tbuckley/cabot-search huggingface dataset:
Class II Histone Deacetylases Are Associated with VHL-Independent Regulation of Hypoxia-Inducible Factor 1α
Authors: David Z. Qian, Sushant K. Kachhap, Spencer J. Collis, Henk M.W. Verheul, Michael A. Carducci, Peter Atadja, Roberto Pili
Journal: Cancer Research (2006)

Abstract Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in transcriptional gene activation involved in tumor angiogenesis. A novel class of agents, the histone deacetylase (HDAC) inhibitors, has been shown to inhibit tumor angiogenesis and HIF-1α protein expression. However, the molecular mechanism responsible for this inhibition remains to be elucidated. In the current study, we investigated the molecular link between HIF-1α inhibition and HDAC inhibition. Treatment of the VHL-deficient human renal cell carcinoma cell line UMRC2 with the hydroxamic HDAC inhibitor LAQ824 resulted in a dose-dependent inhibition of HIF-1α protein via a VHL-independent mechanism and reduction of HIF-1α transcriptional activity. HIF-1α inhibition by LAQ824 was associated with HIF-1α acetylation and polyubiquitination. HIF-1α immunoprecipitates contained HDAC activity. Then, we tested different classes of HDAC inhibitors with diverse inhibitory activity of class I versus class II HDACs and assessed their capability of targeting HIF-1α. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1α at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1α only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1α protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1α protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1α stability and provide a rationale for targeting HIF-1α with HDAC inhibitors against class II isozymes. (Cancer Res 2006; 66(17): 8814-21)
Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review.
Authors: D J Bloomfield
Journal: Journal of Clinical Oncology (1998)

PURPOSE To review objectively the evidence for the use of bisphosphonates for the reduction of skeletal events or the management of pain due to multiple myeloma or bone metastases from other types of cancer. METHODS MEDLINE was searched from 1976 onwards using the MeSH terms "exp diphosphonates/," "exp bone neoplasms/," "exp multiple myeloma/," and "bone metastases" as text words. Bibliographies of reports on these topics and major medical and scientific journals were searched. Experts in the field were approached. The question was defined and the evidence stratified in a hierarchical manner according to classification of study design. There were sufficient studies to enable the use of randomized trials only to address the questions. Effectiveness was defined and the evidence reviewed in a systematic manner. RESULTS AND CONCLUSION Eighteen randomized trials were identified. No meta-analyses are available. There is level I evidence (defined as an appropriately conducted randomized clinical trial with a statistically significant result) for the use of bisphosphonates to reduce both skeletal events and pain in multiple myeloma and in breast cancer patients with metastatic bone disease. There is also level I evidence for their use as part of a pain management program for bone metastases from carcinoma of the breast, lung, and prostate, and for symptomatic myeloma. The bisphosphonates appear to be well tolerated.
An animal model for chronic ulceration
Authors: V. MANNA, J. BEM, R. MARKS
Journal: British Journal of Dermatology (1982)

Few techniques are available for the study of persistent ulceration. In this report we describe a suitable animal model. Intracutaneous injection of sodium tetradecyl sulphate (STD) in guinea-pig flank skin caused a reproducibly sized and shaped superficial ulcer that healed approximately three times more slowly than punch biopsies of comparable size. Histological, immunofluorescent and autoradiographic studies showed that it possesses many of the morphological and kinetic features of human stasis ulceration. STD ulcers treated with a streptokinase/streptodornase solution healed with less slough and tended to re-epithelialize more rapidly than controls, but ulcers treated with dextran polymer beads or a stabilized hydrogen peroxide cream healed at the same rate as their controls.
The immune cell infiltrate populating meningiomas is composed of mature, antigen-experienced T and B cells
Authors: L. Fang, D. E. Lowther, M. L. Meizlish, R. C. E. Anderson, J. N. Bruce, L. Devine, A. J. Huttner, S. H. Kleinstein, J.-Y. Lee, J. N. H. Stern, G. Yaari, L. Lovato, K. M. Cronk, K. C. O'Connor
Journal: Neuro-Oncology (2013)

Meningiomas often harbor an immune cell infiltrate that can include substantial numbers of T and B cells. However, their phenotype and characteristics remain undefined. To gain a deeper understanding of the T and B cell repertoire in this tumor, we characterized the immune infiltrate of 28 resected meningiomas representing all grades.Immunohistochemistry was used to grossly characterize and enumerate infiltrating lymphocytes. A molecular analysis of the immunoglobulin variable region of tumor-infiltrating B cells was used to characterize their antigen experience. Flow cytometry of fresh tissue homogenate and paired peripheral blood lymphocytes was used to identify T cell phenotypes and characterize the T cell repertoire.A conspicuous B and T cell infiltrate, primarily clustered in perivascular spaces, was present in the microenvironment of most tumors examined. Characterization of 294 tumor-infiltrating B cells revealed clear evidence of antigen experience, in that the cardinal features of an antigen-driven B cell response were present. Meningiomas harbored populations of antigen-experienced CD4+ and CD8+ memory/effector T cells, regulatory T cells, and T cells expressing the immune checkpoint molecules PD-1 and Tim-3, indicative of exhaustion. All of these phenotypes were considerably enriched relative to their frequency in the circulation. The T cell repertoire in the tumor microenvironment included populations that were not reflected in paired peripheral blood.The tumor microenvironment of meningiomas often includes postgerminal center B cell populations. These tumors invariably include a selected, antigen-experienced, effector T cell population enriched by those that express markers of an exhausted phenotype.
Jmjd3 Controls Mesodermal and Cardiovascular Differentiation of Embryonic Stem Cells
Authors: Kisho Ohtani, Cong Zhao, Gergana Dobreva, Yosif Manavski, Britta Kluge, Thomas Braun, Michael A. Rieger, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2013)

The developmental role of the H3K27 demethylases Jmjd3, especially its epigenetic regulation at target genes in response to upstream developmental signaling, is unclear. To determine the role of Jmjd3 during mesoderm and cardiovascular lineage commitment. Ablation of Jmjd3 in mouse embryonic stem cells does not affect the maintenance of pluripotency and self-renewal but compromised mesoderm and subsequent endothelial and cardiac differentiation. Jmjd3 reduces H3K27me3 marks at the Brachyury promoter and facilitates the recruitment of β-catenin, which is critical for Wnt signal-induced mesoderm differentiation. These data demonstrate that Jmjd3 is required for mesoderm differentiation and cardiovascular lineage commitment.
Mineral Metabolism and Vascular Damage in Children on Dialysis
Authors: Rukshana C. Shroff, Ann E. Donald, Melanie P. Hiorns, Alan Watson, Sally Feather, David Milford, Elizabeth A. Ellins, Clare Storry, Deborah Ridout, John Deanfield, Lesley Rees
Journal: Journal of the American Society of Nephrology (2007)

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.
Serial Evaluation of Academic and Behavioral Outcome After Treatment With Cranial Radiation in Childhood
Authors: Donald J. Mabbott, Brenda J. Spiegler, Mark L. Greenberg, James T. Rutka, Douglas J. Hyder, Eric Bouffet
Journal: Journal of Clinical Oncology (2005)

To evaluate academic and behavioral outcome in radiated survivors of posterior fossa (PF) tumors.Fifty-three patients (36 males) treated for malignant PF tumors were seen for evaluation of academics and/or behavioral functioning. Forty-six patients were treated for medulloblastoma, and seven patients were treated for ependymoma. Fourteen patients were treated with reduced-dose cranial radiation, and 34 patients were treated with standard-dose cranial radiation (dose was not available for four patients). All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized achievement tests and behavioral questionnaires were administered at different times after diagnosis for each child. First, the influence of demographic and medical variables on outcome was examined. Second, the rate of change in scores was determined using mixed model regression for patients seen for serial assessment.The presence of hydrocephalus was related to poorer academics, but outcome was not related to radiation dose, extent of surgery, or treatment with chemotherapy. Younger age predicted poor reading ability and lower parent rating of academic achievement. Children's performance declined for spelling, mathematics, and reading. Significant declines were also evident in parent and teacher's ratings of academic ability. Behavioral functioning was generally not related to medical and demographic variables, and few clinically significant problems in externalizing behavior were evident. Increases in social and attention problems emerged over time.Cranial radiation is associated with declines in academic ability, social skills, and attention. However, neither psychological distress nor behavior problems were a significant concern for this sample.
Effects of Statins on Platelet Inhibition by a High Loading Dose of Clopidogrel
Authors: Iris Müller, Felicitas Besta, Christian Schulz, Zhongyan Li, Steffen Massberg, Meinrad Gawaz
Journal: Circulation (2003)

Recent studies suggested that some HMG-CoA reductase blockers might inhibit the antiplatelet activity of clopidogrel. Therefore, we analyzed how various statins together with a high loading dose of clopidogrel (600 mg) affect platelet aggregation.Seventy-seven patients with stable angina scheduled for elective coronary stenting were studied. Patients were randomized to receive atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin (each 20 mg), cerivastatin (0.3 mg), or placebo, plus a high loading dose of 600 mg of clopidogrel. ADP-induced platelet aggregation (5 and 20 micromol/L) was determined before and 2 and 4 hours after first clopidogrel administration. All patients were taking aspirin (100 mg/d) regularly. We found that none of the statins significantly influenced inhibition of platelet aggregation by clopidogrel.Concomitant use of statins with clopidogrel does not significantly inhibit antiplatelet activity, at least when clopidogrel is administered at a high loading dose of 600 mg.
Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle.
Authors: A M Pertsov, J M Davidenko, R Salomonsz, W T Baxter, J Jalife
Journal: Circulation Research (1993)

The mechanism of reentrant ventricular tachycardia was studied in computer simulations and in thin (approximately 20 x 20 x 0.5-mm) slices of dog and sheep ventricular epicardial muscle. A two-dimensional matrix consisting of 96 x 96 electrically coupled cells modeled by the FitzHugh-Nagumo equations was used to analyze the dynamics of self-sustaining reentrant activity in the form of elliptical spiral waves induced by premature stimulation. In homogeneous anisotropic media, spirals are stationary and may last indefinitely. However, the presence of small parameter gradients may lead to drifting and eventual termination of the spiral at the boundary of the medium. On the other hand, spirals may anchor and rotate around small discontinuities within the matrix. Similar results were obtained experimentally in 10 preparations whose electrical activity was monitored by means of a potentiometric dye and high-resolution optical mapping techniques; premature stimulation triggered reproducible episodes of sustained or nonsustained reentrant tachycardia in the form of spiral waves. As a rule, the spirals were elongated, with the major hemiaxis parallel to the longitudinal axis of the cells. The period of rotation (183 +/- 68 msec [mean +/- SD]) was longer than the refractory period (131 +/- 38 msec) and appeared to be determined by the size of the spiral's core, which was measured using a newly devised "frame-stack" plot. Drifting of spiral waves was also observed experimentally. Drift velocity was 9.8% of the velocity of wave propagation. In some cases, the core became stationary by anchoring to small arteries or other heterogeneities, and the spiral rotated rhythmically for prolonged periods of time. Yet, when drift occurred, spatiotemporal variations in the excitation period were manifested as a result of a Doppler effect, with the excitation period ahead of the core being 20 +/- 6% shorter than the excitation period behind the core. As a result of these coexisting frequencies, a pseudoelectrocardiogram of the activity in the presence of a drifting spiral wave exhibited "QRS complexes" with an undulating axis, which resembled those observed in patients with torsade de pointes. The overall results show that spiral wave activity is a property of cardiac muscle and suggest that such activity may be the common mechanism of a number of monomorphic and polymorphic tachycardias.
Role of AMP-activated protein kinase in regulating hypoxic survival and proliferation of mesenchymal stem cells
Authors: Carole de Meester, Aurélie D. Timmermans, Magali Balteau, Audrey Ginion, Véronique Roelants, Gauthier Noppe, Paolo E. Porporato, Pierre Sonveaux, Benoît Viollet, Kei Sakamoto, Olivier Feron, Sandrine Horman, Jean-Louis Vanoverschelde, Christophe Beauloye, Luc Bertrand
Journal: Cardiovascular Research (2013)

Mesenchymal stem cells (MSCs) are widely used for cell therapy, particularly for the treatment of ischaemic heart disease. Mechanisms underlying control of their metabolism and proliferation capacity, critical elements for their survival and differentiation, have not been fully characterized. AMP-activated protein kinase (AMPK) is a key regulator known to metabolically protect cardiomyocytes against ischaemic injuries and, more generally, to inhibit cell proliferation. We hypothesized that AMPK plays a role in control of MSC metabolism and proliferation.MSCs isolated from murine bone marrow exclusively expressed the AMPKα1 catalytic subunit. In contrast to cardiomyocytes, a chronic exposure of MSCs to hypoxia failed to induce cell death despite the absence of AMPK activation. This hypoxic tolerance was the consequence of a preference of MSC towards glycolytic metabolism independently of oxygen availability and AMPK signalling. On the other hand, A-769662, a well-characterized AMPK activator, was able to induce a robust and sustained AMPK activation. We showed that A-769662-induced AMPK activation inhibited MSC proliferation. Proliferation was not arrested in MSCs derived from AMPKα1-knockout mice, providing genetic evidence that AMPK is essential for this process. Among AMPK downstream targets proposed to regulate cell proliferation, we showed that neither the p70 ribosomal S6 protein kinase/eukaryotic elongation factor 2-dependent protein synthesis pathway nor p21 was involved, whereas p27 expression was increased by A-769662. Silencing p27 expression partially prevented the A-769662-dependent inhibition of MSC proliferation.MSCs resist hypoxia independently of AMPK whereas chronic AMPK activation inhibits MSC proliferation, p27 being involved in this regulation.
Metabolic Disturbances Identified in Plasma Are Associated With Outcomes in Patients With Heart Failure
Authors: Mei-Ling Cheng, Chao-Hung Wang, Ming-Shi Shiao, Min-Hui Liu, Yu-Yen Huang, Cheng-Yu Huang, Chun-Tai Mao, Jui-Fen Lin, Hung-Yao Ho, Ning-I Yang
Journal: Journal of the American College of Cardiology (2015)
Vascular endothelial growth factor expression, S-phase fraction and thymidylate synthase quantitation in node-positive colon cancer: Relationships with tumor recurrence and resistance to adjuvant chemotherapy
Authors: S. Cascinu, F. Graziano, M. Valentini, V. Catalano, P. Giordani, M.P. Staccioli, C. Rossi, A.M. Baldelli, C. Grianti, P. Muretto, G. Catalano
Journal: Annals of Oncology (2001)
SINE Cousins: The 3'-End Tails of the Two Oldest and Distantly Related Families of SINEs are Descended from the 3' Ends of LINEs with the Same Genealogical Origin
Authors: Y. Terai, K. Takahashi, N. Okada
Journal: Molecular Biology and Evolution (1998)

AFC short interspersed elements (SINEs) were isolated from cichlids from Madagascar, the New World, and Africa and characterized. A new family of long interspersed elements (LINEs), designated the CiLINE2 family, was also isolated from African cichlids, and its consensus sequence was deduced. Upon aligning all of the consensus sequences, we found that the 3'-tail regions of the AFC SINEs and the CiLINE2 family were very similar, providing another example in which a reverse transcriptase responsible for retroposition of SINEs might be contributed in trans by a LINE. Sequence comparisons showed that CiLINE2 in cichlids was closely related to LINE2 in mammals. Furthermore, we found that the 3'-tail sequence shared by the AFC SINEs and CiLINE2 in cichlids was very similar to the 3'-tail sequence shared by the MIR SINEs and LINE2 in mammals, even though the remaining parts of the AFC SINEs and the MIR SINEs were totally different from each other. Thus, the present report not only describes a new pair of SINEs and LINEs with the same 3' tail in cichlids, but also provides a new example of the phenomenon whereby the 3' ends of LINEs with the same genealogical origin can be incorporated into the 3'-end tails of different families of SINEs that have been generated independently in two different lineages during evolution.
Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study
Authors: H.A. Ghofrani, M.M. Hoeper, M. Halank, F.J. Meyer, G. Staehler, J. Behr, R. Ewert, G. Weimann, F. Grimminger
Journal: European Respiratory Journal (2010)

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0–2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP &lt;90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p&lt;0.0001) and PAH (57.0 m from baseline (337 m); p&lt;0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm −5 from baseline (709 dyn·s·cm −5 ; p&lt;0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.
Electrocardiographic Findings in 122,043 Individuals
Authors: ROLAND G. HISS, LAWRENCE E. LAMB
Journal: Circulation (1962)

Electrocardiograms on 122,043 apparently healthy male subjects aged 16 years to over 50 years have been studied. Of this group 5,773 subjects (4.72 per cent) had electrocardiographic abnormalities. The more common abnormalities were expressed in terms of rate per thousand subjects for each 5-year age group. This provides a means of relating incidence to age. Each abnormality and its clinical significance is discussed. In 54,668 subjects incidental findings such as notched P waves, amplitude, and wave forms were tabulated.