tbuckley/cabot-search huggingface dataset:
A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors
Authors: George D. Demetri, Paolo G. Casali, Jean-Yves Blay, Margaret von Mehren, Jeffrey A. Morgan, Rossella Bertulli, Isabelle Ray-Coquard, Philippe Cassier, Monica Davey, Hossein Borghaei, Daniel Pink, Maria Debiec-Rychter, Wing Cheung, Stuart M. Bailey, Maria Luisa Veronese, Annette Reichardt, Elena Fumagalli, Peter Reichardt
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. Experimental Design: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. Results: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. Conclusions: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation. (Clin Cancer Res 2009;15(18):5910–6)
Human endometriosis-derived permanent cell line (FbEM-1): establishment and characterization
Authors: J. de Joliniere
Journal: Human Reproduction Update (1997)

A human epithelial-like cell line derived from peritoneal implants from a patient with gonadotrophin-releasing hormone (GnRH) agonist-resistant endometriosis graded as stage IVd according to the American Fertility Society classification was established in vitro. This cell line, designated FbEM-1, exhibited an epithelial-like morphology, grew in suspension and was immunoreactive for cytokeratins 8, 18, 19, vimentin and human leukocyte class I antigens. The cultured cells were negative for various haematopoietic cell markers, including the lymphoid cell antigens CD3, CD20 and CD45, von Willebrandt factor, carcinoembryonic antigen and the carcinoma antigen-125 (CA-125). In addition, the FbEM-1 cells were found to be moderately positive for periodic acid Schiff's (PAS) solution but were negative for alpha-naphthyl acetate esterase, peroxidase and chloroacetate esterase activities. Using specific antibodies against the progesterone, androgen and oestrogen receptors, approximately 40% and 5-10% of the cells immunostained for progesterone and androgen receptors respectively, while oestrogen receptors were not detected. On cytogenetic analysis using R-banding, these cells showed numerous chromosomal aberrations, including loss of one chromosome X, 4q+, 5q+, trisomy 7,8 and 10 and tetrasomy of chromosomes 17, 18, 19 and 20. These data show that the continuously growing FbEM-1 cell line established from endometriotic implants may be useful in achieving better understanding of the histogenesis of endometriosis.
Dehydration of football referees during a match
Authors: A I Da Silva, R Fernandez
Journal: British Journal of Sports Medicine (2003)

To study hydration status in referees (main) and assistant referees (linesmen) during official football matches.Twelve male football referees were evaluated; all were volunteers. Before and after each match, the referee and one of the assistants were weighed without clothes and a blood sample was taken. Total water loss was determined for each subject from the change in body weight. The main haematological variables were analysed in the blood samples. Total plasma protein concentration and osmolarity were also determined. Variation in plasma volume was determined from changes in packed cell volume and a combination of changes in packed cell volume and haemoglobin concentrations.During a match, total body water loss was 1.60 (0.13) litres, equivalent to 2.05 (0.18)% of body weight. Body weight was reduced by 1.55 (0.12)%, showing that water ingestion during the interval replaces only 24.4% of the body fluids lost during the match. The assistants lost 0.79 (0.19) litre of water, equivalent to 1.05 (0.25)% of body weight. The referees showed a significant decrease in plasma volume of 4.99 (1.33)%. The assistants showed a non-significant increase in plasma volume. The reduction in plasma volume observed in the referees correlated significantly with total body water loss (r = 0.9623). From these data, it is possible to predict that a dehydration of 1% reflects a reduction in plasma volume of nearly 2.5%.Referees are moderately dehydrated after a football match (2%), whereas assistants show a non-significant dehydration of 1% of their body weight.
Giant angiofibromas in tuberous sclerosis complex: A possible role for localized lymphedema in their pathogenesis
Authors: Denisa Kacerovska, Katrin Kerl, Michal Michal, Hana Filipova, Radek Vrtel, Tomas Vanecek, Hana Zelenakova, Jaroslav Kraus, Roman Kodet, Dmitry V. Kazakov
Journal: Journal of the American Academy of Dermatology (2012)
You Can't Run From Inflammation
Authors: Javid Moslehi, Peter Libby
Journal: Circulation Research (2012)

P rolyl hydroxylase domain (PHD) molecules sense oxygen availability in mammalian cells and can serve as drug targets.Recent work from Takeda et al suggest a previously unappreciated role for PHD2-the main HIF prolyl hydroxylase-in arteriogenesis via macrophage skewing.Deletion of PHD2 in macrophages associated with activation of the canonical NF-B pathway and arteriogenesis.
Reducing Risk by Improving Standards of Intrapartum Care
Authors: John A Davis
Journal: Journal of the Royal Society of Medicine (2001)

The article by Peter Young and colleagues (May 2001 JRSM, pp. 226-231) makes depressing reading for those of us who believe that medical management should be adjudged by outcome in terms of somatic or psychic wellbeing. What it shows is that mismanagement (increasing unnecessary intervention) is likely to reduce the number and/or scale of compensation awards to the parents of brain-damaged babies, albeit it is acknowledged that fetal and neonatal brain damage is extremely unlikely to be the result of not undertaking such intervention or to be reduced by making it mandatory; in other words, the transaction is purely a matter of what is or is not regarded as optimal care by a judge and jury misled by expert witnesses citing arbitrary standards or by a sentimental feeling that parents of brain damaged babies should be given the benefit of the doubt even at the expense of the truth, the good repute of the professional birth attendants concerned, and of NHS funds. This will result in cutting back aspects of patient care of proven value in order both to pay the damages awarded and for the meddlesome measures designed to persuade the courts that no possible negligence was involved. Is this really the kind of ‘medicine’ that we want; or should we offer financial succour to those in need of it regardless of whether anyone is to blame for what is in effect an inevitable statistical fall-out of our hazardous way of reproducing ourselves. Where there has been real negligence, the authorities on whom the cost falls could then themselves recover it by due legal process without the onus of doing so falling directly on the injured party. Much anxiety, delay and expense could thereby be avoided and funds made available by the taxpayer for the alleviation of misfortune would not end up mostly in the pockets of lawyers but of those in need.
Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity
Authors: Stefan F. Martin, Jan C. Dudda, Eva Bachtanian, Annalisa Lembo, Stefanie Liller, Christoph Dürr, Markus M. Heimesaat, Stefan Bereswill, György Fejer, Ralitsa Vassileva, Thilo Jakob, Nikolaus Freudenberg, Christian C. Termeer, Caroline Johner, Chris Galanos, Marina A. Freudenberg
Journal: The Journal of Experimental Medicine (2008)

Allergic contact hypersensitivity (CHS) is a T cell–mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rβ2–deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12–independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) β2, or both, we show that the concomitant absence of TLR4 and IL-12Rβ2, but not the absence of TLR4 or IL-12Rβ2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rβ2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12–independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12–competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rβ2–deficient mice, but not in germ-free TLR4/IL-12Rβ2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.
Susceptibility to Aflatoxin B1-Induced Carcinogenesis Correlates with Tissue-Specific Differences in DNA Repair Activity in Mouse and in Rat
Authors: Leanne L. Bedard, Manlio Alessi, Scott Davey, Thomas E. Massey
Journal: Cancer Research (2005)

Abstract To investigate the mechanisms responsible for species- and tissue-specific differences in susceptibility to aflatoxin B1 (AFB1)–induced carcinogenesis, DNA repair activities of nuclear extracts from whole mouse lung and liver and rat liver were compared, and the ability of in vivo treatment of mice with AFB1 to alter repair of AFB1-DNA damage was determined. Plasmid DNA containing AFB1-N7-guanine or AFB1-formamidopyrimidine adducts were used as substrates for the in vitro determination of DNA repair synthesis activity, detected as incorporation of radiolabeled nucleotides. Liver extracts from CD-1 mice repaired AFB1-N7-guanine and AFB1-formamidopyrimidine adducts 5- and 30-fold more effectively than did mouse lung, and ∼6- and 4-fold more effectively than did liver extracts from Sprague-Dawley rats. The susceptibility of mouse lung and rat liver to AFB1-induced carcinogenesis correlated with lower DNA repair activity of these tissues relative to mouse liver. Lung extracts prepared from mice treated with a single tumorigenic dose of 50 mg/kg AFB1 i.p. and euthanized 2 hours post-dosing showed minimal incision and repair synthesis activities relative to extracts from vehicle-treated mice. Conversely, repair activity towards AFB1-N7-guanine damage was ∼3.5-fold higher in liver of AFB1-treated mice relative to control. This is the first study to show that in vivo treatment with AFB1 can lead to a tissue-specific induction in DNA repair. The results suggest that lower DNA repair activity, sensitivity of mouse lung to inhibition by AFB1, and selective induction of repair in liver contribute to the susceptibility of mice to AFB1-induced lung tumorigenesis relative to hepatocarcinogenesis.
Spain plans to legalise abortion on demand
Authors: M. de Lago
Journal: BMJ (2009)

Women in Spain will be able to get an abortion on demand up to 12 or possibly 14 weeks of pregnancy for the first time if a proposed law is passed by parliament.

And under the proposals this time limit will be raised or even removed in cases where the health or life of the woman is at high risk or if the fetus has serious physical abnormalities, malformations, or illness.

The new criteria for abortion were recommended in a report from a cross party parliamentary subcommittee. The government of the ruling Socialist Workers’ Party will now prepare a law that will be put before parliament before the end of …
Slow-Release Sodium Fluoride in the Management of Postmenopausal Osteoporosis
Authors: C Y Pak, K Sakhaee, V Piziak, R D Peterson, N A Breslau, P Boyd, J R Poindexter, J Herzog, A Heard-Sakhaee, S Haynes, B Adams-Huet, J S Reisch
Journal: Annals of Internal Medicine (1994)

Objective: To test whether intermittent treatment with slow-release sodium fluoride and continuous calcium citrate supplementation inhibits vertebral fractures without causing fluoride complications. Design: A placebo-controlled, randomized trial. Setting: Outpatient setting of specialty clinics in Dallas and Temple, Texas. Interventions: Slow-release sodium fluoride (25 mg twice daily) in repeated 14-month cycles (12 months on treatment followed by 2 months off treatment) compared with placebo. Both groups took calcium citrate (400 mg calcium twice daily) continuously. Patients: 110 patients with postmenopausal osteoporosis were randomly assigned to two groups. In the slow-release sodium fluoride group, 48 of 54 patients completed more than 1 cycle of treatment (mean, 2.44 cycles/patient), whereas 51 of 56 patients in the placebo group completed at least 1 cycle (mean, 2.14 cycles/patient) in this interim analysis. Measurements: Vertebral fracture rate and lumbar bone mineral content. Vertebral fractures were quantified from yearly radiographs. Bone mass was determined annually by densitometry. Results: In the sodium fluoride group, the mean L2 to L4 bone mineral content increased by 4% to 6% in each cycle and the mean femoral neck bone density increased by 4.1% and 2.1% during the first two cycles, but the radial bone density did not change. The placebo group showed no statistical change in bone mass at any site. Compared with the placebo group, the sodium fluoride group had a lower individual new vertebral fracture rate (0.057/patient cycle compared with 0.204/patient cycle, P = 0.017), a higher fracture-free rate (83.3% compared with 64.7%, P = 0.042), and a lower group fracture rate (0.085/patient cycle compared with 0.239/patient cycle, P = 0.006). The side-effect profile was similar for the two groups; no patient developed microfractures, hip fractures, or blood loss anemia. Conclusions: Intermittent slow-release sodium fluoride plus continuous calcium citrate, administered for about 2.5 years, inhibits new vertebral fractures, increases the mean spinal bone mass without decreasing the radial shaft bone density, and is safe to use.
Enhanced pulsatile pressure accelerates vascular smooth muscle migration: implications for atherogenesis of hypertension
Authors: T. Tada, J. Nawata, H. Wang, N. Onoue, D. Zhulanqiqige, K. Ito, K. Sugimura, Y. Fukumoto, H. Shimokawa
Journal: Cardiovascular Research (2008)

Clinical studies have suggested that pulsatile pressure is an independent risk factor for atherosclerosis. However, it is unknown whether enhanced pulsatile pressure per se directly accelerates vascular smooth muscle cell (VSMC) migration, an important process of atherosclerosis.Using our original Pressure-loading system with a Boyden chamber, we examined the direct effects of variable pressures and pulse rates on migration of rat aortic VSMCs in vitro. High pulse pressure (180/90 mmHg, pulsatile vs. 180 mmHg, static), high mean pressure (180/90 vs. 90/0 mmHg, with the same pulse pressure), wide pulse pressure (190/110 vs. 170/130 mmHg, with the same mean pressure), and high pulse rate (120 vs. 40 per min) significantly accelerated the VSMC migration (1.35, 2.38, 1.38 and 1.27-fold, respectively). The increase in intracellular calcium levels measured by fura-2/AM fluorescence was proportional to the magnitude of pressure loaded. The pressure-promoted VSMC migration was significantly inhibited by a phospholipase-C inhibitor U-73122 or a calmodulin inhibitor W-7. Inositol 1,4,5-trisphosphate receptor blockers 2-aminoethoxydiphenyl borate or xestospongin-C significantly inhibited the VSMC migration, whereas a ryanodine receptor blocker ryanodine had no effects. Furthermore, a calcium channel blocker (CCB), azelnidipine, and an angiotensin type-1 receptor blocker, olmesartan, also significantly inhibited the VSMC migration.These results provide direct evidence for the pro-atherogenic effects of enhanced pulsatile pressure and also suggest that the anti-atherogenic actions of CCBs and angiotensin type-1 receptor blockers are mediated in part by their direct inhibitory effects on VSMC migration in addition to their anti-hypertensive effects.
Effect of rosiglitazone and 15-deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>on bleomycin-induced lung injury
Authors: T. Genovese, S. Cuzzocrea, R. Di Paola, E. Mazzon, C. Mastruzzo, P. Catalano, M. Sortino, N. Crimi, A. P. Caputi, C. Thiemermann, C. Vancheri
Journal: European Respiratory Journal (2005)

Thiazolidinedione rosiglitazone and 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), are two peroxisome proliferator-activated receptor (PPAR)-γ ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ 2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-γ agonists rosiglitazone (10 mg·kg −1 i.p. ) and 15d-PGJ 2 (30 µg·kg −1 i.p. ) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ 2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-γ antagonist bisphenol A diglycidyl ether (1 mg·kg −1 i.p. 30 min before the rosiglitazone or 15d-PGJ 2 ) significantly antagonised the effect of the two PPAR-γ agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-γ agonists, rosiglitazone and 15-deoxy-Δ 12,14 -prostaglandin J 2 , significantly reduce lung injury induced by bleomycin in mice.
Effect of Patient Socioeconomic Status and Body Mass Index on the Quality of Breast Cancer Adjuvant Chemotherapy
Authors: Jennifer J. Griggs, Eva Culakova, Melony E.S. Sorbero, Michelle van Ryn, Marek S. Poniewierski, Debra A. Wolff, Jeffrey Crawford, David C. Dale, Gary H. Lyman
Journal: Journal of Clinical Oncology (2006)

The purpose of this study was to investigate the relationship between socioeconomic status (SES) and the use of intentionally reduced doses of chemotherapy in the adjuvant treatment of breast cancer.Patients with breast cancer treated with a standard chemotherapy regimen (n = 764) were enrolled in a prospective registry after signing informed consent. Detailed information was collected on patient, disease, and treatment, including chemotherapy doses. Zip code level data on median household income, proportion of people living below the poverty level, and educational attainment were obtained from the US Census. Doses for the first cycle of chemotherapy lower than 85% of standard were considered to be reduced. Univariate analyses and multivariate logistic regression were performed to identify factors associated with the use of reduced first cycle doses.In univariate analysis, individual education attainment, zip code SES measures, body mass index, and geographic region were all significantly associated with receipt of intentionally reduced doses of chemotherapy. In multivariate analysis, controlling for geography, factors independently associated with reduced doses were obesity (odds ratio [OR], 2.47; 95% CI, 1.36 to 4.51), severe obesity (OR, 4.04; 95% CI, 1.46 to 11.19), and education less than high school (OR, 3.07; 95% CI, 1.57 to 5.99).Social disparities in breast cancer outcomes may be in part the result of lower quality chemotherapy doses in the adjuvant treatment of breast cancer. Efforts to address such prescribing patterns may help reduce SES disparities in breast cancer survival.
Identification of intracellular factor XIII in human monocytes and macrophages.
Authors: P Henriksson, S Becker, G Lynch, J McDonagh
Journal: Journal of Clinical Investigation (1985)

Factor XIII is a blood protransglutaminase that is distributed in plasma and platelets. The extracellular and intracellular zymogenic forms differ in that the plasma zymogen contains A and B subunits, while the platelet zymogen has A subunits only. Both zymogens form the same enzyme. Erythrocytes, in contrast, contain a tissue transglutaminase that is distinct from Factor XIII. In this study other bone marrow-derived cells were examined for transglutaminase activity. Criteria that were used to differentiate Factor XIII proteins from erythrocyte transglutaminase included: (a) immunochemical and immunohistochemical identification with monospecific polyclonal and monoclonal antibodies to Factor XIII proteins, (b) requirement for thrombin cleavage to express activity, (c) pattern of fibrin cross-linking catalyzed by the enzyme, and (d) different electrophoretic mobilities in nondenaturing gel systems. By these criteria human peripheral blood monocytes, peritoneal macrophages, and monocytes maintained in culture contain an intracellular protransglutaminase that is the same as platelet Factor XIII. The monocyte-macrophage protein is thrombin-sensitive, and under appropriate conditions there is no enzyme expression without activation of the zymogen. Both the monocyte-macrophage zymogen and enzyme have the same electrophoretic mobilities as platelet Factor XIII zymogen and enzyme. Antibody to A protein reacts with the monocyte-macrophage protein. B protein is not associated with this intracellular zymogen. By immunoperoxidase staining monocyte-macrophage protein seems to be localized in the cytoplasm, similar to the known cytoplasmic distribution of platelet and megakaryocyte Factor XIII. These procedures were also used to study populations of human granulocytes and lymphocytes, and protransglutaminase activity was not observed in these cells.