tbuckley/cabot-search huggingface dataset:
The Introduction of Generic Aromatase Inhibitors and Treatment Adherence Among Medicare D Enrollees
Authors: Joan M Neuner, Sailaja Kamaraju, John A Charlson, Erica M Wozniak, Elizabeth C Smith, Alana Biggers, Alicia J Smallwood, Purushottam W Laud, Liliana E Pezzin
Journal: JNCI Journal of the National Cancer Institute (2015)

Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort. Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided. Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from $183 in the fourth quarter of 2009 to $15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study. The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage.
Does the Renin-Angiotensin System Participate in Regulation of Human Vasculogenesis and Angiogenesis?
Authors: Aarif Y. Khakoo, Richard L. Sidman, Renata Pasqualini, Wadih Arap
Journal: Cancer Research (2008)

Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology.
Induction of eruptive benign melanocytic naevi by immune suppressive agents, including biologicals
Authors: H.J. Bovenschen, M. Tjioe, H. Vermaat, D. de Hoop, B.M.J. Witteman, R.W.A. Janssens, T.J. Stoof, P.C.M. van de Kerkhof
Journal: British Journal of Dermatology (2006)

Background Eruptive naevi have been described to potentially arise in immune compromised patients. Objectives We describe three patients with eruptive benign melanocytic naevi during a phase of immunosuppressive therapy. Methods/diagnosis Two patients with Crohn disease were treated with either azathioprine monotherapy or a combination of azathioprine and infliximab, when eruptive naevi arose particularly at the palms and soles. Our third patient with plaque psoriasis developed eruptive naevi during two episodes of treatment: during a course with the biological agent alefacept and during etanercept therapy. Conclusions We conclude that treatment with the recently available biological agents might be associated with the formation of eruptive naevi. Although positive evidence for the occurrence of malignant pigmented lesions is lacking, alertness to the development of eruptive melanocytic naevi during treatment with biological agents is indicated.
CD34-Positive Cells Exhibit Increased Potency and Safety for Therapeutic Neovascularization After Myocardial Infarction Compared With Total Mononuclear Cells
Authors: Atsuhiko Kawamoto, Hiroto Iwasaki, Kengo Kusano, Toshinori Murayama, Akira Oyamada, Marcy Silver, Christine Hulbert, Mary Gavin, Allison Hanley, Hong Ma, Marianne Kearney, Victor Zak, Takayuki Asahara, Douglas W. Losordo
Journal: Circulation (2006)

Background— We compared the therapeutic potential of purified mobilized human CD34 + cells with that of mobilized total mononuclear cells (tMNCs) for the preservation/recovery of myocardial tissue integrity and function after myocardial infarction (MI). Methods and Results— CD34 + cells were purified from peripheral blood tMNCs of healthy volunteers by magnetic cell sorting after a 5-day administration of granulocyte colony-stimulating factor. Phosphate-buffered saline (PBS), 5×10 5 CD34 + cells/kg, 5×10 5 tMNCs/kg (low-dose MNCs [loMNCs]), or a higher dose of tMNCs (hiMNCs) containing 5×10 5 CD34 + cells/kg was transplanted intramyocardially 10 minutes after the induction of MI in athymic nude rats. Hematoxylin and eosin staining revealed that moderate to severe hemorrhagic MI on day 3 was more frequent in the hiMNC group than in the PBS and CD34 + cell groups. Immunostaining for human-specific CD45 revealed abundant distribution of hematopoietic/inflammatory cells derived from transplanted cells in the ischemic myocardium of the hiMNC group. Capillary density on day 28 was significantly greater in the CD34 + cell group (721.1±19.9 per 1 mm 2 ) than in the PBS, loMNC, and hiMNC groups (384.7±11.0, 372.5±14.1, and 497.5±24.0 per 1 mm 2 ) ( P &lt;0.01). Percent fibrosis area on day 28 was less in the CD34 + cell group (15.6±0.9%) than in the PBS, loMNC, and hiMNC groups (26.3±1.2%, 27.5±1.8%, and 22.2±1.8%) ( P &lt;0.05). Echocardiographic fractional shortening on day 28 was significantly higher in the CD34 + cell group (30.3±0.9%) than in the PBS, loMNC, and hiMNC groups (22.7±1.5%, 23.4±1.1%, and 24.9±1.7%; P &lt;0.05). Echocardiographic regional wall motion score was better preserved in the CD34 + cell group (21.8±0.5) than in the PBS, loMNC, and hiMNC groups (25.4±0.4, 24.9±0.4, and 24.1±0.6; P &lt;0.05). Conclusions— CD34 + cells exhibit superior efficacy for preserving myocardial integrity and function after MI than unselected circulating MNCs.
Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer
Authors: Navneet Dhillon, Bharat B. Aggarwal, Robert A. Newman, Robert A. Wolff, Ajaikumar B. Kunnumakkara, James L. Abbruzzese, Chaan S. Ng, Vladimir Badmaev, Razelle Kurzrock
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration–approved therapies for it, gemcitabine and erlotinib, produce objective responses in &amp;lt;10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored. Results: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for &amp;gt;18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.
Mineralocorticoid versus Glucocorticoid Receptor Occupancy Mediating Aldosterone-Stimulated Sodium Transport in a Novel Renal Cell Line
Authors: Hans-Peter Gaeggeler, Elena Gonzalez-Rodriguez, Nicole Fowler Jaeger, Dominique Loffing-Cueni, Rikke Norregaard, Johannes Loffing, Jean-Daniel Horisberger, Bernard C. Rossier
Journal: Journal of the American Society of Nephrology (2005)

Aldosterone controls sodium balance by regulating an epithelial sodium channel (ENaC)-mediated sodium transport along the aldosterone-sensitive distal nephron, which expresses both mineralocorticoid (MR) and glucocorticoid receptors (GR). Mineralocorticoid specificity is ensured by 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR. The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo. For answering this question, a novel mouse cortical collecting duct cell line (mCCD(cl1)), which expresses significant levels of MR and GR and a robust aldosterone sodium transport response, was used. Aldosterone elicited a biphasic response: Low doses (K(1/2) = approximately 0.5 nM) induced a transient and early increase of sodium transport (peaking at 3 h), whereas high doses (K(1/2) = approximately 90 nM) entailed an approximately threefold larger, long-lasting response. At 3 h, the corticosterone dose-response curve was shifted to the right compared with that of aldosterone by more than two log concentrations, an effect that was fully reverted in the presence of the 11beta-hydroxysteroid dehydrogenase type 2 inhibitor carbenoxolone. Low doses of dexamethasone (0.1 to 1 nM) failed to induce an early response, but high doses elicited a long-lasting response (K(1/2) = approximately 8 nM), similar to that observed for high aldosterone concentrations. Equilibrium binding assays showed that both aldosterone and corticosterone bind to a high-affinity, low-capacity site, whereas dexamethasone binds to one site. Within the physiologic range of aldosterone concentrations, sodium transport is predicted to be controlled by MR occupancy during circadian cycles and by MR and GR occupancy during salt restriction or acute stress.
JAK2 mutation 1849G&amp;gt;T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia
Authors: Jaroslav Jelinek, Yasuhiro Oki, Vazganush Gharibyan, Carlos Bueso-Ramos, Josef T. Prchal, Srdan Verstovsek, Miloslav Beran, Elihu Estey, Hagop M. Kantarjian, Jean-Pierre J. Issa
Journal: Blood (2005)
Likelihood ratios as a function of antibody concentration for anti-cyclic citrullinated peptide antibodies and rheumatoid factor
Authors: X Bossuyt, D Coenen, S Fieuws, P Verschueren, R Westhovens, N Blanckaert
Journal: Annals of the Rheumatic Diseases (2009)

Anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF) are recommended screening tests for rheumatoid arthritis.1 In a meta-analysis,2 the sensitivity of anti-CCP (67%) for diagnosing rheumatoid arthritis was comparable to the sensitivity of RF (69%).2 The specificity of anti-CCP for rheumatoid arthritis (95%) was higher than the specificity of RF (85%).2 Consequently, the positive likelihood ratio was higher for anti-CCP (12.46) than for RF (4.86).2

Studies that addressed the clinical usefulness of anti-CCP used a single cut-off value and, hence, likelihood ratios were calculated based on a single cut-off. In the present letter, we illustrate how likelihood ratios for anti-CCP and RF …
Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells
Authors: Charlotte M Smith, Volker Haucke, Adam McCluskey, Phillip J Robinson, Megan Chircop
Journal: Molecular Cancer (2013)

Abstract Background During metaphase clathrin stabilises the mitotic spindle kinetochore(K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis. Results Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition. Conclusions Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.
Retrotransposition of gene transcripts leads to structural variation in mammalian genomes
Authors: Adam D Ewing, Tracy J Ballinger, Dent Earl, Christopher C Harris, Li Ding, Richard K Wilson, David Haussler
Journal: Genome biology (2013)

Abstract Background Retroposed processed gene transcripts are an important source of material for new gene formation on evolutionary timescales. Most prior work on gene retrocopy discovery compared copies in reference genome assemblies to their source genes. Here, we explore gene retrocopy insertion polymorphisms (GRIPs) that are present in the germlines of individual humans, mice, and chimpanzees, and we identify novel gene retrocopy insertions in cancerous somatic tissues that are absent from patient-matched non-cancer genomes. Results Through analysis of whole-genome sequence data, we found evidence for 48 GRIPs in the genomes of one or more humans sequenced as part of the 1,000 Genomes Project and The Cancer Genome Atlas, but which were not in the human reference assembly. Similarly, we found evidence for 755 GRIPs at distinct locations in one or more of 17 inbred mouse strains but which were not in the mouse reference assembly, and 19 GRIPs across a cohort of 10 chimpanzee genomes, which were not in the chimpanzee reference genome assembly. Many of these insertions are new members of existing gene families whose source genes are highly and widely expressed, and the majority have detectable hallmarks of processed gene retrocopy formation. We estimate the rate of novel gene retrocopy insertions in humans and chimps at roughly one new gene retrocopy insertion for every 6,000 individuals. Conclusions We find that gene retrocopy polymorphisms are a widespread phenomenon, present a multi-species analysis of these events, and provide a method for their ascertainment.
Targeted Inhibition of Src Kinase with Dasatinib Blocks Thyroid Cancer Growth and Metastasis
Authors: Christine M. Chan, Xia Jing, Laura A. Pike, Qiong Zhou, Dong-Jun Lim, Sharon B. Sams, Gregory S. Lund, Vibha Sharma, Bryan R. Haugen, Rebecca E. Schweppe
Journal: Clinical Cancer Research (2012)

There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis.The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant.Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively).These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.
Development and Etiology of Disruptive and Delinquent Behavior
Authors: Rolf Loeber, Jeffrey D. Burke, Dustin A. Pardini
Journal: Annual Review of Clinical Psychology (2009)

This review examines the development and etiology of disruptive behavior [symptoms of oppositional defiant disorder (ODD), conduct disorder (CD), and psychopathic features] and delinquency (particularly violence). We address selected key developmental issues, including (a) to what extent negative emotional ODD symptoms are associated with later internalizing disorders, (b) whether psychopathic features provide added predictive utility beyond traditional disruptive behaviors, and (c) the role of oppositional behavior and conduct problems in the development of violence. This review also focuses on the causes of ODD, CD, psychopathic features, and delinquency and explores the extent to which the causes of disruptive and delinquent behavior are the same. We examine the degree to which risk and promotive factors change with age and whether promotive factors buffer the impact of risk factors. Finally, we explore the question of whether there are developmental shifts in children's exposure to risk and promotive factors.
Association and dissociation of aggregated IgG from rat peritoneal macrophages.
Authors: D W Knutson, A Kijlstra, L A Van Es
Journal: The Journal of Experimental Medicine (1977)

Stable aggregated IgG (A-IgG) of various sizes, having high biological activity, were incubated at 4 degree C with adhering peritoneal macrophages from normal rats and the kinetics of A-IgG binding to the cell surface were studied. Equilibrium constants were high (2.8-11.7 X 10(8) M-1) and varied as a function of aggregate size. The maximum number of A-IgG bound per cell varied from 230,000 for A-IgG9 to 90,000 for A-IgG74. Binding was 50% inhibited by near physiological concentrations of monomeric IgC. These data suggest that A-IgG are bound at multiple sites by attachment of Fc frgments to Fc receptors present on the macrophage surface with larger A-IgG being more avidly bound. Dissociation was slower for larger A-IgG while no clear trend was seen relating associating rates and aggregate size. Thus, differences in the avidity of binding of A-IgG are due primarily to slower dissociation of larger A-IgG. Dissociationissociation of A-IgG was slower from cells exposed initially to higher doses of A-IgG and dissociation did not follow simple first order kinetics. Thus, the avidity of binding appears to be heterogeneous in a population of similar sized A-IgG. As expected, association was dose-dependent, more rapid than dissociation, and followed pseudo first order kinetics. Based on all of the above data, it is proposed that binding of A-IgG proceeds in two steps. First, A-IgG are loosely bound to perhaps a single Fc receptor. Then, depending upon the availability and mobility of Fc receptors, additional Fc fragments are attached and the A-IgG becomes more firmly attached. Thus binding is slow, but once attached A-IgG are avidly held.
Resting energy expenditure and nutritional state of patients with increased oxygen cost of breathing due to emphysema, scoliosis and thoracoplasty.
Authors: M K Sridhar, R Carter, M E Lean, S W Banham
Journal: Thorax (1994)

BACKGROUND--Weight loss is a well recognised feature of patients with emphysematous chronic obstructive pulmonary disease (COPD). It has been suggested that this weight loss could be due to a hypermetabolic state resulting from the increased oxygen cost of breathing (OCB). To clarify the relation between resting energy expenditure (REE), nutritional state, and OCB these indices were measured in patients with respiratory impairment and an increased OCB due to COPD, scoliosis, and thoracoplasty. METHODS--Eighteen patients (six COPD, six scoliosis, six thoracoplasty) of mean (SD) age 59.9 (8.6) years (8M, 10F) and six controls (45.5 (9.9) years; 2M, 4F) were studied. OCB was estimated by the addition of dead space to the breathing circuit and REE was measured by indirect calorimetry using a ventilated canopy system. Height, arm span, weight, triceps skin fold thickness (TSF), mid-arm muscle circumference (MAMC), forced expiratory volume in one second (FEV1), and vital capacity (VC) were measured in all study subjects. RESULTS--OCB was elevated in all patient groups (mean 7.0 ml/l) compared with controls (1.9 ml/l). All patients with COPD, four with scoliosis, three with thoracoplasty, and none of the controls were &lt; 90% ideal body weight. Mean (SD) measured REE as % predicted (Harris-Benedict equation) was 103.8 (7.6) in patients with COPD, 105.5 (10.9) in those with scoliosis, 106.3 (6.9) in the thoracoplasty patients, and 103.3 (3.4) in controls. One patient with COPD, two with scoliosis, two with thoracoplasty, but no controls were hypermetabolic (REE &gt; 110% predicted). In all groups there was a negative relation between OCB and lung function (OCB v FEV1 r = -0.83 in COPD, -0.62 in scoliosis, -0.67 in thoracoplasty, and -0.76 in controls). There was no correlation between REE and OCB or MAMC. CONCLUSIONS--In patients with respiratory disease OCB (augmented ventilation) is related to lung function but not to REE. This is evidence against the hypothesis that hypermetabolism due to increased oxygen cost of breathing at rest is the sole or major cause of malnutrition in patients with lung disease.