tbuckley/cabot-search huggingface dataset:
<i>In vitro</i> and <i>In vivo</i> Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-Interactive Agent
Authors: Michelle A. Rudek, Ming Zhao, Nicola F. Smith, Robert W. Robey, Ping He, Gurulingappa Hallur, Saeed Khan, Manuel Hidalgo, Antonio Jimeno, A. Dimitrios Colevas, Wells A. Messersmith, Antonio C. Wolff, Sharyn D. Baker
Journal: Clinical Cancer Research (2005)

Abstract Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented &amp;lt;2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.
STAPHYLOCOCCAL CLUMPING WITH SOLUBLE FIBRIN MONOMER COMPLEXES
Authors: B. Lipiński, J. Hawiger, J. Jeljaszewicz
Journal: The Journal of Experimental Medicine (1967)

Clumping reaction, using standard suspension of Staph. aureus Newman D-2-C strain and various substrates, was quantitatively tested. It has been shown that clumping occurs in fibrin lysate containing soluble fibrin monomer complexes unclottable by thrombin. The reaction was positive with staphylococcal strains possessing clumping factor regardless of staphylocoagulase production. Clumping reaction is similar to paracoagulation reaction induced by protamine sulfate. The substrate for both reactions is stable at 56 degrees C but is destroyed at 60 degrees C. The kinetics of substrate formation for both reactions during fibrin clot lysis is also similar. Clumping reaction with a strain of Staph. epidermidis possessing no clumping factor was positive when these bacteria were coated with protamine sulfate. The effect of heparin, sodium citrate, urea, 2-mercaptoethanol, merthiolate, and mucin on both reactions was tested. The present findings explain the clumping reaction in serum and emphasize the role of blood clotting and fibrinolytic systems in this phenomenon.
Cost and health implications of cholesterol lowering.
Authors: L Goldman, D J Gordon, B M Rifkind, S B Hulley, A S Detsky, D W Goodman, B Kinosian, M C Weinstein
Journal: Circulation (1992)

BACKGROUND A broad, scientific consensus supports the role of cholesterol as a risk factor for coronary heart disease and agrees that lowering cholesterol levels will reduce coronary heart disease incidence. Cost-effectiveness analysis is a potentially powerful method for measuring the benefits to be achieved by expenditures of health care dollars. METHODS AND RESULTS The literature related to the effectiveness and cost-effectiveness of cholesterol lowering was reviewed. Application of cost-effectiveness methodology to the question of cholesterol reduction generally supports the use of population-wide educational programs and the aggressive use of cholesterol-lowering therapy for the secondary prevention of subsequent coronary events in persons with preexisting coronary heart disease. For primary prevention, however, therapy with medication has a favorable cost-effectiveness ratio only in identifiable high-risk persons, and the different costs of the various available medications should be taken into account. Therapy with medications, especially for primary prevention, would be more appealing if the price of the available medications were lower. CONCLUSIONS High priority should be given to research that could validate these cost-effectiveness projections as well as to further studies of the elderly and women, in whom direct data on the precise costs, risks, and benefits of interventions to lower cholesterol remain sparse.
Enhanced visualization of intravascular thrombus with the use of a thrombus targeting ultrasound contrast agent (MRX408): evidence from in vivo experimental echocardiographic studies
Authors: M. Takeuchi, T.P. McCreary, E. Avelar, M. Sheahan, R. Connolly, A. Santanen, E. Unger, N. Pandian
Journal: Journal of the American College of Cardiology (1998)
Multistate Outbreak of Salmonella Infections Associated With Peanut Butter and Peanut Butter-Containing Products--United States, 2008-2009
Authors: C. Medus, S. Meyer, K. Smith, S. Jawahir, B. Miller, K. Viger, M. Forstner, E. Brandt, S. Nowicki, E. Salehi, Q. Phan, A. Kinney, M. Cartter, J. Flint, J. Bancroft, J. Adams, E. Hyytia-Trees, L. Theobald, D. Talkington, M. Humphrys, C. Bopp, P. Gerner-Smidt, C. Barton, I. T. Williams, S. Sodha, A. Langer
Journal: JAMA (2009)
Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-α–Induced Apoptosis and Cell Growth Arrest
Authors: Xiaojian Wang, Nan Li, Hongzhe Li, Bin Liu, Jianming Qiu, Taoyong Chen, Xuetao Cao
Journal: Clinical Cancer Research (2005)

The current therapeutic approach is not so effective in breast cancer patients. Alternative treatment protocols aimed at different targets need to be explored. We recently reported a novel phosphatidylethanolamine-binding protein, human phosphatidylethanolamine-binding protein 4 (hPEBP4), as an antiapoptotic molecule. The finding led us to explore a promising approach for breast cancer therapy via silencing the expression of hPEBP4.hPEBP4 expression in clinical breast specimens was examined by Tissue Microarrays. RNA interference was used to silence hPEBP4 expression in MCF-7 breast carcinoma cells and the effects on cell proliferation, cell cycle progression, apoptosis, as well as underlying mechanisms, were investigated.hPEBP4 was found to be expressed in up to 50% of breast cancers but in only <4% of normal breast tissues. Silencing of hPEBP4 potentiated tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis and cell cycle arrest in MCF-7 cells, which was due to the increased mitogen-activated protein kinase activation and the enhanced phosphatidylethanolamine externalization. Further investigation showed that silencing of hPEBP4 in MCF-7 cells promoted TNF-alpha-induced stability of p53, up-regulation of phospho-p53ser15, p21waf/cip, and Bax, and down-regulation of Bcl-2 and Bcl-xL, which were shown to depend on extracellular signal-regulated kinase 1/2 and c-jun NH2-terminal kinase activation by hPEBP4 silencing. Moreover, the increased proportion of cells in the G0-G1 phase of cell cycle was observed in hPEBP4-silenced MCF-7 cells on TNF-alpha treatment and the expression of cyclin A and cyclin E was down-regulated more significantly.The antiapoptotic effect and the preferential expression pattern in breast cancer tissues make hPEBP4 a new target for breast cancer therapy. Silencing of hPEBP4 expression may be a promising approach for the treatment of breast carcinoma.
Cloning and Characterization of Rat Density-Enhanced Phosphatase-1, a Protein Tyrosine Phosphatase Expressed by Vascular Cells
Authors: Luis G. Borges, Ronald A. Seifert, Francis J. Grant, Charles E. Hart, Christine M. Disteche, Susanne Edelhoff, Flavio F. Solca, Michael A. Lieberman, Volkhard Lindner, Edmond H. Fischer, Si Lok, Daniel F. Bowen-Pope
Journal: Circulation Research (1996)

We have cloned from cultured vascular smooth muscle cells a protein tyrosine phosphatase, rat density-enhanced phosphatase-1 (rDEP-1), which is a probable rat homologue of DEP-1/HPTPη. rDEP-1 is encoded by an 8.7-kb transcript and is expressed as a 180- to 220-kD protein. The rDEP-1 gene is located on human chromosome 11 (region p11.2) and on mouse chromosome 2 (region 2E). The cDNA sequence predicts a transmembrane protein consisting of a single phosphatase catalytic domain in the intracellular region, a single transmembrane domain, and eight fibronectin type III repeats in the extracellular region (GenBank accession number U40790 ). In situ hybridization analysis demonstrates that rDEP-1 is widely expressed in vivo but that expression is highest in cells that form epithelioid monolayers. In cultured cells with epitheliod morphology, including endothelial cells and newborn smooth muscle cells, but not in fibroblast-like cells, rDEP-1 transcript levels are dramatically upregulated as population density increases. In vivo, quiescent endothelial cells in normal arteries express relatively high levels of rDEP-1. During repair of vascular injury, expression of rDEP-1 is downregulated in migrating and proliferating endothelial cells. In vivo, rDEP-1 transcript levels are present in very high levels in megakaryocytes, and circulating platelets have high levels of the rDEP-1 protein. In vitro, initiation of differentiation of the human megakaryoblastic cell line CHRF-288-11 with phorbol 12-myristate 13-acetate leads to a very strong upregulation of rDEP-1 transcripts. The deduced structure and the regulation of expression of rDEP-1 suggest that it may play a role in adhesion and/or signaling events involving cell-cell and cell-matrix contact.
Partial anomalous pulmonary venous return with intact atrial septum: report of four cases.
Authors: J R Stewart, H V Schaff, N J Fortuin, R K Brawley
Journal: Thorax (1983)

Four patients are reported who underwent repair of partial anomalous pulmonary venous drainage with intact atrial septum. One patient also had azygos continuation of the inferior vena cava and two patients had associated mitral stenosis. Diagnostic considerations and guidelines for operative repair are presented.
Abstract 5207: FGFR inhibitor regulates CD133 expression in FGFR2-amplified gastric cancer cells
Authors: Kazuko Matsumoto, Tokuzo Arao, Kazuyuki Furuta, Tomoyuki Nagai, Kanae Kudo, Hiroyasu Kaneda, Daisuke Tamura, Keiichi Aomatsu, Kazuko Sakai, Yoshihiko Fujita, Hideharu Kimura, Yasuhide Yamada, Kazuto Nishio
Journal: Cancer Research (2011)

Abstract The underlying mechanism regulating the expression of the cancer stem cell / tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. We recently have reported that the expression of CD133 in cancer cells could be regulated though the inhibition of signal transduction by molecular-targeted drugs (Matsumoto K. et al. Cancer Res. 2009). Here, we screened the expression changes of CD133 using wide variety of molecular-targeted drugs in FGFR2-amplified and CD133-overexpressing gastric cancer cell lines. CD133 expression was remarkably upregulated by FGFR inhibitor PD173074 exposure in these cells. Further analysis revealed that PD173074 upregulated the CD133 expression both mRNA and protein levels in dose- and time-dependent manners. In addition, the expression change was correlated with the mRNA expression levels of stem cell factors including OCT3/4, SOX2 and NANOG. As expected, PD173074 exhibited a potent growth inhibitory effect on FGFR2-amplified gastric cancer cells in vitro. These results suggest that the mechanism regulating the expression of CD133 is involved in FGFR2 signaling and also in addicted signaling pathway for cancer cells in FGFR2-amplified gastric cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5207. doi:10.1158/1538-7445.AM2011-5207
Severe Acute Respiratory Syndrome (SARS): A Year in Review
Authors: Danuta M. Skowronski, Caroline Astell, Robert C. Brunham, Donald E. Low, Martin Petric, Rachel L. Roper, Pierre J. Talbot, Theresa Tam, Lorne Babiuk
Journal: Annual Review of Medicine (2004)

Severe acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003, more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. Through real-time application of accumulating knowledge, the world proved capable of arresting the first pandemic threat of the twenty-first century, despite early respiratory-borne spread and global susceptibility. This review synthesizes lessons learned from this remarkable achievement. These lessons can be applied to re-emergence of SARS or to the next pandemic threat to arise.
Letter: Amyloidosis complicating actinomycosis.
Authors: W S Symmers
Journal: BMJ (1973)

had a good initial response to tetracosactrin and those who did not, nor indeed between those with a low level of circulating plasma cortisol and those with a normal level.It is interesting, however, that the one patient who did show signs of a major complication during the attempted substitution had both a low level of plasma cortisol and a very poor response to tetracosactrin.Another observation which we feel is worth making is that all our patients' asthma was well controlled on a maintenance dosage of iprednisone before we attempted substitution with beclomethasone dipro- pionate.We have found that it is extremely difficult, if not impossible, to make this substitution if the asthma is not weU con- trolled initially by corticosteroids admiinistered other than 'by inihalation.-Weare, etc.,
Obsessive-Compulsive Disorder as a Risk Factor for Schizophrenia
Authors: Sandra M. Meier, Liselotte Petersen, Marianne G. Pedersen, Mikkel C. B. Arendt, Philip R. Nielsen, Manuel Mattheisen, Ole Mors, Preben B. Mortensen
Journal: JAMA Psychiatry (2014)

Despite a remarkable co-occurrence of obsessive-compulsive disorder (OCD) and schizophrenia, little is known about the clinical and etiological relationship of these 2 disorders. Exploring the degree to which these disorders share etiological factors might provide useful implications for clinicians, researchers, and those with the disorders.To assess whether patients with OCD experience an enhanced risk of developing schizophrenia and schizophrenia spectrum disorders and to determine whether a family history of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrum disorders.Using individual data from longitudinal nationwide Danish registers, we conducted a prospective cohort study with 45 million person-years of follow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, and place of residence at the time of birth. A total of 3 million people born between January 1, 1955, and November 30, 2006, were followed up from January 1, 1995, through December 31, 2012. During this period, 30 556 people developed schizophrenia or schizophrenia spectrum disorders.The presence of a prior diagnosis of OCD and the risk of a first lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% confidence intervals are used as measures of relative risk.The presence of prior diagnosis of OCD was associated with an increased risk of developing schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrum disorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosed as having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) and schizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remained significant after adjusting for family history of psychiatric disorders and the patient's psychiatric history.A diagnosis of OCD was associated with higher rates of schizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggests that OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a common etiological pathway.
Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Sorafenib
Authors: Ronan J. Kelly, Arun Rajan, Jeremy Force, Ariel Lopez-Chavez, Corrine Keen, Liang Cao, Yunkai Yu, Peter Choyke, Baris Turkbey, Mark Raffeld, Liqiang Xi, Seth M. Steinberg, John J. Wright, Shivaani Kummar, Martin Gutierrez, Giuseppe Giaccone
Journal: Clinical Cancer Research (2011)

Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity.Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. K(ep), was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028).KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.
Wegener's granulomatosis.
Authors: KALMAN KECZKES
Journal: British Journal of Dermatology (1976)

Three patients with Wegener's granulomatosis are reported. All three had skin, nose, sinus, mouth and pulmonary lesions; one had severe renal involvement as well. In two patients combined treatment with low-dosage systemic corticosteroids, azathioprine, and cyclophosphamide resulted in rapid clinical improvement and complete disappearance of the skin, mouth, nasal, sinus and pulmonary lesions. In one of these two patients who had severe renal involvement, proteinuria greatly diminished and arrest of progression of renal insufficiency was observed. In the third patient combined treatment with azathioprine and cyclophosphamide resulted in complete remission of skin, mucous membrane, lung and sinus lesions. The patient with severe renal involvement is alive and ambulant 4 years after the onset of the disease, the other two are completely symptom-free and well 21/2 years and 1 year after the onset of their illnesses, respectively. These results confirm previous reports about the effectiveness of immunosuppressive and cytotoxic agents in Wcgener's granulomatosis, the use of which seems to have improved the prognosis significantly in a disease previously considered to be fatal within 5 months.
Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome
Authors: Seunghoon Han, Yoo-Jin Kim, Jongtae Lee, Sangil Jeon, Taegon Hong, Gab-Jin Park, Jae-Ho Yoon, Seung-Ah Yahng, Seung-Hwan Shin, Sung-Eun Lee, Ki-Seong Eom, Hee-Je Kim, Chang-Ki Min, Seok Lee, Dong-Seok Yim
Journal: Journal of Hematology & Oncology (2015)

This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m2/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm3 (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m2/day, respectively. The median maintenance dose was 7 mg/m2/day. We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m2/day is considered to be the most appropriate starting dose for the regimen studied. Clinicaltrials.gov NCT01277484
Lessons from the TOPCAT Trial
Authors: John J V McMurray, Christopher O'Connor
Journal: New England Journal of Medicine (2014)

Some patients with the clinical syndrome of heart failure have a normal or near-normal left ventricular ejection fraction.13 To date, no treatment has been shown to improve outcomes in this condition, usually designated heart failure with a preserved ejection fraction.2,3 The care of such patients can be difficult and is typically limited to efforts to relieve symptoms.Mineralocorticoid-receptor antagonists such as spironolactone are highly efficacious in patients with heart failure and a reduced ejection fraction.4,5 Pitt et al. now report in the Journal the findings of a trial comparing spironolactone with placebo in patients with heart failure . . .