tbuckley/cabot-search huggingface dataset:
Age-related changes in Purkinje fiber action potentials of adult dogs.
Authors: M R Rosen, R F Reder, A J Hordof, M Davies, P Danilo
Journal: Circulation Research (1978)

To determine the effects of age on electrophysiological properties of Purkinje fibers (PF), we used standard microelectrode techniques to study PF from normal beagles of five age groups: 19.1 +/- 0.8, 63.7 +/- 2.6, 88.3 +/- 1.9, 107.2 +/- 1.6, and 132.3 +/- 4.3 months (mean +/- SE). Maximum diastolic potential (MDP) did not change over this age range. Action potential (AP) amplitude and maximum upstroke velocity of phase 0 (Vmax) attained peak values at 63.7 months and then declined. As age increased there was an increase in phase 1 repolarization, a prolongation in the time to the peak of the plateau, and a decrease in plateau height. AP duration reached a maximum at 63.7 months and thereafter remained unchanged. Fibers were superfused with the slow channel blocker, AHR-2666, and the fast channel blocker, tetrodotoxin (TTX). AHR-2666 had age-related effects on AP duration, phase 1 repolarization, plateau height, and time to the peak of the plateau. There were no age-related changes in TTX effects on phases 0--2. In another series of experiments, Purkinje fibers from dogs 23 +/- 1.2 to 106 +/- 1.4 months old were superfused with a calcium-rich solution in which Na+ was replaced by tetraethylammonium (TEA+). The resultant slow response action potentials, which are calcium dependent, showed an age-related decrease in AP amplitude, Vmax, and time to peak amplitude. When these fibers were superfused with the slow channel blocker, verapamil, there was an age-related effect on AP amplitude. Our studies indicate that in the normal aging heart, major changes occur in repolarization that appear, in the main, to result from change in the slow inward current carried by Ca2+.
Identification of Retinol Binding Protein 1 Promoter Hypermethylation in Isocitrate Dehydrogenase 1 and 2 Mutant Gliomas
Authors: Arthur P. Chou, Reshmi Chowdhury, Sichen Li, Weidong Chen, Andrew J. Kim, David E. Piccioni, Julia M. Selfridge, Reema R. Mody, Stephen Chang, Shadi Lalezari, Jeffrey Lin, Desiree E. Sanchez, Ryan W. Wilson, Matthew C. Garrett, Bret Harry, Jack Mottahedeh, Phioanh L. Nghiemphu, Harley I. Kornblum, Paul S. Mischel, Robert M. Prins, William H. Yong, Timothy Cloughesy, Stanley F. Nelson, Linda M. Liau, Albert Lai
Journal: JNCI Journal of the National Cancer Institute (2012)

Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing. Reduced representation bisulfite sequencing was performed on ten pathologically matched WT and MUT glioma samples and compared with data from a methylation-sensitive restriction enzyme technique and data from The Cancer Genome Atlas (TCGA). Methylation in the gene retinol-binding protein 1 (RBP1) was identified in IDH1 mutant tumors and further analyzed with primer-based bisulfite sequencing. Correlation between IDH1/IDH2 mutation status and RBP1 methylation was evaluated with Spearman correlation. Survival data were collected retrospectively and analyzed with Kaplan–Meier and Cox proportional hazards analysis. All statistical tests were two-sided. Methylome analysis identified coordinated CpG island hypermethylation in IDH1 MUT gliomas, consistent with previous reports. RBP1, important in retinoic acid metabolism, was found to be hypermethylated in 76 of 79 IDH1 MUT, 3 of 3 IDH2 MUT, and 0 of 116 IDH1/IDH2 WT tumors. IDH1/IDH2 mutation was highly correlated with RBP1 hypermethylation (n = 198; Spearman R = 0.94, 95% confidence interval = 0.92 to 0.95, P < .001). The Cancer Genome Atlas showed IDH1 MUT tumors (n = 23) to be RBP1-hypermethylated with decreased RBP1 expression compared with WT tumors (n = 124). Among patients with primary glioblastoma, patients with RBP1-unmethylated tumors (n = 102) had decreased median overall survival compared with patients with RBP1-methylated tumors (n = 22) (20.3 months vs 36.8 months, respectively; hazard ratio of death = 2.48, 95% confidence interval = 1.30 to 4.75, P = .006). RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.
Phase II study of S-1, an oral fluoropyrimidine, in patients with advanced or recurrent cervical cancer
Authors: N. Katsumata, Y. Hirai, S. Kamiura, T. Sugiyama, K. Kokawa, M. Hatae, R. Nishimura, K. Ochiai
Journal: Annals of Oncology (2011)

BackgroundS-1 is an oral fluoropyrimidine. This phase II study was designed to evaluate the efficacy and safety of S-1 in patients with advanced or recurrent uterine cervical cancer.Patients and methodsS-1 35 mg/m2 was given twice daily for 28 days repeated every 6 weeks. Eligible patients were women aged 20–74 years, who had Eastern Cooperative Oncology Group performance status of zero or one, who had stage IVB or recurrent uterine cervical cancer, and who had received no more than one platinum-containing chemotherapy regimen for stage IVB or recurrent disease. The primary end point was overall response rate (ORR) determined by RECIST.ResultsA total of 37 patients were enrolled in the trial and 36 were eligible. The median number of cycles administered was 4. The confirmed ORR was 30.6% (95% confidence interval 15.5% to 45.6%). The response rate for patients who had received platinum-based treatment including chemoradiotherapy was 31.8% (7 of 22). After a median follow-up duration of 25 months, the median time to progression and the median survival time were 5.2 and 15.4 months, respectively. The most frequent grade 3 or 4 adverse events were anemia (16%), anorexia (16%), and diarrhea (22%).ConclusionsThis phase II study of S-1 in cervical cancer suggests a promising response rate and a contribution toward prolonging survival, with modest toxic effects. Phase III studies of S-1 in patients with advanced or recurrent cervical cancer are thus warranted.
ARTERIO-SCLEROSIS IN RELATION TO MENTAL DISEASE
Authors: C. Macfie Campbell
Journal: American Journal of Psychiatry (1908)

I. While arterio-sclerosis of some degree is a commonplace finding in cases of mental disorders, especially in advanced life, there are cases where the cardio-vascular disorder seems to be the central element in the clinical and anatomical picture. II. Certain cases symptomatologically described as melancholia, hypochondria, neurasthenia, etc., may be better grouped on etiological grounds as eases of arterio-sclerotic brain disorder; while the arterio-sclerosis is an important factor, the factors which led to the symptomatological grouping are not to be neglected. This necessitates the analysis of the depressions in advanced life. III. In certain cases of organic dementia the arterio-sclerotic changes are obviously the most important element in the process and the term arterio-sclerotic dementia is justifiable; but the relation of certain mental symptoms to similar ones in the presenile and senile psychoses must be kept in mind. This necessitates the analysis of the presenile and senile psychoses. It is premature to correlate the whole symptomatology with the arterio-sclerotic part of the anatomical findings. IV. The neurological picture in advanced cerebral arterio-sclerosis is still ill-defined; and for the differential diagnosis of the various organic dementias further clinical material is required. V. In certain cases of epilepsy with onset in late life, the convulsions and general symptomatology are closely related to arteriosclerosis.
Chimeric Plastid Proteome in the Florida “Red Tide” Dinoflagellate Karenia brevis
Authors: Tetyana Nosenko, Kristy L. Lidie, Frances M. Van Dolah, Erika Lindquist, Jan-Fang Cheng, Debashish Bhattacharya
Journal: Molecular Biology and Evolution (2006)

Current understanding of the plastid proteome comes almost exclusively from studies of plants and red algae. The proteome in these taxa has a relatively simple origin via integration of proteins from a single cyanobacterial primary endosymbiont and the host. However, the most successful algae in marine environments are the chlorophyll c–containing chromalveolates such as diatoms and dinoflagellates that contain a plastid of red algal origin derived via secondary or tertiary endosymbiosis. Virtually nothing is known about the plastid proteome in these taxa. We analyzed expressed sequence tag data from the toxic "Florida red tide" dinoflagellate Karenia brevis that has undergone a tertiary plastid endosymbiosis. Comparative analyses identified 30 nuclear-encoded plastid-targeted proteins in this chromalveolate that originated via endosymbiotic or horizontal gene transfer (HGT) from multiple different sources. We identify a fundamental divide between plant/red algal and chromalveolate plastid proteomes that reflects a history of mixotrophy in the latter group resulting in a highly chimeric proteome. Loss of phagocytosis in the "red" and "green" clades effectively froze their proteomes, whereas chromalveolate lineages retain the ability to engulf prey allowing them to continually recruit new, potentially adaptive genes through subsequent endosymbioses and HGT. One of these genes is an electron transfer protein (plastocyanin) of green algal origin in K. brevis that likely allows this species to thrive under conditions of iron depletion.
Leukotriene B4 enhances the activity of nuclear factor- B pathway through BLT1 and BLT2 receptors in atherosclerosis
Authors: E. Sanchez-Galan, A. Gomez-Hernandez, C. Vidal, J. L. Martin-Ventura, L. M. Blanco-Colio, B. Munoz-Garcia, L. Ortega, J. Egido, J. Tunon
Journal: Cardiovascular Research (2008)

AimsLeukotriene B4 (LTB4) is a powerful chemoattractant and pro-inflammatory mediator in several inflammatory diseases, including atherosclerosis. It acts through its two membrane receptors, BLT1 and BLT2. The aim of this study was to determine the molecular mechanism involved in the proatherogenic effect of LTB4, BLT1 and BLT2 in atherosclerosis. Moreover, we characterized the expression of 5-lipoxygenase (5-LO) pathway and LTB4 receptors in blood and plaques from patients with carotid atherosclerosis.
Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy
Authors: David Grimwade, Jelena V. Jovanovic, Robert K. Hills, Elizabeth A. Nugent, Yashma Patel, Rajinder Flora, Daniela Diverio, Katy Jones, Hannah Aslett, Elaine Batson, Kristian Rennie, Roger Angell, Richard E. Clark, Ellen Solomon, Francesco Lo-Coco, Keith Wheatley, Alan K. Burnett
Journal: Journal of Clinical Oncology (2009)

Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial.Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia.
Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936
Authors: P A S Evans, Ch Pott, P J T A Groenen, G Salles, F Davi, F Berger, J F Garcia, J H J M van Krieken, S Pals, Ph Kluin, E Schuuring, M Spaargaren, E Boone, D González, B Martinez, R Villuendas, P Gameiro, T C Diss, K Mills, G J Morgan, G I Carter, B J Milner, D Pearson, M Hummel, W Jung, M Ott, D Canioni, K Beldjord, C Bastard, M H Delfau-Larue, J J M van Dongen, T J Molina, J Cabeçadas
Journal: Leukemia (2006)
Recombinant Human Thrombopoietin Attenuates Carboplatin-Induced Severe Thrombocytopenia and the Need for Platelet Transfusions in Patients with Gynecologic Cancer
Authors: Saroj Vadhan-Raj, Claire F. Verschraegen, Carlos Bueso-Ramos, Hal E. Broxmeyer, Andrzej P. Kudelka, Ralph S. Freedman, Creighton L. Edwards, David Gershenson, Dennie Jones, Mark Ashby, John J. Kavanagh
Journal: Annals of Internal Medicine (2000)

Background: Thrombocytopenia is a significant problem in the treatment of cancer. Objective: To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia. Design: Phase I/II clinical cohort study. Setting: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Patients: 29 patients with gynecologic cancer. Intervention: Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy. Measurements: Peripheral blood counts and platelet transfusions. Results: Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 µg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44 × 109 cells/L and 20 × 109 cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count <20 × 109 cells/L, 1 and 4 [P = 0.002]; days with a platelet count <50 × 109 cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013). Conclusions: Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.
Epidermal Growth Factor Receptor Blockade Mediates Smooth Muscle Cell Apoptosis and Improves Survival in Rats With Pulmonary Hypertension
Authors: Sandra L. Merklinger, Peter L. Jones, Eliana C. Martinez, Marlene Rabinovitch
Journal: Circulation (2005)

Background— We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through α v β 3 -integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH. Methods and Results— In this study, we first showed in PA organ culture that MMP inhibition or α v β 3 -integrin blockade with agents in clinical and preclinical use (SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle- or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries. Conclusion— We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.
Epidermal growth factor receptor – but not histamine receptor – is upregulated in seasonal allergic rhinitis
Authors: E. Matovinovic, O. Solberg, D. Shusterman
Journal: Allergy (2003)

Background: We were interested in exploring the molecular mechanisms underlying the observed difference in histamine (H) responsiveness between seasonal allergic rhinitic (SAR) and nonrhinitic (NR) subjects. We hypothesized that SAR subjects express higher nasal mucosal histamine receptor 1 (H1R) and 2 (H2R) levels than do NR subjects. In addition, we examined expression of genes involved in regulating the glandular response, including epidermal growth factor (EGF), EGF receptor (EGFR), and mucins (Muc5Ac and Muc5B). Methods: Fourteen subjects, seven SAR and seven NR, were provoked during pollen season with doubling doses of H (0.125–8.0 mg/ml). Nasal airway resistance (NAR) was measured by active posterior rhinomanometry. Provocation was halted when NAR exceeded 150% of baseline. Prior to provocation, nasal scrapings were obtained and mRNA quantified using two‐step real‐time PCR. Results: The mean PD 50 (concentration of H producing a 50% increase in NAR) was significantly lower in the SAR than NR group (0.36 vs 1.32 mg/ml; P &lt; 0.05). The ratio of relative gene copy numbers between the SAR and NR groups were as follows: H1R, 0.85 ( P = 0.52); H2R, 0.67 ( P = 0.35); EGF, 1.02 ( P = 0.93), and EGFR, 103.5 ( P &lt; 0.05). Conclusions: There were no significant differences in H1R or H2R mRNA levels between SAR and NR subjects in‐season, despite observed differences in H reactivity. SAR subjects, however, did show a significant elevation in EGFR expression, consistent with the observation of mucus hypersecretion in allergic rhinitis.
Enhancement of Antigen-specific functional responses by neutrophils from allergic patients.
Authors: J Monteseirín, M J Camacho, R Montaño, E Llamas, M Conde, M Carballo, P Guardia, J Conde, F Sobrino
Journal: The Journal of Experimental Medicine (1996)

It has been demonstrated that neutrophils from healthy donors or from patients with inflammatory disorders can bind immunoglobulin (Ig) E proteins through binding to Mac-2/epsilon bp. Functional responses to allergens were assessed by measuring the respiratory burst and intracellular Ca2+ levels, and binding of allergens to neutrophils was assessed by flow cytometry analysis and fluorescence microscopy. In this article, we demonstrate that neutrophils sensitized to specific allergens (from allergic patients), but not from healthy donors, are sensitive to allergens of the same type as those that produce clinical allergic symptoms. The activation of neutrophils was analyzed by the induction of a respiratory burst that was detected with luminol-dependent chemiluminescence. Intracellular Ca2+ levels increased parallel to those of the inducing allergens. In addition, the specific binding of allergens on the cell surface was revealed by flow cytometry and allergen-FITC-labeled staining analyses. The present data suggest a restricted recognition of allergen by sensitive neutrophils, probably associated with the specific binding of the allergen to its corresponding IgE molecule, which is bound to the Mac-2/epsilon bp structure. These findings demonstrate a functional role of allergen-associated neutrophils during the allergic state.
Curaxins: Anticancer Compounds That Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT
Authors: Alexander V. Gasparian, Catherine A. Burkhart, Andrei A. Purmal, Leonid Brodsky, Mahadeb Pal, Madhi Saranadasa, Dmitry A. Bosykh, Mairead Commane, Olga A. Guryanova, Srabani Pal, Alfiya Safina, Sergey Sviridov, Igor E. Koman, Jean Veith, Anton A. Komar, Andrei V. Gudkov, Katerina V. Gurova
Journal: Science Translational Medicine (2011)

The quinacrine-related compounds curaxins target multiple procancer pathways through FACT complex.
Genome-wide transcriptional profiling linked to social class in asthma
Authors: E Chen, G E Miller, H A Walker, J M Arevalo, C Y Sung, S W Cole
Journal: Thorax (2008)

<h3>Objectives:</h3> Low socioeconomic status (SES) is one of the most robust social factors associated with disease morbidity, including more severe asthma in childhood. However, our understanding of the biological processes that explain this link is limited. This study tested whether the social environment could get "under the skin" to alter genomic activity in children with asthma. <h3>Design and participants:</h3> Two group design of children with physician diagnosed asthma who came from low or high SES families. <h3>Outcomes:</h3> Genome-wide transcriptional profiles from T lymphocytes of children with asthma. <h3>Results:</h3> Children with asthma from a low SES background showed overexpression of genes regulating inflammatory processes, including those involved in chemokine activity, stress responses and wound responses, compared with children with asthma from a high SES background. Bioinformatic analysis suggested that decreased activity of cyclic AMP response element binding protein and nuclear factor Y and increased nuclear factor κB transcriptional signalling mediated these effects. These pathways are known to regulate catecholamine and inflammatory signalling in immune cells. <h3>Conclusions:</h3> This study provides the first evidence in a sample of paediatric patients diagnosed with asthma that the larger social environment can affect processes at the genomic level. Specifically, gene transcription control pathways that regulate inflammation and catecholamine signalling were found to vary by SES in children with asthma. Because these pathways are the primary targets of many asthma medications, these findings suggest that the larger social environment may alter molecular mechanisms that have implications for the efficacy of asthma therapeutics.