tbuckley/cabot-search huggingface dataset:
Carbonic anhydrase II in the endothelium of glial tumors: A potential target for therapy
Authors: Joonas Haapasalo, Kristiina Nordfors, Sally Järvelä, Helena Bragge, Immo Rantala, Anna-Kaisa Parkkila, Hannu Haapasalo, Seppo Parkkila
Journal: Neuro-Oncology (2007)

Carbonic anhydrase isozyme II (CA II) is a cytosolic enzyme that is highly expressed in most organs, including the brain, where it is mainly located in the oligodendrocytes. Recent studies have shown that its expression is induced in the endothelium of neovessels in melanoma and esophageal, renal, and lung cancer. Immunological studies further indicate that CA II represents a major target antigen stimulating an autoantibody response in melanoma patients. These results prompted us to investigate endothelial CA II expression in two types of brain cancer: oligodendrogliomas and astrocytomas. A series of 255 astrocytoma and 71 oligodendroglial tumor specimens was immunostained for CA II. The staining results were correlated with a number of different clinicopathological factors and survival data. CA II showed weak or no expression in low-grade tumors, while grade 3 mixed oligoastrocytoma and glioblastoma multiforme were the most positively stained tumor types. Survival analysis indicated that endothelial CA II staining is significantly associated with a poor prognosis in patients with astrocytomas. About 17% of patients with CA II-negative tumors (weak or no endothelial signal) were still alive at the end of the follow-up period of five years. The presence of CA II in the tumor endothelium suggests that it may play an important functional role in tumor metabolism. From a clinical perspective, the results also open new avenues for selecting tumor types for dendritic cell therapy trials.
Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury
Authors: Kenichi Imahashi, Michael D. Schneider, Charles Steenbergen, Elizabeth Murphy
Journal: Circulation Research (2004)

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH(i) and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin (Oligo), an F1F0-ATPase inhibitor, the decrease in pH(i) was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH(i) during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.
Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis.
Authors: C J Kelly, W K Silvers, E G Neilson
Journal: The Journal of Experimental Medicine (1985)

BN rats develop interstitial nephritis after immunization with rabbit, but not rat renal tubular antigen. Using RT1n rat strains that differentially express tubular antigen, we investigated the unresponsiveness of BN rats to BN tubular antigen (BN-TBM) using delayed-type hypersensitivity (DTH) responses to BN-TBM as a measure of cell-mediated immunity. Our results indicate that rat strains expressing tubular antigen respond to immunization with BN-TBM with the clonal expansion of antigen-specific, cyclophosphamide-sensitive, OX8+, MHC-restricted suppressor T cells. Such suppression appears to be relevant to the maintenance of tolerance to parenchymal self, since chronic cyclophosphamide therapy abrogates suppression and results in significant interstitial nephritis.
The relative importance of myocardial energy metabolism compared with ischemic contracture in the determination of ischemic injury in isolated perfused rabbit hearts.
Authors: J L Vanoverschelde, M F Janier, S R Bergmann
Journal: Circulation Research (1994)

The mechanical effects of ischemic contracture may be important in the development of irreversible cellular damage as it increases mechanical stress on sarcolemmal membranes and restricts endocardial perfusion. To assess the relative importance of these mechanical effects compared with decreased energy supply in the development of irreversible injury, the effects of inhibiting ischemic contracture with 2,3-butanedione monoxime (BDM), an agent that disrupts excitation-contraction coupling, were delineated in isovolumically contracting isolated rabbit hearts. Administration of 20 mmol/L BDM in 12 hearts subjected to 60 minutes of low-flow ischemia prevented ischemic contracture (left ventricular end-diastolic pressure [LVEDP], 12 +/- 3 compared with 48 +/- 14 mm Hg in 20 control hearts; P &lt; .001), reduced membrane damage (creatine kinase [CK] release, -54% compared with control hearts; P &lt; .05), and enhanced functional recovery during reperfusion (left ventricular developed pressure [LVDP], 86 +/- 10% of baseline compared with 56 +/- 23% in control hearts; P &lt; .01). These observations were not related to increased intracavitary pressure and its effects on flow distribution, since venting the left ventricle in additional hearts did not result in improved function during reperfusion. Although it would be tempting to conclude that BDM protected ischemic myocardium by preventing ischemic contracture, administration of BDM was also associated with reduced depletion of ATP during ischemia, perhaps related to diminished energy demand. To distinguish between the relative importance of inhibiting contracture from provision of adequate energy, the period of ischemia was extended to 120 minutes. BDM still prevented ischemic contracture (LVEDP, 10 +/- 6 mm Hg) and preserved ATP stores, but it did not prevent membrane damage (CK release, 483 +/- 254 U/g dry weight) or contractile failure during reperfusion (LVDP, 68 +/- 7% of baseline). In contrast, increasing the rate of anaerobic glycolysis during ischemia by doubling glucose and insulin in the presence of BDM markedly decreased membrane damage (CK release, 114 +/- 72 U/g dry weight; P &lt; .05) and contractile failure during reperfusion (LVDP, 88 +/- 7% recovery of baseline; P &lt; .01). These results suggest that insufficient energy production is primarily responsible for myocardial ischemic damage, whereas mechanical effects of ischemic contracture appear to play only a minor role.
Gene therapy by intercellular trafficking of p53-VP22 induces regression of orthotopic hepatocellular carcinoma in rats
Authors: Lars Zender, Sebastian Hütker, Bernd Frericks, Matthias Eckhard, Thomas Gösling, Michael Galanski, Christian Krettek, Florian Kühnel, Michael Manns, Stefan Kubicka
Journal: Journal of Hepatology (2002)
Prevention of Hypoxia-Induced Pulmonary Hypertension by Enhancement of Endogenous Heme Oxygenase-1 in the Rat
Authors: Helen Christou, Toshisuke Morita, Chung-Ming Hsieh, Hideo Koike, Burak Arkonac, Mark A. Perrella, Stella Kourembanas
Journal: Circulation Research (2000)

Abstract —We investigated the role of heme oxygenase (HO)–1 in the development of hypoxia-induced pulmonary hypertension. HO catalyzes the breakdown of heme to the antioxidant bilirubin and the vasodilator carbon monoxide. Hypoxia is a potent but transient inducer of HO-1 in vascular smooth muscle cells in vitro and in the lung in vivo. By using agonists of HO-1, we sustained a high expression of HO-1 in the lungs of rats for 1 week. We report that this in vivo enhancement of HO-1 in the lung prevented the development of hypoxic pulmonary hypertension and inhibited the structural remodeling of the pulmonary vessels. The mechanism(s) underlying this effect may involve a direct vasodilating and antiproliferative action of endogenous carbon monoxide, as well as an indirect effect of carbon monoxide on the production of vasoconstrictors. These results provide evidence that enhancement of endogenous adaptive responses may be used to prevent hypoxia-induced pulmonary hypertension.
Age-Dependent Decline of Association Between Obesity and Hyperglycemia in Men and Women
Authors: Ichiro Wakabayashi, Takashi Daimon
Journal: Diabetes Care (2011)

OBJECTIVE The purpose of this study was to determine whether age influences the association between obesity and hyperglycemia. RESEARCH DESIGN AND METHODS The subjects were 57,576 Japanese male and female workers aged 35–70 years. The associations of adiposity indices, including BMI, waist circumference, and waist-to-height ratio, with risk for hyperglycemia were compared among different age groups (35–39, 40–49, 50–59, and 60–70 years) using odds ratios (ORs). RESULTS There were significant trends for the crude ORs of obese subjects versus nonobese subjects for hyperglycemia to be lower as age increased in men and women. Multivariate logistic regression analysis showed these trends of age-dependent decreases in ORs for hyperglycemia were not altered by adjustment for confounders such as smoking, alcohol drinking, and habitual exercise. CONCLUSIONS The results suggest that the association between obesity and hyperglycemia declines with age in men and women.
Comparing cold-air analgesia, systemically administered analgesia and scalp nerve blocks for pain management during photodynamic therapy for actinic keratosis of the scalp presenting as field cancerization: a randomized controlled trial
Authors: A. Klein, S. Karrer, C. Horner, A. Werner, J. Heinlin, F. Zeman, M. Koller, M. Landthaler, R.-M. Szeimies, M. Gruber, B. Graf, E. Hansen, C. Kerscher
Journal: British Journal of Dermatology (2014)

Photodynamic therapy (PDT) using methyl aminolaevulinate (MAL) is an effective treatment for extensive actinic keratosis (AK). However, pain is a major side-effect of this therapy.To investigate whether scalp nerve blocks (group 1) provide adequate pain relief during MAL-PDT of the scalp and forehead in 32 men with baldness.The patients received intravenous (IV) analgesia [piritramide 7.5 mg IV, plus oral metamizole (40 drops 30 min prior to PDT)] in combination with cold-air analgesia (group 2; IV analgesia) and cold-air analgesia alone (group 3). Maximum pain was evaluated by means of a visual analogue scale (VAS) during and up to 300 min after PDT. Pain during PDT was further analysed according to a pain perception scale. Furthermore, we measured haemodynamics and investigated stress hormone levels in blood samples at different time points.Maximum pain during PDT (primary end point) was significantly reduced in the treatment group receiving scalp nerve blocks (VAS 2.1 ± 1.3) compared with the treatment groups receiving IV analgesia (VAS 7.3 ± 1.1) and cold-air analgesia (VAS 8.4 ± 2.0; P < 0.05). No significant difference was found between groups 2 and 3 with regard to pain relief (P = 0.32). The increase in systolic blood pressure during the first 3 min of PDT was significantly lower for group 1 than for groups 2 and 3 (P < 0.001). No correlation between stress hormone levels and pain were found.Scalp nerve blocks provide an effective method for pain management during PDT for patients with extensive AK.
The Reduction of Low Density Lipoprotein Cholesterol by Metformin is Maintained with Long-Term Therapy
Authors: S G H Rains, G A Wilson, W Richmond, R S Elkeles
Journal: Journal of the Royal Society of Medicine (1989)

Changes in serum lipoproteins were studied in 14 non-insulin dependent diabetics on long-term metformin therapy, after 6 weeks' placebo, and again 6 weeks after restarting active drug therapy. Withdrawal of metformin resulted in a rise of fasting blood glucose, HbAl, serum total and low density lipoprotein (LDL) cholesterol. Restarting the drug reversed these changes. Multivariate analysis showed that serum total and LDL cholesterol varied with treatment but not with glycaemic control Metformin can lower serum total and LDL cholesterol in non-insulin dependent diabetics and this effect is maintained long term.
Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130.
Authors: N Nishimoto, A Ogata, Y Shima, Y Tani, H Ogawa, M Nakagawa, H Sugiyama, K Yoshizaki, T Kishimoto
Journal: The Journal of Experimental Medicine (1994)

We analyzed the stimulatory effect of oncostatin M (OSM), leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, and the inhibitory effect of anti-IL-6 antibody (Ab), anti-IL-6 receptor monoclonal antibody (mAb), and anti-gp130 mAb on the growth of human plasmacytoma cells freshly isolated from a patient with multiple myeloma. The purified cells showed a plasmacytoid morphology and expressed CD38, CD54, and CD56 antigens but no CD3, CD5, CD10, CD19, CD20, or very late antigen 5. IL-6 receptor (IL-6R) and its signal transducer, gp130, were expressed on their cell surface at a low level. Dose-dependent proliferation of the cells in response to OSM, LIF, and IL-6, but not to IL-11, was observed using [3H]TdR incorporation in vitro. Both anti-IL-6 Ab and anti-IL-6R mAb inhibited the growth of the cells in the presence or absence of exogenous IL-6. These cells release IL-6 but not OSM or LIF into the culture supernatant during short-term culture. Therefore, an autocrine growth mechanism mediated by IL-6, but not by OSM or LIF, was confirmed. Furthermore, anti-gp130 mAb completely inhibited the proliferation of the cells induced by OSM, LIF, as well as IL-6. These data indicate that OSM, LIF, and IL-6 can act as growth factors of human plasmacytoma cells through a common signal transducer, gp130, on their cell surface, and also suggest the potential therapeutic application of anti-gp130 mAb, as well as anti-IL-6R mAb against myeloma/plasmacytomas.
Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis
Authors: Matthias Nahrendorf, Farouc A. Jaffer, Kimberly A. Kelly, David E. Sosnovik, Elena Aikawa, Peter Libby, Ralph Weissleder
Journal: Circulation (2006)

Background— Noninvasive imaging of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) may identify early stages of inflammation in atherosclerosis. We hypothesized that a novel, second-generation VCAM-1–targeted agent with enhanced affinity had sufficient sensitivity to enable real-time detection of VCAM-1 expression in experimental atherosclerosis in vivo, to quantify pharmacotherapy-induced reductions in VCAM-1 expression, and to identify activated cells in human plaques. Methods and Results— In vivo phage display in apolipoprotein E–deficient mice identified a linear peptide affinity ligand, VHPKQHR, homologous to very late antigen-4, a known ligand for VCAM-1. This peptide was developed into a multivalent agent detectable by MRI and optical imaging (denoted VINP-28 for VCAM-1 internalizing nanoparticle 28, with 20 times higher affinity than previously reported for VNP). In vitro, VINP-28 targeted all cell types expressing VCAM-1. In vivo, MRI and optical imaging in apolipoprotein E–deficient mice (n=28) after injection with VINP-28 or saline revealed signal enhancement in the aortic root of mice receiving VINP-28 ( P &lt;0.05). VINP-28 colocalized with endothelial cells and other VCAM-1–expressing cells, eg, macrophages, and was spatially distinct compared with untargeted control nanoparticles. Atheromata of atorvastatin-treated mice showed reduced VINP-28 deposition and VCAM-1 expression. VINP-28 enhanced early lesions in juvenile mice and resected human carotid artery plaques. Conclusions— VINP-28 allows noninvasive imaging of VCAM-1–expressing endothelial cells and macrophages in atherosclerosis and spatial monitoring of anti–VCAM-1 pharmacotherapy in vivo and identifies inflammatory cells in human atheromata. This clinically translatable agent could noninvasively detect inflammation in early, subclinical atherosclerosis.
Sensitivity to Input Variability of the Adjuvant! Online Breast Cancer Prognostic Model
Authors: Elissa M. Ozanne, Dejana Braithwaite, Karen Sepucha, Dan Moore, Laura Esserman, Jeffrey Belkora
Journal: Journal of Clinical Oncology (2008)

Adjuvant! Online (www.adjuvantonline.org) is a software model that predicts the benefit of adjuvant therapy for women with early-stage breast cancer. The model has been validated, is widely consulted, and has been shown to influence patient choices in the clinical setting. Adjuvant! requires the clinician to input patient age, tumor size, grade, hormone receptor status, number of positive lymph nodes, and comorbidity level. Because comorbidity is strongly and independently associated with survival, this study tested the hypothesis that Adjuvant! predictions would be sensitive to comorbidity inputs.Investigators used single-variable deterministic sensitivity analysis to evaluate the effect of varying each input of the model independently for three representative case examples based on National Comprehensive Cancer Network guidelines (NCCN). The main outcome of interest was 10-year mortality prediction.The analyses show that Adjuvant!'s 10-year mortality predictions are most sensitive to patients' comorbidity levels and the extent of nodal involvement for the cases, particularly among older women. Comorbidity was the most influential input except in younger women, aged 40 years.The Adjuvant! model is sensitive to patient comorbidity, and impact on the model outputs are significant enough that they are likely to affect physician recommendations and patients' treatment choices. For example, incorrect assessments of comorbidities could lead physicians to overtreat or undertreat a patient who is in a gray zone relative to the NCCN guidelines. These results point to the importance of accurately assessing comorbidities in patients with breast cancer when using Adjuvant! and highlight the need for a standardized process of comorbidity ascertainment.
Pneumococcal serotypes and respiratory failure: soil or seed?
Authors: M. Woodhead
Journal: European Respiratory Journal (2014)

When considering the microbial aetiology of community-acquired pneumonia (CAP) we seldom think beyond the name (genus and species) of the causative organism. In a recent study of CAP aetiology in outpatients, Streptococcus pneumoniae was reported to be the most frequent pathogen [1]; unchanged from previous studies. The knowledge that S. pneumoniae is the commonest cause is sufficient to assist the choice of appropriate antibiotics; the most important management decision required for most patients.

However, there is a lot more to this bacterial species than the name might imply. In fact, there are now known to be >90 distinct pneumococcal serotypes, each characterised by a slightly different structure in the pneumococcal capsular polysaccharide. These small molecular differences are an important determinant of immune response; therefore, immunity is serotype specific. Studies in the pre-antibiotic era dealt in depth with serotype distributions, as at that time serotype specific serum was the only available therapy. With the advent of antibiotics, pneumococcal serotypes have received much less attention. Now with the development of pneumococcal vaccines, and the importance of matching vaccines to causative serotypes, this subject is having a renaissance. From this we are starting to understand that there is more to the different serotypes than just a difference in polysaccharide structure. Indeed, the serotype is increasingly being linked, not just with the immune response, but also with the clinical phenotype in individual patients.

In this issue of the European Respiratory Journal , Burgos et al. [2] describe an investigation into the risk factors for respiratory failure (defined as …
Minimal toxicity of stabilized compacted DNA nanoparticles in the murine lung
Authors: Assem-Galal Ziady, Christopher R Gedeon, Osman Muhammad, Virginia Stillwell, Sharon M Oette, Tamara L Fink, Will Quan, Tomasz H Kowalczyk, Susannah L Hyatt, Jennifer Payne, Angela Peischl, J.E Seng, Robert C Moen, Mark J Cooper, Pamela B Davis
Journal: Molecular Therapy (2003)

Nanoparticles containing DNA compacted with poly-l-lysine modified on an N-terminal cysteine with polyethylene glycol can effectively transfect cells of the airway epithelium when applied by the luminal route. To evaluate the toxicity of these nanoparticles, we administered 10 and 100 μg DNA compacted into nanoparticles suspended in normal saline by the intranasal route to mice and determined the pulmonary and systemic responses to this challenge, compared to administration of saline alone, and in some experiments, compared to administration of naked DNA, Escherichia coli genomic DNA, or lipofectin-complexed naked DNA. There was no systemic response to either dose of nanoparticles in serum chemistries, hematologic parameters, serum complement, IL-6, or MIP-2 levels or in the activity, growth, and grooming of the mice. Nanoparticles containing 10 μg DNA induced responses comparable to saline in all measures, including BAL cell counts and differentials and cytokine levels and histology. However, mice dosed with 100 μg DNA in nanoparticles had modest increases in BAL neutrophils 48 and 72 h after dosing, modest increases in BAL IL-6 and KC beginning 24 and 48 h, respectively, after dosing, and, on histology of the lung, a trace to 1+ mononuclear cell infiltrates about the pulmonary veins at 48 h, which were markedly reduced by 10 days and gone by 28 days after dosing. BAL neutrophil and cytokine responses were no greater than those entrained by naked DNA for up to 24 h. However, compared to administration of only 10 μg E. coli genomic DNA, the response to compacted DNA was much less. A low dose of lipofectin-complexed DNA (5 μg DNA) induced the same response as 20-fold higher doses of DNA nanoparticles. These data indicate that DNA nanoparticles have no measurable toxic effect at a dose of 10 μg and a very modest effect, which is not limiting, at a dose of 100 μg, which gives maximal gene expression. This favorable toxicity profile encourages development of stabilized compacted DNA for airway administration.