tbuckley/cabot-search huggingface dataset:
Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs
Authors: Guoren Deng, Sanjay Kakar, Keisuke Okudiara, Esther Choi, Marvin H. Sleisenger, Young S. Kim
Journal: Clinical Cancer Research (2009)

Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined.Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza-2-deoxycytidine or DNA methyltransferase 1 small interfering RNA or a histone deacetylase inhibitor trichostatin A. OSMR mRNA level was determined by reverse transcription-PCR. The acetylation of histone H3 was analyzed by chromatin immunoprecipitation assay.We observed methylation of OSMR in 88 of 98 (90%) colorectal cancers, 34 of 38 (89%) colorectal polyps, 17 of 31 (55%) normal-appearing mucosa adjacent to colorectal cancers, 13 of 40 (33%) gastric cancers, and 2 of 10 (20%) pancreatic cancers. OSMR methylation was absent or rarely detected in normal colonic mucosa from noncancer patients or in cancers of nondigestive organs, including breast, lung, liver, prostate, kidney, and melanoma. We observed a significant correlation between OSMR methylation and loss of mRNA expression in 39 cancer cell lines. Following the treatment of colorectal cancer cell lines with 5-aza-2-deoxycytidine, DNA methyltransferase 1 small interfering RNA, or trichostatin A, the induction of OSMR mRNA and the enrichment in the level of histone acetylation were observed.The epigenetic silencing and DNA methylation of OSMR occur frequently in colorectal cancers and rarely in cancers of nondigestive organs. OSMR methylation is an early event in the colorectal carcinogenesis.
Neuroanatomical Hypothesis of Panic Disorder, Revised
Authors: Jack M. Gorman, Justine M. Kent, Gregory M. Sullivan, Jeremy D. Coplan
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance. METHOD: The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals. RESULTS: There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder. CONCLUSIONS: Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.
Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes
Authors: M. Wasif Saif, Adrienne Choma, Salvatore J. Salamone, Edward Chu
Journal: JNCI Journal of the National Cancer Institute (2009)

Chemotherapy dosing of the fluoropyrimidine 5-fluorouracil (5-FU) is currently based on body surface area. However, body surface area-based dosing has been associated with clinically significant pharmacokinetic variability, and as such, dosing based on body surface area may be of limited use. The clinical activity of 5-FU is modest at standard doses, and in general, dosing is limited by the safety profile, with myelosuppression and gastrointestinal toxicity being the most commonly observed side effects. Various strategies have been developed to enhance the clinical activity of 5-FU, such as biochemical modulation, alterations in scheduling of administration, and the use of oral chemotherapy. Studies that have shown an association between plasma concentration with toxicity and clinical efficacy have shown that pharmacokinetically guided dose adjustments can substantially improve the therapeutic index of 5-FU treatment. These studies have shown that only 20%-30% of patients treated with a 5-FU-based regimen have 5-FU levels that are in the appropriate therapeutic range--approximately 40%-60% of patients are underdosed and 10%-20% of patients are overdosed. To date, 5-FU drug testing has not been widely used because of the lack of a simple, fast, and inexpensive method. Recent advances in testing based on liquid chromatography-mass spectroscopy and a nanoparticle antibody-based immunoassay for 5-FU may now allow for routine monitoring of 5-FU in clinical practice. We review the data on pharmacokinetically guided dose adjustment of 5-FU and discuss the potential of this approach to advance therapeutic outcomes.
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability
Authors: Gunnar Houge, Dorien Haesen, Lisenka E.L.M. Vissers, Sarju Mehta, Michael J. Parker, Michael Wright, Julie Vogt, Shane McKee, John L. Tolmie, Nuno Cordeiro, Tjitske Kleefstra, Marjolein H. Willemsen, Margot R.F. Reijnders, Siren Berland, Eli Hayman, Eli Lahat, Eva H. Brilstra, Koen L.I. van Gassen, Evelien Zonneveld-Huijssoon, Charlotte I. de Bie, Alexander Hoischen, Evan E. Eichler, Rita Holdhus, Vidar M. Steen, Stein Ove Døskeland, Matthew E. Hurles, David R. FitzPatrick, Veerle Janssens
Journal: Journal of Clinical Investigation (2015)

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding–deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.
An economic evaluation of a proprioceptive balance board training programme for the prevention of ankle sprains in volleyball
Authors: E A L M Verhagen, M van Tulder, A J van der Beek, L M Bouter, W van Mechelen
Journal: British Journal of Sports Medicine (2005)

Objectives: To evaluate the cost effectiveness of a proprioceptive balance board training programme for the prevention of ankle sprains in volleyball. Methods: A total of 116 volleyball teams participated in this study which was carried out during the 2001–2002 volleyball season. Teams were randomly allotted to an intervention group (66 teams, 628 players) or a control group (52 teams, 494 players). Intervention teams followed a prescribed balance board training programme as part of their warm up. Control teams followed their normal training routine. An ankle sprain was recorded if it occurred as a result of volleyball and caused the subject to stop volleyball activity. The injured player completed a cost diary for the duration of the ankle sprain. Analyses were performed according to the intention to treat principle. Mean direct, indirect, and total costs were calculated and were compared between the two groups. Results: The total costs per player (including the intervention material) were significantly higher in the intervention group (€36.99 (93.87)) than in the control group (€18.94 (147.09)). The cost of preventing one ankle sprain was approximately €444.03. Sensitivity analysis showed that a proprioceptive balance board training programme aimed only at players with previous ankle sprains could be cost effective over a longer period of time. Conclusions: Positive effects of the balance board programme could only be achieved at certain costs. However, if broadly implemented, costs associated with the balance board programme would probably be lower.
Antibiotic Treatment of Infective Endocarditis
Authors: W R Wilson, J E Geraci
Journal: Annual Review of Medicine (1983)

At least 85% of patients with infective endocarditis can be cured with effective therapy. Streptococci or staphylococci cause 75% of cases of endocarditis. Patients with penicillin-sensitive viridans or nonenterococcal group D streptococcal endocarditis may be treated successfully with aqueous penicillin G alone for four weeks or with combined penicillin and streptomycin for two weeks. Enterococcal endocarditis should be treated for four to six weeks with a combination of aqueous penicillin G together with either streptomycin or gentamicin. Patients with endocarditis caused by Staphylococcus aureus should receive antimicrobial therapy for four to six weeks with a semisynthetic penicillin (nafcillin or oxacillin) or a cephalosporin such as cephalothin or cefazolin. In urgent cases where empiric antimicrobial therapy is necessary before the causative organism is identified, a combination of aqueous penicillin G, nafcillin, and gentamicin is effective therapy.
Endoscopic Colorectal Cancer Screening: a Cost-Saving Analysis
Authors: F. Loeve
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Comprehensive analyses have shown that screening for cancer usually induces net costs. In this study, the possible costs and savings of endoscopic colorectal cancer screening are explored to investigate whether the induced savings may compensate for the costs of screening. Methods: A simulation model for evaluation of colorectal cancer screening, MISCAN–COLON, is used to predict costs and savings for the U.S. population, assuming that screening is performed during a period of 30 years. Plausible baseline parameter values of epidemiology, natural history, screening test characteristics, and unit costs are based on available data and expert opinion. Important parameters are varied to extreme but plausible values. Results: Given the expert opinion-based assumptions, a program based on every 5-year sigmoidoscopy screenings could result in a net savings of direct health care costs due to prevention of cancer treatment costs that compensate for the costs of screening, diagnostic follow-up, and surveillance. This result persists when costs and health effects are discounted at 3%. The "break-even" point, the time required before savings exceed costs, is 35 years for a screening program that terminates after 30 years and 44 years for a screening program that continues on indefinitely. However, net savings increase or turn into net costs when alternative assumptions about natural history of colorectal cancer, costs of screening, surveillance, and diagnostics are considered. Conclusions: Given the present, limited knowledge of the disease process of colorectal cancer, test characteristics, and costs, it may well be that the induced savings by endoscopic colorectal cancer screening completely compensate for the costs.
An early component of delayed-type hypersensitivity mediated by T cells and mast cells.
Authors: H van Loveren, R Meade, P W Askenase
Journal: The Journal of Experimental Medicine (1983)

In four different systems it was shown that murine delayed-type hypersensitivity (DTH) responses at 18-48 h were preceded by early 2-h responses. CBA mice immunized with picryl chloride, BDF1 mice immunized with oxazolone, BALB/c mice immunized with dinitrofluorobenzene, and C57BL/6 mice immunized with L5178Y lymphoma cells, and challenged with the appropriate specific antigen, all gave rise to expected 18-48 h delayed-in-time hypersensitivity reactions, but all of these responses were preceded by early hypersensitivity reactions that peaked at 2 h. These early 2-h reactions are transferable with T cells or with a T cell-derived, antigen-binding factor and are antigen-specific. The early and late components of DTH reactions are mast cell dependent since neither are elicited in mast cell deficient W/Wv or Sl/Sld mice. The T cell activity mediating the early component of DTH is demonstrable as early as 24 h after immunization, while the classical late component of DTH is not demonstrable until days 3-4. The difference in onset after immunization of the early and late components of DTH, and the different kinetics of these components in recipients of cell transfers that were challenged immediately or 24 h after transfer, led to the hypothesis that immunization for DTH leads to rapid induction in lymphoid organs of a certain population of T cells to produce an antigen-binding factor. This factor sensitizes peripheral tissues, probably mast cells, and local challenge with appropriate antigen leads to mast cell activation and release of the vasoactive amine serotonin, resulting in increased permeability of the local vasculature. This allows other circulating antigen-specific T cells, which are induced later after immunization, to enter the tissues and interact with antigen, resulting in production of chemoattractant lymphokines that recruit accessory leukocytes such as monocytes and polymorphs to enter the tissues via gaps between endothelial cells. These inflammatory cells, that are recruited to the site via two different T cell activities, constitute the characteristic infiltrate of DTH responses. Identification of an early 2-h component of DTH that is T cell- and mast cell-dependent provides evidence that the tissue-sensitizing, antigen-binding, T cell factor probably functions in vivo in the early phases of DTH responses.
Use of a plastic insulin dosage guide to correct blood glucose levels out of the target range and for carbohydrate counting in subjects with type 1 diabetes.
Authors: F R Kaufman, M Halvorson, S Carpenter
Journal: Diabetes Care (1999)

OBJECTIVE: To improve glycemic control, a hand-held plastic Insulin Dosage Guide was developed to correct blood glucose levels outside of the target range. RESEARCH DESIGN AND METHODS: Protocol 1: Some 40 children (mean age 10.6+/-4.6 years) were randomly assigned for 3 months to use a written-on-paper algorithm or the Insulin Dosage Guide to correct abnormal blood glucose levels. Mean HbA1c and blood glucose levels and time to teach insulin dosage correction were compared. Protocol 2: The Insulin Dosage Guide was used by 83 subjects (mean age 11.4+/-4.3 years) for 1 year, and mean HbA1c levels, blood glucose levels, and number of consecutive high blood glucose values taken before and after the year were compared. Protocol 3: Some 20 patients (mean age 10.1+/-3.7 years) using rapid-acting insulin and 64 patients (mean age 15.9+/-3.6 years) using an insulin pump and rapid-acting insulin used the Insulin Dosage Guide and had mean blood glucose levels, HbA1c, and percentage of blood glucose levels outside of the target range determined. RESULTS: Protocol 1: There was a significant reduction in mean HbA1c (P = 0.04) and blood glucose levels (P = 0.05) and in the time needed to teach how to correct blood glucose values using the Insulin Dosage Guide compared with the paper algorithm. Protocol 2: There was a decrease in mean HbA1c levels (P = 0.0001) and a decrease in the mean number of consecutive blood glucose levels (P = 0.001) over the 1-year time period. Protocol 3: With rapid-acting insulin, there was a significant increase in the percentage of blood glucose levels within the target range (1 month, P = 0.04; at 3 months, P = 0.03). With the insulin pump, there was a high rate (90%) of blood glucose levels in the target range during pump initiation when the Insulin Dosage Guide was used. CONCLUSIONS: This inexpensive hand-held plastic card, which is portable and easy to use, may help patients improve glycemia and successfully manage diabetes.
Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index
Authors: Milo A Puhan, Judith Garcia-Aymerich, Martin Frey, Gerben ter Riet, Josep M Antó, Alvar G Agustí, Federico P Gómez, Roberto Rodríguez-Roisín, Karel GM Moons, Alphons G Kessels, Ulrike Held
Journal: The Lancet (2009)
Delivery of Interferon-α Transfected Dendritic Cells into Central Nervous System Tumors Enhances the Antitumor Efficacy of Peripheral Peptide-Based Vaccines
Authors: Hideho Okada, Takahiko Tsugawa, Hidemitsu Sato, Naruo Kuwashima, Andrea Gambotto, Kaori Okada, Jill E. Dusak, Wendy K. Fellows-Mayle, Glenn D. Papworth, Simon C. Watkins, William H. Chambers, Douglas M. Potter, Walter J. Storkus, Ian F. Pollack
Journal: Cancer Research (2004)

Abstract We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-α-transfected dendritic cells (DC-IFN-α) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c. challenge with ovalbumin-expressing M05 melanoma (class I+ and class II-negative). Notably, antiovalbumin CTL responses were observed in animals vaccinated with an ovalbumin-derived T helper epitope but only after the mice were challenged with M05 cells. This cross-priming of CTL was dependent on both CD4+ and CD8+ T cells. Because we observed that s.c., but not intracranial, tumors were infiltrated with CD11c+ DCs, and because IFN-α promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN-α-engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN-α prolonged survival. This was most notable for animals prevaccinated with both the CTL and T helper ovalbumin epitopes, with 60% (6 of 10) of mice (versus 0 of 10 of control animals) surviving for &amp;gt;80 days after tumor challenge. DC-IFN-α appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN-α-treated mice exhibited enhanced levels of ovalbumin-specific CTL in draining cervical lymph nodes. On the basis of these results, we believe that local expression of IFN-α by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.
BKM1740, an Acyl-Tyrosine Bisphosphonate Amide Derivative, Inhibits the Bone Metastatic Growth of Human Prostate Cancer Cells by Inducing Apoptosis
Authors: Seong Il Seo, Lajos Gera, Haiyen E. Zhau, Wei Ping Qian, Shareen Iqbal, Nicole A. Johnson, Shumin Zhang, Majd Zayzafoon, John Stewart, Ruoxiang Wang, Leland W.K. Chung, Daqing Wu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Survivin overexpression has been associated with an unfavorable outcome in human PCa; however, its role in metastasis remains elusive. We aim to (a) evaluate the clinical implications of survivin expression in PCa bone metastasis; (b) determine in vivo efficacy of BKM1740, a small-molecule compound, against PCa skeletal growth and survival; and (c) investigate molecular mechanism by which BKM1740 augments apoptosis in bone metastatic PCa cells. Experimental Design: Survivin expression was analyzed in PCa specimens and experimental models. Bone metastatic C4-2 and ARCaPM cell lines were used to evaluate the in vitro effects of BKM1740 and molecular mechanism for the induction of apoptosis. C4-2 cells were grown intratibially in athymic nude mice to evaluate the in vivo efficacy of BKM1740. Tumor growth in mouse bone was assessed by serum prostate-specific antigen and radiography and confirmed by immunohistochemical analyses. Results: Survivin expression is positively associated with clinical PCa bone metastasis. BKM1740 induced apoptosis in PCa cells by repressing survivin. Mice with established C4-2 tumors in tibia showed a marked decrease in serum prostate-specific antigen and much improved bone architecture radiographically after treatment with BKM1740. Immunohistochemical assays of mouse tumor samples confirmed that the in vivo effects were mediated by inhibition of survivin and induction of apoptosis. Conclusions: Survivin expression is associated with PCa bone metastasis. BKM1740 treatment specifically inhibited survivin and induced apoptosis in vitro and was efficacious in retarding PCa skeletal growth in a mouse model. BKM1740 is a promising small-molecule compound that could be used to treat PCa bone metastasis.
Role of radiography in predicting progression of osteoarthritis of the hip: prospective cohort study
Authors: Max Reijman, J M W Hazes, H.A.P Pols, R M D Bernsen, B W Koes, S M A Bierma-Zeinstra
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To investigate which variables identify people at high risk of progression of osteoarthritis of the hip. <b>Design</b> Population based cohort study. <b>Setting</b> Ommoord district in Rotterdam, Netherlands. <b>Participants</b> 1904 men and women aged 55 years and older from the Rotterdam study were selected on the basis of the presence of osteoarthritic signs on radiography at baseline, as defined by a Kellgren and Lawrence score ≥ grade 1. <b>Main outcome measures</b> Radiological progression of osteoarthritis of the hip, defined as a decrease of joint space width (≥ 1.0 mm) at follow-up or the presence of a total hip replacement. <b>Methods</b> Potential determinants of progression of hip osteoarthritis were collected at baseline. x Ray films of the hip at baseline and follow-up (mean follow-up time 6.6 years) were evaluated. Multivariate logistic regression models were used to assess the association between potential risk factors and progression of hip osteoarthritis. <b>Results</b> In 13.1% (1904 subjects) of the study population (mean age 66.2 years), progression of hip osteoarthritis was evident on the radiograph. Starting with a simple model of only directly obtainable variables, the Kellgren and Lawrence score at baseline, when added to the model, was a strong predictor (odds ratio 5.8, 95% confidence interval 4.0 to 8.4), increasing to 24.3 (11.3 to 52.1) in subjects with hip pain at baseline. <b>Conclusions</b> The Kellgren and Lawrence score at baseline was by far the strongest predictor for progression of hip osteoarthritis, especially in patients with existing hip pain at baseline. In patients with hip pain, a radiograph has strong additional value in identifying those at high risk of progression of hip osteoarthritis.