strains. Saccharomicins protected mice from lethal challenges by staphylococci (subcutaneous 50% effective dose range of 0.06 to 2.6 mg/kg of body weight, depending on the S. aureus strain). The 50% lethal dose by the subcutaneous route was 16 mg/kg. Mechanistic studies with Escherichia coli imp and Bacillus subtilis suggested complete, nonspecific inhibition of DNA, RNA, and protein biosynthesis within 10 min of drug treatment. Microscopic examination of drug-treated cells also suggested cell lysis. These data are consistent with a strong membrane-disruptive activity. The antibacterial activities of the saccharomicins against gram-positive bacteria were unaffected by the presence of Ca2+ or Mg2+, but activity against gram-negative bacteria was substantially reduced.
PMCID: PMC90028  PMID: 10898690
9.  In Vivo Pharmacodynamic Activities of Two Glycylcyclines (GAR-936 and WAY 152,288) against Various Gram-Positive and Gram-Negative Bacteria 
The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters studied. These parameters were time above 0.03 to 32 times the MIC, area under the concentration-time curve (AUC), and maximum concentration of drug in serum (Cmax). The bacteriostatic dose remained essentially the same, irrespective of the dosing frequency, for S. pneumoniae 1199 (0.3 to 0.9 mg/kg/day). For E. coli ATCC 25922 and K. pneumoniae ATCC 43816, however, more frequent dosing led to lower bacteriostatic doses. Pharmacokinetic studies demonstrated dose-dependent elimination half-lives of 1.05 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for GAR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarly effective against the microorganisms studied, with small differences in maximum effect and 50% effective dose. The glycylcyclines were also similarly effective against tetracycline-sensitive and tetracycline-resistant bacteria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a better predictor of in vivo efficacy than Cmax or AUC for most organism-drug combinations. The results demonstrate that in order to achieve 80% maximum efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75% of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in humans.
PMCID: PMC89796  PMID: 10722495
10.  In Vitro and In Vivo Antibacterial Activities of a Novel Glycylcycline, the 9-t-Butylglycylamido Derivative of Minocycline (GAR-936) 
The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 μg/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, ≤0.5 μg/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.
PMCID: PMC89200  PMID: 10103174
12.  Cigarette smoking and small irregular opacities. 
A survey of chemical workers by chest roentgenograms was designed to determine whether exposure to acrylic dust and/or cigarette smoking was associated with diffuse abnormalities suggestive of pneumoconiosis. The films were examined without knowledge of dust exposure or smoking habits. The International Labour Office (ILO) classification and standard films were used. Workers with exposure to asbestos were excluded. There was no relation between prevalence of abnormalities and exposure to dust. Among 181 workers 28 had s and/or t small irregular opacities with profusion of 0/1 (23), 1/0 (three), or 1/1 (two). These findings were present in 20% of smokers compared with 2.2% of non-smokers. The prevalence increased with increasing age to 31.6% among smokers aged 50-64. Prevalence was 10% among ex-smokers of cigarettes. Among current cigarette smokers, prevalence was 5.3% in those who smoked less than one pack per day, 31.3% in heavier cigarette smokers, and 52.9% in 17 heavy cigarette smokers aged 50-64. Profusions of 0/1 and 1/0 are classified as "suspect" pneumoconiosis according to the ILO guidelines. The data in this study indicate that such abnormalities are directly related to age and smoking habits among workers not exposed to hazardous dust.
PMCID: PMC1035466  PMID: 1772799
13.  In vitro and in vivo activities of LJC10,627, a new carbapenem with stability to dehydropeptidase I. 
The activity of LJC10,627 was compared with the activities of imipenem and other antibiotics. LJC10,627 was more active against most members of the family Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp. but slightly less active than imipenem against staphylococci and streptococci. LJC10,627 showed stability to mouse dehydropeptidase I and was more effective in vivo than imipenem plus cilastatin against gram-negative bacterial infections and as effective against staphylococcal infections.
PMCID: PMC244971  PMID: 1901698
14.  Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1964-1969.
Tazobactam (YTR-830H), a novel beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam for enhancement of the activity of piperacillin against beta-lactamase-producing, piperacillin-resistant clinical isolates. Piperacillin MICs were determined in media containing a fixed concentration of 2 or 4 micrograms of the inhibitors per ml. The higher concentration was generally more effective. Tazobactam was superior to sulbactam in enhancing the spectrum and potency of piperacillin. Although the calvulanic acid combination was more potent, tazobactam was effective for a similar spectrum of resistant gram-negative clinical isolates containing beta-lactamase. MICs were reduced to the susceptible range for Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella spp., and Shigella spp. Combinations with tazobactam and sulbactam, but not clavulanic acid, were effective against Morganella spp. Some antagonism of the activity of piperacillin was observed with clavulanic acid but not with tazobactam or sulbactam. The inhibitors were similarly effective with piperacillin against beta-lactamase-positive Staphylococcus spp. and the Bacteroides fragilis group. Piperacillin-tazobactam was more effective against a broader spectrum of gram-negative enteric bacteria than ticarcillin plus clavulanic acid was. Combinations with tazobactam or clavulanic acid had a broader spectrum of activity than combinations with sulbactam against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In particular, piperacillin with tazobactam or clavulanic acid, but not with sulbactam, inhibited TEM-1, TEM-2, and SHV-1 enzymes. In vitro activity was reflected in vivo. Tazobactam and clavulanic acid were superior to sulbactam in enhancing the therapeutic efficacy of piperacillin in mice infected with beta-lactamase-positive E. coli, K. pneumoniae, Proteus mirabilis, and Staphylococcus aureus. Only combinations with tazobactam and sulbactam were effective against the Morganella infection. Tazobactam has a good potential for enhancing the clinical efficacy of piperacillin.
PMCID: PMC172796  PMID: 2558615
16.  Lobe of origin in the attribution of lung cancer to asbestos. 
Lung cancer originates most commonly in the upper lobes in the general population but among workers with asbestosis it is most common in the lower lobes. Published data on lobar distribution were used to estimate the probabilities that lung cancer among asbestos workers is attributable to exposure to asbestos. This attribution varies directly with the relative risk. Critical values of the relative risk at which attribution of lung cancer to asbestos equalled its attribution to other causes, mainly smoking, were calculated. At a relative risk above 2.81 upper lobe cancers were more likely to be due to asbestos than not. For middle and lower lobe cancers, the critical relative risk was 1.55. These critical values were compared with published standardised mortality ratios reported for cohorts of workers with asbestosis. Since the ratios ranged from 6.3 to 9.1, the probability that lung cancer in such cases is due to asbestos is high regardless of lobe of origin. In many cohorts unstratified by the presence or absence of asbestosis the risk ratios are below one or both of these critical values. Since risk ratios are so high among workers with asbestosis, the ratios must be lower for workers without asbestosis than the overall ratios for unstratified cohorts. Therefore, the critical values may be useful in workers without asbestosis among such cohorts to estimate the upper limit of the probability that lung cancer in a given lobe is due to exposure to asbestos.
PMCID: PMC1009648  PMID: 3415920
17.  Effect of cimetidine treatment in the prevention of gastric ulcer relapse: a one year double blind multicentre study. 
Gut  1983;24(9):853-856.
One hundred and forty six gastric ulcer patients were given open treatment using 1 g cimetidine daily to heal their ulcers. Of 130 who completed the acute treatment period of eight weeks, 112 (86%) had healed ulcers. Of these 112 patients with healed ulcers, 108 entered a one year double blind study to compare the effect of cimetidine maintenance therapy (400 mg at night) with placebo. Of the 84 patients available for assessment at the end of one year, 86% in the cimetidine treated group were in remission compared with 45% in the placebo treated group (chi 2 = 15.03; p less than 0.001). There were similar losses from non-compliance and drop out in both groups. The incidence of untoward effects and significant drug related laboratory abnormalities was low. The results indicate that cimetidine heals nearly 90% of acute gastric ulcers within eight weeks and that subsequent low dose maintenance treatment at night offers a considerable benefit over placebo therapy.
PMCID: PMC1420086  PMID: 6350116
18.  Coffee consumption and pancreatic cancer: temporal and spatial correlation. 
An examination of available data on per caput consumption of coffee and pancreatic cancer mortality in the United States since 1950 shows a temporal association. A rise and fall in coffee consumption was followed by a rise and fall in the incidence of pancreatic cancer with roughly a 10-year lag. Nevertheless, there were inconsistencies in this relationship was also found between the consumption of coffee and pancreatic cancer mortality in 13 countries. While this relationship suggests an association, major inconsistencies case doubt on the possibility that it is one of cause and effect. This may be due to confounding, particularly by cigarette smoking and cancer of the pancreas is much more consistent with a causal relationship.
PMCID: PMC1495983  PMID: 6800475
19.  Cross-protection between attenuated Plasmodium berghei and P. yoelii sporozoites 
Parasite Immunology  2007;29(11):559-565.
An attenuatedPlasmodium falciparum sporozoite (PfSPZ) vaccine is under development, in part, based on studies in mice withP. berghei. We usedP. berghei andP. yoelii to study vaccine-induced protection against challenge with a species of parasite different from the immunizing parasite in BALB/c mice. One-hundred percent of mice were protected against homologous challenge. Seventy-nine percent immunized with attenuatedP. berghei sporozoite (PbSPZ)(six experiments) were protected against challenge withP. yoelii sporozoite (PySPZ), and 63% immunized with attenuatedPySPZ(three experiments) were protected against challenge withPbSPZ. Antibodies in sera of immunized mice only recognized homologous sporozoites and could not have mediated protection against heterologous challenge. Immunization with attenuatedPySPZ orPbSPZ induced CD8+ T cell-dependent protection against heterologous challenge. Immunization with attenuatedPySPZ induced CD8+ T cell-dependent protection against homologous challenge. However, homologous protection induced by attenuatedPbSPZ was not dependent on CD8+ or CD4+ T cells, and depletion of both populations only reduced protection by 36%. Immunization of C57BL/10 mice withPbSPZ induced CD8+ T cell-dependent protection againstP. berghei, but no protection againstP. yoelii. The cross-protection data in BALB/c mice support testing a human vaccine based on attenuatedPfSPZ for its efficacy againstP. vivax.
PMCID: PMC2955969  PMID: 17944745
CD8+ T cells; cross-protection; P. berghei; P. yoelii; sporozoites
20.  Digitalis 
British Medical Journal  1948;1(4543):224.
PMCID: PMC2089739

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