tbuckley/cabot-search huggingface dataset:
Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression
Authors: Patricia Goldhoff, Nicole M. Warrington, David D. Limbrick, Andrew Hope, B. Mark Woerner, Erin Jackson, Arie Perry, David Piwnica-Worms, Joshua B. Rubin
Journal: Clinical Cancer Research (2008)

Abstract Purpose: As favorable outcomes from malignant brain tumors remain limited by poor survival and treatment-related toxicity, novel approaches to cure are essential. Previously, we identified the cyclic AMP phosphodiesterase-4 (PDE4) inhibitor Rolipram as a potent antitumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target. Experimental Design: Immunohistochemistry was used to evaluate the expression pattern of a subfamily of PDE4, PDE4A, in multiple brain tumor types. To evaluate the effect of PDE4A on growth, a brain-specific isoform, PDE4A1 was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells. To determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts. Results: We found that PDE4A is expressed in medulloblastoma, glioblastoma, oligodendroglioma, ependymoma, and meningioma. Moreover, when PDE4A1 was overexpressed in Daoy medulloblastoma and U87 glioblastoma cells, in vivo doubling times were significantly shorter for PDE4A1-overexpressing xenografts compared with controls. In long-term survival and bioluminescence studies, Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced the survival of mice bearing intracranial xenografts of U87 glioblastoma cells. Bioluminescence imaging indicated that whereas temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression. Conclusions: This study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression.
Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide
Authors: Youhe Gao, Stewart Lecker, Mark J. Post, Antti J. Hietaranta, Jian Li, Rudiger Volk, Min Li, Kaori Sato, Ashok K. Saluja, Michael L. Steer, Alfred L. Goldberg, Michael Simons
Journal: Journal of Clinical Investigation (2000)

Induction of NF-κB–dependent gene expression plays an important role in a number of biological processes including inflammation and ischemia-reperfusion injury. However, few attempts aimed at selective regulation of this transcription factor have been successful. We report here that a naturally occurring antibacterial peptide PR39 reversibly binds to the α7 subunit of the 26S proteasome and blocks degradation of NF-κB inhibitor IκBα by the ubiquitin-proteasome pathway without affecting overall proteasome activity. IκBα phosphorylation and ubiquitination occur normally after PR39 treatment, and binding of valosin-containing proteins is not impaired. The inhibition of IκBα degradation abolishes induction of NF-κB–dependent gene expression in cell culture and in mouse models of acute pancreatitis and myocardial infarction, including upregulation of endothelial adhesion proteins VCAM-1 and ICAM-1. In the latter model, sustained infusion of PR39 peptide resulted in significant reduction of myocardial infarct size. PR39 and related peptides may provide novel means to regulate cellular function and to control of NF-κB–dependent gene expression for therapeutic purposes.
Intermittent preventive therapy for malaria with monthly artemether–lumefantrine for the post-discharge management of severe anaemia in children aged 4–59 months in southern Malawi: a multicentre, randomised, placebo-controlled trial
Authors: Kamija Phiri, Michael Esan, Michael Boele van Hensbroek, Carole Khairallah, Brian Faragher, Feiko O ter Kuile
Journal: The Lancet Infectious Diseases (2011)
When and how to stop etanercept after successful treatment of patients with juvenile idiopathic arthritis
Authors: F H M Prince, M Twilt, S C M Simon, M A J van Rossum, W Armbrust, E P A H Hoppenreijs, S Kamphuis, M van Santen-Hoeufft, Y Koopman-Keemink, N M Wulffraat, R ten Cate, L W A van Suijlekom-Smit
Journal: Annals of the Rheumatic Diseases (2009)

Currently, little is known about when or how to stop etanercept in patients with juvenile idiopathic arthritis (JIA) when a good clinical response is reached, and therefore no guidelines are available.1 We evaluated the disease course of patients with JIA who discontinued etanercept because of a sustained good clinical response.

This study is embedded in the Arthritis and Biologicals in Children (ABC) project, a prospective ongoing multicentre, observational study that includes all Dutch patients with JIA who used etanercept since 1999.2 3 We selected all patients who discontinued etanercept because of sustained good clinical response determined by the treating doctor. The outcome measures to assess disease activity consisted of the JIA core set of …
Epidermal Growth Factor Receptor Variant III–Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression
Authors: Johann Micallef, Michael Taccone, Joydeep Mukherjee, Sidney Croul, Jennifer Busby, Michael F. Moran, Abhijit Guha
Journal: Cancer Research (2009)

Glioblastoma multiforme (GBM) is the most common and most malignant adult brain tumor. A characteristic of GBM is their highly invasive nature, making complete surgical resection impossible. The most common gain-of-function alteration in GBM is amplification, overexpression, and mutations of the epidermal growth factor receptor (EGFR). The constitutively activated mutant EGFR variant III (EGFRvIII), found in approximately 20% of GBM, confers proliferative and invasive advantage. The signaling cascades downstream of aberrant EGFR activation contributing to the invasive phenotype are not completely understood. Here, we show myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. EGFRvIII-expressing or EGF-stimulated human GBM cells increased expression, phosphorylation, and cytosolic translocation of MARCKS in a protein kinase C-alpha-dependent manner. Down-regulation of MARCKS expression with small interfering RNA in GBM cells expressing EGFRvIII led to decreased cell adhesion, spreading, and invasion. Elucidation of mechanisms that promote EGFRvIII-mediated tumorigenesis in GBM, such as MARCKS, provides additional understanding and potential biological targets against this currently terminal human cancer.
Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development
Authors: Caroline Aspord, Alexander Pedroza-Gonzalez, Mike Gallegos, Sasha Tindle, Elizabeth C. Burton, Dan Su, Florentina Marches, Jacques Banchereau, A. Karolina Palucka
Journal: The Journal of Experimental Medicine (2007)

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development.
Co-proxamol and suicide: Licence needs to be changed
Authors: D N Bateman
Journal: BMJ (2003)

EDITOR—We agree with Hawton et al that co-proxamol presents a major overdose hazard, their results illustrating the difficulties for licensing authorities in limiting availability of prescription medicines that are only hazardous in overdose.1

Co-proxamol is more likely to result in death; it causes prolongation …
Relationship of Heart Rate Variability to Parasympathetic Effect
Authors: Jeffrey J. Goldberger, Sridevi Challapalli, Roderick Tung, Michele A. Parker, Alan H. Kadish
Journal: Circulation (2001)

Baroreflex-mediated parasympathetic stimulation has variable effects on heart rate variability (HRV). We postulated that a quadratic function would describe the relationship between HRV and parasympathetic effect better than a linear function.Twenty-nine normal volunteers (15 women; mean age 39+/-12 years) were studied after beta-adrenergic blockade with intravenous propranolol. Five-minute ECG recordings were made during graded infusions of phenylephrine and nitroprusside to achieve baroreflex-mediated increases and decreases in parasympathetic effect, respectively. Time- and frequency-domain measures of HRV were calculated from the R-R interval tachograms. The R-R interval and the vagal-sympathetic effect (VSE=R-R interval/intrinsic R-R interval) were used as indices of parasympathetic effect. The data were fit to both quadratic and linear models. In each case, the quadratic model (with a negative coefficient for the squared term) was superior to the linear model. There was some evidence that age influenced the responsiveness of the HRV parameters with changing parasympathetic effect, although the regression analysis was significant only in the models for MSSD (P<0.03) and pNN50 (P<0.001).The relationship between HRV and parasympathetic effect is best described by a function in which there is an ascending limb where HRV increases as parasympathetic effect increases until it reaches a plateau level; HRV then decreases as parasympathetic effect increases. Because there is marked interindividual variation in this relationship, differences in HRV between individuals may reflect differences in this relationship and/or differences in autonomic effects.
Multiple Alternative Splicing Markers for Ovarian Cancer
Authors: Roscoe Klinck, Anne Bramard, Lyna Inkel, Geneviève Dufresne-Martin, Julien Gervais-Bird, Richard Madden, Éric R. Paquet, ChuShin Koh, Julian P. Venables, Panagiotis Prinos, Manuela Jilaveanu-Pelmus, Raymund Wellinger, Claudine Rancourt, Benoit Chabot, Sherif Abou Elela
Journal: Cancer Research (2008)

Abstract Intense efforts are currently being directed toward profiling gene expression in the hope of developing better cancer markers and identifying potential drug targets. Here, we present a sensitive new approach for the identification of cancer signatures based on direct high-throughput reverse transcription-PCR validation of alternative splicing events. This layered and integrated system for splicing annotation (LISA) fills a gap between high-throughput microarray studies and high-sensitivity individual gene investigations, and was created to monitor the splicing of 600 cancer-associated genes in 25 normal and 21 serous ovarian cancer tissues. Out of &amp;gt;4,700 alternative splicing events screened, the LISA identified 48 events that were significantly associated with serous ovarian tumor tissues. In a further screen directed at 39 ovarian tissues containing cancer pathologies of various origins, our ovarian cancer splicing signature successfully distinguished all normal tissues from cancer. High-volume identification of cancer-associated splice forms by the LISA paves the way for the use of alternative splicing profiling to diagnose subtypes of cancer. [Cancer Res 2008;68(3):657–63]
Brain Natriuretic Peptide Is a Prognostic Parameter in Chronic Lung Disease
Authors: Hanno H. Leuchte, Rainer A. Baumgartner, Michal El Nounou, Michael Vogeser, Claus Neurohr, Michael Trautnitz, Juergen Behr
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: The detection of pulmonary hypertension in patients with chronic lung disease has prognostic implications. The brain natriuretic peptide (BNP) has been suggested as a noninvasive marker for the presence and severity of pulmonary hypertension.Objectives: We evaluated circulating BNP levels as a parameter for the presence and severity of pulmonary hypertension in patients with chronic lung disease.Methods: BNP levels were measured in 176 consecutive patients with various pulmonary diseases. Right heart catheterization, lung functional testing, and a 6-min walk test were performed. The mean follow-up time was nearly 1 yr.Measurements and Main Results: Significant pulmonary hypertension (mean pulmonary artery pressure > 35 mm Hg) was diagnosed in more than one-fourth of patients and led to decreased exercise tolerance and life expectancy. Elevated BNP concentrations identified significant pulmonary hypertension with a sensitivity of 0.85 and specificity of 0.88 and predicted mortality. Moreover, BNP served as a risk factor of death independent of lung functional impairment or hypoxemia in uni- and multivariate analysis.Conclusion: We suggest BNP as a prognostic marker and as screening parameter for significant pulmonary hypertension in chronic lung disease.
Patient dumping. Status, implications, and policy recommendations
Authors: D. A. Ansell
Journal: JAMA (1987)

Patient dumping, or the transfer of patients from private to public hospitals because of economic or social factors, is on the increase throughout the United States. Focusing on the dumping of patients by hospital emergency departments, the authors examine the economic, ethical, legal, and medical aspects of the problem. Although 22 states and the federal government have enacted statutes requiring hospitals to provide emergency care regardless of ability to pay and requiring that patients be stabilized before transfer to another hospital, Ansell and Schiff contend that even the best of these laws are deficient in defining such terms as "emergency" and "patient stability" and that monitoring and enforcement of existing laws and the guidelines of the American College of Emergency Physicians are inadequate. They propose a policy that no patient in need of emergency hospitalization should be denied admission or transferred for economic reasons.
Survival disparity in lung cancer among African American and white females: A population based study in LICH Brooklyn, NY
Authors: W. Razaq, M. Geraghty, F. Dipillo
Journal: Journal of Clinical Oncology (2005)

9629 Background: African Americans are at higher risk for lung cancer than Whites in US. A significant racial difference in survival rates has been reported over the past 30 years, with a poorer prognosis noted in African Americans. The disparity in survival is multifactorial, such as lack of knowledge, low socioeconomic status, lack of surgery in early disease or noncompliance with treatment.The main objective of this study was to compare 2 and 5 year survival rate in African American and White females with lung cancer, who received the same treatment and follow up. Methods: African American and White females, from 1995–2002, with pathologically diagnosed Lung Cancer, were reviewed retrospectively in LICH Tumor Board Registry. Patients who refused biopsy and other ethnicities were excluded from the study. The survival of both groups was compared by Kaplan Meier graph. Results: Total of 166 patients were included in the study depending upon their race and pathological diagnosis. 51% Blacks and 48% were White. Among Black females, 90% presented with NSCLC and 10% with SCLC. The same ratio was noted in White females. Adenocarcinoma was noted to be the most frequent type of Lung cancer among both the races (41% in Blacks and48% in Whites). 51% White and 48% Black females presented with stage IV disease. Histological and stage comparison was done. No survival difference was noted using Kaplan Meier graph (p= 0.83) among females of both groups with lung cancer. Conclusions: The study emphasizes that if both ethnic groups receive same treatment in all four stages (i.e surgery in early stages and chemo/ radiation in advanced stages) then there is no 2 and 5 year survival difference in Black and White females with lung cancer. No significant financial relationships to disclose.
Identification of the mechanism for the inhibition of Na+,K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2.
Authors: P Xia, R M Kramer, G L King
Journal: Journal of Clinical Investigation (1995)

Inhibition of Na+,K(+)-ATPase activity by hyperglycemia could be an important etiological factor of chronic complications in diabetic patients. The biochemical mechanism underlying hyperglycemia's inhibitory effects has been thought to involve the alteration of the protein kinase C (PKC) pathway since agonists of PKC can normalize hyperglycemia-induced inhibition of Na+,K(+)-ATPase activity. Paradoxically, elevated glucose levels and diabetes have been shown to increase PKC activities in vascular cells. The present study tested the hypothesis that the inhibition of Na+,K(+)-ATPase activity is mediated by the sequential activation of PKC and cytosolic phospholipase A2 (cPLA2). In cultured rat vascular smooth muscle cells (VSMC), increasing glucose levels in the medium from 5.5 to 22 mM elevated cPLA2 activity and increased [3H]arachidonic acid release and PGE2 production by 2.3-, 1.7- and 2-fold, respectively. Similar increases in cPLA2 activity were also induced by elevated glucose levels in human VSMC and rat capillary endothelial cells. The activation of cPLA2 was mediated by PKC since the increases in cPLA2 phosphorylation and enzymatic activity were inhibited by the PKC inhibitor GFX. In contrast, elevation of glucose levels decreased Na+,K(+)-ATPase activity as measured by ouabain-sensitive 86Rb uptake by twofold in rat VSMC. Surprisingly, both PMA, a PKC agonist, and GFX, a PKC inhibitor, were able to prevent glucose-induced decreases in 86Rb uptake. Further, the PLA2 inhibitor AACOCF3 abolished both glucose-induced activation of cPLA2 and the decrease in 86Rb uptake. These data indicated that hyperglycemia is inhibiting Na+,K(+)-ATPase activity by the sequential activation of PKC and cPLA2, resulting in the liberation of arachidonic acid and increased the production of PGE2, which are known inhibitors of Na+,K(+)-ATPase.
Which outcomes should we measure in vitiligo? Results of a systematic review and a survey among patients and clinicians on outcomes in vitiligo trials
Authors: V. Eleftheriadou, K.S. Thomas, M.E. Whitton, J.M. Batchelor, J.C. Ravenscroft
Journal: British Journal of Dermatology (2012)

Relevant and reliable outcomes play a crucial role in the correct interpretation and comparison of the results of clinical trials. There is a lack of consensus around methods of assessment and outcome measures for vitiligo, which makes it difficult to compare results of randomized controlled trials (RCTs) and perform meta-analysis.To describe the heterogeneity in outcome measures used in published RCTs of vitiligo treatments, and to report the most desirable outcomes from patients' and clinicians' perspectives.We conducted a systematic review of outcome measures used in RCTs as well as a survey of the most desirable outcomes identified by patients and clinicians as part of a Vitiligo Priority Setting Partnership.Outcomes from 54 eligible trials were analysed and compared with outcomes suggested by patients and clinicians. In the systematic review, 25 different outcomes were reported. Only 22% of trials had clearly stated primary outcome measures. Repigmentation was the most frequently reported outcome in 96% of trials and was measured using 48 different scales. Only 9% of trials assessed quality of life. Thirteen per cent measured cessation of spreading of the disease and 17% of studies reported patients' opinions and satisfaction with the treatment. In contrast, out of 438 suggestions made by patients and clinicians, cosmetically acceptable repigmentation (rather than percentage of repigmentation) was the most desirable outcome (68%), followed by cessation of spread of vitiligo (15%), quality of life (8%) and maintenance of repigmentation (4%).We propose that future vitiligo trials should include repigmentation, cosmetic acceptability of results, global assessment of the disease, quality of life, maintenance of repigmentation, stabilization of vitiligo and side-effects. International consensus among clinicians, researchers and patients is needed to establish an agreed core outcome set for future vitiligo trials.
Treatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene transfer of endostatin and angiostatin-like molecule in mice
Authors: V Schmitz
Journal: Gut (2004)

In this study, we explored the responsiveness of different tumour entities (colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), and the murine Lewis lung carcinoma (LLC)) to angiostatic antitumour treatment with two recombinant adenoviral vectors encoding angiostatin-like molecule (AdK1-3) and endostatin (Adendo).AdK1-3 and Adendo exerted inhibitory biological functions on endothelial cell proliferation, migration, and tube formation in vitro. AdK1-3 inhibited significantly endothelial cell infiltration in vascular endothelial growth factor embedded Matrigel plugs in mice whereas Adendo showed only minor effects. Both AdK1-3 and Adendo induced similar antitumour effects in the LLC tumour model in immune competent C57BL/6 mice but AdK1-3 had stronger inhibitory effects in athymic mice. Furthermore, AdK1-3 inhibited tumour growth in a murine CRC and human HCC model but was ineffective in a human CRC model. In contrast, Adendo did not reduce tumour progress in either of these tumour models although AdK1-3 and Adendo effectively reduced intratumoral microvessel density in LLC tumours.Our data demonstrate that angiostatic gene therapy may form a feasible strategy for the treatment of established hepatocellular carcinomas and that in vivo antitumour efficacy of angiostatic proteins is tumour specific.